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PMC005xxxxxx/PMC5370980.txt | The Use of Prophylactic Drugs for Asthma in
General Practice
A. G. WARD MAN, MRCP (UK), Research Registrar, and
N. J. COOKE, BSc, FRCP, Consultant Physician
Department of Respiratory Medicine, The General Infirmary Leeds
V. BINNS, Statistical Assistant, and
A.. D. CLAYDEN, BSc, PhD, Senior Lecturer in Medical Statistics
Department of Community Medicine and General Practice, University of Leeds
Good control of asthma frequently depends on the correct
use of an appropriate prophylactic drug. Enquiries into
the circumstances of deaths from asthmafl] suggested
that such therapy is often under-used or not used at all in
chronic unstable asthma. This has been confirmed in new
hospital out-patient referrals; patients with asthma were
either not prescribed prophylaxis[2] or used the agents
irregularly[3], and supported by a limited study of adult
asthma in a single London general practice[4]. These
reports indicate a need for improving the care of asthma
in the community.
Patients and Methods
Tn 1982-83 patients (aged 16-80 years) from five group
practices in three cities in West Yorkshire were inter-
viewed. Patients were selected by two methods: in one
practice with a disease index asthmatics receiving drug
therapy were included. In the other practices doctors
recorded all asthmatics given a prescription for airflow
obstruction during a two-month period. Patients were
asked to attend their surgery for an interview during
which a questionnaire was completed by one author
A.G.W. (who worked independently of the practices).
Disease severity was assessed by a symptom score (Table
1). This score was modified from a published daily diary
for asthma assessment[5]. The patient was asked to grade
day and night-time symptoms in the month before inter-
view. Statistical analysis was by the standard chi-squared
test.
Results
A total of 201 asthmatics (mean age 45 years, maleifemale
1:1) was interviewed; 134 (67 per cent) used either
corticosteroids (inhaled or oral), sodium cromoglycate
(SCG) or ketotifen; 32 (16 per cent) did not use these
drugs despite a score of 2 or 3 for day or night-time
symptoms.
Table 1. Symptom score for asthma.
Daytime
0 No wheeze. Able to do all activities.
1 Slight wheeze. Able to do most activities.
2 Moderate wheeze. Activities limited regularly by frequent
wheeze.
3 Severe wheeze. Activities constantly curtailed by wheeze.
Night-time
0 No nocturnal wheeze.
1 Slight nocturnal wheeze. Woken occasionally
(<once a week).
2 Moderate nocturnal wheeze. Woken frequently
(1-3 times a week).
3 Severe nocturnal wheeze. Woken very frequently
(>3 times a week).
Table 2. The number and percentage of patients using
different types of prophylactic drug.
Patients No_ %
Total patients 201
Total using prophylactic drugs 134 67
Using inhaled corticosteroids (IC) 79 40
?via an aerosol 70
?via a dry powder inhaler 9
Using sodium cromoglycate (SCG) 50 25
?SCG Compound 28
?SCG Plain 18
?SCG aerosol 4
Using systemic corticosteroids (SC) 29 14
Using Ketotifen 3 1
The numbers of patients using prophylactic drugs are
shown in Table 2: 26 patients (13 per cent) used combina-
tions of drugs, including 15 (7 per cent) using inhaled
corticosteroid (IC) and systemic corticosteroid (SC) and 8
(4 per cent) using IC and SCG.
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 45
Problems with the Use of Prophylactic Inhalers
Of 121 patients using prophylactic inhalers 13 (11 per
cent) took treatment entirely on demand. The rest used
regular treatment, but 23 (19 per cent) took extra doses
on demand, 27 (22 per cent) omitted at least one pre-
scribed dose daily and a further 9 (7 per cent) admitted to
both errors. More patients using SCG compound took
therapy on demand (either partially or totally) (18 of 28,
64 per cent) than those using SCG Plain (8 of 22, 36 per
cent) (i5<0.05).
When compared with those who never used prophylac-
tic drugs on demand (60 of 76, 79 per cent), significantly
fewer (,P<0.01) patients using therapy on demand (total-
ly or partially) understood the concept of a prophylactic
drug (19 of 45, 42 per cent). In the first group the concept
was understood by equal proportions of those who were
fully compliant (37 of 49, 76 per cent) and those who
omitted at least one treatment daily (23 of 27, 85 per
cent).
Of 74 patients using aerosol IC or SCG, 10 (14 per
cent) had doubtfully efficient and 4 (6 per cent) totally
inefficient inhaler techniques[6].
Problems with Prescribing Prophylactic Inhalers
Fourteen compliant patients (12 per cent of prophylactic
inhaler users) were prescribed below standard doses
(<400/ig beclomethasone dipropionate or equivalent, or
<4 capsules SCG daily) and 19 (15 per cent only)
standard doses, despite both groups having a score of 2 or
3 for day or night-time symptoms suggesting that ad-
ditional therapy might have been beneficial. The pres-
cribed daily dosage of IC and SCG are shown in Table 3.
Combining the problems of use and prescribing, 32 (26
per cent) patients using prophylactic inhalers had a score
of 2 or 3 for day or night-time symptoms but all these
patients had a poor inhaler technique, used therapy
entirely on demand, omitted at least one treatment daily,
or were compliant but were prescribed a below standard
dose.
The Use of Systemic Corticosteroids
Twenty-nine (14 per cent) patients used regular SC; 12
(41 per cent) did not use IC and 8 (28 per cent) had never
had IC at any time. Of the 29, 27 had been on continuous
therapy for at least five years.
Previous Out-patient Attendance
One hundred and forty-three (71 per cent) of the asthma-
tics had attended a hospital out-patient department at
some time with chest symptoms and 52 (26 per cent) had
attended within the previous year.
Discussion
Owing to the selection methods employed there was a bias
in this study towards symptomatic asthmatics on regular
drug treatment. Estimates of the prevalence of adult
asthma in the community vary[7] but if a prevalence of 3
per cent is accepted, our study represents a selected
sample of 23 per cent.
The importance of the general practitioner in the
management of asthma is emphasised by the finding that
only a quarter of patients had attended a hospital clinic in
the previous year. With the advantage of continuity of
care general practice management may be preferable[8]
and therefore knowledge of the main therapeutic prob-
lems in the community is important.
SCG Compound was more popular than SCG Plain
but there is little evidence to support the use of the
combination preparation[9]. Frequent use on demand
suggests that the immediate relief obtained by the iso-
prenaline in the compound may mean that patients are
confused about the role of the drug[10].
Though standard doses are usually sufficient, some
patients may improve on larger doses of SCG[11] and
IC[12]. It is certainly difficult to defend the prescription
of less than standard doses for patients with poorly
controlled symptoms. Non-compliance was a major prob-
lem with prophylactic inhaler therapy and two main types
were found: the use of treatment on demand and the
omission of daily doses in an otherwise regular inhaler
user. The latter type was not associated with a poor
understanding of prophylactic therapy and this may
explain why education may fail to improve compli-
ance[13]. The prescription of less frequent daily dose
regimes may be helpful in these circumstances.
The use of inhaled rather than systemic corticosteroids
where possible is now established practice and 400/ig of
beclomethasone dipropionate and 7.5mg of prednisolone
are considered to be roughly equivalent[14]. It was a
surprise to find, therefore, that 41 per cent of those on SC
did not use IC. It is likely that substantial reductions in
the use of SC would be possible in these patients.
Table 3. The prescribed doses of inhaled corticosteroid and sodium cromoglycate (2 puffs being 100ng beclomethasone
diproprionate or equivalent, 1 capsule being 20mg sodium cromoglycate or equivalent), and the number (%) of patients taking
each dose.
Daily dose
Drug Unknown 4 puffs 6 puffs 8 puffs >8 puffs
2 caps 3 caps 4 caps > 4 caps
or less
Inhaled corticosteroid 3 (4%) 12 (17%) 22 (32%) 37 (54%) 5 (7%)
Sodium cromoglycate 3 (6%) 14 (28%) 17 (34%) 15 (30%) 1 (2%)
46 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
This survey indicates the occurrence of major problems
in the use of prophylactic drugs for bronchial asthma in
general practice, despite postgraduate education in this
field promoted both by the profession and the pharma-
ceutical industry in recent years. Clearly this effort must
be sustained and attempts made to encourage general
practitioners, who have not done so, to attend relevant
meetings. Apart from stressing the importance of the
recognition of asthma, many general practitioners require
re-education in the therapeutics of prophylactic drugs.
Acknowledgements
We wish to thank: the Yorkshire Regional Health Au-
thority and Allen & Hanbury Limited for financial
support; Mrs Kathryn Marsden for secretarial assistance;
and the general practitioners who allowed us to interview
their patients in their surgeries.
References
1. British Thoracic Association (1982) British Medical Journal, 285,
1251.
2. Stellman, J. L., Spicer, J. E. and Cayton, R. M. (1982) Thorax,
37, 218.
3. MacFarlane, J. T. and Lane, D.J. (1980) Thorax, 35, 477.
4. Shee, C. D., Poole, D. and Cameron, I. R. (1980) Thorax, 35,
236.
5. Stark, J. E. (1980) In Topical steroid treatment for asthma and rhinitis,
p.81. (ed N. Mygind and T.J. Clark). London: Bailliere Tindall.
6. Paterson, I. C. and Crompton, G. K. (1976) British Medical
Journal, 1, 76.
7. Gregg, I. (1977) In Asthma, p.214. (ed T. J. H. Clark and S.
Godfrey). London: Chapman and Hall.
8. Editorial (1981) Journal of the Royal College of General Practitioners, 31,
323.
9. Godfrey, S. (1977) In Asthma, p.272. (ed T. J. H. Clark and S.
Godfrey). London: Chapman and Hall.
10. Gregg, I. (1982) In Child care in general practice, p.283. (ed C. Hart).
Edinburgh: Churchill Livingstone.
11. Bernstein, L. (1981) Journal of Allergy and Clinical Immunology, 68,
247.
12. Toogood, J. H., Lefcoe, N. M., Haines, D. S. M. et al. (1977)
Journal of Allergy, 59, 298.
13. Sackett, D. L., Haynes, R. B., Gibson, E. S. et al. (1975) Lancet,
1, 1205.
14. British Thoracic and Tuberculosis Association (1975) Lancet, 2,
469.
|
PMC005xxxxxx/PMC5370981.txt | The Medical Career Structure in 1985
R.EH. THOMPSON, dm, frcp
Consultant Physician, St Thomas' Hospital, London
The recent cuts in National Health Service staffjl], small
though they may be for doctors, should have stimulated
the profession to consider the rapidly increasing problems
with its career structure. The Select Committee on Social
Services concentrated in its Fourth Report (the Short
Report)[2] on medical manpower, and made some perti-
nent suggestions for improvements, most of which have
been accepted in principle by the Department of Health
and Social Security[3], Unfortunately, long-term solu-
tions will require greater resources, at a time when
unplanned cuts are suddenly imposed, and annual inter-
regional relocations of money make 'losing' regions des-
perately short of money for maintaining services, let alone
allowing for increases of staff.
Mr David Bolt has projected that in the year 2000 there
will be about 130,000 active doctors in the UK, compared
with 89,000 in 1979[4], This increase over 21 years is due
to the gradual increase in the number of medical students
qualifying, now about 4,000 a year, fewer doctors emi-
grating, and substantial immigration. Fears of mass
unemployment among doctors are fuelled by the increas-
ing number registering as unemployed[5], although this
can only be an approximation of the true number unem-
ployed. Interestingly, more than half the unemployed
doctors are in the four Thames regions, suggesting that a
reluctance to move to other regions may be a contributory
factor; the DHSS insists that there are at present jobs for
everyone, albeit some are less attractive and in less
attractive areas of the country.
At the end of 1983 the British Medical Association
estimated that 3,000 doctors were unemployed[6], al-
though this does include temporary unemployment. Will
there be large-scale unemployment? Breaking down Mr
Bolt's figures, one sees that if the policy of reducing the
average list to 1,700 continues, the number of general
practitioners will have increased by 50 per cent by the
year 2000, leaving perhaps as many as 25,000 extra
career (i.e. permanent) posts to be found in the hospital
and community services. At the present slow rate of
consultant expansion this seems impossible. However,
such estimates have in the past frequently been altered by
unforeseen events. There are three reasons why the
number of extra hospital posts needed may be substantial-
ly lower than predicted.
First, the age of retirement is likely to continue to fall,
owing to hospital doctors being able to increase their
pension rights by buying added years, and to the well-
founded pressure to prevent any doctor over 65 practising
in the Health Service. The statistic that doctors retiring at
60 live to a greater age than those retiring later may also
give impetus to earlier retirement. Second, it is projected
that 40 per cent of active doctors in the year 2000 will be
women, and therefore a number (perhaps also of men)
will be working part-time, which will reduce the number
of whole-time equivalents. Third, there is scope for a
substantial reduction in the number of overseas doctors
staying in the UK in career posts. The effect of these three
variables together could reduce Mr Bolt's projection for
the year 2000 by 30,000 doctors, although this would be
optimistic.
Most of us concentrate our energies on the problems of
our own specialty and our own region. Although there are
shortage specialties such as Geriatrics, Histopathology,
Anaesthetics and Radiology, in which there are more
career posts than suitably trained applicants, most hospi-
tal specialties are now full or over-full. For example, in
oral surgery there are only 5-7 consultant vacancies
annually, but 38 senior registrars[7]. Each senior regis-
trar is therefore likely to have to wait about six years in
the grade, which is surely a waste of his talent and
training. The current slowing down in the creation of new
posts makes the future ever more gloomy.
The Royal College of Surgeons has analysed the
prospects for junior general surgeons[8], and their figures
suggest that the number of senior registrars was just
about right for the consultant appointments in 1978-9,
but since then the fall in the number of consultant
appointments[9-l 1] may have upset this balance. The
numbers in the more junior surgical grades are more
unbalanced, for there are three times as many registrars
and senior house officers as senior registrars. However,
many registrars move from general surgery into the
surgical sub-specialties, and about half of the surgical
registrars and SHOs qualified overseas. If overseas doc-
tors continue to come for a limited period of training
only, it should be possible to retain most of these grades.
The College suggested that there should be a substantial
reduction in the number of juniors, and consequently
more sharing of them between consultant firms, together
with an expansion in the number of consultants and
senior registrars. Similar or worse problems exist in
medical specialties such as rheumatology, gastroenterol-
ogy and cardiology[12].
The Short Report[2] suggested, and the DHSS has
implemented[13], a standstill in the number of SHO
posts in each region. The DHSS insists that there are
sufficient SHO posts in the country to allow all UK
graduates to spend at least three years in the grade.
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 31
Presumably, therefore, the current difficulties post-regis-
tration doctors experience in obtaining SHO posts are
due to limiting their choice to the more attractive posts in
certain parts of the country. Increasing immobility within
the grade may also be due to current SHOs having
difficulty in finding registrar posts to which to move.
There are even minor problems when placing newly
qualified students in House Officer posts, although in
1983 only a handful were without a post[14], and it is
understood that these posts are to be protected against
manpower cuts.
The problem therefore lies in the imbalance between
SHO and registrar numbers on the one hand and senior
registrar and career posts on the other. This was caused
by a rapid expansion of junior posts, the majority of
which are now filled by overseas graduates[15], and only
a slow expansion of the senior grades. In certain special-
ties there is also an imbalance between senior registrars
and likely consultant vacancies. What is the solution?
First, the General Medical Council has proposed[16] a
system of careful sponsorship for overseas graduates
(Overseas Doctors Training Scheme) and the BMA has
made similar proposals[17]. Overseas doctors would be
granted limited registration for up to five years, provided
the post offered suitable education and training, and not
just service. Full registration, and therefore the possibility
of remaining in the UK, would be severely limited, for it
cannot be right to take young doctors from developing
countries, and encourage them not to return and use their
skills there. This scheme of sponsorship should allow
overseas doctors to continue the long tradition of medical
training in the UK[18].
Second, I oppose reducing the number of SHOs.
Under the sponsorship scheme many SHO posts will
continue to be filled by overseas graduates, and, provided
the posts are properly supervised, their incumbents
should gain proper education. It will be more necessary
than ever for the College's Sub-Committee on General
Professional Training of the Committee on General
Internal Medicine to ensure that these overseas incum-
bents are not abused. However, the Short Report sugges-
tion^], supported by the DHSS[3], that we should no
longer rely on their service contribution, must be wrong,
for doctors surely know that learning to ride a bicycle or
to practise medicine needs personal practice. Standing on
ward rounds or behind surgeons' broad backs as a
supernumerary is not learning and deludes those coming
to the UK for training.
However, if there should be a large decrease in the
number of overseas graduates coming to the UK, the
number of SHO posts will have to be reduced, which will
place a severe strain on senior staff, particularly in less
well staffed hospitals and in shortage specialties. In my
opinion, the number of SHO posts should not be reduced
at least until consultant numbers are increased. Another
option is for the Colleges to insist on an increased
minimum time in the SHO grade before entering general
practice. This would probably be unpopular but, with the
increased amount of broad knowledge required by to-
day's general practitioners, is worth considering. At
present the sudden, unplanned freeze of SHO posts has
made worthwhile local changes in junior staffing difficult
and, like the recent imposition of financial cuts, does
nothing to encourage the profession to plan ahead.
Third, part-time working should be encouraged, neces-
sarily predominantly among women. This will be difficult
in some specialties, but easier in others.
Fourth, retirement before 65 should be stimulated, if
necessary financially by the DHSS, and in my opinion the
rule in the hospital service that no doctor should be
allowed to practise beyond the 65th birthday should be
extended to general practice.
Fifth, more flexibility[3] between specialties and be-
tween hospital and general practice should be encour-
aged. Many younger members of the profession feel that
the Colleges and Faculties have acted unwisely in forcing
the ramshackle edifice of the Joint Committee on Higher
Medical Training on them. It may have been necessary to
provide a form of accreditation for entry into the Euro-
pean Community, and inspection and approval of posts
has helped to force health authorities to improve their
educational content, but the rigidity imposed on training
programmes has produced junior doctors worried about
how to obtain accreditation, and health authorities and
appointments committees unsure of how much weight to
attach to this new label. A candidate's ability and promise
ought to be more important than an approved course of
training that may have failed in its objective, and in many
cases the new appointee in a career post does work which
is quite different from that in his last training post. This
rigidity has made it difficult to change from specialty to
specialty, or from hospital to general practice, and in
particular discourages junior doctors in popular special-
ties from moving to shortage specialties. In my view
individuals should be accredited only after appointment
to a career post.
Another form of flexibility might be for part of the work
of shortage specialties to be taken on by other specialists.
There is a welcome move towards combining geriatrics
with general medicine[19]; but the radiology or histopath-
ology of a specialty could be combined with clinical work
in that specialty, so that a nephrologist, for instance,
might examine renal biopsy specimens and intravenous
urograms. Some lateral thinking could be beneficial.
Finally, there must be a sustained increase in the
number of hospital career posts, as suggested in the Short
Report[2] and supported by the Secretary of State[3,13]
when he asked Regional Health Authorities to plan to
double the number of consultants by 1996. But because of
shortage of money there is a decreasing number of new
consultant posts being created[9,10], although the Health
Minister disputes this[20], so there will have to be many
new appointments in 1995 if this pledge is to be fulfilled.
It is also the policy of the DHSS to increase the number of
general practitioners and thus to move to an average list
size of about 1,700[4]. Although senior hospital doctors
seem to be divided over the need to increase consultant
posts, it seems reasonable that more patients should be
seen and treated by fully trained doctors; doctors arrange
for their colleagues, rather than their colleagues' regis-
trar, to treat them or their friends. The fear of a greatly
changed consultant style of work without help from
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
juniors is understandable[8, 21-23], but a carefully ex-
panded consultant grade will provide a better career
structure for a larger number of junior doctors. The
concept of a sub-consultant grade was rejected, correctly I
believe, in the Short Report[2].
Expansion of the consultant grade requires extra re-
sources, for I am not convinced by the suggestion made in
the Short Report[2] and later in the debate in the House
of Commons[24], that consultants save money by using
resources more efficiently. It may be so, but there is no
good evidence for or against this. Every comparison of the
Health Service with the resources of those of our Euro-
pean neighbours or with North America confirms our
miserly attitude[25,26]. It may not be possible to increase
our gross national product, but the percentage spent on
the Health Service[27], the number of doctors[25] and the
number of medical students[25] is far below that of most
comparable countries. Although successive governments
trumpet their financial allocations to the Health Ser-
vice[28], repeated analyses of the resources allocated over
the years[29-31] and the 1983-84 cash limits[32,33] show
that we are not even providing for the increased needs of
an ageing population or expensive technology[34,35], let
alone allowing for any growth to try to close the gap with
other health services[36].
If the UK wants a Health Service that will in future
compare in quality with those of other countries, the
numbers of consultants and general practitioners will
have to be increased, and this will go a long way towards
solving the present frozen manpower structure. New
money will be required, as well as redistribution within
budgets. We must not bury our heads in the sand and
hope that the present juniors will somehow all make it to a
career post.
References
1. Deitch, R. (1983) Lancet, 2, 583.
2. Fourth Report of the Social Services Committee (Short Report)
(1981) Medical Education. London: HMSO.
3. Government response to the Fourth Report of the Social Services
Committee (1982) DHSS. London: HMSO.
4. Bolt, D. E. (1983) Medical manpower in the year 2000. London: British
Medical Association.
5. 'Medical Unemployment'. Information from DHSS, February
1983.
6. Hospital Doctor (1983) Vol. C3, No. 47.
7. Alty, H. M. (1983) Health Trends, 15, 64.
8. Report on surgical manpower and the career structure (1981) London.
Royal College of Surgeons.
9. British Medical Journal {1983) 285, 1591.
10. British Medical Journal (1983) 287, 1395.
11. British Medical Journal (1983) 286, 1675.
12. British Medical Journal (1983) 287, 243.
13. DHSS (1982) Health Circular HC/82/4.
14. British Medical Journal {1983) 287, 1152.
15. Todd, G. B. and Sheldrick, K. B. (1983) British Medical Journal,
286, 1997.
16. Williams, D. I. (1983) in Report of General Medical Council for 1982.
London: GMC.
17. British Medical Journal (1983) 286, 1916.
18. Williams, D. I. and Paton, A. (1983) British Medical Journal, 287,
1492.
19. Grimley Evans, J. (1983) Lancet, 1, 1430.
20. British Medical Journal (1984) 288, 657.
21,
22.
23.
24.
25.
26.
27.
28,
29.
30
31
32
33,
34.
35
Pentecost, A. (1983) British Medical Journal, 28 7, 305.
Batchelor, G. N. (1983) British Medical Journal, 286, 479.
Kathel, B. L. ibid, p. 806.
Hansard, 18th June 1982.
Day, S. C. (1983) Lancet, 2, 339.
Lancet (1984) 1, 749.
Wilson, M. A. (1983) British Medical Association document (HJS
14a).
British Medical Journal (1983) 286, 1079.
Hansard, Social Services, 25th April 1983.
Deitch, R. (1983) Lancet, 1, 659.
Russell, W. (1984) British Medical Journal, 288, 873.
British Medical Journal (1983) 287, 374.
Ibid. (1983) p. 700.
Maxwell, R.J. (1981) Health and Wealth. Lexington, USA: Lexing-
ton Books.
Royal College of Nursing (1983) British Medical Journal, 287, 1566.
Maxwell, R. J. (1984) in Health Care UK 1984 (ed A. Harrison and
J. Gretton.) CIPFA.
|
PMC005xxxxxx/PMC5370982.txt | Governments may Damage your Health
The FitzPatrick Lecture 1984
SIR GORDON WOLSTENHOLME, obe, MB, FRCP
Harveian Librarian, Royal College of Physicians
For a Harveian Librarian it is a particular honour to give
the FitzPatrick Lecture. It was a former Harveian Librar-
ian, Dr (later Sir Norman) Moore, who as 'an intimate
friend' of Dr Thomas FitzPatrick is credited with the idea
of a College lecture on the history of medicine. He
declared in fine Victorian style that Thomas FitzPatrick's
'intellectual attainments were the ornament of solid vir-
tues, and (that) he deserves to be remembered with
honour in this honourable place'fl]. It was another
Harveian Librarian, Dr Joseph Frank Payne, who in
1903 gave the first FitzPatrick Lecture, early in which he
stated 'this lectureship owes its existence to the munifi-
cence of a lady, Mrs FitzPatrick, who desires in this way
to honour the memory of her late husband, Dr Fitz-
Patrick, member of this College, a physician of great
worth, learning and accomplishments'[2]. My brilliant
and much-loved predecessor, Dr Charles Newman, gave
the lectures in 1954 and 1955 and again in 1968, and also
in 1958 gave an 'unofficial' FitzPatrick lecture to mem-
bers of the College, in which, characteristically, he
summed up the man in these words: 'Dr Thomas FitzPa-
trick was a pleasant person, a congenial companion, an
able linguist, perhaps a good doctor, but his immortality
results from the fact that his wife was fond of him'.
Thomas FitzPatrick was born in 1832 at Virginia, a
small Irish country town. He qualified in 1856, won the
silver medal of the Dublin Pathology Society in the same
year, graduated MD at Trinity College, Dublin, in 1862,
obtained his MD Cambridge in 1867 and his MRCP in
1868. There are three biographical details of relevance to
my subject. FitzPatrick was rather more than 'an able
linguist'; in Latin and Greek he was a classical scholar far
above the average; he spoke Italian, German, French and
Spanish, and had some knowledge of modern Greek,
Hebrew, Turkish and Danish; he was clearly a man who
made an effort to understand his fellow men and to meet
them on their own ground. The second point is that soon
after qualifying he joined the East India Company as an
Assistant Surgeon, saw service in Bengal, and no doubt
would have made his career in India but for a severe
illness, after which he was persuaded to enter practice in
London; he had therefore some insight into the conditions
in which vast numbers of poor people were living in the
Indian sub-continent. The third point is that FitzPatrick,
although successful in his practice in Sussex Gardens, and
supported by English aristocrats with Irish connections,
demonstrated his concern for less privileged sections of
society by writing about the social and sanitary conditions
of the labouring classes in Ireland[3].
The terms of the FitzPatrick Lecture call for the precise
subject to be announced beforehand. My title is clear but
it is easy to imagine more ways in which governments
damage health than the examples given here.
Patriotism, Nationalism and World Co-operation
My main argument runs as follows: for me, patriotism,
towards a native locality, community or country, can be a
legitimate and inspiring source of pride in traditions of
Fig. 1. Dr Thomas FitzPatrick.
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
17
service, of deep-rooted intellectual and aesthetic culture,
of emotional development, of high social standards of
behaviour, and of joy in shared experience and compan-
ionship. Patriotism in these terms promotes the well-
being, the spice, variety and creativity of the human
species. In contrast, nationalism, which in our modern
world becomes more and more divisive, competitive and
intolerant, poses an ever more critical threat to the very
survival of humankind. Dr Lewis Thomas[4] recently
described the infinite expression of individuality within
most, if not all, living species; such 'selfishness' presum-
ably has great survival value, but certainly not for our
human species when carried to excess in chauvinism,
racism, religious bigotry and self-righteous superiority.
Aggressive nationalism is as dangerous to the human
species as is a cancer, a cardiac infarct, or an inevitably
fatal genetic defect to an individual. In our present
wretched state of world affairs we may have to accept that
it is impossible in our lifetime to achieve peace or non-
violence or social and economic justice for the greater part
of the earth's population, but in regard to the gross
inequalities in the enjoyment of health throughout the
world, I suggest that we could do a great deal more than
we do already, but that if we leave it to government, we
shall wait in vain. I believe that professional, united and
non-controversial effort to relieve avoidable ill-health and
prevent disease might even put world politics on a new
course, away from confrontation and destruction, and
towards co-operation and even optimism for, in the words
of Addison, 'Health and cheerfulness mutually beget each
other'.
National Defence against Pestilence
Nations learned early in history to fear pestilence coming
from foreign lands. For most countries diseases such as
plague, cholera, typhus, smallpox and syphilis came from
elsewhere, so that strangers and foreigners were readily
associated with suspicion and dread. That the fears were
justified may be illustrated by the role of plague in the
overthrow of Athens, of malaria in the decline of Rome,
in the slaughter of at least a quarter of Europe's popu-
lation by probably pneumonic plague in the Black Death
of the fourteenth century, and by the death of about one-
fifth of London's population in the Great Plague of 1665.
In the middle of the sixth century, when plague was
killing tens of thousands throughout Europe, the Emper-
or Justinian, among his many other laws for the better
ordering of society, imposed regulations to ensure that
travellers arriving in Constantinople from plague-stricken
countries should be held in special camps until they were
'purified' and appeared to be free from disease, when
they were released with a certificate of health.
Protective measures were taken within countries as well
as between them: for example, a cordon sanitaire was
imposed in the seventh century in Provence, by Padua
and in Poland in the fourteenth century, and directed
with terror-driven savagery around Marseilles in 1720. In
England in 1625 the Court moved to Windsor to escape
the plague in London and a gallows was erected to hang
anyone who dared to follow. When Napoleon, returning
from the Egyptian campaign, disembarked at Frejus in
1799, without permission, the local 'Sante' in Marseilles
seriously considered having him shot.
Attempts to exclude ship-borne pestilence appear to
have been initiated by the island of Rhodes in 1306,
followed by the city of Ragusa (now Dubrovnik) in 1377;
ships coming from lands where plague was endemic were
held under observation at sea, at first for 30 days, and
then by Venice from 1403 onwards for 'quaranta' (40)
days?a period seemingly arrived at on no more scientific
a basis than that that had been the period spent in the
wilderness by Moses and by Jesus. The Venetian quaran-
tine of 40 days was soon copied by Genoa and Marseilles
and then by ports in England. In the eighteenth century
two famous Fellows of the Royal College of Physicians
became outstanding authorities on quarantine, namely
Richard Mead (1673-1754) and Gilbert Blane (1749?
1834). Under the British Quarantine Act of 1710, a ship
found to be carrying passengers with plague or cholera
could be forfeited and burnt. If sickness was found aboard
the victims were isolated in lazarettos where gunpowder
smoke and vinegar were used against contamination, and
the attendants wore oilskin suits and wooden clogs and
handled everything with tongs; the doctors were encour-
aged to fortify themselves with a few glasses of wine
before seeing the patients, though it was usual for them to
employ or blackmail students to carry out the actual
examination.
But nations were no less self-centred and competitive in
those days than they are now. Very soon quarantine
became the excuse for exposing the ships and crews of
commercial rivals to bureaucratic delays, extortion, accu-
sations of spying, and what was known as 'rummaging',
that is inspecting the cargo in such a way as to spoil or
ruin it. As a major maritime power, England was intoler-
ant of delays and inspections; when, at the first Interna-
tional Sanitary Conference, a British delegate declared
that 'time was money' a Spanish doctor replied 'but
public health is gold'. In 1854 Pacini in Italy described
the cholera vibrio as an 'organic, living substance of a
parasitic nature, which can communicate itself, repro-
duce itself, and thereby produce a specific disease' and he
worked out the dynamics of dehydration. All of which, he
said, was received with 'a sardonic smile of compassion'
and 30 years later the vibrio had to be rediscovered by
Koch. When the water-borne communication of cholera
was clearly described in England by Snow in 1849 and
Hassall in 1855, the British led the way in refusing to
recognise such inconvenient facts. As The Times put it,
'We prefer to take our chance of cholera and the rest than
be bullied into health', and the Royal College of Physi-
cians, in a report as late as 1892, dismissed all idea that
cholera might be contagious. But the British were the first
to impose common-sense regulations for the observation
of contacts in preference to the centuries-old and now
discredited rules of international quarantine.
International Sanitary Conferences
The dominating consideration in all the early health
measures between countries was national self-preserva-
18 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
-k tion and self-interest. This was still true when nations
began to exhibit concern for what was actually happening
in other countries in regard to epidemics. For example, in
1847 the French stationed medical men in Constan-
tinople, Smyrna, Alexandria, Cairo and Damascus to
; , give France advance warning of the approach of epide-
mics of plague and cholera. Later in the century Adrien
Proust (1834-1903), the father of Marcel, advocated
control of pestilential diseases at their source in endemic
centres, in preference to quarantine. It was a Frenchman
> also, Segur du Peyron, Inspector of the French Sanitary
Service, who proposed in 1834 that an international
meeting be held to try to bring some agreed international
order into the confusing multitude of both national and
individual port quarantine regulations, but this was at
t > first vetoed by Austria on the grounds that there was no
basis for co-operation. Such a meeting eventually took
) ' place in Paris in 1851, the first of 14 international
sanitary conferences[5] to be held, at intervals of two to
15 years, right up to 1938.
- V At that first conference, each of the 11 participating
nations was represented by one diplomat and one doctor
and each had an individual vote, so that a country often
^ , disfranchised itself. After six months it was said in the
closing speeches that much had been 'gloriously accom-
.-?> plished', and each delegate received the Legion of Hon-
our. The practical results, however, were nil.
But the French had at least established for the first time
that health was a suitable subject for international co-
operation. At the Second International Sanitary Confer-
ence in 1859 the participating nations were represented
only by diplomats, partly because the scientific questions
were thought to have been settled and partly because at
the first conference 'the doctors had disputed too much'.
However, at the Third Conference in 1866, medical
scientists were readmitted because in the previous year
cholera had spread alarmingly across the Mediterranean
to Europe from Egypt. The Fourth Conference, in Vien-
na, was called by Russia to protest against vexatious
hindrances to Russian shipping in the Bosphorus arising
from Turkish abuse of quarantine regulations; and the
Fifth was held in Washington in 1881, when the US
Congress tried to prevent the introduction of yellow fever
into the USA by insisting, though with no international
legal justification, that certificates of the sanitary state of a
ship must be obtained in all ports of origin before sailing.
Only at the Seventh Conference in 1892 was there a
measure of practical agreement in the form of an Interna-
tional Sanitary Convention. This was expanded to an
impressive 184 articles at the Eleventh Conference in
Paris in 1903, when the historical decision was taken, on a
proposal by Adrien Proust, to create in Paris an Office
International d'Hygiene Publique (OIHP). This began
work at the end of 1907, at first with nine participating
countries, but very soon with no less than 60. For 40 years
it was to provide, always in temporary quarters in Paris, a
v first world assembly for a new breed of doctors: knowl-
edgeable, experienced and concerned about the health of
people wherever they were situated in the world, and
prepared to communicate directly with each other, and
not through governmental and diplomatic channels, in
order to achieve improvements in health. On the govern-
mental side, the French were still unable to get agreement
even on the exercise of moral pressure: for the politicians'
sovereignty had to remain sacrosanct, and international
co-operation was to be informational only.
Health Organisation of the League of Nations
At the end of the First World War, when among other
woes 15 million people were dying of influenza, when
Russia had some 25 million cases of typhus and people
there were so starved that they were reduced to cannibal-
ism, the president of OIHP, Santoliquido of Italy, com-
mented sadly that 'five centuries have passed in five
years', and he called for well-organised health services in
all countries 'to repair the conscience of the world'.
Article 23 of the Treaty of Versailles confirmed that
member states of the League of Nations should 'take steps
in matters of international concern for the prevention and
control of disease'. The League of Nations and its Health
Organisation were both boycotted by the USA, which,
however, contrived that the work of OIHP should contin-
ue, wastefully, in parallel. The USSR also did not
recognise the League of Nations until 1934, but well
before that time the People's Commissar for Health,
Semashko, consulted with the Health Organisation, say-
ing that he was satisfied they were 'dealing with humani-
tarian and not political questions'[6],
The Health Organisation is generally acknowledged to
have been the one great success story of the League in the
years between the two World Wars. Its work included
epidemiological intelligence, collection and collation of
medical statistics worldwide, study of methods of organis-
ing health services, interchange of skilled health person-
nel, joint action on epidemics, and co-ordination of
scientific research, especially in regard to the production
of therapeutic sera, tests for the diagnosis of syphilis, and
the standardisation, efficacy and lack of toxicity of bio-
logical products. The Organisation also established ex-
pert committees on such diverse subjects as malaria,
leprosy, maternal welfare, infant hygiene, nutrition,
housing and rural sanitation. Try to imagine what a great
stride forward this was in world civilization. Yet during
its 20 years of high activity, the Health Organisation is
said to have cost the member nations less than the price of
one battleship of the time[7], and even then it relied
significantly on private financial support from the Rocke-
feller Foundation.
United Nations Relief and Rehabilitation
Administration
During the Second World War the United Nations Relief
and Rehabilitation Administration (UNRRA) began
work in November 1943, on Roosevelt's initiative, main-
ly to provide help to the estimated 13 million people in
Europe who had been displaced from their own countries,
but it also demonstrated, in collaboration with the Rocke-
feller Foundation, the feasibility of eradicating malaria
from islands such as Mauritius and Sardinia, and it acted
for two years as the world centre of information on
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 19
epidemics. UNRRA's efforts were described as 'the
greatest act of charity the world has ever seen' [8], but that
did not protect it from the attacks made on Roosevelt and
all his works, and there were the usual political stupidi-
ties; for example, when UNRRA arranged for desperate-
ly needed nurses to be trained in the USA, the United
States refused visas to the Yugoslav trainees, so Yugo-
slavia, badly in need of aid, withdrew from the whole
project. I find it sadly fascinating that the great United
States should fear political contamination by a few com-
munist trainee nurses rather than see the opportunity to
impress them with the virtues of democracy and freedom.
The World Health Organisation
It is common knowledge, I think, that when plans were
made at the end of the Second World War for a United
Nations Organisation, no specific arrangements were
made for health, despite the unique success of the Health
Organisation of the League of Nations. The preliminary
Dumbarton Oaks proposals referred to 'international
economics, social and other humanitarian problems', but
it was left to the initiative of the Brazilian and Chinese
delegates to insist upon a World Health Organisation
(WHO). Over the past 36 years WHO has striven to give
reality to its principles: to aim, for all the earth's people,
at a state of physical, mental and social well-being, to set
clearly in the minds of everybody?perhaps most impor-
tantly in the minds of doctors?that the enjoyment of
health is a fundamental right of all individual human
beings without distinction of race, religion, political belief
or economic and social condition; to regard the health of
all peoples as essential to long-term peace and security
and a matter of co-operative concern among all nations;
and to acknowledge that the achievement of better health
by any one nation is of value to us all, that inequalities in
world health constitute a common danger, that children's
health in every country is the basis of the well-being of
society, that the informed opinion and active co-operation
of the general public everywhere are essential to health;
and that every government has a responsibility for the
promotion of health.
The principles are all that the most idealistic of doctors
could desire and WHO has had conspicuous successes,
most notably in regard to smallpox eradication?though
in that respect I still feel apprehensive, remembering
from my own experience the inaccessibility of the high-
lands of Ethiopia where the disease was endemic. In
practice WHO operates on an annual budget of around
500 million dollars, that is about one-thirtieth of the
yearly cost of Britain's NHS, and less than one-thou-
sandth of the amount spent annually in the world on
arming sections of the human race against each other.
Unfortunately, WHO's membership is governmental,
and many nations wheel and deal for benefits of direct
consequence to themselves, with neither the compassion,
imagination nor vision to aim for the good of the world at
large. Even health can be viewed by governments with
indifference, suspicion and opposition. For instance, the
United States' ratification of the WHO agreement was
delayed for two years, through fears of internationalism
and socialisation of medicine; the Soviet Union and
China boycotted WHO for seven and five years respec-
tively; and at different times the politics of Taiwan, South
Africa, the German Democratic Republic, Vietnam and
Zimbabwe have mattered more than any regard for
people's health in those countries. Such obsession with
politics and economics demonstrates the validity of my
contention that even when governments are not actually
damaging our health, they often reveal a neglect, even a
contempt for what, after all, matters most in life to the
individuals and families who together make up the hu-
man species.
Inequalities in World Health
The size of the problems relating to health on this planet
are familiar to all: more than a billion people hungry to
the point of failure of physical and mental development
and resistance to disease; nearly a billion below a poverty
line of ?40 a year; a billion also debilitated by infestations
with a variety of worms; 500 million exposed to malaria
and schistosomiasis; 10-15 million with leprosy; 12 mil-
lion blind; child deaths in the worst areas 30 times greater
than in the more advanced places; 80 per cent of world
diseases caused by lack of clean water; this and much
more add to rural desolation, chronic fuel shortage,
rapidly spreading urban squalor, widespread illiteracy,
and the degree to which manageable afflictions may
advance in the absence of medical care. This is surely
enough, from a long catalogue of misfortune, to destroy,
among doctors at least, any lingering sense of apathy and
complacency.
What might be done to improve this situation? It is
easy to condemn national governments for false priorities.
But are we ourselves powerless, helpless in the face of
national governments which think of their own people
largely in economic terms and which are content, if not
even secretly satisfied, to see the economic potentialities
of other nations weakened by mass hunger, disability and
disease?
International Organisations t
There are organisations and there have in the past been
individuals who have managed to influence a few govern-
ments to some extent in regard to medicine and health. I
have already mentioned the Rockefeller Foundation, the
Sanitary Commission of which did so much early in this
century to overcome hookworm in the southern USA and
whose International Health Board has so generously
supported world health and medical science, including
specific aid to at least five British medical schools, and
which has claimed to operate its justifiably renowned
fellowships 'with freedom from political ends, interna-
tional as much as national'. And as just one of many
possible examples of important organisational contribu-
tions to world health, I must include the United Nations
International Children's Emergency Fund (UNICEF)
which, when it gained the Nobel Peace Prize in 1965, had
an income for that year equivalent to the then world
expenditure on arms for two hours.
20 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
Individuals with Remarkable Influence
As for remarkable individuals, I can mention only a few
of them. At the end of the eighteenth century Johann
Peter Frank (1745-1821), working mainly in Baden,
Lorraine and Lombardy, recognised that the strength of
any nation ultimately depends on the health of its people;
he demanded accurate statistics of births, marriages and
deaths, and information on the extent of poverty, serf-
dom, child labour and the incidence of diseases. Frank
also advocated a Supreme Medical Board to regulate the
practice of medicine on an international basis, to super-
vise medical schools and hence the whole of medical and
health systems. For him 'saving one single life must come
to be regarded as a deed loftier than the bloody conquest
of a province'.
Undoubtedly one of the greatest individuals to influ-
ence governments beneficially was Henri Dunant (1828-
1910) of Geneva, who witnessed the horrific slaughter of
some 40,000 Austrians and Frenchmen at the battle of
Solferino, Italy, in 1859, and in particular noted the total
inhumanity of the medical staff of the one side to the
wounded of the other. Dunant's description of that
terrible day, and his personal direct approaches to heads
of state led in 1864 to the establishment by himself and
five personal friends of the International Red Cross, and
the general acceptance of the principle of treatment of
casualties 'irrespective of nationality'. Dunant incidental-
ly was also a founder of the International YMCA,
actively deplored the use by Christians of rum, opium
and gunpowder in colonial exploitation, and advocated in
the middle of the last century the establishment of a
national home for Jews in Palestine under a French
mandate. When people had long forgotten him, he won
the first Nobel Peace Prize in 1902.
Then there, was John Howard (1726-90), the prison
and hospital reformer, who deliberately chose to travel on
a plague-infected ship to study the operation of quaran-
tine, and upon whose tomb in Russia is written: 'Who-
ever thou mayst be, thou standest at the grave of thy
friend'; and Florence Nightingale (1820-1910), with her
passionate concern not only for British soldiers in the
Crimean War and in India but also for all the natives in
India under British protection, who wrote 'it would be a
noble beginning to the new order of things to use hygiene
as the handmaid of civilization'. Nikolai Ivanovitch
Pirogov (1810-81) was Florence Nightingale's Russian
opposite number in the Crimean War, a great anatomist
and surgeon, founder of a school for nurses, who intro-
duced health education into Russian schools and was also
deeply concerned about the education and fate of minor-
ities. Such great men as Pasteur (1822-95), Koch (1843-
1910), and Lister (1827-1912), in the words of Sir George
Buchanan[9] 'were all good patriotic nationals, but it goes
without saying that their work was done for and taken by
the whole world . . . their nationalities trouble us as little
as those of the great composers'. And I would include
Henry Pomeroy Davison (1867-1922) who, having di-
rected the American Red Cross extremely well in the First
World War, and mistakenly believing that the public
would continue to subscribe as generously, set up in 1919
the League of Red Cross Societies 'to anticipate, diminish
and relieve the misery produced by disease and calamity,
and to devise a world health programme'. Unfortunately,
after four good years the money failed, though the League
continues to play a valuable international role. Lastly, Dr
Mahler, the present Director General of WHO, who has
spoken of his wish 'to use health as a lever for social and
economic development' and 'more than that, to use it as a
platform for peace'.
The Role of the Medical Profession
Where does the medical profession stand in all this? From
1851 onwards doctors, especially those with research
interests, began organising a great many international
meetings. After the first International Medical Congress
in Paris in 1867 the Lancet[ 10] noted that 'if after this trial
an international medical gathering is ever again thought
of, it could not take place anywhere but in the French
capital' and considered it a pity that Latin was not kept
up and spoken as the language of the learned of all
countries. After the London Medical Congress in 1881
the Lancet[ 11] felt that 'the welfare of the whole human
race was promoted'. No less than 8,000 attended the
Medical Congress in Rome in 1894, which called forth
another noble statement from the editor of the Lancet[ 12]:
Fig. 2. Henri Dunant, founder of the International Red Cross.
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
21
'it was in Rome, according to Suetonius, that professors
and practitioners of healing were first given the rank of
citizens by Julius Caesar. It is in Rome that the profession
is making another stage on its path to that still higher
citizenship?the brotherhood of the nations, the citizen-
ship of the world\
Most of the congresses and conferences became estab-
lished as regular periodic meetings of medical societies
and associations. The Yearbook of International Organiza-
tions[ 13] for 1981 listed over 200 such bodies in medicine
and biology and there are similar numbers of active
medical associations in regions such as Western Europe;
there are also many biomedical journals which have
international boards of editors. The emphasis is naturally
on the exchange of information about research, and the
practising profession appears to be less internationally or
globally concerned. Apart from the interests of the profes-
sion itself and regulations for ethical and professional
conduct, as discussed in a body like the World Medical
Association, or the admirable efforts of such international
societies as the Ophthalmologists and Dermatologists,
who organise prevention and relief in the Third World,
there is little evidence that our profession views the
intolerable burden of unnecessary or preventable disease
afflicting about a quarter of our fellow humans as an
affront to our special skills and our humanitarian princi-
ples.
We have made some progress in establishing in the
European Community at least minimal standards for
basic medical education and specialist training, and have
given some consideration to common standards of pro-
fessional conduct, but we have a long way to go before
such standards can be universally applied?and yet, why
not? The medical profession is often regarded, as Bernard
Shaw saw it, as 'a conspiracy against the public'. No tears
are shed over anything which reveals the profession's
weaknesses or its financial preoccupations. To secure and
deserve a better reputation, and perhaps enjoy an easier
conscience, could not the practising profession form an
alliance of its members worldwide, preferably together
with members of closely allied health professions, not to
concern itself with status or conditions of service, but
purely to take steps to reduce unnecessary suffering,
prevent disease and promote better health?
An Alliance for World Health
I have in mind not an organisation of well-meaning 'do-
gooders', but the highly efficient, multi-disciplinary,
technical service of which we are capable[14]. Some two
million doctors in the world, and many times that number
of other health professionals, are not too small a body to
exercise considerable influence, if they cared to co-
operate.
I have outlined elsewhere how I think such an alliance
might be structured and financed[15]. Compared with
the potential benefits the costs could, I believe, be
comparatively low?a tiny fraction of the huge sum
gambled away each year in the UK and almost negligible
compared with what is spent daily in adding to already
overwhelming armaments.
There would surely be a significant role for those who
are rich in experience and have retired while still youthful
in spirit. Even more importantly, such an alliance for
service might well provide the best possible outlet for the
undoubted ideals and energies of the otherwise unem-
ployed young in all countries, who could act in support of
the professionals and greatly extend their competence.
We are all sick almost to death of increasing nuclear
tension, callous terrorism, criminal violence, racial ha-
tred, religious fanaticism, ideological intolerance and
nationalistic obstacles to freedom of movement. Migrat-
ing birds exploit the whole planet for the survival of their
species; can the human species afford to do less? It seems
to me that doctors are in a unique position to demonstrate
to governments that by this stage in the history of the
world nothing less than a global concern for human life is
appropriate or acceptable. In determining that care and
cure be extended equally to all who need them, we might
give all people and governments grounds for a renewal of
confidence and hope.
References
1. Payne, Joseph Frank (1904) in English Medicine in the Anglo-Saxon
Times, FitzPatrick Lecture, RCP, 1903, p. 3. Oxford: Clarendon
Press.
2. Ibid., p. 1.
3. FitzPatrick, T. (1862) Transactions of the National Association for the
Promotion of Social Science, 1861, pp. 504-509.
4. Thomas, Lewis (1984) 'The Smell of Self: a Link between Olfactory
and Immunological Signals'. Lilly Lecture given at the Royal
College of Physicians of London (unpublished).
5. Howard-Jones, Norman (1975) In The Scientific background of the
International Sanitary Conferences, 1851-1938. Geneva: WHO.
6. Howard-Jones, Norman (1978) In International Public Health between
the Two World Wars?the Organizational Problems. Geneva: WHO.
7. Goodman, Neville M. (1971) In International Health Organization,
2nd ed. Edinburgh and London: Churchill Livingstone.
8. Ibid., p. 138. (Noel-Baker, Philip, 1946 quote).
9. Buchanan, Sir George (1934) Lancet, 1, 880.
10. Ibid. (1867) 2, 247.
11. Ibid. (1881) 2, 342.
12. Ibid. (1894) 1, 808.
13. Yearbook of International Organizations (1981) 19th ed. Union of
International Associations and International Chambers of Com-
merce. Paris and New York: ICC Publishing.
14. Wolstenholme, G. E. W. (1969) In Health of Mankind, pp. 254-61.
Ciba Foundation Symposium. London: Churchill.
15. Wolstenholme, G. E. W. (1973) In The Greater Medical Profession.
New York: Josiah Macy Jr. Foundation.
22 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
|
PMC005xxxxxx/PMC5370983.txt | Physicians and Infection
At the beginning of this century Britain led the world in
providing facilities for the isolation and management of
patients suffering from contagious diseases. Large fever
hospitals were constructed outside most cities and were
run by Physician-Superintendents who combined admin-
istration with clinical duties; many also acted as the
Medical Officer of Health to the adjacent city or town.
With the decline in the incidence of the traditional
infectious diseases many of these hospitals closed and
eventually only one remained as a referral centre and
teaching unit in most NHS regions. The number of
infectious diseases physicians also decreased. Changes
have also occurred outside hospital. At the time of the
1974 reorganisation of the Health Service many exper-
ienced Medical Officers of Health retired, and their
successors, who commonly have wider responsibilities,
have little or no practical experience of infectious dis-
eases.
Hospital accommodation for patients with suspected or
confirmed tropical disease was also gradually reduced as
the Empire declined and the influence of war receded,
and the numbers of physicians trained in tropical medi-
cine fell.
As a result of the above, the numbers of clinicians in
England and Wales who are trained in communicable
and tropical diseases has declined to around 30 and there
are many areas where such expertise is no longer avail-
able. This is in marked contrast to other countries, most
notably the USA and Canada, where every hospital has at
least one infectious disease physician.
The reduction in the incidence of the traditional conta-
gions has been matched by an increase in many other
types of infection, which commonly occur in general
hospitals where advice on their diagnosis and manage-
ment is usually provided by microbiologists. Infections
contracted in tropical countries continue to be imported
by the ever-increasing numbers of travellers and many of
these require a knowledge of tropical medicine for diag-
nosis and treatment.
The College Committee on Communicable and Tropi-
cal Diseases has produced a report recommending an
increase in the number of physicians and paediatricians
with training and experience in infection, with the aim of
providing an improved service to patients, especially
those in general hospitals where complex and often life-
threatening infections are an everyday and increasing
problem. General practitioners and community physi-
cians would also benefit from the availability of local
expert advice on the diagnosis, management and preven-
tion of infection. What should these new clinicians be
called? Confusion has resulted from the various titles used
at present?these include infectious diseases, communi-
cable diseases, microbial diseases, communicable and
tropical diseases, and tropical medicine. Perhaps these
might all be abolished and replaced by a single designa-
tion such as physician or paediatrician with an interest
and training in infection. The College Committee might
also be re-designated as the Committee on Infection.
Names such as those of Jenner, Lister, Nightingale,
Manson, Ross and Fleming recall landmarks in the
control and management of infection in which Britain has
played a leading role. The future will continue to provide
challenges from diseases caused by micro-organisms and
we must be equipped to deal with them.
A. M. Geddes
|
PMC005xxxxxx/PMC5370984.txt | Systemic Sclerosis
The Watson Smith Lecture 1984
N. R. ROWELL, md, FRCP
Consultant Dermatologist, The General Infirmary at Leeds, and Reader in Dermatology,
The University of Leeds
Sydney Watson Smith, who died in 1950, was Honorary
Consulting Physician and Dermatologist to the Royal
Victoria and West Hampshire Hospital, Bournemouth,
, and in 1934 was President of the British Medical Associ-
ation. His bequest to the College, in memory of his wife
and himself, stipulated that an annual lecture be given on
any subject in medicine, including dermatology. It
seemed appropriate to choose a subject which demon-
? strates that dermatology is probably one of the few
specialties embracing all aspects of clinical and investiga-
tive medicine from childhood to old age.
My interest in systemic sclerosis started over 25 years
ago. Research has been carried out on many features of
this disease but I want to concentrate on three aspects:
first, clinical subsets of the disease; second, immunologi-
cal abnormalities; third, genetic aspects and possible
initiating and precipitating factors. My experience is
based on the study of 131 patients at Leeds since 1958.
Although systemic sclerosis has been described under
various names since the early 19th centuryfl], it was
Goetz in 1945 who named the condition progressive
A systemic sclerosis[2]. As many patients live for years, I
feel that the term progressive is unnecessarily daunting
for patients, and prefer the shorter title systemic sclerosis.
Scleroderma means sclerosis of the skin, which can occur
in various conditions, and to avoid confusion this term
should not be used for the disorder.
Systemic sclerosis is a multi-system disease and starts
* with Raynaud's phenomenon in over 90 per cent of
patients. After an interval, which is longer for females
than for males, changes occur in the skin. The skin of the
face becomes shiny, the nose is beaked, there are radial
furrows around the mouth and mat-like telangiectases on
the cheeks. Mouth opening is restricted. In the early
stages the hands may be swollen but later the skin of the
hands becomes tight and shiny with absorption of the
terminal phalanges and small ischaemic scars on the tips
of the fingers. Calcinosis develops in the soft tissues of the
hands and elsewhere. It occurs predominantly in females.
The skin of the arms and frequently of the neck below the
clavicle becomes tight and shiny. Pigmentation occurs in
one-third of cases and may resemble Addison's disease.
Changes occur in the feet, with loss of toes due to
ischaemia. Ischaemic leg ulcers occur in 30 per cent of
patients. The oesophagus is dilated, air-containing and
lacking in peristalsis. The results of radiology in 50
Table 1. Radiological observations of the oesphagus in 50
patients with systemic sclerosis.
No. %
Radiological involvement demonstrated 38 76
Dilatation 30 60
Absent or diminished peristalsis 32 64
Gastro-oesophageal reflux 20 64
Hiatus hernia 13 26
Stricture 6 12
patients are shown in Table 1. Oesophageal reflux is
more common than dysphagia. Stricture occurs in 12 per
cent. Oesophageal manometry shows abnormalities more
frequently than does radiology but it is not required as a
routine investigation. The third part of the duodenum
may be dilated and aperistaltic segments and strictures
occur in the ileum. We evaluated small intestinal involve-
ment in 20 patients by jejunal biopsy, small bowel
radiology and tests for bacterial overgrowth and malab-
sorption, and in 55 per cent found abnormalities which
were unrelated to disease in other organs[3]. Malabsorp-
tion is not due to poor intestinal permeability. In 17
patients permeability was normal[4]. Malabsorption is
mainly due to bacterial overgrowth which is found in one-
third of patients[5]. Barium enema shows characteristic
wide-mouthed diverticulae of the colon. The extent of the
involvement of the gastrointestinal tract is shown in Table
2. The oesophagus, duodenum and colon are most fre-
quently involved. Basal fibrosis of the lungs can be shown
radiologically in nearly half the patients, but abnormali-
ties of pulmonary function occur before radiological
changes. Impaired gas transfer is, in our experience, the
Table 2. Radiological involvement of the gastrointestinal tract.
%
Oesophagus 76
Stomach 6
Duodenum 34
Jejunum 11
Ileum 17
Colon 43
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 23
most delicate test and is abnormal in 75 per cent[6], The
heart can be involved, electrocardiographic abnormalities
being the most frequent findings. Even the teeth show
changes. Widening of the periodontal membrane occurs
in 30 per cent and is not related to the degree of
involvement elsewhere[7].
In my series 73 per cent of patients had radiological
oesophageal involvement, 49 per cent had an abnormal
ECG, 46 per cent had radiological signs of fibrosis of the
lungs and 41 per cent had impaired renal function.
The overall five-year survival rates reported are be-
tween 34 per cent[8] and 73 per cent[9], the differences
between series depending upon different clinical criteria
and the proportion of males and females. The prognosis
of systemic sclerosis is worse in males than in females[10,
11]. The disease also advances more rapidly in men than
in women. The shorter mean interval between the onset
of Raynaud's phenomenon and the onset of cutaneous
changes, when they can be dated, in my series is shown in
Table 3. All the men had developed cutaneous changes
Table 3. Mean interval between onset of Raynaud's phenom-
enon and onset of cutaneous changes of systemic sclerosis when
this could be dated.
Males 0.25 + 0.8 years
Females 5.10 + 7.0 years
P< 0.005
within two years, in contrast to females in whom the
interval was as long as 28 years.
The criteria for diagnosing systemic sclerosis have
recently been considered by a sub-committee of the
American Rheumatism Association[12] and are shown in
Table 4. These preliminary criteria gave a 97 per cent
Table 4. Preliminary criteria for systemic sclerosis 1980[12].
Sole major criterion
or
Two or more minor criteria
Proximal scleroderma
Sclerodactyly
Digital pitted scars of
fingertips or loss of
substance of distal finger
pad
Bilateral basilar
pulmonary fibrosis
sensitivity and 98 per cent specificity for definite systemic
sclerosis in 797 patients seen in 29 American medical
centres between 1973 and 1977. Patients with advanced
disease are not difficult to diagnose but these criteria do
help to provide standards for identifying mild cases and
allow comparison between series.
Subsets of Systemic Sclerosis
Undoubtedly there are subsets of systemic sclerosis and
their recognition will become increasingly important in
relation to immunological and other factors, to prognosis
and to treatment. In 1962 Tuffanelli and Winkelmann
studied 727 cases from the Mayo Clinic[13], They consid-
ered that systemic sclerosis should be divided into diffuse
and acrosclerotic forms. The diffuse form was rare,
involving approximately 5 per cent of patients. The sex
distribution was equal, as compared with four females to
one male in acrosclerosis. In the diffuse group Raynaud's
phenomenon was absent or infrequent, sclerosis was
generalised and the course was more rapid and likely to
be fatal within a few years. It is difficult to be certain
whether diffuse systemic scleroderma is an entity or not.
Undoubtedly the sex distribution differs and the con-
dition has a poor prognosis but some patients with
acrosclerosis also have a short course; one of my patients
died within two years of onset of the disease.
Since 1964 considerable interest has been shown in the
so-called CRST syndrome of calcinosis, Raynaud's phe-
nomenon, sclerodactyly and telangiectasia^ 4], With the
addition of oesophageal involvement this later became the
CREST syndrome, the E representing the American
spelling of oesophagus. Is this an entity? In an analysis
some years ago[ll], 12 of 84 (14 per cent) of my patients
with systemic sclerosis showed features of CRST. All had
involvement of the internal organs characteristic of sys-
temic sclerosis, and two died from malignant hyperten-
sion, so all cases do not have a good prognosis, as has
been claimed. The male to female sex ratio of patients
with CRST syndrome did not differ from that of the
whole series and the mean interval between the onset of
Raynaud's phenomenon and the onset of cutaneous
changes, if these could be dated, did not differ between
patients with CRST syndrome and patients without these
features. From the clinical point of view I would regard
the CRST or CREST syndrome as only mild systemic
sclerosis, but I will deal later with some immunological
evidence to suggest that it might be a definite subset.
In 1972 Sharp[15] described 25 patients with features
of systemic lupus erythematosus, systemic sclerosis and
polymyositis, using the term mixed connective tissue
disease. A haemagglutinating antibody to saline extract-
able antinuclear antigen (ENA) could be demonstrated in
all. This was RNA-ase sensitive. All had speckled antinu-
clear factor (ANF), none had Sm antibody, and anti-
DNA antibody, if present, was in low titre. Clinically,
renal disease was infrequent, the prognosis was good and
patients responded to oral corticosteroids. Further obser-
vations showed that 80 per cent were women and one-
third present like rheumatoid arthritis, one-third like
systemic sclerosis and a few like systemic lupus erythema-
tosus. Probably the most characteristic clinical feature is
the swelling of the back of the hands with sausage-shaped
swelling of the fingers. The face may also be swollen and
shiny. The skin manifestations fall into three main
groups: those of systemic sclerosis with erosions of the
finger tips and disorders of pigmentation; those of lupus
erythematosus, either scarring discoid or non-scarring
subacute cutaneous lupus erythematosus, and those of
dermatomyositis with violaceous appearance of the eye-
lids, plaques on the chest and periungual telangiectasia.
Raynaud's phenomenon occurs in 90 per cent and vascu-
24 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
lar changes may be very severe, resulting in gangrene
which may involve the whole hand. Arthritis is the most
common feature and may resemble rheumatoid arthritis.
There may be features of muscle involvement, as in
polymyositis, and changes in the gastrointestinal tract
and other organs identical to those of systemic sclerosis.
The immunological abnormalities included speckled
ANF and antibody to ribonucleoprotein (RNP), immune
complexes in 90 per cent and decreased T cells. Patients
with overlap of polymyositis and systemic sclerosis may
also have precipitating antibodies recently designated
PM-Scl[16] and Ku[17]. In some cases direct immuno-
fluorescence of normal exposed skin shows particulate
staining of epidermal cells[18] and occasionally nucleolar
staining[19], Immunoglobin at the dermo-epidermal
junction occurs in one-third. The inflammatory aspects
rapidly respond to prednisone but over the course of time
about half the patients are left with the features of chronic
systemic sclerosis[20].
Is mixed connective tissue disease a subset of lupus
erythematosus or of systemic sclerosis? Many patients
fulfil the American criteria for systemic lupus erythema-
tosus, despite having the digital erosions, oesophageal
changes and colonic diverticulae of systemic sclerosis.
Anti-RNP antibodies have been demonstrated in one-
third of my patients with systemic sclerosis, although only
10 per cent have had other evidence of mixed connective
tissue disease. Antibody to RNP is found in 25 per cent of
patients with systemic lupus erythematosus and occasion-
ally in other patients[21]. Do these patients then have
latent mixed connective tissue disease? Examination of
nail-fold capillaries suggests a link with systemic sclerosis.
Of the patients with mixed connective tissue disease 54
per cent have the capillary changes of systemic scler-
osis[22]. Do these abnormal capillaries indicate the
patients that go on to systemic sclerosis? Or is mixed
connective tissue disease an entity in its own right? Two
aspects suggest that it may be. Abnormalities of immuno-
regulating T-cell circuits in mixed connective tissue dis-
ease are different from those found in systemic lupus
erythematosus, systemic sclerosis and rheumatoid arthri-
tis[23]. Second, although one cannot define this disorder
only by antibody to RNP, there is some evidence that
patients with RNP antibodies may be genetically different
from patients with uncomplicated systemic lupus erythe-
matosus, systemic sclerosis or polymyositis[24, 25].
About 10 per cent of patients with systemic sclerosis
have ragged cuticles and nail-fold capillaries visible to the
naked eye. Capillary microscopy shows a characteristic
pattern of capillary abnormalities in over 90 per cent of
patients with systemic sclerosis. Normal nail-fold capillar-
ies occur as regular loops evenly spaced, whereas in
systemic sclerosis the nail-fold capillaries are enlarged and
distorted and there is loss of capillaries and disruption of
the normal capillary bed. Haemorrhage is frequent.
There does not appear to be any correlation with the
extent of cutaneous disease[26], but Maritq, who has
done the most work on this subject, suggests that there
may be correlation with the extent of visceral involve-
ment[27]. Loss of capillary loops characterises the
changes in systemic sclerosis and it may be that this
vascular ischaemia is the factor related to disease duration
and systemic involvement[28]. The systemic sclerotic
type of pattern of skin capillaries is also seen in dermato-
myositis and mixed connective tissue disease and it has
been suggested that the nail-fold capillary changes may
indicate some common pathogenic factor. Abnormal nail-
fold capillary changes occur in some patients with Ray-
naud's phenomenon[29], and future long-term
prospective studies may show that nail-fold microscopy is
a useful tool in predicting those patients with Raynaud's
phenomenon who will develop systemic sclerosis. It is
difficult to estimate the proportion of patients with Rayn-
aud's phenomenon who will eventually develop systemic
sclerosis. From the evidence available, I suggest it may be
about 1 per cent of females and 6 per cent of males.
Patients with systemic sclerosis do not usually notice
any precipitating factor, so what about so-called occupa-
tional scleroderma? About 6 per cent of polyvinyl chloride
workers develop a syndrome resembling systemic scler-
osis[30]. The skin of the face is shiny and tight, the hands
are ischaemic with shortened bulbous finger tips. Patients
have various immunological abnormalities and immuno-
histology of the skin shows an immune complex vascu-
litis^]. A genetic susceptibility is indicated by the
increased incidence of DR5 in patients compared with
controls and of B8 and DR3 in those severely affect-
ed[32]. Similar syndromes have occurred after exposure
to organic solvents, pesticides and the vapour of epoxy
resins, but these are very rare[33]. There is also an
association between a systemic sclerosis-like illness and
silicosis. Because of the occupational risk?to miners,
sandblasters and quarrymen?the condition occurs
almost exclusively in men. In East Germany[34] it has
been estimated that males exposed to silica dust are 25
times more likely to develop a systemic sclerosis-like
illness than are males not exposed to silica. Although
visceral symptoms resembling those of systemic sclerosis
occur in about half the cases and ANF can be demon-
strated in one-third, I am not yet convinced that they
suffer from true systemic sclerosis. The incidence is much
higher than the suspected gene frequency of classical
systemic sclerosis, and the situation is rather similar to the
relationship of the systemic lupus erythematosus syn-
drome due to drugs like hydralazine and procainamide
and true systemic lupus erythematosus. We do not know
how silica acts but it may be by stimulating the produc-
tion of collagen directly or indirectly by macrophages.
Alternatively, occupational substances may inhibit a de-
fence mechanism to which I will refer later. These
syndromes should alert us, however, to possible unsus-
pected environmental triggers. Sclerodermatous skin
changes are a late feature of the Spanish toxic oil syn-
drome[35], the nature of which is also unknown, but
there is some evidence that there are genetic differences
between affected and unaffected individuals.
Immunological Aspects
A variety of humoral and cellular immunological abnor-
malities can be demonstrated in the disease. Over 20
years ago, Beck et al., using rat liver as substrate, found
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
25
ANF in 78 per cent of patients at Leeds and Glasgow with
systemic sclerosis[36], Homogeneous factor was most
frequently demonstrated, but nucleolar factor occurred
more frequently in systemic sclerosis than in other con-
nective tissue diseases. Recent experience at Leeds using
rat liver has given an almost identical figure of 77 per cent
but speckled ANF is now more frequent than homogen-
eous. In the last few years tissue culture cells have been
used as the substrate as an alternative to rat or mouse
liver, and antinuclear antibody has been detected in
almost all cases of systemic sclerosis. Tan and his col-
leagues^], using Hep 2 cells?a human laryngeal carci-
noma cell line?showed that 96 per cent of sera were
positive for ANF which is similar to our figure of 94 per
cent. Various staining patterns have been described[38].
Centromere staining results from the presence of an
antibody which reacts with the centromere region of
metaphase chromosomes. This is shown as large, bright,
round or ovoid granules occurring through the interphase
nucleus and on the chromosomes of dividing cells. Other
staining patterns using Hep 2 cells include homogeneous,
peripheral (specific to systemic lupus erythematosus), fine
and gross speckling and a diffuse 'frosted glass' pattern
which is seen only in sera containing an antibody to Scl 70
antigen. Scl 70 antibody is usually demonstrated by a
precipitin reaction to a soluble nuclear antigen Scl 70
which occurs in about 20 per cent of patients with
systemic sclerosis. In addition, three distinct nucleolar
patterns have been described?homogeneous, speckled
and clumpy.
Ninety per cent of patients with anticentromere anti-
body have CREST syndrome[38] and 50-70 per cent of
patients with CREST syndrome have anticentromere
antibody. Anticentromere antibody is associated with
long duration of disease, a low incidence of pulmonary
involvement and rarity of renal involvement[39]. There is
no consistent change in titre with time[40], Anticentro-
mere antibody, however, is not always present in patients
with the CREST syndrome. It may be present in patients
with Raynaud's phenomenon before the clinical features
of the CREST syndrome occur[41], and be useful, like
nail-fold capillary changes, as a marker to distinguish
patients with Raynaud's phenomenon who are likely to
develop systemic sclerosis. Anticentromere antibodies
occur in about 2 per cent of patients with Raynaud's
phenomenon, 6 per cent of patients with systemic lupus
erythematosus and 6 per cent of patients with mixed
connective tissue disease. Anticentromere antibody has
been found in about 9 per cent of patients with primary
biliary cirrhosis and these patients had the CREST type
of systemic sclerosis[42]. Of patients with primary biliary
cirrhosis 17 per cent have systemic sclerosis[43],
Anti-Scl 70 antibody occurs in about 20 per cent of
patients with systemic sclerosis and appears to be particu-
larly associated with a high frequency of lung involve-
ment[44]. It may be a marker for systemic sclerosis, as it
has not been found in other diseases such as systemic
lupus erythematosus or rheumatoid arthritis[37 ].
Tuffanelli and his colleagues[45], using cells from a rat
kangaroo epithelial cell line as substrate, reported four
patients with an antibody to centriole, which is a repro-
ducing cellular organelle that organises the mitotic appa-
ratus during cell division. One patient had Raynaud's
phenomenon with telangiectasia, another had CREST
syndrome and the other two definite systemic sclerosis.
The relevance of these and other humoral antibodies to
pathogenesis is not known. They may, however, define
immunological subsets.
Various aspects of cell mediated immune mechanisms
have been studied at Leeds and Sheffield in co-operation
with Dr Hughes and his colleagues. Delayed skin reac-
tions are depressed. Leucocyte migration inhibition oc-
curs with a wide variety of autologous and homologous
antigens?autologous lymphocytes, liver microsomes and
mitochondria, and human myelin basic protein, but not
to porcine thyroglobulin[46]. In our experience lympho-
cyte transformation to phytohaemagglutinin (PHA) is
also depressed and the degree of depression is related to
the severity of the disease, elevation of the ESR and the
incidence of circulating antibodies[47]. There is a strong
correlation between decreased lymphocyte . transforma-
tion to PHA and deficiency of circulating T cells. Both
total and T lymphocytes are reduced in systemic sclerosis
as compared with controls. In our research work we have
found it useful to have a grading system to define mild
and severe systemic sclerosis (Table 5). Addition of points
Table 5. Criteria of systemic involvement in patients with
systemic sclerosis.
Disease score
System (points allotted
involved Criteria for involvement)
Skin Sclerosis?face 1
hands 1
trunk 1
GI tract Radiological changes 3
Lungs Radiological changes and/or
abnormal C02 transfer factor 3
Heart ECG changes 3
Kidneys Creatinine clearance <60ml/min
and/or proteinuria 3
Other Sjogren's syndrome,
myositis, etc. 3
allocated to the features shown gives a disease score.
Using this grading there is a positive correlation between
the deficiency of T lymphocytes and the extent of the
disease. To what is this deficiency of T lymphocytes due?
We do not know, but it may be due to a redistribution of
lymphocyte populations, a secondary effect of the disease
or the result of chronic antigenic stimulation such as that
seen in 'host versus graft' disease. Studies of T-cell
subsets by other workers have shown that helper cells are
increased[48] and suppressor cell function is decreased in
systemic sclerosis. Whiteside and her colleagues have
reported that depressed suppressor cell function is not
related to severity of the disease or to other immunologi-
cal abnormalities[49]. Unlike T cells, B cells are not
reduced even in severe disease.
26 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
Reduced lymphocyte cytotoxicity can also be demon-
strated in systemic sclerosis. There are several possible
lymphocyte tissue damaging mechanisms, first, T lym-
phocytes with specific cytotoxicity to target cells, second,
a combination of non-T lymphocytes, or killer (K) cells,
and antibody to target cell tissue antigens (so-called
antibody-dependent cytotoxicity) and third, spontaneous
lymphocyte-mediated cytotoxicity produced by natural
killer (NK) cells which are mainly T cells; NK cells may
take part in immune surveillance. Patients with systemic
sclerosis with extensive disease, according to our grading
system, and low T cells have both reduced antibody-
dependent cytotoxicity and reduced PHA-induced T cell
cytotoxicity to Chang liver cells when compared with
mildly-affected patients and with controls[50]. We do not
know the cause of this defective cell-mediated cytotoxicity
but circulating factors capable of blocking or inhibiting
these two types of cytotoxicity have been demonstrated in
some of our patients and these could be lymphocyte
toxins, immunosuppressive globulins or immune com-
plexes.
We have also demonstrated decreased NK cell cytotox-
icity to Chang liver cells in severe systemic sclerosis, but
not in mild cases compared with controls[51]. It has been
impossible to substantiate the claims of Trayanova et
al. [52] and Currie et al. [53] that lymphocytes from
patients with systemic sclerosis have increased cytotoxi-
city to cultured muscle, fibroblasts and epithelial cells,
but this may be due to technical reasons, i.e. to differ-
ences in the time of incubation of the lymphocytes with
the target cells[54],
Dr Hughes and colleagues have allowed me to present
some results on antibody-dependent cellular cytotoxicity
to human vascular endothelium[55]. Serum from about a
quarter of our patients with systemic sclerosis produces
cytotoxicity of human umbilical vein endothelium when
co-cultured with human peripheral blood mononuclear
cells. Sera from normal controls and patients with athero-
sclerosis or diabetes do not show similar cytotoxicity. The
serum factor(s) in patients with systemic sclerosis is
present in IgG fractions and the effector cells have all the
characteristics of K cells. There is some evidence that
these serum factors may be immune complexes, but
antinuclear antibodies could also be involved. This anti-
body-dependent cellular cytotoxicity to vascular endothe-
lium was found particularly in patients with circulating
immune complexes, anti-nuclear and ENA antibodies,
and more severe disease. Only one serum causing cyto-
toxicity had anticentromere antibody, which is normally
associated with the mild CREST variant of systemic
sclerosis. Kahaleh et al. [56] have reported direct cytotox-
icity of vascular endothelium which they attributed to a
circulating protease-like factor in serum from patients
with systemic sclerosis. This non-immunological cytotoxi-
city has not been confirmed by others. Serum from our
patients, with or without added complement, did not
cause direct cytotoxicity.
We have also studied immune complexes in systemic
sclerosis using three techniques: Raji cell radioimmune
assay, Ciq binding and K cell inhibition[57]. The Raji cell
test is the most sensitive but immune complexes were
found in 58 per cent of patients by at least one technique,
an incidence similar to that found in systemic lupus
erythematosus. Complexes were associated with elevated
IgG and IgA levels, a high incidence of auto-antibodies
and severe visceral involvement. They occurred in 41 per
cent of mild cases compared with 76 per cent of severe
cases. Other workers have produced some evidence that
C i q binding immune complexes seem to be associated
with lung involvement[58].
More recently we studied the mean finger temperatures
during a standard vasodilating stimulus in patients with
systemic sclerosis[59] and showed that patients with the
disease have cooler hands than the controls, with more
variation in temperature between digits than in controls.
Patients with circulating immune complexes have much
lower resting temperatures than those without complexes,
and the rate of vasodilation under stimulation was also
slower in patients with immune complexes. These two
features suggest that immune complexes could be a factor
in the production of ischaemia in the hands of some
patients with this disease. Other workers, using a differ-
ent technique, have shown a relationship between the
presence of immune complexes and Raynaud's phenom-
enon[60].
How do immune complexes work? We do not know,
but they could have a direct action on blood vessel walls,
although we have been unable to demonstrate immune
complexes in arteries by immunofluorescent techniques
in autopsied cases. They are more likely to arm K cells
with antibody-dependent cytotoxicity. They could in-
crease platelet aggregation or they could inhibit the
release of prostacyclin from vascular endothelium.
Widespread vascular changes of intimal hyperplasia
and endothelial damage occur in systemic sclerosis, and
there is considerable evidence to indicate that the micro-
vasculature may be the prime target in the disease[61,
62]. It has been suggested that ischaemia or the release of
vasoactive substances may initiate the excessive collagen
synthesis which leads to the characteristic fibrosis of the
disease. Circulating antibodies to collagen Types I and
IV occur in systemic sclerosis[63], and Type IV collagen
is found in blood vessel walls. It is interesting, however,
that anticollagen antibodies appear to be inversely related
to the severity of the disease.
Genetic Aspects
That there is a genetic predisposition to systemic sclerosis
has been suggested by the occasional familial cases, by the
finding of abnormalities of serum proteins and by the
increased incidence of ANF in first-degree relatives of
patients. The United Kingdom Study Group studied 50
British patients and their blood relatives and found
antibodies to collagen in 49 per cent of patients and in at
least one relative in 87 per cent of families, whether or not
the patient had anticollagen antibody. Various chromoso-
mal abnormalities have also been found in the disease[64,
65],
HLA typing has been done in several studies. In 71 of
our patients with systemic sclerosis no significant alter-
ation in the incidence of HLA type was found when the
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 27
group was considered as a whole. However, further
analysis showed that the incidence of HLA-B8 was
greatly increased in the severe cases with extensive vis-
ceral involvement. Patients with B8 had more rapidly
progressive and extensive disease than B8 negative
patients[66]. Moreover, the more severely involved
patients had a higher mean ESR, decreased circulating T
cells and depressed lymphocyte responses to PHA. This
association of impaired cell-mediated immunity and ge-
netic factors has been confirmed by Kallenberg and
colleagues[67], who found an association between haplo-
type B8/DR3 and impaired cellular immunity. Recently
Black and her colleagues[68] reported an increase in
DR2, DR3 and DR5 and a reduced incidence of DR2 in
systemic sclerosis. The increased incidence of DR3 was
attributed to an increase in the Al, B8, DR3 haplotype.
Mild cases, i.e. those with the CREST syndrome, had an
increased incidence of DR1 and DR5 and decrease of
DR2 when compared with the severe cases. They noted
that patients with anticentromere antibody were mainly
DR1 or DR5 but there was no relationship between HLA
and Scl 70 antibodies. They found no association with
any specific organ involvement in their series, but Lynch
et al. [69] noted an increase of DR3 and a decrease of DR4
in a subset of patients with systemic sclerosis and pulmon-
ary fibrosis.
A Unified Concept
One of the most neglected aspects of a disease is the
interpretation of its age and sex distribution. The age at
onset of Raynaud's phenomenon in our patients is shown
in Table 6. The onset in males is later than in females.
Table 6. Age at onset of Raynaud's phenomenon in 131
patients with systemic sclerosis (Leeds).
Age (yr) Females Males
0-9 2 0
10-19 14 2
20-29 19 4
30-39 20 5
40-49 17 11
50-59 17 6
60-69 2 1
70-79 1 0
92 29
Professor Burch carried out a mathematical analysis of
age and sex specific incidence rates as a function of age on
my original cases over 20 years of age[70]. Plotting the
age-specific incidence rates for each sex versus age at
onset on log/log scales results in curves which rise to a
peak and then fall steeply to zero. The meaning of these
curves, which are similar in type but not in detail to those
found in other autoaggressive diseases like systemic[71]
and discoid lupus erythematosus[72], is that the disease in
question is confined to genetically predisposed individuals
and that each disease is characterised by one or more
specific genotypes. The characteristic female sex pre-
dominance in systemic sclerosis, about 3-4 females to
every male affected, together with other evidence, sug-
gests that the genotype involves one dominant X-linked
allele as well as autosomal factors.
Mathematical analysis of these curves indicates that the t
disease appears to be initiated in predisposed individuals
by a small number of random events; the average rate of
such events is effectively constant throughout life and is
independent of secular and geographical factors. These
random events, Burch and I suggest, are somatic muta-
tions in predisposed lymphoid stem cells. How does one,
or a small number of mutations cause widespread dis-
ease? We believe that forbidden clones of lymphocytes
synthesising cellular autoantibodies develop and, after a
proliferative phase or latent period which is longer in
females, attack the primary target tissue, which, in the
case of systemic sclerosis, is possibly vascular endotheli-
um. The body appears to have an endogenous defence
mechanism, probably involving both immunoglobulins
and cell-mediated immunity, which can be modified or
inhibited by environmental factors which, in the case of
systemic sclerosis, could include exposure to vinyl chlo-
ride or silica.. This defence mechanism, partly dependent
on genetic factors involving the X-chromosome, is thus
more effective in females, which accounts for the slower
progress of the disease and the better prognosis in females
than in males. Other factors, for example HLA B8 and
DR3, seem also to govern prognosis. That genetic factors a
may be concerned in the progression of disease can also
be seen in other conditions. For example, alcoholic
cirrhosis occurs more rapidly in patients with HLA B8
and DR3[73], Defective humoral and cell-mediated im-
munity may allow forbidden clones to proliferate. The
former would account for the high incidence of auto-
aggressive disease in agammaglobulinaemia.
Clinical and immunological subsets are probably gen-
etically determined, and this could be confirmed by
studies of the onset patterns of precisely defined groups.
The pattern of organ involvement in a particular patient
may depend on several factors, for example on particular
forbidden clones, on genetic differences in the antigeni-
city of target tissues, on local defence antibodies or on
local vascular factors. Antinuclear antibodies arise as the
result of release of nuclear material by damaged tissues.
They may themselves enhance tissue damage, as can be
demonstrated in animal experiments[74, 75], The fact
that they are not present in all patients may, in part, be
due to the genetic inability of certain individuals to
produce these antibodies. Patients with overlap syn-
dromes probably have the genetic factors for more than
one disease or, alternatively, certain alleles may be
pleiotropic and predispose to more than one disease.
This unified concept (Fig. 1) though obviously contro-
versial, is consistent with the sex and age distribution, the
spontaneous onset in many cases, environmental factors,
clinical and immunological subsets, multiple immunolog-
ical abnormalities, differences in prognosis between males
and females and overlap with other autoaggressive dis-
eases. Our theory, however, is much less controversial
but perhaps not so startling as Sir Fred Hoyle's concept of
disease being due to viruses, bacteria and genes descend-
28 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
*
ing on the earth from outer space[76]. But Hoyle does,
however, point out that 'old style genetics . . . failed to
give proper emphasis to stochastics . . which we have
endeavoured to correct in our consideration of age and
specific incidence rates in the disease.
At present there is no specific or effective treatment but
what of the future? Recombinant DNA technology and
drug- or virus-induced gene switching could modify
genetic aspects, and in time it may be possible to develop
antibodies to specific forbidden clones which will allow a
more rational approach to therapy. These aspects high-
light the need for more precise definition of clinical and
immunological subsets. The outcome of a disease de-
pends on the balance between attack and defence. Attack-
ing factors have attracted most attention in the past.
Perhaps we should now concentrate more on enhancing
defence mechanisms. The pace of advance is now so rapid
that I can see all these developments occurring in my life-
time.
Wulff has discussed two philosophical concepts of
disease?the nominalistic and the essentialistic (or de-
monic)[77]. In the first concept a disease consists of
patients with similar clinical, immunological or patho-
logical features, that is, a disease is a collection of sick
people. In contrast, the essentialistic concept suggests
that, like demons, diseases actually attack people. I
recognise both concepts in systemic sclerosis, which is not
a homogeneous condition but consists of several groups or
subsets of patients. Demons also exist and possibly attack
primarily the endothelial tissue of blood vessels.
Acknowledgements
Research is a co-operative effort and I would like particu-
larly to thank John Beck, Philip Burch and Peter Hughes,
who have been my main companions, with many others,
on this Odyssey.
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INITIATION PHASE
Spontaneous somatic mutation of genes
in lymphocytic stem cells
DEVELOPMENT PHASE
Propagation of forbidden clone(s) in part
genetically determined. Phase vulnerable
to extrinsic factors such as silica,
vinyl chloride, etc.
t
CLINICAL PHASE
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il College of Physicians of London Vol. 19 No. 1 January 1985
|
PMC005xxxxxx/PMC5370985.txt | Editorial
Had a nice day? Did every one and thing slot nicely into your clinical
programme? If so, then lucky you and congratulations on your
organisation. Alas, experience shows that the nitty-gritty of routine
hospital work is commonly full, of the gritty. Despite management,
administration, operational research and whatever, the pattern of
work is usually flawed. We get inured to a level of delay and muddle;
and so do the patients. For the patient a hospital visit is too often like
war, 95 per cent boredom and 5 per cent fright. An hour's wait for
five minutes with the doctor and another hour waiting for blood tests
and X-rays is not a programme that would be tolerated by a customer
in a shop. So will the new Griffiths-type 'business' managers address
this problem? They certainly cannot succeed without considerable
effort from the medical profession. We should all be aiming at making
patients satisfied customers, not with a transient burst of efficiency
but as an accepted routine.
So much of today's hospital work concerns the use of its facilities to
spare the traditional beds. But even the best-intentioned doctor can
still be guilty of disrupting his patient's life by admitting him to a bed
without a clear thought as to why he should be in it. Well-run day
investigation units and special clinics do give the patient a great deal
of benefit with minimal cost in time out from ordinary life. These
successes come from a mutually agreed aim enthusiastically pursued
by all those involved. The less concentrated efforts in routine practice
suffer from a fragmentation of purpose, each person doing his own
thing while feeling little responsibility for the whole task.
Many doctors see their hospital life through a haze of overwork and
over-commitment. Juniors may see themselves as transient prisoners
in a system they cannot change. Seniors are too busy battling for more
resources to take the time to 'fine tune' those they have. It is indeed a
constant struggle for a hospital to deal effectively with the amount of
disease that presents; there is little left over to consider the conve-
nience of each patient. The public is faced with taking pot luck with
the way things go or waiting endlessly for an appointment. So it
would seem to be special pleading for a magic administrative wand to
save the individual patient's time. But saving that time benefits all
those responsible for clinical care.
Happy are the clinicians whose administrative colleagues consider
their prime task is to make it easy for a doctor to see patients. Yet
happier are the patients when administrators and clinicians combine
to make it easy for the patient to complete his hospital treatment. It is
a pity that we cannot monitor the process by putting a volunteer
'patient' through the system every day, much as a standard is run
through an auto-analyser. We can at least ask patients how they
fared, a necessary but neglected bit of audit. We also have to realise
our responsibility for ensuring each hospital visit is of real value to the
patient and that our colleagues the secretaries and clerks have an
important role we should acknowledge and applaud.
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
|
PMC005xxxxxx/PMC5370986.txt | Computer-Based Research by Disabled
Engineers: A Case Study
VIVIEN MORRIS, ma, DPhil
Senior Research Assistant, Department of Fluid Engineering and Instrumentation, Cranfield
Institute of Technology, Cranfield, Bedford
It is well known that unemployment is particularly com-
mon among disabled people[l] and even highly trained
graduates are often unable to find work appropriate to
their qualifications. However, recent advances in com-
puter technology mean that, in this area at least, it may
be possible to mitigate the physical handicaps imposed by
disability. Consequently, disabled people should be better
able to achieve their vocational potential in computation-
al work than in many other professions.
Objectives
The aim of the project was to allow a small number of
severely disabled technology graduates with skills and
interests in computing to work professionally for industry
by providing them with training and technical equip-
ment. Initially it was hoped that the group would become
self-financing, but, in practice, constraints were identified
which suggest that a small amount of external funding
will probably always be necessary for a group of this kind.
Participants
It took longer than expected to find suitable participants,
probably because highly-trained specialists were needed
and such people are not numerous even among the able-
bodied. Publicity on TV, in the national and local press,
relevant technical journals and appropriate confer-
ences^], together with approaches to UK universities
and polytechnics, professional institutions, associations
concerned with disabled people[3], regional health au-
thorities, spinal and rehabilitation units, etc., led to
contact with four graduates with appropriate interests and
abilities. Their background training covered mechanical
engineering, electronic and electrical engineering, math-
ematics/computer science and civil engineering, and their
respective disabilities were tetraplegia, congenital deaf-
ness and limited speech, blindness, and a rare form of
muscular disorder.
Organisation
Cranfield Institute of Technology is a postgraduate uni-
versity which works closely with industry, earning ap-
proximately half of its income from contract research.
Much of the work of the Department of Fluid Engineer-
ing and Instrumentation (DFEI) on the analysis of flow is
carried out for industrial clients so that it is particularly
suitable for an enterprise of this kind, which requires
industrial collaboration.
Work undertaken by participants was linked to re-
search in progress at DFEI, but a period of training was
generally necessary before they were able to begin work-
ing on commercial contracts. The management of the
project was shared between several members of DFEI
staff. It would have been preferable to appoint a full-time
co-ordinator to arrange training programmes, select and
modify computing equipment, liaise with industry, or-
ganise contract work, manage financial matters, as well as
make some contribution to technical work. In practice, it
proved impossible to find such a co-ordinator, possibly
because those with relevant technical skills were unwilling
administrators. It was particularly disappointing when
the appointment of a disabled co-ordinator for a trial
period was unsuccessful, though this may have been
largely due to factors connected with his illness (multiple
sclerosis).
Each participant lived and worked as seemed best
suited to individual circumstances. Only one of the four
was able to live on campus where there is close contact
with academic staff and easy access to well-maintained
computing equipment. Two participants worked from
home, using microcomputers or telephone links to the
mainframe computer at Cranfield. The civil engineer's
disability required residential care and he lived in the Part
III accommodation associated with the Spastics Society's
Professional Workshop in Milton Keynes. Nevertheless,
he found it difficult to endure the short taxi journey to
Cranfield.
Equipment
Each participant was provided with a microcomputer and
accessories but it was sometimes necessary to modify this
equipment to take account of disability. The tetraplegic
engineer operated his microcomputer very effectively
with a mouthstick (Fig. 1) though slight modifications
were necessary, e.g. to the shift key. He was also able to
load and unload floppy discs by means of a specially
designed rack. Small programs, or sections of large
programs, were developed on this computer but access to
the mainframe computer became necessary at a later
34 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
y! 1
stage to link individual sections together. A commercial
v ' company, CASE (Computer'and Systems Engineering),
kindly donated additional equipment to allow him to
operate a telephone link to the mainframe computer at
?> Cranfield. In addition, a large working surface was
installed in his home, allowing access from a wheelchair,
with a vertical section to support textbooks, manuals,
etc., so that pages could be turned with a mouthstick (Fig.
I
2). Manipulation of heavier items was difficult and a
microfilm reader was purchased jointly with Imperial
College so that he could access large amounts of infor-
mation stored on film, according to his particular require-
ments, without handling paper copies.
Major problems with computing equipment were ex-
perienced by the blind mathematician. Although regis-
tered blind, he used his residual vision to operate a large
scale CCTV magnification system (Fig. 3). The screen
had to be continually switched between cameras focused
on the VDU and on notes, as a split screen gave
insufficient magnification, so the assimilation of infor-
mation was slow and laborious. A voice synthesiser was
attached to his microcomputer to give an audible record
of input and output, but this by no means solved the
problem. After discussions with the Royal National Insti-
tute for the Blind, the Manpower Services Commission
(MSC) provided financial support to allow a sighted
assistant to read aloud for 10 hours a week and, at a later
stage, supplied a Brailink machine. This machine could
be used independently to record and store information in
Braille, or with the microcomputer (or telephone link to a
mainframe) to provide a tactile record of computer input
and output.
In view of the laborious process required to access
information, it was not surprising that the mathematician
worked much more slowly than a sighted person might
have done. Research work at Southampton University[4]
has suggested that blind subjects using a voice synthesiser
take 3-6 times as long as sighted people to obtain
information from a Prestel system. A much larger time
factor would probably be appropriate if the user were
attempting to assimilate complicated technical ideas. It
remains to be seen whether the tactile Braille display
proves to be more helpful than the audible record from
the voice synthesiser or the visual image from the CCTV.
At present, it seems appropriate to restrict the work to
relatively short programs which can be retained mentally
without too much difficulty. No special modifications to
computing equipment were necessary for the two remain-
ing participants.
Research Topics
During the period covered by this report, the DFEI
undertook a major contract for a commercial manufac-
turer of electromagnetic flowmeters. The exact nature of
the work is confidential but it accounted almost exclusive-
ly for about 18 months of^the electronic engineer's time
and produced substantial income for the project. This
Fig. 1. Tetrablegic engineer operating microcomputer with
mouthstick.
Fig. 2. Raised working surface with access from wheelchair.
Fig. 3. Computer operation by means of large-scale CCTV
magnification system.
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
35
work also formed the basis for his MSc thesis, which was
successfully submitted towards the end of 1983. Two
other participants also carried out varying amounts of
computational work linked to this contract and the com-
pany was charged for their time at DFEI's normal rates.
The mathematician undertook calculations connected
with the design of specially shaped electrodes in an
electromagnetic flowmeter for a project funded by the
Science and Engineering Research Council (SERC) and
began work linked to a flowmeter project carried out
jointly by Cranfield and the University of Salford.
SERC provided some support for the civil engineer's
work on computer modelling of systems of drains which
become full during flooding. At the time of writing, this
work is not complete so commercial exploitation is not yet
feasible.
Other research topics involved developments of earlier
work by members of DFEI staff and were not supported
by external funds. This category includes work on an
existing computer program to predict pressure surges
occurring in the cooling system of a power station on the
Isle of Grain. Recent tests allowed the actual pressures to
be measured so that comparison of empirical and theor-
etical values became possible. The mathematician modi-
fied the orginal program so that it could be used on
modern microcomputers.
The mechanical engineer was co-author of a report on
the effects of installation on a 12-inch turbine flowmeter.
The detailed nature of the work is confidential but it
involved examination of the effects of sudden changes in
flow on the meter's performance. Experimental values of
various parameters were compared with theoretical pre-
dictions obtained from a computer program developed by
this participant. The client was charged for his time at
DFEI's normal rates. Since then, various aspects of the
work have been developed beyond the scope of the
original contract.
Output
The length of training required before participants were
sufficiently expert to cope with work for commercial
contracts varied enormously. In some cases, contract
work was possible almost immediately, but in others it
was still not feasible even after two years of training.
Three of the participants registered for higher degrees
and continued working for them in addition to contract
work. Cranfield's close links with industry mean that
thesis topics are directly related to industrial problems
and results of contract research can often be used as the
basis for a thesis. When necessary, the university accept-
ed registration for a higher degree on the basis of part-
time work from home. At the time of writing, the
registration periods required for the two PhD pro-
grammes are still incomplete, while the author of the
successful MSc thesis has begun work on a more substan-
tial topic suitable for a PhD. This participant's deafness
accounted for his enviable ability to concentrate on the
task in hand despite the distractions of a noisy environ-
ment and, apart from speech therapy and help with
telephone calls, little was needed to compensate for his
disability. He was the only member able to work a full
working week with normal efficiency. For various rea-
sons, the other three all had restricted outputs. Difficul- j
ties in accessing information reduced the blind
mathematician's efficiency to a tenth or a twentieth of
that of a fully sighted graduate, and although the tetra-
plegic engineer worked effectively, his disability quickly
produced exhaustion, so that he was able to spend only
about ten hours a week on computational work. The
fourth graduate suffered continual periods of sickness,
some of which required hospital treatment, so that he
made very little progress. It also seemed possible that the
powerful drugs required by his disability may have
affected his concentration. These restrictions inevitably
led to a lower earning capacity than had originally been
estimated.
Finance
The main source of income, apart from the two grants
from charitable foundations, was from fees charged to u
industrial clients for whom research was undertaken.
DFEI's normal practice is to charge customers overheads <
of more than 100 per cent, in addition to charges for time,
and the same procedure was followed in this case. Thus,
the major factor affecting income was the amount of work
which could be satisfactorily completed in a given time.
There were many sources of expenditure. The initial
cost of computing equipment was high, with the possi-
bility of extra charges for specialised items to overcome
disability. The graduates were paid for their work, but
this was not administratively straightforward and the
details varied between participants. It was sometimes '
possible to pay a student bursary to cover the initial
training period, and to replace this with a salary as
expertise developed. Alternatively, participants were paid t
as each piece of work was completed. Rates were based on
commercial levels applicable to fully able graduates,
regardless of the time actually taken to complete the
work. Whenever necessary, payments conformed to
DHSS requirements for disabled people in receipt of (
social security benefits. These sometimes seemed to be
unnecessarily harsh and to actively discourage disabled 1
people from working at home. At present, those whose
earnings just exceed the ?22.50 a week allowed as 'thera-
peutic' earnings are heavily penalised by withdrawal of
benefits. The financial loss can amount to two or three
times the earned income. Unless disabled people are able
to guarantee earnings which exceed the benefits by at
least ?22.50, they lose money by working. The restricted
working hours sometimes associated with severe disability
mean that it may not be possible to overcome this
financial barrier. At present, the DHSS does not recog-
nise partial incapacity for work. The assumption is that
one is either able to work, or completely unable to work,
and no provision is made for those whose disability
restricts potential earnings to the difficult band where
earned income would exceed 'therapeutic' earnings but
fall short of state benefits.
Additional charges for time, travel, etc. were incurred
by members of staff who provided advice and guidance
36 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
Table 1. Estimated income and expenditure, 1980 83.
Year
No. of
participants
Expenditure (?)
Income (?)
Equipment
Other
Total
Members'
Work
Student
Support
Total
Income as
% of
expenditure
1980
1981
1982
1983
2,000
6,000
3,000
3,000
4,000
5,000
13,000
*18,000
6,000
11,000
16,000
21,000
11,000
13,000
4,000
3,000
* includes small contribution from early 1984.
15,000
16,000
0
0
94
76
for disabled participants, co-ordinated research work,
modified equipment, managed financial affairs and dealt
with other administrative aspects.
Table 1 summarises income and expenditure through-
out the four-year project. The figures show that a sub-
stantial proportion of costs was recovered as the project
progressed. However, a large part of the income in 1982
and 1983 arose from one particular contract and it is
almost impossible to achieve a steady flow of contract
work. A shortage produces a corresponding drop in
income, but an excess is undesirable if high standards are
to be maintained. Consequently, it would not be realistic
to expect to recover as high a proportion of costs as in
1982 and 1983 on a regular basis, particularly if numbers
of participants increase. Each new recruit requires ad-
ditional expenditure on computing equipment and this
may not be offset by an increase in earning capacity until
after an initial training period.
Discussion
The therapeutic value of the work was apparent through-
out. Participants stressed the frustration of unemploy-
ment and the fulfilment associated with the opportunity of
undertaking interesting and stimulating work despite
severe disability. During the period of the work, activities
such as the International Year of Disabled People pro-
duced an increase in general awareness of the problems
faced by disabled people and the discrimination to which
they are often exposed. The Manpower Services Com-
mission (MSC) now administers several schemes to assist
disabled workers, e.g. fares to work, aids to employment,
etc., but provision in the UK still falls short of that in
countries such as The Netherlands and Sweden[5]. The
MSC has always been sympathetic to the work but the
present group of graduates are highly trained profession-
als whose needs do not seem to be effectively served by
government-sponsored schemes, such as Sheltered Indus-
trial Groups, which cater for workers with a wider range
of less specialised skills. This is particularly regrettable, as
professional people may well be less handicapped in their
work by physical disability than manual workers. Never-
theless, help was sought from the MSC, whenever poss-
ible, so that precedents and contacts could be established
for use in the future when external funds from charitable
sources might not be available.
The original aim of a self-financing consultancy group
was not achieved for the following reasons:
1. Training periods were generally required before com-
mercial contract work could be undertaken. These were
sometimes unexpectedly long.
2. Severe disability sometimes restricted working hours,
e.g. only 10 hours a week were possible for the tetraplegic
engineer. Periods in bed or hospital reduced output.
3. Disability sometimes reduced working efficiency, e.g.
difficulty in assimilating and retaining information was
associated with blindness. Specialised equipment to coun-
teract this is relatively expensive, e.g. a Braille computer
terminal costs ?5,000. In addition, drugs needed to
overcome disability may reduce working ability.
4. Some degree of isolation was associated with work
from home. Repairs to computing equipment took longer
to arrange and there were sometimes delays while waiting
for visits from academic advisers. There was a tendency
to spend too long wrestling alone with a particular
problem before seeking advice.
Nevertheless, the work suggests that it would be realis-
tic to expect to recover a substantial proportion of costs.
The percentage recoverable by disabled people in intellec-
tual disciplines almost certainly exceeds that achieved by
similar workers with less specialised skills. For example,
Remploy, a government-sponsored organisation in which
about 80 per cent of the workers are mentally or physical-
ly handicapped, trades in areas such as textiles, furniture,
packaging and assembly. In 1981/82 it recovered just
under 50 per cent of its costs[6], a figure exceeded by a
comfortable margin in the present project.
Conclusion
It appears that the external funding required to enable
these engineers to work professionally is relatively low,
probably of the same order of magnitude as the state aid
which would automatically be paid if they were unem-
ployed. However, the returns in terms of self-fulfilment
are high and, in addition, are associated with useful
contributions to engineering research. It might well be
desirable to modify existing government-sponsored
schemes to allow a nationwide network of such groups,
possibly based in universities, so that computational
research could be undertaken by severely disabled profes-
sionals in other parts of the country. Although the
interests of the original group were confined to industrial
fluid mechanics, there seems to be no reason why the
concept should not be extended to computer applications
in other disciplines.
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 37
Acknowledgements
None of this work would have been possible without the
enthusiastic support of Professor Roger Baker, Head of
DFEI, who obtained the initial funding. We are grateful
to the Nuffield Foundation for the original grant and to
the Gatsby Charitable Foundation for additional assist-
ance and the opportunity to continue the work for a
further three years. We would also like to thank the Aidis
Trust for the permanent loan of an Apple microcomputer
and accessories.
References
1. Kettle,. M. (1979) Disabled people and their employment. Banstead:
Association of Disabled Professionals.
2. Enever, K. J. (1981) Distech '81. Proceedings of a conference at /
Sussex University, March 30-April 3. London: The Spastics So-
ciety. (
3. Baker, R. C. and Morris, M. V. (1981) Contact, No. 30, p. 15.
London: Royal Association for Disability and Rehabilitation.
4. King, R. W. (1983) Personal communication.
5. Greaves, M. and Massie, B. (1977) Work and Disability. London: ;
Disabled Living Foundation.
6. Marsh, P. (1982) New Scientist, 95, 218.
|
PMC005xxxxxx/PMC5370990.txt | I
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!
Observations on Indian Neurology
R K. NEWMAN, MB, MRCP(UK), Consultant Neurologist
M. SAUNDERS, MB, FRCFJ Consultant Neurologist
Middlesbrough General Hospital, Ayresome Green Lane, Middlesbrough, Cleveland
The common neurological diseases of the West are, with
j - some exceptions, frequently seen in Indian practice, but a
further catalogue of neurological affliction is associated
) with the twin factors of infection and malnutrition, and
J 4 these conditions must feature prominently in any account
of neurology in India. Headache, epilepsy, cervical spon-
dylosis, cerebrovascular disease and Parkinson's disease
will dominate a neurology clinic anywhere in the world,
but the Indian neurologist will also see many other
j , diseases regarded as exotic in the UK and as common-
place in India. The first generation of immigrants to the
% UK from the Indian sub-continent, and to a lesser extent
later generations, continue to manifest some of these
conditions and, in urban areas of the UK with a high
? immigrant population, the clinician must therefore con-
sider these unusual diagnoses. These points are illustrated
by a recent study from Leicester[l] in which it was noted
that 15 of 17 cases of tuberculous meningitis (TBM) were
in Asian patients and that late diagnosis was sometimes a
problem. This article highlights some of the neurological
diseases which lie outside the routine experience of the
English trained doctor, but are familiar to his Indian
colleague.
Tuberculosis of the Nervous System
Tuberculous Meningitis (TBM)
The incidence of TBM in the UK is of the order 1.5-2.0
I v cases per million per year[2,3]. Comparable figures for
India are not available but a busy neurology unit will see
well over 100 cases each year and many more patients will
be treated by general physicians and paediatricians.
There is no doubt that TBM is over-diagnosed in India;
this is inevitable where isolation rates are low[4] and
when treatment is urgent. However, late diagnosis can be
a problem in the UK, where clinicians may not think of
TBM, particularly when the presentation is atypical. The
overall clinical picture, laboratory findings and prognosis
are similar in India and the UK, but some differences are
seen. The Indian patients are more likely to be children,
more likely to have miliary or pulmonary disease, and a
history of direct tuberculosis exposure is frequently ob-
tained. The less usual presentations of TBM are seen in
abundance in India, for instance subacute blindness due
to chiasmatic and optic nerve arachnoiditis, and acute
hemiplegia in which meningeal disease may have oc-
eluded major cerebral vessels. The treatment protocols in
India have concentrated on the less expensive antibiotics,
often without rifampicin, and it is therefore interesting
that morbidity and mortality statistics do not differ
significantly between the UK and India[3,5,6] and are
very similar to those obtained in the early days of anti-
tuberculous chemotherapy[7], It is surprising that we are
still unclear about the indications for steroid treatment
and intrathecal therapy, but prompt initiation of standard
anti-tuberculous treatment as soon as the diagnosis is
suspected is the main guarantee of a successful outcome.
Intracranial Tuberculoma
In the UK, intracranial tuberculoma is usually seen in
recent immigrants, although rare cases appear in the
indigenous population[8]. In India, this condition is
common and studies of incidence in neurosurgical units
gives a range of 4.1-30.5 per cent of all intracranial
tumours[9,10]. Now that CAT scanning facilities are
becoming widespread in India, more cases are identified
at an early stage, multiple lesions are frequently found
and the response to a combined medical and surgical
approach, or to medical treatment alone, can be moni-
tored precisely[l 1]. The clinical features of intracranial
tuberculoma are similar in both countries, lesions may be
found in the background of a known tuberculous infection
or the presentation may be that of any cerebral space
occupying lesion, with a progressive neurological deficit
in the presence or absence of symptoms of raised intra-
cranial pressure.
Adhesive Spinal Arachnoiditis
Adhesive spinal arachnoiditis of presumed tuberculous
origin accounted for nearly 10 per cent_of paraplegia in a
large representative Indian study[12]; a British neurol-
ogist will occasionally see this entity. The patient will
characteristically be Indian, but of the three cases seen in
the UK by one of the present authors, two have been
young English males. The condition may arise by spread
from a tuberculous basal meningitis or less commonly
from spinal tuberculous caries. A subacute progressive
myeloradiculopathy, the primary spinal type, is also seen
and here a wide differential diagnosis must be exer-
cised[13]. Myelography by lumbar or cisternal route and
spinal fluid analysis are mandatory, and while treatment
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
13
of the likely underlying active tuberculosis is important,
medical and surgical attempts to reduce the deficit due to
the arachnoiditis have not met with great success. Recent
work with hyaluronidase has suggested a further treat-
ment option in both spinal[14] and cranial[15] arachnoi-
ditis, although further studies are necessary to evaluate
the therapy.
Neurological Complications of Leprosy
Mycobacterium leprae has a peculiar predilection for the
peripheral nervous system, but in India as elsewhere
these problems are usually dealt with by the leprologist
rather than the neurologist. Nevertheless, a case can be
made for the more active involvement of neurologists in
the study and treatment of this disease. The Ridley-
Jopling classification 16] subdivides leprosy into the polar
types of tuberculoid (high resistance) and lepromatous
(low resistance), their borderline variants and the inter-
mediate forms. The peripheral nervous system is involved
in all types of the disease and there is also a controversial
pure neuritic variant, in which careful enquiry and
examination fail to provide evidence of cutaneous lesions.
The facial, ulnar, median, radial and common peroneal
nerves are frequently affected in leprosy and the Indian
patient with a Bell's palsy or ulnar neuropathy must be
meticulously examined for the presence of cutaneous
lesions or nerve thickening. Conversely, in Indian prac-
tice, the temptation to diagnose leprosy without adequate
clinical grounds or biopsy must be resisted, as cases of
amyloidosis, porphyria, congenital insensitivity to pain
and especially hereditary sensorimotor neuropathy may
all appear neurologically similar to leprosy. The tragedy
is that such patients may be sent to a leprosy establish-
ment and thereby become exposed to the disease. The
treatment of leprosy with dapsone and the newer anti-
leprotics will arrest the infection, but regrettably continu-
ing fibrosis within the nerve may increase the deficit
despite otherwise successful treatment, and repeated trau-
ma to anaesthetised extremities may result in dreadful
deformity.
Cysticercosis
Cerebral cysticercosis is endemic in the non-Muslim
populations of the developing countries and India is no
exception[17]. The presence of the cysts of Taenia solium
in the brain usually results in one of three symptom
groups. The patient may exhibit features of raised intra-
cranial pressure, a mental disturbance or convulsions, or
a combination of these. Occasionally the disease is identi-
fied on radiological examination for other complaints,
and rarely cysts may be found in the brain of autopsied
patients who have died from other conditions and shown
no indication of cysticercosis in life. If cysts are present in
the muscle of human hosts a striking muscular hyper-
trophy may be seen, and the calcified lesions are readily
observed radiologically. The treatment of cysticercosis
with drugs or surgery is often unsatisfactory and control
of this disease will only be possible through effective
public health education.
Virus Infections of the Central Nervous System
Poliomyelitis remains a relatively common disease in
India. Vaccination programmes are widespread, but in
this population more booster doses of vaccine than those
given in the West appear to be necessary to achieve
adequate immunity[18], Cases occur sporadically in the
UK but, with the present general trends against vaccina-
tion and towards more widespread foreign travel, it seems
possible that poliomyelitis may re-emerge and it is wise to
consider this infection in the differential diagnosis of cases
of post-infective polyneuropathy.
Acute haemorrhagic conjunctivitis due to infection with
enterovirus 70 has associated neurological features that
are in many ways similar to those of poliomyelitis.
Widespread epidemics were seen in India in 1971 and
1981, male adults were predominantly affected, and the
clinical features were a rapid paralysis of the limbs and
the cranial nerve innervated musculature. A detailed
study[19] has suggested that the major neurological lesion
is at the level of the anterior horn cell, and a permanent
poliomyelitis-like disability may follow the acute illness.
Japanese encephalitis caused by a Group B arbovirus
occurs in epidemics but is also endemic in parts of India,
particularly the south. This mosquito-borne infection
finds a reservoir in pigs, cattle and some species of bird. A
prodromal phase is followed by an acute encephalitis from
which only one-third of affected individuals recover, a
further third remain neurologically damaged and one-
third die[20]. A vaccine is available and, as with acute
haemorrhagic conjunctivitis, control of these devastating
conditions is theoretically possible. Recently, a tick-borne
epidemic encephalitis occurring in the forests of the State of
Karnataka has attracted attention. Having bitten infected
monkeys, the ticks fall to the forest floor to await the next
meal from an unsuspecting human host, in whom haem-
orrhagic complications often prove fatal.
Other Neurological Infections
In a single year there were 227 cases of tetanus seen at the
J. J. Group of Hospitals, Bombay[21] and 70 of these
patients died of the disease. Improved supportive care
may now be reducing the mortality but tetanus remains
an important but preventable neurological infection.
The scourge of rabies continues in India; few have
access to diploid cell anti-rabies vaccine. Imported cases
may not become unwell until after entry to the UK[22].
Neurosyphilis, while declining in incidence, may still be
seen, especially in the acute or subacute meningovascular
forms, but many Indian neurological departments may
not have one case in a year. There is an impression that
subacute sclerosing panencephalitis is more common in India
than in the UK, and it is possible that a widespread
measles vaccination programme may reduce the preva-
lence of this 'slow virus' disorder.
Non-infective Spinal Cord Disorders
In South India the most common form of myelopathy is a
subacute spastic paraplegia with peripheral sensory
14 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
symptoms, dorsal column involvement and, frequently,
bladder disturbance[23]. Identification of known causes
of paraplegia will allow categorisation of a few cases, but a
large enigmatic group of patients remain. There are
similarities to the tropical paraplegia seen elsewhere,
notably in Jamaica and Africa, but in all cases intensive
study has failed to reveal a nutritional, toxic or infective
cause for this entity.
Lathyrism
Lathyrism, an acute or subacute corticospinal tract de-
generation, is common in Central India, and may be
found in 4-6 per cent of landless labourers in endemic
areas. This disease follows the consumption of the seeds of
Lathyrus sativus, and was recognised by the ancients, as
illustrated by the 'immortal verse' of lathyrism, thus 'the
black pea with its yellow flower, from eating it, comes
trouble in the legs, flopping top knot and swaying hips:
behold the ill effects of eating matra'[24]. This easily
grown crop is used when there is a shortage of conven-
tional food but detoxification of the pulse is possible and
health education could banish this disorder to the realms
of medical history.
Endemic Fluorosis
The high concentration of fluoride in the drinking water
of many parts of India may result in endemic fluorosis,
which is particularly likely to occur when the water source
is further concentrated by evaporation. Mottling of the
teeth is an early sign, but a generalised osteosclerosis may
become neurologically manifest when the spinal cord and
spinal roots are compressed by vertebral disease[25].
Once again, the major prospect for prevention of this
condition lies in appropriate public health activity, in this
case the provision of unaffected water supplies, which
poses insurmountable engineering and financial difficul-
ties in a country as vast and populous as India.
Atlanto-axial Dislocation
In Western practice, disease of the atlanto-axial joint is
likely to be associated with rheumatoid arthritis, but in an
Indian population a congenital form of atlanto-axial
dislocation is relatively common. This entity may present
with cervical pain and stiffness, transient attacks of
neurological disturbance or a progressive spinal cord
syndrome. Clinical suspicion can usually be confirmed by
plain radiology of the cervical spine with attention to the
distance between the odontoid and the anterior arch of
the atlas, and to the dimensions of the cervical canal, but
myelography may sometimes be necessary when the
diagnosis is not clear. Surgical reduction of the disloca-
tion and lateral fusion are successful, especially in early
cases[26].
Other Neurological Diseases common in India
Painful ophthalmoplegia, also referred to as the superior
orbital fissure syndrome or the Tolosa-Hunt syndrome, is
disproportionately common in India and a para-infective
aetiology has been postulated where an association with
past tuberculous or filarial infection has been found [27],
This may be fortuitous and, as in the much rarer UK
cases, a dramatic response of the facial pain, ophthalmo-
paresis and raised erythrocyte sedimentation rate is seen
following corticosteroid treatment.
Classical motor neurone disease occurs in India with a
frequency similar to that in the UK, but an unusual
juvenile variant, with onset before the end of the third
decade, is seen in India, particularly the south[28].
Bulbar and asymmetrical limb involvement is characteris-
tic and a more benign prognosis can be anticipated. The
involvement of the pyramidal tracts and the absence of a
family history differentiate this group from cases of spinal
muscular atrophy and no association with the polio virus
has been found. A further unusual form of motor neurone
disease, a monomelic variant, has also been observed,
and a number of Indian cases have recently been studied
in detail[29].
Cerebrovascular disease afflicts the Indian to the same
degree as the Westerner, but there is an impression that
strokes in younger patients may be more prevalent in
India. An obliterative aortic arch syndrome appears to be
quite common and it is possible that a greater proportion
of strokes are due to an underlying arteritis, rather than
to the familiar embolisation from large vessel arterioscler-
osis[30]. Conversely, it was thought that intracranial
aneurysm was less common in India than elsewhere, but
this observation most likely reflects only the difficulty in
collecting statistical data in India. Large scale epidemi-
ological studies are under way, both in cerebrovascular
disease and in wider aspects of neurology, and the results
will be of great interest.
A fascinating form of reflex epilepsy has been described
in which partial or generalised seizures are induced by
bathing with hot water. In a large series of patients with
epilepsy[31], 108 (9 per cent) were found to have hot water
epilepsy in which attacks were precipitated by pouring
mugfuls of hot water on to the head and body, a popular
method of bathing in India. This remarkably high fre-
quency contrasts with the very rare Western case reports
of hot water immersion epilepsy[32]. Treatment may
simply be to use tepid water for bathing, although
anticonvulsants have been used in some cases.
A mention should be made of the high incidence of
some of the genetically-mediated neurological disorders
in India. Spino-cerebellar degenerations are prevalent in
some areas, and mental handicap, caused by obstetric and
genetic factors, is a major health problem. Wilson's disease
shows remarkable clustering. The personal series of one
neurologist in India, collected largely from the local
population, stands at 52 cases[33]. It is possible that in
rural areas consanguinity is an important factor in the
determination of these conditions.
Conclusion
Neurological disease varies enormously worldwide and
this brief review has detailed some of the conditions which
are commonly seen in India and the Indian, but rarely
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
15
appear in a British consulting room or ward. The reasons
for the high incidence of infective and nutritional disease
in India are obvious, but there is no known reason for the
superior orbital fissure syndrome or hot water epilepsy
being so common in the practice of an Indian neurologist
and so rare in the UK. The study of comparative
neurology affords fascinating glimpses into the aetiology
of these conditions, and the neurologist in training as well
as the established clinician should take every opportunity
of examining his subject in another environment.
Acknowledgements
The authors recently re-visited India with the financial
assistance of a Medicine-Gilliland Travelling Fellowship.
We wish to thank our many colleagues in India who
showed us their departments, patients and kindness, and
in particular Professor K. Srinivas, Madras; Professor J.
Abraham and Dr S. Prabhakar, Vellore; Professor M.
Gourie-Devi and Dr H. Swamy, Bangalore; Dr K. Bose,
Rourkela, and Dr V. Saxena, Calcutta.
References
1. Swart, S., Briggs, R. S. and Millac, P. .(1981) Lancet, 2, 15.
2. Medical Research Council Tuberculosis and Chest Disease Unit
(1980) British Medical Journal, 281, 895.
3. Bateman, D. E., Newman, P. K. and Foster, J. B. (1983) Journal of
the Royal College of Physicians, 17, 106.
4. Sinclair, S., Prabhamani, V. S., Shrinivas and Ghai, O. P. (1977)
Indian Paediatrics, 14, 967.
5. Kennedy, D. H. and Fallon, R. J. (1979) Journal of the American
Medical Association, 241, 264.
6. Tandon, P. N. and Pathak, S. N. (1973) in Tropical Neurology, pp.
37-51. (ed J. D. Spillane.) Oxford University Press.
7. Smith, H. V., Vollum, R. L., Taylor, L. M. and Taylor, K. B.
(1956) Tubercle, 37, 301.
8. Thrush, D. C. and Barwick, D. D. (1974) Journal of Neurology,
Neurosurgery and Psychiatry, 37, 566.
9. Tandon, P. N., Banerji, A. K., Das, B. S. and Dar, J. (1970)
Bulletin of the All India Institute of Medical Sciences, 4, 119.
10. Dastur, H. M. and Desai, A. D. (1965) Brain, 88, 375.
11. Bhargava, S. and Tandon, P. N. (1980) British Journal of Radiology,
53, 935.
12. Mani, K. S. (1973) in Tropical Neurology, p. 81. (edj. D. Spillane.)
Oxford University Press.
13. Wadia, N. H. and Dastur, D. K. (1969) Journal of the Neurological
Sciences, 8, 239.
14. Gourie-Devi, M., Padmini, R. and Satish, P. (1980) Indian Journal
of Medical Research, 71, 581.
15. Gourie-Devi, M. and Satish, P. (1980) Acta Neurologica Scandinavica,
62, 368.
16. Ridley, D. S. and Jopling, W. H. (1966) International Journal of
Leprosy, 34, 255.
17. Srinivas, H. V., Rao, T. V. and Deshpande, D. H. (1980) Clinical
Neurology and Neurosurgery, 82, 187.
18. John, J. (1976) British Medical Journal, 1, 812.
19. Wadia, N. H., Wadia, P. N., Katrak, S. M. and Misra, V. P.
(1983) Journal of Neurology, Neurosurgery and Psychiatry, 46, 599.
20. Gourie-Devi, M. and Deshpande, D. H. (1982) in Paediatric
Problems, pp. 340-356. (ed L. S. Prasad and L. L. Kulczycki.) New
Delhi: S. Chand.
21. Wadia, N. H. (1973) in Tropical Neurology, p. 27. (ed J. D.
Spillane.) Oxford University Press.
22. Cohen, S. L., Gardner, S., Lanyi, C. et al. (1976) British Medical
Journal, 1, 1041.
23. Mani, K. S., Mani, A.J. and Montgomery, R. D. (1969) Journal of
the Neurological Sciences, 9, 179.
24. Srinivas, K., Shivan, U., Saravanan, P. K., Ramachandran, J.
and Rajasekharan, E. A. (1983) Proceedings of the Neurological Society
of India, p. 153.
25. Singh, A. and Jolly, S. S..(1961) Quarterly Journal of Medicine, 30,
357.
26. Wadia, N. H. (1967) Brain, 90, 449.
27. Mathew, N. T. and Chandy, J. (1970) Journal of the Neurological
Sciences, 11, 243.
28. Sundaram, E. M., Jagannathan, K. and Ramamurthi, B. (1970)
Neurology (India), 8, Suppl. 1, 104.
29. Gourie-Devi, M., Suresh, T. G. and Shankar, S. K. (1984) Archives
of Neurology, 41, 388.
30. Abraham, J. (1973) in Tropical Neurology, pp. 86-91. (ed J. D.
Spillane.) Oxford University Press.
31. Mani, K. S., Mani, A.J. and Ramesh, C. K. (1974) Transactions of
the American Neurological Association, 99, 224.
32. Szymonowicz, W. and Meloff, K. L. (1978) Canadian Journal of
Neurological Sciences, 5, 247.
33. Swamy, H. S. (1984) Personal communication.
|
PMC005xxxxxx/PMC5370991.txt | Audit Reviewed: Medical Audit in North
America
W. VAN'T HOFF, MB, FRCP
Consultant Physician, North Staffordshire Hospital Centre, Stoke-on-Trent
This review is based on a recent visit to North America
during the tenure of a Medicine-Gilliland Travelling
Fellowship. I visited a number of hospitals in Ontario,
Canada, and in Boston, Massachusetts, which enabled
me to study different approaches to medical audit in
various centres.
Medical audit is now an accepted part of American
hospital life; all the hospitals I visited had active pro-
grammes. In the USA the Joint Commission on Accredit-
ation of Hospitals, which is a Federal institution, visits all
hospitals every three years. It demands a rigorous quality
assurance by the hospital, and also more specifically by
the various medical services. In Canada a similar organi-
sation exists, the Canadian Council on Hospital Accredit-
ation, which visits hospitals regularly in order to accredit
them. Although this is not compulsory, failure to obtain
accreditation would result in losing the licence to train
junior medical staff (their residents and interns). Most
hospitals therefore desire accreditation. As in the USA, a
hospital is visited every three years if the report is
satisfactory. If the required standards are not met then
advice is given and the hospital will be re-surveyed in two
years or sometimes after only one year. One of the
requirements is that there be a 'process of analysis and
evaluation of the performance and outcome of the pro-
fessional clinical work of a unit, department or service'.
In this particular context the concern is the quality of
patient care and, as in the UK, there has been a search for
terms other than medical audit. Those suggested are
clinical appraisal, clinical assessment, clinical audit and
clinical review.
Responsibility for seeing that medical audit takes place
had been given to an Audit Committee in all the hospitals
I visited. In Ontario the Audit Committee is answerable
to the Medical Advisory Committee (MAC) which is the
executive committee consisting of the executive and
medical directors of the hospital, the chiefs of the various
medical departments and some other members. The
MAC is usually appointed by the Board of Directors of
the hospital and is therefore not exactly equivalent to its
namesake in the UK. In the USA the Audit Committee is
answerable to the Executive or Medical Executive Com-
mittee, which is roughly equivalent to the MAC in
Canada.
The chairman of the Audit Committee is appointed
rather than selected, and is usually a motivated and
medically qualified member of the hospital staff. The
Committee is composed of representatives from the main
medical departments, but there is considerable variation,
and in some hospitals specialties such as psychiatry are
not included. The medical records staff is always repre-
sented, there is an administrator or member of the
executive staff, and the nursing staff is usually represent-
ed, although not in all hospitals.
Most Audit Committees meet monthly but the manner
of their work and their effectiveness is very variable.
Although responsible for seeing that medical audit is
practised, the Audit Committee does not usually do all
the work itself. Most hospitals have a Tissue Committee
which reviews surgical histopathology and, in some cases,
all surgical deaths.
The main divisions of medicine, surgery, radiology and
other specialties are usually responsible for carrying out
medical audit within their specialty, and their results or
conclusions are reported to the main Committee. The
most common pattern is for each department to organise
one project a year, which can be a retrospective or a
prospective survey. If a department is devoid of ideas a
project can be suggested, and in most hospitals Audit
Committees welcome suggestions from different sources.
The kinds of topic studied can be very variable. A simple
one would be length of stay of patients with a particular
condition, or the complication rate of a medical or
surgical condition, or the effectiveness of communication
with patients' own doctors. In some hospitals all deaths
are studied, in others various forms of selection are made.
In Ontario, in order to help doctors and hospitals, the
Ontario Hospital Association and the Ontario Medical
Association have jointly prepared a handbook called
'Patient Care Appraisal'. Quite apart from the legal
requirements and those of the Canadian Council on
Hospital Accreditation, the handbook states that partici-
pation in a patient care appraisal programme is 'the
ethical responsibility of a self-governing profession. This
requires that all physicians be involved in some review
process and that this be used as a method for patient care
improvement'. A further reason given is that it demon-
strates accountability to the public. Patient care appraisal
benefits the medical staff by providing feedback on
performance or patterns of practice which can encourage
a critical attitude to clinical work by identifying topics for
inclusion in continuing education programmes, or areas
in need of clinical research, and providing useful motiva-
tion for physicians to keep up-to-date. The handbook
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 53
gives suggestions and provides help in setting up projects.
One useful guide is the definition of useful criteria in a
review study and seven steps are listed.
1. Choose a topic.
2. Set objectives.
3. Establish the criteria.
4. Retrieve the data.
5. Collate and present the results of the study.
6. Analyse by peer review and make up a report.
7. Take action and follow it up.
In the USA medical audit is organised on similar lines.
Hospitals are currently required to carry out at least four
audits or quality review studies annually. The Pro-
fessional Standards Review Organisation (PSRO), which
is mandated by the Federal government, decides on two
studies which all hospitals in a particular area are then
required to do, and each hospital then decides on two
further studies which they choose themselves. Most active
hospitals carry out considerably more than the required
four, and, as in Canada, most medical divisions or
departments also have their own projects.
In most hospitals the medical records department plays
a considerable role in the organisation and performance
of medical audit. The calibre of the staff in medical
records departments is considerably higher than is usual
in the UK. The Director of Medical Records is normally
a graduate, one has a BA in Medical Records and also an
MA in Education. In one hospital there were three
further graduates, and most records personnel had also
taken a two year course in Health Records Adminis-
tration. The usual practice is that records of all patients
discharged from hospital are coded. Most departments,
however, do considerably more than this. One looks
through samples of notes such as 25 records of patients
admitted as emergencies. Another department looks ev-
ery month at 10 records from one service, usually in
rotation, critically examining the standard of notes, pro-
cedures carried out, length of stay and how long after
discharge the summary was sent. This particular job is
undertaken by a research medical records librarian. In
another hospital every set of notes is studied in detail. In
surgical cases this includes checking whether a patient
received a transfusion, whether there were any results of a
wound swab and, if positive, whether the clinical notes
commented on the presence of wound infection. This
process can take from 10 minutes to three hours. Records
that are considered unsatisfactory are returned to the
clinician, and they are not filed until complete.
In some hospitals there is a Medical Records Commit-
tee which includes medical members, and it decides on
the format of notes and standards expected in the depart-
ment. The better staffed records departments play an
active and major role in both retrospective and prospec-
tive surveys conducted by many clinical departments.
Results of surveys are reported to the Audit Committee
and the chief of the relevant department is informed if any
action is required. Where necessary a follow-up survey is
done.
In Ontario, as in some other provinces, hospitals
subscribe to a Hospital Medical Records Institute
(HMRI) which receives copies of all in-patient summar-
ies. The Institute has medical and lay members and
provides a service for hospitals in analysing and dissemi-
nating information and statistics. The HMRI has a
Medical Audit Advisory Committee which has developed
a number of 'Care Appraisal Programs'. These have
covered a variety of fields and include the management of
overdoses; the diagnosis, management and outcome of
acute cerebrovascular disease; the indications for and
complications of transurethral prostatectomy; the accura-
cy of diagnosis and outcome of myocardial infarction; and
the indication, accuracy of diagnosis and outcome of
surgical procedures such as appendicectomy, cholecystec-
tomy and Caesarian section. These programmes have
been researched and prepared and are available for use by
hospitals in the province. It is a voluntary scheme and
some hospitals prefer to organise their own projects, but
the programmes have been designed to help hospitals
with limited resources that might have difficulty in setting
up projects of their own. The HMRI is able to analyse the
programmes it has suggested and return the results to the
individual hospital. The HMRI does not establish stan-
dards of practice but selects criteria and provides facilities
for analysing the results. Individual hospitals are not
identified although they themselves are able to make
comparisons, and it is up to the hospital to take any action
that may be required.
The College of Physicians and Surgeons of Ontario is
responsible for issuing the licence to practise medicine in
the province, and it therefore in part fulfils the role of the
General Medical Council in the UK. The Council of the
College has recently accepted in principle the establish-
ment of a 'Peer Assessment Program'. This consists of the
assessment of work done outside hospital, in the offices
(consulting rooms) of general practitioners and of a
number of specialists in, for example, paediatrics, inter-
nal medicine, obstetrics and gynaecology, and general
surgery. Assessors are chosen by a committee of the
Council and consist of a general practitioner and a
specialist. Work assessed has been that of physicians and
surgeons who had agreed to take part in the programme.
The assessment is made by examining a representative
number of case records such as those of the last 30
patients seen. On the whole, both assessors and those
assessed considered that records were a reasonable reflec-
tion of the care provided. There are five possible categor-
ies of finding:
A. Satisfactory in all respects.
B. Satisfactory with minor suggestions.
C. Records deficient but care satisfactory.
D. Records of such deficiency that care could not be
assessed.
E. Inadequate care with or without adequate records.
Over the last three years 81.3 per cent of those assessed
were considered to be providing satisfactory care and to
have adequate records. There was concern about records
in 8.7 per cent (Category C).
When the practice is considered to be in Categories D
or E, copies of the assessment report are sent to the
physician concerned who is then invited to an interview
with the Peer Assessment Committee; 10 per cent of
doctors assessed were invited for interview in the last
54 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
three years; 13.3 per cent of general practitioners assessed
were interviewed for this reason as opposed to 2.3 per
cent of specialists. Age played an important role in the
assessment of general practitioners; 47.6 per cent of those
over 70 years were interviewed compared to 11.5 per cent
under 70 years, and only 5.7 per cent of those under 40
years were interviewed.
Two other significant observations were made. The
proportion of female doctors in Categories D and E was
4.0 per cent compared to 14.4 per cent males, and only
2.8 per cent of practitioners who had a Certificate of the
College of Family Physicians of Canada were interviewed
compared to 16.2 per cent of non-certificants.
The majority of those interviewed had corrected the
deficiencies when next assessed and in only a small
number of cases was there serious concern resulting in
reference to the Executive Committee of the College.
Medical audit, clinical review, or patient care appraisal
is welcomed with more enthusiasm by some doctors than
others but it is now generally accepted to be an integral
part of hospital life in North America. Nor are doctors the
only group to look critically at the service they provide.
All hospital departments, including those of adminis-
tration and building, are accountable and subject to
review. In some hospitals the nursing staff have also
initiated projects to evaluate procedures and look at the
quality of care they provide.
Overall I was much impressed by the way medical
audit is organised and carried out and I think in the UK
we might well benefit from a much wider acceptance of
clinical review, medical audit?call it what you will?
responsibility, accountability and constructive self-criti-
cism.
Acknowledgements
This work was carried out during the tenure of a MEDI-
CINE-Gilliland Travelling Fellowship, administered by
the Royal College of Physicians of London and funded by
the Medical Education Trust, a charitable trust founded
by The MEDICINE Group, the publishers of MEDI-
CINE International.
I am very grateful to the large number of people who
willingly gave up much of their valuable time in order to
discuss medical audit with me.
|
PMC005xxxxxx/PMC5370992.txt | The Role of the Pharmacist in the
Anticoagulant Clinic
M. PEGG, BPharm, Staff Pharmacist
J. BOURNE, MSc, BPharm, Staff Pharmacist
A. D. MACKAX MD, MRCP(UK), Senior Medical Registrar, Department of Respiratory
Medicine, City General Hospital, Stoke-on-Trent
W. A. LAWTON, BA, Statistician, Computer Centre, North Staffs Royal Infirmary
R. B. GOLE, MD, FRCP, Consultant Physician, Department of Respiratory Medicine,
City General Hospital, Stoke-on-Trent
Approximately 50,000 patients in Britain receive oral
, anticoagulant treatment every day and over two million
tests of anticoagulant control are performed in a yearfl,
2]. Close supervision of the patients is necessary because
dose requirements are variable and there is an ever-
present risk of drug interactions and even major bleed-
Jng[3].
Good anticoagulant control is also influenced by diet,
intercurrent illness and poor compliance, and recent
reviews suggest that in the UK the standard of control is
often inadequate [4-6]. One factor which may lead to
inconsistent management is the delegation of responsi-
bility to junior doctors who do not stay long enough in
each training post to learn the patients' idiosyncrasies[4,
51"
With the dual objectives of obtaining a consistent
standard of anticoagulation control and of bringing the
pharmacist more directly into the arena of patient care,
an anticoagulant clinic managed jointly by pharmacists
and physicians was started in the North Staffordshire
Hospital Centre in September 1979. This article describes
the management and organisation of such a clinic (the
'combined clinic') and retrospectively compares the re-
sults achieved with those obtained by other physicians
who retained the supervision of anticoagulant therapy
entirely in the hands of medical staff (the 'standard
> clinics').
Methods
The combined clinic supervises the patients of four
consultant physicians and is held twice weekly to run
concurrently with the medical clinic of a consultant
physician (R.B.C.). The pharmacist has access to the
patient's medical file in which anticoagulant control is
recorded on a special chart. He counsels the patient,
adjusts dosage as necessary, decides when the patient
should next attend and dispenses a supply of tablets. To
ensure a consistent standard of practice, guidelines (see
Appendix) were prepared for the management of the
anticoagulant clinic by pharmacists, based on those used
in the Division of Clinical Pharmacy at the University of
California, San Francisco (Dr Steven Kayser, personal
communication). The pharmacist's decisions are checked
and initialled by a doctor at the medical clinic to whom
patients may be referred if problems arise. Medical
review is otherwise limited to one consultation at three
months in the case of patients receiving a short course of
anticoagulant therapy, or twice yearly consultations for
those on long-term treatment.
The standard clinics are managed as an integral part of
the normal medical out-patient clinics. The patients'
anticoagulant control is supervised either by the consul-
tant physician or the junior medical staff. The patients
are frequently seen by different doctors at successive
appointments.
The names of 116 unselected patients who had received
anticoagulant therapy during the calendar year 1980 were
taken from the laboratory records. Sixty-two patients had
attended the combined clinic and 54 had been supervised
at standard clinics. The following information was ob-
tained from the patients' medical records: sex, age,
weight, smoking history, alcohol consumption, the indi-
cation for anticoagulant treatment, biochemical indices of
liver and kidney function, dose and duration of heparin
therapy, loading dose of warfarin, length of in-patient
stay after commencement of warfarin, and duration of
anticoagulant therapy. Treatment with drugs known to
interact with warfarin during in-patient and out-patient
management, evidence of bleeding or other unwanted
effects, and factors which might affect control such as
poor compliance and intercurrent illness were also record-
ed.
In this hospital centre warfarin dosage is adjusted by
reference to a prothrombin index (PI) which is the
reciprocal of the British Comparative Ratio (BCR),
expressed as a percentage. The desired therapeutic range
was defined as a PI of between 50-30 per cent (corre-
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
sponding to a BCR of 2-3.3) except for one consultant in
the standard clinic group whose chosen range was 40-20
per cent (corresponding to a BCR of 2.5-5).
Anticoagulant control was assessed by several methods.
1. The average interval between appointments was cal-
culated by dividing the total number of weeks for which a
patient received treatment by the number of his atten-
dances.
2. The number of occasions on which the PI was above
or below the desired therapeutic range (representing
under-anticoagulation and over-anticoagulation respec-
tively) was totalled and expressed as a percentage of the
total number of PI readings for each group.
3. The degree of fluctuation in PI was determined by
averaging the PI changes between one attendance and the
next throughout each patient's course of treatment.
The number of patients experiencing unwanted effects
from anticoagulation was obtained from reports of these
events in the patients' medical records. Unwanted effects
sought included bruising, epistaxis, microscopic haema-
turia, haematemesis, melaena, frank haematuria and
further episodes of thrombosis or embolisation. The
duration of treatment of single episodes of deep vein
thrombosis (DVT) or pulmonary embolism (PE) was
compared by calculating the mean duration of therapy for
these indications in each group. The comparison was
carried out retrospectively, since a prospective study
would have influenced the management of the patients so
as to invalidate the comparison.
Results
The characteristics of the patients attending the two types
of clinic are shown in Table 1. There was no significant
Table 1. Patients studied
Cases
Combined Routine
Clinic Clinics
Male 24 32
Female 38 22
Age in years (mean and range) 57 (25-77) 52 (23-79)
Weight in kg (mean and range) 72 (46-96) 73 (46-101)
Renal Function*
Normal 44 32
Abnormal 10 11
Unknown 8 11
Liver Function**
Normal 43 32
Abnormal 9 14
Unknown 10 8
* Renal function was recorded as abnormal if serum creatinine was
outside the normal range.
** Liver function was recorded as abnormal if two or more liver function
tests (plasma bilirubin, aspartate transaminase, lactate dehydrogenase,
alkaline phosphatase) were outside the normal range.
difference between the groups in age, weight, or renal and
hepatic function. Similarly, Table 2 shows that the two
clinics were comparable with regard to the reasons for
which anticoagulant therapy was given.
Table 2. Indications for warfarin therapy. DVT?deep vein
thrombosis. PE?pulmonary embolism.
Cases
Combined Routine
Indications Clinic Clinics
DVT single 11 13
DVT recurrent 8 6
PE single 25 25
PE recurrent 13 8
Mitral valve disease 3 0
Atrial fibrillation alone 0 1
Heart valve prosthesis 2 1
The average actual duration of anticoagulant treatment
for single episodes of DVT and PE and the intended
duration of treatment as previously declared by the
physicians are shown in Table 3. In all cases the actual
Table 3. Duration (and range) of warfarin therapy. DVT?
deep vein thrombosis. PE?pulmonary embolism.
Weeks of Treatment
Combined Routine
Clinic Clinics
DVT (single) Intended 12 6
Actual 13.6 (8-26) 8.2 (3-16)
PE (single) Intended 12 12
Actual . 14.2 (9-29) 12.4 (4-20)
duration was comparable to the intended duration, but it
is also apparent from this table that the clinicians of the
combined clinic normally maintained anticoagulation for
12 weeks after a single episode of DVT, while those of the
routine clinics did so for only six weeks. Table 4 illustrates
Table 4. Control of anticoagulation. PI?prothrombin index.
Combined Routine
Clinic Clinics
Interval between
appointments (weeks)* 1.82 (0.3-4.0) 1.81 (0.3-13.0)
Percentage of PI
readings above desired range
(under-anticoagulation) 19% 26%
Percentage of PI
readings below desired range
(over-anticoagulation) 11 % 7 %
Difference in PI (%)
between attendances* 9.93 (0-58) 9.88 (0-59)
*Mean and range
our assessment of the management of therapy by the two
types of clinic, both of which achieved a similar average
standard of anticoagulant control among their patients
with a similar range of variation in frequency of attend-
ance and PI fluctuation. The number of patients exper-
iencing unwanted effects during anticoagulation is
40 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
Table 5. Unwanted effects. PE?pulmonary embolism.
Number of Patients
Combined Routine
Effect Clinic Clinics
Bruising 2 0
Epistaxis 1
Microscopic haematuria* 17 10
Frank haematuria 1 0
Haematemesis/melaena 1 ?
Further PE 0 1
No. unwanted effects 40 42
Total 62 54
* Detected by reagent strip urinalysis.
illustrated in Table 5 which indicates no major differences
between the two types of clinic. The most common
unwanted effect was microscopic haematuria detected by
reagent strip urinalysis. One" patient in the combined
clinic group had frank haematuria while the PI was
fv within the therapeutic range, and one patient with
chronic liver disease had melaena while under-anticoagu-
lated (PI 52 per cent), which was subsequently found to
be due to gastritis.
Discussion
Oral anticoagulant therapy is sufficiently hazardous to
warrant special measures to ensure safe and effective
treatment, and continuity of surveillance is an important
factor in avoiding mistakes. Our increasing awareness of
the problems coincided with the pharmacists' aspiration
to become more directly involved in patient care, and the
idea of a joint pharmacist/physician anticoagulant clinic
was conceived to satisfy these views. The concept of
* pharmacist responsibility for dosage adjustment of anti-
coagulants has been tried out in the USA[7-9], and
shared responsibility between a physician and a pharma-
, cist working together has been described both in the
USA[10] and in Britain[ll], but in general such treat-
ment is traditionally managed by doctors. The task of
supervising treatment and making dosage adjustments is
regarded as fairly simple and commonly falls to junior
doctors, who periodically move from one post to the next
in order to satisfy training requirements. We believe that
continuity of care can more easily be maintained by a
pharmacist who is interested in applying his knowledge of
pharmacology to the practical treatment of patients.
?> Before embarking upon so radical a change in estab-
lished practice it was important to ensure that junior
doctors should not lose the opportunity of gaining experi-
ence in monitoring oral anticoagulation; and that the
statutory requirements for the issue of prescribed drugs
by qualified medical practitioners should be met. We
considered that the training needs of junior hospital
doctors were adequately provided for by the experience
they gained in initiating warfarin therapy while the
patient was still in hospital; and the statutory need for the
prescription of warfarin by a doctor would be satisfied by
the shared responsibility of the combined pharmacist/
physician anticoagulant clinic, where there would always
be a medical presence and where all warfarin prescrip-
tions advised by the pharmacist would be checked and
initialled by a doctor.
Once the new system had been put into practice it
became necessary to compare it objectively with the
established practice of medically supervised anticoagulant
therapy running concurrently. The results of this com-
parison between similar groups of patients receiying
warfarin therapy for similar indications show that in both
sorts of clinic there was considerable variation in the
duration of therapy, which was sometimes as much as two
months shorter or three months longer than the intended
duration. The more extreme variations were due to
compliance failure (2 cases), to an alteration in the
diagnosis (2 cases), to persistence of the underlying
condition which had led to thromboembolic disease such
as prolonged immobilisation (2 cases), or to unexplained
decisions on the part of the supervising doctors to prolong
or cut short treatment (5 cases). These variations were
seen equally in the combined and standard clinics, and it
was clear that the duration of anticoagulant treatment for
a single episode of DVT or pulmonary embolism varied
considerably from one physician to the next, lying be-
tween six weeks and six months. In the combined clinic
we now ask clinicians to state the intended duration of
treatment at the outset and the pharmacist draws it to the
clinician's attention if treatment appears to be running on
too long, but the decision to stop treatment rests always
with the clinician and would be taken at a medical follow-
up attendance, depending on the medical assessment of
that patient's need. The routine three-month medical
appointment is intended to prevent inadvertent prolonga-
tion of treatment, but a clinician could always decide
whether it should be cut short or prolonged according to
the clinical situation. The general standard of anticoagu-
lant control and the degree of fluctuation in prothrombin
index were the same in both combined and standard
clinics, and the low incidence of unwanted effects was
common to both groups of patients. It should be borne in
mind that the comparison was made retrospectively, so
that the usual practice of the participating doctors and
pharmacists was not modified by a feeling of being
overlooked.
Our experience in the combined clinic showed that the
pharmacist never had any hesitation in consulting his
medical colleagues, and would do so, on average, once in
25 patient attendances. Since the doctor and the pharma-
cist worked in adjoining rooms access between them was
easy, and if the patient complained of any symptoms
unrelated to the anticoagulant treatment the pharmacist
automatically sought medical advice without further ado.
On the strength of these observations it cannot be said
that the results obtained by the pharmacist and physician
working together were better or worse than the standard
clinics managed by clinicians alone, and no significant
cost benefit is obtained by substituting a pharmacist to do
this work in place of a junior doctor. Critics have argued
that the additional cost of assigning a staff pharmacist for
4 hours per week to this role is not justified in the absence
of objective evidence of an improvement in the service
provided, but this criticism overlooks the subjective bene-
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
41
fits of the combined pharmacist/clinician clinic which we
observed, namely:
1. Dual'participation reduces the risk of mistakes.
2. Medical confidence is increased by a system in which
the supervision is carried out by a pharmacist with
continuing responsibility.
3. The pharmacist's professional role is enhanced.
We believe that these are significant benefits, and
efforts are being made to expand the clinic to cope with
requests for access from other groups of clinicians. The
service is limited at present to those physicians whose
clinics happen to coincide with the pharmacist's availabil-
ity, because the essential principle of this concept is that
the pharmacist who runs the clinic should always have at
hand a clinician who is responsible for the patients' care.
Acknowledgements
We acknowledge with thanks the co-operation of the
physicians who allowed us to study the records of the
patients under their care. We are grateful to Dr John
Mucklow who gave us valuable advice and criticism, and
to Mrs Helen Theobold for her help with the manuscript
and tables. We also acknowledge the help and interest of
Professor Malcolm Rowland, Department of Pharmacy
in the University of Manchester.
References
1. Sharp, A. A. (1982) British Medical Journal, 285, 242.
2. Anon (1983) Drug and Therapeutics Bulletin, 21, 33.
3. Fenech, A., Winter, J. H. and Douglas, A. S. (1979) Drugs, 18,48.
4. Duxbury, B. McD. (1982) British Medical Journal, 284, 702.
5. Mclnnes, G. T. (1981) Lancet, 2, 88.
6. Harries, A. D., Birtwell, A. J. and Jones, D. B. (1981) Lancet, 1,
1320.
7. Reinders, T. P. and Steinke, W. E. (1979) American Journal of
Hospital Pharmacy, 36, 645.
8. Nappi, J. M. (1980) The Wisconsin Pharmacist, 49, 164.
9. Chenella, F. C., Klotz, T. A., Gill, M. A. et al. (1983) American
Journal of Hospital Pharmacy, 40, 1642. ,,
10. Davis, F. B. and Sczupak, C. A. (1979) Postgraduate Medicine, 66,
100.
11. Kemp, C. G. and Carrington, D. W. (1978) Pharmaceutical Journal,
222, 564. ,
APPENDIX: MANAGEMENT OF THE
ANTICOAGULANT CLINIC BY PHARMACISTS
Objectives
The objective for pharmacists who are responsible for
warfarin anticoagulation therapy is to achieve consistent
management and surveillance of therapy in order to
promote maximum effectiveness of the drug and minimal
risk from adverse effects and over-dosage.
Rationale
Close supervision of warfarin therapy is considered neces-
sary for the following reasons:
1. Warfarin exhibits pronounced inter-individual elimi-
nation kinetics. This variation is primarily ascribed to
differences in the amount of free fraction of the drug in
the serum.
2. There are many drugs, both prescription and over-the-
counter preparations, which can produce clinically
important interactions with warfarin.
3. There are many diseases which can alter the pharma-
cological response to warfarin.
4. The major unwanted effect of warfarin ? bleeding ?
is a highly dangerous one.
5. Elderly patients are particularly at risk from problems
associated with warfarin therapy because they com-
monly suffer from more than one disorder and are
receiving several drugs.
Methods
Organisation of the Clinic
(a) On the appointment date the patient will first report to
the Haematology Department for a prothrombin test.
The result of the test will be entered in the patient's copy
of the DHSS Anticoagulant Treatment Booklet by the
haematologist. The patient will then report to the Anti-
coagulant Clinic and the result of the prothrombin test
will be transferred by the pharmacist to the Anticoagulant
Treatment Chart (Fig. 1). The Anticoagulant Treatment
Chart will remain permanently in the patient's notes.
(b) The patient's warfarin dosage will be determined by
the pharmacist and will be entered on the Anticoagulant
Treatment Chart and also in the patient's Treatment
Booklet. The entry in the Treatment Chart will be
regarded as a prescription and a physician's signature will
be obtained before a supply of warfarin is dispensed.
(c) The dispensing of the patient's supply of warfarin will
take place at the clinic. The completed prescription will
be checked by the pharmacist and the Treatment Booklet
will be returned to the patient.
(d) All supplies of containers, labels and warfarin tablets
will be obtained from the central out-patients pharmacy
department by the pharmacist before commencement of
the clinic. These supplies will be returned to the phar-
macy department for safe-keeping at the end of each
clinic.
General Responsibilities
(a) The pharmacist shall assist the physician in the
management of patients on warfarin.
(b) The pharmacist will adjust warfarin dose when indi-
cated, maintain a record of this information, and educate
the patient concerning the use of warfarin.
(c) The aim of anticoagulation therapy with warfarin is to
maintain a prothrombin index (PI) of between 30 and 50
42 Journal of the-Royal College of Physicians of London Vol. 19 No. 1 January 1985
per cent (i.e. a prothrombin time of between approxi-
mately 2 to 3 times the value of the control), unless
otherwise required by the physician in charge of the
patient's care.
(d) Patients whose PI remains stable will be maintained
on the existing dosage of warfarin.
(e) For Pis outside the desired range, the pharmacist will
establish the cause for non-control, decide whether dosage
alteration is necessary and schedule the time for the next
clinic visit. In all cases when any discontinuation of
therapy or the use of vitamin K is indicated the pharma-
cist will consult the physician.
Specific Responsibilities of the Pharmacist
1. Review of the patient's medical records. Each time a
patient is started on warfarin and is to attend the
Anticoagulant Clinic, the medical records will be ob-
tained and reviewed for the following information:
(a) Name, address, sex, date of birth, occupation, unit
number and referring consultant.
(b) Indication for anticoagulation therapy and anticipated
duration of therapy.
(c) Concurrent drugs: prescription and over-the-counter
preparations.
(d) Concurrent diseases and relevant past medical his-
tory.
(e) Social factors that may influence warfarin therapy (i.e.
home medication situation, availability of transportation
to clinic, etc).
(f) Alcohol use.
(g) Name, address and telephone number of patient's
GP.
The above information will be entered on the patient's
Anticoagulant Treatment Chart and amendments made
if necessary at each attendance. Dates of the next appoint-
ment are placed in the Anticoagulant Clinic appointment
book.
2. The Patient-Pharmacist Interview
(a) During the first visit to the Anticoagulant Clinic, the
pharmacist will, if necessary, interview the patient in
order to supplement information gained by review of the
medical records. In addition, the pharmacist will ascer-
tain the patient's level of understanding of disease and
therapy, and assess his ability or willingness to comply
with therapy and clinic visits.
(b) The second part of the interview will consist of the
education of the patient concerning the use of warfarin.
Generally, the information in the DHSS leaflet entitled
'For Patients on Anticoagulant Treatment' will be im-
parted. The pharmacist will ensure that each new patient
has received a copy of the DHSS Anticoagulant Treat-
ment Booklet and leaflet.
(c) Special instructions will be given to competent persons
caring for the patient when the patient is unable to
understand or comply with therapy.
(d) The pharmacist will note at the time of the medical
record review and/or first interview, any potential prob-
lems arising from warfarin therapy. These problems will
be underlined in red on the Anticoagulant Treatment
Chart and will be brought to the attention of the physician
at the Clinic. These problems include:
(i) Inability of the patient to comply with therapy.
(ii) A questionable reason for anticoagulant therapy.
(iii) Significant predisposition to bleeding.
(iv) History of severe, chronic or intermittent alcohol
abuse.
(v) Significant drug-warfarin interaction.
3. Patient Follow-up Clinic Visits
(a) All follow-up visits to the Anticoagulant Clinic as
decided by the pharmacist will be entered in the Anti-
coagulant Clinic appointment book on the Anticoagulant
Treatment Chart and in the patient's DHSS Anticoagu-
lant Treatment Booklet. Follow-up visits to see the physi-
cian will be at the discretion of the physician. The
Anticoagulant Treatment Chart will be kept in the
patient's medical records until the next appointment.
(b) Each time a patient is seen in the clinic he is
questioned about the following:
(i) The current dose of warfarin.
(ii) Symptoms of exacerbation of disease.
(iii) Suspected side effects of therapy or any bleeding
episodes.
(iv) Development of any other problems.
ANTICOAGULANT TREATMENT CHART
CONSULTANT
NAME
ADDRESS
OCCUPATION
INDICATION FOR
ANTICOAGULANT THERAPY
ANTICIPATED DURATION OF Rx
CONCURRENT DRUGS (Rx AND OTC)
CONCURRENT DISEASES
SMOKING HABITS
FAMILY DOCTOR
ADDRESS
SOCIAL FACTORS
TEL.
INTERVIEW CHECKLIST
APPOINTMENTS
DATE OF TEST: 7PROTHROMBIN DAILY WARFARIN
NEXT APPOINTMENT INDEX DOSAGE (MGI
COMMENTS
Fig. 1. Anticoagulation treatment chart.
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 43
(v) Addition or cessation of any concurrent medica-
tion (this may be recorded in the 'comments'
section of the Anticoagulation Treatment Chart).
(c) If there has been a significant increase or decrease of
the prothrombin time to a value considered out of control,
the following questions are asked of the patient in order to
determine the cause of^the prothrombin time change:
(i) Has the patient started or stopped taking any
other medication, including proprietary drugs?
(ii) Has there been a change in the patient's alcohol
consumption?
(iii) Have any other illnesses developed such as infec-
tion, acute hepatitis, diarrhoea, CCF, etc?
(iv) Is the patient taking the warfarin correctly, i.e.
correct dose, omission or addition of doses?
(v) Has the patient developed fever?
(vi) Has the patient altered his diet significantly?
(d) Based on what has been determined to be the cause of
the prothrombin time change, the pharmacist, if neces-
sary in consultation with the physician, will decide on
further warfarin therapy. The pharmacist will convey this
information to the patient.
(e) In the event of the patient being admitted to hospital,
the pharmacist will make at least one check on the
patient's anticoagulation therapy. A brief summary of the
admission will be indicated in the Anticoagulant Treat-
ment Chart.
(f) Discharge from the Anticoagulant Clinic will occur
after adequate duration of therapy, or where the risks of
therapy are considered greater than the benefits, or at the
request of the patient, on the decision of the physician.
Acknowledgement
This appendix is adapted from a document produced by
Dr Steven Kayser, Associate Clinical Professor in the
Division of Clinical Pharmacy at the University of Cali- ?
fornia, San Francisco.
|
PMC005xxxxxx/PMC5370993.txt | A Patient of Sir Thomas Browne's
G. C. R. MORRIS, dm, mrcp
Lately Senior Lecturer in Applied Physiology, Institute of Basic Medical Sciences, London
Among three dozen patients mentioned in Sir Thomas
Browne's letters of 1670-82 to his son Dr Edward Browne
in Londonfl], only a few are described in enough detail to
give a clear clinical picture, notably those who were
referred for consultation on urinary or venereal condi-
tions with 'cosen Hobbes', the anatomist Thomas Hobbs
(1648-98), surgeon for the stone at St Bartholomew's
Hospital from 1680 (two years before Edward Browne
became physician there)[2,3]. One more clinical descrip-
tion by Sir Thomas Browne, with the advantage of a
parallel account of the same patient by his apothecary,
can now be added to those few, from Chancery deposi-
tions at the Public Record Office[4]. The background is
complicated, but not without its own interest.
The patient was Richard Berney (1621?-1680) of
Reedham, Norfolk, second son of Sir Richard (d. 1668),
first baronet (1620), whose eldest son Thomas (d. 1693)
inherited little but the title. Sir Richard's will[5] was one
cause of the trouble that led to the Chancery actions.
Extending earlier dispositions, it left Park Hall, Reed-
ham, and the rest of his real estate to descend in tail male
through his second son Richard (the patient) and Rich-
ard's only son, also Richard (1650-95), who became the
plaintiff. Apart from annuities to the eldest son Thomas
and his children, with legacies for the children at 21, Sir
Richard's large personal estate was to be divided equally
between his second son Richard and Richard's son, who
were the executors. The grandson was a minor when Sir
Richard died, and did not join in proving the will until
26th June 1671. His father, Browne's patient, was in sole
control from January 1669: his handling of the inheri-
tance was another cause of the trouble.
According to the plaintiff, young Richard Berney[6],
grandson of the first baronet, in actions brought within
weeks of his father's death on 26th January 1680, his
father had allowed him only ?300 a year, which fell far
short of his requirements. He was therefore compelled to
borrow. Unable to give any other security than his
expectations, he was forced to accept increasingly onerous
terms for the loans. By February 1677, when he borrowed
?400 from Robert Foster, he had to promise to repay
?1,000 on his father's death. In September of the follow-
ing year ?500 from Dr James Fairclough[7] was to cost
?2,000 on the death of his father?when he would also
have to pay ?100 a year (since 1678) for Fairclough's life,
which the latter said was a retaining fee for his attendance
as a physician. The heavy repayments were assured in
both instances by penal bonds.
The day before he died, Richard Berney senior made a
will[8] in which ?10,000 was to be settled on his nephew
Richard, eldest son of Sir Thomas Berney, the second
baronet, and a further ?500 was to go to each child of Sir
Thomas at 21. After ?100, a coach and a horse for his
wife, the residue (besides the entailed real estate) was for
young Richard, who lost no time in proving his father's
will. A week later he instituted proceedings in Chancery
against Foster and Fairclough[9], among his numerous
creditors[10], claiming that the terms of the loans were
harsh and oppressive, considering that his father had
been old, ill and likely to die soon. The defendants denied
knowledge of the father's illness. Fairclough went further,
asserting that old Richard Berney was as healthy as
himself, whereas the plaintiff was 'very infirme and
subject to greate distempers' and might well die first,
when he would lose his money. J
Young Richard Berney called for evidence from Nor-
folk to support his case. The parish priest who had doled
out his 'meagre' allowance quarterly, his father's lawyer,
man of business and servant, together with his physician
and apothecary, were asked a series of questions designed
to elicit answers favourable to the plaintiff[l 1].
The first deposition was taken at the house of John
Berney 'comonly called the signe of the Kings head' in
the parish of St Peter Mancroft, Norwich, on 20th
September 1680. Three more, including the apothe-
cary's, were taken there a week later, followed by the
deposition of 'Sr Thomas Browne Knt & Dr of phisick
. . . aged seaventy yeares or thereabouts', taken at his
own house in the same parish[12]. The last witness was
heard at the house of John Berney (possibly the plaintiffs
uncle) on October 1st.
In answer to the first question, Sir Thomas said that he
had known the plaintiff for 20 years and his grandfather '
for several years before his death, 'but how long it is since
he dyed this deponent now remembreth not'. To the
second question he replied that
He did know Richard Berney esq1" the Complts father
for about twenty six yeares before his death & beleiveth
that he was betweene fifty & sixty yeares old when he
dyed And saith that when the Complts father was high
Sheriffe of the County of Norff at the time of the
Assizes in Norwich (being about nine yeares since) he
was very short breathed & his leggs were much
swelled, & he consulted this dept about the same, &
not wthout much difficulty was releived, but for many
yeares after he was forced to make use of remedyes
against Scurvye & dropsye haveing an ill habit of body
which required the same & about two or three yeares
Correspondence to: Terrysfield, Downe, Orpington, Kent BR6 7JT.
56 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
before his death he had an ulcer in his legg which
(though troublesome) proved beneficiall unto him, but
when ever that ulcer stopped or issued not as usually
he then fell ill & soe as to be in danger of death, and his
legg would sometimes alsoe be soe inflamed & painfull
that he was in danger of a gangreene And this dept &
most men about him thought that he would live no
longer then his ulcer releived him, if it could be kept
from a gangreene. And a little before his death it
slacked & ran little or nothing soe that considering his
long ill habit of body & great uncertainty how long his
ulcer would releive him, he lived much longer then this
dept expected.
Sir Thomas's answer to the third question was that the
plaintiff 'was ever of a healthful Constitucon for ought
this dept hath heard to the contrary And therefore in a
probability to outlive his father', whose only child he was.
As Browne went on attending Berney after the initial
illness in Norwich in 1670[13], he presumably visited him
at Reedham, 15 miles away to the east. That he knew
Park Hall earlier, in Sir Richard's time, is shown by his
letter to Evelyn in 1663, reporting a large oak in the
park[14]. Also, among the notes on the natural history of
Norfolk that Browne prepared for Dr Christopher Merret
about 1668 was one on the cormorants 'building at
Reedham upon trees, from whence King Charles the first
was wont to bee supplyed'[15].
However, it is clear from the apothecary's evidence
that he was sometimes sent to see the patient on behalf of
Sir Thomas Browne. He was Richard Clarke, of Nor-
wich, aged about 50, according to the deposition. This is
not the 'Dr Clark' whose presence at Browne's house
when a dolphin was dissected, during Charles II's visit to
Norwich in September 1671, was repeatedly recalled in
Sir Thomas's letters to his son five to ten years after-
wards. That was Dr Timothy Clarke, FRCP and FRS,
physician to the King, whose anatomical studies were
being prepared for publication at his death in February
1672. The apothecary ('Mr Clark' in two letters of Sir
Thomas's last year) was the Richard Clarke in whose
name a silver flagon, bearing his arms, was given to the
church of St Peter Mancroft in 1683[16]. He was buried
at Marlingford, six miles west of Norwich, where he had
bought an estate, as 'Generosus, Medicus, et Pharmaco-
peus praestantissimus, utpote Magni Illius apud Norwi-
censes ^Esculapii, Thomas Browni, Equitis aurati, fidus
Minister et Comes'[17], He died in May 1682, aged 52,
five months before Sir Thomas Browne[18].
Clarke deposed that he had known the plaintiff for 20
years and his grandfather for about six years before his
death, about 11 years earlier; then that
he did know Richard Berney esqr the Complts father
for twenty four years before his death (being about fifty
six yeares of age when he dyed) & that about nine
yeares since when the Complts said father was high
Sheriffe of the County of Norff he this dept being an
Apothecary was sent by Sr Thomas Browne Dr of
Phisick to visit the Complts said father where he found
him very sick labouring under a Scorbutick Astma
even to that degree that he turned black & was almost
suffocated when he stirred from which distemper he
was not free to his death, and that many times after the
said visit this dept hath gone by the direccon of the said
Sr Thomas to the said Complts fathers howse at
Reedham to visit him & hath administred to him
diverse portions of phisick & medicines & hath con-
stantly found him afflicted with that infirmity but
especially for two yeares next before his death the said
Complts father had a Complicacon of divers other
distempers reigning upon him as Catarhs, Dropsye
and Scurvye to that height and degree that his life was
in danger every day for the said two yeares before his
death by which meanes he was confined to his howse
for about two yeares before his death for the most part
And this dept & others that knewe him never expected
he would have lived soe long as he did.
The plaintiff had never had any disease or distemper and
would probably outlive his father.
The other witnesses were asked further questions.
Their answers gave estimates of the grandfather's person-
al estate (of which the plaintiff should have had half) as
about ?30,000 and of the annual value of the father's real
estate (entailed to the plaintiff) as over ?5,000. Naturally,
none of the witnesses referred to the plaintiff's extrava-
gance, which must have been the main cause of all the
trouble?and which continued until his death in 1695,
deep in debt, with virtually all the real estate, including
Reedham, sold or mortgaged and most of the legacies
from his grandfather and father to his cousins, the
children of Sir Thomas Berney, still unpaid[19].
Perhaps surprisingly, the court considered that the
lenders had indeed taken oppressive and unfair advantage
of him and decided both cases in favour of Richard
Berney, who had to repay only the principal of each loan
with interest [20]. Sir Thomas Browne may even have
approved. He was clearly sympathetic, a few months after
this deposition, to a man aged 54 whose 'old father dyed
the last weeke & left him a fayre estate in lands besides
good summes of money, which may paye the debts, which
the oversparing hand of his father made him contract by
borrowing & taking up of money'[21].
Acknowledgement
I thank Sir Julian Berney, Bt, for his interest in the
publication of this account and for information on the
pronunciation of his family's name.
References and Notes
1. Keynes, G. (ed) (1964) The Works of Sir Thomas Browne, vol. 4, pp.
48-232. London: Faber & Faber.
2. Morris, G. C. R. (1972) Transactions of the London and Middlesex
Archaeological Society, 23, 204.
3. Morris, G. C. R. (1975) Notes & Queries, n.s. 22, 558.
4. Transcripts of Crown-copyright records in the Public Record
Office appear by permission of the Controller of HM Stationery
Office.
5. Dated 10 Dec. 1667, with a codicil of 19 Dec. 1668, proved
(P.C.C.) 21 Jan. 1669: PRO, PROB 11/329, f. 4.
6. Barney in one deposition. That was the usual spelling in the
previous century and it is the pronunciation still used by one
branch of the family. The word 'barney' for an altercation is
unconnected.
7. James Fairclough (1630??1685) was a Cambridge graduate (BA
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
57
1655, MA and licence to practise medicine 1658, MD by Royal
letters 1661) who practised in London?largely as a money-lender,
to judge by his will (PRO, PROB 11/379, f. 19).
8. Dated 25 Jan., proved (P.C.C.) 6 Feb. 1680: PRO, PROB 11/
362, f. 14.
9. Bills of complaint dated 14 Feb. with answers 24 and 25 Feb. 1680:
PRO, C 7/24/60 (Foster), C 10/201/12 (Fairclough).
10. At least six more similar actions were being heard with these two in
1680-81: Chancery Decrees & Orders, PRO, C 33/255, 257.
11. The interrogatories and depositions are the same in (PRO) C 22/
225/10 for Foster and C 22/326/16 for Fairclough.
12. Sir Thomas was nearly 75. His letters show that he was immobi-
lised by illness in Dec. 1670, April 1677 and Jan. 1679. It was 'a
sickly time' on 22 Sept. and 15 Oct. 1680.
13. Richard Berney or Barney was High Sheriff for the year starting
11 Nov. 1669. His father was appointed to the office in 1622, his
brother Thomas in 1646 and his son (the plaintiff) in 1691.
14. Keynes, G. (ed) (1964) The Works of Sir Thomas Browne, vol. 4, p.
280. London: Faber and Faber.
15. Ibid., vol. 3, p. 403.
16. Blomefield, F. (1805-10) History of Norfolk, vol. 4, p. 192. London: ,1
Miller.
17. Ibid., vol. 2, pp. 457-8. Gentleman, doctor and outstanding i
apothecary, as the faithful assistant and companion of that great
/Esculapius among the people of Norwich, Sir Thomas Browne, jT-
knight.
18. Buried 18 May; his will dated 16 April, with a codicil of 4 May,
was proved 17 June 1682 in the Consistory Court of Norwich
(Norfolk Record Office: O.W. 13). Sir Thomas died 19 Oct. 1682,
a month before his seventy-seventh birthday: see Morris, G. C. R.
(1983) Notes & Queries, n.s. 30, 420. ,
19. Will of Richard Berney, dated 28 Jan. 1694, with a codicil of 18
Oct. 1695, proved (P.C.C.) 7 Dec. 1695: PRO, PROB 11/429,
f. 227.
.20. Chancery Decrees & Orders, 5 March 1681: C 33/255, ff.269, ^
307.
21. Keynes, G. (ed) (1964) The Works of Sir Thomas Browne, vol. 4, p.
202. London: Faber and Faber.
|
PMC005xxxxxx/PMC5370994.txt | Use of Hospital Resources by Acute Stroke
Patients
D. T. WADE, MB, MRCP(UK), Neurology Research Registrar
VICTORINE A. WOOD, Research Assistant
R. LANGTON HEWER, MB, FRCP) Consultant Neurologist
Department of Neurology, Frenchay Hospital, Bristol
Stroke is not only a devastating but also an expensive
disease. However, there have been very few studies
investigating the actual use of hospital resources by stroke
patients, and no prospective ones. In 1976 it was estimat-
ed[l] that in Scotland, while stroke patients only account-
ed for 2.1 per cent of all discharges (including deaths)
they occupied 6.2 per cent of all hospital beds at a cost of 6
per cent of the local NHS budget. The effect was largely
felt in general medical and geriatric wards, where stroke
patients accounted for 12 per cent and 25 per cent of all
bed-days respectively. Another study[2] on 1,094 patients
with acute stroke admitted to a London hospital over six
years found that, for those discharged alive, the average
length of stay was 37 days for men and 50 days for
women. In Edinburgh[3], minimally disabled patients
stayed in hospital for an average of 27 days, while those
who were more disabled stayed in for an average of 47
days. Lastly, in a Midlands hospital stroke patients
accounted for 8 per cent of all male and 11 per cent of all
female admissions to general medical wards[4].
The high use of resources by patients with stroke has
prompted suggestions that more economic ways of man-
aging these patients need to be investigated[5]. For
example, it is possible that patients managed in stroke
units may not only spend less time in hospital but may
also recover function faster[6]; a second study[7] failed to
confirm this. In order to develop new policies, it is
important to have some estimate as to the current load on
hospitals and present patterns of management. We have
conducted such an investigation in our own hospital,
trying to look for ways of improving efficiency. In
particular we wished to discover:
1. How many stroke patients are admitted with acute
stroke?
2. How are they referred to hospital?
3. How long do they stay, and how many are in at any
one time?
4. Where do they go at discharge?
5. What use is made of specialised investigations, or of
follow-up facilities?
Method and Patients
Patients were included in this study provided that (a)
their clinical diagnosis was of acute stroke (based on the
WHO definition[8]), (b) they were admitted within three
months of the stroke, or had the stroke while in hospital,
and (c) they were in hospital between 22nd June 1981 and
27th September 1982. Those admitted with long-standing
strokes were not included, even if the admission related to
their old stroke. A three-month cut-off was used because
most recovery has occurred by then[9], making it unlikely
that admission was related to the acute stroke.
Patients were identified by two means. First, one
investigator (V.W.) visited the medical wards weekly and
compiled a register of all stroke patients. Second, using
Regional Health Authority discharge information based
upon Hospital Activities Analysis (HAA) coding, all
patients discharged with stroke (codes 430-438) were
identified. The diagnosis of stroke was based, where
possible, upon history and examination (by D.W.).
When patients had died or left the hospital before being
seen, their notes were scrutinised (by D.W.) to ensure
that the clinical diagnosis was stroke.
Results
Over the 15 months (July 1981?September 1982), 443
patients were admitted with a diagnosis of acute stroke.
Because Frenchay Hospital has specialist departments
(i.e. neurology, neuroradiology, neurosurgery, and a
Stroke Unit), some patients were admitted specifically to
use facilities within these units (e.g. CAT scan). We
have, therefore, divided these 443 episodes into two
major groups. The first, 'Group 1', includes 351 single
admissions related to an acute stroke. Four of these 351
admissions were patients admitted with a second acute
stroke within the study period. Three patients from
Group 1 were re-admitted shortly after their first dis-
charge, for reasons relating to their stroke, e.g. failure of
a trial home visit. These have been included in the
analysis of bed occupancy, but excluded from all other
analyses. 'Group 2' included the 88 patients referred for
reasons relating to the specialist facilities within this
hospital. One patient admitted with an acute stroke 21
48 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
months before the study commenced has been excluded
from all analyses.
Group 1: General Characteristics
The mean age of the 351 stroke patients was 68.2 years,
but the 179 men (mean age 65.9 years) were significantly
younger than the 172 women (mean age 70.7 years;
P<0.001). In total, 59 (33 per cent) men and 90 (52 per
cent) women died: the average age of those who died was
71.6 years, with no statistically significant difference
between the sexes. Weakness was left-sided in 136 and
right-sided in 137 patients; it was difficult to categorise 43
patients because they either died before the side of their
weakness could be identified, or they had bilateral symp-
toms, e.g. from a brain-stem stroke; 35 (10 per cent)
patients had no significant weakness, being admitted, for
example, with aphasia.
Admission
In this study 186 (53 per cent) patients were admitted on
the day of their stroke, 42 (12 per cent) the next day and a
v, further 48 (14 per cent) during the rest of the first week;
22 (6 per cent) were admitted in the second week, with the
remaining 20 being admitted randomly over the next nine
weeks. Overall, 156 (44 per cent) patients were referred
directly by their GP, with a further 26 (7 per cent) being
referred by the Deputising Service; 91 (26 per cent) were
admitted through Casualty, 33 (10 per cent) were already
in hospital, 33 (10 per cent) were admitted from out-
patients or from a domiciliary visit, and 12 (3 per cent)
were transferred from other hospitals to be nearer home.
Only 248 (71 per cent) of these Group 1 patients came
from within the geographically defined Frenchay Health
District (population approximately 210,000): 78 (22 per
cent) came from neighbouring health districts and 25
came from farther afield.
Bed Occupancy
-r This was calculated for the 351 acute episodes, together
with the three recurrent admissions as described earlier.
k The calculation of bed occupancy was based on the dates
of admission, or stroke for those already in hospital, and
discharge or death. During the study period, the number
of stroke patients in hospital ranged from 14 to 33, the
average being 22.9 per day. The average number of men
was 10.7 (range 6-17), and women 12.2 (range 6-21); this
difference is statistically significant (P< 0.001). The aver-
age number of patients in hospital under the general
^ physicians was 13.8 per day; under the neurologists it was
4.3 per day. There was no significant monthly variation
in the admission rate, death rate, or bed occupancy
, throughout the year.
During the period of this study, Frenchay Hospital had
542 beds and there was an average of 407 patients in
hospital at any time; 67 of these were under the care of
general physicians, 36 under the geriatrician, 22 under
the neurologists and the rest under other consultants.
Thus, stroke patients occupied 5.6 per cent of all occupied
beds. Those under the care of general physicians occupied
20.6 per cent of all their beds, while those under neurol-
ogists occupied 19.5 per cent of their beds.
Outcome: Discharge and Follow-up
The outcome of the 351 admissions is shown in Table 1;
149 (42 per cent) patients died, 161 (46 per cent) returned
Table 1. Discharge of Group 1 patients.
Men Women
Discharged alive to:
Own home 103 56
Relative's home 1 1
Institutional care 4 2
Hospital care 12 23
Total 120 82
Died in hospital 59 90
home or to live with relatives, and 41 (12 per cent) were
transferred to some form of institutional care; none
remained in this hospital after October 1983. Women
were not only more likely to die (P< 0.001) but were also
more likely to need long-term care (/><0.01) if they
survived. Of the 167 patients leaving hospital (i.e. includ-
ing the six going to Part III accommodation), 88 (53 per
cent) returned for at least one medical out-patient ap-
pointment and 66 (40 per cent) attended for out-patient
rehabilitation.
Length of Stay
This was calculated from the day of admission (day of
stroke for those in hospital) to the day of discharge or
death (i.e. those leaving on the day of admission stayed 0
days, those leaving the next day stayed 1 day, etc.). The
proportion still in hospital is plotted against time in Fig. 1
for three groups of patients: (a) those dying in hospital
(n = 149); (b) those leaving to enter institutional care
Fig. 1. Proportion of patients in hospital plotted against time.
Days Weeks Months
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 49
(n = 41); (c) those returning home or to relatives
(n = 161). Overall, of the 351 patients, those dying occu-
pied 3,129 bed-days, those going home 4,717 bed-days
and those passing on to institutional care 5,391 bed-days.
The length of stay of the 149 patients dying in hospital
ranged from 0 to 488 days (median 5; mean 21). Those
returning home (mean age 63.7 years) stayed between 0
and 250 days (median 16; mean 29.3). Those discharged
to institutional care (mean age 74 years) stayed between 2
and 770 days (median 83; mean 131.5): this group was
significantly older (P<0.001) than those going home,
which may account for the preponderance of women. For
the 161 discharged home, there was no significant corre-
lation between age, sex or side of weakness and length of
stay.
Another way of considering the fate of these patients is
to calculate, as a function of the time elapsed since stroke,
the likelihood of a patient still in hospital going home,
dying or needing long-term care. This is illustrated in
Fig. 2 which shows, for example, that of the 129 patients
still alive and in hospital at three weeks post-stroke, 55
per cent went home, 26 per cent to long-term care and 19
per cent died. Only 37 patients remained in hospital at 12
weeks after the stroke: 54 per cent went to long-term care,
22 per cent died and 24 per cent returned home or to
relatives.
Investigations
Most of the 351 patients had some routine investigations
(e.g. full blood count) while in hospital, but our analysis
only considers those likely to be related specifically to
stroke. A CAT scan was performed on 189 patients (54
per cent), an arteriogram on 24 (7 per cent) and 25
patients had a lumbar puncture (7 per cent). Other
investigations were rare; two patients had an EEG, three
had carotid ultrasound scans, one an isotope brain scan,
and two had brain biopsies. A post-mortem was carried
out on 30 (20 per cent) of those dying.
Variations between Consultants
The patients were under the care of a variety of consul-
tants: 252 (72 per cent) were cared for by the three
general physicians, 61 (17 per cent) by the two neurol-
ogists, 16 by the one geriatrician, 5 by two neurosur-
geons, and 17 by various other surgeons. The patients
cared for by the three general physicians were almost all
admitted randomly as emergencies under the physician
on duty. We have compared the outcomes of patients
admitted under each physician (Table 2). Considering
Table 2. Comparison of three general physicians
General physician
No. patients 81 94 77
Average age (yr) 67.4 70.1 70.5
No. who died 42 (52%) 48 (51%) 32 (42%)
No. to institutional care 7 (9%) 9(10%) 9(12%)
No. to home/relatives 32 (39%) 37 (39%) 36 (47%)
Average length of stay (days)
of those going
home or to relatives 27.0 37.8 19.5*
*3 v 2: t = 2.96, PcO.Ol
3 v 1: t = 1.53, NS
3 v 1&2 combined: t = 2.89, P<0.01
those patients who returned home or to relatives, Consul-
tant 3 discharged his patients significantly quicker than
Consultant 2, and significantly quicker than Consultants
1 and 2 combined. Although fewer of his patients died,
this was not statistically significant.
Group 2: The Excluded Patients
The 88 excluded patients were obviously very different.
Most (86) were transferred from other hospitals, most
were referred to the neurosurgeons (50) or neurologists
(35), most (83) had a CAT scan, 35 (39 per cent) had
arteriography and 15 (17 per cent) had a lumbar punc-
ture. Only 19 (21 per cent) died in this hospital and the
average length of stay for the remaining 69 was 15 days.
This group occupied an average of 2.8 beds per day,
totalling 1,022 bed-days each year, usually in the neuro-
surgical wards.
Discussion
This study confirms that stroke is still an expensive
disease in our hospital. (This refers only to patients in
Group 1, as does all further discussion.) During one year
252 patients were admitted with an acute stroke and a
further 28 suffered a stroke while in hospital. These 280
stroke patients occupied 8,358 bed-days. The Frenchay
District finance department costed a general medical bed
Patients dying in hospital
I
Patients discharged home or to relatives
100-1
o E
90-
80-
70-
60-
50
40-
30-
20-
10-
Patients discharged to long-term care
Weeks Months
Time post-stroke
Fig. 2. Discharge destination of patients in hospital plotted
against time post-stroke.
50 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
at ?67 per day in 1982, which means that these patients
cost ?560,000 for one year or 4 per cent of the Unit's
?14.1 million annual budget for 1981/1982. Of this total,
41 per cent was accounted for by patients who were
discharged to instititutional car.e, 36 per cent by patients
discharged home alive and 23 per cent by those dying in
hospital. Before discussing these findings any further, a
v. few comments are needed regarding any bias in the
selection of patients.
First, our hospital contains specialist departments
which might bias the referral of patients. We have
attempted to counteract this by excluding those patients
who were clearly referred to one of these specialist
services, although it was occasionally difficult to be
certain of the reasons for referral. Otherwise we feel that
our hospital serves a fairly typical Health District, having
a catchment area which includes urban, suburban and
rural populations.
Second, and counteracting the first bias, acute stroke
patients from the Health District are admitted to several
other hospitals, both within and outside the District.
Figures from a community study, conducted throughout
the period of this study[10], show that 74 per cent of
stroke patients within the Frenchay Health District were
admitted to hospital. Of these, 56 per cent were admitted
to this hospital, with a further 30 per cent going to one of
the other two 'District' hospitals, leaving 14 per cent
going to hospitals outside the District. We have not
investigated admissions to these other hospitals, but in
our study 22 per cent of 'normal' admissions were of
y patients from outside the District.
Interpretation of these findings is also affected by many
factors which will vary from hospital to hospital and area
to area. For example, in this hospital stroke patients are
accepted as part of the emergency medical 'take', but in
some areas more patients may be admitted to geriatric
hospitals. In this District, hospital admission is usually
easily achieved, but in some areas it can be quite difficult
to admit a patient who has suffered a strokefll]. Al-
though the majority of patients were admitted under
general physicians to general medical beds, some were
admitted to other wards or under the care of other
consultants. Factors unrelated to the stroke may have
prolonged some patients' stay in hospital.
One particular item that might have affected our
findings was a controlled trial of a domiciliary service for
acute stroke being conducted in the Health District[10].
This might have slightly reduced the number of patients
y admitted from the trial area, and shortened their length of
stay. Any effect was probably small, and only 240 (68 per
cent) of the 351 patients came from that study population.
It will have reduced the number attending for therapy
after discharge.
The factors just discussed may affect the absolute
findings to a small extent, but the general outlines are
probably similar for most hospitals and indeed our find-
ings are consistent with other work. For example, patients
admitted with an acute stroke can be neatly divided into
?v three outcome categories ? those who die, those return-
ing home, and those needing long-term care ? and our
study supports others[12,13] which have found that the
stay in the acute hospital is shortest for those who die and
longest for those needing institutional care. We are
unable to demonstrate any influence of either age or sex
on the length of stay of those going home. It is likely that
the difference in age between those going home and those
needing care may account for the correlation between age
and length of stay previously reported[2,13]. Similarly,
the fact that women seem more likely to need long-term
care may account for the earlier observation that they are
in hospital longer[2]. The observation that in the USA it
is younger patients who stay in longer[14] perhaps con-
firms that extrinsic (social) factors influence length of stay
more than intrinsic (patient) factors.
How can the cost be reduced? There is evidence that
the need for nursing support, rather than a need for
medical expertise, is the usual reason for hospital admis-
sion^]. Therefore, one possible way would be to reduce
the number admitted by providing more home support
services which might particularly reduce the need for
admission of the 35 per cent admitted after the first 24-48
hours. However, as only 44 per cent of patients were
referred by their GPs, knowledge of and access to any
such service would need to be widely based if the
admission rate is to be reduced.
A second, complementary, approach would be to re-
duce the length of stay of those admitted. In this study
about 12 per cent of all patients were referred on to
institutional care, a similar proportion to that in North
London[2]. These patients were responsible for a dispro-
portionate amount of the resources used (41 per cent) and
it must be asked whether their stay in the acute hospital
needed to be so long. It will be obvious very quickly that
many of these patients will never recover sufficiently to
return home. For example (see Fig. 2), of those in
hospital 10 weeks after their stroke, 51 per cent will need
long-term care, 21 per cent will die and 28 per cent will go
home. It is likely that those going on to long-term care or
going to die will only need the facilities of the acute
hospital for a few weeks. Recent studies[15,16] have
shown that reasonable prediction of functional recovery is
possible within the first 3-4 weeks using simple clinical
measures. Assuming that alternative accommodation
(long-stay ward or Part III accommodation) is cheaper,
one should consider identifying those patients who no
longer need the expensive resources of an acute hospital,
and transferring them earlier to less expensive places of
care.
Apart from identifying and moving those destined for
long-term care, it may also be possible to reduce the
length of stay by concentrating stroke patients into
specialised wards[6]. In this hospital there were, on
average, enough patients to fill a ward (23 patients).
However, there was a considerable fluctuation in the
number of patients in hospital at any one time (14-33),
which means that any ward dedicated exclusively to
stroke patients will either have to turn patients away on
occasions or, if it is large enough to cope with every
potential patient, it will often have many unused beds. A
more practical alternative would be to designate two
wards (1 male, 1 female) as being priority wards for
stroke patients, taking other general medical patients as
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
51
well. Our figures suggest that such wards would usually
be about half full of stroke patients. Such an arrangement
would allow staff to gain expertise in managing stroke
patients while maintaining a variety of patients, thus
lightening the physical and emotional nursing load.
This study suggests that it may also be possible to
reduce the length of stay of stroke patients going home
even without creating 'stroke wards'. Consultant 3 dis-
charged patients sooner than his general medical col-
leagues. This observed difference may have several
explanations: the patients admitted by Consultant 3 may
have been less severely affected (particularly if he selec-
tively admitted patients to other hospitals in the District),
the findings may just be due to chance, Consultant 3's
patients may all have done badly at home because they
were not fit to be discharged, or his patients may have
had better home circumstances. This study has not
collected the information necessary to explain the differ-
ences which only became apparent after analysis. Fur-
ther, even if he does actually discharge patients sooner,
any saving of hospital resources he achieves will need to
be balanced against extra community costs, any increased
stress on the patient and his family, and any reduction in
the patient's recovery. Nevertheless, this variation be-
tween consultants should be utilised to investigate differ-
ent policies. There may also be equally large variations
between different districts: in Oxford only 40 per cent of
patients suffering a first stroke are admitted to hospital
(Sandercock; personal communication), as against 74 per
cent in Frenchay.
In conclusion, this study highlights the considerable
variation in many aspects of the patterns of care of stroke
patients; for example, only 46 per cent were admitted by
their GP, 35 per cent were admitted more than two days
after their stroke, 54 per cent had a CAT scan and 53 per
cent came back for medical appointments. This variabil-
ity may simply reflect the wide variability in the manifes-
tations of stroke. However, it may also reflect uncertainty
about the best management of stroke patients, this uncer-
tainty leading to different policies being applied to similar
patients. If this is the case, there may be scope for
reducing the use of hospital resources. For example, in
this study one consultant physician discharged his
patients considerably sooner than the other two physi-
cians; to investigate this further a more complete audit of
stroke care would be needed. In addition, it is possible
that the development of a 'District policy' would improve
the management of stroke patients by, for example,
pointing out that a lumbar puncture cannot reliably
detect cerebral haemorrhage. This policy would take the
form of general guidelines and would need to be widely
disseminated both within the hospital and outside it. Such
guidelines might profitably be combined with an audit so
that variations in policy, whether accidental or deliberate,
could be evaluated more fully.
Acknowledgements
We gratefully acknowledge the considerable help we
received from Mrs P. Guyatt, Assistant Patients Services
Officer, and all her staff in tracing over 750 sets of
medical notes, Miss M. Philpott, District Statistical
Officer, for supplying discharge coding information and
general hospital statistics, and Miss P. Watts at the
Regional Computer Centre for supplying. us with the
discharge statistics. We also acknowledge the co-oper-
ation of all the doctors and ward staff involved with stroke
patients, Mr W. Healing and the finance department in
producing the costing information, Dr P. Begley for
permission to publish bed occupancy figures and Mr P.
Cox for the illustrations.
References
1. Carstairs, V. (1976) In Stroke, pp.516-28. (ed F.J. Gillingham, C.
Mawdsley and A. E. Williams.) Edinburgh: Churchill Living-
stone.
2. Sheikh, K., Meade, T. W., Brennan, P. J., Goldenberg, E. and
Smith, D. S. (1981) Community Medicine, 3, 210.
3. Garraway, W. M., Akhtar, A. J., Smith, D. L. and Smith, M. E.
(1981) Journal of Epidemiology and Community Health, 35, 39.
4. Acheson, J., Acheson, H. W. K. and Tellwright, J. M. (1968)
Journal of the Royal College of General Practitioners, 16, 428.
5. Wade, D. T. and Langton Hewer, R. (1983) Lancet, 1, 807.
6. Garraway, W. M., Akhtar, A. J., Prescott, R.J. and Hockey, L.
(1980) British Medical Journal, 281, 827.
7. Stevens, R. S., Ambler, N. R. and Warren, M. D. (1984) Age and
Ageing, 13, 65.
8. Aho, K., Harmsen, P., Hatano, S., Marquardsen, J., Smirnov,
V. E. and Strasser, T. (1980) Bulletin of the World Health Organisa-
tion, 58, 113.
9. Skilbeck, C. E., Wade, D. T., Langton Hewer, R. and Wood, V.
A. (1983) Journal of Neurology, Neurosurgery and Psychiatry, 46, 5.
10. Wade, D. T., Langton Hewer, R., Skilbeck, C., Bainton, D.,
Burns Cox, C. and West, P. (1983) International Journal of Rehabili-
tation Research, 6, 510.
11. Warren, M. D., Cooper, J. and Warren, J. L. (1967) British
Journal of Preventive and Social Medicine, 21, 141.
12. Gibson, C. J. (1974) Archives of Physical Medicine and Rehabilitation,
55, 898.
13. Granger, C. V., Kaplan, M. T., Jones, B. and Fell, N. (1982)
Archives of Physical Medicine and Rehabilitation, 63, 352.
14. Walker, A. E., Robins, M. and Weinfeld, F. D. (1981) Stroke, 12,
suppl. 1, 13.
15.' Prescott, R. J., Garraway, W. M. and Akhtar, A.J. (1982) Stroke,
13, 641.
16. Wade, D. T., Skilbeck, C. E. and Langton Hewer, R. (1983)
Archives of Physical Medicine and Rehabilitation, 64, 24.
52 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
|
PMC005xxxxxx/PMC5370995.txt | A Plagiarist Plagiarised
When the De Fabrica was published in 1543, Vesalius had
obtained what privileges he could which theoretically
prevented anyone from reprinting his book on much of
the continent; but he appears to have failed to do the same
for England, or else had not thought it necessary. Imag-
ine his dismay, therefore, when two years later there was
published in London a work which borrowed not a few,
but a majority of the illustrations from the De Fabrica, as
well as some from the Epitome?Compendiosa totius anato-
miae delineatio, aere exarata: per Thomam Geminum?a title
which refers only to the engravings, the text being added
perhaps as an afterthought. This Thomas Geminus, also
known as Lambrit, came from Flanders, and besides
being an engraver, was an empiric, a printer, and a
maker of mathematical instruments. His manual of
anatomy contains some of the earliest copper plate en-
gravings to have appeared in England; its publication
may have induced Geminus to practise medicine and
surgery. In consequence he was prosecuted by the College
for practising without a licence, and fined. John Caius,
who was President at the time, was asserting the right of
the College to extend its authority over the whole coun-
try; to this end he armed its agents with a letter which
Geminus had undertaken to print in remission of his fine.
This was in 1556.
Three years later (1559) the second edition of an
English translation of his manual was published. There
are two copies in the College library, one of which
belonged to a George Frederick Boyd, whose identity
presents something of a puzzle. An apothecary of this
name served in the 84th Regiment, and in the American
War of Independence, and died at Basingstoke in 1801; a
surgeon of the same name also served in the 84th
Regiment, but died at Halifax in 1789. The previous
owner was John Patch, a surgeon of Exeter. An interest-
ing note in his hand written 20th May 1728 reads: 'The
first Edition of this Book (formerly in my Study) was
publish'd in Latin by the same Author at London An?
1545 under the following title Andreae Vesalii Bruxellen-
sis suorum de Humani Corporis Fabrica Librorum Epit-
ome: this was about two years after that Vesalius obliged
the World with his first and one of the famous Basil
Editions of his Anatomy, with wooden Cutts, whereof, I
think, these are very good Copys.' This 'title' is in fact
continued on page 47
44 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
Continued from page 44
the head-title on the first page; perhaps the title page in
the copy that once belonged to Mr Patch was lacking, for
that makes no mention of Vesalius.
When the Barber-Surgeons' Company received their
charter of incorporation in 1540, one of the tasks they
concerned themselves with was the improvement of the
teaching of anatomy. One of the the earliest Readers of
Anatomy was John Caius, who is known to have lodged
with Vesalius, when in Padua; and it has been suggested
that Caius influenced Geminus to publish his manual of
anatomy. That it was a success is apparent from the
preface to the first English translation published in 1553.
The text in the translation bears more resemblance to the
Anatomie of Thomas Vicary, a Master of the united
company, than to Vesalius. The translator was Nicholas
Udall, well-known as the father of English comedy, and
the author of Ralph Roister Doister; his translations of
Erasmus had gained considerable renown. The transla-
tion was made because it 'might greatly availe to ye
knowlage of the unlatined Surgeons'. The second edition
published in 1559 has two points of interest. In the new
title is a portrait of Elizabeth, probably the first published
after her accession; in the book itself are two additional
woodcuts?seated nude figures of a man and woman?
with movable flaps, capable of being lifted to expose the
internal organs, one of the first examples of an illustration
with movable flaps.
The value and success of the Compendious Anatomy
quickly resulted in the publication of plagiarisms in
England and on the continent, particularly those of
Jacques Grevin and Jacob Bauman; but Geminus is
never mentioned, and what reference is made to the
source of borrowing is always to Vesalius. Nevertheless,
the influence of Geminus continued to be felt for at least a
century after the publication of his book. Truly has it
been said: 'Few plagiarisms have been flattered by so
much imitation'.
Leonard Payne
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 47
|
PMC005xxxxxx/PMC5370996.txt | Correction
We apologise for an error in the article
'Metabolic
Responses to Beta2 Stimulants'
in Vol. 18 No. 3
(July 1984). Page 193, lines 7-10 should have read:
. In one report normal subjects were challenged
with intravenous salbutamol before and after the
administration of 1,600 micrograms of inhaled sal-
butamol daily for 2 weeks.'
12 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
|
PMC005xxxxxx/PMC5370998.txt | . . . A Doctor in the House?
'Who would not desire to have a physician always in his
house, and one that attends without fee or reward?' asks
John Wesley. A rhetorical question, perhaps, but his
experience, as he journeyed up and down the country
preaching and meeting people, and thus being made
aware of the needs of the poor, may well explain in part
how he came to compile his Primitive Physic. He began by
starting a fund to provide the poor with food and
clothing, and then, deciding to prepare and give them
physic himself, he opened a dispensary at the Foundery in
Moorfields in 1746. Wesley obtained the assistance of an
apothecary and an experienced surgeon, 'resolving at the
same time not to go out of my depth, but to leave all
difficult and complicated cases to such physicians as the
patients should choose'. In five months medicines were
given to more than 500 persons. This dispensary, a
pioneer effort following the closure of the College dispen-
sary some 20 years earlier, prospered so greatly that two
months later he opened a similar one in Bristol which was
no less successful. It was but a natural step for Wesley to
write out his prescriptions so that they could become
generally available to destitute people. Wesley spent only
three months over the composition of Primitive Physic.
Published in 1747, it was a pocket-sized volume of 119
pages, nearly a quarter of which was given over to a
preface. It is arranged alphabetically, listing 243 condi-
tions from 'Ague' to 'Wounds' with 725 'cures'; ailments
and cures are numbered consecutively and separately?a
device which tends to obscure the alphabetical arrange-
ment. It is written in simple English, with the directions
concisely given; 'to cure a tooth-ache, put a clove of
garlick into the ear'. It was intended to be 'an easy and
natural method of curing most diseases'. Wesley had no
doubt that identifying the ailment would present no
difficulty; 'unless in a complication of disorders, and then
you would do well to apply to a physician that fears God'.
He generally provides several remedies, which he recom-
mends should be tried in order, if necessary. He realised
that not all were easy to obtain, and that what cured one
would not always cure another. He prefaces his remedies
with the advice given by Dr Cheyne in his Essay of Health
and Long Life: extolling the virtues of pure air; suit the
quality and quantity of food to the strength of the
digestion; go to bed at nine and rise at four or five;
exercise is indispensible ('Those who read or write much
should do it standing; otherwise it will impair their
continued on page 58
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985 55
Continued from page 55
health'); costiveness cannot long conflict with health;
beware the influence of the passions.
It was in his early days at Oxford that Wesley first read
this book, and later he read Cheyne's Natural Method of
Curing Diseases; indeed 'for six or seven and twenty years
I had made anatomy and physic the diversion of my
leisure hours'. He was acquainted with the writings of
Boerhaave, Dover and Sydenham, as well as those of
Cheyne. Wesley, however, distrusted the medical profes-
sion as a whole because they had introduced into their
writings an abundance of technical terms, and into their
practice countless compound medicines 'consisting of so
many ingredients, that it was scarce possible for common
people to know which it was that wrought the cure'.
Wesley felt that cures can and should be discovered by
accident. Discovering cures and experimenting with them
was the primitive way by which was gathered up the
whole corpus of healing. Physic was in the first ages
chiefly traditional. Hence his title of 'primitive' physic.
Within a hundred years of its first appearance no less than
38 editions of Primitive Physic had appeared, 22 of them in
Wesley's life-time. It was published in America, and once
translated into French; copies of the latter are rare,
though there is one in the College library together with
the first edition, which was published anonymously. It
was not until 1760 that Wesley's name appeared on the
title-page. In this edition, too, he added 'Tried' to those
remedies which he had found to be of the greatest
efficacy, and enthusiastically commended electricity as
coming 'the nearest an universal medicine, of any yet
known in the world .
Leonard Payne
58 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
|
PMC005xxxxxx/PMC5370999.txt | >
I
I
International Epidemiology of Cancer
J. A. H. WATERHOUSE, PhD
Director, Regional Cancer Registry, and Cancer Epidemiology Research Unit,
Department of Social Medicine, University of Birmingham
Within the range of this title I have chosen to limit
consideration of the subject first to morbidity. Mortality
data for many parts of the world are available from
WHO, but their quality is very uneven, and the data
generally refer to the whole of a country: only the
developed countries can claim a reasonable degree of
homogeneity of data for such areas. Cancer morbidity
data come from cancer registries which, though scattered
around the world, are much more plentiful in the more
advanced countries, and scarce or non-existent in many
places where they would be, for epidemiological and other
reasons, very desirable. Nevertheless, they are usually
reliable sources of data and more accurate in diagnosis
than are death certificates since they will often be support-
ed by histological reports or by the results of other
investigative or therapeutic methods.
My general objective is to examine the variations in the
manifestation of cancer across the world, in relation to
different ethnic or national groups. As a principal source
of data I have taken the latest (fourth) volume of that
tabulation of international cancer morbidity data known
as Cancer Incidence in Five Continents[ 1]. There are 104
populations or sub-populations included in the volume,
each tabulated by sex, age and site for incidence rates,
and each subject to checks and quality controls before
admission. The volume represents the most comprehen-
sive and homogeneous source of such data at present
available.
Since the various populations differ so much in their
structure by age and sex, some common 'denominator' is
necessary in order to render them properly comparable.
For this purpose the 'world standardised rate' (WSR) is
probably the most useful. For any given population and
site of cancer, the incidence rates by age are applied to a
standard population ? the 'world standard population',
constructed originally by the Japanese epidemiologist,
Segi, as a form of average between the very young
populations of the developing countries and the rather
older (in the sense of having a greater proportion of their
people in the older age groups) pattern of the developed
countries. Applied in this way the rates produce an
'expected' number of cases in the standard population
from which the WSR is obtained. These rates can then be
properly compared because they all result from the same
( basic population.
The list of sites is taken from the second chapter
(Neoplasms) of the eighth revision of the ICD[2], which
has been condensed to provide just over 40 sites for each
sex. I have further condensed it by excluding certain sites
mostly of minor importance, such as small intestine,
bone, connective tissue, skin, male breast, chorion epith-
elioma, other female genital, eye, other endocrine, mono-
cytic and other rare leukaemias, polycythaemia vera,
myelofibrosis. Skin is an important site which it is
unfortunate to have to exclude: melanoma is included but
the squamous and basal celled forms of skin cancer are
not, since many registries find it difficult to capture all
such cases. These varieties seldom cause death, but they
are useful indicators of exposure to carcinogenic agents
such as ultra-violet light, e.g. intense sunlight, and a
number of substances, e.g. hydrocarbons, occurring in
various occupations.
Basis of Analysis
With the limitations mentioned above, the data source is
reduced to a WSR for each of 104 populations and rather
more than 30 sites, and for both sexes, providing more
than 6,000 figures for comparison. In order to heighten
the comparison and attempt to typify the patterns rep-
resentative of the various groupings, I took first the upper
10 percent of the WSRs for each sex and site, arranged in
descending order of magnitude. Later, for greater sim-
plicity, I took only the first five populations showing the
highest rates within each site by sex, reducing the number
of indices to just above 300 (Table 1).
Results
When placed in rank order, what is lost is the absolute
value of the index, here the WSR. Sometimes the five
values form a group close together in size and ordered by
only small variations; sometimes one may stand out well
above the others. In lip cancer, for instance, the WSR for
males in Newfoundland is 22.8 per 100,000 and the next
figure is 13.3, for Saskatchewan. It has been suggested
that the very high rate of 22.8 relates to fishermen
accustomed to repair their tarred nets by holding them in
their mouths, or alternatively to the reflection of the sun
from the water on to their lips. Nasopharyngeal cancer in
Singapore Chinese men has a rate of 19.4, the next being
14.6 among Bay Area Chinese men, and then 7.1 for Los
Angeles Chinese, the rate for Shanghai, the only rep-
resentative of mainland China, being 5.6. Among
women, the highest rate for tumours of the gall bladder is
22.2 in the American Indians of New Mexico, the next
10 Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
Table 1. World standardised rates for cancerfl].
KEY
(Wh) = Whites
(Bl) = Blacks
Sing. Ind. = Singapore,
Indian
NWT = North Western
Territories (Canada)
NW(UK) = North West
Region (United
Kingdom)
Hawaii (Haw) = Hawaii,
Hawaiian
Hawaii (Ch) = Hawaii,
Chinese
Jews (E/A) = Jews born
Europe or
America
Hawaii (F) = Hawaii, Filipinos Jews (I) = Jews born in Israel
Bay Area (Ch) = Bay Area,
Chinese
Bay Area (J) = Bay Area,
Japanese
LA = Los Angeles
NSW = New South Wales
MALE
Tongue
Bombay 10.2
Doubs 7.8
Bas-Rhin 7.4
Poona 7.2
Puerto Rico 6.0
Mouth
Poona 10.0
Bas-Rhin 9.6
Sing. Ind. 8.8
New Orleans (Bl) 7.0
Sao Paulo 6.8
Oropharynx
Bas-Rhin 11.6
Doubs 6.8
Geneva 5.7
Antilles 5.5
Bombay 4.7
Hypopharynx
Bas-Rhin 10.2
Doubs 8.7
Bombay 8.0
Neuchatel 4.4
Geneva 4.2
Nasopharynx
Sing. (Ch) 19.4
Bay Area (Ch) 14.6
LA(Ch) 7.1
Hawaii (Ch) 6 2
NWT 6.2
Larynx
Doubs 17 6
Varese 16.0
Sao Paulo 15.8
Spain Navarra 15.0
Poona 13.6
Oesophagus
Shanghai 24.7
Atlanta (Bl) 19.3
Sing. (Ch) 18.9
Hong Kong 18.6
Hawaii (Haw) 18.3
Stomach
Nagasaki 100.2
Miyagi 88.0
Osaka 78.0
Fukuoko 75 0
Shanghai 55.7
female
Bombay
Poona
Hawaii (Wh)
Puerto Rico
Bay Area (Wh)
Sing. Ind.
Bombay
Poona
Hawaii (Haw)
Hawaii (Wh)
Hawaii (Wh)
NWT
Alameda (Bl)
Bay Area (Bl)
Bombay
Sing. Ind.
Bombay
Hawaii (Wh)
Alameda (Wh)
NW(UK)
Bay Area (Ch)
Sing. (Ch)
LA (Ch)
Shanghai
Hawaii (Ch)
Bombay
Poona
Detroit (Bl)
Sao Paulo
Bay Area (Bl)
Bombay
Poona
Antilles
Sing. Ind.
Hong Kong
Nagasaki
Miyagi
Osaka
Fukuoko
Cali
MALE
Pancreas
4.1 Bay Area (Bl)
2.4 Alameda (Bl)
1.8 NZ (Maori)
1.6 New Orleans (Bl)
1.5 Detroit (Bl)
Bronchus
8.6 New Orleans (Bl)
5.8 Maori
4.3 Scot. West
3.8 Hawaii (Haw)
3.8 Detroit (Bl)
Brain and Nervous System
2.7 Jews (E/A)
2.4 Sweden
1.6 Jews (all)
1.4 Nowy Sacz
1.3 Spain Navarra
Bladder
3.2 Geneva
2.2 Varese
1.0 New Orleans (Wh)
0.7 LA (Wh)
0.7 Hawaii (Wh)
Melanoma
7.7 NSW
7.5 S. Australia
4.0 NZ (Wh)
2.5 Hawaii (Wh)
1.6 LA (Wh)
Multiple Myeloma
2.6 Bay Area (Bl)
2.2 Maori
2.0 Hawaii (Haw)
1.9 Detroit (Bl)
1.8 Alameda (Bl)
MALE ONLY
10.7 Prostate
10.4 Alameda (Bl)
8.7 Atlanta (Bl)
7.7 Bay Area (Bl)
5.5 LA (Bl)
Detroit (Bl)
51.0 Penis
42.0 Jamaica
38.5 Puerto Rico
38.4 Poona
27.3 New Orleans (Bl)
Atlanta (Bl)
FEMALE
18.3 NWT
18.0 New Mexico (Ind)
14.8 NZ (Maori)
14.3 Alameda (Bl)
12.0 Bay Area (Bl)
107.2 Maori
105.7 Hawaii (Haw)
96.8 NWT
96.2 Bay Area (Ch)
90.7 Bay Area (Wh)
10.0 Sweden
9.2 Jews (E/A)
9.0 Jews (all)
9.0 Jews (I)
8.9 Cracow
30.2 NWT
24.6 New Orleans (Wh)
24.5 LA (Wh)
23.6 Hawaii (Haw)
23.5 Alameda (Wh)
16.6 NZ (Wh)
13.0 NSW
12.3 S. Australia
11.8 New Mexico (Wh)
10.2 Norway
8.4 Hawaii (Haw)
8.2 Alameda (Bl)
7.5 Bay Area (Bl)
7.4 LA (Bl)
7.3 New Orleans (Bl)
FEMALE ONLY
Breast
100.2 Hawaii (Haw)
95.7 Hawaii (Wh)
92.2 LA (Wh)
79.1 Bay Area (Wh)
73.2 New Mexico (Wh)
Cervix
5.7 Cali
4.1 Sao Paulo
3.4 Maori
2.8 NWT
2.1 Poona
11.5
10.8
10.2
9.9
9.9
48.8
40.5
34.7
25.1
24.7
9.1
8.3
8.0
7.9
7.3
7.6
6.5
6.2
6.2
6.1
18.8
18.1
17.6
9.5
9.1
5.9
5.6
5.6
5.6
5.6
87.5
85.6
85.3
83.7
78.7
52.9
37.5
32.6
31.4
30.7
rate being 12.3 for women in Warsaw City. The last
example that I give is cervical cancer in Cali, Colombia,
with a rate of 52.9, the next being 37.5 in Sao Paulo,
Brazil.
The populations of Bombay and Poona are the only
representatives of India, and in them we find tongue,
mouth, oro- and hypopharynx, nose and sinuses, larynx
and oesophagus, with cervix and penis also in Poona.
Journal of the Royal College of Physicians of London Vol. 19 No. 1 January 1985
These sites, especially the area of the mouth, have long
been typical of India, but we find a very similar grouping
in France (Bas-Rhin and Doubs), and several in Switzer-
land. The Swiss also include high levels of testis, bladder,
lymphosarcoma, Hodgkin's Disease, other reticuloses
and leukaemia, some of which could be associated with
the high standard of living typical of Geneva, Vaud and
Neuchatel.
The Chinese, represented chiefly by their migrant
populations in Hong Kong, Singapore, Hawaii and
California, show, in addition to the highest rates for
nasopharynx, high rates for oesophagus, stomach, colon,
liver, nose and sinuses, and thyroid. There are four
registries in Japan itself, and the Japanese have, for both
sexes, the highest rate of stomach cancer in the world;
after them come Shanghai and the South American towns
of Cali and Sao Paulo. Japanese in Nagasaki and Miyagi
show high rates of gall bladder carcinoma, while expatri-
ate Japanese have an excess of rectal cancer. Jews have
high rates for rectum, and also for lip and ovary, but
especially, in both sexes, for brain and nervous system.
Native Hawaiian women have the highest breast can-
cer rate, to which are added mouth, salivary gland, liver,
bronchus, thyroid, lymphosarcoma and myeloma; for the
men there are oesophagus, bronchus, lymphosarcoma,
myeloma and myelocytic leukaemia. The Maoris, of both
sexes, have very high rates for pancreas, bronchus,
myeloma, myelocytic leukaemia, and for women, cervix.
Norway, Sweden and Denmark have high rates for
ovary, other urinary, brain and nervous system, and for
Denmark the testis, and for Norway, melanoma. In the
Antipodes, New South Wales, South Australia and New
Zealand whites have the top three rates in both sexes for
melanoma, followed by some US whites and the Norwe-
gians. Other forms of skin cancer are known to be high
there and are likely to result from excess exposure to
intense sunlight.
The sites found among American whites are breast,
colon, melanoma, endometrium, bladder, Hodgkin's dis-
ease, and lymphosarcoma, sites which could be said to be
characteristic of a high standard of living. Among Ameri-
can blacks are found the highest rates of pancreas,
prostate, myeloma, and bronchus. For the latter site the
New Orleans blacks lead with a rate of 107.2, followed by
the Maoris at 105.7, and the west of Scotland at 96.8;
among women, the Maoris lead with 48.8.
These are the principal highlights, though the cata-
logue is far from exhausted. But apparently isolated facts
form a poor diet and quickly amount to a surfeit. In some
instances it is possible to put forward plausible 'explana-
tions' for observed high rates, in others there is no clear (
relationship. A general conclusion would support an
environmental rather than a genetic basis for most malig-
nant disease, though culture patterns are evidently influ-
ential. The work of Haenszel[3] and his colleagues on
comparing the pattern of cancer among emigrants with !
both host and parent countries has shown that there can
be at least two manifestations of an effect: one that, with
increasing period of residence, approximates the risk in '
emigrants towards the host's risk, and another that
requires a new generation, born in the host country,
before a sizeable change is seen. One of the strongest
arguments for the environmental effect is, of course, the
large fraction of cancer attributable to cigarette smoking,
now increasingly evident among women as male rates
have reached saturation. Another is the striking change in
the pattern of cancer in Japan as dietary habits change
towards a western model. Though we may be able, from
analysis of these data, to infer methods that may help to
reduce or prevent certain kinds of cancer, there are still
many variants that remain unexplained, and secular
trends that elude a current rationale.
This article is based on a paper read at the Conference on
Diseases in Ethnic Minorities held at the Royal College of
Physicians in May 1984.
I
References
1. Waterhouse, Muir, C.S., Shanmugaratnam, K. and
Powell, D.J. (1982) Cancer Incidence in Five Continents, Vol. IV.
Lyon: IARC.
2. International Classification of Diseases ? Manual of the International
Statistical Classification of Diseases, Injuries and Causes of Death (1967)
Geneva: WHO.
3. Haenszel, W. (1975) in Persons at High Risk of Cancer, pp. 361-71.
(ed J.F. Fraumeni.) New York: Academic Press.
|
PMC005xxxxxx/PMC5371002.txt | A Surgeon's Expectations of the Autopsy
C.G. CLARK, MD, ChM, FRCS, FRCSEd
Professor of Surgery, University College, London, and
Director, Department of Surgery, The Rayne Institute
In many ways the surgeon may have less apparent
interest in the autopsy than the physician. This is because
he has already had a preview at operation, made a
diagnosis and perhaps found widespread dissemination of
a cancer about which he could do nothing except ensure
that the patient's remaining days were made as comfort-
able as possible. This attitude should not be regarded as
showing lack of scientific interest, but more as an accept-
ance, after seeing this all too common occurrence, that
there is little more to be learned from yet another
disseminated cancer. When the primary cancer is un-
discovered, efforts are made to obtain permission for
autopsy, though this is sometimes thwarted by the rela-
tives, who feel that the operation was sufficient opportu-
nity, and are reluctant to agree to further mutilation.
These two circumstances have some bearing on the
degree of enthusiasm with which permission for an
autopsy is sought. There are also special problems in any
district which has a high proportion of elderly, usually
females, who live alone and have either no relatives, or
relations who, for various reasons, are reluctant to give
permission for further examination. Problems of permis-
sion sometimes arise with ethnic minorities such as
orthodox Jews or Muslims. The relatives may resent the
failure of treatment, or there may have been real or
imagined antagonism from the staff, both of which can
lead to a request for an autopsy being refused. All these
reasons account for up to 40 per cent of requests for
autopsy being refused.
To some extent the autopsy rate depends upon the
method of approach. In a surgical unit it is likely that the
person available to meet the relatives is the house sur-
geon, whose experience of the situation is one of learning
and finding his way. He should be taught to deal with the
situation with sympathy and understanding, together
with a degree of firmness. It is important that he should
explain why an autopsy is necessary, and the degree of
conviction with which he does this will largely be deter-
mined by the attitude of his seniors. Attitudes to autopsy
vary widely. At one time the rule was to try in all cases,
but, with a greater understanding of what was likely to be
achieved and taking into account the natural resistance of
the relatives, permission is usually sought only when a
question needs to be answered. The surgeon's guide for
an autopsy request might be:
(a) Unexplained Death. The patient is admitted and dies
before investigations are complete and any diagnosis has
been made.
(b) Unexpected Death. The diagnosis is established, and
perhaps an operation successfully performed, but the
patient dies, perhaps from an embolus or a myocardial
infarction.
(c) Expected Death, but cause unknown as in disseminated
malignancy with an unknown primary.
(d) Something went wrong. An operation appears satisfac-
tory but complications such as septicaemia, fistula forma-
tion or undisclosed sepsis such as subphrenic abscess, lead
to death.
(e) Teaching. There are lessons to be learned by students
in comparing the pathology with the results of pre-
mortem investigations such as X-rays, CAT scans, etc.
(f) Research. It may be valuable to study the effect (or
lack) of treatment, as in the case of treatment of malig-
nancy by cytotoxic drugs.
The attitudes of staff to autopsy can be determined by
their response to the question: 'How often is an autopsy
helpful?' and by grading the answers into 'usually',
'sometimes' and 'seldom'. Table 1 provides responses
Table 1. Responses from different grades of staff from a
number of professorial surgical units in the UK to the question:
'How useful is an autopsy?'.
No. Usually Sometimes Seldom
participating No. % No. % No. %
Prof./Reader 27 18 66 6 22 3 11
Sen. Lecturer 28 15 53 10 36 3 11
Lecturer 19 12 63 4 21 3 16
Registrar 29 14 48 8 27 7 24
SHO 16 10 62 4 25 2 12
Houseman 19 10 52 8 42 1 5
Total 138 79 57 40 29 19 14
from different grades of staff in professorial surgical units.
All responses are qualified by the fact that selection of
autopsy is the mode. Even so, enthusiasm is muted,
though reasonably consistent in the different grades.
Under 'seldom', registrars appear more cynical than
others. Such a survey does little more than provide a
general guide to the approach to asking permission for an
autopsy. The timing of the approach, the seniority of the
staff member, and the particular circumstances of the
patient all have a bearing on the response. However, in
answer to the question: 'How often do you obtain
permission for an autopsy when the professor says "We
72 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
must'", the answer was 'Almost always'. This seems to
indicate that success in obtaining permission is deter-
mined by attitudes of the senior staff.
The number of deaths in the Professorial Surgical Unit
at University College Hospital is recorded in Table 2.
Table 2. Number of autopsies performed on patients dying ir
Surgical Unit, UCH, in 1983.
Deaths Autopsies
Cancer of stomach 10
Cancer of pancreas
Non-malignant
9 2
1
Colo-rectal cancer '
Other cancer 10
10 7
rZr 49 19(39%)
Though classed as a general surgical unit, the bulk of the
work is gastroenterological, with breast disease as the
only other major component of the routine work. It is
important to note that the unit maintains a policy of
admitting patients with recurrent cancer when it is no
longer possible for them to be cared for adequately at
home. This may partly account for the fact that, of 49
patients dying, only 19 came to autopsy, though it should
also be noted that there were 36 patients who died of
malignant disease. Table 3 subdivides the patients into
Table 3. Department of Surgery, University College, Autop-
sies, 1983. CA = cancer. TUR = transurethal resection of pros-
tate. PE = pulmonary embolism.
Medico-Legal (Coroner)?3
Assault
Anaesthetic (CA breast)
Multiple injury
Unexplained Hospital Deaths?
No Diagnosis
Myocardial infarct
Myocardial infarct
Perforated CA stomach
Expected deaths?8
Unknown Primary
CA Bronchus
CA Bronchus
CA Pancreas
CA Kidney
A utopsy Refused?4
Unexplained
Post-op. rectal prolapse
Post-op. TUR (myeloma)
Post-op Deaths (Pre-mortem diagnosis)
Myocardial infarct
Pulmonary embolus
Faecal peritonitis (obstruction)
Faecal peritonitis (resection)
Mesenteric infarction (pancreas)
Unusual Diagnosis
Retroperitoneal sarcoma?PE
Leiomyosarcoma
Squamous CA chest wall
Sup. mes. artery thrombosis
Expected
Primary unknown
Primary unknown
unexplained deaths and those in which the disease was
known and death was expected, but the case was such that
it was hoped to gain further information. The infor-
mation which is difficult to provide is: 'How helpful was
the autopsy to the understanding of the problem?', and
such information, being generally subjective, will be
regarded differently by different members of staff. Table
4 shows requests for autopsy, and the number of autop-
sies actually performed. Permission was refused in 35 per
cent.
Table 4. Request for autopsy and number carried out.
Request for Autopsy
Unknown primary
Death within one month
of surgery
Coroner
Unexpected death or no
diagnosis
More information
Total
No. Autopsies Performed
6 4
8 6
3 3
7 3
5 3
29 19
It is possible that the need for students to see the
ravages of disseminated disease have not been suitably
catered for. The alterations to the curriculum are such
that students spend much less time than in the past on
individual firms, and probably less time on clinical work.
Surgical students in particular may be less available to
attend the autopsy because of other commitments. The
timetable is far too crowded, and the only solution
appears to be to arrange for the autopsy to take place at
some time when nothing else is programmed, which is
usually in the lunch hour.
The value of the autopsy is not in doubt. Evidence that
the pre-mortem diagnosis is incorrect occurs sufficiently
often to warrant autopsy in almost every situation.
However, the negative value has not been accurately
assessed, and there is little doubt that surgeons, with their
'preview' of the situation, feel that there is little more to
be learned in many patients, particuarly those with
disseminated cancer. Unfortunately, this view may well
deny the students the salutary lesson of seeing the ravages
of cancer.
It seems likely that the only way to ensure that there are
adequate autopsies for the teaching and training of
pathologists is by personal liaison between the surgeons
and the pathologists. Many already have such a liaison,
particularly those with a special interest such as gastro-
enterology where good practice usually means a regular
weekly meeting to discuss biopsy material. However, this
regular meeting may be the only occasion on which
surgeons and pathologists meet, and there is room for a
meeting in the autopsy room on occasions.
This article is based on a paper read at the Conference on
Death Certification and the Autopsy held at the Royal College of
Physicians in May 1984.
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 73
|
PMC005xxxxxx/PMC5371003.txt | Organising a Clinical Examination [
JOSEPH PANG, MB, MRCP(UK), Lecturer, Department of Medicine, The Chinese
University of Hong Kong
Clinical examinations are an important part of under-
graduate and postgraduate medicine. Not only do trivial
things like the future careers of medical students and
junior doctors depend on them, but they also give
examiners a chance to meet old friends, make new
acquaintances, settle old scores and keep abreast of recent
advances. A clinical examination is therefore a double-
edged weapon. If it is well organised, it brings immeasur-
able prestige to the department as a whole and to the host
examiner in particular. On the other hand, if it is chaotic,
those responsible may become a laughing stock. Crafty
host examiners would of course ensure that they take the
credit if things go well, and that their minions take the
blame if things do not. It was said that if the New York
Yacht Club ever lost the Americas Cup, the skipper's
head would replace the trophy on its stand. As it turned
out, this did not quite happen, and in any case, the
medical profession is far more tolerant of failure than the
N.Y.Y.C. Nevertheless, it would not be surprising if the
culprits who made a mess of organising a clinical examin-
ation were required to relinquish less important parts of
their anatomy. These would then be preserved in pots in
the anatomy museum and exhibited as warnings to their
successors. The fate of the remnants of these culprits is
often unknown; rumours suggest that they end their
remaining days in disgrace somewhere in outer Mongolia
or the steppes of Russia.
I had the privilege (misfortune) of being asked (or-
dered) to organise two clinical examinations?one for the
MRCP(UK) and one for the University of London's
Final MB. Lady Luck smiled on me on both occasions: I
survived and emerged physically, if not psychologically,
intact. It is to those future gladiators who will be asked
(ordered) to organise clinical examinations, and to the
consumers of these commodities that I dedicate the
following 'rules' of survival.
Preliminaries
Get a good secretary. A good secretary is the key to
success. If necessary, beg, borrow or steal one who has
previous experience and is mad enough to want to do it
again. She should be efficient, highly organised, hard
working, charming and understanding, especially when
your wife/husband starts complaining that you are spend-
ing all your evenings with her, and preferably a good cook
(the reasons for this will be apparent later). Under no
circumstances must she fall ill before the examination is
over.
Get a good nurse. A good sister is almost as important
as a good secretary, since she will be the one who
organises the examination area and makes sure that all
the necessary equipment is assembled.
Negotiate for time off clinical duties before the examin-
ation.
Find a suitable area for the examination. The best
place is usually a large, well-lit ward, ideally with:
1. Sufficient cubicles where pairs of examiners can grill
their victims without disturbance. Examiners function in
pairs, not to intimidate, but to observe each other in
order to be fairer to the candidates. Also, it is less likely
that both of them will fall asleep at the same time.
2. Several 'bays' of 6-8 beds each, with curtains, for
patients who need to undress.
3. A large sitting area for patients who do not need to
undress. They are usually used as 'short cases'.
4. A room which can be darkened so that a patient's fundi
can be examined to best advantage. The alternative of
dilating the pupil with topical drugs is not suitable for
some patients.
5. An examination room for urine testing.
6. Nearby toilets for all those under stress.
7. A relatively secluded waiting area for candidates.
Finally, a sketch map of the examination area, com-
plete with bed numbers and chair numbers, is invaluable.
About Eight Weeks before the Examination
This is the time when the real work begins, namely, the
selection of suitable cases. For medicine, there appear to
be three modern trends in clinical examinations:
1. Recently admitted patients, who can be used to test the
candidate's ability to evaluate and manage their various
medical problems, are preferred.
2. Patients with exotic diseases who have been used for
examinations from time immemorial ('museum' cases)
are to be avoided.
3. Candidates will be examined on all major systems of
the body, without reduplication. For example, if someone
had a neurological 'long case', he would be taken to
patients with diseases in systems other than the CNS in
the 'short cases'.
Invariably, these trends will have a critical influence on
patient selection. My personal 'rules', therefore, are:
Try to get an optimum mixture of 'cold' and 'hot'
cases. I think their ideal ratio is about 7:3. 'Cold' cases
include those 'old faithfuls' who are frequently used for
examinations and teaching (most examination-orientated
hospitals have lists of these) and, better still, new unused
patients who are in the wards several weeks before the
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 93
examination. The latter should be approached before
they are discharged, and arrangements made for them to
return on the required day(s). 'Hot' cases are those
recently admitted patients who are still in hospital during
the examination. They have the advantage of being on
site so that outside transport arrangements are unneces-
sary. However, by definition, most cannot be approached
until very near the examination, so there is always a risk
of not getting enough patients, or too many with diseases
of one system and not enough with diseases of another. A
further drawback, perhaps the real one if the truth be
known, is that it is exceedingly hard work for both the
organiser and the secretary to find these patients and
prepare case summaries at the busiest time on the eve of
the examination.
Aim for a balanced group of patients, (a) There should
be enough patients with diseases in each major system,
(b) There should be enough patients for the 'long case'
and the 'short case' parts of the examination. Some
patients are suitable both as a long case and a short case.
They are ideal because administration, cost and total
patient number can be kept down, (c) Despite the direc-
tive on 'museum' cases, it is wise to include one or two.
Host examiners can be most upset if their favourite
neurosyphilitic is consistently left out, and indeed, the
loyal patient can also be displeased if he is no longer
invited. You may think that the latter does not matter,
but you are wrong because he will surely complain
bitterly to your boss the next time he is seen in out-
patients.
Enlist the help of colleagues. Sending them written
requests for suitable patients may help, but tends to be
less effective than cornering them and asking them face to
face who they have on the wards at the moment.
Approach suitable patients for consent with care. Most
patients are reasonable and will agree if they are asked
tactfully. Some may refuse because they live far away or
have other commitments. On the whole, it is probably
better not to pressurise reluctant patients because they
may agree under duress and then simply not turn up on
the day.
Prepare brief case summaries, including only the most
relevant points. Long discourses waste time and will not
be read by the examiners. Needless to say, it is important
to check the patient's history and signs before preparing
the case summary. A pocket size tape recorder is very
useful for on-the-spot dictation, thus saving removing the
notes and X-rays from the ward to the secretary's office.
Organise the most reliable means of transport for out-
patients. Some patients can come on their own, but others
require transport. If hired cars need to be used, choose a
reliable firm since punctuality is vital. Patients living near
one another can come (and leave) in the same car, but
allow plenty of time for delays.
Two Weeks before the Examination
The activities mentioned above intensify during this
critical period. In addition, the all-important task of
allocating long cases can now begin. Short cases do not
need to be assigned. The following rules are helpful.
Always use in-patients as long cases at the beginning of
each day because they are not dependent on outside
transport.
All out-patients should be asked to arrive well before
the start of the examination, but they should be allocated
as long cases later in the day. The reason for this is that
even if they come late, or do not arrive at all, there will
still be time to find replacements.
Take into account patients' personalities as far as rj
possible. Human nature being what it is, allowances
should be made for patients' prejudices. For example, it is *?
obviously inappropriate to assign a patient who is a
known male chauvinist pig to the secretary of the local
women's liberation society. It is surprising how much you *
do know about the candidates, some of whom will have
worked with you.
Ask the host examiners' advice on case allocation.
Their opinion is often very helpful. In addition, most of
them do not want to do more work than necessary (and
getting to know several brand new long cases each day is
hard work), so they may prefer to be given some of their
favourite patients whom they know inside out.
Always aim to have a few spare patients each day.
Liaise with the hospital porters and all relevant depart- ...
ments. Porters always know what goes on (often before
you do), but details like when their services will be
particularly required, positioning of signposts and so on, t
need to be discussed with them. Hospital administrators
also need to know, but, unlike porters, some of them do
not know what goes on even though you have written to
them several weeks ago. Perhaps it is the timing; if you *
tell them too early, no one will pay any attention; if you
tell them too late (like two weeks before the examination),
your memo will not be read until the pass list has been i
published.
A Day or Two before the Examination
1. Finalise patient lists, allocation lists and transport lists.
2. Check on all the arrangements that have been made.
3. Assemble files for the examiners, which should include
a map of the examination area with numbered beds and ,
chairs, list of candidates, list of allocated long cases and
summaries of all patients.
4. Work out a timetable for the examination. Sometimes,
one will be provided by the examining body. Basically,
this is a list of times when certain activities need to be
performed. These include introducing the candidates to
their long cases, bringing them to the examiners, change-
over from long to short cases or vivas, serving coffee
during breaks and so on. It is very important, because
time-keeping is vital to the smooth running of a clinical
examination.
On the Days of the Examination r
This period is like what is sometimes said of giving
anaesthetics?mostly boredom punctuated by spells of
blind panic. The major problem occurs when out-patients
cannot come or cannot arrive on time for one reason or
another. Most responsible patients will ring up the secre-
94 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
tary, who would have established a hot line just for this
purpose. Sometimes the problem can be solved but on
other occasions it may be necessary to switch patients
round or use spare cases. Rarely, even the best laid plans
can go astray: this happened when a clinical examination
organised by one of my colleagues coincided with a public
transport strike so that many patients and candidates
found it impossible to be punctual. The chaos that existed
before God created the universe was nothing compared to
what ensued. Somehow, to their great credit, things were
sorted out without too much delay. My colleague gained
much respect, and it s now rumoured that he is practising
walking on water with some success.
Still, there are several rules to be observed.
1. Introduce each pair of examiners to their long cases
before the examination starts. They are expected to
familiarise themselves with these patients, and a few
words about any potential problems the candidates may
have with them can be very helpful.
2. Try to put the candidates at ease. Anyone who has
gone through the rigours of a clinical examination will
undoubtedly have a lot of sympathy for them. However,
it is sound to advise them not to discuss patients they have
seen with their colleagues. To do so is unhelpful and can
be fatally misleading. Examiners detect such exchanges
very easily, and many have remarked how successive
candidates make identical mistakes on the same patients,
or worse still, find the 'correct' signs on the wrong patient
while acting on a tip from their predecessors.
3. Keep time strictly. Examiners and candidates must be
reminded of their allotted time. Some examiners invari-
ably go on longer than they should, and sometimes this
will delay the whole examination. All one can do is to try
hard to prevent this.
4. Direct examiners towards little-used short cases. It is
almost unavoidable that some short cases are much more
popular than others. This tends to tire out some patients,
and makes others feel totally unloved.
5. Be ready to respond promptly to examiners' and
candidates' requests. Candidates usually want to borrow
equipment. Requests from examiners are more unpre-
dictable. Some examples are: help to find missing specta-
cles/stethoscopes, to leave messages for wives/husbands/
secretaries, to confirm signs that you have missed in some
patients and to arrange for a call from America to be
received during the coffee break. (Those who wish to
practise one-upmanship please note.) Sometimes you will
need to be in three places at once, but by now this should
be no problem.
6. Keep an eye on valuable pocket-size equipment. Many
ophthalmoscopes have been unintentionally removed by
shell-shocked candidates at the end of their ordeal so that
they are unavailable for later use.
7. Thank the patients before they leave, and remind those
who have been asked to come on another day when they
are required again.
Conclusions
At the end of it all, organising a clinical examination is
not as bad as it sounds. It often gives amusing moments.
Two incidents stand out in my memory. In one, I mixed
up the case summaries of two patients with identical
names, and neither I nor the examiners detected this
before the examination started. To their credit, they kept
a straight face when the candidate presented a totally
different history from the one in the case summary. They
then examined the patient, agreed with what the candi-
date found, and took great delight in pointing out my
blunder to me. In another, when I went round to thank
the patients, I found one of them sweaty, pale and talking
nonsense. Intravenous dextrose cured his hypoglycaemia,
but it was difficult to tell how long he had been in that
state. Neither the candidates nor the long case examiners
(one of whom was a diabetician) had noticed anything
amiss, so one must presume that the patient became
symptomatically hypoglycaemic after they had seen
him?or can one?
In both the examinations I helped to organise, I was
extremely fortunate to have an excellent secretary. There
were many occasions when I was saved from a fate worse
than death by her foresight and organisation. In addition,
she provided all the examiners and staff with fresh ground
coffee and a different snack every single day, culminating
in a farewell tea on the final day which was a gastronomic
tour de force. She is now well-known in the marble
corridors of the hallowed halls. Without her, I would not
have survived to tell this tale.
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 95
|
PMC005xxxxxx/PMC5371004.txt | Editorial
'How bad is it, doctor?' can be a difficult question to answer. We are
all used to the question and tend to accept that we share the patient's
concept of badness. But, of course, the concept is too all-embracing to
assume agreement. Badness goes from immediate threat to life down
to transient discomfort; it ranges through the odds on permanent
disability to loss of a job and distress of relatives. It is easy to see that a
first epileptic fit will cost a lorry driver his job but will not affect a
clerk's income, or that the private hell of schizophrenia encompasses
the patient and those who love him. The usual situation is not so
clear-cut and our answers tend to combine a good guess with
encouragement. We sometimes over-stress the bad to get the patient
to accept an unpleasant treatment. Not to be recommended was the
ploy of a surgeon long ago who told every patient with a broken wrist
that it was the worst fracture he had ever seen; any restoration of
function was received with thanks.
For some diseases we do have a rational scale of severity. The
histological staging of cancers enables us to give informed answers on
threat to life and hazards of necessary treatment. We lack such a scale
for the less dire illness. In this issue of the Journal Professor Lambert
points this out most clearly for whooping cough and shows how he has
devised methods to construct an objective scale of distress. This is
better than the doctor having to wait until his own children are
afflicted before he realises what this infection is all about. We could
certainly be helped by more research of this nature in order to build
up an all-round view of what is faced by the patient and his relatives.
It is indeed very difficult to quantitate the effect of an illness on an
individual. Come to think of it, even our vital statistics have to be
crude. The epidemiological criteria of health are based on death,
which is inevitable. Translation of death rates into tables of life
expectancy puts a term to death postponed but adds no hint of
medical expectations for that slice of life. Maybe that is far enough on
safe ground, for we are not in the business of prophecy. But we are in
the difficult position of presenting to people their most probable
medical future. No patient can give informed consent to treatment
unless adequate information has been supplied. Here we are back to
the currently popular concept of perceived risk. At the moment the
perception of any risk to health seems to be dominated by pronounce-
ments in the media. Accurate assessment is not so publicised. While
some wish to decide for themselves on the data presented to them and
others still wish to do what the doctor suggests because they feel the
expert is primarily concerned with doing his best for them, the only
basis for progress is in real knowledge. In these days of retrenchment
most of us are involved in making out the strongest case for
preserving and extending facilities. This is a poor climate in which to
collect objective scientific facts to illuminate the emotive field of
badness in illness. But we need the facts for our decisions and to help
the patient decide.
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
|
PMC005xxxxxx/PMC5371005.txt | Cimetidine in the Treatment of Herpes Zoster
D. W. LEVX MB, FRCR Consultant Physician
A. K. BANERJEE, MB, FRCP! Consultant Physician
Department of Medicine for the Elderly, Bolton General Hospital
HELEN R GLENNy PhD, Clinical Research Scientist
Smith Kline and French Research Ltd, The Frythe, Welwyn, Herts
Herpes zoster can be a distressing event in the elderly,
causing confusion and distress in the acute phase and
incapacitating post-herpetic neuralgia in a high percent-
age of cases[l].
The preliminary observations of Van der Spuy et al. [2]
suggested that cimetidine may have a beneficial effect in
several herpes virus infections, including herpes zoster.
In an uncontrolled open assessment of one patient,
cimetidine relieved the pain and shortened the course of
herpes zoster. A subsequent uncontrolled trial of cimeti-
dine in 21 patients with herpes zoster produced encourag-
ing results in all but three patients.
More recently, Mavligit and Talpaz[3] reported that
cimetidine 300 mg q.d.s. for seven days produced a rapid
improvement in the pain and pruritus of herpes zoster in
four cancer patients whose immune systems were pro-
foundly suppressed.
Herpes zoster is thought to be associated with a state of
depressed cellular immune function[4]. It is theoretically
possible for H2 receptor antagonists such as cimetidine to
modify cell-mediated immune responses since thymus
dependent T-lymphocytes have been shown to possess H2
receptors[5-7]. In addition to a possible direct anti-viral
effect[2], cimetidine may augment the immune defences
of the body which produce early control of the herpes
zoster virus.
The present trial, more extensive than that of Van der
Spuy et al. [2], was designed to establish whether cimeti-
dine was effective in the treatment of herpes zoster. Since
herpes zoster has a variable and unpredictable natural
history, it was necessary for this study to be placebo
controlled.
Patients
Sixty-three patients aged 27 to 92 years (mean 66.4 years)
with herpes zoster, suitable to be treated as out-patients,
entered the study. Of these patients 41 were female (mean
age 67 years) and 22 were male (mean age 65 years).
Local general practitioners and other hospitals in the
Bolton area co-operated in recruiting suitable patients.
Patients with herpes who had involvement of the ophthal-
mic division of the trigeminal nerve were not included in
the study.
Patients with herpetic infections other than herpes
zoster and those who had received cimetidine treatment
for other diseases within the past month were excluded
from the study, as were patients receiving specific anti-
herpetic medications; calamine lotions (for local relief of
discomfort) and analgesics such as aspirin and paraceta-
mol were permitted. Pregnant or lactating patients,
patients with severe renal impairment and those receiving
oral anticoagulant therapy were also excluded from entry.
Methods
The study was conducted in accordance with the Declara-
tion of Helsinki. The nature of the trial was fully ex-
plained to all patients before entry and their consent
obtained. All patients were informed of their right to
withdraw from the study at any time. The permission of
the hospital ethical committee was obtained and the
patients' general practitioners were informed by the
investigator.
The diagnosis of herpes zoster was made entirely on
clinical grounds. The infection was identified by the
presence of erythema and/or vesicles corresponding to the
unilateral distribution of a sensory nerve. In most
patients, pain was experienced at the affected area. In
those patients in whom herpes zoster was diagnosed on
the basis of erythema and pain, vesicles subsequently
developed within 48 hours of entry to the trial.
Patients were seen at the earliest possible stage of
infection. At the initial visit the distribution, site and
stage of the lesions and presence or absence of pain were
recorded. Any medications for concomitant disease were
noted. Patients were then randomly allocated in a double-
blind manner to treatment with either cimetidine 200 mg
t.i.d. and 400 mg nocte, or matching placebo tablets.
Treatment continued for 28 days.
Patients were reviewed daily for the first two days and
again at one and four weeks. At each review the distribu-
tion, site and stage of the lesions and presence or absence
of pain were recorded as for the initial visit. The presence
and distribution of any new lesions were also recorded. At
the two and four week visits the presence or absence of
complications was noted. At three months and six
months, patients were assessed for development of com-
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
plications including post-herpetic neuralgia (defined as
pain which outlasts the lesions by more than one month).
During the treatment period patients were requested to
complete diary cards daily to record the presence or
absence of pain and its duration.
Statistical Analysis
Demographic parameters (the number of days lesions and
pain were present before the start of the trial) were
compared between the two treatment groups using the
Wilcoxon two sample rank-sum test. A chi-squared test
was used to compare the incidence of healing of lesions
and pain after one month of treatment. Two-tailed tests
were used throughout.
Results
Forty-nine patients completed the one month's treatment
period as planned; 24 of these patients (18 women, 6
men; mean age 65 years) received cimetidine and 25
patients (13 women, 12 men; mean age 63 years) received
placebo treatment. Fourteen of the 63 patients who
entered the study were excluded or withdrawn before
completion of the treatment period. The reasons for
patient withdrawal/exclusion were as follows: default (5
patients); ophthalmic herpes (5 patients); death which
was unrelated to treatment (2 patients); inadequate re-
cords (2 patients).
The two treatment groups were comparable with re-
spect to the duration of signs of infection (lesions and
pain) before the start of the trial. The median number of
days vesicles were present in the cimetidine group was
three (1-7), compared to two (range 0.5-6) in the placebo
group. The median number of days of pain before the
trial in the cimetidine group was three (range 0.5-14),
compared to five (range 0-12) in the placebo group. The
stage of the lesions in the two treatment groups was
roughly comparable at the start of the trial.
Efficacy of the treatments was compared by examining
the incidence of healing of the vesicles and the incidence
of pain at the end of the one month treatment period
(Table 1).
Table 1. Efficacy of treatments compared by examining inci-
dence of healing of vesicles and incidence of pain after 28 days'
treatment. H = 100% healed. N = not healed. P = present.
A = absent.
Cimetidine Placebo
Healing of lesions at Day 14 6H, 18N 6H, 19N
Day 28 18H, 6N 24H, IN
Pain at Day 28 6A, 18P 15A, 10P
Incidence of post-herpetic neuralgia at
Month 3 12A, IIP 17A, 8P
Month 6 16A, 9P 20A, 5P
No statistically significant difference between the ef-
fects of the two treatments on healing of vesicles was seen.
Eighteen out of 24 (67 per cent) healed in the cimetidine
group compared with 24 out of 25 (96 per cent) in the
placebo group (0.05 < P< 0.1, in favour of placebo). A
statistically significant (/3<0.05) difference between the
incidence of pain after one month of treatment was found.
A higher proportion of patients in the placebo group (15
out of 25, or 60 per cent) experienced no pain, compared
with the cimetidine group (6 out of 24, or 25 per cent).
There was no statistically significant difference be-
tween the two treatment groups with respect to the
incidence of post-herpetic neuralgia at 3 months and 6
months (Table 1). No clinically significant untoward
events related to cimetidine therapy were reported by any
patient.
Discussion
There is no evidence from the study data that cimetidine
relieves the pain or accelerates the rate of healing of
lesions in herpes zoster. This conclusion does not support
the clinical observations of Van der Spuy et al. [2] and
Hayne and Mercer[8], It is possible, though unlikely,
that the dosage of cimetidine (1.0 g/day) used in the
present study was not sufficient. Van der Spuy et al. [2]
reported that relief of pain was the main criterion for
judging the success of treatment of herpes zoster with
cimetidine (1.6 g/day for the first two days, followed by
1.0 g/day for five days). In our study only the incidence of
pain at the beginning and end of treatment was examined
statistically. It was not possible to compare the effects of
cimetidine and placebo on the relief of pain throughout
the period of treatment as only some of the patients
completed the diary cards with a record of pain they had
experienced.
Hayne and Mercer[8] claimed that cimetidine (1.8 g/
day for 8| days) accelerated the rate of healing of lesions
of one patient with herpes zoster, on the basis that the
duration of the disease can be predicted from the length of
time it takes for all the vesicles to erupt[9]. From our data
it was impossible to determine the precise time taken for
all the vesicles to erupt and therefore to predict the
duration of the active phase for each patient. Neither
could any effect of treatment on the duration of the active
phase be assessed, since the time course of healing of the
vesicles after they had crusted was recorded only at days
7,14 and 28 of treatment and was not monitored between
these visits. However, as there was no statistically signifi-
cant difference between the two treatments given with
regard to the number of patients with lesions which were
healed, it is unlikely that cimetidine affected the rate of
healing of the vesicles.
The discouraging outcome of this large controlled trial,
unlike that of previous, smaller, uncontrolled tri-
als[2,3,8], suggests that further trials of cimetidine in
herpes zoster would not be worthwhile.
Acknowledgements
We are grateful to Caroline Franks and Elisabeth Else for
performing the statistical analyses. This study was sup-
ported in part by funds from Smith Kline & French
Research Ltd.
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 97
References
1. de Moregas, J. M. and Kierland, R. R. (1957) American Medical
Association Archives of Dermatology, 75, 193.
2. Van der Spuy, S., Levy, D. W. and Levin, W. (1980) South African
Medical Journal, 58, 112.
3. Mavligit, G. M. and Talpaz, M. (1984) New England Journal of
Medicine, 310, 318.
4. Rand, K. H., Rasmussen, L. E., Pollard, R. B. et al. (1976) New
England Journal of Medicine, 296, 1372.
5. Plant, M., Lichtenstein, L. M., Gillespie, E. et al. (1973) Journal of
Immunology, 111, 389.
6. Plant, M., Lichtenstein, L. M. and Henney, C. S. (1975) Journal
of Clinical Investigation, 55, 856.
7. Rocklin, R. E. (1976) Journal of Clinical Investigation, 57, 1051.
8. Hayne, M. S. T. and Mercer, J. B. (1983) Canadian Medical
Association Journal, 129, 1284.
9. Burgoon, C. F. Jr., Burgoon, J. S. and Baldridge, G. D. (1957)
Journal of the American Medical Association, 164, 265.
Harveian Memorials
It must have been a long day's pilgrimage to rural Essex
on St Luke's Day, 1883. On that day at Hempstead
church the remains of William Harvey, lapt in lead, were
transferred to a new sarcophagus inscribed 'The remains
of William Harvey, discoverer of the circulation of the
blood, were reverentially placed in this sarcophagus by
the Royal College of Physicians of London in the year
1883'. Preceded by the vicar of Hempstead, the Rev. Mr
Eustace, and his curate, the sarcophagus was borne into
the church by Fellows of the College, followed by four
members of the Harvey family, the President of the
College, Sir William Jenner, robed and carrying the
caduceus, and then the College officers, gowned, with
Fellows of the College bringing up the rear. The proces-
sion went into the Harvey chapel to lay the sarcophagus
on its final resting place. After a short service, with
hymns sung by the village choir, the President placed in
the sarcophagus a bound copy of Harvey's works sealed
in a metal box and a scroll describing the event and
lauding Harvey as a munificent benefactor of the College.
The College had been concerned with the state of
Harvey's remains since the first report in 1847 that the
lead coffin was damaged. In 1859 a deputation from the
College found the coffin was half full of water and further
damage was reported in 1878. On 28th January 1882 the
tower of Hempstead church and part of the nave col-
lapsed, causing further damage. The College forthwith
appointed a committee to consider the matter. They
rejected a suggestion that Harvey's remains should be
reinterred in Westminster Abbey to join such distin-
guished Fellows as Thomas Willis, Richard Mead and
Thomas Young, and suggested the ordering of an appro-
priate sarcophagus which was purchased for ?155. As a
matter of history the church at Hempstead was not fully
repaired until 1961, the work being aided by substantial
sums from the William Harvey Memorial Fund and the
Harveian Society of London. The choice of St Luke's
Day for the 1883 reinterment was made because for many
years that had been the day for the Harveian Oration.
Indeed the July Comitia in 1884 resolved that the Oration
should henceforth be given on St Luke's Day.
The Harveian Oration and Dinner was, of course,
instituted by Harvey. Old, infirm, rich and childless, he
considered how he could benefit the College. He was the
'anonymous' donor of a library building and, after its
ceremonial opening in 1656, the College elected Harvey
as President. This offer was received and declined with
perfect dignity and with the recommendation that Dr
Prujean should continue as President; a recommendation
speedily accepted. By an indenture of 21st June 1656,
Harvey transferred his patrimonial estate at Burmarsh,
Kent, to the College. From the proceeds of this he asked
that the College, 'to maintain friendship', should at
'every meeting once a month' prepare a 'small collation'
and that 'once every year' there should be 'a general feast
for all the Fellows'. The idea of the feast comes before the
Oration, as he laid down that 'on the day when such a
feast be kept . . . some one person of the said College
shall make an oration in Latin publicly'. He exhorted the
orator to commemorate the College's benefactors and
encourage others to follow their example and he also
exhorted 'Fellows and Members to search and study out
the secrets of nature by way of experiment'.
The first Harveian Oration was given in July 1656,
only a month after Harvey's gift, by Dr Edward Emily, a
physician to St Thomas's Hospital. This proved a disas-
ter. In Comitia of 28th July 1656, Dr Emily 'was accused
of having declaimed more bitterly than was proper
against military matters, and also of disparaging the
present rule of the Commonwealth'. Dr Emily affirmed
that 'he had said nothing in a bad spirit'. However,
Comitia decided that in future no such oration should be
given in the College unless the President and Censors had
read and approved the text one month before the oration
was due to be given.
The College was anxious to remain on good terms with
Cromwell's major-generals so the decision to let Emily go
without rebuke but to introduce censorship of future
orations must have been thought sufficient to ward off
official displeasure. What remains puzzling is the choice
of Dr Emily as the first Harveian Orator. At the start of
the Civil War Emily had hinted in a letter that he sided
with the Parliamentarians, so his oration suggests that he
had become disillusioned by that cause. Emily's career
showed no distinction and any promise of achievement
went unfulfilled, as he died in November 1657.
98 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
|
PMC005xxxxxx/PMC5371006.txt | Ulcerative Colitis in a North Indian Hospital:
Current Trends
M. E SHARMA, MD, Assistant Professor
S. K. SARIN, MD, Lecturer
Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
Owing to the frequency and chronic nature of the disease,
its propensity for complications and the need for institu-
tionalised specialty care, there has been extensive re-
search in the field of ulcerative colitis in the Westfl].
Ulcerative colitis is, however, not uncommon in In-
f dia[ 2 ]; there have been a number of reports in the past
two decades[2-7], Most of them were based on observa-
tions made on a limited number of patients and are
therefore conflicting. The true incidence and clinical
picture of ulcerative colitis in Indian patients is still not
clear. Subtle differences have been suggested between
patients with ulcerative colitis seen in India and those
seen in the West[3,4], This article attempts to highlight
the incidence, clinical features and complications based
on our experience of observing 218 patients with ulcer-
ative colitis in the apex referral hospital of India. A
comparison with disease trends as reported from the West
is made.
Materials and Methods
This retrospective study includes 218 consecutive patients
with ulcerative colitis seen at the Gastroenterology Ser-
vices of the All India Institute of Medical Sciences
(AIIMS), New Delhi, between 1972 and 1981. The
diagnosis of ulcerative colitis was made on the basis of (a)
a history of chronic diarrhoea, with passage of blood and
mucus, uncontrolled by adequate anti-bacterial and anti-
amoebic treatment, together with (b) negative results
from two fresh stools examined for parasites, and sigmoi-
doscopic findings of congestion, oedema, ulceration,
granularity and fragility of the mucosa[8]. The patients
were grouped into mild, moderate and severe disease
according to standard criteria[9].
In every patient a thorough clinical evaluation and
routine investigations like haemogram, stool for tropho-
zoites and cysts, and sigmoidoscopic examination were
carried out. In a majority of the patients a plain X-ray of
the abdomen, barium enema, amoebic serology, liver
function tests and rectal biopsy were also carried out.
Results
There were 136 males and 82 females, a ratio of 1.6:1. Of
the patients, 172 (89 per cent) were between 16 and 45
years of age. Disease was rare below 15 (4 per cent) and
above 60 (3 per cent) years of age. The mean age was 33.1
years (Table 1). There were 27 patients (12.4 per cent)
with mild, 144 (66.1 per cent) with moderate and 47 (21.5
per cent) with severe ulcerative colitis (Table 2).
Table 1. Age and sex distribution of ulcerative colitis in 218
patients.
Age (years) Male Female
0-15 6 2
16-30 65 37
31-45 37 33
46-60 22 10
61-75 6 ?
>75 ? ?
136
82
Table 2. Duration of the presenting episode
Duration Mild Moderate Severe
0-1 yr?
0-6 mth 7 88 32
7-12 mth 6 33 11
1-2 yr 8 12 4
2-3 yr 4 8?
3-4 yr 1 1 ?
>4 yr 1 2 ?
Total patients 27 144 47
The total duration of the illness varied from three days
to 25 years. While 49 per cent of the severe ulcerative
colitis patients had the illness for less than one year, 85
per cent of the moderate and 81 per cent of the mild
ulcerative colitis had the disease for more than one year
(Table 3).
Sixty-four patients (29 per cent) presented with their
first attack of ulcerative colitis. The remainder (154
patients) had a variable number of relapses during the
course of their disease (Table 4).
The most important presenting complaint was the
history of passage of blood mixed with stools which was
seen in 98 per cent of the patients. In 94 per cent the
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 99
Table 3. Total duration of ulcerative colitis.
Period (years) Mild Moderate Severe
< 1 5 22 23
1-4 5 67 8
5-8 8 33 6
9-12 6 11 6
13-16 1 6 4
17-20 2 4 ?
>20 ? 1 ?
Total patients 27 144 47
Table 4. Number of relapses experienced by patients with
ulcerative colitis.
No. of relapses No. of patients %
1 37 17
2 35 16
3 40 19
4 12 6
5 13 6
6 5 2
7 3 1
>7 9 4
stools were loose and frequent. Nocturnal frequency was
recorded in 78 per cent. The onset of the illness was mild
to moderate in most of these patients. Abdominal pain
was present in 53 per cent; it was usually periumbilical or
diffuse in distribution and mild to moderate in intensity.
Significant weight loss was complained of by 35 per cent
of the patients (Table 5).
Table 5. Clinical features.
Symptoms Mild Moderate Severe Total patients %
Blood in stool 26 144 46 214 98
Mucus in stool 26 144 46 214 98
Loose motions 24 135 46 205 94
Increased frequency 24 135 46 205 94
Abdominal pain 9 82 25 116 53
Fever 1 30 9 40 18
Pallor 3 59 27 89 41
Weight loss 2 55 17 75 35
Pedal oedema ? 14 10 24 11
Hepatomegaly ? 22 6 28 13
Splenomegaly ? 5 ? 5 2
Abdominal tenderness ? 18 9 4
Lump in abdomen ? 22 ? 2 1
Physical examination was generally unremarkable.
Pallor and pedal oedema were recorded in 41 per cent and
11 per cent of the patients respectively. Hepatomegaly
was found in 13 per cent. It was generally minimal and
firm, with round edges. Both hepatomegaly and pedal
oedema were more common in patients with moderate
and severe disease. While mild abdominal tenderness was
present in most of the patients, significant tenderness was
present in only 4 per cent (Table 5).
Important systemic complications of ulcerative colitis
were seen in seven patients (3 per cent) and included
polyarthralgia in five (2 per cent), ankylosing spondylitis
(HLA-B-27 positive) in one and monoplegia of the upper
arm without any other neurological sign in another
patient. A number of other diseases was found associated y
with ulcerative colitis, such as haemorrhoids in 22 (10 per
cent), pulmonary tuberculosis in six (2.7 per cent),
bronchial asthma in six (2.7 per cent), hypertension in
four (2 per cent), etc., as shown in Table 6.
Table 6. Complications and diseases associated with ulcerative
colitis.
Haemorrhoids 22
Polyarthralgia 5
Renal stone 3
Lichen planus 2
Fistula in ano 2
Ankylosing spondylitis 1
Parotid abscess 1
Monoplegia 1
Sigmoidoscopic appearances were graded as I, II, and
III, according to Bacon's classification[8]. Sigmoidoscopy
was normal in seven cases with clinically mild or moder-
ate disease. In all the other cases varying degrees of
abnormality were observed. No clear correlation was seen
between the clinical severity of the disease and the
sigmoidoscopic findings. This was evident, as 27 patients
(5 per cent) with severe colitis had only mild to moderate
changes on sigmoidoscopy (Table 7).
Table 7. Sigmoidoscope findings.
Sigmoidoscopy Mild Moderate Severe
Normal 4 3 ?
Proctitis 2 5 ?
Grade I changes 13 17 3
Grade II changes 8 96 24
Grade III changes ? 23 20
Severe anaemia was seen in only 23 patients (15 per
cent). Liver function tests, including serum proteins,
serum bilirubin and serum transaminases were done in 96
patients. Hypoalbuminaemia (<2.5 g per cent) was
found in 27 patients (28 per cent). Mean serum albumin
was 2.9 ? 1.13 g. Serum transaminases were abnormally
raised in only 3 patients (Table 8). Plain X-ray of the
abdomen was done in 184 patients. It showed dilated
small and/or large bowel loops in 25 patients (11 per
cent). Six patients (2.7 per cent) had marked colonic
dilatation (> 7 cm) on plain X-ray of the abdomen and
clinically they were consistent with the diagnosis of toxic
megacolon. In two other patients, free gas under the
dome of the diaphragm was detected, which was sugges-
tive of perforation.
Barium enema was carried out in 126 patients to see
the distribution of lesions (Table 9). In more than half (54
100 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
Table 8. Laboratory investigations.
Abnormal investigation Moderate Severe
Hb(< 7 g %) 28 4
TWBC (> 12,000/mm3) 8 7
ESR (>20 mm/lst hr) 84 36
* Abnormal plain X-ray abdomen 18 7
tPositive amoebic serology 2
Hypoalbuminaemia (<2.5 g %) 17 16
'Done in 184 patients only
fDone in 93 patients only
Table 9. Extent of ulcerative colitis as assessed by barium
enema (126 patients).
Barium enema findings Mild Moderate Severe
Normal 8 15 1
Recto-sigmoid 3
Right colon total
15 6
22 5
Descending colon ?
Transverse colon ? 22 7
15 5
Ileum ? 2 ?
11 91 24
per cent) of the patients disease was found to be limited to
the left side of the colon. Pseudopolyposis was seen in 19
patients (9 per cent). Malignancy was suspected in seven
patients with radiologically demonstrated single or multi-
ple strictures or an irregular filling defect or a mass in the
colon. Malignancy was, however, confirmed at surgery in
only one patient.
Rectal biopsy was done in all except three patients and
the histopathological findings of distortion of glands,
cryptitis and crypt abscesses were reported to be compat-
ible with the clinical diagnosis of ulcerative colitis.
Discussion
Though ulcerative colitis is a disease of the West, it is not
rare in India[2-7], where its frequency has been reported
to be from 9.4 to 24.4 cases per 10,000 hospital admis-
sions^]. Two hundred and eighteen cases of ulcerative
colitis seen in a single unit of a referral hospital during a
period of 10 years is a further indication that the disease is
not rare in India. This is comparable with 624 patients in
a period of 24 years reported by Edwards and True-
love[10].
The observations of the present study show certain
differences between Indian and Western patients with
ulcerative colitis.
In contrast to Western series in which females are
equally[ll] or more commonly[12] affected than males,
the present and other Indian studies have found a higher
male to female predilection[2-5]. This cannot be due to a
smaller number of female beds, as a patient with ulcer-
ative colitis will definitely seek hospital admission because
of the severity of the disease[2,4]. About half of our
patients were between 16 and 30 years of age, a signifi-
cantly younger group than that found in the West[9].
There are no clear data about the severity of the initial
episode of ulcerative colitis in India. Vakil and Mehta[6]
reported mild disease in 68.5 per cent, severe in 28.0 per
cent and fulminant in 3.5 per cent of the patients.
Tandon and co-workers[3] recorded mild ulcerative coli-
tis in 43.5 per cent of the patients and severe disease in
the rest. In the present series, mild disease was seen in
12.4 per cent, moderate in 66.1 per cent and severe in
21.5 per cent. This is in contrast to the Western series in
which the frequency of mild, moderate and severe disease
has been reported to be 66.4 per cent, 22.9 per cent and
10.7 per cent respectively[9]. This pattern of disease in
our series may not represent the whole picture, as most of
our patients were referred cases.
In the present study the duration of the illness was
looked at from two angles, the duration of the presenting
episode, and the total duration of the disease. This gave
us valuable information. It was found that about 42 per
cent of patients continued to suffer from the disease for a
period of more than six months, due either to delayed
diagnosis or inadequate treatment before attending the
specialty clinic. This proportion is much higher than in
the West, where only 22 per cent of patients required such
a long period of management. This is probably related
both to lack of awareness of the disease and to the widely
held belief among the medical fraternity in India that
ulcerative colitis is uncommon and these cases are most
probably due to chronic amoebic dysentery.
Of the patients 71 per cent had more than one attack of
ulcerative colitis and only 29 per cent presented during
the first episode, compared with the Western figure of 39
per cent. Earlier studies have also suggested that relaps-
ing, remitting or chronic continuous ulcerative colitis are
the commonest modes of presentation of the disease[7].
Systemic complications related to ulcerative colitis were
infrequent (3 per cent) and included polyarthralgia,
HLA-B-27 positive ankylosing spondylitis and monople-
gia. In earlier studies from our centre[3] and by others[4],
systemic complications were not reported. Manifestations
like sclerosing cholangitis, uveitis and skin lesions were
not seen in our patients as compared to the incidence of 7
per cent[13], 5-10 per cent[14], 3 per cent (erythema
nodosum), 1-4 per cent (pyoderma gangrenosum)[15],
respectively reported in the Western series. All these
reports therefore suggest that ulcerative colitis in India is
not usually associated with the extracolonic lesions that
have been observed in Western countries. The reason for
this is not clear, but it could be due to less frequent and
lower levels of circulating immune complexes and auto-
antibodies in our patients[16].
The incidence of associated diseases like pulmonary
tuberculosis and bronchial asthma was 2.7 per cent in the
present series and was comparable with the figures of 2.4
per cent and 2.6 per cent reported by the Oxford group of
workers[9].
The incidence of local complications like fistula in ano
was less than 1 per cent as compared with 6-20 per cent in
Western series[10,17]. None had perirectal abscess. Pseu-
dopolyposis was seen in 9 per cent of the radiologically
studied cases. The incidence of pseudopolyposis has been
reported as being from 10-32.5 per cent in the West[9],
Toxic megacolon was seen in 2.7 per cent and colonic
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 101
perforation in 1 per cent of patients, compared with a
Western incidence of 1.6 per cent and 3.2 per cent
respectively[l 1]. Colonic stricture was found in 3.2 per
cent of patients in the present series, which is comparable
with other reports from India[5] and much less than the
6.3-11.2 per cent reported from the Westfll],
Carcinoma of the colon was detected in only one
patient (0.5 per cent). Other Indian studies have not
commented on this important complication [2,5], except
one report from our centre where carcinoma of the colon
was found in 2.9 per cent. In the West, the incidence of
carcinoma of the colon has been variably reported from
0.5 per cent to 30 per cent[18,19],
Sigmoidoscopic appearances were suggestive of grade I
changes in 15 per cent, grade II in 59 per cent and grade
III in 20 per cent, and showed normal mucosa or distal
proctitis in 6 per cent of the patients. This is in agreement
with some of the earlier Indian studies[2,3]. On the
whole, sigmoidoscopic changes in the majority of Indian
patients are milder as compared with changes seen in
Western patients. A rough correlation between the clini-
cal severity of the disease and the sigmoidoscopic findings
was seen in mild and moderate disease; however, this was
not true for severe colitis.
Of patients with severe colitis, 57 per cent had only
grade II changes on sigmoidoscopy. Moreover, it is worth
remembering that normal sigmoidoscopic findings can
occasionally be seen in patients with ulcerative colitis[20].
Barium enema studies showed the disease to be limited
to the left half of the colon in 75 (60 per cent) of the 126
patients in whom this examination was carried out.
Similar observations have been reported in earlier Indian
studies[2-5]. This is a much higher rate than that report-
ed in the West. On the other hand, total colonic involve-
ment was seen in only 17 per cent of patients in the
present series, compared to 34 per cent in the West[10],
In brief, ulcerative colitis is not an uncommon disease
in India. A high index of suspicion will obviate delay in
diagnosis. Slight male predominance, younger age, lower
incidence of systemic and local complications, rarity of
carcinoma, milder sigmoidoscopic changes and localised
left-sided involvement of the colon are some of the
distinguishing features of patients with ulcerative colitis
in India as compared with the West.
References
1. Farmer, R. G. (1980) in Clinics in Gastroenterology, Vol. 9, p. 229.
New York: Saunders.
2. Maroo, M. K., Nag, N. K., Sortur, S. V. and Patil, R. S. (1974)
Journal of the Indian Medical Association, 63, 350.
3. Tandon, B. N., Mathur, A. K., Mohapatra, L. N., Tandon, H.
D. and Wig, K. L. (1965) Gut, 6, 448.
4. Chuttani, H. K., Nigam, S. P., Sama, S. K., Dhanda, P. C. and
Gupta, P. S. (1967) British Medical Journal, 4, 204.
5. Pimparkar, B. D. (1973)Journal ofthe Indian Medical Association, 61,
217.
6. Vakil, B. J. and Mehta, A. J. (1967) Journal of the Association of
Physicians of India, 15, 460.
7. Mehta, S. K. (1981) in Progress in Clinical Medicine in India, Series 4,
pp. 275-300. (ed M. M. S. Ahuja.) New Delhi: Arnold Heine-
man.
8. Bacon, H. E. (1958) Ulcerative colitis. Philadelphia: Lippincott.
9. Truelove, S. C. and Witts, L. J. (1955) British Medical Journal, 2,
1041.
10. Edwards, F. C. and Truelove, S. C. (1963) Gut, 4, 299.
11. Mendeloff, A. I. (1980) in Clinics in Gastroenterology, Vol. 9, pp.
259-70. New York: Saunders.
12. Goligher, J. C., de Dombal, F. T., Graham, R. G. and Watkin-
son, G. (1967) British Medical Journal, 2, 193.
13. Greenstein, A., Janowitz, H. and Sachar, D. (1976) Medicine, 55,
401.
14. Wright, R., Lumsden, K., Luntz, M. H. et al. (1965) Quarterly
Journal of Medicine, 34, 229.
15. Johnson, M. L. and Wilson, T. H. (1969) Gut, 10, 255.
16. Sharma, M. P., Kar, P. and Malviya, A. N. (1982) Journal of the
Association of Physicians of India, 30, 29.
17. Huizenga, K. A. (1980) in Inflammatory Bowel Disease, 2nd edn, pp.
202-16. (ed J. B. Kirsner and R. G. Shorter.) Philadelphia: Lea
and Febiger.
18. Edwards, F. C. and Truelove, S. C. (1964) Gut, 5, 15.
19. Thayer, W. R. (1980) in Inflammatory Bowel Disease, pp. 265-78.
(ed J. B. Kirsner and R. G. Shorter.) Philadelphia: Lea and
Febiger.
20. Lennard-Jones, J. E., Morson, B. C., Ritchie, J. et al. (1977)
Gastroenterology, 73, 1280.
102 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
|
PMC005xxxxxx/PMC5371007.txt | The Implications of Demographic Changes
on Resource Allocation
KEITH ANDREWS, MD, MRCP(UK), Senior Lecturer; Geriatric Medicine,
University of Manchester, Clinical Science Building, Hope Hospital, Salford
J. C. BROCKLEHURST, MD, FRCP, Professor of Geriatric Medicine,
University of Manchester, Withington Hospital, Nell Lane, Manchester
Much publicity is given to the provision of a health
service relevant to the ageing population. Terms, such as
the 'rising tide', express the concern that many feel about
the problems of coping with an increase in very old people
with complex or chronic disabilities. In spite of this, the
DHSS has suggested to the chairmen of Regional Health
Authorities that the recommended norm for the number
of geriatric beds be decreased from the long-accepted 10
beds to 8.5 beds per 1,000 population 65 years and over.
One of the arguments for this seems to be that the
projected populationfl ,2] of those aged 65 years and over
will not change significantly over the next 20 years (Table
1). Within this group there are, however, very large
disproportionate increases of those 75-84 and those 85
years and over. It could be argued that, since there is no
change in the total number of elderly people, there will be
no alteration in bed requirements. In view of this we felt
that it was important to examine how the projected age-
sex demographic changes are likely to influence geriatric
unit management during the next few years.
Method
We visited 36 (13 per cent) of the 268 geriatric units in
Great Britain, selected to represent different styles of
practice (e.g. mixed flow, progressive care and age
related patterns), in industrial, urban, rural, retirement
Table 1. Projected population changes 1981-2006.
Year
Population (thousands) 1981 1986 1996 2006
Males
65-74 2160 2075 (-3.9%) 2082 (- 3.6%) 2000 (- 7.4%)
75-84 866 951 ( + 9.8%)' 941 ( + 8.7%) 956 (+ 10.4%)
>85 129 140 ( + 8.5%) 177 ( + 37.2%) 180 ( + 39.5%)
Total 3155 3166 ( + 0.3%) 3200 ( + 1.4%) 3136 ( -0.6%)
Females
65-74 2775 2717 (- 2.1%) 2628 (-5.3%) 2392 (- 13.8%)
75-84 1634 1785 ( + 9.2%) 1759 ( + 7.1%) 1725 ( + 5.6%)
>85 422 460 ( + 9.0%) 548 ( + 29.9%) 559 ( + 32.5%)
Total 4831 4962 ( + 2.7%) 4926 ( + 2.0%) 4676 (-3.2%)
All 7986 8128 (+ 1.8%) 8126 (+ 1.8%) 7812 (-2.2%)
and academic settings throughout the country. Infor-
mation was obtained from the case notes of a one-in-five
sample of patients in these units (2,152 patients
altogether) concerning their length of stay for the present
admission as well as noting the age and sex of the patient.
Results
Table 2 shows that the age structure of patients in these
units, as a proportion of those 65 years and over, did not
follow their distribution in the general population. Fig-
ures for the population structure were not available for
the study areas and it has been assumed that they follow
the national pattern. Although men over 85 years are only
4 per cent of the male population aged 65 years and over,
they occupied 19 per cent of male geriatric beds. Similar-
ly, females over the age of 85 years, being 9 per cent of the
elderly female population, occupied 33 per cent of female
geriatric beds. In addition, although the number of bed
days per patient does not change much for the male
groups, there is an increase with advancing age for
females. This is further seen in that whereas 50 per cent of
all the beds occupied by patients 65-74 years were used
by males, this fell to 19 per cent occupied by males in the
85 years and over age group. The proportion of the bed-
days occupied in each age group was lower for the males
than the actual proportion of beds they occupied (Table
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 109
Table 2. Age and sex distribution of patients over the age of
65 years in 36 geriatric units.
Age
65-74 75-84 >85 All
Males (646)?
in hospital group 31% 50% 19% 100%
in the population 68% 27% 4% 100%
bed-days occupied
by males 35% 47% 18% 100%
Mean days/patient
in hospital 306.7 257.5 260.8 285.2
Females (1,391)?
in hospital group 14% 53% 33% 100%
in the population 57% 34% 9% 100%
Bed-days occupied
by females 12% 47% 40% 100%
Mean days/patient
in hospital 361.5 376.8 511.1 426.3
Males/females
in each age group
in hospital 50% 30% 19% 31%
Bed-days in
each age group
occupied by males 46% 23% 11% 24%
2), further indicating the excessive length of stay of the
females. This will be relevant in the presence of differen-
tial expected demographic changes for males and females.
One further point was that 5 per cent of the geriatric
unit beds were occupied by patients under the age of 65
years?with an average length of stay of 686 days.
The effect of these demographic changes on future bed
requirements may be demonstrated by calculating, from
present occupancy and the projected population changes,
the number of bed-days for each age-sex group over the
next 20 years (Table 3). The decrease in the number of
bed-days occupied by people of 65 to 74 years of age is
more than compensated for by a striking increase in the
bed-days required by those 75 years and over. Based on
Table 3. Projected patient bed-days for 36 geriatric units
throughout Great Britain.
1981
Bed-days for year:
1986 1996
2006
Males
65-74
75-84
>85
Total
61342
82947
32351
176640
% change from 1981
Females
65-74
75-84
>85
Total
71944
277750
236609
586303
% change from 1981
All 762943
% change from 1981
58950
91076
35101
185127
+ 5%
70433
303303
257904
631640
+ 7.7%
816767
+ 7.1%
59134
90163
44386
193683
+ 9.7%
68131
297470
307355
672956
+ 14.8%
866639
+ 13.6%
56803
91573
45130
193506
+ 9.6%
62016
293304
313507
668827
+ 14.1%
862333
+ 13.0%
Table 4. Average length of stay on different types of ward
Average days in hospital on wards:
Acute Rehabilitation Long-stay
Male 31.1 71.9 630.6
Female 34.4 120.2 807.8
Total 33.3 103.5 760.0
these figures 13-14 per cent more bed-days will be
required over the next 15-20 years to maintain present
standards.
Table 4 shows that where the type of ward could be
identified in the 36 hospitals, the length of stay was about
one month in acute wards, three months in rehabilitation
wards and two years in long-stay wards.
The age and sex distribution differs for each type of
ward. Projecting these figures (Table 5), males will
Table 5. Projected change in bed-days required from 1981-
2006 related to the type of geriatric ward.
% increase in bed-days from 1981
for year:
1986 1996 2006
Acute ward
Male
Female
All
Rehabilitation ward
Male
Female
All
Long-stay ward
Male
Female
All
7.1
6.6
6.7
6.6
5.9
6.0
3.6
7.9
7.0
12.0
8.0
9.2
13.4
12.2
12.4
8.1
16.6
14.9
12.9
5.5
7.8
14.1
10.2
10.9
7.5
16.3
14.5
require more acute and rehabilitation facilities, while
females will need more long-stay facilities. Overall, the
increase required will be 9 per cent for acute, 12 per cent
for rehabilitation and 15 per cent for long-stay facilities in
the next 15 years.
Discussion
The future demographic trends show no change in the
total number of elderly people in the population over the
next 20 years. However, within these figures the 65-74
age group will decrease in numbers but this decrease will
be balanced by an increase in the 75 years and over
population. If the elderly were a homogeneous group this
would not influence future planning in the Health Ser-
vice. However, those over 85 years are more likely to be
in hospital than those of 65-69 years[3] and the age-
specific admission rate increases with age[4].
This study shows that, with present patterns of care,
the 36 units visited will require 14 per cent more beds in
15 years' time?with a greater increase in the bed
requirements for the females than the males. This is very
110 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
similar to the figure estimated by Clarke for Leicester-
shire^]. However, these figures assume that there will be
no change in patterns of care. The political solution[6] is
that more patients will be treated in the 'community'.
The attraction of this policy is that transferring long-stay
patients to the community may compensate for the
demographic changes, as one long-stay bed is the equiv-
alent of treating 24 acute patients or 8 rehabilitation
patients (Table 4). Unfortunately, the evidence is that
Social Service residential places[7], meals-on-wheels[8]
and home help[9] services are already falling far behind
the demographic trends. There is already concern[10]
that many elderly people do not receive satisfactory
support in the community. Residential homes are now
caring for heavily dependent individuals and require a
considerable increase in resources to maintain present
service levels[ll]. It is, therefore, unlikely that there will
be a significant shift from the hospital long-stay services
to Social Service care.
Private rest and nursing homes are contributing to
long-term support, though there is concern[12,13] about
the control of standards of care and the tendency to accept
the less disabled at the expense of those most in need.
How significant a role these homes will continue to play
will depend largely on political encouragement and Social
Security funding. Even if they are to play a significant
role the figures from this study show that, to cope with the
present long-stay bed requirements, the equivalent of 15
per cent of the long-stay beds in geriatric units will have
to be available in the 'community'. As the increased need
for rehabilitation and acute services can only be met by a
further decrease in long-stay beds, this figure will have to
be much larger than 15 per cent.
There is certainly evidence that an increased turnover
can be achieved by more efficient use of beds[14] and by
better discharge planning[15,16]. This, of course, de-
pends on patients being reasonably fit for discharge.
Unfortunately, the major cause of long-stay care is
dementia; social and physical disability play a relatively
small rolef 17,18], A poor mental state is badly tolerated
by families[19] and extremely difficult to cope with in the
community.
Support of heavily disabled individuals in their own
homes depends on very large increases in district nursing
and Social Service resources. As 0pit[20] has shown, the
cost of community support of the heavily disabled person
is probably as expensive as institutional care, while the
quality of care decreases as the amount of support
required increases.
These problems of demographic change are not only
applicable to geriatric and psychogeriatric units. The
length of stay in medical, surgical and orthopaedic units is
also increased in the elderly[21-23]. In 1977 one-fifth of
medical and surgical beds were occupied by people 75
years and over[24]. In addition, blockage at any point in
the hospital system inevitably results in pressure on other
services and this applies especially to geriatric units,
which have a high transfer rate from other departments.
Figures presented here indicate that, taking demo-
graphic changes into account, a norm of 8.5 geriatric beds
per 1,000 population of 65 years and over will be the
equivalent of 7.3 beds by 1996. We suggest that the
planning of future services must take into account the
differential requirements of the age-sex distribution of the
elderly population for different periods throughout the
next 20 years.
Acknowledgements
We wish to thank the King Edward's Hospital Fund for
London for their generous financial support and our
colleagues in the geriatric units visited for their time and
help.
References
1. OPCS (1983) Census 1981. National Report, Part 1, London:
HMSO.
2. OPCS (1975) Population Projections No. 5. London: HMSO.
3. Downie, B. N. (1972) The elderly in Scottish Hospitals 1961-1966.
Scottish Health Services Studies No. 21. Scottish Home and Health
Department.
4. Evans, G. J., Hodkinson, H. M. and Mezey, A. G. (1971) Lancet,
2, 539.
5. Clarke, M. (1984) Journal of the Royal College of Physicians of London,
18, 128.
6. Department of Health and Social Security (1981) Care in the
Community. London: DHSS.
7. Grundy, E. and Arie, T. (1982) British Medical Journal, 284, 799.
8. Department of Health and Social Security (1979, 1981) Personal
Social Services Local Authority Statistics: Meals Services. A/F79/2, A/F81/
2. London: DHSS.
9. Department of Health and Social Security (1979, 1981) Personal
Social Services Local Authority Statistics. Staff of Local Authority Social
Service Departments. S/F79/1, S/F81/1. London: DHSS.
10. Hunt, A. (1979) Health Trends, 11, 21.
11. Clarke, M., Hughes, A. O., Dodd, K.J. etal. (1979) Health Trends,
11, 17.
12. Godber, C. (1984) British Medical Journal, 288, 1473.
13. Andrews, K. (1984) ibid., p. 1518.
14. O'Brien, T. D., Joshi, D. M. and Warren, E. W. (1973) British
Medical Journal, 4, 277.
15. Cable, E. P. and Meyers, S. P. Jr. (1983) Archives of Physical
Medicine and Rehabilitation, 64, 57.
16. Shrager, J., Halman, M. and Myers, D. (1978) Social Work Health
Care, 4, 65.
17. Rainey, C. G. E., Russell, W. F. and Silver, C. P. Age and
Ageing, 4, 247.
18. Rosin, A. J. (1970) Gerontologia Clinica, 12, 40.
19. Sanford, J. R. A. (1975) British Medical Journal, 3, 471.
20. Opit, L. J. (1977) British Medical Journal, 1, 30.
21. Seymour, D. G. and Pringle, R. (1982) British Medical Journal, 284,
1921.
22. Rubin, S. G. and Davies, G. H. (1975) Age and Ageing, 4, 142.
23. Medical Manpower Steering Group (1980) Developments in health
services for the elderly?implications for medical manpower. London:
HMSO.
24. Office of Population Censuses and Surveys for Government Actu-
ary's Department (1977) Hospital In-Patient Enquiry, London:
DHSS.
Journal of ihe Royal College of Physicians of London Vol. 19 No. 2 April 1985
|
PMC005xxxxxx/PMC5371008.txt | Oral Anticoagulants: a Cost-Effectiveness
Approach /
E. J. STAMF! B Med Sci, Medical Student
S. J. JONES, M Phil, Research Assistant
Department of Community Health, University Hospital and Medical School, Nottingham
D. R. RYRIE, MB, FRCPEd, FRCPath, Senior Lecturer and Consultant Haematologist,
Department of Haematology, City Hospital, Nottingham
A. J. HEDLEX MD, FRCPEd, FFCM, Professor of Public Health, Ruchill Hospital,
Glasgow
Oral anticoagulants have been adopted for general use in
venous thromboembolic and arterial thrombotic diseases
[1-3], The aim of treatment is to achieve a stable reduced
blood coagulability within a desired therapeutic range.
This is maintained by regular standardised laboratory
testing of the patient's blood at appropriate intervals.
In this study a conventional method of achieving
anticoagulant control was compared with two alternatives
using a cost-effectiveness technique. Cost-effectiveness
studies demand (a) definition of the objective of treatment
or programme being studied; (b) definition of the various
options for available management; (c) a measure of
outcome which is valid and applicable to all the options,
and (d) an estimation of all the costs involved [4],
The Options for Treatment
Option 1: This was the conventional system in operation
at the hospital in which patients attend a clinic approxi-
mately every four to six weeks for adjustment of their dose
of anticoagulants. Changes in treatment are recorded on
a patient-held card and clinic record; no direct contact is
usually made with the GP except at the onset and
cessation of treatment.
Option 2: This alternative is in operation in two general
practices in Nottingham. Patients attend their local sur-
gery for venepuncture. Blood is then sent to the hospital
laboratory for testing and adjustment of dose; patients
obtain the results by telephoning the surgery the same
day.
Option 3: This was a theoretical model based on the
Dutch Thrombosis Service [5]. A nurse would visit the
patients in their home, collect a blood sample by vene-
puncture and take it to the hospital laboratory for testing
and assessment of drug dose. Patients and GPs would be
informed of the results and recommended dose by post
the next day.
The aims of this study were to calculate and compare
the total cost for each system; to measure the level of
effectiveness for the two 'operational' alternatives (op-
tions 1 and 2) and determine if this was affected by the
'decentralisation' of treatment control; and to assess the
acceptability of the three alternatives to patients and their
GPs.
The measure of effectiveness used was the proportion
of 'Thrombotest' [6] results within the therapeutic ranges
of 5-10 per cent and 5-14 per cent. This was found for all
tests performed over the past year; for patients treated for
less than a year the value was found for the period of time
they had been on treatment. It was assumed that the
effectiveness of the theoretical model (option 3) would be
the same as that found in the conventional clinic system
(E. A. Loeliger, personal communication).
Patients and Methods
Clinic Patients
Clinics are held twice weekly, with an average of 63
patients attending each clinic. A l-in-3 systematic sample
of patients attending 12 consecutive clinics was selected.
This comprised 236 of the total of 419 patients currently
attending for anticoagulant treatment. The sample was
similar to the total clinic population in age (mean = 56
years) and sex (M:F = 1:1.3) distribution.
Practice Patients
All 24 patients being anticoagulated at one urban general
practice were included in a detailed study. The mean age
was 57 years and the male/female ratio was 1.4:1. The
records of a further 23 patients at a second practice were
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 105
available for measurement of effectiveness of anticoagu-
lant control.
Information Collection
Information was extracted from medical records about
dose of anticoagulants, level of control, frequency of
checks and reason for treatment. For patients attending
the hospital and general practice clinics a self-adminis-
tered questionnaire was used to obtain information about
patient costs, knowledge of anticoagulant therapy and
other treatments, patient attitudes and their preferred
choice for monitoring anticoagulant control.
Twenty substitutions were made at the clinic for
patients who did not wish to complete the questionnaire
(6 due to illness, 9 due to poor sight and 5 refusals). Non-
attenders, from the original sample, were sent a question-
naire and all of these were returned. In the health centre,
22 out of 24 (92 per cent) patients completed the question-
naire.
A random sample of the GPs of clinic patients was sent
a questionnaire to assess their attitudes, choice of system
and reason for their choice.
Costs
The total average cost for a patient visit was calculated for
each option, including costs incurred by both the NHS
and patient. The directly attributable NHS costs included
were pharmaceutical costs, equipment and tests, staff and
administration costs and ambulance costs. These were
obtained from published sources and relate to 1980 prices
[7-9], Estimates were made of costs incurred by patients
including consultation, waiting and travel time, costs of
travel and any escort costs. Under the theoretical option,
patients had no travel time cost but a waiting time of one
hour was assumed which was comparable with that found
in the hospital clinic (1.2 hours). In estimating patient
time costs for the theoretical model, the employment
status of the clinic patients was assumed to be similar to
that of the general population.
Results
Effectiveness
The mean proportion of tests in the range 5-10 per cent
was 58 per cent for all clinic patients, and 59 per cent for
the 47 patients in the GP-operated systems; the difference
was not significant. If the acceptable therapeutic range
was extended to 5-14 per cent there was an improvement
of 20 per cent in the proportion of tests in the range for all
patients (Table 1). These results are comparable with
other recent studies of levels of control in anticoagulated
patients [10-12].
Costs
For the sample studied, the distributions of total cost,
time cost and travel cost were negatively skewed with
between 60 per cent and 81 per cent of values below the
Table 1. Effectiveness of anticoagulant therapy in clinic and
health centre setting as measured by Thrombotest.
Mean proportion (%) of tests
in Thrombotest range
Category of patient 5-10% 5-14%
Clinic 58 78
(n = 236)
Health centres 59 84
(n = 47)
mean. Patients in the high cost category tended to be
those who were employed (high time cost) or who used the
ambulance service (high travel cost). The NHS and
patient costs are itemised in Table 2, the mean total cost
is analysed in Table 3.
Table 2. NHS costs
Hospital Clinic ?
Treatment 0.22
Staff and Administration 0.72
Ambulance* 3.62
Total 4.56
*28% of patients travel by ambulance at ?1.00 per mile
Average return trip is 13.5 miles.
Domiciliary-based system
Treatment 0.27
Staff and Administration 2.04
Nurse Travel 3.14
Total 5.45
Health Centre
Treatment 0.27
Staff and Administration 1.12
Total 1.39
Table 3. Mean total cost per attendance by occupation and
method of travel for patients using different types of care.
Option 2 Option 3
Option 1 (Health (Domiciliary
(Clinic) centres) visit)
Patient category (n = 236) (n = 47) (n = 236)
? ? ?
All 11.43 3.89 6.75
Occupation:
Employed 13.55 5.68 8.59
Other 10.87 2.46 5.73
Method of travel to
clinic or health centre:
Walk 4.82 2.53 5.82
Bus 6.61 3.19 5.94
Car 11.09 4.54 6.78
Ambulance 16.05 ? 7.34
Option 1. Of clinic attenders, 25 per cent were employed
and their mean time cost was ?7.97 compared with ?1.92
106 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
for those not in employment. Patient mean time costs
were ?3.44.
The 28 per cent of patients who required an ambulance
had a mean travel cost of ?12.94 compared with ?4.52 for
car users and ?1.76 for bus users.
The mean ambulance cost (NHS cost) per attendance
was ?3.62 and patient mean travel costs were ?2.46. The
mean NHS cost per attendance for drugs, tests, staff and
administration was ?0.94, so total NHS costs per attend-
ance were ?4.56. Mean total patient costs, including
escort costs of ?0.97, were ?6.87. Therefore, the mean
total cost per attendance was ?11.43.
Option 2. No patients used an ambulance to attend the
health centre and the mean patient travel cost of ?0.72
was low because no patient travelled more than three
miles. Seven patients (29 per cent) were employed, with a
mean total cost of ?5.68, compared with ?2.22 for those
not employed. NHS costs, based on an average of 10 tests
performed each week, amounted to ?1.39. Thus the mean
total cost per patient visit was ?3.89 which was cheaper
than either of the other two systems.
Option 3. NHS costs for the theoretical model, calculated
for an average clinic of 63 patients, were ?5.45 (?0.90
drug treatment, administration and staff costs, ?1.41
nurse wages, ?3.14 nurse travel costs). The distribution
of costs was affected by a few high values for those
patients living farther from the hospital. The decrease in
patient time, escort costs and use of the ambulance
service, led to a reduction in mean total cost (?6.75) of 40
per cent compared with the clinic system (t = 23.39;
degrees of freedom = 235; P<0.001).
Discussion
As in many economic studies of health care the costs used
are the best available estimates and as such are only
indicative of the absolute and relative costs. Nevertheless,
the results show that for some patients the management of
anticoagulant treatment could be carried out in the
community with no decrease in the standard of control
but with considerable savings to both the NHS and
patients. Although the number of patients studied in the
health centre was small, other comparisons of hospital
care and community care have also found the latter to be
cheaper and more convenient for patients [13-16].
In this study the assumption was made that no alter-
ation in the level of control would occur in the theoretical
model although in the Leiden Thrombosis Service 83 per
cent of all Thrombotests were within the range 5-10 per
cent compared with 58 per cent in this study (E. A.
Loeliger, personal communication). This may be import-
ant in taking decisions to implement other systems al-
though other factors may be involved such as the age
structure of the population, reasons for anticoagulation,
therapeutic regimen and dosage schedule. Certainly de-
centralisation of care in Leiden has not resulted in a
decrease in standard of control.
This study clearly shows that, from the NHS view-
point, high cost patients are those requiring ambulance
transport. With 28 per cent of patients using an ambu-
lance the mean NHS cost for a clinic attendance is ?4.56
compared with ?5.45 for the theoretical model using a
nurse. However, if 35 per cent or more of patients require
an ambulance the theoretical model becomes cheaper. At
the same time patient costs are ?6.87 for clinic atten-
dances and ?1.30 for domiciliary visits by the nurse.
Table 3 classifies patients by employment status and
their mode of travel to the hospital clinic or health centre
and shows the difference in mean total costs for each
group for the various options. The actual costs for clinic
and health centre attenders are shown along with the
projected mean costs for the 236 current clinic attenders if
they were transferred to the domiciliary visiting scheme.
Cost-effectiveness ratios, comprising the cost of a single
clinic visit and the proportion (%) of patients in the
Thrombotest range 5-10 per cent, were ?11.43/58 per
cent for the hospital clinic, ?3.89/59 per cent for the
health centre and ?6.75/58 per cent for the domiciliary-
based service.
Acceptability
Seventy per cent of the 236 patients put the clinic as their
first choice; 17 per cent (of whom 45 per cent were
employed) chose the GP system, and 32 per cent (of
whom over 60 per cent were aged over 60) chose the
theoretical domiciliary system. Nearly two-thirds found
attendance at the clinic 'inconvenient but necessary'. A
total of 63 (76 per cent) out of 83 GPs returned question-
naires after two reminders. More than half (57 per cent)
of these GPs did not know how many of their patients
were undergoing anticoagulant treatment. Ten (16 per
cent) preferred the GP-centred model, 14 (22 per cent)
the theoretical model and 39 (62 per cent) put the clinic
system first. Reasons given against the alternatives to the
present clinic system were lack of facilities (21 per cent);
too complicated (19 per cent); risk of error in communi-
cating results (19 per cent) and extra work for the GP (16
per cent). The reasons given in favour of the alternative
chosen included more convenience for patients (19 per
cent), more GP involvement (14 per cent) and more
economical use of resources (16 per cent).
Perhaps more importantly, if the theoretical model
were to be implemented, the nurse would not return to
the hospital between each patient-visit (which was as-
sumed here as the most convenient way to calculate and
compare costs), thus reducing the cost still further to the
NHS.
It should be borne in mind that the costs quoted in this
study are average costs. Consideration of the implemen-
tation of any particular model of care would concentrate
on the marginal costs. For example, there will be a
miminum number of patients that would make the em-
ployment of a specialist nurse worthwhile. Once that
number is achieved the marginal cost of each extra
patient will be relatively low until the point at which
another nurse needs to be recruited, who may then have
spare capacity. However, if resources, such as nurses, can
be reallocated as required, marginal costs may be close to
average costs.
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
The major component of patient costs was time costs
for employed patients. The reduction in total costs of
care, if such patients were seen outside the hospital clinic
setting, would be high. Since all the employed were
assumed to use work time, if the change from hospital
clinic to general practice clinic meant a change to use of
leisure time, then patient costs would be further reduced
as leisure time is generally assumed to be worth less.
Implementation of the two alternative options would
decrease the burden on crowded out-patient clinics and
release resources in an over-burdened ambulance service.
Although it is unnecessary, at present, for all patients
to be transferred to alternative forms of care, nearly 40
per cent of general practitioners appear willing to adopt
these methods of working and patients already provided
with such facilities do not wish to change. The best
practical solution would probably be to offer a mixture of
options, with interested general practitioners taking over
care of their patients, particularly those in employment,
while a nurse could care predominantly for those who
require an ambulance. In this way, maximum savings in
the provision of anticoagulant control services could be
made by making the most efficient use of available
resources.
Acknowledgements
This work is based on a B.Med.Sci. dissertation by E.J.S.
in the Department of Community Health, University of
Nottingham.
We thank Professor Gavin Mooney and Mr John
Henderson, Health Economic Research Unit, Depart-
ment of Community Medicine, University of Aberdeen,
for helpful advice, and the hospital clinic staff and
Doctors Alan Murphy and John Skinner and their gen-
eral practitioner colleagues for support and collaboration.
References
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2. Prentice, C. R. M. (1976) Prefcribers Journal, 16, 116.
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(1978) British Medical Journal, 1, 272.
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Bulletin, 39, 21. 1
5. Jordan, F. L.J. (1958) Thrombosis et diathesis haemorrhagica, 2, 527.
6. Owren, P. A. (1959) Lancet, 2, 754. .
7. Department of Health and Social Security (1981) Health Services
costing returns 1978/1979. London: HMSO.
8. Department of Employment (1981) New earnings survey. London:
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12. Duxbury, B. McD. (1982) British Medical Journal, 1,702.
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14. Mooney, G. A. (1978) Scottish Journal of Political Economy, 25, 149.
15. Gallow, R. J. (1979) Journal of the Royal College of General Prac-
titioners, 29, 478.
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108 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
|
PMC005xxxxxx/PMC5371009.txt | j The Thyroid and Osier
SIR RAYMOND HOFFENBERG, KBE, MD, PRCP, William Withering Professor of
Medicine, University of Birmingham Medical School, Birmingham
Osier made no major contribution to the study of the
thyroid but he was at the peak of his career at the most
exciting time of thyroid, indeed endocrine, conceptual
development and he was characteristically quick off the
mark in recognising the importance of contemporary
work and in adding his own observations to the burgeon-
ing literature of the time.
The scene has to be set roughly 150 years ago. In 1835
Robert Graves[l] described the condition of hyperthyroi-
dism which still bears his name, despite the fact that, as
with so many diseases, Parry's description had preceded
his by 10 years. Caleb Hillier Parry[2] was of Welsh
descent, the name being derived from ap Harry, and
incidentally a lifelong friend of Edward Jenner with
whom he was at school in Cirencester. Both were mem-
bers of the Gloucestershire Medical Society which met in
the parlour of the Fleece Inn, Rodborough, and became
known as the Fleece Medical Society. It was before this
society in July 1788 that Parry presented his famous
paper entitled 'An Inquiry into the Symptoms and
Causes of the Syncope Anginosa, commonly called An-
gina Pectoris' in which he clearly stated the coronary
origin of the symptom. He failed to publish his observa-
tions until 11 years later (1799), a delay that also
characterised his publication on exophthalmic goitre, for
he had seen his first case in 1786 and correctly recognised
it to be a new and distinct syndrome; publication did not
take place until 1825, three years after his death, but still
well in advance of Graves' description of the disease. The
first edition of Osier's textbook of 1892 discusses exoph-
thalmic goitre under the eponyms of Graves and von
Basedow, whose description followed in 1840. The third
edition of 1898 refers to it as Parry's disease and contains
a defence of Parry's right to the eponym.
Both Parry and Graves recognised the important triad
of the disease?exophthalmos, palpitations and goitre?
but they failed completely to appreciate the role of the
thyroid in its genesis. The goitre was regarded as a
swelling or diverticulum designed to siphon off the
superfluous blood in the circulation, thereby preventing a
serious flooding of the brain. Graves, in fact, referred to
the thyroid as 'analogous to those tissues properly called
erectile'. At the time there was no comprehension of the
role of endocrine glands as organs which secreted materi-
als into the circulation and certainly not of disease which
might follow excessive secretion. The fact that these
organs were known to be ductless must have contributed
to this lack of comprehension. I should like to review how
the light gradually dawned.
The story is sometimes said to have started with John
Hunter, but his experiments on transplantation of a
cock's testis appear to have been carried out as experi-
ments in transplantation rather than studies of the or-
gan's function and there is nothing to suggest that he
comprehended their endocrine significance. Arnold Adolf
Berthold published in 1849 the results of similar experi- i
ments[3] in which he removed the testes from four young
cocks, transplanted them to another site in two of the
birds, keeping two as controls in the best scientific mode.
He showed that the cock's comb developed normally in
the transplanted birds but did not do so in the non-
transplanted pair. To us, today, it would seem incompre-
hensible in the face of this evidence that the role of the
testes as secreting organs was not immediately under-
stood. Yet Berthold did not directly express this opinion.
Indeed, he favoured the view that they functioned by
extracting matter from the bloodstream.
In the same year (1849) Addison[4], somewhat imper-
fectly, described the features of the hypoadrenal state that
now bears his name. In 1855 he produced a more
accurate, less confused and still pertinent clinical descrip-
tion of the consequences of adrenal failure[5]. He, too,
failed to appreciate the significance of his findings al-
though he recognised that destruction of the adrenal
glands constituted an integral part of the disease. Brown-
Sequard, the eminent neurophysiologist, followed up
Addison's report with a superb set of experiments, analo-
gous to those of Berthold, in which he showed that
removal of the adrenal glands was followed by severe
disease and death, and that this could be prevented by
transplantation of the adrenals to another site[6]. Both he
and Addison attributed to the adrenals a role in detoxify-
ing substances which, in the absence of adrenal function,
led to severe or fatal consequences.
Brown-Sequard, of course, later achieved notoriety
through his publication of 'The Pentacle of Rejuvenes-
cence', in which he ascribed his own youthful exuberance
at the age of 72 years to regular injections of testicular
extract, a practice which rapidly became fashionable and
may be seen as the beginning of the organotherapy
movement.
It was through the thyroid that a proper appreciation
was gained of the role of endocrine glands and their
secretions and Brown-Sequard's organotherapy was
given more acceptable scientific support. The story really
starts with the clinical descriptions of hypothyroidism.
Cretinism was one of the earliest diseases ever to be
delineated, and its endemic nature was fully appreciated
80 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
in the Middle Ages. But endemic cretinism had largely
died out in Britain by 1850, the year in which Thomas
Blizzard Curling read a paper before the Royal Medical
and Chirurgical Society, with Thomas Addison in the
chair, on 'Two Cases of Absence of the Thyroid Body and
Symmetrical Swellings of Fat Tissue at the Sides of the
Neck, connected with Defective Cerebral Develop-
ment'^]. He noted the absence of the thyroid gland at
postmortem examination and said: 'I am not acquainted
with any case on record in which a deficiency of the
thyroid gland has been observed in the human body.'
Again, he and others might previously have been misled
by the association of the cretinoid condition with goitrous
enlargement, not absence of the thyroid gland. It would
have required great perspicacity, indeed clairvoyance, to
have appreciated at the time that an enlarged gland was
functioning too little, not too much. In 1874 Sir William
Gull[8] presented to the Clinical Society of London five
cases of 'A cretinoid condition supervening in adult life in
women', to which four years later Ord[9] applied the
name 'myxoedema' in recognition of the characteristical-
ly mucoid oedema shown by the patients. This led to
separation of the well-known endemic cretinism with
goitre from a sporadic disorder of similar clinical presen-
tation but characterised by absence of the thyroid gland.
Hilton Fagge could claim priority in clearly recognising
this distinction in a paper he wrote in 1871 [10].
At about this time, through improvements in anaes-
thesia and advances in aseptic technique, European
surgeons were beginning to carry out thyroidectomy for
large endemic goitres. The Reverdin cousins in 1883
noted the postoperative sequel of a myxoedematous syn-
drome in many of their patients [11] and in the same year
Theodor Kocher, the Swiss surgeon, presented the results
of his operations to a Berlin conference; 30 of his first 100
thyroidectomised patients developed a similar syndrome,
to which he gave the name cachexia thyroprival2].
Kocher attributed this syndrome to operative damage to
the trachea with consequential disturbance of cerebral
oxygenation. In the same year at a clinical presentation of
a case of myxoedema to the London Clinical Society, Sir
Felix Semon[13], aware of Kocher's publication, sugges-
ted that his postoperative cachexia thyropriva, Curling's
cretinism and Gull's adult myxoedema might all be
related and he established a committee to investigate this.
Ord was chairman of this committee and Victor Horsley,
about whom more will be said, was a member. The
famous report of the London Clinical Society in 1888[14]
concluded that all three diseases were in fact related and
due to deficiency of the thyroid gland. This was a
stupendous conceptual advance?that a gland which was
known not to possess a duct was able to secrete something
into the circulation, and that this secretion was necessary
for health. But, the committee concluded, there was no
hope of cure; its recommended treatment included a
warm room, a warm climate, tonics and so on. In 1890
Victor Horsley proposed transplantation of the thyroid
gland from a sheep as a means of arresting the progress of
myxoedema[15] but this idea was superseded by the far
simpler solution of George Murray of Newcastle, a pupil
of Horsley's, who in 1891 [ 15] reported the successful
treatment of a patient by injection of an extract of sheep's
thyroid. Brown-Sequard's organotherapy was on its way.
Within a very short time it was appreciated that
Graves' disease was the antithesis of sporadic myxoe-
dema. In the latter the thyroid was usually absent; in
Graves' it was enlarged. In myxoedema there was torpor,
slow pulse, dry skin, coldness, etc.; in Graves' hyperacti-
Fig. 1. Robert Graves.
Fig. 2. C. H. Parry.
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
vity, tachycardia, heat intolerance and sweating. And,
most convincingly, over-enthusiastic treatment of myxoe-
dema with thyroid extract was soon shown to reproduce
the clinical picture of Graves' disease. It was then gener-
ally accepted that the disease resulted from excessive
secretion by the thyroid gland. Again, this was a remark-
able conceptual breakthrough?the recognition that se-
cretion from a gland was not only necessary for health
but, if excessive, could lead to disease.
Osier included a section on exophthalmic goitre in the
first edition of The Principles and Practice of Medicine. He
accepted that worry, fright and depressing emotions
preceded the disease in some cases but admitted that its
true nature was unexplained. He lent some support to the
nervous hypothesis of its cause, originally propounded in
1860 by Trousseau, and discussed the possibility of
sympathetic paralysis or 'affection of the medulla oblon-
gata'. In retaining this view he lagged behind the growing
acceptance that the thyroid gland was the primary seat of
trouble. In the third edition of 1898 he cites Moebius and
Greenfield who regarded Graves' disease as a primary
thyroidal disturbance (hyperthyrea as opposed to the
athyrea of myxoedema). Osier's reluctance to accept this
view may have been influenced by statements such as
those of the pathologist McCullum, who held that 'organs
hypertrophy only to meet the needs of the body, not to
insult it' [ 16].
Excluding chapters for textbooks, I have counted ten
contributions by Osier, which are related to the thy-
roid[ 16-25]; three of these are unsigned editorials in
Medical Atezw[16-18]; there are a few case reports and
clinical notes[ 19-23], and two substantive publications on
sporadic cretinism in America, that of 1893 presented to
the Association of American Physicians[24] and of 1897
to the Washington Congress of American Physicians and
Surgeons[25], It is to the earliest of his unsigned editorials
that I wish to turn. Headed 'The Thyroid Gland and
Myxoedema' it refers to the work of Professor Victor
Horsley, a man with whom Osier formed a close associ-
ation, about whom he was later to contribute an obituary
for the British Medical Journal, and of whose biography by
Stephen Paget[26] he was to write a review from his bed
during his last illness in 1919.
Victor Horsley was a remarkable man, probably the
best experimentalist of his time. He was, regrettably, a
surgeon, but would have endeared himself to present-day
Fellows of the Royal College of Physicians by the article
he wrote for the Students' Medical Society in 1883 (the
year he was admitted FRCS) 'on the evil effects of
tobacco'. His later crusade against alcohol might have
been less well received. The following year (1884) he was
appointed Professor-Superintendent of the Brown Insti-
tute which had been established in 1871 as a result of a
legacy from Mr Thomas Brown of Dublin 'for investigat-
ing, studying and, without charge beyond immediate
expenses, endeavouring to cure maladies, distemper and
injuries, any quadriped or birds useful to man may be
found subject to'. The Brown Institute preceded the
Lister and, at that time, there were no research depart-
ments in our medical schools. It was thus an important
new venture and, through a succession of distinguished
investigator-superintendents (Burdon Sanderson, Green-
field, Roy, Horsley, Sherrington, Rose Bradford and
Brodie), it came to exert great influence and authority on
British medicine. Horsley stayed there from 1884 to 1890
and pursued three lines of research?localisation of func-
tion within the brain, protection against rabies, and the
relation of myxoedema and cretinism to thyroid function.
He was a member of the London Clinical Society's
Committee on Myxoedema .and was asked by the Com-
mittee to study the function of the thyroid gland by
experiment. It was through these studies that he devel-
oped the idea of treating myxoedema by thyroid gland
transplantation that I referred to earlier; despite the
success of injections of thyroid extract and later oral
therapy for myxoedema, Horsley held on to his idea of
transplantation for over 20 years.
In his obituary[27] on Horsley, who died in 1916,
Osier refers to a meeting that had taken place one
summer evening in 1878 with 'two young students (of
University College) whose bright eyes held the light of
high promise'; one of these was Victor Horsley, whose
'upward path', Osier says he followed 'from afar with an
affectionate interest'.
In 1885 Osier came to London to give his Goulstonian
Lectures and he visited Horsley at the Brown Institute. It
is an analysis of Horsley's work as Osier must have seen it
that is presented in the first of his unsigned editorials on
the thyroid. In it he says?and this precedes the report of
the London Clinical Society by three years?'it seems
reasonable to attribute . . . cretinism, myxoede-
ma . . . and cachexia strumipriva?to disturbance or ar-
rest of the functions of this gland, and the possibility of
the supervention of this state will make the operation of
thyroidectomy almost unjustifiable'. Osier's dismissal of ?>
thyroid surgery was, to say the least, a trifle hasty.
Horsley and Osier met several times thereafter and
remained excellent friends. In 1892 Osier attended the
annual meeting of the British Medical Association in
Nottingham. Horsley was then President of the Section of
Pathology and with his pupil, Murray, provided what
was generally regarded as the outstanding contribution of
the meeting on 'The Pathology and Treatment of Myxoe- ,
dema' which included a report of the first four cases cured
by the juice of thyroid glands. When Sir John Burdon
Sanderson later approached Osier to come to Oxford, he
mentioned in his letter, presumably in an attempt to
influence Osier's decision, that Sir Victor Horsley would *
approve. Osier, in his obituary on Horsley, equated his
technical skill as a surgeon to the brilliant diagnostic skill
of Gowers. The two men clearly shared great liking and
respect for one another.
Osier's two papers on sporadic cretinism in America
contained characteristically clear clinical descriptions of
the disease: 'The stunted stature, the semi-bestial aspect,
the blubber lips, retrousse nose, sunken at the root, the
wide-open mouth, the lolling tongue, the small eyes, half
closed with swollen lids, the stolid, expressionless face,
the squat figure, the muddy, dry skin, combine to make
the picture of what has been well termed the "pariah of
nature".' In the first paper he quotes extensively from
Horsley, provides a detailed review of the history of
82 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
cretinism and criticises the confusion of cretinism with
other forms of idiocy. He attempted a survey of both
endemic and sporadic forms of the disease based on the
literature, inquiries made of superintendents of asylums
for the insane throughout the country, 'as well as of many
friends'. He found 11 cases but on the basis of such a
limited and selective survey wisely avoided any firm
statistics about its prevalence in America. By 1897 he had
collected 60 cases and reported on the results of treat-
ment: 'not the magic wand of Prospero, or the brave kiss
of the daughter of Hippocrates ever effected such a
change as that which we are now enabled to make in these
unfortunate victims, doomed heretofore to live in hope-
less imbecility, an unspeakable affliction to their parents
and to their relatives'. How excited he would have been
by the modern approach to the diagnosis of cretinism by
neonatal screening and measurement of TSH on the
Guthrie filter paper strips used for the detection of
phenylketonuria. Neonatal hypothyroidism affects about
one in 3,500 births and, it seems, this 'unspeakable
affliction' may now be prevented by early detection and
treatment.
Two of his case reports are of interest. The first[20]
concerns an acute myxoedematous condition with goitre
affecting a 23-year-old man possibly, in retrospect, a case
of autoimmune thyroiditis of rather rapid onset and short
duration: the history of 3^ months and lack of mention of
thyroidal tenderness make a viral subacute thyroiditis less
likely. Osier treated this myxoedematous patient with
ergot but wisely refrains from commitment about its
efficacy. Followers of Osier might have been a little
confused in that year because the concurrent first edition
of his textbook offers ergot as a treatment for exophthal-
mic goitre.
The second report[23] is entitled 'An acute myxoede-
matous condition, with tachycardia, glycosuria, melaena,
mania and death'. He starts this report by referring to the
patient of his first report who, he now says, had 'for a
period of five or six months a myxoedematous condition
of the hands and face, which disappeared completely'.
Not a word about ergot.
The subject of the second report was a 31-year-old male
who six months earlier had rapidly increased in size, to
the extent that he had to get 'a completely new outfit of
underclothes and outer garments'. His weight went up
from 145 to 182 pounds in four months. 'Everyone
remarked on the extraordinary increase in his size, and a
personal friend asked him if he had been drinking as he
looked so bloated'. There was a stage when he got 'queer
in his head' and developed delusions, some paranoid. His
face became almost purple. When Osier saw him he noted
large supraclavicular pads but could not feel the thyroid.
The abdomen was large and full and 'the skin presented
in concentric lines on either side on the flanks and in the
iliac regions the most extraordinary atrophic lineae, six
on either side'. The largest 'was fully three-fourths of an
inch in breadth at its widest part'. 'All were curved and
presented a purplish red colour'. Osier does say 'while he
was bloated and puffy, the general appearance was not at
all that of a case of myxoedema'. And, of course, Osier
was right, for the combination of rapidly increasing
truncal obesity, supraclavicular fat pads, a swollen purple
face, purplish-red abdominal striae, mania and (as later
described) severe muscular weakness and glycosuria
makes the diagnosis of Cushing's Syndrome ineluctable.
Did Harvey Cushing, his pupil and later biographer,
know of Osier's early recognition of his syndrome, more
than 30 years before his classical report?
We all know of Osier's great gift of firing the enthusi-
asm and imagination of colleagues and students. He
influenced many physicians, some of whom were later to
become eminent endocrinologists?Harvey Cushing,
William S. Halsted, James H. Means.
David Marine was another of these[28]. He entered
Johns Hopkins Medical School in 1900 to study zoology
and chemistry, and the Hospital in 1901 as a medical
student. Here he fell under Osier's spell. Dr Josip
Matovinovic, of Ann Arbor, writes that David Marine
confided to him that he was influenced by Osier's brilliant
education, general and professional, his kindness and his
dignity[29]. Osier suggested to Marine that he should
institute a study of pregnant women and treat them with
iodine or dessicated thyroid. This early interest in the
thyroid burgeoned when Marine was appointed to Cleve-
land, a famous epicentre of endemic goitre. Writing
about this to Matovinovic in 1968, Marine, then 88 years
old, described how on the morning he arrived in Cleve-
land from Baltimore, walking from his hotel to the
hospital he saw many dogs with swollen necks; he stopped
three or four of them and found that the swelling was due
to enlargement of the thyroid gland. This decided him to
follow up the early interest in goitre induced by Osier's
influence, and to make this his major research. Iodine
treatment of goitre had long been practised in Europe
(Switzerland, Germany, France) but had fallen into
disrepute because of the high incidence of iodism and,
especially, of hyperthyroidism due to excessive iodine
intake (Jod Basedow). Marine spent six months in 1913-
14 with Theodor Kocher who strongly opposed the use of
iodine in goitre therapy and whose prestige at that time
was such that the practice was all but abandoned. Despite
this Marine remained convinced as a result of his own
experiments that endemic goitre was due to absolute
iodine deficiency.
Marine initiated the first proper goitre prevention trial
in Akron, Ohio, from 1917 to 1920, and showed conclu-
sively that iodine was able to prevent endemic goitre and,
indeed, cure many of those that had already developed.
By using small doses of iodine he minimised the incidence
of iodism and obviated the hazard of hyperthyroidism. It
has been estimated that 200 million people throughout the
world currently suffer from endemic goitre, often with
cretinism or the neurological syndrome of iodine de-
ficiency. Through the use of injections of slowly-released
organic iodide-containing oils much of this is now being
prevented, a benefit we can attribute directly to David
Marine, in whose early work we may discern the guiding
hand of Osier.
In his writings on the thyroid, Osier showed all of his
familiar characteristics. He was quick to spot the import-
ance of research that was going on in the field, especially
in Horsley's laboratory; he was able to place it in its
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
historical perspective and to discern the connection with
cretinism, his clinical descriptions of which could not be
bettered today; he spoke and wrote about it only after his
own reading, observation and surveys had provided a
sound and thoughtful basis for speculation. His contribu-
tion to the field was not large but it exemplified his oft-
quoted statement: 'That man can interrogate as well as
observe nature, was a lesson slowly learned in his evolu-
tion'.
This article is based on the Oslerian Oration delivered to the
Osier Club of London in July 1984.
References
1. Graves, R. J. (1835) In Medical Classics (1940) pp. 25-43. (Com-
piled by E. C. Kelly.) Baltimore: Williams and Wilkins.
2. Parry, C. H. (1825) Collections from the Unpublished Papers of the Late
Caleb Hillier Parry, Vol. 2, pp. 111-128. London: Underwood.
3. Berthold, A. A. (1849) quoted by Rolleston, H. D. (1936) The
Endocrine Organs in Health and Disease. London: Oxford University
Press.
4. Addison, T. (1849) London Medical Gazette, 43, 517, 562.
5. Addison, T. (1855) In A Collection of the Published Writings of the Late
Thomas Addison, MD, p. 209. (ed Wilks and Daldy 1868.) London:
The New Sydenham Society.
6. Brown-Sequard, C. E. (1856, 1858) quoted by Rolleston (see
reference 3).
7. Curling, T. B. (1850) Medical and Chirurgical Transactions, 33, 303.
8. Gull, W. W. (1874) Transactions of the Clinical Society of London, 7,
180.
9. Ord, W. M. (1878) Medical and Chirurgical Transactions, 61, 57.
10. Fagge, C. H. (1871) Medical and Chirurgical Transactions, 54, 155.
11. Reverdin, J. L. and Reverdin, A. (1883) Revue medicale de la Suisse
romande, 3, 360.
12. Kocher, T. (1883) Archiv fur klinische Chirurgie, 29, 254.
13. Semon, F. (1888) Transactions of the Clinical Society of London, XXI,
(suppl.), 10.
14. Clinical Society of London (1888) Transactions of the Clinical Society of
London, XXI, (Suppl.), 21.
15. Murray, G. R. (1891) British Medical Journal, 2, 796.
16. Editorial (by Osier, W.) (1886) Medical News, 49, 661.
17. Editorial (by Osier, W.) (1885) The Medical News, XLVI, 381.
18. Editorial (by Osier, W.) (1887) Medical News (Philadelphia), 1, 523.
19. Osier, W. (1889) Medical News (Philadelphia), lv, 257.
20. Osier, W. (1892) Johns Hopkins Hospital Bulletin, 21, 42.
21. Osier, W. (1898) Journal of Cutaneous and Genitourinary Disease, xvi,
127.
22. Osier, W. (1895) Archives of Pediatrics, New York, xii, 105.
23. Osier, W. (1899) Journal of Nervous and Mental Disease, xxvi, 65.
24. Osier, W. (1893) Transactions of the Association of American Physicians,
viii, 380.
25. Osier, W. (1897) American Journal of the Medical Sciences, 114, 377.
26. Paget, S. (1919) Sir Victor Horsley: a study of his life and work. London:
Constable.
27. Osier, W. (1916) British Medical Journal, 2, 165.
28. Matovinovic, J. (1978) Perspectives in Biology and Medicine, 21, 565.
29. Matovinovic, J. (1984) Personal communication.
|
PMC005xxxxxx/PMC5371010.txt | Recruitment and Training in Community
Medicine ? A Decade's Experience
ROSEMARY RUE, CBE, MB, FRCFJ Regional Medical Officer and General Manager,
Oxford Regional Health Authority; Chairman, Midlands and South Western Inter-Regional
Training Scheme in Community Medicine
A. G. W. WHITFIELD, CBE, MD, FRCFJ Assistant Director, Royal College of Physicians
Research Unit; Convener, Midlands and South Western Inter-Regional Training Scheme in
Community Medicine
It is now ten years since the inaugural meeting of the
Faculty of Community Medicine of the Royal Colleges of
Physicians, the first MFCM examinations and the first
registration of Fellowships and Memberships of the Fac-
ulty with the General Medical Council. With the help of
Lord Rosenheim the Faculty had however been estab-
lished and many of its foundation Fellows and Members
elected two years earlier.
The new specialty comprised several heterogeneous
groups of doctors including medical officers of health,
those administering the hospital service, those employed
at the Department of Health and Social Security, the
Scottish Home and Health Department, the Welsh Office
and Northern Ireland Department of Health and Social
Services, those in the medical services of the armed forces
and those in academic departments of community medi-
cine whose main interest was usually epidemiology or
operational research. To assimilate doctors with such
divergent areas of responsibility into one specialty was a
daunting task. In addition, community physicians have
had to guide the profession through two reorganisations
and help it to adjust to a period of severe recession in
place of continuous expansion and limitless finance which
had been its staple diet since the establishment of the
National Health Service in 1948.
Although the specialty has developed an attitude of
extreme modesty and self-criticism, its contribution has
been remarkable considering the lack of proper training
available until a decade ago. Moreover, it has had to face
and live with much disharmony within the Health Ser-
vice, which has led to the rapid growth of private medical
care.
Although some doctors wishing to pursue a career in
community medicine prepare themselves for the Part I
MFCM examination and largely arrange their own Part
II project and service training, the majority in England
and Wales are employed as registrars by health authori-
ties and attend the MSc course at the London School of
Hygiene and Tropical Medicine or the University of
Manchester, the MPH course at Leeds or one of the three
consortia training schemes.
The 1983 report of the joint working party set up by the
Regional Medical Officers and the Community Medicine
Consultative Committeefl] indicated that a minimum
intake into the specialty of 80 trainees per year is
necessary to fill the 200 existing career vacancies for
Specialists in Community Medicine (SCMs) and those
which will arise from death or retirement in England and
Wales. This article describes the work of one of the three
consortia, the Midlands and South Western Inter-Re-
gional Training Scheme, which the joint working party
suggested should aim at an intake of 26 trainees per year.
The Scheme
Geographically, the scheme covers the Oxford, South
Western, Wessex and West Midlands Regions and the
whole of Wales apart from Clwyd and Gwynedd. The
participating universities are Oxford, Bristol, Wales,
Southampton, Exeter and Birmingham. Reading also
contributed until the DHSS withdrew the funding of its
operational research unit. Twenty weeks of modular
training, covering Appendix I of Specialist Training in
Community Medicine [2], is provided by the universities
and a further week by the DHSS. Between modules,
registrars receive in-service training as outlined in Ap-
pendix II of Specialist Training in Community Medicine [2].
Approximately one-third of the in-service training is at
the Regional Health Authority and the remaining two-
thirds is normally split between two disparate but geo-
graphically adjacent districts. During in-service training
registrars spend about half a day each week with their
academic tutor. The scheme is of two years' duration and
after passing the Part I MFCM and approval by a Senior
Registrar Assessment Committee the trainees are up-
graded to senior registrar.
Recruitment
Since the scheme started in 1973, 132 doctors have been
accepted for training (Table 1). It will be seen that it has
never been possible to reach the target of 26 per year; in
fact even if this number of suitable candidates applied it is
at present doubtful whether so many posts could be
112 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
Table 1. Entrants to Midland and South Western Inter-Regional Training Scheme in Community Medicine by year, age and sex.
1973
1974
1975
1976
1977
1978
1979
1980
1981
1982
1983
1984
Total M
7
11
8
5
11
10
9
9
14
12
18
18
10
4
4
4
2
4
4
5
1
5
4
10
Mean age (years)
Total M F
35.4
37.9
36.3
31.2
33.1
32.8
31.3
34.6
33.6
32.8
30.7
31.1
35.0
36.1
33.5
27.0
34.0
33.3
28.8
34.5
35.1
33.5
29.5
32.9
35.8
38.5
39.0
37.5
31.5
32.0
32.4
25.0
31.2
31.8
31.7
29.0
20-29
3
2
3
3
4
4
4
2
7
4
10
Age range (years)
30-39 40-49
2
5
2
1
6
4
4
5
3
6
7
10
50-59
132 77 (59%) 55(41%)
32.8 32.9 32.7
53 55 18 6
funded or satisfactory service placements arranged. In-
itially there was a great shortage of acceptable applicants
but over the last four years the number and quality of
candidates have improved greatly. This is thought to be
due to several factors. First, greater undergraduate expo-
sure to the specialty, second, the intense competition in
the major clinical specialties together with worldwide
over-production of doctors, third, a growing appreciation
that community medicine is an interesting, challenging
and important specialty, and fourth, the increased female
intake into the profession, many of whom find com-
munity medicine best suited to their professional aspira-
tions and family commitments. However, more male (59
per cent) than female (41 per cent) doctors have entered
training; it will be seen that the mean age of males and
females has been similar and that entrants are a little
younger now than they were when the scheme started.
This is due mainly to the diminishing numbers of mature
senior clinical medical officers wishing to obtain the
MFCM and become community physicians and to fewer
older general practitioners seeking to transfer to com-
munity medicine.
Of the 132 entrants, 66 had obtained higher qualifica-
tions before starting training in community medicine; 21
held the MRCP, FRCS, FRCOG, MRCOG or
MRCGP, 6 had doctorates of medicine and 2 of philos-
ophy, 21 had degrees of BSc or B Med Sci, 4 had obtained
the DPH, 16 the DCH, 17 the DRCOG and 8 held other
diplomas.
Wastage
Seventeen (12.9 per cent) of the 132 entrants have left the
specialty; 13 of the 17 transferred to general practice
before vocational training became mandatory. In two the
change resulted from failure to pass the Part I MFCM
examination and in another two because of difficulty over
the Part II dissertation; 6 of the 13 had already passed the
Part I examination and the demands of Part II coupled
with a reluctance to relinquish clinical work and the
attraction of the higher income and tax allowances in
general practice appeared to be the major influences. The
other 4 of the 17 lost to the specialty included one who has
transferred to audiological medicine, one to genito-uri-
nary medicine and two to occupational medicine. One of
the latter was working in the Employment Advisory
Service when he joined the scheme in order to obtain the
MFCM, but he was unsuccessful in the examination. He
has since obtained the MFOM and DIH.
A wastage of 12.9 per cent is considerably lower than
that envisaged by the joint working party of the Regional
Medical Officers and Community Medical Consultative
Committee[l] and in the 1980 report of a Joint Working
Group entitled Recruitment to Community Medicine[3], who
assumed a trainee wastage rate of 45 per cent. The low
wastage is thought to reflect increasingly stringent selec-
tion of entrants.
Progress of Trainees
Of the 132 trainees, 36 have not yet been in the scheme
long enough to sit the Part I examination, 48 have
completed Part I but have not yet obtained Part II, while
26 have obtained Part II. Eleven have not passed either
Part I or Part II but are still in the specialty and 11 of
those who have left the specialty had not passed any part
of the examination.
Of the 115 remaining in the specialty, 37 have already
achieved SCM (consultant equivalent) status, of whom
one has died and 3 are overseas; 6 who have SCM or
equivalent status were unsuccessful in the Part I MFCM
examination despite repeated efforts, being appointed
SCM because it was felt that the scheme had given them
sufficient knowledge and experience to enable them to
fulfil their duties and that their personal qualities fitted
them for the job (Table 2).
The interval between passing the Part I examination
and completing Part II is shown in Table 3. The delay has
been a source of some anxiety and appears attributable to
several factors; first, with the present staff shortage in the
specialty senior registrars have been overburdened with
service work and are often called upon to fill vacant DMO
posts on a locum basis. Second, some projects chosen
have by their nature required several years to elapse
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 113
Table 2. Progress of 132 entrants into scheme
Passed Part I MFCM
Completed MFCM
Not passed Part I MFCM but still in specialty?
as consultant or equivalent 6
as SCMO 3
Left specialty?
with Part I MFCM
without Part I MFCM
Consultants (DMOs, SCMs, Senior Lecturers
or equivalent)
Senior Registrar or Lecturer
Registrar?
Not yet 2 years in post
Failed Part I MFCM once
Failed Part I MFCM twice
Passed Part I MFCM and
awaiting Senior Registrar
Assessment Committee
Passed Part I MFCM gaining
further clinical experience
in general practice 1 /
'Includes 1 died, 3 abroad and 5 not yet completed Part II and
special salary scale
nl
36
1
1
48
26
17
44
Table 3. Interval between passing Part I and obtaining Part II
of the MFCM examination.
Years Number of Trainees Mean age at entry to scheme
0 1 43.0
1 1 32.0
2 5 38.0
3 4 30.0
4 10 32.2
5 1 28.0
6 1 37.0
7 1 26.0
before the information sought could be available. Third,
other projects have been intended to serve also as MD
theses and their magnitude has inevitably involved sev-
eral years' work. Fourth, some senior registrars have not
decided on a Part II project until they have been in post
some little time and fifth, within the Faculty there has
been some delay in granting approval to project protocols
and in assessing dissertations. Delay in obtaining Part II
did not appear to be age-related. Senior registrars are
currently urged to give priority to and to complete their
Part II during their first year in post and to select their
project and get its protocol approved immediately they
pass Part I or before.
Failure to pass Part I is age-related, the mean age of
those who are successful being 31.7 years as compared
with 41.5 years in those who fail. It appears more difficult
for the mature general practitioner or senior clinical
medical officer to grasp the skills required of a community
physician today.
Discussion
The current situation suggests that recruitment to com-
munity medicine is improving and that the trend is likely
to continue and accelerate.
The Faculty of Community Medicine is to be congratu-
lated upon setting up a satisfactory Membership Examin-
ation in only a little over ten years. It is hoped that the
Faculty will continue its efforts to reduce delays in the
second part of the examination and that its assessors will
adopt realistic standards. If this can be achieved, there
should be no delay in advancement to SCM status for the
foreseeable future and the use of the special salary scale
should rarely be required. While in general it is probably
wise and kind to dissuade mature doctors from entering
the specialty because of the examination difficulties that
they may encounter, a mean age at entry of over 30
indicates that nearly all those recruited to the specialty
will have had much more than the one mandatory year of
post-registration clinical experience. In these circum-
stances four or five years of training in community
medicine should suffice. Even this means that the average
trainee will be about 37 before becoming an SCM and
will have only 28 years in a career post before him, or 23
if he retires at 60 as so many do.
While the standard of the National Health Service will
always depend on the skill and devotion of its clinicians,
nurses and paramedical personnel, it is unrealistic to
think of any increase in the funds that can be made
available to it for many years, if ever. In these circum-
stances the community physicians' skills of epidemiology,
statistics, health services management and research, in-
formation systems, planning, manpower, health care
evaluation and the behavioural sciences provide the es-
sentials of good housekeeping. The Royal Colleges of
Physicians of London, Edinburgh and Glasgow have
every reason to be proud of the progress and achieve-
ments of the Faculty they helped to establish ten years
ago.
References
1. Recruitment and Training in Community Medicine (1982) Report of
Regional Medical Officers/Community Medicine Consultative
Committee Working Party.
2. Specialist Training in Community Medicine (1982) The Faculty of
Community Medicine.
3. Recruitment to Community Medicine (1980) Report of Joint Working
Group from the Profession and Central Government Departments.
114 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
|
PMC005xxxxxx/PMC5371011.txt | The Enigma of Pertussis *
The Marc Daniels Lecture 1984
// '/ ??J
H. P LAMBERT, md, frcr ffcm
Professor of Microbial Diseases, St George's Hospital Medical School, London
Marc Daniels died at the age of 46, in 1953. Most of his
working life was spent in the study of tuberculosis. After
the Second World War he worked in many European
countries in which tuberculosis was rife and then, in
1946, joined the Medical Research Council. The work in
which he was so deeply involved, on the emerging forms
of chemotherapy and on BCG vaccination, set a gold
standard for the conduct of clinical trials, which still
operates. These early MRC studies were the first proper-
ly controlled trials in tuberculosis but had an impact far
beyond this particular disease. They showed the import-
ance of such trials, the need for their careful planning, the
solution of the many statistical and ethical problems and
the organisation required. It is hard now to remember
how relatively recent these ideas are; one reason why the
work of innovators is easily forgotten is that it becomes so
firmly embedded in the ideology of science that later
generations assume that the ideas have existed for ever.
Another lesson is that trials need to be done quickly and
early: the first MRC report on isoniazid was published a
mere six months from its start.
We are still sadly short of much important information
about pertussis, some of it susceptible to the kind of study
of which Marc Daniels was such an effective protagonist.
By the mid-1970s it was possible for the author of an
extensive review of pertussis to say that the disease had
become something of a medical curiosity. Even at that
time this was certainly not true in the developing coun-
tries. In several of the wealthier countries, notably Brit-
ain, the situation was just about to change in a very
dramatic way, which brought pertussis back into promi-
nence as a subject of great public health importance and
led to a resurgence of studies on many basic aspects of the
disease.
The Recent History of Pertussis
At the beginning of this century pertussis was a major
cause of childhood mortality, causing more deaths than
any of the infective diseases of children except measles. In
infants, it was a more frequent cause of death than
measles. Then, throughout the century there followed a
major decline in case fatality, long before immunisation
was introduced and continuing after its general introduc-
tion in the post-war decades. Notifications, however, fell
sharply only after the mid-1950s and other countries, for
example the USA, experienced similar changes, one of
the many controversies being whether this decline could
be related in any way to vaccination programmes, or
whether it represented a continuation of previous trends
unrelated to immunisationfl].
In 1974 the question of possible brain damage follow-
ing pertussis-containing vaccine was brought into sharp
public focus as a result of a television programme and
many articles in newspapers, leading to a loss of confi-
dence in the vaccine among parents and Health Service
staff, and a steep fall in vaccination rates. So, in 1975-76,
pertussis posed several very important practical ques-
tions. The first one, was the vaccine having any effect,
was answered by two large epidemics of pertussis, the
largest since a general programme of immunisation
against the disease was introduced in 1957. The sequence
of events does not, of course, itself prove that a previous
vaccine had an effect, but there is much detailed epidemi-
ological evidence which makes this conclusion inescap-
able. The question of whether the vaccine carried a risk of
neurological damage was answered about as fully as it
was possible to do by the National Childhood Encephalo-
pathy Survey carried out by Miller et al. [2]. The unan-
swered questions were: What impact does pertussis have
on the current generation of patients who develop the
disease? What sort of an illness is it, how serious is it,
what complications may ensue? Does it cause long-term
pulmonary damage? The reasons why these questions
could not be answered were twofold. First, the steep fall
in mortality and more anecdotal evidence about decline
in severity made it clear that the disease had changed in
recent decades so that older studies could not be validly
used in any cost-benefit equation. The same argument
applied to the problem of long-term damage, but here a
second difficulty also emerged; the older studies address-
ing this question were few in number and, by modern
standards, lacking in control data which would ensure
their epidemiological validity.
The Illness and its Complications
The main features of pertussis are well known, the
paroxysmal bouts of coughing and choking often culmi-
nating in vomiting and cyanosis, which may occur as
many as 50 times in 24 hours. The apnoeic attacks,
especially common in infancy and at that age often
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
occurring without a preceding coughing bout, and the
generally long duration of the illness make an intensely
unpleasant experience.
There is much misunderstanding between affected
families and doctors because the patients generally look
well and have few or no abnormal signs on examination
between the attacks, and the attacks are seen by mothers
at home and by nurses in hospital but less often by doctors
in either case. There is a great list of complications, and
clinical or radiographic evidence of lung involvement is
quite common. In the series collected at St George's
Hospital, 24 per cent had abnormal chest radiographs
and similar findings have been reported from many other
countries. Fits are not uncommon and encephalopathy
still occasionally occurs.
However, although chest complications especially are
potentially important, we believe that attempts to
measure the impact and severity of pertussis merely by
enumerating complications are misleading. Some so-
called complications are of little or no importance, the
definition of a complication being to some extent arbi-
trary and, most importantly, the use of complications as
an index of severity diverts attention from the central
features of the disease which give it its chief impact.
Impact on the Patient and Family
Another aspect of severity to which little attention has
usually been paid is the extent to which the illness affects
the life of the patient and his family. There have been
many studies of this kind in relation to chronic illness, but
few have focussed on acute illnesses and none on whoop-
ing cough. As part of a group of studies carried out
recently at St George's Hospital, we decided to examine
this aspect of the disease[3]. Dr I. D. A. Johnston and
Miss M. Hill, an MSc student in clinical psychology,
interviewed the parents of 21 children admitted to hospi-
tal with pertussis. They did this on two occasions, the first
shortly after admission and the second during convales-
cence at the patients' homes. The questions were of a
structured but relatively open-ended kind, useful in pro-
viding a systematic approach without unduly limiting the
scope of the answers, and were aimed at providing
information about the illness and the problems it posed
for patient and family, at determining the effect of the
illness on the behaviour of patient and family and at
identifying the parents' attitudes and fears. They includ-
ed behaviour checklists for the patient and the family
which could be roughly quantified. One incidental find-
ing, which the late convalescent interview made possible,
was confirmation of the prolonged nature of the illness,
with a mean duration of 11.7 weeks but lasting over 16
weeks in more than a quarter of the children. The
behaviour of the children was severely affected during the
illness and had still not returned to normal at the second
interview about two months later; the effect of admission
to hospital, which has been extensively studied in other
contexts, may have contributed at this later stage. Famil-
ies, too, were greatly affected in their behaviour patterns,
although these had generally returned to normal by the
time of the second interview.
There is no doubt that pertussis was an intensely
distressing experience for the parents as well as for the
patient. Not surprisingly, the apnoeic or choking attack
was most distressing and many parents commented on
their feeling of helplessness at these times. During the
acute stage most parents were concerned that their child
might die; later their main worry was of permanent chest
damage. The possibility of brain damage was also of
concern in the acute stage. There was much physical
stress, too, particularly the extensive disruption of sleep
and consequent fatigue of the parents. Most parents were
being woken at least five times every night, for a mean of
24 nights (range 7-60) before the patient's admission.
Some were awakened 10-15 times each night or sat up
with their child all night. It is not surprising that in these
circumstances strains on the marriage often emerged
especially as some husbands, like some doctors, doubted
the severity of the illness, as they were often away when
the child had its worst episodes.
Pertussis in Adults
These patients were all children, but pertussis is not
uncommon in adults. In Dr W. O. Williams' study in
South Wales 10 per cent of the cases were adults [4] and
even the crude notification figures showed adults as 3.3
per cent of cases in the 1977-79 epidemic. Pertussis is
often said to present atypical features in adult life and
some of the few studies of adults indicate that whooping is
uncommon. Others, however, show a picture very similar
to that found in children and it seems that the disease
often goes undiagnosed because it is unexpected in adults.
Certainly it can be severe at any age. In the recent
epidemics a general practitioner in his thirties developed
cough syncope following the paroxysms; Williams saw
grandparents aged 77 both with the disease and I have
seen a woman of 65 with its typical features.
Nevertheless, the disease in adults may be atypical or
mild and this is of epidemiological importance, since
Nelson in the USA has provided evidence that, in his
community, adults may be the main source of infection
for susceptible children[5]. One reason why adult pertus-
sis may have become more common is the decline in
immunity in the population generally. At the turn of the
century the median age for pertussis was < 4 years and 85
per cent of the population had had the disease by the age
of seven years, so that few adults were susceptible. The
spread of pertussis from and to adults in hospitals has
been observed on several occasions.
Pertussis in the Third World
A final clinical point is the contrast between pertussis in
wealthy and poor countries. Some years ago Morley[6]
showed that whooping cough in Nigeria was very severe
and that, as for measles, the mortality rate approximated
to that found in fever hospitals in London in the first
decades of this century; the actual figures were 15.5 per
cent of 479 admissions in Nigeria from 1957 to 1981, and
11.9 per cent deaths of 17,003 admissions to the London
Fever Hospital between 1911 and 1929. Certainly this fits
68 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
in with the records of the Grove Fever Hospital, now the
site of St George's Hospital and Medical School. The
postmortem books show many records of children who
died there of pertussis well into the 1940s. Recent data on
pertussis in the Third World is, however, much more
scanty and much less information is available than in the
case of measles. A study in Kenya[7] in the mid-1970s
estimated the infant fatality rate at 3.2 per cent and
WHO figures of the late 1970s estimated that pertussis
accounted for the deaths of 250,000-450,000 child deaths
P-a., making it about as important as tuberculosis as a
cause of death in childhood [8]. Accurate recent records
about Third World pertussis are very definitely needed,
but the data we have suggest that, as in other infections,
the impact of the disease is greater than it is in wealthier
countries.
Treatment
Can pertussis be treated? A multitude of treatments has
been employed at various times and it is sad to note,
many decades after clinical trial methods were firmly
established, that the evidence for many of the more
modern remedies is little greater than for the traditional
ones. One reason for this was the decline of interest in the
disease before its recent resurgence, another is the great
difficulty in assessment of severity, making pertussis a
peculiarly difficult disease to measure.
As regards antibiotics, MRC trials in the 1950s[9]
established that the number of coughing spasms was
lessened by the use of chloramphenicol or chlortetra-
cycline both given in high doses. The effect was, however,
a small one and could be detected only in the patients
treated early in the disease. The disease has changed since
these trials were done, and in any case these two agents,
for well-known reasons, are not now considered suitable
for childhood infections. There is now some evidence that
erythromycin mitigates the severity of the disease but no
adequate trials of substantial size have been carried out
and any effect is likely to be small[10]. Some anti-
microbial drugs, including erythromycin, have been pro-
posed as chemoprophylaxis for family or institutional
contacts as an alternative to control by immunisation.
This could be especially useful in young infants who are
both susceptible to the disease yet too young to have been
fully immunised against it. Scattered reports have ap-
peared suggesting that erythromycin could be used in this
way but two recent placebo controlled trials showed no
benefit from this method. The treated contacts showed no
advantage over their controls and the method was in fact
difficult to apply in field conditionsfll, 12]. Indeed, one
reason for failure may have been the problem of timing
since in the larger study an average of two weeks elapsed
between the first sympton in the index case and the
administration of drug, or placebo, to the contact.
Whether or not antibiotic treatment has any effect on
established disease or in preventing it in contacts, some,
especially erythromycin, do reduce naso-pharyngeal car-
riage of the organism, so that one justification for their
use is that the risk to contacts may be diminished. This
may be so, but many failures to prevent infection in this
way have also been described, perhaps because the effect
of erythromycin in reducing naso-pharyngeal carriage is
not as rapid or as complete as is sometimes supposed.
More studies of these relationships are needed, especially
in closed communities in which a point source of infection
is sometimes identifiable.
Does Pertussis damage the Lungs?
The paucity of previous controlled observations and the
changes in the disease in recent decades have deprived us
of valid information on possible long-term lung damage
caused by pertussis. This problem has now been studied
by I. D. A. Johnston working jointly in the Department
of Communicable Diseases and the Department of Social
Medicine and Clinical Epidemiology at St George's
Hospital Medical School. The study involved the identifi-
cation, from both hospital and from community sources,
of children who had had whooping cough in 1971-79, and
the use of controls, two for each index case, randomly
selected from the same class as the index case. Groups of
cases and controls were studied at their schools, at the
same session, the observer being 'blind' to their identity
as cases or controls. This school-based study had the great
advantage of eliminating many potentially confounding
variables such as local exposure to respiratory infection,
air pollution and, to some extent, socio-economic varia-
bles. Respiratory questionnaires were used, employing
well-validated questions from the large body of previous
work on childhood respiratory disease, together with
other relevant questions, giving information on such
matters as breast feeding, previous hospital admission,
vaccination, family size, parental smoking, social class
and aspects of family history. The questionnaire was
blandly entitled to avoid any particular attention to
whooping cough. At the school visits the groups of
children were measured to obtain weight, height, skin-
fold thickness at four sites and arm circumference, and
the chest was inspected and auscultated, including assess-
ment of the 'loose cough' sign. Spirometry was performed
using an 'S' model spirometer, measuring the FEVo.75,
FEVi and FVC and deriving the FEV/FCV%, the
FEF25-75; the mean transit time was read on a printout
from the microprocessor.
The opportunity was taken to apply the respiratory
questionnaire to all children in the classes containing an
index case plus control group, so that, on completion of
the study, we had 360 cases and 711 controls but, in
addition, about 4,000 additional questionnaires which
acted as another set of control data underpinning this
aspect of the survey.
The results have been published elsewhere[13], but, in
brief, questionnaire data revealed a significant excess, in
children who had whooping cough, of previous chest
illnesses, hay fever and eczema, especially marked in the
group who had been in hospital for whooping cough, who
showed a two- to three-fold excess of past respiratory
illness (Table 1). The same trends were observed in the
tendency to current symptoms, that is, within the preced-
ing year (Table 2).
In the lung function tests, however, although there
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
69
Table 1. Reported chest symptoms at any age (%).
Croup
Pneumonia
Bronchitis
Wheezy bronchitis
Wheeze
Asthma
Hay fever
Eczema
* PC0.05 ** /><().01 *** P<0.001
Cases Controls
n = 360 n = 711
18 9
8 3
16 8
15 8
17 9
7 4
12 7
19 12
Table 2. Reported chest symptoms in last year (%)
Morning cough
Day/night cough
Morning phlegm
Day/night phlegm
Wheeze
Breathlessness
Cough/cold lasting 2 weeks
* /><0.05 *** P<0.001
Cases Controls
n = 360 n = 711
23 13
6 3
8 4
25 12
16 7
38 33
were small differences in some of the sub-groups, none
was significant and, overall, the mean measurements
were the same in test and control groups, with the
observations sharing narrow confidence limits (Tables 3
and 4).
Table 3. Lung function tests
Adjusted Difference 95% confidence
Lung Function* between cases limits for
Test Cases Controls and controls difference
FEVo.75 1-571 1.564
FEV, 1.689 1.686
FVC 1.904 1.896
FEF 1/s 2.119 2.127
* Lung function adjusted to height = 128
+ 0.007 -0.017 to 0.030
+ 0.003 - 0.022 to 0.028
+ 0.008 -0.021 to 0.036
-0.008 -0.058 to 0.073
Table 4. Lung function tests. Forced expiratory ratio and mean
transit time (MTT).
Cases Controls
FEV,/FVC % n = 333 n = 670
89.2 89.1
MTT (sec) n = 211 n = 458
0.47 0.47
It appears, therefore, that children who have had
pertussis have had and do now suffer an excess of
respiratory illnesses compared with their controls. Is this
excess caused by whooping cough or does it precede it,
indicating a susceptibility to respiratory infection which
might include an increased likelihood of developing per-
tussis, or pertussis of increased severity? Or, of course,
both these factors might be operating. We cannot answer
this question with complete confidence but an analysis of
the ages at which the cases had whooping cough suggests
that the undue susceptibility to chest illness shown by
these children preceded their attack of whooping cough
and then continued after it.
The lung function tests do exclude any possibility that,
in the present generation of British children, whooping
cough has any substantial effect on ventilatory function.
Two caveats are necessary. First, the size of the study
would not suffice to detect reliably rare pulmonary
complications: for example, if, as was long ago supposed,
whooping cough was followed by bronchiectasis in one in
200-300 children, such an effect could only have been
detected in a much larger study. Second, in view of the
abnormal experience of respiratory infections of these
children and the controversy about methods of testing for
small airways disease, could important findings be missed
by our measurements? This seems unlikely but, in col-
laboration with Dr J. Warner, we have carried out
another study, now being analysed, in which a number of
children who had pertussis in infancy, together with
suitable controls, have been tested at Brompton Hospital
for bronchial sensitivity to histamine, together with skin
tests and detailed lung function studies including flow-
volume curves and nitrogen washout tests.
Advances in Pathogenesis
Bordetella pertussis shows an astonishing variety of bio-
logical effects in experimental animals (Table 5), some of
Table 5. Biological activities of Bordetella pertussis
Pertussigen Lymphocytosis-promoting factor
histamine sensitisation
islet activation
Filamentous haemagglutinin
Agglutinogens
Endotoxin (lipopolysaccharide)
Dermonecrotic toxin
Adjuvant effects
Extracytoplasmic adenylate cyclase
the most striking being the induction of lymphocytosis, a
high degree of sensitivity to the lethal effects of histamine,
and resistance to the hyperglycaemic action of adrenaline,
and there Ws been much effort to characterise these
effects more fully, both chemically and by analysis of their
precise physiological mechanisms[14]. In addition to the
well-established actions, a recent addition is the finding of
an extracytoplasmic adenylate cyclase which is ingested
by leucocytes and diminishes their phagocytic ca-
pacity[15]. At one level these actions may seem obscure
experimental findings of no practical importance but they
do point to actions which might have some significance in
accounting for the strange pathogenesis of pertussis and
70 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
perhaps too for the unwanted effects of vaccine. It is still,
however, not possible to make a clear line of explanation
between the experimental findings and the human dis-
ease, although it is hard to escape the conclusion that the
lymphocytosis is likely to have the same origin in man as
in the experimental animal. A major advance has been
the isolation in crystalline form of a material which carries
three of the best recognised actions of the organism. This
has been named pertussigen or pertussis toxin. Its sub-
unit structure is beginning to be analysed. There is
certainly enough evidence to include pertussis as a 'toxin
disease analogous to cholera or tetanus. There are pro-
found general and systemic effects, yet only local activity
of the organism on the respiratory mucosa, with no
evidence of systemic invasion. So obvious targets to be
borne in mind in improved vaccines are the main pertus-
sis toxin, and other toxins shown to be relevant in
experimental systems.
Another focus of interest is the earliest stage of infec-
tion, when the organism attaches to human ciliated
respiratory epithelium to which it shows a specific attach-
ment. This has been known from morphological data for
a very long time but the mechanisms and antigens
involved are now being elucidated in much greater detail.
Workers at the Centre for Applied Microbiology and
Research are studying a number of pertussis components
as candidates for a subcellular vaccine. In Japan two
infants died after pertussis vaccination in 1974 and 1975,
so vaccination was discontinued and then reintroduced
for older children only. As in the UK a large epidemic
followed, with a peak of 41 deaths from the disease in
1979. Japanese workers have now developed a com-
ponent vaccine containing two main protective antigens;
the filamentous haemagglutinin, thought to be concerned
with attachment to cilia, and the leucocytosis promoting
factor haemagglutinin, thought to represent the main
toxin[16]. This has now been given to four million
Japanese children and, with help from WHO, is being
tested in several other countries. There are problems in
assessing the results, as few infants have been included in
the series so far, and other questions of the appropriate-
ness of different laboratory models for the newer vaccines
are still to be defined. There are hopes, too, for vaccines
from recombinant DNA techniques, since E. coh plas-
mids have been inserted into B. pertussis and transforma-
tion of plasmid-derived DNA has been demonstrated.
Conclusion
In summary, over the last decade we have found that
pertussis is still an important disease in many countries
and that current vaccines, although imperfect, are strong-
ly protective. Our study has shown that children who
have had pertussis have an abnormally high morbidity
from respiratory disease. This may well precede or in part
precede, the attack of pertussis, but whatever the mixture
of pre-existing susceptibility and effects of the disease
itself, we see a group of children who warrant special
attention in preventive programmes.
Progress on analysis of the active components of B.
pertussis has been rapid. One component vaccine has been
extensively tested and others are on the way. The ethical
and administrative problems involved in efficacy and
safety testing of these vaccines are great.
There are still great gaps in our understanding of how
the pertussis toxins relate to the human disease. In
particular the pathophysiology of the choking bouts and
the apnoeic attacks which give the disease its particular
character is still mysterious, and our capacity for making
useful interventions in the progress of this distressing
disease is still sadly limited. The epidemiological data
make it clear that, until extremely effective vaccines can
be universally and continuously used, pertussis will re-
main with us and continue to deserve study both for its
public health importance and for its fundamental interest
as a model of a particular kind of host-parasite relation-
ship, the pathogenesis of which is at last becoming
susceptible to detailed analysis in biochemical and im-
munological language.
At present, parents of children with whooping cough
are as distressed as Mary Barker, who wrote to her
husband Abel on 26th May 1661, to say, 'I am in a sad
condition for my pore children who are all so trobled with
the chincough that I am afraid it will kill them. I am fane
to have a candell stand by me to go into them when the
fitt comes', and a few days later, '. . . all sadly troubled
by the chincough. Moll is much the worst. They have
such fitts that it stopes theare wind, and puts me in such
frits and feares that I am not myselfe'.
References
1. Department of Health and Social Security (1977) Whooping Cough
Vaccination. London: HMSO.
2. Miller, D. L., Ross, E. M., Alderslade, R., Bellman, M. H. and
Rawson, N. S. B. (1981) British Medical Journal, 282, 1595.
3. Johnston, I. D. A., Hill, M., Anderson, R. and Lambert, H. P.
(1985) British Medical Journal, In press.
4. Royal College of General Practitioners (Swansea Research Unit)
(1981) British Medical Journal, 282, 23.
5. Nelson, J. D. (1978) American Journal of Disease of Childhood, 132,
371.
6. Morley, D., Woodland, M. and Martin, W.J. (1966) Tropical and
Geographical Medicine, 18, 169.
7. Mathieu, J. M., Muller, A. S., Voorhoeve, A. M. and Dikken,
H. (1978) Bulletin of the World Health Organisation, 56, 773.
8. Walsh, J. A. and Warren, K. S. (1979) New England Journal of
Medicine, 301, 967.
9. Medical Research Council (1953) Lancet, 1, 1109.
10. Lambert, H. P. (1979) Journal of Antimicrobial Chemotherapy, 5, 329.
11. Grob, P. R. (1981) Lancet, 1, 772.
12. Spencely, M. and Lambert, H. P. (1981) Lancet, 1, 772.
13. Johnston, I. D. A., Anderson, H. R., Lambert, H. P. and Patel,
S. (1983) Lancet, 2, 1104.
14. Manclark, C. R. and Cowell, J. L. (1983) In Bacterial Vaccines (ed
R. Germanier.) New York: Academic Press.
15. Confer, D. L. and Eaton, J. W. (1982) Science, 217, 948.
16. Satq, Y., Kimura, M. and Fukumi, H. (1984) Lancet, 1, 122.
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
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PMC005xxxxxx/PMC5371012.txt | The Short Report ? What Next?
The time is right for yet another push to solve our career
imbalance with all its implications for medical manpower.
This saga is similar to The Mousetrap, as both have
complicated plots, have had an exceedingly long run and
a fairly obvious solution when it is revealed. Whereas The
Mousetrap gives up its secret every night, the solution to
our career imbalance is revealed at less frequent intervals
but is always greeted with surprise by the audience,
although the remedy has remained unchanged for almost
as long as The Mousetrap has been running.
The problem remains, at heart, a very simple one. For
one reason or another too many junior hospital posts were
created, particularly at SHO and registrar level, so that
the career prospects for medical graduates entering these
posts are now very poor indeed. As in The Mousetrap, a
red herring is drawn across the stage, as the sub-plot of
student numbers is often produced to explain how best to
deal with the problem. Unfortunately, this is misleading
and misconceived, as the apparent excess of student
numbers is a product of the career imbalance with only a
very small contribution from financial stringency. The
growth in investment and output from medical schools is
well within our sluggish national economic means and is
required to enable a greater spread of trained doctors into
those parts of the health service still short of medical
skills. Increased numbers of graduates are necessary to
cut waiting lists and increase the consultation time that
patients have in general practice. There is no perceived
need for fewer doctors from the viewpoint of the patient.
The apparent excess at junior level arises mainly from the
great competition for the better training posts which
ensure that graduates progress quickly to career posts
within the health service. We now have a system where
there are two classes of junior hospital post: the first,
mainly occupied by British graduates, leads reasonably
quickly to a consultant post or to general practice,
whereas the second, mainly in shortage specialties and
occupied by overseas graduates, leads nowhere. These
two classes of post have obscured the problem of career
imbalance but the increased number of British graduates
and a continuing failure to expand consultant posts has
brought the problem into the open. If there is an import-
ant sub-plot, it is not student numbers but the need to
upgrade or abolish many of these so-called training posts
occupied by juniors with no future. Any solution to our
career imbalance demands an answer for this problem.
If reducing student numbers will not solve the problem,
or only solve it at a cost to patient care, we are left with
two other options which are as well known as the plot of
The Mousetrap. The first is to have a sub-consultant
grade, suitably disguised and probably particularly tail-
ored to the part-time married woman, and the second is
to expand the consultant grade either as such or with two
levels of responsibility and activity. These solutions have
been repeatedly debated in the past, and on every
occasion the profession preferred to see consultant expan-
sion. More consultants and fewer juniors will inevitably
change the pattern of work in hospitals and sooner or later
this nettle will have to be grasped. The prospect is
uncertain for medical graduates, whichever decision is
reached. Either a substantial proportion of them will not
achieve a full career post and will become a sub-consult-
ant of one form or another or they will enter consultant
ranks with the job somewhat different from today. The
present system cannot continue for much longer although
it has defied gravity for so long that it may have life left in
it for a few more years.
Apart from the unwillingness of the profession to grasp
the nettle, there is another more difficult problem. Even
when the profession and the central government agree on
the solution, which they do from time to time, it has
proved virtually impossible to translate this agreement
into action. This is because the link between central
exhortation from the DHSS and execution of health
service policy by the Health Authorities is inadequate for
its task. It is like having a powerful car with no clutch
therefore the engine cannot drive the wheels. Until we
find a clutch mechanism it remains difficult to translate
national agreements on manpower and career structure
into realistic hospital and general practice staffing at
district level. It is unrealistic to expect District Health
Authorities to organise their staffing as if they were self-
sufficient nations concerned with medical student train-
ing and career structure as well as health care, so the
initiative is unlikely to come from them to find a mechan-
ism for ensuring that they conform to a centrally agreed
policy. A clutch mechanism is badly required and prob-
ably requires more urgent attention than finding a solu-
tion to the career imbalance, which is to hand and has
been debated almost to death in the past.
The not too recent expansion of our medical school
output, coupled with a financial slow-down, has made it
more urgent than ever to correct our career imbalance.
One of the these days The Mousetrap will be taken off, but
I hope before then we will have rung down the final
curtain on the career imbalance saga. We all know how to
solve this problem; now is the time to roll up our sleeves
and finish the job.
T. J. H. Clark
66 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
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PMC005xxxxxx/PMC5371013.txt | In Sickness and in Health
A. G. W. WHITFIELD, cbe, md, frcp
Emeritus Professor of Medicine, University of Birmingham
Honorary Consultant Physician, United Birmingham Hospitals
In less than ten years after his death virtually all that the
Prince Consort had done to increase the popularity and
importance of the monarchy had been dissipated. The
Queen's self-imposed seclusion and refusal to carry out
her public duties were the main factors. Though physical-
ly well, she lived chiefly at Osborne and her people rarely
saw her. They felt they were not getting value for money
and posters appeared outside Buckingham Palace: 'These
commanding premises to be let or sold, in consequence of
the late occupant's declining business'. Sir William Jen-
ner, her physician and President of the College 1881-88,
repeatedly pronounced the Queen unfit to accept engage-
ments when he must have known that continued seclusion
would make her worse. Perhaps he feared to cross her.
On All Fools Day 1864 The Times included a paragraph:
'Her Majesty's loyal subjects will be very well pleased to
hear that their sovereign is about to break her protracted
seclusion'. She did not open Parliament until 1866 and
then with little grace and only because she wanted a Civil
List allowance for Prince Alfred, who had just come of
age, and money for Princess Helena, who was about to
marry the impoverished Prince Christian of Schleswig-
Holstein. The same year she did visit Aldershot, held
garden parties and attended the Braemar Gathering but
in 1868 it required all the diplomacy and powers of
persuasion of her old friend and physician, Sir James
Clark, to obtain a promise to open the new St Thomas'
Hospital. Her obsession with her Highland servant John
Brown was a source of further criticism and for a time she
was referred to as 'Mrs Brown'.
The extravagant pleasure-seeking way of life of the
Prince of Wales and his love of racing, shooting, cards
and beautiful women was an additional source of public
dissatisfaction. This was greatly increased in 1870 when
he was subpoenaed to give evidence in an action for
divorce by Sir Charles Mordaunt, who cited two of the
Prince's friends, Sir Frederick Johnstone and Lord Cole,
as co-respondents. The Prince had known Harriet Mor-
daunt, a beautiful woman of 21, since childhood, as her
father, Sir Thomas Moncrieffe, lived close to Balmoral.
Harriet confessed to her husband that she had committed
adultery with Cole, Johnstone and others, including the
Prince of Wales, and it transpired that the Prince had
visited Lady Mordaunt on several occasions and written
her a dozen letters. There was, however, no corrobora-
tion of her confession in respect of the Prince. A counter
petition was filed on the grounds of Lady Mordaunt's
insanity and the Prince was not cited, but he was
understandably worried about being cross-examined by
Mr Serjeant Ballantine, Mordaunt's counsel. By the time
the action began on 16th February 1870 before the full
Court of Divorce and Matrimonial Causes Lady Mor-
daunt required institutional care. The Prince of Wales
gave evidence for only seven minutes and said that there
was 'never any improper familiarity between him and
Lady Mordaunt'. The jury found that Lady Mordaunt
was not of sound mind, an opinion shared by Lord
Penzance and Lord Justice Keating but not by the third
judge, Chief Baron Kelly. Mordaunt's action therefore
failed. However, for some time after the trial the Prince
was hissed in the streets and at the theatre in London and
some four months later when he drove up the course at
Royal Ascot.
In 1871 the Queen was physically ill. A sting on her
arm at Osborne led to an axillary abscess at Balmoral and
Jenner summoned Lister, then Professor of Surgery at
Edinburgh and the previous year appointed Surgeon in
Ordinary to the Queen in Scotland, to incise it. Lister was
kept at Balmoral for a week and Dr William Marshall of
Crathie was appointed resident medical attendant to Her
Majesty. The Queen doubtless experienced great pain,
felt very ill, and lost considerable weight and, though her
doctors professed great concern, there was little public
sympathy.
A few weeks later the Queen's health and the ever-
decreasing respect for the monarchy were transformed by
the grave illness of the Prince of Wales. Returning from
Abergeldie the Prince and Princess of Wales stayed from
October 30th to November 4th with Lord Londesborough
at Londesborough Lodge in Scarborough. From there the
Prince went to Marlborough House for two days before
returning to Sandringham. A week later, after a day's
shooting, he developed fever and a whitlow appeared on
the index finger of his right hand. He was seen by Dr
John Lowe of King's Lynn, medical attendant to the
Prince and Princess of Wales at Sandringham, and the
following day he went to stay with Lord Carrington at
Gayhurst but as the whitlow became more troublesome
Mr Oscar Clayton, Extra Surgeon in Ordinary to the
Prince of Wales, was summoned from London and
remained at Gayhurst until November 17th when the
Prince went to Marlborough House. He saw a play in the
evening and returned to Sandringham the following day.
The whitlow had subsided, as had a second whitlow on
the left hand, but the Prince was still very unwell and
when Dr Lowe saw him on November 20th he diagnosed
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 115
typhoid and again sent for Mr Oscar Clayton who agreed
with Lowe's opinion. Jenner was detained with the
Queen at Balmoral so Dr William Gull, the Guy's
Hospital physician, whom the Prince had previously
consulted, was sent for and when he saw the Prince on
November 22nd he too agreed that it was typhoid, as did
Jenner when he arrived from Scotland the following day.
Jenner had had long experience of typhoid at the London
Fever Hospital and was the first to differentiate typhoid
and typhus fevers. He had been one of the four physicians
attending the Prince Consort when he died from typhoid
in 1861. A bulletin signed by Jenner, Gull, Clayton and
Lowe was issued, stating that the Prince had typhoid but
that there were no unfavourable symptoms, and there-
after Jenner and Gull remained at Sandringham.
For the next two weeks the illness appeared to be
running a normal course apart from a persistently high
respiration rate. However, on December 7th there was an
increase in fever, delirium and marked deterioration due
to a chest infection, which was hardly a surprising
complication in view of the vast number of cigars and
cigarettes smoked by the Prince. For some days his life
was in imminent danger and there was intense anxiety in
London in particular but also all over the country and in
India, Canada, Australia and America. The Prince Con-
sort had died from typhoid at Windsor Castle on Decem-
ber 14th ten years previously and as the anniversary of his
death approached it appeared impossible that the Prince
of Wales would survive. The Archbishop of Canterbury
issued a form of prayer to be used on or after December
10th in all chapels and churches of the Establishment and
a slightly altered version was used in Catholic churches
and in the synagogues. Jenner, Gull and Lowe issued
bulletins five times a day, which crowds clamoured to
read. Inevitably they were very repetitive, hence the
future Poet Laureate, Alfred Austin's, lines: 'Flashed
from his bed, the electric tidings came. He is not better;
he is much the same'. The bellringers were summoned to
St Paul's Cathedral to toll out the Prince's death but
miraculously that weekend he began to improve and
thereafter made slow but continuous progress towards
recovery.
The royal children were sent to Windsor early in the
illness but the Princess of Wales and Princess Alice of
Hesse were at Sandringham throughout, and the Duke of
Edinburgh, Prince Leopold, Princess Louise, Princess
Beatrice and the Duke of Cambridge for the critical
period. The Queen travelled from Balmoral to Windsor
as soon as she heard the news of the Prince's illness and
from there she went to Sandringham, which she had
never visited previously, on November 29th. She stayed
two days and returned when she heard of the severe
deterioration that had taken place, in deep snow and
intense cold, on December 8th. On Boxing Day she wrote
a letter to her people from Windsor, to be published in the
newspapers, thanking them for their prayers, sympathy
and support.
Jenner and Gull were both at Sandringham for five or
six weeks. The development of periostitis at the upper end
of the femur, accompanied by fever, necessitated their
return to Sandringham at the close of the year and Sir
James Paget was called in. Not surprisingly the bony
complication took some time to settle down and caused
temporary lameness; a mild exacerbation towards the end
of February necessitated Paget seeing the Prince again.
Paget himself had been gravely ill at the beginning of
1871 with septicaemia from an autopsy infection. Jenner
and Gull were among the ten doctors attending him and
after his recovery he resigned from St Bartholomew's
Hospital and Christ's Hospital. The Prince of Wales, as
President of St Bartholomew's, had thanked him for his
services and in July 1871 he had been created a baronet.
From Sandringham in letters to Lady Paget he wrote of
'the Prince's patience and courtesy' and remarked that
'the Princess is the sweetest nurse you ever saw'.
The Earl of Chesterfield had occupied the bedroom
used by the Prince of Wales at Londesborough Lodge
from October 7th?21 st. He returned to Scarborough on
October 31st, staying at 3 Belvoir Terrace and leaving on
November 4th, returning in due course to his home at
Bretby Park near Burton-on-Trent where about Novem-
ber 17th he too developed typhoid. He was attended by
Dr George Evans, a Fellow of the College, who had been
physician at the General Hospital, Birmingham, for over
30 years and Evans called in Dr Charles Murchison, a
Fellow of the College and of the Royal Society and
physician first to the Middlesex and later to St Thomas'
Hospital. He had had much experience of typhoid at the
London Fever Hospital and had published 'A treatise on
the continued fevers in Great Britain'. Unfortunately,
Lord Chesterfield developed a perforated bowel and died
from peritonitis on December 1st. He was only 40 years
of age and had never married.
Blegg, one of the Prince of Wales' grooms, also died
from typhoid at Sandringham on December 14th, despite
a visit from Queen Victoria and Princess Louise. How-
ever, he had travelled direct from Abergeldie to San-
dringham and was not at Londesborough Lodge or at
Scarborough. In addition, Mr Christopher Sykes' under-
butler, who deputised for Lord Londesborough's butler
during the royal visit, staying at the Royal Hotel, also
developed typhoid on November 19th.
The press showed even less sense of responsibility than
they do today, hounding poor Lord Londesborough
mercilessly on the grounds that defective drainage and
sewer gas at Londesborough Lodge were responsible for
causing the illnesses of the Prince of Wales, the Earl of
Chesterfield and the butler. Fortunately, Lord Londes-
borough had taken the precaution of having the sanitation
and drainage at Londesborough Lodge carefully exam-
ined before the royal visit and everything had been found
to be in perfect order. Mr G. P. Dale, FRCS, a general
practitioner at Scarborough, sprang to the defence of
Lord Londesborough and the town in a letter to the
Lancet. Moreover, Lord Londesborough had taken care
to provide only Bristol water for drinking during the royal
visit. The Eberthella typhi was not isolated until 1880 and
it was several years later before the mode of spread of the
disease was fully understood. In 1871 sewer gas was
thought to be responsible and it was erroneously reported
that there was a sewer beneath the floor of the Prince of
Wales' bedroom at Londesborough Lodge. The Lancet
116 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
and the British Medical Journal both appointed sanitary
commissioners to investigate the matter and Lord
Londesborough generously allowed them to examine his
house in any way they wished and Mr Dale and the
builders and plumbers employed in the maintenance of
Londesborough Lodge gave every assistance. Though
everything was found to be as perfect as anywhere in the
country at that time both journals condemned Lord
Londesborough. Moreover, it is significant that no impu-
rities were found in Scarborough water, the water at
Londesborough Lodge or the Bristol water which the
guests drank. The British Medical Journal appointed Dr
John Murray as their sanitary commissioner but there is
no record as to who James Wakley, then editor of the
Lancet, employed to stir the pot. At that time there were
120,000 cases of typhoid each year in England, and of
these one in six died.
The Times, the Lancet and British Medical Journal gave
much gratuitous advice as to the honours that should be
awarded to Jenner and Gull for their care of the Prince.
Jenner received a KCB and Gull a baronetcy. In addition
Gull was appointed Physician Extraordinary to the
Queen and Physician in Ordinary to the Prince of Wales.
Poor Lowe, who had made the diagnosis and attended the
N Prince most assiduously, got nothing, while Clayton in
due course collected the CB, CMG and a knighthood and
when he died left ?150,000. Although a Fellow of the
Royal College of Surgeons he was essentially a fashion-
able general practitioner.
Lowe did not even get the full credit for his early
diagnosis of the Prince's illness. The British Medical
Journal stated that Clayton had first recognised that it was
typhoid and on 4th January 1872 Gull wrote to Clayton
saying that there was a rumour about that Lowe had not
suspected typhoid and Clayton had diagnosed it. Clayton
replied ackhowledging that this was not so but he said he
had not heard the rumour. Thirteen years later an article
about the illness, written by Dr W. H. Russell, appeared
in the April number of Harper's Magazine. It stated that
Clayton and not Lowe had made the diagnosis. Lowe
approached Clayton about it and Clayton arranged for
the mistake to be corrected in the July issue. Even when
Clayton died in 1892 the British Medical Journal reiterated
in his obituary that it was he who had first recognised that
it was typhoid, showing how difficult it is to correct
erroneous press reports. When Lowe saw the obituary he
wrote a very restrained letter to the British Medical
Journal, enclosing copies of Gull's and Clayton's letters
written in 1872, which they published.
A thanksgiving service for the Prince's recovery, held
in St Paul's Cathedral on February 27th, was attended by
13,000 people. The Prince was still lame, could only walk
slowly and looked pale and drawn but he, the Princess of
Wales and the Queen were given a rapturous reception by
a huge crowd who went mad with joy. Sweet are the uses
of adversity. Though the Prince nearly died, the Queen's
health and the standing of the monarchy had been
restored.
After two weeks at Osborne the Prince went to the
south of France on March 9th for three months' convales-
cence. He was accompanied by Dr George Vivian Poore,
a Member of the College and a keen sanitarian, who had
just been appointed an assistant physician and lecturer in
jurisprudence at Charing Cross Hospital at the age of 29
and had previously travelled with Prince Leopold as his
medical attendant. In 1876 he became an assistant physi-
cian at University College Hospital and the following
year was elected a Fellow of the College.
To what extent it was recognised by the doctors or the
Prince that the respiratory complication which so nearly
proved fatal was largely attributable to smoking is uncer-
tain. However, after his recovery the Prince resumed
smoking cigars and cigarettes incessantly. His regular
habit was 12 large Havana cigars and 20 cigarettes daily.
In addition he was throughout adult life considerably
overweight due to four or five very large meals every day,
including a dinner often of 12 courses. The College
reports on Smoking and Obesity were not published until
nearly a century later but in 1897 the Prince accepted an
Honorary Fellowship of the College and though Punch
depicted him looking down a microscope, with a caption
'HRH Dr Wales FRCP The popular physician', he
found it quite impossible to follow advice to reduce his
consumption of food and tobacco. In consequence in his
later years he was never free from cough and in 1890 a
severe attack of bronchitis prevented him from going to
Germany. In 1891 Sir Morell Mackenzie saw him six
times at Marlborough House on account of huskiness of
the voice and was rewarded with a gift of a jewelled
breast-pin. Mackenzie was a Member of the College who
had attended Queen Victoria's son-in-law, Prince Fred-
erick William of Prussia, later Emperor Frederick III of
Germany, when he died from carcinoma of the larynx.
His book The Fatal Illness of Frederick the Noble was so
Fig. 1. Sir Felix Semon, KCVO, MD, FRCP, Physician
Extraordinary to King Edward VII.
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 117
critical of his German colleagues that Sir Henry Pitman,
the Registrar of the College, wishing to save Mackenzie
the ignominy of having his Membership withdrawn,
tactfully suggested that he should resign from the College,
which Mackenzie very sensibly did. After Mackenzie's
death in 1892 the Prince consulted his friend, Sir Felix
Semon, and Professor Sir St Clair Thomson on a number
of occasions regarding his recurrent laryngitis. Semon
and Thomson, though laryngologists, were both Fellows
of the College and Semon was Physician Extraordinary to
the Prince. There were frequent attacks of bronchitis and
the Prince became short of breath on stairs and hills;
later, when king, he developed glycosuria and an inci-
sional hernia through the scar of his appendicectomy,
which had necessitated postponement of his coronation in
1902. During his later years violent paroxysms of cough-
ing caused intense cyanosis and he developed a tendency
to fall asleep at lunch or dinner or at the theatre. On 8th
February 1909 he had an episode of cough syncope at the
British Embassy in Berlin. Sir James Reid, his physician
and a Fellow of the College, managed the situation with
the utmost skill and tact but everyone could see the
deterioration in the King's condition. In February 1910
he had a further attack of bronchitis at Biarritz, with
severe breathlessness, and although when he returned to
Buckingham Palace at the end of April he endeavoured to
continue all his normal duties and activities, he steadily
deteriorated and died on May 6th. In his last days he was
attended by Sir Francis Laking (who was a Member of
the College but never a Fellow and who had risen from r
being Surgeon Apothecary to much respected and trusted
Physician in Ordinary), Reid, Sir Douglas Powell, who
had been President of the College from 1905 to 1910, Dr 1
Bertrand Dawson, later Viscount Dawson of Penn, Se- 'j
mon and St Clair Thomson.
Sir Thomas Barlow, who had attended the King when
he had his appendix removed in 1902, succeeded Powell "'(
as President of the College and at Comitia on May 26th
moved that messages of condolence from the College j
should be sent to King George V and to Queen Alexan- >
dra.
The change in management of royal illness was strik-
ing. When the King, as Prince of Wales, nearly died in
1871, Jenner and Gull issued up to Five bulletins in 24
hours. There were only two in all when the King died.
The first was issued on May 5th because he was not fit to
meet the Queen at the station on her return to England.
'The King is suffering from bronchitis and has been
confined to his room for two days. His Majesty's con-
dition causes some anxiety'. The second was issued on the
following day, before he died at 11.45 p.m. 'The King
has passed a comparatively quiet night, but the symptoms
have not improved and His Majesty's condition gives rise
to grave anxiety.'
Bibliography
Annual Register, 1870, 1871 and 1872.
British Medical Journal, 1871, 1872, 1879, 1885, 1892, 1902 and 1910.
Sir James Clark's Diaries.
Debrett's Peerage, Baronetage, Knightage and Companionage.
Godlee, R. J. (1917) Lord Lister. London: Macmillan.
Hibbert, Christopher (1976) Edward VII. London: Collins.
Lancet, 1871, 1872, 1879, 1885, 1892, 1902 and 1910.
Longford, Elizabeth (1964) Victoria RI. London: Weidenfeld and Nicol-
son.
Magnus, Philip (1964) King Edward the Seventh. London: John Murray.
Medical Directory.
Medical Times and Gazette, 1871 and 1872.
Munk's Roll.
Paget, Stephen (1901) Memoirs and Letters of Sir James Paget. London:
Longmans.
Plarr's Lives of the Fellows of the Royal College of Surgeons of England.
Punch, 1897.
St Aubyn, Giles (1979) Edward VII. London: Collins.
Stevenson, R. Scott (1946) Morell Mackenzie. London: Heinemann.
The Times, 1864, 1870, 1871, 1872 and 1910.
Whitfield, George (1981) The First Thirty-Seven Registrars of the College,
Birmingham University.
Whitfield, George (1983) Beloved Sir James. Birmingham University.
Fig 2. Sir Francis Laking, Bart., GCVO, MD, MRCP,
Physician in Ordinary and Surgeon Apothecary to King
Edward VII.
118 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
|
PMC005xxxxxx/PMC5371014.txt | Psychiatric Illness in Expatriates
PETER DALLY MB, FRCR FRCPsych
Department of Psychological Medicine, Westminster Hospital, London
Men and women and their families, whose work involves
living abroad, are said to be more likely to break down
than those who stay at home. Because of this it is
estimated that one in seven Americans working overseas
have to return home earlier than expected. If this is so,
what are the particular stresses encountered abroad which
make expatriates more vulnerable to psychiatric disorder?
A number of factors need to be considered; the expatri-
ate's personality; his or her expectations; the nature of the
foreign country, its climate, political and ethnic press-
ures, and the availability of social and leisure activities;
their status, whether he or she is married, and with or
without a family. The strains felt by a wife and children
are inevitably different from those met by the husband.
There have been virtually no studies of the psychiatric
health of expatriates in the last 20 or 30 years, a period
during which the life of foreigners, in Africa, the Middle
East and the Far East especially, has changed rapidly and
often unpredictably. Studies of immigration do not throw
much light on the expatriates' problems.
To look more closely at the matter I collected data from
50 consecutive British white expatriates referred to me
(men, women and children) who had returned home
because of psychiatric disorders.
These examples came from all over the world; 52 per
cent were in Far or Middle Eastern countries, 10 per cent
in Africa, 8 per cent South America, 12 per cent in North
America and the Caribbean, 14 per cent in Europe and
Scandinavia, and 4 per cent from Iron Curtain countries.
The strains of living behind the Iron Curtain are very
different from those of Bangkok, Malawi or Bermuda.
The people involved worked for a variety of organisations
and institutions. Most expected to move every three or
four years, but 6 per cent were static and intended to stay
in the same place until they retired.
Sample
The sample was made up of 22 men (two-thirds married)
and 6 women employees (all unmarried) whose ages
ranged from 26 to 53. Forty-four per cent were depen-
dents: 17 wives (not of course of the men in the sample)
and 5 teenage females. The ages of the wives ranged from
28 to 50 years. The teenagers were between 13 and 17.
Findings
Depression was the most common condition among men
and wives, followed by psychosomatic disorders and
anxiety states. Alcoholism as a primary problem was rare,
although alcohol abuse occurred in 23 per cent of expatri-
ates with affective disorders. A paranoid psychosis devel-
oped in half the female employees and one man. All five
teenage children had anorexia nervosa. (This reflects my
known interest in the illness.)
Clearly there is likely to be a difference, both in
presentation and course of the illness, between those who
break down soon after going abroad and those who do so
later. I have taken three time intervals: (a) the first nine
months, (b) between nine months and four years and (c)
after more than four years. I have chosen nine months
because it is during this period of their new life that
students who have neurotic or inadequate personalities
are most likely to break down and give up.
Nearly one-third collapsed in the first nine months (41
per cent male and half the female employees, but only one
wife). Half the sample became ill in the second period.
This included 41 per cent of the men, the rest of the
female employees, and 70 per cent of the wives, a
significant difference. Only 20 per cent of expatriates
became disabled after four years.
The majority of the men and women employees who
broke down in the first nine months did so because they
were unable to adjust to their new life abroad. They felt
homesick, were disappointed with what they found, and
increasingly missed the support of family and friends.
Some withdrew into themselves, others tried the distrac-
tion of living hectically and beyond their means, but all
eventually became liabilities and had to be sent home. For
most it was their first posting abroad. These people were
emotionally insecure and lacking in confidence, although
this was often disguised by their efficiency and drive at
work. They had difficulty in communicating socially and
in establishing friendships. The single expatriate in par-
ticular had unrealistic expectations about life abroad.
After nine months the remaining expatriates had, for
the most part, settled down and adapted. The exceptions
were the three women and one man who developed
paranoid psychoses. Their social isolation and communi-
cation difficulties continued. Their perception of events
became increasingly distorted, and eventually psychotic.
In the second period other factors began to assume
increasing importance, notably marital dissatisfactions,
which were responsible for 88 per cent of the breakdowns
of wives, and played a part in 40 per cent of male illness.
The expatriate wife syndrome is probably a universal
one, developing out of the emptiness and frustration of
her life. Her husband is ambitious and successful, ab-
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 103
sorbed in his work, popular with his colleagues and in
demand socially. She cannot work, either because she has
small children, or is unable to obtain a work permit, or
her husband says 'No' for fear of lowering his status. She
seeks friendship with other expatriate wives, but this is
rarely satisfactory. She feels isolated and unhappy. She
looks to her husband for understanding, but he is too
busy with his professional life to respond other than
perfunctorily. He expects her support rather than vice
versa ? to entertain his boss and important friends, to
enhance his reputation, and ensure that his life at home is
as easy as possible. As this truth dawns on her so her
demands on her husband increase. There are frequent
rows. He spends more and more time at work, relieved to
be away from his querulous wife. Their sexual relation-
ship deteriorates. She may start an affair, attempting to
boost her morale and attract his attention, but this
is rarely helpful. Often, when reduced to a state of des-
pair and near collapse, she returns home with the
children.
Work itself occasionally became an intolerable strain.
Negotiations with government representatives over con-
cessions and agreements, particularly when prolonged
and difficult, resulted in disabling anxiety. Nepotism and
xenophobia sometimes created frightening situations. A
middle-aged man who had enjoyed working in an African
state for 12 years ran into trouble with a black employee.
The latter believed that he had been refused promotion
out of malice and complained to friends in the govern-
ment. For almost a year the Englishman was repeatedly
investigated and threatened with expulsion. He was
eventually able to prove that he had not discriminated
against his employee, but the strain had been so great that
a subsequent minor car accident caused him to collapse
with acute depression and he had to be flown home for
treatment.
What happened to the expatriates after recovery? In 13
per cent the marriage ended; this is twice as likely when
the wife is the patient. Of the employees, 16 per cent, all
of whom had broken down in the first nine months, had
their employment terminated; 31 per cent were trans-
ferred to jobs in the UK, two-thirds of them to be
reviewed after two years to decide their fitness for further
posting overseas; 40 per cent returned to their jobs after
treatment, but more than half continued on medication,
sometimes prolonged. One wife remained on imipramine
for 16 years; her husband insisted that she continue on the
drug 'for as long as I need to work'.
Family tensions often contribute to the development of
anorexia nervosa in adolescents. Many mothers were
depressed long before their daughters dieted and lost
weight. Of the five teenagers who were sent home because
of anorexia nervosa, four came from unhappy families.
None of the mothers worked, all were dissatisfied with
their lives and angry with their husbands. They felt
trapped. The picture was that of the expatriate wife
syndrome, complicated by the daughter's reaction to her
mother's unhappiness. In at least two of the five cases the
daughter's illness resulted in the mother leaving her
husband.
Discussion
It is difficult to assess how great the psychiatric morbidity
of expatriates is, compared to that of those who stay at
home. Anxiety and depression are common conditions
but, in one's own country, with friends and relations to
turn to for support and comfort, and competent psychia-
trists at hand, the sufferer can be helped and treated,
often without serious disruption to either working or
private life.
The strains encountered abroad differ in degree rather
than in kind from those at home. The first nine months
are a time of adjustment, and those who broke down
during this period did so mainly because of an inadequate
personality structure. It has been suggested that candi-
dates for posts abroad should be screened, and sub-
sequently excluded if they seem vulnerable. But this is
easier said than done. Only half those expatriates who
broke down in the first nine months would have shown
clear signs of vulnerability at interviews, and in any case,
to rule out everyone with a neurotic personality from
working abroad would be like throwing out the baby with
the bathwater. Every neurotic is not necessarily subject to
breakdowns and many are highly talented, successful and
reliable.
Marital difficulties were a common source of strain.
Tensions developed, often in subtle ways at first, and
eventually began to affect both partners, but particularly
the wife, who all too often abroad, in predominantly
male-orientated cultures, is prevented by consideration
for her husband's career from pursuing her own interests.
It must be admitted that many wives cannot, or will not,
take advantage of the new situations in which they find
themselves. Nevertheless, it is unrealistic to suggest that
employers try to analyse the quality of their employees'
marriages. Few couples are likely to co-operate honestly
with a stranger over what goes on between them, particu-
larly if they are keen to go abroad, but a friendly
discussion of the problems that they may have to face in
the other country could be useful.
It is salutary to note that the majority of expatriates
develop no serious psychiatric problems abroad. On the
contrary, the lives of many are greatly enhanced and
enriched by the experience. In general they are financial-
ly better off, have servants and maybe a pleasant climate,
new diversions and a ready-made social life among the
other expatriates. Afterwards, returning home for good
can often be something of a let-down. It is then that their
troubles can start.
104 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
|
PMC005xxxxxx/PMC5371015.txt | Endothelium Derived Relaxant Factor
T. M. GRIFFITH, MB, MRCP(UK), Registrar in Radiology
D. H. EDWARDS, British Heart Foundation Technician
E COLLINS, MB, MRCP(UK), British Heart Foundation Junior Research Fellow
M. J. LEWIS, MB, PhD, Senior Lecturer in Pharmacology
A. H. HENDERSON, MB, FRCF! Professor of Cardiology (BHF Sir Thomas Lewis Chair)
University of Wales College of Medicine, Heath Park, Cardiff
The phenomenon of endothelium mediated vasodilata-
tion has become apparent only in the last few years. It is
likely to be of considerable physiological importance,
though there is much that is yet unknown about it.
We first became aware of it when we were developing
an isolated coronary artery preparation, as a more appro-
priate model than conventional strip preparations, with
which to investigate vasomotor control mechanisms in
large coronary arteries. It is, of course, the large coronary
arteries that are particularly relevant to the pathogenesis
of coronary artery disease in man. The preparation
consisted of an isolated intact left coronary artery of the
rabbit, perfused at constant flow, with monitoring of
pressure as a measure of constrictor tone. Initially we
observed the expected increase in perfusion pressure
upon infusion of a variety of vasoconstrictor agents, but
as we gained experience with the preparation we became
less able to elicit these conventional constrictor responses.
We then noted that localised damage to the arterial wall
in an otherwise unresponsive artery would result in a
localised response[l]. The nature of this phenomenon
became clear when in 1980 Furchgott published his
evidence that endothelium possesses vasodilator proper-
ties^]: he showed that acetylcholine, generally regarded
as an arterial constrictor, exerted a paradoxical dilator
effect if the vessel wall endothelium was carefully pre-
served during preparation (Fig. 1). We therefore devel-
oped ways of preserving or removing endothelium in our
preparation, validated always by en face silver staining,
and proceeded to study its contribution to vasomotor
control.
Using the perfused coronary artery preparation of the
rabbit we compared concentration-response curves, with
and without endothelium, to a number of physiologically
relevant constrictors?histamine, acetylcholine, 5-hy-
droxytryptamine and phenylephrine. The influence of the
endothelium was striking: it markedly suppressed, to the
point of almost abolishing, the constrictor responses (Fig.
2). We also found that deliberate localised damage to the
artery made it susceptible to localised constriction?
reversible, reproducible and non-specific. Local endothe-
lial damage had converted one dose-response into the
other and, in effect, had reproduced a model of 'coronary
spasm'.
Parallel experiments were performed in conventional
isometrically mounted aortic strip preparations of the
rabbit?again with and without endothelium (Fig. 3). In
this preparation, by contrast to the perfused coronary
preparation, the endothelium exerted relatively little in-
fluence on the responses. Statistical comparison showed
that there was nevertheless a significant difference be-
tween the responses with and without endothelium, albeit
in the opposite direction with all the constrictors except
acetylcholine which was known from Furchgott's work to
stimulate the endothelium-dependent dilator response.
The paradoxically greater constrictor response to the
other three agents in the presence of intact endothelium
was subsequently explained by the fact that the response
starts from a lower baseline in the presence of endotheli-
Fig. 1. Effect of acetylcholine (Ach) (10~6M) in aortic strips
preconstricted by 5-hydroxytryptamine (5HT). In preparations
with an intact endothelium (left panel) relaxation occurs: in
preparations denuded of endothelium (right panel) further
constriction occurs.
74 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
um, due to basal activity of the endothelium-dependent
dilating effect, and that the ceiling of the constrictor
response is the same with or without endothelium, as the
constrictor response over-rides the basal endothelium
derived relaxant factor (EDRF) actitivity[ 1 ].
The phenomenon of endothelium-dependent vasodila-
tation is likely to be of general physiological relevance: it
has been demonstrated in all mammalian species so far
studied, including man, and in all types of blood vessel.
Our data with the coronary arteries show furthermore
that it can be very potent. Its underlying mechanism has
become a subject of intensive investigation.
The Nature of EDRF
Furchgott postulated that the phenomenon was mediated
by a humoral agent released from endothelial cells. To
test such a hypothesis we developed a bioassay for the
putative vasodilator substance (or EDRF)[3], Figure 4
shows the bioassay system schematically. An intact aorta
possessing endothelium is perfused in series with a coron-
ary artery which has been denuded of endothelium and
preconstricted by the infusion of a constrictor agonist.
The pressure response of the coronary artery allows
detection of vasomotor substances in the coronary perfu-
sate. The length of the intervening tubing can be altered
to give a range of transit times between aorta and
No endothelium Intact endothelium
Fig. 2. Coronary artery responses to histamine (A), acetylcho-
line (M)t 5-hydroxytryptamine ( 6 ) and the -agonist phenyl-
ephrine (+) are markedly depressed by the presence of intact
endothelium (right panel), compared to responses in prepara-
tions denuded of endothelium (left panel).
_8 -7 -6 -5 -4-3-2
Logio molarity
No endothelium
16OO-1
Intact endothelium
-9 -8 -7-6-5 -4
Logio molarity
Fig. 3. Aortic responses to histamine (A), acetylcholine (W),
5-hyd.roxytryptam.ine (* ) and phenylephrine (+) are relatively
similar in the presence of endothelium (right panel) and in its
absence (left panel). Responses to acetylcholine are depressed in
the presence of endothelium, but those to the other agents are
(paradoxically) enhanced by the presence of endothelium.
Flow
I
,4k
AORTA
Intact endothelium
G>
CORONARY
No endothelium
preconstricted
Y
?Proximal (P)
-Distal (D)
Fig. 4. Diagram of bioassay system, t = pressure transducer.
Fig. 5. Representative trace of a bioassay experiment. The
coronary artery is preconstricted by infusion of 5HT (10'5M)
and acetylcholine (Ach) (10~6M). a, = introduction of unstimu-
lated aorta into circuit. A, = stimulation of aorta by Ach,
infusion of which is transposedfrom post- to pre-aortic (see Fig.
4). Basal release from an unstimulated aorta and enhanced
release from stimulated aorta are shown.
ai \
\ f )
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 198o
coronary artery. Drugs can be infused into the interven-
ing tubing either proximally or distally to allow different
interaction times with EDRF in transit.
Figure 5 shows a typical experiment, where the coron-
ary has been preconstricted by infusion of 5-hydroxytryp-
tamine plus acetylcholine. When an aorta possessing
intact endothelium is introduced into the circuit a small
fall in pressure is seen, due to basal release of EDRF into
the aortic effluent. When the aorta is perfused by acetyl-
choline, the fall in pressure is much larger, as acetylcho-
line stimulates EDRF release from the aortic
endothelium. Such experiments demonstrate that EDRF
is indeed a humoral agent released continuously in the
basal state and whose release can be stimulated by
acetylcholine (for up to an hour in good preparations).
By altering the transit time between the aorta and
coronary it was possible to measure the half-life of EDRF
(Fig. 6). From the straight line relationship between the
logarithm of dilatatiomand transit time, the half-life of
EDRF was calculated as about six seconds. Other
workers have subsequently performed similar experi-
ments using different experimental models and different
mammalian species, and found an almost identical half-
life: 5.4 + 0.4 sec for EDRF from cultured bovine cells[4],
and 6.3 ?1.2 sec with EDRF from dog femoral arte-
ries[5]. Recent data indicate that the exact half-life is
influenced by molecular oxygen and has been obtained as
24 + 3 sec with EDRF from rabbit aorta[6] and 49 + 5 sec
with EDRF from dog femoral arteries[6] at lower oxygen
tensions than used in the above experiments. The present
evidence suggests that the EDRF molecule is similar if not
identical in all mammalian species.
To characterise the chemical nature of EDRF, different
agents were tested to see which might inhibit its action. A
large number of compounds was screened in aortic strip
preparations. Those found to be effective were then
studied using the bioassay system (Fig. 7) to distinguish
those which interacted chemically with EDRF in transit
from those which influenced its production or its action
on smooth muscle. The two chemical properties that
emerge as common to agents which inhibited endotheli-
um-mediated relaxation by direct chemical interaction
with EDRF are that they are either antioxidants or
combine with carbonyl groups?properties that are mutu-
ally consistent. Analysis of concentration-inhibition
curves provides evidence that the interaction of EDRF
with the four inhibitors?phenylhydrazine, potassium
borohydride, dithiothreitol and phenidone?obeys first-
order kinetics[7]. We were also able pharmacologically to
exclude the possibility that EDRF is a cyclo-oxygenase
product, such as prostacyclin, or a lipoxygenase product,
such as a leucotriene. We conclude that EDRF probably
possesses a carbonyl group at or near its active site[3].
However, the chemical identity of this unstable agent
remains to be defined.
Mechanisms of Action of EDRF
There is now a substantial body of evidence that nitrodi-
lators such as glyceryltrinitrate and nitroprusside act by
elevating smooth muscle cyclic guanosine monophos-
Fig. 6(a). Increasing transit time between aorta and coronary
artery from 4 to 21 sec causes a marked fall off in EDRF
induced vasodilatation, (b) A logarithmic plot of dilatation
against transit time yields a straight line allowing calculation of
EDRF half-life as 6.3 ? 0.3 sec.
Fig. 7. Bioassay experiment, showing dilator response to
EDRF released from stimulated aorta (A,) and the effect of
infusing the EDRF inhibitor, potassium borohydride, into the
intervening tubing. Distal infusion (D) to allow 0.5 sec
interaction time has little effect. Proximal infusion (P) to allow
a 4 sec interaction time results in complete inhibition. Phenylhy-
drazine and antioxidant inhibitors gave similar results.
76 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
phate (cGMP) levels[8, 9]. Their physiological and bio-
chemical effects can be inhibited by methylene blue
(which inhibits the enzyme guanylate cyclase)[8, 9] and
potentiated by MB22948 (which prevents cGMP hydroly-
sis by inhibiting the enzyme cGMP phosphodiesterase)^,
10]. Evidence that EDRF might act in an analogous
manner appeared when Austrian and American workers
demonstrated elevation of arterial cGMP when endotheli-
um was stimulated to produce EDRFfll, 12]. Further-
more, EDRF and nitrodilator-induced relaxation are
associated with identical alterations in the phosphoryla-
tion!^] ?f proteins, including contractile proteins. Using
these pharmacological probes infused at different sites
into the bioassay system, we have confirmed that they
influence the action of EDRF at the level of the smooth
muscle response (Fig. 8) and shown that they do not exert
an additional effect on EDRF release or by interacting
with EDRF in transit[14], It thus appears that EDRF
behaves functionally as an endogenous 'nitrite'. Relevant
to our hypothesis that EDRF contains a carbonyl group is
the finding that carbonyl agents stimulate guanylate
cyclase[15].
The intracellular control of tension development in
smooth muscle is inadequately understood. cGMP is
thought to mediate one mechanism of relaxation through
altered phosphorylation of contractile proteins. We have
recently shown that EDRF-mediated dilatation is also
associated with a reduction of net influx of calcium, which
might contribute to its mode of action[16]. This finding
may explain the apparently greater sensitivity of the
coronary artery than the aorta to the dilator action of
EDRF[1]: vasoconstriction in the rabbit coronary artery
is very largely dependent on influx of extracellular
Ca+ +, whereas in the aorta it is more dependent on
mobilisation of Ca+ + from intracellular sites (unpub-
lished observations).
Production of EDRF
Basal release can be demonstrated from the rabbit aortic
preparation, and its stimulated release can likewise be
maintained for up to an hour. Endothelium-dependent
relaxation has been found to be stimulated by a large
number of agents, with some differences between differ-
ent vessels and different species (Table 1). Consideration
of the naturally occurring substances which appear in this
list must provide pointers to the possible physiological
role of EDRF. It should perhaps be noted that not all
observed endothelium-dependent dilatation has yet been
confirmed by bioassay as indeed being due to EDRF,
though this seems likely.
Notably, EDRF release is stimulated by the calcium
ionophore A23187. We have confirmed that it is depen-
dent on the presence of extracellular calcium[33]: in
bioassay experiments its production can be abruptly
stopped by removal of extracellular calcium and equally
rapidly restored by its replacement (Fig. 9). It is not
known if calcium is required for de novo biosynthesis or for
release of stored EDRF from intracellular vesicles. The
presence of some oxygen also appears to be a necessary
requirement[2].
Duration of Effect
The half-life of EDRF in well oxygenated aqueous buffer
at 37?C is 6 sec. The duration of its effect in the vascular
compartment in vivo is almost certainly much shorter. We
have shown that a heat labile component of plasma blocks
EDRF activity in aortic strips (unpublished observa-
tions). Endothelial permeability is increased under these
unphysiological in vitro conditions so that plasma proteins
probably penetrate the endothelial barrier[34]. The im-
plication is that EDRF will be rapidly inactivated in the
intravascular compartment in vivo, so localising its effect
to adjacent smooth muscle, with no downstream effect.
Therefore EDRF may be regarded as an autocoid.
It has recently been observed that the vascular effects of
EDRF can be inhibited by > 10" 7M free haemo-
globin^], an observation which may be relevant in a
number of pathological conditions.
Possible Endogenous Analogues of EDRF
It is of considerable interest that an inhibitory neurotrans-
mitter isolated from retractor penis and anococcygeous
muscle of a number of species has many characteristics in
common with EDRF[36], It relaxes both vascular and
non-vascular smooth muscle[37], and is thought to do so
by elevating smooth muscle cGMP levels[38]. It is also
known to be unstable and appears to be a carbonyl
compound[39]. EDRF may therefore represent one of a
family of physiologically important and previously unde-
scribed substances.
1 min
X -i105
E
E
J80
i?.
I D
j 5HT 10~5M + ACh 1Q-6M
,100
50
ACh 3.10"6M
?L
Methylene
blue 10"6M
MB22948 10~6M
Fig. 8. Bioassay experiment showing effect of (a) methylene
blue and (b) MB22948. Left traces show negligible effects of
adding these agents solely to the coronary perfusate (control, C).
Right traces show EDRF mediated dilatation by effluent from a
stimulated aorta (A;), with addition of agents distally (D) or
proximally (P) into the intervening tubing. In each case the
effects of proximal and distal infusion are identical (unlike those
of direct EDRF inhibitors, Fig. 7).
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985 77
Table 1. EDRF stimulation in different species.
Receptor type/
EDRF Stimulant mechanism Species
A23187 (calcium ionophore)
acetylcholine
adenosine diphosphate (ADP)
adenosine triphosphate (ATP)
clonidine
ergometrine
ergometrine
histamine
hydrallazine
5-hydroxytryptamine
noradrenaline
thrombin
Peptides:
vasoactive intestinal polypeptide
bradykinin
substance P
cholecystokinin
Electrical stimulation
Non-specific:
saturated/unsaturated fatty acids
(may stimulate or block)
? increased calcium influx
muscarinic
P2
Pa
0i2
not 5HT or a
p
H,
p
?5HT,
a2
heparin-sensitive receptor
VIP
bradykinin
substance P
? substance P
? increased calcium influx
? membrane fluidity
man[17], rabbit[3, 18, 19]
man[17], rabbit[2],
guinea-pig[2], cat[2],
rat[2], dog[20]
rabbit[3, 21], dog[20], pig[22]
rabbit[3, 21], dog[20], pig [22]
dog[23]
rabbit[24]
man[l 7]
dog[25], rat[26], NOT rabbit[l]
rabbit[27]
dog[24, 28], NOT rabbitfl]
dog[24], pig[24]
dog[29]
rat[30]
man[31], dog[31], NOT cat[31]
rabbit[21], dog[21], cat[21 ]
rabbit[21]
rabbit[32], cat[32], monkey[32]
rabbit[2], dog[21]
Physiological and Pathophysiological Role for EDRF
The physiological role of this newly recognised and potent
dilator substance remains to be established, as does its
potential role in disease states. The vasomotor control
I
mechanisms that exist in the intact circulation are clearly
multiple and complex. We may nevertheless speculate on
the physiological and pathophysiological roles of EDRF,
mindful of the number of naturally occurring agents
capable of influencing EDRF activity.
In large arteries EDRF is likely to act as a physiological
regulator in response to intravascular events. Thrombosis
will expose the endothelium to agents such as adenosine
diphosphate (ADP) and 5-hydroxytryptamine (5HT)
which are released from platelets and are known to
stimulate EDRF. This would represent a short-term
negative feedback. That such a phenomenon may be
important in vivo is suggested by tissue bath experiments 1
showing that arterial smooth muscle relaxes in response to
aggregating platelets when intact endothelium is present
and contracts when the endothelium is removed[40], The
possibility of local spasm where endothelium is function-
ally impaired, particularly in arteries susceptible to its
action such as the coronary, may be relevant to pathoge-
netic mechanisms in variant angina. We have shown that
ergometrine maleate, an agent used to provoke coronary ,
artery spasm in susceptible patients, is able to stimulate
EDRF release[25]; functional impairment of endothelium
and consequent lack of EDRF effect may therefore ex-
plain its usefulness in this test. Inactivation of EDRF by
haemoglobin and plasma proteins may be relevant to the >
prolonged arterial spasm which is sometimes seen after
subarachnoid haemorrhage.
Endothelium-dependent dilatation has been described
in relation to flow rate[41], acting presumably through
shear stress on the endothelium, though it has not yet
been proved that this phenomenon is mediated by EDRF
itself. Flow-dependent endothelium-mediated dilatation
I 1 min
i
ACh 10-5M
Fig. 9. Bioassay experiment demonstrating dependence of
EDRF production on extracellular calcium: left trace shows a
control experiment demonstrating EDRF mediated vasodilata-
tion by effluent from the stimulated aorta (At) while this is in
circuit (horizontal bar). Right trace shows loss of vasodilator
response when calcium is omitted from the aortic perfusate (but
infused into intervening tubing to maintain normal calcium in
coronary perfusate) and demonstrates the immediate recovery of
dilator responses (with overshoot) on re-introduction of calcium
into aortic perfusate.
78 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
may be an important homeostatic mechanism coupling
large artery calibre to changes in microvascular resis-
tance, thus optimally distributing shear stress at the
blood-intimal interface throughout the vascular tree.
The influence of EDRF activity on resistance vessels
has not been adequately investigated. Peptides such as
vasoactive intestinal polypeptide (VIP), whose action is
endothelium-dependent in large arteries at low concentra-
tions[30], have been demonstrated histochemically in
nerve endings found in the adventitia around small
vessels[42]. It is possible therefore that there is neurogeni-
cally-mediated control of EDRF in the microvasculature,
the stimulus in this case arriving from outside these small
vessels where diffusion distance is small. Concentrations
of VIP known to stimulate EDRF release in vitro can be
detected in the effluent from some isolated organ prepara-
tions when their nerve supply is stimulated and there is
accompanying vasodilation[43]. This action may be a
component of the complex neurogenically mediated vaso-
motor mechanism of penile erection[44]. Substance P,
derived from sensory nerve terminals, is also a stimulant
of EDRF and has been shown in rat hind limb prepara-
tions to mediate neurogenic vasodilatation[45]. Acetyl-
choline and VIP have been shown histochemically to co-
exist in the same nerve terminals[42] and of course both
are potent stimulants of EDRF. Does EDRF participate
in the ultimate mechanism of the neurogenic vasodilata-
tion that results from vagal activity, as in vasovagal
syncope?
It is intriguing to speculate whether alterations in
EDRF activity play any part in atherogenesis. Experi-
mental atheroma is associated with increased calcium
influx, can be induced experimentally by alteration of
calcium metabolism and prevented by calcium antagon-
ists^, 47], We have shown that EDRF reduces calcium
influx in vitro as measured with 45Ca flux studies. Con-
versely, the presence of atheroma, an intimal disease,
may itself affect EDRF activity, either by altering its
production or by interposing a physical barrier between
the endothelium and the smooth muscle. Indeed, it has
recently been reported that endothelium-dependent relax-
ation is diminished by atheroma in both human coronary
arteries[17] and in rabbits fed a cholesterol-supplemented
diet[48].
This article is based on a paper read by Dr T. M. Griffith at
the College Regional Conference in Oxford in September 1984.
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Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
|
PMC005xxxxxx/PMC5371016.txt | r-
Are Calcium Antagonists Cardioprotective?
M. J. KENDALL, MD, FRCP, Senior Lecturer
R. C. HORTON, BSc, Medical Student
Department of Therapeutics and Clinical Pharmacology, Queen Elizabeth Hospital, Edgbaston,
Birmingham
Calcium antagonists are establishing themselves as major
therapeutic agents in the management of hypertension
and angina. Both conditions put the patient at risk from a
myocardial infarction (MI) and treatment should ideally
reduce this risk. Beta-blockers, perhaps the major class of
drugs used in these two conditions, have acquired a
reputation for being cardioprotective. In this context, the
term is used to indicate that they reduce heart work,
decrease arrhythmias and modify platelet function, effects
which may diminish the adverse effects of coronary artery
disease. In addition, beta-blockers have been given pro-
phylactically to animals whose coronary arteries are to be
? occluded[l,2], to hypertensives[3], and, both acutely[4,5]
and chronically[6,7], to patients after cardiac infarction.
- ? In each situation they appear to improve the prognosis. If
calcium antagonists are to become first-line treatments
for angina and hypertension, should they also have a
cardioprotective role?
Clinical data on cardioprotection can only be obtained
from large-scale trials. In the case of calcium antagonists
such data may not be available for many years. However,
since these drugs are already in widespread use, it seems
? _ reasonable to ask now:
(a) Are there theoretical reasons for supposing they may
reduce the adverse effects of ischaemic heart disease?
(b) Are there animal data suggesting that these drugs
reduce infarct size?
(c) Are there any clinical data on the use of calcium
antagonists in patients at or after a myocardial infarction?
^ - These questions will be considered in turn.
Possible Cardioprotective Actions of Calcium
Antagonists
Calcium antagonists could reduce infarct size by their
impact on the supply and demand imbalance in the
myocardium. This may be achieved by improving coron-
< ary blood flow or by reducing heart work. Calcium
antagonists might also reduce mortality by reducing the
damage caused by hypoxia and by having an anti-
arrhythmic action.
Coronary Blood Flow
(a) Vasospasm. Calcium antagonists reduce coronary ar-
tery spasm[8,9] and act as vasodilators[10]. These effects
have been of interest in recent years as it has been
increasingly appreciated that angina and infarction are by
no means always the result of a fixed obstruction. The
fact that recurring anginal episodes occur at rest, when
there is no increased demandfl 1-13], and take place
despite considerable variability in fixed coronary le-
sions[14], shows that another, spontaneous, process is
operating. Such vasospasm may be assumed to play a role
in Prinzmetal's angina, in situations where angiographic
evidence or ergonovine injection testing is positive and
where anti-vasospastic drug treatment is helpful.
In their investigations into the pathophysiology of MI,
Maseri's group[15] showed that infarction occurred in 37
of 76 patients with rest angina involving coronary spasm
as shown by angiography. The infarcted area was closely
associated with the region supplied by the vessel undergo-
ing spasm.
Calcium antagonists have been repeatedly shown to
possess anti-vasospastic properties. Through their block
of excitation-contraction coupling in coronary artery
smooth muscle[8] they reduce vascular tone, and there-
fore resistance, with a subsequent increase in coronary
blood flow[9].
(b) Platelets. Platelet aggregation exacerbates the effects of
diseased coronary arteries by predisposing to occlusive
thrombus formation[16] and by the release of vasocon-
strictor substances[17,18]. Calcium antagonists reduce
platelet aggregation, a calcium dependent process[19], an
effect which has been demonstrated both in vitro[20] and
in patients with angina[19,21].
(c) Viscosity and Flow. Some drugs are reputed to improve
tissue perfusion by modifying the flexibility of red blood
cells and thereby facilitating their flow down narrow
blood vessels. There is evidence that an increase in red
cell calcium decreases deformability[22] and that calcium
antagonists increase it[23].
Heart Work
The ability of calcium antagonists to improve cardiac
haemodynamic efficiency and thereby reduce demand on
the heart is well known. By their actions on cardiac
muscle and arterial smooth muscle, calcium antagonists
may reduce wall tension and peripheral resistance. Of
these, the dilating effect on the peripheral arteries is
probably the most important[10].
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
Protection from Hypoxic Damage
At the onset of a myocardial infarct several processes may
lead to an increase in intracellular calcium which may be
the cause of cell death[24,25]. First, catecholamines
released at this time will markedly increase calcium
uptake into myocardial cells[26]; this causes activation of
the calcium-dependent myofibrillar ATPase and results
in an abnormally high consumption of energy-rich phos-
phates. In addition, the mitochondria try to take up
calcium ions from the cytosol and so consume energy.
This causes decoupling of oxidative phosphorylation and
structural damage. A reduction in the cellular uptake of
calcium across the cell membranes could therefore be
expected to produce a protective effect. This may be
achieved by blockade of the slow calcium channels[10]
and also by an effect on calmodulin[27,28]. If calcium
antagonists have this effect on the hypoxic cells in a
human myocardial infarct, it is possible that they might
reduce muscle damage.
Anti-arrhythmic Action
Beta-blockers reduce the risk of sudden death from
myocardial re-infarction and this might be due to their
ability to reduce the extent of ischaemia and to block the
development of arrhythmias[29]. This is of interest since
beta-blockers do not have a major therapeutic role in the
treatment of ventricular tachyarrythmias. The hope that
calcium antagonists may reduce mortality in the same
way has received little attention.
Correction of calcium influx into ischaemic myocardial
cells can retard the development of ventricular fibrilla-
tion[30]. Originally, the retardation was ascribed to
increased coronary blood flow and reduced cardiac work,
as shown by studies of verapamil in dogs with com-
plete^ 1] or temporary[32] coronary artery occlusion.
Recently, however, it has been demonstrated that cal-
cium antagonists can directly suppress ventricular fibril-
lation induced by ischaemia[30,33,34]. Nifedipine,
widely thought to have few anti-arrhythmic actions,
reduces the incidence of ventricular fibrillation, ventricu-
lar tachycardia and ventricular ectopic activity in rats[35]
and inhibits calcium-dependent myocardial excitability in
dogs with one-day-old infarcts[36].
Evidence of Cardioprotection from Animal Studies
The three major calcium antagonists currently in clinical
use?verapamil, nifedipine and diltiazem?have all been
investigated in a wide variety of animal models. The data
from these have to be interpreted with caution. Drugs
which act as vasodilators must be expected to have
different effects in animals which readily form a collateral
circulation, such as dogs[37], compared with those which
do not, such as pigs and baboons[38]. Second, where
infarct size is the end point, care must be taken to ensure
that the time allowed for its development is compar-
able^]. Third, the effects of surgery and anaesthesia
have to be considered[40]. Finally, different calcium
blockers have very different actions[41-43]. Nifedipine
causes coronary and peripheral vasodilatation while hav-
ing few chronotropic effects. Verapamil and diltiazem
prolong atrioventricular nodal conduction and have less
effect on vascular smooth muscle. In addition, verapamil
and nifedipine are negative inotropic agents, while diltia-
zem is probably not.
Verapamil and its Analogues
In open chest anaesthetised dogs, pre-treatment with
verapamil reduces the extent of tissue necrosis as
measured histologically following left circumflex artery
occlusion[44]. DaLuz[45] found that treatment both be-
fore and after occlusion increased collateral blood flow to
the ischaemic myocardium, reduced heart rate, thus
reducing metabolic demand, and reduced ST elevation,
indicating a decrease in infarct size. In addition,
Wende[46] demonstrated that verapamil infusion during
coronary artery ligation reduced infarct size as measured
by epicardial ST segment changes. Verapamil also selec-
tively depressed ischaemic myocardium, thereby reduc-
ing injury to the ischaemic tissue[47]. However, the
favourable effects of intravenous verapamil treatment
after ligation have been challenged[48,49].
In conscious dogs, DeBoer[50,51] was the first to find
that verapamil administered one hour after infarction
produced a short-term significant decrease in infarct size.
Yellon[52] extended this by showing the longer term
tissue sparing effect of verapamil treatment. Urqu-
hart[40], using physiologically equipotent doses of vera-
pamil, nifedipine and diltiazem, showed that all three
drugs caused coronary and systemic vasodilatation, re-
duced heart rate and reduced myocardial contractility
following left circumflex artery ligation. Two other
studies have yielded negative results[53,54].
Cardioprotective effects have also been demonstrated
in other animals including the open chest anaesthetised
baboon[55], rabbits[56] and in the isolated rat heart[34].
Verapamil and its analogues clearly appear to have
significant cardioprotective effects in most animal mod-
els, but a number of studies[47,57] have emphasised the
need to use low doses of verapamil since higher doses will
precipitate heart failure with consequent extension of the
infarcted area.
Dihydropyridines (nifedipine and related compounds)
Using open chest anaesthetised dogs to assess cardiopro-
tection, the dose of dihydropyridines, like that of verapa-
mil, was found to be important. Low doses improve
regional myocardial blood flow and cause reduced cre-
atine kinase (CK) release while higher doses cause an
increased heart rate and hypotension, with resultant
extension of the infarcted area[58-60]. Heart rate and
blood pressure readings should therefore be used to
monitor dosage. Henry[61] demonstrated the efficacy of
nifedipine in producing increased collateral perfusion to
ischaemic myocardium and reduced vascular resistance
distal to the occlusion, and Clarke[62] showed a reduction
in the injury volume. Weintraub[63] emphasised the
direct effects of nifedipine on myocardial cells and found
86 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
an increase in sub-endocardial blood flow in non-ischae-
mic tissue with improved muscle function in the ischae-
mic zone.
In conscious dogs it has been shown that nifedipine
increased collateral blood flow to ischaemic myocardium
and reduced ischaemic injury as measured by enzyme
< losses[64,65], Melin[66] attempted to mimic the clinical
situation further by delaying nifedipine intervention until
three hours after coronary artery occlusion. Even then
? ^ there was a reduction in infarct size combined with an
increased collateral blood flow.
** As with verapamil, studies using the baboon, rabbit
and rat hearts[67-69] have confirmed the results found in
the dog.
The cardioprotective actions of dihydropyridine cal-
cium antagonists have been demonstrated in many differ-
ent centres. Geary[70] is the only worker to have shown
no effect of nifedipine on infarct size. He used the open
chest anaesthetised baboon, an animal with little potential
for developing a collateral supply.
Diltiazem
Diltiazem, given soon after coronary occlusion, improved
> ischaemic muscle function in anaesthetised open chest
dogs[71,72]. In the same preparation, diltiazem reduced
infarct size as measured by ST elevation and percentage
of tissue at risk, increased regional myocardial blood
flow, increased tissue ATP, reduced lactate levels and
- > improved ischaemic muscle function[73,74].
In chronically instrumented dogs, Franklin[75] showed
that diltiazem improved collateral blood flow to the
ischaemic tissue. Clozel[76] reinforced this finding by
demonstrating improved function of hypokinetic muscle
segments after treatment with diltiazem.
Confirmatory studies on the efficacy of diltiazem have
also been performed on pigs[77], rats[78] and isolated
preparations[79]. These studies and those in dogs indi-
cate that diltiazem is a useful protective agent. A number
of authors have actually stressed the advantages of diltia-
zem over the other calcium antagonists. In comparative
studies, Urquhart[40] examined left ventricular function
in healthy conscious dogs and showed that at equipotent
doses diltiazem did not alter the indices of left ventricular
^ -> contractility, whereas verapamil and nifedipine reduced
them.
Evidence from Clinical Trials
Verapamil
Several studies have been reported, but as yet no long-
term clinical trial has been completed. Over a three-
<> month period Hansen[80] found no reinfarctions in 28
patients randomised for intravenous verapamil therapy,
compared with four of 23 patients in the control group.
r Verapamil had no adverse effects on cardiac conduction.
Brachetti et al. [81] showed that treatment within eight
hours of the occurrence of symptoms reduced ST segment
vector magnitude, implying a reduced myocardial infarct
size. Chew[82], in 25 patients, subsequently distin-
guished between two groups. One involved subjects with
mild cardiac disease, defined haemodynamically, in
which the vasodilatory actions of verapamil exceeded its
depressant actions. However, in patients with more
severe cardiac disease, the depressant actions became
important, causing reduced stroke volume and reduced
mean arterial blood pressure. Blood pressure therefore
needs to be monitored closely during such therapy.
Similar findings have also been reported by Singh and
colleagues[83].
Hasin's group[84] found that intravenous verapamil
therapy for 16 patients admitted with imminent subendo-
cardial or transmural myocardial infarction caused a
reduction in transmural ischaemia as measured by ST
segment elevation.
Heikkila and Neiminen[85] conducted the first study of
the effect of verapamil on myocardial contractile perform-
ance in patients. They found that verapamil given intra-
venously caused increased regional contractile function
without inducing a more widespread depression of nor-
mal myocardial tissue.
Finally, one study[86] has shown that intravenous
treatment in the range of 0.5-12 hours (with a mean of 4
hours) after onset of pain produced no evidence of a
reduction in infarct size (as measured by CK release) in
119 patients. The authors attributed this negative finding
to the delay in treatment.
Dihyd.ropyrid.ines
Several studies of nifedipine given to patients soon after
infarction[87-89] have shown that the drug is well tolerat-
ed and tends to have beneficial haemodynamic effects,
but the studies have been too small to demonstrate any
cardioprotective effect.
Muller et al. [90] have conducted the only randomised
double-blind, placebo-controlled multicentre trial, using
a 20 mg oral dose of nifedipine. In 181 patients selected
from a sample size of 3,143, no prevention of progression
of threatened myocardial infarction or limitation of necro-
sis in patients with acute MI was found. The study
sample was not large enough to make any estimates of
effects on mortality. This discouraging result may have
been because treatment was not given early enough
(4.6 ? 0.1 hr after onset of pain). As previously described,
early treatment is required to obtain myocardial salvage.
Diltiazem
In view of the comparatively recent addition of this drug
to the list of calcium antagonists, very few human studies
have been conducted. In patients who have had a recent
MI it has been found that diltiazem treatment has no
deleterious haemodynamic effects[91] and Nakamura[92]
has shown that in 12 patients, diltiazem reduced rest
angina after MI. No reports of definitive cardioprotection
have yet been produced.
Conclusion
On the basis of the evidence considered in this review the
following conclusions may be drawn about the possible
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
cardioprotective actions of the calcium antagonists. First,
there are a number of well-documented mechanisms by
which these drugs might reduce the size of an infarct and
the complications that may result from it. They may
improve flow, reduce demand and help to control poten-
tially lethal ventricular arrhythmias. Second, in the ma-
jority of animal studies, calcium antagonists have
successfully reduced infarct size. Finally, some of the
small-scale clinical trials have yielded encouraging re-
sults. These, of course, must be interpreted with some
caution since the relationship between various measures
of infarct size, such as ECG changes and enzyme release,
the amount of myocardial damage and the prognosis may
not be a close one. Furthermore, the only study of any
size yielded a negative result and further data based on
much larger double-blind controlled trials are needed.
Nevertheless, taken overall, the evidence must suggest
that calcium antagonists may have a cardioprotective
role, and interest in this subject is certain to continue and
probably to increase.
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|
PMC005xxxxxx/PMC5371018.txt | Book Review
Advanced Medicine 20.
Edited by Anne Ferguson. Pitman
Publishing, London, 1984. Price ?20.
I enjoyed reading this book. The Advanced Medicine
Conferences organised by the College are an important
part of its educational activities, particularly so since
there is now a tradition of rapid publication in book form.
Advanced Medicine 20 contains papers presented at the
meeting held in London in February 1984, and has been
edited by Dr Anne Ferguson of the Western General
Hospital, Edinburgh. The eight sections cover inflamma-
tory bowel disease, general gastroenterology, the preven-
tion of cardiovascular disease, chronic disease in
adolescence, clinical immunology, an assessment of four
'new' diseases, four papers on cancer management and
finally two papers on breast cancer.
In trying to assess the value of this book for the general
physician I found myself looking for discussions on
controversial or difficult areas of current practice; for
articles which encourage 'lateral thought' (by discussing a
topic in a field outside my own interests but leading me to
new thoughts about my own patients); for comprehensi-
ble reviews of the 'state of the art' in current research
fields; and for 'interface' articles exploring the fascinating
ways in which different fields within medicine interact
with each other.
From these standpoints this volume has much to
commend it. Clearly, the comments that follow are
personal reflections, but I have tried to give a flavour of
the contributions.
Of the two sections on gastroenterology, I particularly
enjoyed firstly the paper on the varied presentations of
coeliac disease which illustrates neatly how textbook
descriptions of disease can become out of date, and
secondly the chapter on the oesophagus as a cause of chest
pain which one might characterise as a new explanation
for an old symptom. There is a comprehensive review by
Misckiewicz of H2 antagonist treatment for peptic ulcer-
ation, and the general points made by Lennard-Jones in
his discussion of corticosteroid and immunosuppressant
treatment in inflammatory bowel disease are sure to be of
interest to physicians in other specialties.
From a total of five papers discussing the epidemiolog-
ical evidence for the value of preventive measures in
cardiovascular disease, one would have hoped that a clear
picture would emerge of the pathological processes which
it is hoped to prevent, and of the 'best buys' from the
candidates for programmes. However, this is not the case
and one has instead a thought-provoking article about
pathogenesis, and two somewhat opposing views about
coronary heart disease screening from Professor Oliver
and Professor Marmot. I think the article upon mild
continued on page 89
84 Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
Continued from page 84
n
hypertension might have been better deferred until the
>, full results of the MRC study are known.
Adolescence is an example of an interface area where
both paediatricians and general physicians might have
reason to feel somewhat out of their depth. I found the
rather unlikely subject of retarded growth and develop-
ment in teenagers by Dr Preece an interesting example of
how careful simple clinical measurements (in this case
height and family history) can lead to important conclu-
sions and diagnoses. In this respect it reminds me of the
use of peak expiratory flow rate charts in chest medicine.
Margaret Mearns' and Dr Taylor's comments on the
psychological difficulties of chronically ill teenagers are
surely important reviews for any doctor dealing with such
?s patients.
The section on clinical immunology was clearly intend-
^ -> ed to summarise research fields and was easily the most
difficult to comprehend. There are, however, comprehen-
sive reviews for the erudite, and Professor Kay's overview
-> of the mediator maze in asthma is an example. Professor
LessoPs paper on mediators in food intolerance might
have been better supported by, for example, a separate
^ discussion of the important difference between food intol-
erance and food allergy which has recently been high-
lighted so admirably by the Working Party Report
prepared by the College and chaired by him.
Factitious illnesses are surely not 'new' diseases, and
\
one would imagine that Munchausen patients have pre-
sented to physicians for centuries. However, Professor
Meadow's article rightly fascinates one with his account
of parents who fabricate symptoms and illnesses in their
children. One remains as baffled as ever to understand
the motivation of, for example, parents who deliberately
suffocate their children to induce epileptic fits. I also
much enjoyed Dr Lacey's description of the hyperphagic
syndrome (bulimia) as a counterpoint to the more notori-
ous anorexia nervosa, and the comprehensive account of
AIDS by Harris and Weber.
The last two sections concentrate on cancer therapy.
Several of these articles are of direct interest to the general
physician since most of us now deal with cancer either
frequently or rarely, and I found in this respect a
discussion of cancer care delivery, the lucid account of
breast screening by Dr Chamberlain, and particularly the
thought-provoking article by Maguire on the psychologi-
cal difficulties which patients experience when they un-
dergo cancer chemotherapy, were the most memorable.
There is now, perhaps belatedly, intense interest in
oncology in the measurement of >the quality of life that
these patients experience. Dr Maguire once again forces
us to remember the importance of the whole patient when
we apply treatment, and I thought it an apposite way to
end this valuable collection of papers.
MARTIN MUERS
Journal of the Royal College of Physicians of London Vol. 19 No. 2 April 1985
|
PMC005xxxxxx/PMC5371031.txt | Conference on Sports Medicine
J. H. ROSS, MC, MD, FRCjR Retired Physician, Hereford
It is time that the profession appreciated that sports
medicine is not just about the treatment of injuries and
that those concerned with the subject are not only figures
in track suits who run on to sports fields carrying little
bags and icepacks. The present interest in improving
performance by the study of the physiology and the effects
of exercise has received little publicity. There are now of
course numerous sports enthusiasts, marathon runners
and joggers in every general practice and hospital popu-
lation, and it has become important to know to whom to
turn to for expert advice when unusual medical problems
arise. A valuable step in stimulating interest in the subject
as well as educating those already interested and helping
them to exchange ideas was taken by the College in
arranging a 'Conference on Sports Medicine' in March of
this year, organised by Dr J. Howel Jones from Coventry,
an Honorary Medical Adviser to the Commonwealth
Games Federation.
The President chaired the first morning's session on
'Exercise Physiology'. The working of muscles is obvi-
ously of prime interest to athletes and their doctors and it
was right that the first two lectures were devoted to this
subject. Dr N. C. Craig Sharp from the Motor Perform-
ance Laboratory in the University of Birmingham spoke
about the development of muscle strength. He stressed
the need, in research with sophisticated methods, to
simulate as accurately as possible the use to which the
athletes being studied put their muscles, and to discover
from coaches exactly what is to be achieved.
Muscular strength can be improved by recruiting the
percentage of fibres in use at any one time and also
increasing metabolic activity within the fibres. These
aims are achieved not only by repeated contraction of the
muscles against resistance but also by slow controlled
relaxation after contraction. Traditionally, training for
strength has been carried out every other day but there is
evidence now that daily training is better and that for
maintenance a programme one third as active as the
initial training is needed.
The speed of muscle activity necessary to achieve
optimum results in various sports has been studied in
detail and is determined by the different types of muscle
fibre. Marathon runners have 79 per cent of slow twitch
Type 1 fibres and 21 per cent of fast twitch fibres in their
running muscles, and sprinters have almost exactly the
opposite. These studies have influenced training and have
led to more careful attention to muscle loading and to
variation in the training exercises. Nowadays the longer
careers of athletes and sportsmen and the large cash sums
involved make avoidance of injuries most important. It
was interesting to hear that nervousness leads to muscles
over-acting, especially early in games or competitions,
and that this can be of benefit to sprinters but not to
others; also that, on the whole, an athlete's specific ability
is determined genetically. For we are born with set
populations of-slow and fast muscle fibres but these are
capable of some modification. Increasing the endurance
of muscle activity has also been studied; muscle capillaries
can be increased as can myoglobin content, and mito-
chondria can multiply up to 300 per cent.
Professor Clyde Williams from the University of
Technology, Loughborough, went into more detail about
muscle metabolism with particular reference to energy
yields from aerobic and anaerobic metabolism. The
different substrates used by muscle can alter energy
production but require varying consumption of oxygen.
The amount of oxygen required by different individuals
to achieve the same speed of running can also vary
considerably. Blood lactate accumulates earlier in
untrained individuals; the amount produced by an indi-
vidual at a given stage of training is reproducible and
determination of this can indicate the optimum running
speed. Type 2 fibres have a greater oxidative capacity
than Type 1 and are recruited as activity continues with
anaerobic metabolism complementing aerobic. Lactate
accumulation and the consequent fall in pH influences
enzyme performance and is responsible for fatigue in
muscles.
Many factors can influence the development of muscle
endurance, particularly diet and training. Elite runners
can thus develop a capacity for promoting aerobic metab-
olism and can manage to metabolise lactate and to buffer
the fall of pH in muscle. They have a surprising ability to
reproduce good performances after only short recovery
periods, but studies can be confusing as treadmills do not
accurately simulate marathon conditions because they
produce a 'softer' activity.
The physiological session concluded with 'Thermo-
regulation in Athletes' by Professor C. T. M. Davies. A
former Director of the MRC Muscle Research Group in
Nottingham, he is now Head of the Department of
Physical Education and Sports Science in Birmingham.
The study of heat dissipation is obviously fascinating, but
perhaps not of immediate value to sportsmen, although
we learned that cold spongeing when overheated is sound
practice physiologically. The maximal aerobic power and
maximal evaporative (cooling) capacity of an individual
are closely matched under normal conditions. Endurance
athletes operate at over 75 per cent of their maximum
aerobic power; at levels of work over 85 per cent there is
evidence of vasoconstriction, the skin remains cool and as
exercise progresses there is a spiralling increase in core
294 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
temperature. Thermal control during the later stages of
such exercise (equivalent to elite marathon running)
appears to be 'passive' and thus extremely sensitive to
small changes in climatic conditions. Trained athletes
control their temperature better at high work loads than
do the untrained. The low skin temperature may actually
suppress sweating and in thin endurance athletes a major
portion of the heat produced by the muscles may be
transferred directly to the environment through overlying
skin and subcutaneous tissue. It is also possible to train to
produce more sweat but this does not alter exercise
capacity. Oxygen consumption becomes greater in cold
conditions whilst exercise capacity decreases. Children
are less efficient mechanically.
The speakers during the first afternoon considered
some of the consequences of exercise and sport in a
session chaired by Professor P. Fentem, a physiologist
from Nottingham and an aviation medicine consultant.
Mr J. S. Fox, consultant obstetrician and gynaecologist
and a member of the British Athletic Board, discussed the
menstrual cycle and sporting activities. It is no longer
considered that exercising during menstruation is harmful
and performance at that time is unchanged but the
premenstrual phase does seem to be associated with
poorer performance both in training and competition.
Dysmenorrhoea and midcycle pain can also cause
problems. Oral contraceptives can reduce menstrual
problems but may impair performance and increase body
fat and weight. The menarche may be delayed in athletes
and they may have more menstrual disturbances than
non-athletes but this could be related to the type of
individual rather than be a consequence of the training.
There does appear to be a relationship between exercise
taken and amenorrhoea and amenorrhoeic runners are
said to have greater endurance. Possibly the psychological
and physical stresses associated with competition, low
body weight, reduced percentage of body fat and hyper-
prolactinaemia are factors leading to a progression from
deficient luteal activity through anovulation to amenorr-
hoea. Progesterone may not be produced and endo-
metrium and breast could be subjected to unopposed
oestrogens with an increased risk of malignant change.
Oestrogen deficient states may arise if there is profound
gonadal suppression with a possibility of osteoporosis
developing. Athletic activities can lead to infertility, but
this is reversible.
Dr D. Tunstall-Pedoe, Chairman of the British As-
sociation of Sport and Medicine and President of the
International Marathon Medical Directors Association,
spoke on 'Normal and Abnormal Cardiac Responses to
Exercise' and covered a broad field. He believes that the
present increased exercising of the public is a reaction to
'automobile culture' and that there is a variety of reasons
for running in marathons:
1. To see if you can do it for the first time;
2. To improve performance;
3. To deny illness, (a worrying reason);
4. To raise money;
5. Exhibitionism.
The limiting factor in middle distance running is maxi-
mum oxygen consumption. This can be increased by
training, with consequent greater cardiac stroke volume
and enlargement of the heart, a physiological hyper-
trophy accompanied by bradycardia. There is a great
variation in this response and it may be associated with
unusual physical signs and a range of ECG changes that
can disturb doctors unfamiliar with such manifestations.
There can occasionally be worrying responses to exercise
with excessive tachycardia, bradycardia or other arrhyth-
mias which can lead to sudden death.
Dr M. Harries, from Northwick Park, explained that
lung function, unlike that of the heart, changed little with
training. He had studied airways obstruction in athletes
using portable devices capable of measuring air flow and
volume changes. Exercise induced asthma may occur,
probably due to the release of mediators from mast cells
and to vagal action; a variety of irritants can also
precipitate bronchoconstriction in athletes. Studies in
cold chambers have shown that subjects exercising at
+14?C exhibit slight bronchodilation but at -10?C and
below bronchoconstriction occurs. Asthmatics develop
bronchoconstriction with exercise even at +14?C and at
the lower temperatures without exercise. There is no
reason however why asthmatics should not take part in
competitive sports; antispasmodics are acceptable if their
use is declared before an event.
Dr John Ross reviewed the renal and haematological
changes occurring with exercise with particular reference
to studies made during selection courses for an army unit.
These studies had been initiated following the treatment
of acute renal failure in a participant who developed
rhabdomyolysis. Very severe increasing exercise over a
three week period was associated with considerable
elevation in serum myoglobin and some enzymes, the
elevation becoming less with training. No light was
thrown on the mechanism of renal failure that can arise
with myoglobin elevation. 'Sports anaemia' was also
discussed and considered to be, for the most part, a
'pseudoanaemia' occurring with plasma volume expansion.
Erythropoietin production is probably not stimulated as
the oxygen requirements of the tissues are satisfied and
the decreased haemoglobin concentration is not corrected.
Haemolysis and iron deficiency may arise during training
but are not usually of importance.
The next session concerned with 'Sports Injuries and
Sport in an Abnormal Environment', was chaired by Dr.
C. R. A. Clarke, the neurologist and mountaineer.
Dr P. Sperryn, Consultant in Physical Medicine at
Hillingdon Hospital and Medical Officer to the British
Amateur Athletic Board, gave a comprehensive talk on
'Sportsmen and Soft Tissue Injuries'. Much can be done
by doctors to advise sportsmen and their trainers about
avoiding injury. In the first place, careful history taking is
essential in order to discover exactly what muscles the
sportsman uses and what he does with his body and his
time, then advice can be given about modifying equip-
ment, clothing, shoes, spectacles and even indoor run-
ning tracks. Sport will inevitably become more dangerous
as the public and the media display more interest in what
can only be described as gladiatorial exhibitions, and
stress to competitors will continue to increase in view of
the financial rewards. Dr. Sperryn thought that 'Sports
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 295
Medicine' was a poor name for what is really 'Medicine
and the Science of Health and Fitness in Exercise'.
Dr Wendy Dodds, a rheumatologist from Bradford, a
runner, swimmer and skiing orienteer, told us that the
aims of the 'Treatment of Soft Tissue Injuries' were to
relieve pain, resolve inflammation, and promote healing.
She described the simple first aid use of ice, compression
and elevation and the various non-invasive methods of
treatment now available. Analgesics and non-steroidal
anti-inflammatory drugs can be valuable, the use of
corticosteroid injections is controversial and enzyme
preparations are not recommended. Many methods for
physical rehabilitation are used, helping muscle function
to be restored, mobility to be regained and propriocep-
tion, which can be impaired by injury, to be retrained.
We elderly physicians in the audience wondered why our
knocks and blows took so much longer to settle down than
they used to and were sorry to hear that little can be done
to help this state of affairs, the slow recovery of our aged
tissues being due to many factors including changes in
collagen structure and probably relative ischaemia.
Dr J. S. Milledge, of Northwick Park Hospital, an
experienced climber who has made many studies on
exercise and altitude at the famous 'Silver Hut' high
altitude laboratory, in the Western Cwm on Everest and
elsewhere spoke about 'Exercise Limits at Altitudes'. The
barometric pressure at the top of Everest is only one third
of that at sea level and it was not surprising to learn that it
is possible to climb only one hundred feet in an hour at
that height. If ventilation did not change, the alveolar
oxygen would become intolerably low. Pa02 decreases to
35 mm Hg with the induced changes in ventilation, about
the lowest level that can be tolerated. Arterial oxygen falls
to a far greater extent as work increases at high altitudes
than it does at sea level, equilibration with oxygen being
much slower along the alveolar capillaries; this is the
crucial limitation to exercise at such heights. Those
climbers with naturally low hypoxic ventilatory rates drop
their alveolar oxygen more than those with high rates and
did not do so well on Everest. However one climber who
reached the summit without oxygen had a low hypoxic
ventilatory rate, having been born and bred at a high
altitude, as had some Sherpas who also had low rates but
nevertheless reached great heights. The handling of
oxygen from atmosphere to pulmonary vessels has been
studied in detail, work which must have been difficult
under such extreme conditions. Dr. Milledge's clear
description made it all sound very easy.
From problems at high altitudes we descended to the
'Clinical Problems of Sports Diving' described by Dr N.
K.I. Mclver, a general practitioner who also works with
the North Sea Medical Centre at Great Yarmouth giving
medical advice to commercial and Scuba divers. The
subject is clearly important: in 1985, 165 diving 'inci-
dents' were reported including 14 deaths and 57 episodes
of decompression sickness occurring in 1,500 North Sea
commercial and 50,000 British Scuba divers. Joint pains,
pruritus, skin rash, oedema and general malaise with
fatigue and anorexia are the symptoms associated with
Type I decompression sickness; the more severe Type II
is manifested by peripheral neuropathy, respiratory
symptoms and hypovolaemic shock. Localised pain is the
single most common presenting complaint. Problems can
arise at comparatively shallow depths, only 5 metres
descent being accompanied by an increase of half an
atmosphere. Early recognition of the condition and the
correct action are extremely important, the initial presen-
tation sometimes being mild and many unfortunate cases
have been recorded as a result of lost time. As with so
many hazardous activities, good training and discipline
can minimise accidents.
The final session was chaired by Sir Roger Bannister,
Master of Pembroke College, Oxford, whose famous mile
was mentioned several times by previous speakers. The
four papers were concerned with 'Sports Problems and
Prospects'. The damage which can be done to children by
demanding too much physical exertion from them had
been referred to by earlier speakers but was dealt with
fully by Dr I. D. Adams, an accident and emergency
physician from Leeds. It is easy to ask too much of
children and adolescents who try to please their parents
and coaches; they must be thought of as children first and
athletes second. We heard some extraordinary facts from
Dr. Adams. Marathons have been run by a 15-year-old
boy in 2 hours 29 minutes and by a 16-year-old girl in
2 hours 46 minutes, sports injuries constitute 4 per cent of
new accident and emergency cases of which 17.4 per cent
are in children, and a 16-year-old swimmer may need a
diet of over 7000 kcals, but work and training may leave
little time for swallowing this large amount of food. Such
facts, and the knowledge that growing bones are so
vulnerable to damage, make the care and protection of
competing children a matter of concern to many doctors
other than sports experts. Much can be done in the way of
helping them by arranging general rather than specific
training, by safety devices particularly in gymnasia,
proper maintenance of facilities, matching of opponents,
adaptation of rules and avoiding unreasonable pressure to
win.
Dr J. Howel Jones started his talk on 'Doping in
Sport' by giving an example of drug abuse in which an
individual had used seven different substances, some
possibly to help him and some to counter consequent side
effects?a depressing story. The International Olympic
Committee Medical Commission produces lists of banned
drugs and most individual federations do adhere to them.
There are however problems; some banned drugs may be
present in preparations used therapeutically in a perfectly
acceptable way.
There is conflicting evidence about the benefits to be
gained from some drugs; amphetamine for example may
only lead to small physical effects. But as Dr. Howel Jones
pointed out very minor improvements can make con-
siderable differences to athletes' success. This was illus-
trated by the fact that after Sir Roger Bannister ran the
mile in 1954 in 3 minutes 59.4 seconds, 10 new records
were set in the next 11 years with an overall reduction of
only 10 seconds. Studies on caffeine show that it probably
does improve sub-maximal long-term exercise perform-
ance. It was removed from the banned list in 1972 but is
now prohibited again because of its abuse by injections
and suppositories. It is known that androgenic steroids do
296 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
not help aerobic performance but do increase strength
and decrease fatigue, knowledge that has unfortunately
led to their increased use. It is shocking to hear that, in
order to avoid detection, gradually increasing daily doses
of steroids and testosterone derivatives are taken for some
weeks and then reduced in the week prior to competition
when human chorionic gonadotrophin is also taken: a
diuretic is used on the final day to produce dilute urine for
testing. Beta blockers are now banned from shooting
contests in which they could reduce tremor, unfortunate
for some hypertensives. Athletic training at high altitudes
increases oxygen transport by the blood and improves
performance on return to lower levels; this is permitted by
the Olympic Authorities. 'Blood doping', the transfusion
of whole blood or packed cells, has the same effect and is
banned; but now that storage methods have been
improved autologous reinfusion can be used and is not
easily detected. It was sad but interesting to hear how
much deceit has been introduced by competitiveness in
sport.
Dr R. Budgett, an Olympic Gold Medallist who had
stroked the victorious coxed four in 1984, gave the
competitor's view of the preparation for such a contest.
This took him four years during which there was the
constant anxiety that he might be sacrificing time, money
and the formation of a career with the possibility of not
eventually being selected to compete. He emphasised the
need to use stress and the 'adrenaline surge' to improve
performance, to work and think as a team and to
maintain motivation by envisaging the joys of winning.
The advice of sports doctors throughout training was
valuable to help avoid injuries which could wreck
ambitions. It all sounded incredibly hard work and the
winners of any event deserve lasting admiration.
Dr B. B. Lloyd, former Chairman of the Health
Education Council, looked at the future of athletic
records. He had found that the records for various
running events, expressed as metres per second, rose as
straight lines over many years. It appeared that women's
records were now improving faster than men's but it
seemed unlikely that improvement would continue in a
linear fashion.
The recently formed London Sports Medicine Institute
has produced a pamphlet which states '. . . there has
been no base for sports medicine in Great Britain and the
average athlete is less well served than in many other
countries where there is government money for sports
medicine and where well established sports medicine
clinics and research institutes exist'. At this conference I
do not think that the speakers were just addressing the
converted; there were many non-sports doctors and
students from all over Great Britain who will have taken
home with them the message that more attention to the
subject is needed. More sports clinics, perhaps in university
settings, are required. These might stimulate more
research in departments of physiology, orthopaedics and
physical medicine. Well controlled trials of treatment
for injuries are much needed. More doctors should be
affiliated to sports clubs. There do seem to be experts
throughout the country who would be happy to give
advice on these matters and to be included in coordinated
projects.
|
PMC005xxxxxx/PMC5371032.txt | Editorial
Events change the impact of words. Add 'nuclear' to 'power' or
'bomb' and you will stir the emotions, if not the reason, of all. Fifty
years ago these words would have been greeted with incomprehen-
sion. On a lower plane of disturbance is that ambivalent word 'drug'.
In the 18th century it had a comfortable existence as 'a general name
for all spices and other commodities brought from distant parts and
used in the business of medicine, dyeing and the mechanical arts.' In
the business of today's medicine we use, and seek, curative medica-
ments but call them drugs, the same word we use for agents of
addiction brought from distant parts and the so-called drug culture.
The pharmaceutical industry is handicapped by their representatives
being called 'drug reps', an abbreviation that hints at drug pedling.
Semantics do matter whenever a matter of medicine is the subject
of public discussion. Public perception can so easily be based on
misconception. Any kind of drug can be perceived as a symbol having
power over a person, as something that can save or enslave. The term
'drug dependence' has a sinister ring to it. So the act of prescription
can be construed as a dispensation of power. A prescription is both
desired and feared. If it is only a substitute for communication the
patient will feel rejected. If the drug prescribed has an adverse effect
then the doctor may be seen as an adversary. Fortunately, these
considerations seldom arise in the humdrum world of daily prescrib-
ing but they can easily be invoked and exploited. We have not learnt
an accepted language to explain the benefits and risks of each
prescription. Merely reciting a litany of all possible adverse effects is
of little help to the patient, particularly if there has not been a recital
of the benefits to be derived from the prescription. To mount a private
hobby-horse, adverse effects are inherent in the drug's structure, they
are not 'on the side'. The rare catastrophe of drug-induced death has
to be called 'adverse' rather than by the trivialising term 'side effect'.
Adversity can be quantified in terms of frequency of occurrence
and severity of event. But numbers, however useful to the doctor, do
little to adjust public perspective. The one disaster stays in the
imagination long after its rarity is forgotten. In the continuing public
debate on medicines there is a noticeable lack of information on the
positive benefits of drugs. People need to be reminded over and over
again of the morbidity and mortality that is prevented by modern
medicines.
Of course, giving due praise to certain treatments needs the
backing of correct prescription. Every doctor knows that no drug
should be prescribed unless it is necessary and proper for both disease
and patient, and given in the right dose for the right time. Why every
prescription does not fulfil these obvious criteria remains a mystery
that needs a solution if the public are to trust the doctor's medicine.
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 233
|
PMC005xxxxxx/PMC5371034.txt | Senior Registrars' views on
Geriatric Medicine
PAUL V. KNIGHT, mb, mrcp(UK)
University Department of Geriatric Medicine, Southern General Hospital, Glasgow
The ideal relationship between geriatric and general
medicine, in terms of training and service commitment,
has been frequently contested[l,2]. The practice of geriat-
rics and its association with general medicine at present
remains diverse[3,4]. This study attempts to describe the
attitudes of senior registrars (SRs) in geriatrics to the
specialty's affiliation with general medicine.
Method
Questionnaires were mailed to 157 SRs whose names
were obtained from the British Geriatrics Society trainee
list. The questions were phrased in a pragmatic form and
the replies were made anonymously. There was space in
the questionnaire for additional comments.
Results
One hundred replies suitable for analysis were received; a
64 per cent response rate. The answers are detailed in
Tables 1-3.
Table 1. Length of registration and experience in geriatric
medicine; job description.
Years registered with GMC:
Months (post-GMC registration) of
experience in geriatrics prior to SR
appointment
SR job description:
Full-time geriatrics
Integrated with general medicine
Mean 7.4 No. of people
0 28
1-6 26
6-12 17
>12 29
59
41
More than half the sample had less than 6 months'
geriatric experience before being appointed SR. Although
a majority (68) felt that further training in general
medicine as an SR was desirable, a minority of 35 were
unable to undertake it. In contrast, 62 respondents
preferred the career option of whole-time geriatrician and
the same number wished geriatric medicine to remain
separate from general medicine.
Approximately 15 per cent of the respondents made
further comments, independent of the questionnaire.
Many of these views overlapped and most were related to
the integration of geriatric and general medicine.
Table 2. Accreditation and rotation with general medicine.
(Number of answers received)
In training future consultant geriatricians, do you believe dual
accreditation with general medicine is desirable, in contrast to
training (at SR level) mainly or wholly in geriatrics'.
Desirable 68
Undesirable 9
Irrelevant 23
Would one year's experience in general medicine, at SR level,
enable you to apply for dual accreditation?
Yes 62
No 33
Don't know 5
Can you to rotate to general medicine during SR training, if
desired?
Yes 65
No* 35
*15 in Thames Regions. 5 lecturer posts in University Departments.
Table 3. Career choice; future of specialty.
Choice of consultant post:
Whole-time geriatrician 62
Physician with an interest 30
No stated preference 8
How geriatrics should proceed?
Separate specialty 62
Total with general medicine 21
Other 17
Of those favouring some form of integration, several
expressed some confusion at what this implied, i.e.
whether it was sharing of beds, staff, or resources such as
radiology. A popular view was that in rural or semi-rural
areas integration would be more logical than in urban
environments; however, specialist university departments
should continue to exist to guide research and policy.
Other people believed that geriatrics would be more
viable as an age-related speciality like paediatrics, and
interestingly only two respondents wished geriatrics to be
a medical sub-specialty like cardiology. A further two
respondents stated that other reasons for dual accredit-
ation were to give them as wide as possible a career choice
and to silence critics of the calibre of trainees in geriatric
medicine.
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 271
The more entrenched 'separatist' attitude was that
wholesale integration would once more lead to general
physicians with neglected and unsupervised long-stay
beds. Indeed, they felt that far from encouraging geriatric
medicine SRs to train further in general medicine, it
should be made compulsory for general medical SRs to
spend a period in geriatrics. One respondent expressed
concern that some senior geriatricians now seemed to
believe that training as a pure geriatrician was in some
way inferior to the integrated approach.
The replies of the 28 respondents who had no previous
geriatric experience prior to SR appointment were exam-
ined. It transpired that 15 had integrated SR posts, 19
only required one further year in general medicine to
qualify for dual accreditation (providing two years of
geriatrics was also completed), and four had already
claimed accreditation in general medicine prior to SR
appointment. The majority (23) believed further training
in general medicine at SR level to be desirable, but equal
numbers were in favour of each career choice. Only nine
wished geriatrics to integrate totally with general medi-
cine.
Discussion
The response rate of 64 per cent seems small. However,
theJCHMT gives an approximate figure of 120 approved
geriatric medicine training posts in the UK. Some are not
necessarily funded, and others may be vacant because the
incumbent has moved on to another post and a replace-
ment has yet to be appointed. Thus the true reply rate
may be in excess of 85 per cent, which makes the views
expressed more representative of the general SR popu-
lation.
It is disappointing that there remains a minority of SRs
(28) who have no previous geriatric .experience on ap-
pointment. This number includes over one third of those
in designated integrated SR posts and almost one half
(13) of those wishing to become physicians with an
interest in the elderly. They are not significantly longer
registered with the GMC than other respondents nor do
they necessarily wish for the integration of geriatrics into
general medicine.
There are more integrated SR posts than likely consult-
ant vacancies of this sort. Only a minority (30) wish to
have their consultant practice integrated in this fashion.
The desirability of further training in general medicine
appears to have as much to do with its possible political
implications as with its probable training content.
In my opinion the suggestion that geriatric medicine is
an ideal career option for surplus trainees from other
general medical specialities[3] is fraught with difficulties.
To imply that surplus-to-requirements purely means
failed candidate would be grossly unfair to the many
excellent recruits geriatrics has gained in this way. A
recent survey by Donaldson has clearly shown that
trainees who arrive by this route would still rather be
doing something else[5], Donaldson's survey had a sub-
stantially different SR population from my own study,
but both show that these people wish, in the main, to keep
in touch with their general medical roots by choosing a
consultant post as a physician with an interest in the
elderly. It is possible that applicants with longer general
medical training may be considered more favourably for
these integrated posts. However, as their SR training is
often integrated with general medicine, their geriatric
experience may not always be of sufficient duration.
It is a worrying, although perhaps an over-pessimistic
view that, in suggesting all geriatric departments should
be a subset of general medicine we will recruit a cadre of
dissatisfied general physicians who may in the future be
inclined to give a lower priority to their elderly patients.
As these types of departments work almost exclusively on
acute admissions with little or no home visiting it is
inevitable that a high turnover of patients will be
achieved. What then becomes of the difficult rehabili-
tation problems, who do not fall into the acutely-ill
category?
I believe that closer liaison with general medicine
brings benefits. However, I suggest these lie in having
assessment beds in the main hospital with access to all
investigative facilities and perhaps also a common pool of
staff. I think that, because of its development from the
chronic care wards, the very modus operandi of geriatric
practice in the UK, precludes it from being treated in the
same way as another medical subspeciality. If a consult-
ant is busy doing general medical out-patient clinics,
specialist clinics and practising skills such as endoscopy,
there will simply be little or no time to do day hospital,
chronic care and rehabilitation rounds and domiciliary
assessments. Geriatricians should co-operate very closely
with their general medical colleagues. Regular visits to
the general medical ward, to advise on problems and not
just to provide a 'take-away' service, can be particularly
beneficial[6].
The majority of SRs in geriatric medicine would, for a
variety of reasons, welcome the opportunity of having
further training in general medicine, although at present
some are unable to achieve this. Despite this, the majority
of SRs in geriatrics wish to be whole-time consultant
geriatricians. Therefore, such training, however desirable
it may be for the trainee, should not intimate to trainers
that geriatric medicine requires wholesale integration
with general medicine. This represents a diametrically
opposite view to that of other policy makers[7].
Acknowledgements
I would like to thank Professor F. I. Caird for his help.
References
1. Evans, J. G. and Graham, J. M. (1984) Journal of the Royal College of
Physicians of London, 18, 18.
2. Williamson, J. (1984) Guinness Lecture to the British Geriatrics
Society.
3. Irvine, R. E. (1984) Journal of the Royal College of Physicians of London,
18, 21.
4. Horrocks, P. (1982) In Recent Advances in Geriatric Medicine, No. 2,
p.259 (ed B. Isaacs) London: Churchill Livingstone.
5. Donaldson, M. (1985) Age and Ageing, 14, 8.
6. Burley, L. E., Currie, C. T., Smith, R. C. and Williamson, J.
(1979) British Medical Journal, 2, 90.
7. Royal College of Physicians (1977) Report of a working party on medical
care of the elderly. London: Royal College of Physicians.
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
|
PMC005xxxxxx/PMC5371035.txt | The Female Life Span
SIR RICHARD BAYLISS, kcvo, md, frcp
SIR CYRIL CLARKE, kbe, md, frcr frs
A. G. W. WHITFIELD, cbe, md, frcp
Royal College of Physicians Research Unit, London
There is widespread awareness of the increased longevity
of the population of Great Britain and of the socio-
medical problems which the care of those no longer
capable of an independent life impose upon the nation.
The actual numbers involved and the progressive in-
crease in those living to an advanced age are not so fully
appreciated. Figure 1 and Table 1 show the position in
England and Wales over the last half century. In 1981
there were more than four times as many women over the
age of 85 as there had been 40 years earlier in 1941, while
over the same period the number of males of this age
trebled[l-5]. The proportion of very old people relative to
the total population of each sex has steadily increased and
by 1991 may for women exceed 2 per cent. This demogra-
phic and social change was considered in an earlier
publication[6] which this contribution endeavours to am-
plify and to take a step further.
The factors underlying increased life expectation are
multiple. Progressive improvement in social conditions is
probably the most important. Better housing, better
nutrition, clean air, central heating and improved water
supply and sanitation have become available to the
majority. In addition, free medical care, the advent of
Table 1. Population of England and Wales over age 85 by
Decade and Sex.
Number over 85 Percentage over 85 of
total of sex
Male Female Male Female
1941 42,000 89,000 0.24 0.41
1951 59,000 132,000 0.28 0.58
1961 92,000 205,000 0.41 0.86
1971 107,000 313,000 0.45 1.25
1981 125,500 410,700 0.52 1.61
Fig. 1. Population of England and Wales over age 85 by sex and percentage of the total population of their sex.
500, 000-,
Females
Males
400,000-1
5 300,000^
200,000H
ioo,oooH
? ?
??"
r~1' 5
M -0
r0'5
1941
1951
?I?
1961
Year
-0-0
1971
1981
290 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
antibiotics and improved surgical and anaesthetic skill
must have played their part. The virtual conquest of great
killers of a bygone age such as tuberculosis and smallpox
and the effective prophylaxis of poliomyelitis, whooping
cough, diphtheria and other infections have reduced the
death rate from these diseases while the enormous reduc-
tion in perinatal mortality has allowed more babies, who
previously would not have survived, to live to swell the
population in their second and subsequent years.
The extent to which life span can continue to increase
may have a finite limit. To date, authentic records show
the longest surviving male^in England and Wales to have
died at 111 in 1968 and the longest surviving female at
112 in 1973[7], It may well be that in the future a few will
live for longer than this but the probable trend will be for
more men and women to live to extreme old age and for
there to be more centenarians; but the numbers living
beyond 110 are likely to remain small.
That more females than males survive to an advanced
age has long been known. In 1841 there were 78 female
and only 36 male centenarian deaths[8] and in 1910 the
numbers were 43 female and 22 male[9]. The extent of
the increasing female preponderance is shown in Figure 1
and Table 1. Figure 2 shows the number of men and
women aged 100 or more who died in England and Wales
in 1982[ 10].
The causes underlying the sex difference in longevity
are complex. In the years 1941-81 the total population of
England and Wales contained a million more women
Table 2. Population England and Wales
Male Female
*1941 17,228,000 21,515,000
1951 21,049,000 22,751,000
1961 22,346,000 23,820,000
1971 23,797,000 25,097,000
1981 24,121,000 25,472,000
* Figures influenced by 1939-45 war
Table 3. Number and sex of babies born in 1941-81 in
England and Wales.
Female M/F ratio
1941 280,000 268,000 1.045
1951 346,000 328,000 1.055
1961 403,000 382,000 1.055
1971 401,500 380,100 1.056
1981 324,900 309,500 1.050
than men (Table 2) although at birth there was a slight
male preponderance (Table 3) which was maintained
until the age of 50-54 years. This was despite a higher
perinatal mortality in males than in females and despite a
higher death rate in male infants from congenital malfor-
mations. Indeed more male than female deaths occurred
until the age of 80 years (Table 4) when the reduction in
the number of male deaths resulted chiefly from the fact
that there were fewer men than women of that age
available to die rather than a smaller proportion of the
Table 4. Number of deaths in 1981 in England and Wales by
sex.
Age
0-4
5-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85-89
90-94
95-99
100-104
105-109
110 +
Male
4,770
447
573
1,734
1,576
1,427
1,754
2,143
3,392
5,920
10,969
19,688
27,170
40,298
51,891
50,959
35,815
19,406
7,357
1,563
161
8
1
Female
3,431
302
368
650
642
718
1,103
1,451
2,291
3,820
6,693
11,268
15,943
25,100
37,662
49,320
54,234
43,416
22,827
6,627
940
60
2
Total
289,022
288,068
Fig. 2. Centenarian deaths England and Wales 1982 (actual
number)
over
Age
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
male population in that age group dying[l-5]. In 1976,
and earlier, the death rate in women overtook that in men
in those aged 75-79 and this upward change reflects the
enhanced life expectation for men.
It is remarkable that with the wide differences in the
number of male and female deaths from birth onwards
the numerical supremacy of men in the population is not
finally eroded until the age of 50-54, but with a total
population of 50 million in England and Wales it requires
a disproportion of deaths between the sexes of half a
million to produce a one per cent change in the sex
structure of the population. It must be emphasised too
that in the fourth and fifth decades the difference in the
sex population is small and before 1981 the change over in
numerical sex supremacy occurred at an earlier age,
being in the age group 45-49 in 1971 and 35-39 in
1961 [1-5]. The recent upward trend again reflects the
improved life expectancy of men and possibly also the
receding effects of the 1939-45 war.
From birth up to quite an advanced age, therefore,
more men than women die each year. Each death, male
or female, depletes the numbers entering the next and
subsequent years and the excess of male over female
deaths up to the age of 80 means that each year there are
more women going forward to the next year than men.
From the age of 80 onwards there are even more females
than males surviving to enter the subsequent year because
the male population over the age of 80 is so small.
The causes of the higher male death rate are shown in
Table 5 which lists the diseases in which there is a
significant sex difference in the numbers dying. Tubercu-
losis, neoplasms (particularly of the lung and bronchus),
ischaemic heart disease, chronic obstructive airways dis-
ease, accidents and suicide are largely responsible. These
deaths remove large numbers of males in middle life,
leaving fewer to progress with their contemporaries and
with females of the same age to the next and subsequent
years. The excess of some 27,000 male over female deaths
in 1981 is paralleled in other years but is often less in
degree. It occurs despite the large numbers of women
dying from breast, uterine and ovarian cancer and the
predominance of females among those dying from cere-
brovascular disease. However, most females who die
from strokes do so between the age of 70 and 95: of the
43,047 women who died of a stroke in 1981, 35,467 were
aged 70 or over[5].
It is obvious that the age at death plays a crucial part in
determining the numerical disproportion between the
sexes. If the years lost by death are considered in the
principal causes of death in men and women, the extent
to which the male population is depleted in middle life
will be immediately evident (Table 6). While cerebrovas-
cular disease causes marginally more years lost in women
than in men, the years lost to age 65 and to age 85 from
deaths due to neoplasms, ischaemic heart disease, chronic
obstructive airways disease, accidents, and suicide are
very much greater in men than in women[5].
It must be emphasised that a larger female population
and a higher male than female mortality rate have been a
feature of England and Wales since accurate records have
been kept[8,9,11-13], Currently, a considerable number
Table 5. Major causes of death where there is marked dispro-
portion between the sexes England and Wales 1981.
Number of deaths
Male Female
Tuberculosis 385 172
All neoplasms 69,920 61,771
Oesophagus (2,242) (1,613)
Stomach (6,305) (4,347)
Colon (4,428) (5,940)
Rectum (3,281) (2,772)
Lung & bronchus (26,297) (8,430)
Female breast (12,513)
Cervix, uterus & ovary (7,239)
Prostate (5,151)
Diabetes 1,994 2,632
Thyroid disorders 76 375
Mental disorders 1,137 2,304
Senile dementia (534) (1,441)
Rheumatic heart disease 896 2,224
Ischaemic heart disease 89,104 66,092
Hypertensive heart disease 2,458 2,955
Cerebrovascular disease 26,604 43,047
Chronic obstructive airways
disease 17,587 7,309
Musculoskeletal disorders 823 2,289
Congenital anomalies 1,665 1,374
Perinatal 1,605 1,054
Injury and poisoning 11,588 8,200
Road traffic accidents 2,889 1,156
Suicide 2,761 1,658
Total 231,582 204,612
Note: Items in parenthesis are part of 'All neoplasms' or Mental
disorders' and so do not add to the total.
of the male deaths in middle life appear likely to have
resulted from smoking. How then can a similar situation
in respect of male mortality be explained during a long
period before the cigarette arrived? Table 7 shows some
of the causes of death in 1911 where it will be seen that
infections, particularly tuberculosis and pneumonia, sui-
cide and violence, and perinatal mortality were respon-
sible for very many more male than female deaths[14], A
similar pattern was seen throughout the second half of the
nineteenth and early decades of the twentieth centuries.
Why perinatal death claims more male than female
infants is uncertain. The higher congenital malformation
rate in males only explains a small part of the difference.
If the consumption of tobacco is reduced by health
education it is possible that in a decade or so men may
have a life expectation similar to women. Of the 1,975
deaths certified in 1981 as due to senile dementia 574
were male and 1,441 female[5]. It will be of interest to see
whether, when men live longer, they experience the same
incidence of senile dementia as do women now, or
whether women are particularly prone to this disorder.
It may well be, however, that in blaming tobacco for
male attrition one is tending to overlook other factors
which may be of equal or greater importance. Under
good laboratory conditions the male mole rat lives longer
than the female, probably as a result of protection from
predators (see also a similar situation in mice[15]), and
292 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
Table 6. Mortality rates per 10,000 population, age at death and years lost by death?England and Wales 1981
All neoplasms
Ischaemic heart disease
Cerebrovascular disease
Chronic obstructive airways
disease
Accidents
Road traffic accidents
Suicide
Male Female
Mortality Mean age Years lost Mortality Mean age Years lost
rate at death to age 65 to age 85 rate at death to age 65 to age 85
29 68.8
37 69.8
11 74.1
6 73.4
3 45.1
1 37.4
1 48.1
1131.5 4663.3
229.1 1371.2
38.0 298.4
20.6 159.4
173.9 303.4
84.1 137.7
51.4 101.9
24 69.3
26 76.8
17 78.6
2 73.6
2 65.7
0 49.1
1 55.7
687.3 1124.0
49.9 577.6
33.3 307.6
12.9 67.3
52.9 113.2
22.9 41.6
20.4 48.6
Table 7. Some major causes of death in England and Wales
in 1911.
Male Female
All causes 272,512 255,298
Infections 49,551 43,377
Tuberculosis (29,227) (23,893)
Pneumonia 21,582 16,060
Perinatal mortality 19,560 15,144
Violence and suicide 14,405 5,929
not having to compete for food and living space[16]. In
the Hutterite and Amish communities in the USA males
live longer than females, 55.6 per cent of the Amish over
60s being male. This is thought to result from their large
family size, their self sufficient agrarian existence and
their social and cultural isolation. It certainly appears to
be environmental rather than genetic for the Amish came
to the USA from Berne via Alsace Lorraine only about
two and a half centuries ago[17]. Among humans in this
country those with Down's syndrome are probably the
most protected group; they do not have to serve in wars,
they are not often exposed to the risk of accidental death
and they are provided with food and a home either by
their parents or by the state. Their life expectation has
increased since 1929 from nine years[18] to about 50
years now[19-23] and today the major cause of death is
premature senility (Alzheimer's disease). While it may
reasonably be argued that much of this improvement
stems from the prevention or control of infections there
seems little doubt that the unavoidable pattern of living
imposed on patients with Down's syndrome favours their
increasing life span and male survival. There is a male
preponderance among mongols born alive[20,21]. Al-
though earlier writers report the majority dying in their
first year to be female, this is no longer evident[23] and
after one year there is no clear difference between male
and female mortality. In consequence, a male preponder-
ance remains until death.
So, therefore, it may be with normal humans. The
female has a more sheltered life than the male and is
under less risk of physical injury; other indirect factors
which threaten life affect her less and so she usually lives
longer than her male counterpart. Evidence currently
available strongly favours environmental rather than
genetic influences in female longevity and it may well be
that a more wholesome lifestyle for the male might result
in his living as long as the female.
References
1. Registrar General's Statistical Review of England and Wales for the year
1941. (1945). London: HMSO.
2. Ibid, for the year 1951. (1953). London: HMSO.
3. Ibid, for the year 1961. (1963). London: HMSO.
4. Ibid, for the year 1971. (1973). London: HMSO.
5. Office of Population Censuses and Surveys. (1983), Mortality
Statistics England and Wales 1981. London: HMSO.
6. Clarke, Sir Cyril. (1986). Journal of the Royal College of Physicians of
London, 20, 122.
7. Thatcher, A. R. (1981). Population Trends, 25, 11.
8. Fourth Annual Report of the Registrar General of Births, Deaths and
Marriages in England. (1842). London: HMSO.
9. Seventy-third Annual Report of the Registrar General. Abstract of 1910.
(1912). London: HMSO.
10. Office of Population Censuses and Surveys. (1985), Mortality
Statistics England and Wales 1982. London: HMSO.
11. Fourteenth Annual Report of the Registrar General of Births, Deaths and
Marriages in England. (1855). London: HMSO.
12. Supplement to the Thirty-fifth Annual Report of the Registrar General of
Births, Deaths and Marriages in England. (1875). London: HMSO.
13. Registrar General's Statistical Review of England and Wales for the year
1931. (1932). London: HMSO.
14. Registrar General's Statistical Review of England and Wales for the year
1921. (1923). London: HMSO.
15. Miihlbock, O. (1957) In Ciba Foundation, Colloquia on Ageing. Vol.
3. London: J. and A. Churchill.
16. Nevo, E. (1985). Personal communication.
17. Cross, H. E. and McKusick, V. A. (1978) In Medical Genetic Studies
of the Amish. Baltimore: Johns Hopkins University Press.
18. Penrose, L. S. (1932) Journal of Genetics, 25, 407.
19. Penrose, L. S. (1949) Journal of Mental Science, 95, 685.
20. Record, R. G. and Smith, A. (1955) British Journal of Preventive and
Social Medicine, 9, 10.
21. Carter, C. O. (1958). Journal of Mental Deficiency Research, 2, 64.
22. Collmann, R. D. and Stoller, A. (1963). Journal of Mental Deficiency
Research, 7, 53.
23. Gill, M., Murday, V. and Slack, J. (1986). Submitted for
publication.
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 293
|
PMC005xxxxxx/PMC5371036.txt | Graves of Graves' Disease, 1796-1853
SELWYN TAYLOR, dm, MCh, frcs
Dean Emeritus, Royal Postgraduate Medical School, London
It is just over 150 years since Graves described the disease
which we associate with his name. The description ap-
peared in the London Medical and Surgical Journal for
Saturday, 23rd May, 1835 and was part of his clinical
lectures at the Meath Hospital in the 1834/35 sessions[l].
He reported three cases of tachycardia and thyroid
enlargement in young women and added a fourth with
severe exophthalmos who had been referred by a col-
league. He was not the first to identify the symptoms and
the eponym should properly have been claimed by Parry.
To digress, Caleb Hillier Parry was born in Gloucester-
shire, studied medicine in Edinburgh and practised in
fashionable Bath. He went to school with Jenner, who
remained a lifelong friend, and dedicated his famous book
on vaccination to him. Parry's account[2] of eight cases of
the disease was published posthumously by his son in
1825. Basedow, whose name is used for hyperthyroidism
in most of the other member countries of the European
Community, came from an aristocratic German family
and practised in Merseburg. He described, but not until
1848, the postmortem appearances of a patient dying with
exophthalmic cachexia.
There is no doubt, however, that Robert James Graves
should be remembered for his immense contributions to
medicine. He revolutionised the clinical instruction of
medical students in the UK. He wrote a standard two-
volume work[3] on medical treatment, which was trans-
lated into French, German and Italian and also published
in the USA. In it he described many conditions for the
first time; for example, intermittent pallor of the fingers
and toes is clearly defined 10 years before Raynaud and
so is angioneurotic oedema, 30 years before Quincke.
Robert Graves was born on 28th March 1796, the sixth
of the 10 children of the Reverend Richard Graves, a
Fellow of Trinity College, Dublin, who later became
Regius Professor of Divinity and Dean of Ardagh. His
mother was Elizabeth Drought, the daughter of another
Professor of Divinity also of TCD, as it is affectionately
called. The Irish branch of the Graves' family, who hailed
from Mickleton in Gloucestershire, was founded by Wil-
liam Graves, a colonel commanding a horse regiment in
Cromwell's army which wrought such havoc in Ireland,
who as a reward received a grant of land in 1650. The
family over the years have been distinguished for their
contributions to learning, especially theology, and to the
Government services, from admirals and governor-gener-
als to professor of divinity, authors and poets.
Young Graves had a happy childhood and after being
tutored by an uncle of Oscar Wilde, passed into TCD at
the top of the entry list. He subsequently took the highest
award, the Gold Medal, when he graduated, as did two of
his brothers. This was a degree in the classics and for the
rest of his life he enjoyed quoting from his knowledge of
Latin and Greek authors. Qualifying in medicine three
years later in 1820, he made the most important decision
of his career, which was to go abroad, and he spent the
next three years in postgraduate study travelling round
Europe.
Training to be a doctor in the 1820s, be it in Dublin or
London was at best haphazard and at worst scandalous.
Eoin O'Brien in his biography of Dominic Corrigan[4]
paints a graphic picture of the scene in Ireland, and it is
little wonder that the General Medical Council for Edu-
cation and Registration, our own GMC, was set up in
1858 albeit after 18 years of parliamentary debate, for the
reform of the medical profession. As the Council stated,
the two chief reasons for legislation were 'the deep felt
necessity for a radical improvement in the education for
the main body of medical practitioners, and reciprocity of
professional privileges in the three divisions of the king-
dom'[5].
Fig. 1. Graves as a young man.
298 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
Graves had been disappointed at the poor training,
especially in clinical medicine, he received in Dublin;
indeed, many of his contemporaries went to Edinburgh
which at that time offered more systematic instruction.
Even at this early age Graves was probably contemplating
setting up a better eductional programme in his own city,
because his first stop was with Sir William Blizard who
had founded The London Hospital Medical College in
1785. He must have enjoyed Blizard's company with his
great respect for anatomical knowledge, his meticulous
attention to detail, not least in his personal appearance,
and his gifts as a teacher. He moved on to Gottingen
where Stromeyer (1776-1835) was professor of what today
we would call clinical pharmacology. Graves was after-
wards in the forefront of therapeutics, always describing
in his publications precisely what he used and why. The
other attraction in Gottingen was Blumenbach (1752-
1840) the father of anthropology, about whom Dr Freed-
man[6] wrote in 1984 describing how he introduced the
term Caucasian, a term still in current use in America.
Graves moved on to Berlin to study with Hufeland
(1762-1840) who was pre-eminent in infectious diseases
and epidemiology. This was to stand him in good stead
when he returned to Ireland and was almost immediately
confronted with a typhus epidemic and later one of
Asiatic cholera; typhoid was then endemic. He also spent
some time with Colsman (1771-1830) in Copenhagen and
concluded his tour in Edinburgh. He never missed a
chance to travel further afield and had an exciting time,
as young travelling fellows in medicine still do. He spent a
couple of weeks in prison in Austria suspected of spying,
for he was a great linguist. He met and sketched with
Turner in the Alps and had a remarkable escape in a
Sicilian brig which was caught in a storm in the Mediter-
ranean^].
Returning to Ireland he made an enormous impact on
the Dublin medical world. As a young man he was a
striking figure, tall, dark haired, with flashing eyes and a
very animated way of expressing himself. To these rich
gifts must be added that of eloquence, to which the Irish
brogue adds a certain golden timbre. His daily lectures at
Sir Patrick Dun's Hospital at four o'clock were the talk of
the town, and this in Dublin in the 1820s was praise
indeed.
He was of a serious frame of mind and apart from his
great affection for his brother Hercules, seems usually to
have preferred the company of older men. He was never a
lady's man, nor a frequenter of the drawing-rooms of
Dublin, which in his day were like courts for anyone who
was socially conscious. His three years of postgraduate
study in Europe, a true hegira in those days of difficult
travel, moulded his character and influenced the rest of
his professional life more than anything else he ever did.
Indeed, he continued for the rest of his life to correspond
with distinguished colleagues overseas and occasionally
made further visits abroad to talk to them. At heart he
was a true natural philosopher in a period when that
subject was just beginning to blossom. He loved to use his
classical knowledge, and was equally at home discussing
problems in biology, geology, chemistry or epidemiology;
he was a natural enquirer. However, as a true physician,
when confronted with a patient he became totally in-
volved with the individual and thus his contributions to
medical literature were not only very practical in terms of
treatment, but showed that he never lost the common
touch; he was involved in every detail of prescribing and
nursing and even with the psychology of coping with
relatives. When epidemics of typhus, cholera and typhoid
struck the undernourished population in the West of
Ireland he immediately went to their help with a team of
medical assistants[8], He was fearless in this regard, at a
time when many doctors were dying from these conta-
gions.
His return to Dublin in 1821 caused quite a stir in the
rather closely-knit medical profession of the day. Here
was a brilliant and talented young man with good connec-
tions and better informed about the progress of medicine
in Europe than anyone else. His gift of eloquence and his
powerful presence would have swept most people off their
feet and he was elected almost at once to the staff of one of
the city's most prestigious hospitals, the Meath, which
had just been rebuilt.
Within two years he had been elected a Fellow of the
Irish College of Physicians and a year later was co-
founder with his colleagues of a new medical school in
Park Street. Simultaneously he became a lecturer in the
Institutes of Medicine. With his burgeoning private
medical practice, and many patients will always flock to a
new doctor because he is new, he was at once a force to
reckon with in both town and gown.
With his excellent papers appearing in the medical
journals and his lectures each evening at Sir Patrick
Dun's, he was the leading light in those golden years of
Irish medicine which positively scintillated with men of
talent whose names are still household words from their
eponymous links with disease: Stokes, Adams, Corrigan,
Colles, to mention only the most famous.
He had not been back a year in his home city when he
married Matilda Jane Eustace, but within four years she
was dead and so was their daughter Eliza. A year later he
again plunged into matrimony with Sarah Jane, the
daughter of John Brinkley, the Professor of Astronomy
and an outstanding mathematician who had come to
Dublin from Cambridge. A stimulating intellectual, he
became a friend of Graves with whom he co-operated in
the field of probability in relation to epidemic diseases,
but tragedy struck again and Sarah Jane died within a
year, as did her baby daughter. He clearly immersed
himself in work at this time but once again he essayed
matrimony, and his choice of Anna, daughter of the
Reverend Grogan of Slaney Park, very much the county
family, seems perhaps out of character. However, they
had six children and she outlived him by 20 years.
I have the impression that as a young man Graves was
mildly hypomanic, a not uncommon occurrence among
individuals as brilliant as he was, and that his wonderfully
ebullient out-going character suffered a sea-change in the
early 1840s, for in 1841 he resigned his chair of medicine
and although he accepted the Presidency of the Royal
College of Physicians of Ireland in 1843, he forthwith
resigned from the Meath Hospital. It must have been an
unexpected step, as the hospital minutes record that a
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 299
deputation should wait on him and try to persuade him to
change his mind. But he stuck to his decision. For the
next 10 years, apart from his election to the Royal
Society, his contributions to the academic world were
small and his portrait at that time shows a tired, rather
cross individual, indeed one who looks depressed?and
there is a coarsening of his features.
What contributed to this change of mood from one so
sparkling to one of depression is difficult to say. Could it
have been that slowing of the faculties which accompanies
a falling-off in activity of the thyroid gland? That would
indeed have been a tragic fate for one whose name was to
be afterwards identified with over-activity of the thyroid.
There were of course flaws in Graves' character and the
greater the man, the greater the attention and condemna-
tion they are likely to receive. He did not suffer fools
gladly and he sometimes spoke out far too clearly with his
strictures. But to his credit he never bore a grudge and
even his slanging match with Corrigan in the pages of the
Dublin Quarterly Journal of Medical Science[4] contained a
generous admission of the latter's great contribution to
the organisation of improved health services in the com-
munity. In his deductions he was probably too quick to
draw analogies which really did not exist, but his ap-
proach to natural phenomena was often one of his
strengths, and his essays, whether on such diverse sub-
jects as the Dead Sea or the progress of Asiatic cholera,
always showed the impact of an original mind.
His greatest gift to the medicine of his day was his
system of clinical teaching which was a subject long
neglected. He treated senior students as colleagues and
the manner and quality of his instruction was greatly
enhanced by his continuing involvement in research,
allied with warm compassion for his patients. The clarity
of his written word produced a standard text on clinical
medicine that was used for many years, not only in the
British Isles and North America, but, through transla-
tion, in much of Europe. He pioneered studies on the
spread of infectious diseases in his own country and, on a
broader canvas, worldwide. He was a pioneer in the
nutrition of the sick patient and hoped that his epitaph
might be 'he fed fevers'. Above all, he was the epitome of
a good physician.
He succumbed after a long period of pain and discom-
fort to cancer of the liver and died on 20th March 1853.
His great friend and pupil William Stokes[7] gave a
touching account of his death in his biographical notice
and his tomb is in the cemetery of Mount Jerome in
Dublin.
This article is based on a biography of Robert Graves to be
published.
References
1. Graves, R. J. (1835) London Medical and Surgical Journal, 7, (pt/2),
516.
2. Parry, C. H. (1825) Collections from the Unpublished Papers of the late
Caleb Hillier Parry, Vol. 2, pp. 11-128. London: Underwood.
3. Graves, R. J. (1843) Clinical Lectures on the Practice of Medicine, 2 vols.
Dublin.
4. O'Brien, E. (1983) Conscience and Conflict. A Biography of Sir Dominic
Corrigan. Dublin: Glendale Press.
5. Pyke-Lees, W. (1958) Centenary of the General Medical Council 1858-
1958. London: GMC.
6. Freedman, B. J. (1984) British Medical Journal, 288, 696.
7. Stokes, W. (ed) (1863) Studies in Physiology and Medicine by the late R.
J. Graves. 'The life and labours of Graves'. London: John Churchill.
8. Graves, R. J. (1824) Transactions of the Association of the King and
Queen's College of Physicians, 4, 408.
Fig. 2. Graves as an older man. (Courtesy the National
Gallery of Ireland).
300 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
|
PMC005xxxxxx/PMC5371038.txt | Anomalies and Ambiguities in the Disposal
of the Dead
S. LEADBEATTER, MB, ChB, DMJ (Path), Lecturer in Forensic Pathology.
B. KNIGHT, MD (Wales), MRCFJ FRCPath., DMJ, Barrister-at-Law, Professor of Forensic
Pathology.
University of Wales College of Medicine, Institute of Pathology, Royal Infirmary, Cardiff
During the past 150 years legislation relating to the
disposal of the dead has developed in a somewhat piece-
meal fashion, causing several inherent anomalies that
reduce its efficiency and the accuracy of information
derived from it.
The Medical Certificate of Cause of Death
It is the statutory duty[l] of the registered medical
practitioner who has been in attendance upon the de-
ceased to issue the medical certificate of cause of death.
This duty includes deaths which fall within the coroner's
jurisdiction although it is standard practice in such cases
to withhold the 'death certificate'. The Registrar General
recommends that the statutory duty should be strictly
observed[2] but the death certificate in such cases is of
little practical use because the Registrar of Births and
Deaths must register the details as provided by the
coroner. For those deaths falling within the coroner's
jurisdiction because their causes are unknown, any death
certificate completed by the attending doctor obviously
would be meaningless.
There is no obligation to view the body of the deceased
in respect of whom the death certificate is to be issued;
such a view of the body is a legally acceptable alternative
to having seen the deceased within 14 days before
death[3]. The fact of death, the identity of the deceased
and the absence of signs of extraneous violence cannot be
ascertained without seeing the body. Examination of the
external surface of the body, in the absence of recent
clinical attendance, is inadequate evidence upon which to
base an opinion of the cause of death.
In National Health Service hospitals most death certifi-
cates are completed by pre-registration house officers, the
least experienced members of the clinical staff. Many of
these certificates do not contain a true cause of death,
merely unqualified modes of death[4], and it is not
uncommon for these certificates to escape the notice of the
Registrar of Births and Deaths despite his statutory duty
to report such deaths to the coroner[5]. Imprecise or
inadequate recording of causes of death may lead to
requests for further information from the Office of Popu-
lation Censuses and Surveys; there is no statutory duty to
reply to these requests. No matter how firm the opinions
upon which causes of death are based or how accurate
their wording, subsequent autopsies reveal an appreciable
proportion to be incorrect[6]. It is apparent that data
derived from medical certificates of cause of death may be
subject to considerable error.
The Medical Act 1956, s.29, states that 'a certificate
required . . . from any physician ... or other medical
practitioner shall not be valid unless the person signing it
is fully registered'. It is standard practice, however, for
the provisionally registered house officer to issue the
death certificate. It would appear that this certificate is
not only frequently inaccurate but also always invalid.
Still-birth
A certificate of still-birth may be issued by a registered
medical practitioner (or registered mid-wife) who has
seen the body of a still-birth but was not present at that
birth; if a certificate is requested by a qualified informant
in these circumstances it cannot be withheld. It is difficult
enough to ascertain the 'cause of death' at autopsy; a
mere view of a still-birth cannot be considered adequate
for certification. It remains a legal alternative, where a
certificate of still-birth cannot be obtained, for a qualified
informant to make a statutory declaration that a child was
not born alive[7]. A qualified informant is allowed 42
days in which to register a still-birth; there may be much
delay before a need for further enquiry becomes appar-
ent. The Registrar of Births and Deaths, unlike the
medical practitioner or mid-wife, has a statutory duty to
report to the coroner any case where he has reason to
believe that the child may have been born alive[8]; he is
not required to report a case in which the cause of death is
unknown[9]. Such legislation is hardly a deterrent to
subtle child destruction or infanticide.
The format of the cause of death on the certificate of
still-birth is different from that on the medical certificate
of cause of death: it has three parts, divided into five
sections labelled (a) to (e). There is an apparent lack of
appreciation of the principles underlying death certifica-
tion[4]; it seems somewhat sanguine to increase the
complexity of the cause of death when the certifying
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 273
medical practitioner or mid-wife may have made only an
external examination of the still-birth.
There is no obligation to notify the Registrar of Births
and Deaths of the disposal of the body of a still-birth.
Cremation
The Acts and Regulations pertaining to cremation date
from 1902, the latest regulations having come into force
on 1st April, 1985; these latter regulations, which dis-
pense with the necessity for the confirmatory Form C in
certain circumstances, represent the only major departure
from the essence of the original Regulations of 1903.
Before the Births and Deaths Registration Act 1926 there
was no legal obligation to obtain a certificate of disposal
from the Registrar of Births and Deaths before disposing
of a body and it was therefore possible to dispose of that
body before the death had been registered; it was also
possible to register a death without a medical certificate of
cause of death having been issued by a registered medical
practitioner. The original Cremation Regulations were
designed to prevent the near-total destruction of a body
before the appropriate authority was aware of any need
for investigation. Since the Act of 1926 any need for
investigation should be indicated during the process of
certification and registration of a death: the fundamental
argument upon which the necessity for the cremation
certification procedure was based has not existed for the
last 60 years.
The Cremation Regulations 1930, upon which all later
regulations are based, refer to the 'registered medical
practitioner'. Provisional registration was introduced in
the Medical Act 1950; it is the opinion of the Home Office
that those duties which may be carried out by a provision-
ally registered practitioner as though he were fully regis-
tered do not include duties imposed under the Cremation
Regulations. As mentioned in relation to death certifica-
tion, s.29 of the Medical Act 1956 implies that it is not
legal for the provisionally registered house officer to issue
Form B.
There appears to be some ambiguity as to whether the
practitioner who issues Form C is under obligation to
view the body of the deceased. At the time of the Brodrick
Report (1971)[ 10] there was no necessity to view the
body; no new regulation regarding this has been issued
since that time but it is now stated in the rubric of Form C
that 'the doctor must see the body of the deceased'.
The Brodrick Committee gave its opinion that '. . . a
certificate in Form C not given by a pathologist after an
autopsy is, in our views, no more than a statement of
confidence in the judgement of the Form B doctor'.
Home Office guidance that the practitioners issuing
Forms B and C should be clinically independent would
tend to reinforce this opinion: it seems strange to continue
to charge a fee for a mere statement of confidence but to
dispense with that fee when a post-mortem examination,
which provides verification or otherwise, is performed[l 1],
The situation of the Medical Referee is similarly
ambivalent. Regulations require him to be 'satisfied that
the fact and cause of death have been definitely ascer-
tained'^]; such satisfaction is impossible to obtain
without post-mortem examination. Even post-mortem
examination may fail. The Coroner's Certificate E for
Cremation, Form 102, may be issued when an inquest
has been opened but does not state the cause of death: the
bodies in five of nine cases known to the authors in which
the cause of death remained unascertained at the close of
the inquest were cremated!
The Regulations state that when a death 'might be due
to poison, to violence, to any illegal operation, or to
privation or neglect' the Medical Referee 'shall require a
post-mortem examination to be held'[12]. Except when
directed by the coroner all post-mortem examinations are
subject to the Human Tissue Act 1961: the Medical
Referee cannot 'require a post-mortem examination'
without ensuring that there is lack of objection on the part
of the deceased or his nearest relative. Even when there is
no objection to such an examination, the Regulations do
not empower the Medical Referee to pay for one. More-
over he has no statutory duty to report such deaths to the
coroner.
Her Majesty's Coroner
There is no statutory duty upon a medical practitioner to
report a death to H.M. Coroner although, as 'a person
about the deceased', there is a common law duty 'to give
information which may lead to the coroner having notice
of circumstances requiring the holding of an inquest'[13],
This common law duty, long fallen into desuetude,
applies to any 'person about the deceased'; a medical
practitioner may be considered to be better placed than
the man in the street to know what circumstances require
the holding of an inquest but the current decline in
education in medico-legal matters[14] does not permit
confidence in such an opinion.
The Registrar of Births and Deaths has a statutory duty
to report such deaths as are cited in his Regulations[15].
The information available to him upon which to make a
decision is limited to the medical certificate of cause of
death and the answers to questions he may put to the
qualified informant: he may be at a disadvantage in
comparison with the medical practitioner. He must report
to the coroner any death 'the cause of which appears to be
unknown'[5], Many medical certificates of cause of death
do not contain a true cause of death[4] and, therefore,
should be reported to the coroner. However, the coroner
has no jurisdiction over a death the cause of which
appears to be unknown unless it is 'a sudden death'[16];
there is no legal definition of the word 'sudden'.
If a death is reported by the Registrar of Births and
Deaths because of inaccurate or imprecise wording on a
death certificate, but the coroner, after preliminary en-
quiry, does not assume jurisdiction, the Registrar must
nevertheless register that imprecise or inaccurate cause of
death[17],
H.M. Coroner may direct[18] or request[19] any
legally qualified medical practitioner to carry out a post-
mortem examination although such an examination
'should be made, when ever practicable, by a pathologist
with suitable qualifications and experience and having
access to laboratory facilities'[20], A recent report[21]
274 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
suggests that such an examination has not always been
'practicable'.
An inquest may be held without a post-mortem exam-
ination. The only situation in which the coroner must
direct that a post-mortem examination be performed is on
the written requisition of his jury[22]; by the time such a
requisition may be made there has been usually both
release and disposal of the body. In the absence of a post-
mortem examination, the inquest might be quashed on
the grounds of insufficiency of enquiry. There is little
evidence that the 'psychological autopsy' developed in the
USA in the investigation of 'equivocal deaths'[23], forms
a part of the medico-legal investigation of death in the
UK. Might not the lack of such an autopsy sometimes be
described as insufficiency of enquiry?
Comment
Much of the legislation pertaining to disposal of the dead
is anachronistic, ambivalent and ambiguous. Medical
undergraduates (and post-graduates) find it difficult to
grasp even when tuition is adequate. These qualities
detract from the accuracy of death certification and may
permit inadequate enquiry into equivocal deaths.
There should be both consolidation and streamlining in
new legislation which would:
(a) make it the statutory duty of the fully registered
medical practitioner, who had attended during the last
illness, to view the body and to either issue the death
certificate (if the cause of death can be stated with
accuracy and precision) or report the death to H.M.
Coroner. Still-births should be treated in an identical
manner;
(b) define precisely the circumstances in which a
practitioner cannot issue a death certificate and thus
clarify the role and duties of H.M. Coroner;
(c) abolish cremation certification.
It is a final anomaly that these recommendations were
made 15 years ago by the Brodrick Committee when
education in the legal aspects of medical practice was
more prominent in the curriculum that it is today.
References
1. Births and Deaths Registration Act 1953, s. 22 (1).
2. Forms for Medical Certificates of the Cause of Death (1985) Notes
for Medical Practitioners.
3. The Registration of Births, Deaths and Marriages Regulations
1968, reg.51 (1) (c).
4. Leadbeatter, S. (1986) Journal of the Royal College of Physicians of
London, 20, 129.
5. The Registration of Births, Deaths and Marriages Regulations
1968, reg. 51 (1) (d).
6. Cameron, H. M. and McGoogan, E. (1981) Journal of Pathology,
133, 273.
7. Births and Deaths Registration Act 1953, s. 11 (as amended by
Population (Statistics) Act 1960 s.2 and Nurses, Midwives and
Health Visitors Act 1979, s.23 (4) and Sch.7.)
8. The Registration of Births, Deaths and Marriages Regulations
1968, reg. 43.
9. Forms for Certificates of Still-Birth (1985), Statement of the Cause
of Death.
10. Brodrick Committee (1971) Report of the Committee on Death Certifica-
tion and Coroners. Cmnd No. 4810. London: HMSO.
11. The Cremation (Amendment) Regulations 1985, reg. 3.
12. Cremation Regulations 1930 (as amended by Regulations of 1952
and 1965) reg. 12(4).
13. Knapman, P. A. and Powers, M. J. (1985) The Law and Practice of
Coroners. Chichester: Barry Rose.
14. Knight, B. and Thompson, I. M. (1986) Journal of Medical Education
(in press).
15. The Registration of Births, Deaths and Marriages Regulations
1968, reg. 51 (1) (a)-(g).
16. Coroners Act 1887, s.3 (1).
17. Form 100, Notification to the Registrar by the Coroner that he does
not consider it necessary to hold an inquest, Part A, Instructions to
Registrar.
18. Coroners Act 1887, s.21 (2).
19. Coroners (Amendment) Act 1926, s.22 (1).
20. The Coroners Rules 1984, r.6 (1).
21. Scott, K. W. M. (1986) Lancet, i, 277.
22. Coroners Act 1887, s.21 (3).
23. Litman, R. E., Curphey, T., Shneidman, E. S., Farberow, N. L.
and Tabachnik, N. (1963) Journal of the American Medical Association,
184, 924.
|
PMC005xxxxxx/PMC5371039.txt | Pain Control in Advanced Cancer:
Pharmacological Methods
G. W. HANKS BSc, mrcp(UK)
Consultant Physician
E J. HOSKIN BSc, MRCP(UK), FRCR
Cancer Research Campaign Research Fellow and Honorary Senior Registrar
Royal Marsden Hospital, Sutton, Surrey
Pain is a major symptom in some 60 per cent of patients
managed in a general oncology unit[l] and up to 85 per
cent of patients referred for hospice care[2]. Pain control
is therefore an essential component of the modern man-
agement of malignant disease.
Pain is a complex subjective experience, combining the
perception of a painful stimulus with a variable emotional
response to it. Chronic pain associated with progressive
malignancy is quite different from acute pain following
trauma or surgery, or the minor acute pains (headache or
toothache) of normal day to day life. Unlike acute pain,
chronic pain is of unpredictable duration and is maladap-
tive: it has no positive function. Thus a major component
of chronic cancer pain is the associated emotional reac-
tions of fear, anxiety, anger or depression. Invariably the
patient is also troubled by other symptoms such as
anorexia, nausea, constipation, fatigue and sleep disturb-
ance, all contributing to a lowered pain threshold and
impaired pain tolerance. The clinical picture of the
patient with chronic cancer pain is a summation of the
physical effects of the original nociceptive stimulus, the
patient's emotional response to this, and other symptoms
associated with the underlying malignancy or caused by
the pain. The situation is further complicated by the fact
that 80 per cent of patients in pain will have more than
one pain and approximately 20 per cent will have four or
more separate pains[3].
Management of Chronic Cancer Pain
As the nature of chronic cancer pain is so complex it is
necessary before embarking upon treatment to identify
each individual pain and its underlying aetiology, to
appraise the patient's mental state and to evaluate any
associated physical symptoms. A body chart is often
helpful and will also provide a valuable baseline for future
assessments.
Once the underlying nature of the patient's pain has
been identified a logical treatment strategy can be de-
vised. The mainstay of treatment will be pharmacologi-
cal. It is, however, important not to neglect the role of
other treatment modalities and at this early stage to
identify those pains which may respond to specific non-
drug measures, such as the use of radiotherapy for
localised bone pain.
A further important step at the outset of treatment is
careful explanation to the patient and reassurance that
pain control can be achieved. Realistic goals should be
set, with three stages of pain control in mind: to be pain
free at night, pain free at rest and pain free on movement.
The first two of these will almost always be possible to
achieve and confidence will be built up as each objective is
realised. Complete pain control on movement may be
more difficult and sometimes simple modifications to life
style, in addition to specific treatment, are needed.
Drug Treatment of Chronic Cancer Pain
Effective drug treatment is founded on the regular use of
an appropriate analgesic given in an adequate dose.
Initial choice of drug is based on the severity of the pain
and its response to previous treatment. In general, a
simple scheme using a limited number of drugs familiar
to the prescriber is recommended, ranking drugs accord-
ing to analgesic strength with a range from simple non-
opioid analgesic, to weak opioid, to strong opioid. One
drug in each class should be used routinely, for example
paracetamol, dextropropoxyphene/paracetamol, and
morphine; only rarely will an alternative be necessary. If
a drug is no longer effective there is no value in using
alternatives from the same group, and it is inappropriate
to use two drugs of similar strength in the hope of an
additive or synergistic action. Proprietary tablets contain-
ing combinations of drugs, in particular those combining
several simple analgesics, are best avoided unless careful
consideration has been given to the individual constitu-
ents and their doses.
There is no place for intermittent 'as required' anal-
gesia in the management of chronic cancer pain. The aim
of treatment is to control and prevent further symptoms
by regular medication, maintaining constant effective
blood concentrations in the steady state. A recommended
scheme of drug use in chronic cancer pain is outlined in
Table 1.
276 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
Table 1. Recommended scheme of drugs for use for chronic cancer pain
Pain
Mild pain
Analgesic group
Drug of choice
Simple peripherally-acting
analgesic
Paracetamol 1 g 4-hourly
Alternative drugs Soluble aspirin 600-1200 mg
4-hourly
Drugs to avoid Compound preparations
Other measures Co-analgesic
Unresponsive to simple analgesics
Unresponsive to weak opioids
Weak opioid
Dextropropoxyphene/paracetamol 2 tabs.
4-hourly
Dihydrocodeine 30-60 mg 4-hourly
Pentazocine
Co-analgesic
Strong opioid
Morphine or diamorphine.
orally 5-200 mg 4-hourly
Phenazocine, levorphanol,
oxycodone suppositories
Short-acting opioids,
combinations, opioids with
cumulative toxic effects
Co-analgesic
Simple Analgesics
Paracetamol is the preferred simple analgesic where no
anti-inflammatory action is required. A derivative of
para-aminophenol, it has analgesic and antipyretic effects
similar to those of aspirin at equivalent doses up to 1 g.
Paracetamol is rapidly absorbed from the small bowel but
hardly at all in the stomach: hence gastric emptying may
significantly affect the overall rate of absorption. Peak
plasma concentrations are reached at 30 to 60 minutes
after a single oral dose[4]. In addition to tablets a
suppository for rectal use is available for those patients
unable to take drugs by mouth. The plasma elimination
half-life is 1.5-3.0 hours[5], and regular 4-hourly oral
administration of 1 g (two tablets) is the recommended
dose.
The principal advantage of paracetamol over other
simple analgesics is that it is well tolerated by most
patients with no gastric irritant effect. Serious toxicity is
not seen when it is used in the above doses. The alkylating
metabolite responsible for hepatotoxicity in overdosage is
produced only in small amounts at normal therapeutic
doses and is rapidly detoxified by conjugation with
reduced glutathione[6].
Alternative simple analgesics are not usually required
since intolerance to paracetamol is unusual. Failure of a
simple analgesic to control pain is an indication for a drug
with a stronger analgesic action.
Aspirin (acetylsalicylic acid) is recommended by some
authors[3] as the simple analgesic of choice. It has the
advantage, in high dosage (4-6 g/day), of additional anti-
inflammatory action which may be of value, particularly
in the treatment of bone metastases. However, side-
effects, including gastric intolerance and metabolic dis-
turbances, are much more common at these doses and the
use of one of the newer non-steroidal anti-inflammatory
drugs is generally preferable when an anti-inflammatory
action is required. At low doses aspirin has no advantage
over paracetamol and is generally less well tolerated.
Weak Opioids
These drugs are recommended where simple analgesics
are ineffective or in mild to moderate visceral pain which
often does not respond to paracetamol.
Dextropropoxyphene/paracetamol (Coproxamol) is our drug
of choice in this group, despite continued controversy
over its efficacy and potential dangers[7,8], Dextropro-
poxyphene is a synthetic opioid structurally related to
methadone and a weak opioid agonist. It is readily
absorbed from the gastrointestinal tract with peak serum
levels at about two hours after administration. The mean
elimination half-life is about 15 hours with steady state
levels being reached after three to four days of regular 6 to
8-hourly administration. In elderly patients the half-life
may be very long (over 50 hours)[9], Dextropropoxy-
phene undergoes extensive first pass metabolism, its
principle metabolite being norpropoxyphene which also
has analgesic activity and a longer half life (about 23
hours) than dextropropoxyphene itself. This metabolite
therefore accumulates in plasma[10]. Both dextropro-
poxyphene and norpropoxyphene reach plasma concen-
trations in the steady state which are five to seven times
greater than those found after the first dose.
It follows from this that studies using single doses of
dextropropoxyphene are assessing a very different situ-
ation to that which exists in the steady state during
regular administration for chronic painfll]. This may
explain why extensive clinical experience with a dextro-
propoxyphene/paracetamol combination in patients with
chronic pain due to malignant disease and in patients
with rheumatic disorders[12] suggests that the prep-
aration is effective and well tolerated, but controlled
clinical trial data are conflicting. There is, however,
substantial evidence to support the efficacy of dextropro-
poxyphene itselff 13] and a single published controlled
study in rheumatology patients[14] which indicates the
superiority of a dextropropoxyphene/paracetamol combi-
nation over paracetamol alone.
The recommended dose is up to two tablets of Coprox-
amol 4-hourly (each tablet contains dextropropoxyphene
32.5 mg and paracetamol 325 mg). At these doses serious
side effects are unusual but confusion, dysphoria and
lightheadedness may occur, particularly in the elderly.
Nausea and vomiting are infrequent and constipation is
less troublesome than with other opioids. Addiction has
been reported[15] but is rare and does not arise in the
treatment of chronic pain. Coproxamol will potentiate the
effects of warfarin, carbamazepine and central nervous
system depressants.
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 277
Alternative weak opioids should be restricted to pure
opioid agonists such as codeine or dihydrocodeine.
Dihydrocodeine is probably the alternative drug of choice
being a semi-synthetic analogue of codeine and approxi-
mately 30 per cent more potent than the parent drug.
Both drugs are chemically closely related to morphine
(codeine is 3-methylmorphine). After an oral dose of
codeine some 10 per cent is converted by demethylation
to morphine, which may contribute to the analgesic
effect. The principal disadvantage of codeine or dihydro-
codeine compared with Coproxamol is that they tend to
be more constipating at equi-analgesic doses[3].
Pentazocine is a mixed opioid agonist and antagonist
which, although in common use, is not recommended for
chronic pain due to malignant disease. It is a derivative of
phenazocine, a strong opioid agonist. An evaluation in
patients with chronic pain[16] showed an analgesic poten-
cy of one sixth that of morphine, and another single dose
study[17] has suggested that standard doses are less
effective than standard doses of dextropropoxyphene with
paracetamol. Thus no clear advantage of pentazocine
exists in terms of analgesic efficacy and there are two
major drawbacks; first, it may antagonise opioid agonists
and, second, there is a high incidence of psychotomimetic
effects, occurring in 20 per cent of patients in one
series[18], half of which resulted in a major disturbance.
Strong Opioids
When pain is no longer controlled by a weak opioid in
standard doses, then a strong opioid should be used in its
place, titrating the dose to the patient's pain.
Morphine sulphate is the drug of choice for oral use,
most readily taken in aqueous solution or in chloroform
water as morphine elixir. Morphine is the pharmacologi-
cally active constituent of opium. Despite its widespread
use, dating from the third century B.C., accurate data on
the pharmacokinetics of morphine are sparse, primarily
due to the difficulties in measuring morphine distinct
from its metabolites in serum[19]. Absorption from the
gastrointestinal tract occurs readily (mainly in the upper
small bowel) but oral bioavailability varies considerably
(between 15 and 64 per cent in one study in cancer
patients[20]). The effect of an oral dose is significantly
less than that of the same dose given intravenously due to
a considerable first pass effect. In rats, 85 per cent of an
oral dose is eliminated due to metabolism in both gut wall
and liver[ 21 ]. While a role for the kidney has been
recently proposed[22], the relative importance of renal
glucuronidation is disputed[23]. Almost certainly the
metabolism of morphine is principally hepatic, the main
pathway resulting in the formation of morphine-3-glucur-
onide and morphine-6-glucuronide. The elimination half
life also shows considerable variation from one to
hours after low single oral doses in cancer patients[20],
although it is not clear how this relates to steady state
conditions after chronic high dosage. During chronic
dosing, accumulation of the main metabolites occurs, the
average ratio for morphine-3-glucuronide to morphine
being 35:1 and for morphine-6-glucuronide 4:1 [24],
There is evidence to suggest that morphine-6-glucuronide
also has significant analgesic activity[25]. The presence of
high concentrations of morphine-6-glucuronide may ex- ?
plain the apparent increased sensitivity to morphine of
patients with renal impairment and the possible misinter-
pretation of kinetic data obtained using an assay method
which could cross react with this metabolite[26, 27],
Despite the variation in plasma half-life, in clinical
practice regular 4-hourly administration provides con-
stant analgesia in doses ranging from 5 mg to 200 mg
every four hours, although occasionally much higher
doses are required. The dose is titrated to achieve pain
control and around 70 per cent of patients will not require
more than 30 mg 4-hourly[28]. The need for a dose to be
given in the middle of the night can usually be avoided by
a double dose at bedtime.
The use of a slow release preparation of morphine
sulphate (MST Continus) has gained increasing popular-
ity over recent years. Peak concentrations of morphine in
the blood are not achieved until up to four hours after
administration[29], but there are claims that overall
bioavailability may be better than with 4-hourly oral
morphine sulphate[30]. Although a useful means of deli-
vering regular morphine in a stable situation, it is
important to emphasise that this preparation should not
be used for acute exacerbations of pain, nor, because of
uncertainty over the time to achieve steady state plasnia
levels, is it ideal for patients starting morphine or requir-
ing regular dose adjustments. MST does appear to be
effective when given twice a day, and used appropriately
it allows a more convenient regimen for patients requir-
ing long-term morphine therapy[31].
The principal side effects of morphine in chronic use
are drowsiness, constipation, nausea and vomiting. Most
patients experience drowsiness initially which may cause
considerable concern for both patients and relatives,
particularly if associated with confusion. However, this is
usually transient and not an indication to reduce an
effective pain-relieving dose of morphine, but rather
should be dealt with by careful explanation and reassur-
ance. Constipation is universal and regular laxatives such
as Dorbanex (containing a faecal softener, poloxamer,
and a peristaltic stimulant, danthron) should be given
from the outset. Nausea and vomiting are not inevitable,
up to one third of patients receiving regular oral mor-
phine requiring no anti-emetics[32]. In those patients
who do become nauseated, haloperidol taken once or
twice daily is usually effective with fewer side effects than
the phenothiazines. Where a more sedative anti-emetic is
required, prochlorperazine or chlorpromazine taken 8- or
4-hourly is suitable.
Other reported side effects, including pupillary con-
striction, biliary spasm, increased bladder tone and peri-
pheral vasodilatation, do not usually present a clinical
problem in chronic cancer pain patients. Respiratory
depression does not occur in patients who are in pain[28]
and is not a justification for using inadequate doses.
Addiction does not occur in patients receiving long
term opioids for chronic cancer pain. Addiction is based
on three separate components: physical dependence,
psychological dependence and habituation (Fig. 1). De-
spite prolonged treatment with high doses of opioids
278 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
neither psychological dependence nor habituation is seen.
Tolerance to the physical effects of opioids may occur and
physical dependence may develop after continuous use for
periods of longer than about two weeks. Despite this, in
patients whose pain improves or resolves, dose reductions
and discontinuation of the opioid may be achieved with-
out difficulty [3].
Diamorphine (diacetylmorphine) is the strong opioid of
choice for use by subcutaneous or intravenous adminis-
tration, and may also be substituted for morphine orally.
It is a semi-synthetic derivative of morphine and is
rapidly deacetylated m the body to monoacetyl-morphine
and morphine. Its onset of action after intravenous
injection is more rapid than that of morphine and it is
associated with less vomiting and less sedation. There is
some evidence that diamorphine is better absorbed from
the gastrointestinal tract than morphine. However, dia-
morphine is essentially a prodrug for morphine, diacetyl-
morphine and monoacetylmorphine being undetectable
in blood after an .oral dose[33]. Diamorphine has no
unique advantages or disadvantages for the relief of
pain[34, 35] and its effects are indistinguishable from
those of morphine when given 4-hourly for chronic
pain[36].
The principal advantage of diamorphine lies in its
much greater degree of solubility, enabling high doses to
be administered by injection in small volumes suitable not
only for intravenous use but also for subcutaneous injec-
tion or infusion. The limit of solubility is about 400 mg/
ml although a concentration of 250 mg/ml (25 per cent w/
v) is probably the maximum that should be used for
continuous subcutaneous infusion[37].
It is important to consider the differences in bioavaila-
bility when changing from an oral morphine preparation
to parenteral diamorphine, dividing the oral dose of
morphine by three to obtain an equivalent parenteral
dose of diamorphine. Because of the better oral bioavaila-
bility of diamorphine, an oral dose of diamorphine should
be divided by two to obtain the equivalent parenteral
dose.
Alternative Strong Opioids
None of the alternative strong opioids possess particular
advantages which make them preferable to oral morphine
or parenteral diamorphine. Commonly used drugs in this
group are shown in Table 2 together with their equivalent
Table 2. Alternative strong opioids
Drug
Dose Oral morphine sulphate
(mg) equivalent dose (mg)
Buprenorphine
(Temgesic)
Dextromoramide
(Palfium)
Dipipanone (Diconal
when combined with
cyclizine 30 mg)
Nepenthe
Papaveretum
(Omnopon)
Pethidine
Phenazocine
(Narphen)
Methadone
(Physeptone)
0.2"
10
lml
(10ml of
10% solution)
10
50
5t
10-15
10
5
12
5
6
25
5
"Usually given 8-hourly; the equivalent dose of morphine indicated is
a 4-hourly dose.
tin single doses only; diie to accumulation considerably more potent
in chronic usage.
oral morphine doses. As can be seen, some are consider-
ably more potent than morphine and this can cause
problems in changing from one to another.
Buprenorphine is a partial opioid agonist which means
that it may have both agonist and antagonist effects. It
may be given sublingually or by injection. In acute pain
postoperatively it appears effective, but in chronic use it
has a high incidence of side effects, in particular nausea
and vomiting, dizziness and drowsiness[38]. This limits
its effective dose range and together with its potential
antagonist action outweighs the advantage of sublingual
absorption which may in any case be delayed and unrelia-
ble in patients with malignant disease who frequently
have dry sore mouths.
Dextromoramide is a potent analgesic but usually has an
effective duration of action of only lj-2 hours. It is
unsuitable for the treatment of chronic cancer pain.
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
Dipipanone has no specific advantages and the import-
ant drawback of being available only in a fixed dose
combination tablet containing dipipanone 10 mg with
cyclizine 30 mg.
Nepenthe used to be an alcoholic tincture of opium but
is now formulated almost entirely as morphine hydrochlo-
ride)^]. Since it can be made up in various strengths this
can cause confusion as to the equivalent dose of morphine
and it has no advantages over morphine sulphate.
Pethidine is a synthetic opioid agonist which is generally
shorter acting than morphine, its duration of effective
analgesia being two to four hours. Its other main draw-
back for chronic use lies in its conversion to norpethidine
by 7V-demethylation. Although this metabolite does not
reach detectable levels after a single dose of pethidine, it
accumulates with chronic usage, particularly where there
is renal impairment[40]. The elimination half-life of
norpethidine is about 17 hours compared with 3.5 hours
for pethidine[41],Norpethidine differs from pethidine in
its effects on the central nervous system, having predomi-
nantly excitatory effects which are manifest in patients by
tremor, twitching, agitation and convulsions. Clinically
significant accumulation of norpethidine is seen with
doses of pethidine greater than 200-300 mg given 3-
hourly, and at lower doses when there is renal impair-
ment.
Methadone is marginally more potent than morphine in
single doses. When given regularly, however, its half life
increases considerably, with cumulation; plasma concen-
trations may take two to three weeks to reach a steady
state[42]. Furthermore, no clear relation exists between
plasma levels and analgesic activity. This tendency to
cumulation in regular use can be particularly troublesome
in the debilitated and elderly in whom sedation, confusion
and, occasionally, respiratory depression may be seen.
Opioid mixtures have been advocated in the past, based
on the traditional 'Brompton Cocktail', and the current
British National Formulary[43] still contains four such
formulations containing morphine or diamorphine with
cocaine in a sweetened alcoholic base. Use of such
cocktails confers no advantages but has a number of
disadvantages. The inclusion of cocaine appears to in-
crease side effects particularly in the elderly, and the use
of any combination preparation reduces flexibility in
dosage.
Route of Administration
The majority of patients will have their pain well con-
trolled on oral medication until the final hours or days of
their illness, and over 50 per cent will never require an
injection[44]. Some patients, however, will be unable to
tolerate oral drugs, because of nausea and vomiting,
general debility, or impaired consciousness.
Rectal administration is a good alternative but may be
unacceptable to some patients. Morphine suppositories
are given 4-hourly in the same dose used by mouth and
are widely available in a range of strengths. Oxycodone
suppositories are an alternative which have the advantage
of a longer duration of action (6 to 8 hours). Oxycodone
30 mg is equivalent to morphine 20 mg.
As discussed above, when parenteral medication is
required, diamorphine is preferred. The optimum means
of administration is by subcutaneous infusion using a
syringe driver which avoids the need for repeated skin
punctures. An anti-emetic such as haloperidol can be
included in the subcutaneous infusion if necessary.
Parenteral opioid analgesics are not inherently better
than oral medication when given in equi-analgesic doses,
and in practice the indications for the use of subcutaneous
infusions are relatively limited.
Co-analgesics
A co-analgesic is any therapeutic agent which may not
have intrinsic analgesic activity but which will contribute
significantly to pain relief when used with a conventional
analgesic[45]. Table 3 gives some common examples.
Table 3. C o-analgesics.
Drug Type of pain
NSAID Musculoskeletal pain, e.g. bone metastases
or soft tissue infiltration.
Corticosteroid Raised intracranial pressure
Nerve root compression
Soft tissue infiltration
Hepatomegaly
Diuretic Lymphoedema
( + compression
sleeve, massage)
Antibiotic Infected ulcer
Discharging sinus
Muscle relaxants Muscle spasm
Anticonvulsants Nerve root pain
Post herpetic neuralgia
Non-steroidal anti-inflammatory drugs (NSAIDs) do not
have a place as primary therapeutic agents but when used
in conjunction with an opioid may be very effective
particularly in the relief of bone pain. Prostaglandins are
involved in peripheral nociceptive mechanisms, sensitis-
ing free nerve endings to pain-inducing vasoactive amines
and kinins and hence facilitating pain transmission. They
are also specifically involved in the development of bone
metastases, stimulating osteoclastic bone resorption.
Some tumours produce prostaglandin-like substances
which may promote their metastatic potential in bone; the
use of a prostaglandin synthetase inhibitor has a rational
basis in the treatment of bone pain.
NSAIDs have a considerable potential, however, for
producing adverse effects particularly on the gastrointes-
tinal tract and in elderly patients[46]. It is important to
closely monitor the therapeutic response of each patient
and discontinue the drug at an early stage if no clear-cut
benefit is seen. Despite a wide range of drugs in this class,
none appears to have specific advantages in this indi-
cation. Soluble aspirin 600-1200 mg 4-hourly, may be
appropriate for patients receiving 4-hourly morphine. In
general, drugs which require less frequent administration
are preferable for other patients, such as piroxicam 20 mg
nocte or flurbiprofen 100 mg b.d.
280 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
Benorylate is an ester of paracetamol and aspirin which
can be administered as an oral suspension. It has fewer
side effects than aspirin used alone and has the additional
advantage of 12-hourly dose intervals. It is de-esterified in
vivo, each gram of benorylate producing 600 mg aspirin
and 440 mg paracetamol. It may be a suitable alternative
in certain patients where gastrointestinal tolerance is a
problem with anti-inflammatory doses of aspirin, or with
other NSAIDs. A dose of 10 ml (4g) b.d. is equivalent to
4.8 g/day of aspirin.
Corticosteroids are of use in headache due to raised
intracranial pressure, nerve root pain due to compression
or tumour infiltration, and may also reduce pain due to
soft tissue infiltration. Dexamethasone has advantages
over prednisolone because of its weaker mineralocorticoid
(salt and water retaining) effects, with a lesser tendency to
cause oedema and weight gain.
Diuretics may be useful in conjunction with massage
and compression for painful lymphoedema.
Antibiotics are helpful for pain from an infected ulcer or
discharging sinus, and for dysuria due to a urinary tract
infection.
Muscle relaxants are indicated where pain is due to
increased muscle tone, spasm or clonus. Baclofen 5-20
mg three times daily is the preferred drug, having less
sedative action than diazepam. Some patients, however,
have intolerable gastrointestinal side effects and in these
diazepam 2 to 5 mg t.d.s. may be used as an alternative.
Anticonvulsants may be helpful in some patients with
lancinating or stabbing dysaesthetic pains associated with
nerve compression or infiltration, and post-herpetic or
post-traumatic neuralgias. Carbamazepine 100 mg t.d.s.,
sodium valproate 200 mg t.d.s. or clonazepam 0.5-2.0
mg once or twice daily, may all be helpful. Individual
patients may respond better to one particular drug.
Clonazepam tends to cause more sedation and the choice
of drug should be tailored to the individual patient.
Conclusion
The principles of effective pain control are: make a
diagnosis; individualise the treatment; and keep it simple.
Familiarity with a simple analgesic ladder will facilitate
rational changes in analgesic and dose modifications as
appropriate. Predictable side effects such as constipation
should be prevented. The appropriate use of co-analgesics
including non-drug treatments such as radiotherapy or
nerve blocks should also be considered. With this ap-
proach it should be possible to control pain in almost all
patients with malignant disease without the need for
exceptional measures.
Acknowledgement
We are grateful to Mrs F Fleetwood for the typing of this
manuscript.
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Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 281
|
PMC005xxxxxx/PMC5371041.txt | The Relationship between Physicians and the
Pharmaceutical Industry
A REPORT OF THE ROYAL COLLEGE OF PHYSICIANS
Membership of the Working Party
Sir Raymond Hoffenberg (President and Chairman)
Dr O. L. Wade (Honorary Secretary)
Dr Barbara M. Ansell
Sir Douglas Black
Dr A. M. Breckenridge
Dr T. L. Chambers
A. J. Collier Esq
Dr M. J. Denham
Miss Patricia Lamburn
Dr S. P. Lock
Dr D. R. London
Dr M. F. Muers
Dr P. C. Reynell
The Rt Hon Sir Kenneth Robinson
Dr P. P. Turner
Dr D. W. Wall
Dr D. A. Pyke (Registrar)
In attendance
Mr G. M. G. Tibbs (College Secretary)
Mrs Myra Dawson , . ? . c ? \
? 7 , (Working Party Secretaries)
Mrs Sarah Green v
Contents Page
Introduction 236
Evidence Received 237
Drug Prescribing 237
Clinical I^search and Trials 237
Recommendations 238
Meetings 238
Hospitality and Gifts 239
Research Projects and Clinical Trials 239
Appendices
1. Evidence Given 241
2. Relationship between Postgraduate Medical
Centres and Pharmaceutical Houses 241
3. Statement by The British Journal of Clinical
Pharmacology 242
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 235
INTRODUCTION
There needs to be a close and constructive relationship
between the medical profession, which prescribes drugs
for patients and the pharmaceutical industry, which
produces and markets them. Such a relationship brings
benefit to patients, the pharmaceutical industry and our
nation. It furthers the well-informed and safe use of the
drugs which are available and it encourages the co-
operative research that is essential in the development of
new drugs. It contributes to our national economy be-
cause our research-based pharmaceutical industry has an
enviable record of innovation and success in its export
trade.
New drugs can be properly developed only if doctors
evaluate them in patients. The pharmaceutical industry
depends on independent and impartial clinical assessment
of their drugs by physicians. This brings chemists and
scientists in pharmaceutical companies into a relationship
with doctors which is necessary and constructive. It must,
however, be conducted on strictly professional lines and
neither party should abuse its position for financial or
other gain or mislead the other on factual evidence about
the drugs under trial.
Once a drug is developed and marketed, a new re-
lationship comes into existence between pharmaceutical
companies and doctors; a relationship in which compan-
ies in a competitive industry are trying to persuade the
medical profession to prescribe their products while at the
same time seeking the views of the profession about their
efficacy and safety.
This Report has been produced by a Working Party
and approved by the College as a guide to practising
physicians. It is not a critique of the pharmaceutical
industry, nor an examination of recent, well-publicised
cases of apparent misdemeanour on the part of doctors
although its origin lies in anxiety over those cases. It is
intended to help doctors when they have to decide how
best to handle their complex relations with the pharma-
ceutical industry.
There has been increasing concern in recent years
about the relationship between doctors and the pharma-
ceutical industry in two respects:
1. Prescribing. Doctors spend large sums of public money
with fewer restrictions than in almost any other area of
public expenditure. In return for the trust placed in him
the doctor is expected to prescribe for his patients on the
basis of the known efficacy and safety of drugs and it is
essential that there should be no suspicion that his
professional judgement may have been impaired by the
receipt of gifts, hospitality, payment or subsidy from
pharmaceutical companies. Consultant physicians have
an additional responsibility inasmuch as they are opinion
leaders in drug usage and influence the prescribing
patterns of their junior staff and of general practitioners
in their area.
2. Clinical Research and Clinical Trials. There has been
concern that some of the interactions between companies
and physicians who are clinical investigators could com-
promise the autonomy and independence of the doctors in
a way that might reflect adversely on the integrity of the
profession.
That these concerns in both fields are widely shared is
apparent from comments made in three published docu-
ments:
1. The General Medical Council's booklet Professional
Conduct and Discipline: Fitness to Practise (1985) states
'doctors should avoid accepting any pecuniary or ma-
terial inducement that might compromise, or be regarded
by others as likely to compromise, the independent
exercise of their professional judgement in prescribing.
The seeking or acceptance by doctors of unreasonable
sums of money or gifts from commercial firms which
manufacture or market drugs or diagnostic or therapeutic
agents or appliances may be regarded as improper.'
2. The Department of Health and Social Security
(DHSS) has recently re-issued a notice on the acceptance
of funding, gifts and hospitality which states that 'it is a
basic principle in all parts of the public service that staff
should not only be scrupulously impartial and honest but
beyond the reach of suspicion.' The notice goes on to
state that 'whenever an officer wishes to attend an
educational conference or other occasion that is to be
financed wholly or partially from promotional or com-
mercial sources he should seek approval from the employ-
ing authority . . .'
3. The Code of Practice for the Pharmaceutical Industry
(1984) published by the Association of the British Phar-
maceutical Industry (ABPI) states (section 19) that 'no
gift or financial inducement shall be offered or given to
members of the medical profession', but excepts inexpen-
sive gifts, which in this context are presumably pens,
diaries, books, rulers or similar articles related to a
doctor's work.
The Code also states (section 20) that 'entertainment or
hospitality offered . . . should always be secondary to
the main purpose of the meeting . . not extend beyond
members of the profession, be appropriate and not out of
proportion to the occasion . . . not exceed that level
which the recipients might normally adopt when paying
for themselves'.
Comments in television and radio programmes, in The
Times, the Guardian, the Economist, a number of medical
journals and by the Consumers' Association demonstrate
that the media and the public expect and demand that the
conduct of doctors, both as prescribers and investigators
of drugs, should be above criticism.
In the light of this concern, and because of the responsi-
bilities that physicians have for the care and treatment of
patients, the President called a meeting of Fellows on 15
February 1984. It was agreed that a College Working
Party should be established to examine the relationship
between physicians and the pharmaceutical industry. The
emphasis of the enquiry was to be on the behaviour of
physicians and not on the relationships between commer-
cial organisations and clients. The Working Party met
twelve times and received both documentary and oral
evidence (see Appendix 1.)
236 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
EVIDENCE RECEIVED
Drug Prescribing
We found that there was widespread acceptance that a
pharmaceutical company has a duty to inform doctors of
its products and collect information on clinical experi-
ence, but the provision of social functions for doctors or
other inducements to use its products was not considered
to be part of that duty. We were reassured by the general
standard of the relationship between physicians and the
pharmaceutical industry but were aware of frequent
examples of minor infringements of the accepted codes
and a few examples of gross abuse.
Sponsored Meetings
There has been considerable and welcome development
of postgraduate centres and of graduate medical edu-
cation in the last 20 years. Possibly because the DHSS
was slow in giving adequate support to these activities,
drug companies began to sponsor educational meetings
many years ago. This help was welcomed, but in some
postgraduate centres almost every meeting now held is
financially dependent upon funding by a pharmaceutical
company. We were informed that the National Associ-
ation of Clinical Tutors was concerned that at these
meetings there was not always appropriate separation of
promotional and educational activities.
Hospitality
We were given evidence that many doctors receive hospi-
tality on a scale beyond that recommended in the ABPI
Code. We were informed that doctors occasionally de-
mand hospitality before agreeing to receive a pharma-
ceutical representative, and that this demand has even on
occasions included hospitality for the doctor's spouse. We
heard of instances in which a company wished to show a
promotional and/or informational film but doctors had
made it clear they would not attend unless the film was
shown with a meal organised at a restaurant of their
choice. If such a film is to be shown to resident medical
staff at a hospital it is often understood that there should
be accompanying hospitality from the pharmaceutical
company which may vary from in-house food and wine to
a more formal dinner at a restaurant.
Gifts and Inducements
The offer of small gifts such as diaries, memo pads or
pens by pharmaceutical representatives to doctors is
commonplace and acceptable but occasionally hints or
demands for more substantial gifts may be made. We
heard evidence of doctors being offered gifts or cash
payments for every patient started on a product and of a
recent approach to a number of physicians who were
offered the sum of ?500 for each five patients treated with
a new non-steroidal anti-inflammatory drug; offers of
even larger sums are apparently made at times. We are
concerned that such inducements might influence the
prescribing patterns of doctors.
Visits Abroad
We were informed that pharmaceutical companies re-
ceive many letters from doctors soliciting funds to attend
meetings abroad. The majority of such requests are
refused. Sometimes requests are accompanied by state-
ments which indicate that the doctor is a frequent pre-
scriber of the company's products and one doctor even
stated that unless his request was granted he would stop
prescribing the company's products.
A television programme (Panorama) showed some doc-
tors agreeing that their attendance at conferences was
influenced by their being held in locations of interest and
the likelihood that hospitality would be generous. Justifi-
cation for holding meetings abroad is sometimes based on
their ease of international accessibility and lower costs,
but we were told of a meeting of physicians who all lived
in one NHS Region which was organised by a pharma-
ceutical company to take place on a Mediterranean
island, which could not have had the advantage of
convenience, and of other meetings abroad in which the
professional and scientific content was minor in compari-
son with the social content and hospitality.
Clinical Research and Clinical Trials
We were given much evidence concerning the conduct of
research projects and clinical trials. For the most part
these studies are carried out with a great sense of
responsibility by members of the medical profession and
the medical and scientific staff of the pharmaceutical
companies. In such work the companies are usually
seeking co-operation with physicians of high scientific and
clinical repute; there is considerable mutual respect. We
wish to continue to encourage a close working relation-
ship between physicians and research workers in the
pharmaceutical industry, but are concerned about certain
new developments in the conduct of clinical trials which
have little scientific value and are of the nature of
promotional exercises, designed to modify prescribing by
doctors or to influence hospital formulary committees.
Such trials threaten to undermine the trust of patients,
and the respect of the public for the profession. Large
sums of money are now being paid to clinical investiga-
tors to conduct drug trials, and we are aware of compan-
ies, partnerships and individual doctors who contract to
carry out clinical trials. These organisations or individ-
uals arrange clinical trials and recruit healthy subjects or
patients to take part in them. They act as links between
the pharmaceutical companies and members of the medi-
cal profession and are often set up in association with
hospital clinic units or university departments. Other
companies are purely commercial enterprises, indepen-
dent of hospital or university associations. In some
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
instances physicians are directors of or have a significant
financial interest in the success of the company. Some
trials are carried out making use of Health Service or
university facilities, without proper recompense to the
Authorities. Physicians may receive payment which is not
made through the appropriate employing authority,
whose facilities are being used.
The use of healthy volunteers for the testing of pharma-
ceutical products is increasing. This special problem has
been examined in the Royal College of Physicians'
Report on Research in Healthy Volunteers (J Roy Coll
Phycns 20, p. 243). Our Report should be read in
conjunction with this.
Publishing
Some research workers expressed concern about their
right to publish data being sometimes unduly restricted to
serve the commercial interests of the companies with
whom they had collaborated.
Dissatisfaction was also expressed at the way some
companies arranged for the proceedings of symposia to be
published as supplements to the normal circulation run of
a journal: the papers in these supplements are not always
subject to the peer review process of the journal and the
reprints are used by the company for promotional pur-
poses. Such papers also contribute to undesirable duplica-
tion of published work.
CONCLUSION AND RECOMMENDATIONS
We believe that a close relationship between doctors and
the pharmaceutical industry is important for the treat-
ment of patients and for the future development and
assessment of new drugs. Because this relationship is so
important both to medicine and to the pharmaceutical
industry, we recommend that Fellows and Members of
the College ensure that their behaviour in relation to the
pharmaceutical industry is always seen to be scrupulously
impartial and honest.
The overriding principle is that any benefit in cash or
kind, any gift, any hospitality or any subsidy received
from a pharmaceutical company must leave the doctor's
independence of judgement manifestly unimpaired.
When it comes to the margin between what is acceptable
and what is unacceptable, judgement may sometimes be
difficult: a useful criterion of acceptability may be 'would
you be willing to have these arrangements generally
known?'
Meetings
At Postgraduate Centres
The establishment of postgraduate centres, the develop-
ment of graduate education and the increasing joint
participation of doctors in scientific and educational
meetings is much to be commended. It is convenient for
many of these meetings to take place at lunch time or in
the evening and it is reasonable that light refreshment
should be available. We regret that this refreshment is so
often sponsored by pharmaceutical companies. As a
regular practice this degrades our profession. We believe
that the DHSS should encourage Health Authorities to
contribute to the support of meetings attended by hospital
staff as they do for general practitioners and GP trainees
who attend educational and scientific meetings.
We commend to all physicians the Code of Practice of
the National Association of Clinical Tutors (see Appendix
2). The Code insists that the selection of programmes and
the choice of speakers are in the hands of clinical tutors.
We believe that these selections should be independent
of any sponsor. The Code insists that any display of
promotional material by a pharmaceutical company is
limited and kept apart from the educational and scientific
part of the meeting. It allows a pharmaceutical company
which sponsors a meeting to provide modest refreshment
in the form of a working lunch or a buffet supper. As
stated earlier, we regret the need for this and do not
accept that the cost of entertaining non-medical guests
should fall on a sponsor. The expenses and fees paid to
lecturers must be moderate. The Code recommends that
no film be shown without a consultant whose specialty is
featured in that film being present and allowed to com-
ment.
For Resident Medical Staff in Hospitals
We are concerned about meetings and interviews that
take place between pharmaceutical representatives and
junior hospital doctors because these junior doctors have
considerable influence on prescribing patterns in hospi-
tals and may not yet have the experience necessary for the
critical assessment of new products. These meetings often
take place on an ad hoc basis in which representatives
come to a hospital hoping to find doctors who are free to
be interviewed. We recommend that such ad hoc meetings
and interviews should be discouraged; meetings should
take place only by appointment.
We recommend that meetings with pharmaceutical
representatives should be arranged in advance and at-
tended by both senior and junior staff to encourage open
and critical discussion, and that pre-registration house
doctors should never be approached by pharmaceutical
representatives except with the permission of a supervi-
sory consultant.
Other meetings of scientific or educational merit for
junior medical staff should be arranged in accordance
with the Code of Practice of the National Association of
Clinical Tutors and should take place within a hospital or
university setting. If promotional material is displayed an
independent consultant should be present. If such scienti-
fic or educational meetings are held outside a university
or hospital they should conform with the above recom-
mendations.
238 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
Meetings and Conferences organised by or with the
help of Pharmaceutical Companies
These vary from conferences of high scientific value to
meetings which are patently promotional exercises. The
distinction rests primarily on the quality and indepen-
dence of the scientific programme. Physicians should
participate in and attend only meetings of educational or
scientific value, the content of which has been selected
independently of the sponsor.
International meetings may be held at locations which,
although exotic, are convenient for access of doctors from
a number of countries, but the attractiveness of the venue
is not of itself a good reason for attendance. The criteria
of educational or scientific value and independent selec-
tion of contributions should be paramount.
A physician may accept fees for travelling or other
expenses of attending a meeting but the primary invita-
tion should come from the organising body or delegate of
an organisation, e.g. a university department.
Support from the pharmaceutical industry for scientific
and educational meetings is invaluable, but sponsorship
of speakers and attenders should be decided independent-
ly and payment should not be arranged directly between a
pharmaceutical company and a physician. Companies
should be encouraged to make their donations for these
purposes to the organising committees and proper ac-
knowledgement of their support should be made. If a
company offers travel funds in the form of scholarships,
its name may be indicated but applications for such
support should be submitted to the organisers and the
selection made independently by them and not by the
company.
Payment of travelling or other expenses by the organ-
isers for the spouse of a physician attending a meeting is
not normally acceptable.
Hospitality, Gifts, Payments and
Investments
Hospitality
A physician should not accept inordinate or excessive
hospitality from any pharmaceutical company. The bor-
derline of acceptability is not easy to define. The pro-
vision of modest refreshment at a conference should be
construed as reasonable; a lavish private dinner party at a
restaurant should not. A pharmaceutical company should
not be expected to extend hospitality to the spouse of a
physician.
We believe that medical students, pre-registration
house officers and all trainees should be made aware
during their training of the dangers of compromising
their professional judgement by accepting or demanding
inordinate hospitality or other favours from pharma-
ceutical companies.
Gifts
It is unacceptable for a physician to receive any gift or
other inducement from a pharmaceutical company be-
yond those specified in the Code of Practice for the
Pharmaceutical Industry (ABPI 1983) which are 'inex-
pensive and relevant to the practice of medicine'.
Payments
Reasonable payment to a physician for giving an ad hoc
expert opinion to a company is acceptable if the physician
takes time and trouble in dealing with it. If such work is
carried out in normal working hours for which the
physician is already being paid, no additional payment
should be accepted.
He should not receive payments from a pharmaceutical
company for seeing their representative, for sending
letters to journals or for reporting adverse reactions to
drugs, such reporting being part of normal clinical prac-
tice.
Consultancy Fees
A physician may act more formally as consultant to a
pharmaceutical company. The arrangements, which
should be agreed in advance, should be those of any
business contract and may include fees and reimburse-
ment of travel and other expenses. If he is an employee of
a Health Authority, university or Research Council, he
must obtain permission from his employer to enter such a
contract. It is inappropriate for a physician to receive
payments unless the work for the company is done in his
own time or unless he is specifically allowed by his
employer to do the work during normal working hours. It
is always necessary for a physician to declare a relevant
financial interest in a company, to remove any suspicion
about the relationship; this applies whether money is
received personally or paid into a departmental account.
Research Projects and Clinical Trials
Contracts, Payments and the Responsibility of
Physicians
Physicians, pharmaceutical companies and ultimately our
patients have much to benefit from the close co-operation
of physicians with the officers of pharmaceutical compan-
ies in research projects and clinical trials of drugs. In
providing opinions and services to companies the princi-
ples of confidentiality, honesty and decorum must prevail
as in other professional activities. Formal arrangements
are essential and should be negotiated through pro-
fessional colleagues in the pharmaceutical companies, not
informally by loose arrangement with a company rep-
resentative. The physician responsible for the project or
trial is responsible for informing his employer, for ensur-
ing that proper accounting procedures are adopted with
independent audit and for fulfilling all legal require-
ments. We recommend that the financial arrangements
should be made through the finance office of a Health
Authority or a university and the accounts supervised by
their financial officers.
The monies may be used to finance the execution of the
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 239
studies which may include salaries of research workers,
technicians, nurses or secretaries. They may be used to
purchase equipment or expendables, to meet hospital or
university overheads, to fund other research projects or to
fund attendance of staff at scientific or educational meet-
ings. It is undesirable for a physician to have any personal
financial interest in studies carried out on patients under
his care, and it is reprehensible to advertise the availabil-
ity of his own or his colleagues' patients for use as
research subjects. Payments must be reasonable in terms
of the time and effort given to the trial and openly
declared.
It is also the responsibility of the physician to ensure
that:
1. The studies are of scientific merit, are competently
planned and will be carried out wherever possible in
properly equipped hospital or university premises.
2. The studies have the approval of an independent
research ethical committee to whom all details of the
financial arrangements are reported.
3. There is prior agreement with the company that the
results may be submitted to journals of the physicians'
choice and that the company will not seek to influence the
publication of the results of the trial. Physicians might
however accede to reasonable requests by companies to
delay publication if, for instance, patent rights might
otherwise be jeopardised. When the results of multi-
centre trials are to be published, all physicians participat-
ing in the trial should see and agree the final draft of any
paper.
4. Appropriate arrangements are made by the company
to indemnify healthy subjects or patients in the event of
untoward harm arising because of the trial. (Negligence
is, of course, covered by existing law.)
Companies
Research companies or organisations which contract to
carry out clinical trials or studies on normal volunteers
should be willing to have their laboratories, or other
places where studies are performed, open to inspection in
order to ensure that high standards are maintained (see
the Royal College of Physicians Report on Research on
Healthy Volunteers).
Arrangements with such companies should be con-
sidered with particular care by Ethical Committees in
view of their intrinsic commercial nature. It is important
that physicians responsible for the care of the patients or
subjects in these studies should not have a significant
financial interest in the company or organisation.
Some research companies have recently advertised
their capability of supplying patients suffering from
specific diseases, e.g. of the liver or kidney. Any such
practice should be monitored most carefully by the
Ethical Committees and the welfare of patients must be
safeguarded as recommended in the Guidelines to Ethics
Committees published by the Royal College of Physicians
in 1984.
Declaration of Interest
We believe that a physician has a duty to declare his
interest in a pharmaceutical company or contract re-
search company to ensure that opinions or decisions are
seen to be free of bias. This is particularly important if:
1. He is a member of a committee, national, regional or
local, considering matters relating to the pharmaceutical
industry, e.g. purchase of drugs, decisions on drug safety
etc.
2. He publishes data that are the result of work with a
company.
Publishing
We approve of the views expressed by the Editorial Board
of the British Journal of Clinical Pharmacology, concerning
the publishing in medical or scientific journals of papers
presented at sponsored meetings (see Appendix 3). It is
our view that offprints of such papers should clearly
indicate that the papers were presented at a sponsored
meeting and were not routinely published papers. It is
desirable that the pagination of such papers is distinct
from the normal journal pagination. Such submissions
should only be published if the meetings were of edu-
cational or scientific value and the content was selected
independently of the sponsors.
Conclusion
We believe that our recommendations substantially re-
present the present practice of most physicians and of
those in training as physicians. However, in the light of
the evidence we have received, we believe that the
publication of these recommendations will be welcomed.
240 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
APPENDICES
1. Evidence given to the Working Party
The following gave oral
Dr V. R. Bloom
Dr A. Bowyer
*Dr D. M. Burley
Mrs Ruth Bycroft
*Dr J. Clifford
Mr Philip Cox QC
Dr C. T. Dollery
Dr J. G. Domenet
Mr J. J. Dower
Rev Prof G. R. Dunstan
*Dr O. Gillie
Dr E. L. Harris
*Dr A. Herxheimer
Dr B. H. Mascie Taylor
*Dr O. Morton
*Dr M. D. Rawlins
Dr P. R. Read
Dr E. S. Snell
Dr A. Thillainayagam
Dr P. Turner
Sir John N. Walton
evidence to the Working Party
Editor, Journal of the Royal
Society of Medicine
Association of Clinical
Tutors
Association of Medical
Advisors to the
Pharmaceutical Industry
Chairman, National
Association of
Postgraduate Educational
Centres Administrators
Association of Medical
Advisors to the
Pharmaceutical Industry
Chairman, ABPI Code of
Practice Committee
Department of Clinical
Pharmacology, Royal
Postgraduate Medical
School
Ciba Geigy
Deltakos (UK) Ltd
Department of Theology,
University of Exeter
Medical correspondent of the
Sunday Times
Deputy Chief Medical
Officer, DHSS
Department of Clinical
Pharmacology, Charing
Cross and Westminster
Hospital Medical School
St James's University
Hospital, Leeds
Association of Medical
Advisors to the
Pharmaceutical Industry
Department of Clinical
Pharmacology University
of Newcastle upon Tyne
Hoechst, UK, Ltd
Association of the British
Pharmaceutical Industry
(ABPI)
Manchester Royal Infirmary
Department of Clinical
Pharmacology, St
Bartholomew's Hospital
Medical School
General Medical Council
*Also supplied documentary evidence.
The following provided documentary evidence for the
Working Party
Dr S. Brandon
Dr G. M. Besser
Dr B. W. Cromie
Dr B. McConkey
Dr R. N. Smith
Department of Psychiatry,
University of Leicester
Chairman of Ethical Committee, St
Bartholomew's Hospital, London
Hounslow
Dudley Road Hospital, Birmingham
Glaxo Group Research Ltd
The Working Party also received a copy of A Guide to
Ethical Principles in the Relationship between Physicians and
the Pharmaceutical Industry prepared by a sub-committee of
the Royal Australasian College of Physicians in 1984.
2. The Relationship between Postgraduate
Medical Centres and Pharmaceutical Houses
Representatives of the Association of the British Pharma-
ceutical Industry, the National Association of Clinical
Tutors and the Advisory Committee of Deans of the
Council for Postgraduate Medical Education in England
and Wales have agreed that:
1. Meetings sponsored by a pharmaceutical house may
be allowed in a postgraduate medical centre subject to
the decision of the clinical tutor.
2. Arrangements for all sponsored meetings should al-
ways be made through the clinical tutor. Staff from
the sponsoring pharmaceutical house should be invit-
ed to attend.
3. Some vetting of lecture material and films should
always be undertaken.
4. An independent opinion by a doctor sufficiently ex-
perienced in the topic should always be available at
such meetings.
5. Publicity by the pharmaceutical house is allowed but
should be separate from the educational content of the
meeting.
6. Sponsorship by the pharmaceutical house should be
limited to a grant paid to the Postgraduate Dean or to
the provision of light refreshments and the printing of
programmes. Meetings sponsored in other ways can-
not be approved under Section 63, but may be
recognised for the postgraduate training allowance on
application by the Postgraduate Dean to the Depart-
ment of Health and Social Security.
Council for Postgraduate Medical Education in England
and Wales
7 Marylebone Road Revised May 1978
London NW1 5HH Reaffirmed 1985
We are grateful to the Council for their permission to publish
these guidelines.
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 241
3. Statement by the British Journal of
Clinical Pharmacology
Supplements
The British Journal of Clinical Pharmacology is willing to
consider publishing Supplements at the request of a
sponsoring organisation. The papers included will nor-
mally have been prepared for oral presentation at a
symposium, but manuscripts submitted for publication
should adhere to the format of original papers published
within the Journal itself. However, review papers cover-
ing the background of an area of pharmacology or
therapeutics and serving as an introduction to original
papers can be included where appropriate in a Sup-
plement. Sponsors and authors are asked to give some
thought to the potential problem of duplicate publication
in preparing a manuscript on data that have already been
published or are being prepared for publication else-
where. Although the Editors realise the advantages of
collecting together up-to-date information on a new drug,
they are committed to minimising duplicate or repetitive
publication. Problems which are anticipated in this area
should be discussed with the Editorial Secretary.
The Editorial Board insists upon retaining editorial
control of Supplements with the right to reject any paper
considered to be of an inadequate scientific standard. The
sponsors are therefore asked to discuss with the Editorial
Secretary nomination of a member of the Editorial Board
to act as one of the editors of the Supplement (most
Supplements have two or three editors, but at least one
should represent the Journal). This can be most easily
achieved by ensuring that an appropriate member of the
Board participates in the symposium, and problems
would therefore be avoided if an approach to the Editorial
Secretary is made at the time of planning the symposium,
rather than at a later stage.
We are grateful to the Editorial Board for permission to publish
this statement.
|
PMC005xxxxxx/PMC5371042.txt | Local Arterial Complications of Left Heart
Catheterisation
GRAHAM A. H. MILLER, dm, frcp
Consultant Cardiologist, Brompton Hospital, London
It is axiomatic that comparisons between two techniques,
both of which have a low complication rate, will be
meaningful only if based on a large experience of those
techniques. In a recent issue of this Journalfl] Chiverton
and Murie contrasted the local arterial complications
following a brachial arteriotomy for left heart catheteris-
ation with those that followed the percutaneous, trans-
femoral (Seldinger) approach. While the low (0.1 per
cent) local complication rate for the trans-femoral
approach was based on a large experience of 2,602
procedures during the five year study period, the much
higher (3.8 per cent) local complication rate for brachial
arteriotomy was based on an experience of only 158 such
procedures. It is the purpose of this brief communication
to report the incidence of local arterial complications
associated with the two techniques based on an experience
of 5,278 brachial arteriotomies and 2,648 percutaneous
trans-femoral procedures over a 10-year period.
Material and Methods
At the Brompton Hospital a computer-based data logging
and retrieval system has been employed since 1970 for
recording details of all cardiac catheterisations per-
formed. Among a total data base of 17,407 procedures
there were 7,926 which fulfilled the following criteria;
patient aged 20 years or more, procedure performed in
the 10-year period from 1975 to 1985 and a procedure
which included arterial catheterisation either via a
brachial arteriotomy or via a percutaneous approach from
the femoral artery. These patients form the data base for
this report. The system allows retrieval of all patients in
whom any complication had been logged; in this instance
the search was limited to local arterial complications. The
records of these patients were then studied for details of
the complication which had occurred and the patient's
subsequent progress.
Results
1. Brachial arteriotomy. There were 5,278 brachial arterio-
tomies performed in patients aged 20 years or more
during the 10-year period. Local arterial complications
were recorded in 43 of these studies; a complication rate of
0.8 per cent.
Of the 43 local complications that occurred, 18 were
dealt with by re-exploration in the catheterisation
laboratory, 16 were referred to the surgical teams for
re-exploration in theatre and 9 were dealt with 'conserva-
tively' by heparin infusion. A good radial pulse was
restored in 15 of the 18 re-explored in the laboratory (83
per ceht) and 12 of the 16 dealt with in theatre (75 per
cent). Seven patients (3 dealt with in the laboratory and 4
in theatre) had no palpable pulse at the time of discharge
but had a good peripheral circulation and no symptoms.
Of the 9 patients treated conservatively, 7 (78 per cent)
had a good radial pulse at the time of discharge but 2 did
not and one of these patients still has mild postural
claudication in the limb?the only patient with a residual
disability following brachial arteriotomy.
Of the 5,278 brachial arteriotomies, 1,559 were per-
formed by an experienced operator with local compli-
cations occurring in 9 (complication rate 0.5 per cent); for
all other operators combined the complication rate was
0.9 per cent.
2. Percutaneous trans-femoral approach. There were 2,648
percutaneous trans-femoral arterial procedures
performed in patients over the age of 20 during the same
10-year period. Local arterial complications requiring
treatment occurred in 12 (complication rate 0.45 per
cent). Ten of the 12 patients were referred to the surgical
teams with a good outcome in 8. One patient required
evacuation of a two-pint retroperitoneal haematoma fol-
lowing perforation of the femoral or iliac artery and died
on the table?possibly as a result of an intercurrent
myocardial infarct. A second patient sustained a deep
venous thrombosis leading to (non-fatal) pulmonary
embolism following evacuation of a large haematoma in
the groin. The surgical procedures performed were (a)
evacuation of haematoma/arterial repair?4 patients, (b)
repair of false aneurysm?3 patients, (c) thrombectomy
for loss of leg pulses?2 patients and (d) repair of arterio-
venous fistula?1 patient.
In two patients, one with prolonged bleeding which
eventually responded to local compression and one in
whom hypotension following partial dissection of the
femoral artery lead to the procedure being abandoned,
surgical intervention was not needed.
Discussion
In any study of the complications of cardiac catheteris-
ation a number of factors will influence the reported
incidence of local arterial complications. These will
288 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
include the experience of the operators, the technique
used to obtain haemostasis and the reporting system
employed for recording the occurrence of complications.
It is impossible to discover, from published reports, the
complication rates produced by individual operators,
experienced or inexperienced, but the total number of
studies from which the complication rate is derived
provides insight into the experience of the unit. Studies
based on a large number of cases are likely to reflect the
results obtained by experienced personnel as well as being
of more value from a statistical point of view. Thus a local
arterial complication rate from brachial arteriotomy has
been reported to be as high as 28 per cent[2] and as low as
0.56 per cent[3]. The former study was based on an
experience of 96 procedures in 1972 and the latter, a
multicentre prospective study reported in 1982, on 23,040
brachial arteriotomies.
The technique employed for brachial arteriotomy is of
the utmost importance if local complications are to be
avoided. Good technique includes (i) a transverse (not
vertical) incision in the artery (ii) repair by interrupted
6/0 (or finer) sutures (not a 'purse-string' suture) and (iii)
whole body heparinisation (1 mg/kg body weight); instil-
lation of small quantities of heparin into the distal vessel is
quite inadequate. In addition, trauma due to clumsy
catheter or guide-wire insertion must be avoided as must
the use of too large a catheter for the calibre of the vessel.
Other details include the trimming of any free intimal
flaps[4] and, most importantly, rejection of the concept of
'spasm' as the cause of an absent or weak radial pulse
following the repair. Spasm does, sometimes, occur and is
always the result of introducing too large a catheter with
resulting pain. But spasm is too often used as an excuse
for an inadequate technical repair. No patient should be
allowed to leave the laboratory after brachial arteriotomy
unless there is a good volume arterial pulse. If a good
pulse is not present the most experienced available oper-
ator should be called to re-fashion the repair. The results
reported above suggest that re-exploration of the artery in
the laboratory by an experienced physician is at least as
effective as a repair by the surgical team, although it is
probably true that it was the more difficult or 'failed'
repairs which were referred to the surgical teams.
The nature of the reporting system used to determine
the complication rate is of crucial importance. In the
report by Chiverton and Muriefl] the recording of only
the complications that resulted in referral to the surgical
team for operative repair will certainly underestimate the
true complication rate. In the present study, 63 per cent
of the local brachial complications that occurred were
dealt with in the laboratory or resolved spontaneously so
that the complication rate, as seen by the surgical team,
would have appeared to be much lower (0.3 per cent)
than the true figure of 0.8 per cent reported here. It is
probable that almost all studies (including the present
one) underestimate the complication rate since only those
complications that have been recorded will be counted;
and recording is unlikely to be without some omissions.
This is particularly true if a complication occurs after the
patient has left the laboratory (or the hospital) and the
laboratory personnel are not informed. On the other hand
the reported complication rate based on immediate events
is much higher than the late complication rate. Only one
patient in the present series had long standing (mild)
disability following a brachial arteriotomy. The approach
used will also affect the accuracy with which compli-
cations are reported. A 'lost pulse' following a brachial
arteriotomy is immediately noticeable and reported; a
large haematoma in the groin is not reported unless
needing surgical evacuation or repair but is not an
infrequent complication?particularly as whole-body
heparinisation is widely practised to prevent coronary
embolisation during coronary arteriography.
The close similarity between our own overall arterial
complication rate of 0.69 per cent and that of 0.57 per
cent reported in another large recent series, the Registry
study[3], suggests that there is a minimum complication
rate of between 0.5 and 1.0 per cent and that a lower
figure is unlikely to be achieved in any laboratory where
operators include physicians in training. The lower figure
of 0.5 per cent complications for brachial arteriotomy
achieved by an experienced operator, as reported here,
points to the importance of experience in reducing com-
plications and the importance of assessing the risk on the
basis of studies involving large numbers of patients.
It is probable that the local arterial complication rate
following the trans-femoral approach is slightly lower
than that following the trans-brachial approach; of the
291 patients with local vascular complications (0.57 per
cent incidence) reported in the Registry study[3], 62 per
cent were associated with the brachial approach. Our own
results also show a slightly higher complication rate for
the brachial approach (0.8 vs 0.45 per cent) though non-
reporting of haematoma formation makes the latter figure
artificially low. However the difference is so small as to be
outweighed by other considerations. These include the
greater ease with which a stenotic aortic valve may be
crossed when the approach is from the arm as well as the
ability to perform studies on a 'day case' basis when
haemostasis is obtained by repair of an artery, as against
the need for the patient to remain in bed until a stable
fibrin plug has formed at the site of a femoral artery
puncture.
It is generally agreed that the trans-femoral approach is
contraindicated when there is known ilio-femoral disease
and relatively contraindicated in the presence of gross
obesity (especially in females). Similarly, the brachial
approach is best avoided in those in whom the artery is
likely to be of small calibre?female patients or Asians of
slender build. The wise operator will suit the approach to
the patient and to the problems to be solved and will make
sure that he is equally adept at both the brachial and
femoral approach.
References
1. Chiverton, S. G. and Murie, J. A. (1986) Journal of the Royal College of
Physicians, 20, 126.
2. Brener, B. J. and Couch, N. P. (1973) American Journal of Surgery,
125, 521.
3. Kennedy, J. W. et al. (1982) Catheterisation and Cardiovascular Diag-
nosis, 8, 5.
4. Grossman, W. (1986) Cardiac Catheterisation and Angiography, Third
Edition. Philadelphia: Lea and Febiger.
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 289
|
PMC005xxxxxx/PMC5371043.txt | Medical Problems of Cold Weather
The Oliver-Sharpey Lecture 1985
WILLIAM KEATINGE, MB, BChir, PhD, MRCFj Professor of Physiology,
The London Hospital Medical College, London
Mortality caused by cold weather among elderly people
has been one of the most widely discussed of all medical
problems in Britain in recent years. In the public mind,
this mortality has come to be associated almost exclusive-
ly with hypothermia. Hypothermia does cause some
deaths and it contributes to others, but, although it has
been a major cause of losses of life in special situations in
the past, current evidence suggests that it is not a major
factor in approximately 40,000 excess deaths that occur
every winter in England and Wales, mainly among
elderly people. The public interest shown in these prob-
lems has helped to direct attention to the problems of
elderly people in winter. A negative side of the public
interest is that popular preoccupation with hypothermia
came to affect scientific thinking, and delayed the investi-
gation of other, and more large-scale, causes of death in
cold weather. Winter mortality is, in fact, only the latest
example of popular beliefs diverting investigation of cold-
induced problems, and much of the misconception on this
occasion resulted from initial successes in identifying
hypothermia as the cause of earlier problems.
The most striking of these was death in the water after
shipwreck. Observant individuals throughout history re-
alised that shipwreck victims often died of cold rather
than by drowning. The earliest known example both of
this and of seasonal influence on mortality was recorded
by Herodotus in the first book written on the mainland of
Europe, in the Fifth Century BC[ 1 ]. In recording the
wreck of Darius's fleet invading Greece, early in the year,
he states that cold rather than drowning caused many of
the deaths, but at the Battle of Salamis, fought in
summer, the Greeks lost few men as they were able to'
swim to safety if their ships were sunk. Later, however,
by a kind of international literary and journalistic conven-
tion, people lost after shipwreck were routinely assumed
to drown. Shakespeare gives an example of this in the
opening scene of The Tempest. In more recent times,
'drowned at sea' was the phrase almost exclusively used
in newspaper accounts of people lost at sea up to 1960,
and is sometimes used today. Although this was little
more than a verbal convention, it affected people respon-
sible for lifesaving equipment at sea, to the extent that
they seldom considered anything except the need for
flotation equipment. It was only towards the end of the
Second World War that the consequences of this became
clear, when a Committee under Rear-Admiral A. G.
Talbot reported that most of the Royal Navy men lost in
that war, some 20-30,000 men, died in the water rather
than from battle injuries, and that without thermal
protection they had often died from simple body cooling
rather than drowning. This was further documented a
decade later[2].
It was largely due to this realisation that extensive
studies were made during the next two decades of the
internal factors that control body heat loss and heat
production in cold water[see 3, 4 for reviews]. The results
of that work provided a useful background to consider-
ation of other hazards of cold, since immersion largely
eliminates external thermal insulation, leaving survival
dependent on the uncomplicated operation of internal
mechanisms of heat conservation and heat loss. The
results showed that once people were in cold water, and
vasoconstriction developed, most of the internal insula-
tion of the body was provided by subcutaneous fat (Fig.
1), so that fat people could maintain body core tempera-
ture indefinitely in water at 12?C, while thin people often
cooled progressively in water as warm as 25-29?C.
Figure 1. Effect of subcutaneous fat on body cooling during
30-minute immersions in water at 15?C (Courtesy Journal of
Physiology).
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 283
Children usually cooled rapidly in cold water[5], partly
because young children, particularly boys, are usually
thinner than adults, and partly because the small size of
young children gives them a high surface area/mass ratio.
Another point of practical importance was that exercise
greatly accelerated heat loss by increasing blood flow to
limb muscles; in cold water, with little external insula-
tion; this outweighed the increase of heat production in
exercise, thus increasing the rate of fall of body tempera-
ture. It was also found that in water colder than 12?C
cold vasodilatation caused blood flow to return to the
limbs and so led to rapid body cooling even in relatively
fat people. This reaction, which was largely due to cold
paralysis of blood vessels of the extremeties, seemed to
put a lower limit on the environmental temperature that
even fat people could survive for long periods. However,
an unusually fat Icelandic fisherman recently survived for
five hours swimming in water at 5-6?C, and was brought
to London by Professor Johann Axelsson; in laboratory
experiments, we found that he could stabilise body
temperature in such water with little cold vasodilatation,
apparently because an unusually thick layer of limb fat
protected the limb arteries from serious cooling[6]. For
other people exposed to such a degree of cold, extended
survival depends on the wearing of clothing or other
external protection to keep skin temperature above the
threshold for cold vasodilatation. Even with deaths in
water, cold does not produce hazards solely by causing
lethal cooling of the body core. Some result from cardio-
vascular and respiratory reflexes induced by cooling of
the skin[7]. The most important of these is inhalation of
water due to inability to control respiration during the
intense inspiratory drive caused by the reflexes, which
readily causes drowning in waves that splash over the
head. In addition, reflex drive to the heart occasionally
causes sudden death from ventricular fibrillation during
the first few minutes of cold immersion[8]. Apart from
this, the high viscosity of cold water near 0?C can
combine with the reflex effects of cold to cause death from
drowning as even fit, healthy young people become
rapidly exhausted as they try to swim short distances to
shore in very cold water without buoyancy aids[9]; that
may be the most important cause of immersion death in
inland waters.
Insidious Hypothermia and Memory
It has recently become clear that in special circumstances
minor degrees of hypothermia can occur without much
discomfort during quite mild exposures to cold, and can
indirectly be a serious hazard to life in people carrying out
demanding work in potentially dangerous circumstances.
We have seen that the rate at which an individual's body
core temperature will fall in water at 15?C can be
predicted quite accurately from fat thickness alone. How-
ever, if people are immersed in relatively warm water,
and then in progressively colder water until they become
just unable to stabilise core temperature, the size of their
metabolic response to cold is as important as fat thickness
in determining the coldest water in which they can
stabilise. Experiments[10] showed that although such
people's fat thickness did correlate with the temperature
of the coldest water allowing them to stabilise, the
relationship was not a close one. On the other hand, the
subjects' body insulations at the time they stabilised in the
coldest possible water were closely related to fat thickness,
both at rest and in exercise. The discrepancy was due to
metabolic rates, which were very varied and had no,clear
relationship to fat thickness, so that while body insulation
and heat loss could be predicted, metabolic rate and
minimum water temperature for stability in this marginal
situation could not.
This marginal situation for heat balance is one with
wide applications, but the most striking example of these
has been in deep commercial diving. Loss of heat to the
respiratory gas and from the body can be lethal at depths
greater than about 100m, where pressure is more than 10
times atmospheric, and where water on the seabed is at
4-6?C, even in the tropics. Heating is therefore supplied
to the diver, usually by an open-circuit hot-water system
in which warm water pumped from the surface is used to
flood the inside of the diving suit. The popularly accepted
principle that if people do not feel cold they are not
seriously cold, often led to the assumption that as long as
divers were within their limits of voluntary tolerance, cold
could be discounted as a cause of any serious problems.
By 1976, it became clear that something was causing
serious and unexplained problems. The report of the
Science Research Council taskforce on marine technology
in that year[ll] gave unexplained losses of consciousness
and confusional states in divers as the problem of top
priority for research to assist development of North Sea
resources. Childs and Norman[12] obtained notes of 114
such incidents up to 1978. There was also a high rate of
fatalities, usually six or seven each year in a diving
population of only a few hundred. Although the cause of
death could usually be given as diver error, there was
often no explanation why a highly skilled man had made
some gross mistake, leading to a fatal result. In 1979, we
had the co-operation of a North Sea diving company in
making measurements of divers' temperatures, as urine
temperature, when they returned to the bell at the end of
saturation diving shifts[ 13]. In four of 13 cases, tempera-
ture was below 36?C, and one diver was in hypothermia
at 34.7?C. At the same time, another was seriously
overheated at 38.3?C. Some of the divers felt cold, so the
heating water was then clearly on the cool side, and the
hot-water system sometimes failed, whereupon the dives
were continued without heating for a time while attempts
were made to restart the hot-water supply. However, two
of the coldest of the divers had neither felt particularly
cold nor experienced any failure of heating.
A diver being supplied by water that is a little on the
cool side for comfort is essentially in a bath of lukewarm
water. Laboratory experiments showed that people in
lukewarm water always suffered falls in core temperature,
sometimes to hypothermic levels, and again often with
little sensation of cold[14]. Figure 2 shows the most
dramatic case, in which the subject was a thin man who
had undergone considerable recent cold exposure. His
rectal temperature fell steadily to 34.7?C with very little
shivering and only slight feelings of cold. At this point, he
284 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
developed atrial fibrillation, which reverted to sinus
rhythm when he was rewarmed. However, the main
hazard that these levels of body cooling presented to
divers was that they impaired memory and reasoning[15].
When volunteers' body temperatures were lowered ex-
perimentally by immersion in cold water, cold discomfort
could be abolished immediately by transferring them to
warm water. The deep body temperature remained low
and even fell more rapidly for a few minutes in the well-
known afterdrop. So it was possible during this time to
test reasoning and memory with low core temperature but
without the complication of distraction by cold discom-
fort. Such experiments showed that ability to memorise
facts was greatly reduced at body core temperatures
below about 36?C. Ability to recall facts learned at
normal body temperature was, interestingly, not im-
paired, but there was marked slowing of the speed at
which complex reasoning tasks could be performed. For
example, the time needed to perform a series of double-
digit sums was increased by about 50 per cent at body
temperatures below 35?C. These difficulties in memoris-
ing new facts-and in reasoning could obviously be danger-
ous to a diver facing an unexpected, complex and
demanding situation on the seabed. We cannot say in
retrospect how many diving incidents in the 1970s were
due to low body temperature, but during the last six
years, care has been taken to adjust water temperatures so
as to keep divers thermally comfortable and to bring them
in at once if heating fails. During that time, such
incidents have become uncommon in the North Sea, and
measurements by urine temperature at the end of dives
from the diving ship Arctic Seal in the North Sea in 1982,
at 75 and 135m, showed no cases of core temperature
below 36.8 or above 37.5?C (nine cases; personal
observations).
Careful control of the hot-water supply to maintain full
thermal comfort can therefore prevent hypothermia, even
with an even skin temperature, but more reserve can be
provided by allowing the hands and feet to cool and so
provide the sensory input needed to activate shivering
and vasoconstriction if core temperature does fall. This
restores the kind of thermal gradients normally present in
cold air, which the human thermoregulatory system is
geared to deal with, and it can restore normal thermore-
gulation to people who otherwise cool progressively with
an even skin temperature around 29?C[16]. This prob-
lem of mild hypothermia leading to dangerous misjudge-
ments is a hazard specifically to people working in
potentially dangerous situations with an even pattern of
mild skin cooling. It may be important in a number of
occupations in cold weather, but it obviously raises the
question whether such insidious cooling could lead direct-
ly to death from hypothermia in people exposed to such
patterns of skin cooling in air.
Winter Mortality in the Elderly
The hazards of hypothermia had become firmly fixed in
the public mind by the early 1960s, so it was perhaps
inevitable that when increased mortality among elderly
people in cold weather started to attract marked public
attention, this mortality should come to be associated
with hypothermia. It had been realised at least since 1841
that mortality in Britain increases in winter[17]. Mortal-
ity statistics over the last two decades show that this
winter mortality is tending to become less, but that there
are still about 40,000 excess deaths in an average winter
in England and Wales. Analyses of these deaths, particu-
larly by Bull and Morton[18] show strokes and myocar-
dial infarcts accounting for most of them, while
hypothermia causes only about one per cent of the excess
deaths in winter. It can be argued that the mortality
statistics may be distorted by failure to recognise deaths
that are due to hypothermia and it has been suggested
that the latter might, in fact, be common[19]. Sublingual
readings often give an indication of low body temperature
in cold surroundings, but sublingual readings give false
low indications of body core temperature in cold sur-
roundings, mainly because of parotid saliva entering the
mouth via parotid ducts in cold cheeks[20]. The most
reliable measurement of core temperature in this situation
is by a thermoelectric rectal probe at an adequate depth
(>80 mm), and reports that rely on this or on another
dependable measure seldom show low core temperatures
in people either at home or entering hospital. Most cases
of hypothermia admitted to an intensive care unit in
Glasgow[21] (from a total of 44 cases in 15 years) were a
result of collapse in cold surroundings. The commonest
cause of this collapse (25 cases) was poisoning or intoxi-
cation by alcohol, drugs or carbon monoxide. Severe
physical illnesses such as cerebrovascular accident, myo-
cardial infarct, malignancy or broken limb caused
another eight such cases. Another seven of the cases of
hypothermia were a result of hypothyroidism or other
endocrine disease, or of malnutrition and dehydration,
often combined with alcohol. Only two were attributable
to cold exposure combined with old age or mental
disability alone.
It could be argued that this low incidence of hypother-
Figure 2. Progressive fall in body temperature during immer-
sion in water at 29? C (Courtesy British Medical Journal).
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
mia was due to failure to detect low body temperature in
many patients entering hospital. Accordingly, routine
measurements of sublingual temperature, with rectal
readings if sublingual values below 36?C were obtained,
were made on all new patients entering the Emergency
and Accident Department of The London Hospital,
Whitechapel in January and February 1985. Only three
(0.04 per cent of all patients) had core temperatures below
35?C; one of these had suffered a cerebrovascular acci-
dent, one a fractured hip, and one with mental impair-
ment had fallen out of bed and been unable to get back
onto the bed[22]. Such observations suggest that hypo-
thermia is not only uncommon but, when it does occur, is
usually a secondary, and not always important, compli-
cation of a serious underlying condition. Effective treat-
ment is, of course, particularly important in those cases in
which hypothermia does play a major role in the illness,
such as hypothyroidism. People with mild myxoedema
are prone to cool in cold surroundings because of defec-
tive heat production, while undernutrition can both
reduce heat production in the cold[23, 24], and increase
heat loss[25]. It is likely that malnutrition has been
responsible for rare cases of elderly people with clearly
defective responses to cold, who are prone to cool rapidly
as a result[26]. Elderly people are often slow to act to
correct changes in their thermal environment[27]. There
are rare cases of grossly defective thermoregulation caus-
ing hypothermia in otherwise normal and well-nourished
adults, who are often not elderly, perhaps due to hypotha-
lamic defects. It is less clear whether elderly people in
general have impaired responses to cold; reduced re-
sponses have been reported in groups of elderly
people[28, 29], but variability in the response of both
young and old is very great[30] and normal metabolic
response to cold has been found in well-nourished elderly
people[24]. The present evidence indicates that deaths
caused directly by all types of hypothermia in cold
environments, though individually important, represent
only a small part of the overall excess mortality in cold
weather in Britain, even among the elderly.
The problem then is to explain the large number of
excess deaths that occur in winter, particularly from
arterial thrombosis. We made experiments[31] on eight
young adults to see whether any relevant changes were
produced by mild surface cooling with rapidly moving air
at 24?C. This rapidly lowered skin temperature to near
air temperature, while rectal temperature fell slowly by
0.4?C, and then stabilised before the end of the 6-hour
experiments. Shivering developed with increased meta-
bolic rate but, even at the end, was only moderate. This
was therefore a mild, sustainable and closely controlled
cold stress with little fall in core temperature. Systolic and
diastolic arterial pressures both increased in the cold, on
average by 12 and 18 mmHg respectively. Pulse rate fell,
probably due to baroceptor reflexes as arterial pressure
rose, while cardiac output did not change significantly.
The increase in arterial pressure, which occurs to at least
this degree in elderly adults[32], could have some long-
term effect on increasing arterial thrombosis, but seemed
insufficient to explain the rapid cold weather mortality
from coronary thrombosis which Bull and Morton[18]
showed to reach a peak within 24 hours on a cold day.
The probable explanation of this was provided by in-
creases in platelets, as well as red cell count and haemato-
crit, during the exposure to cold (Table 1). An increase in
haematocrit is a known effect of cold, though it does not
previously seem to have been associated with cold weath-
er mortality. It was of particular interest, since arterial
thrombi in their early stages are largely formed by
deposition of platelets, that the mean size of circulating
platelets, as well as platelet count, increased in most
cases. The increase in platelet number, like the increase
in red cells, could be partly attributed to haemoconcen-
tration following vasoconstriction, but the tendency to
increased size of platelets suggests addition of large and
therefore young and active platelets to the circulation.
These changes in platelet size and numbers would clearly
tend to increase arterial thrombosis, in cold weather,
among elderly people with atheromatous vessels. There is
recent evidence that increases in red cell count also
markedly increase platelet deposition, probably by phys-
ically driving platelets against the vessel wall, so the
increase in red cells in the cold is also important. There
was also an increase in neutrophil polymorphs during
Table 1. Changes in blood cells and platelets. Values are means (SE in parentheses)[31].
Before experiment
(n = 8)
Change during
1st hour (n = 6)
Change during
6 hours (n = 8)
Red cell count
(1012/1 blood)
Packed cell volume
Platelet count
(1071 blood)
Platelet volume (fl)
Platelets as fraction of
plasma by volume (10~3)
Neutrophil count
(1071 blood)
Cold
Control
Cold
Control
Cold
Control
Cold
Control
Cold
Control
Cold
Control
4.65
4.63
0.395
0.391
291
287
8.8
8.7
4.12
4.01
3.79
3.45
(0.23)
(0.15)
(0.025)
(0.017)
(27)
(28)
(0.5)
(0.4)
(0.21)
(0.22)
(0.31)
(0.33)
+ 0.11 (0.06)
-0.15 (0.05)c
+ 0.007 (0.004)
-0.012 (0.004)c
- 10 (4)
- 15
0.0
0.0
-0.07
-0.23
+ 0.42
-0.17
(5)c
(0.2)
(0.1)
(0.11)
(0.07)c
(0.28)
(0.06)c
+ 0.35 (0.07)M
-0.03 (0.03)
+ 0.029 (0.005)b,e
0.000 (0.003)
+ 23 (9)c
+ 7 (5)
+ 0.2 (0.1)
0.0 (0.1)
+ 0.61 (0.13)M
+ 0.12 (0.11)
+ 2.04 (0.47)a>d
+ 0.74 (0.29)c
Difference from control: a p < 0.05; b p < 0.01
Difference from initial value: c p < 0.05; d < 0.01; e p < 0.001
286 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
these exposures to cold, and these changes together
caused an increase in whole blood viscosity which rose by
20 per cent in the cold. Very little of these changes took
place in the first hour but they were well developed in six
hours. Plasma protein ratios of high-to-low-density pro-
tein did not change in the cold, but plasma cholesterol, in
all its fractions, increased. The increases in platelets, red
cells, blood viscosity, arterial pressure and plasma choles-
terol could clearly all contribute, to different degrees, to
the increase in arterial thromboses in cold weather.
Other Problems in Hot and Cold Weather
An explanation is incidentally also needed for the fact that
mortality increases if minimum daily temperature rises
above about 20?C[18, 33], This heat-induced mortality is
a much greater problem in North America than in
Britain, but even in Britain heatwaves produce marked
rises in mortality every two or three years[34]. Again,
although most work[35] on heat-induced mortality has
concentrated on the effects of simple overheating of the
body, mortality statistics show arterial thrombosis as
responsible for about half the deaths in major heat-waves,
and heat-stroke for rather few. Although changes in blood
composition and arterial pressure offer a straightforward
explanation for the increased mortality from arterial
thrombosis in the cold, many questions remain to be
answered on this as well. Efforts to optimise the level of
home heating are obviously desirable, if only for the sake
of general comfort and welfare. However, it is by no
means certain that this alone will prevent excess mortality
in winter, and substantially more information may be
needed to find ways of minimising this mortality.
References
1. Herodotus. Translated by A. de Selincourt, revised by A. R. Burn
(1972) The Histories. Harmondsworth: Penguin Books.
2. McCance, R. A., Ungley, C. C., Crosfill, J. W. L. and Widdow-
son, E. M. (1956) The Hazards to Men in Ships Lost at Sea, 1940-44,
Medical Research Council, Special Report Series no. 291.
3. Burton, A. C. and Edholm, O. G. (1955) Man in a Cold Environment.
London: Edward Arnold.
4. Keatinge, W. R. (1969) Survival in cold water. The physiology and
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5. Sloan, R. E. G. and Keatinge, W. R. (1973) Journal of Applied
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6. Keatinge, W. R., Coleshaw, S. R. K., Millard, C. E. and
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8. Keatinge, W. R. and Hayward, M. G. (1981) Journal of Forensic
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A. and Garrard, J. (1986) Clinical Science, 70, Suppl. 13, 93.
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(1985) Clinical Science, 69, 525.
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Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 287
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PMC005xxxxxx/PMC5371044.txt | Audit of the Assessment of Mental
Impairment in the Elderly
J. P IREDALE, Medical Student
A. J. SYMONS, SRN, Research Assistant
R. S. J. BRIGGS, MB, MRCP(UK), Senior Lecturer in Geriatric Medicine
Faculty of Medicine, University of Southampton, Southampton General Hospital.
The accurate assessment of mental state in elderly
patients admitted to hospital has long been recognised as
essential in the identification and management of demen-
tia and toxic confusional states. The failure to diagnose
such syndromes is associated with the misplacement of
patients[l]; mental impairment itself is associated with
difficulty in discharge from hospital[2] and increased
mortality[3]. A Royal College of Physicians Report rec-
ommended in 1981 the administration of a mental test
score to all elderly patients admitted to hospital[4].
There has been considerable interest over the last few
years in the role of medical audit, not only in the
identification of poor practice but also as a means towards
improving the effectiveness and efficiency of care. Al-
though studies may show that the initiation of audit
coincides with improvements in outcome[5], the extent of
the change attributable to audit remains doubtful. A
recent review suggested that 'it would appear that simply
feeding back information on performance has almost no
impact on changing clinical behaviour'[6]. We have
attempted a controlled study of the effect of audit on the
assessment of impairment in elderly patients admitted to
hospital wards.
Methods
Over a two-month period the case notes of 195 patients
were reviewed. These patients were consecutive admis-
sions over the age of 65 years to three medical wards
under six general physicians, four orthopaedic wards
under six surgeons, or three wards used by three geriatric
firms. The information sought in the notes comprised
whether or not a formal mental test score had been
carried out, whether there was any statement describing
the patient's mental state, and whether any corroborative
history had been obtained from a third party. One of the
investigators then performed a simple mental test score
with the patient[7], as shown in Table 1. Using ward
registers, each patient was followed up at one month to
Table 1. Abbreviated mental test score of Hodkinson (1972);
(each question scores 1 mark).
1. Age
2. Time (to nearest hour).
3. Address for recall at end of test ? this should be repeated by
the patient to ensure it has been heard correctly: 42 West
Street.
4. Year.
5. Name of hospital.
6. Recognition of two persons (doctor, nurse).
7. Date of birth.
8. Year of First World War.
9. Name of present monarch.
10. Count backwards, twenty to one.
determine the date and destination of discharge. The
purpose of the study was concealed from ward staff at this
stage; each consultant involved had given permission for
an audit of case notes of elderly patients under his care to
be performed, but had been asked not to divulge this to
junior medical or nursing staff.
After the results of this initial audit had been collated, a
summary of the findings was sent to the consultants in
charge of one general medical firm and one geriatric firm
in one ward block ? the 'audit-wise' group. No specific
suggestions were made as to how the results should be
interpreted or acted upon, other than a request to discuss
them with their own junior staff but not with staff on
other firms. One month later, a repeat audit was conduct-
ed on the notes of 17 consecutive elderly patients admitted
to the audit-wise general medical firm and 21 patients to
the audit-wise geriatric firm. For comparison, a control
group of 27 patients under the care of an 'audit-blind'
geriatrician (who had no knowledge of the results of the
first audit) was studied in a separate ward block.
Results
Initial Audit
Considerable variation was seen between the different
ward groups in terms of age, sex ratio and mean level of
Correspondence to: Dr R. S. J. Briggs, Senior Lecturer in Geriatric
Medicine, Centre Block, Level E, Southampton General Hospital,
Southampton, Hampshire S09 4XY.
268 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
mental impairment. To simplify comparisons, patients
were grouped according to their mental test score as
'mentally normal' (7-10 points), 'mentally impaired' (4-
6) and 'severely mentally impaired' (0-3). The distribu-
tion of the patients between the geriatric, medical and
orthopaedic wards is shown in Table 2. The fact that
Table 2. Age, sex and mental test score in patients over 65 years
admitted to geriatric, medical and orthopaedic wards: initial
audit.
Ward group (n) Mean (S.D.) % Female Mean (S.D.)
age years mental
test score
Geriatric medicine
(100) 83 (6.9) 71 5.6 (2.7)
General medicine
(50) 75 (5.9) 52 7.6 (3.2)
Orthopaedic
surgery (45) 82 (6.3) 96 6.1 (3.3)
admissions (in the over 65 age-group) to geriatric wards
tended to be older, were more likely to be female and had
a higher prevalence of mental impairment than on gen-
eral medical wards is not surprising in view of an 'age-
related' admission policy. The orthopaedic wards studied
were devoted to acute admissions, and the data reflect the
preponderance of elderly women with fractured neck of
femur.
Analysis of the case notes on geriatric wards showed
that only 8 per cent of patients had had a formal mental
test score, and none on more than one occasion (to
determine progress). In the absence of formal testing, 17
per cent had a documented corroborative history from a
third party, and 69 per cent a reference in the notes to
their mental state. However, in 17 of these 69 patients the
statement in the notes was misleading: for example, the
notes recorded 'not confused' but a formal mental test
score by the investigator showed severe mental impair-
ment. Of the 23 patients with no reference at all to mental
state, five had some degree of mental impairment on
formal testing (severe in three).
Of the 50 general medical patients, none had received a
formal mental test score, six (12 per cent) had a corrobo-
Table 4. Mental assessment in casenotes of elderly patients admitted to general medical and geriatric wards, on initial audit and on
repeat audit.
Patient Formal mental Corroborative Appropriate Misleading Impaired, but
group (n) test (%) history (%) description (%) description (%) no description %
Geriatric wards:
initial audit (100) 8 17 52 17 5
Medical wards:
initial audit (50) 0 12 30 8 12
Geriatric 'audit-blind'
repeat audit (27) 7 7 33 15 7
Geriatric 'audit-wise'
repeat audit (21) 5 10 71 0 5
Medical 'audit-wise'
repeat audit (17) 0 24 60 0 6
rative history, and 19 (38 per cent) some description of
their mental state, four of which were misleading. Of the
31 (62 per cent) with no reference to their mental state,
six showed impairment on formal testing (severe in four).
The notes of 45 orthopaedic patients revealed no
formal mental testing, two (4 per cent) corroborative
histories and 24 (53 per cent) references to mental state
(misleading in four). Of the 21 patients (47 per cent) with
no assessment of mental state documented in the notes,
five were impaired (two severely so).
Taking these 195 patients overall, 18 had died within
one month of admission; 15 per cent of those severely
mentally impaired, compared with only 4 per cent of
those who were mentally normal (p<0.01, chi-squared
test). Similarly, the degree of intellectual impairment was
a significant (0.01 >p>0.001) adverse prognostic indica-
tor for discharge (Table 3).
Table 3. Proportion of patients successfully discharged from
hospital one month after admission, compared with mental test
score (MTS).
Patient group
(MTS) n % Successful discharge
Severely impaired 42 31
(0-3 points)
Impaired 43 47
(4-6 points)
Mentally normal 110 64
(7-10 points)
Repeat Audit
The further audit of case notes one month after the results
of the initial audit had been collated, is shown in Table 4;
the findings of the repeat audit on 'audit-wise' and 'audit-
blind' firms are compared with the original results.
As before, no formal mental testing was carried out by
the 'audit-wise' general medical firm, whilst the geriatric
firms continued to test at a rate close to that of the original
audit, whether 'blind' or 'wise'. However, misleading
comments were now absent from the notes of both 'audit-
wise' firms, and there was a significant increase in the
frequency with which appropriate descriptions of mental
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 269
state were made on both the geriatric (52 to 71 per cent;
0.01>p>0.05) and general medical (30 to 60 per cent;
0.05 >p> 0.02) 'audit-wise' firms, which was not seen in
the geriatric 'audit-blind' ward.
Discussion
Although 85 of the original 195 patients studied (43 per
cent) had evidence of mental impairment, only eight
patients (4 per cent) had formal mental test scores
recorded in the notes. This is disappointing in view of the
recommendations of the Royal College of Physicians
Report, in 1981 [4], Copies of a longer mental test are
available on our geriatric wards, but even after the initial
audit their use did not increase. Since the completion of
the study, the 'audit-wise' general physician has request-
ed copies of the short mental test score used, which was
contained in an appendix to the 1981 College Report.
'Passive feedback' of the results of initial audit did not
change the practice with regard to formal mental testing,
consistent with the view that 'active feedback' is more
successful in modifying clinical behaviour[6] ? perhaps,
in this case, by supplying wards with a copy of this paper
together with copies of the mental test score.
However, even in the absence of recording of formal
mental test score (or of documenting a corroborative
history), what is most important is that misdiagnosis
should not result in mistaken management decisions[8].
Thus the fact that a mentally normal elderly person is not
recorded as such in the notes may not be of any conse-
quence, but to miss cognitive impairment in a dement
who is socially well-preserved may lead to unexpected
difficulties. In this context it is important to note that the
original audit showed 22 per cent of geriatric and 20 per
cent of medical admissions to be misdiagnosed in terms of
an absent or a misleading description, when subsequent
formal mental testing revealed mental impairment. The
rate of such misdiagnosis remained at 22 per cent on the
'audit-blind' geriatric firm, but it is encouraging that the
rates fell significantly to 5 and 6 per cent on the geriatric
and general medical 'audit-wise' firms respectively. All
these latter errors would have been obviated had a mental
test score been done, there being no misleading descrip-
tions recorded in the notes at the repeat audit in the
'audit-wise' groups: only the 'audit-blind' group missed
any cases of severe mental impairment.
The Birmingham audit group have placed emphasis on
the adequacy of admission notes and the documentation
of the subsequent course of illnesses, reporting that the
poor quality of notes seen initially on audit quickly
improves and that a high standard is maintained[9]. Such
changes are limited to 'audit-wise' clinicians[ 10], as in
our present study. We would support the view that
regular audit is helpful in the development and mainten-
ance of good clinical standards, and have instituted in the
geriatric unit regular audit meetings modified from the
Birmingham model. We further suggest that assessment
of mental function is an important aspect of the manage-
ment of elderly patients, and our study has shown
improved identification of mentally impaired subjects
simply as a result of audit. However, to sustain such
improvement in the longer term may also require more
positive educational measures[6]. As a first step, we
recommend that copies of a mental test score are available
on all wards dealing with elderly patients, and that
consultants ask their junior staff the results of such tests
? in the knowledge that successful treatment, rehabili-
tation and discharge of mentally impaired elderly may
prove difficult, particularly where impairment is unrecog-
nised.
References
1. Langley, G. E. and Simpson, J. H. (1970) Gerontologia Climca, 12,
149.
2. Leif, C. and Thogren, K. (1982) Lancet, 2, 1097.
3. Hodkinson, H. M. (1973) Journal of the Royal College of Physicians of
London, 7, 305.
4. College Committee on Geriatrics (1981) Journal of the Royal College of
Physicians of London, 15, 141.
5. Gruer, R., Gordon, D. S., Gunn, A. A. and Ruckley, C. V. (1986)
Lancet, 1, 23.
6. Mitchell, M. W. and Fowkes, F. G. R. (1985) Journal of the Royal
College of Physicians of London, 19, 251.
7. Hodkinson, H. M. (1972) Age and Ageing, 1, 233.
8. Denham, M.J. and Jeffreys, P. M. (1972) Modern Geriatrics, 2, 275.
9. Heath, D. (1980) Journal of the Royal College of Physicians of London,
14, 200.
10. Heath, D. (1981) Journal of the Royal College of Physicians of London,
15, 197.
270 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
|
PMC005xxxxxx/PMC5371045.txt | ?)
Research on Healthy Volunteers
A REPORT OF THE ROYAL COLLEGE OF PHYSICIANS
Members of the Working Party
Sir Raymond Hoffenberg (Chairman)
Dr W. van't Hoff (Honorary Secretary)
Dame Elizabeth Ackroyd
Sir Douglas Black
Mr I. Dodds-Smith (Legal Adviser)
Dr V. Dubowitz
Dr R. E. Gillon
Dr M. J. S. Langman
Dr D. R. Laurence
Dr P. Richards
Dr K. B. Saunders
Dr E. S. Snell
Dr J. D. Swales
Dr D. A. J. Tyrrell
Observer from the Medical Research Council
Dr Barbara J. Rashbass
In attendance
Dr D. A. Pyke (The Registrar)
Mr G. M. G. Tibbs (The Secretary)
Miss Alice Overton (Committee Secretary)
Miss Ann Cowell (Committee Secretary)
Mrs Janet Vernon (Secretary to the Hon. Secretary)
Contents
Page
Introduction 244
Justification for Research on Healthy Volunteers 244
Description of a Healthy Volunteer 245
Definition of Risk 245
Recruitment and Selection 245
Special Groups
Women 246
Children 246
The Elderly 247
The Mentally Handicapped 247
Prisoners 247
Students 247
Junior Colleagues 248
Other Groups 248
Financial and Other Inducements 248
Safeguards 248
Design and Protocol 249
Ethics Committees 250
Consent, Contract and Liability 251
Personal Insurance 252
SUMMARY OF RECOMMENDATIONS 253
APPENDICES
1. Check list for healthy volunteer consent and
contract forms 254
2. Oral Evidence 255
3. Written Evidence 256
4. Edited abstracts of the Royal College of
Physicians Guidelines on the Practice of Ethics
Committees in Medical Research. 256
BIBLIOGRAPHY
257
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 243
Introduction
This Working Party was set up in April 1984 at the
request of the Medicines Commission which had become
concerned about the testing of new drugs on healthy
volunteers. We are aware of and uneasy about the
growing commercial interest in the establishment of units
doing drug research, not only in private institutions, but
also in university and National Health Service (NHS)
premises. It appears that early drug development studies
on healthy volunteers have increased in volume over
recent years. A factor in this may be the belief in industry
that the Licensing Authority will look more favourably on
applications for a Clinical Trial Certificate (CTC), or for
an exemption from the need for holding such a Certificate
(CTX), if studies on large numbers of healthy volunteers
form part of an application, rather than the small studies
precisely designed to produce essential information for
scientific and regulatory purposes. The Licensing Au-
thority should consider this matter and should state
clearly its policy regarding the role and scope of drug
studies on healthy volunteers in the development of
medicines.
Although the primary stimulus for this Report came
from the Medicines Commission's concern about the use
of drugs, we decided to examine research on healthy
volunteers in general and not to confine ourselves to
pharmacological studies. Thus the Report also covers
products that might be used in surgery and diagnostic
procedures as well as drugs. Our deliberations have been
independent of the Medicines Commission and our Re-
port reflects views taken after receipt of written and oral
evidence from a wide selection of individuals and organi-
sations. Previously published documents and guidelines
(see Appendix 3 and Bibliography) have been helpful.
We accept and emphasise the need for research on
healthy volunteers, but we are concerned about their
health, their safety and their rights.
We have described the healthy volunteer, defined the
possible risks, and the safeguards required for the subject
and for the investigator. Safeguards for the healthy
volunteer are concerned with selection, consent, conduct
of the research and compensation for any injury that may
result.
We have produced guidelines for the volunteer, the
investigator, the sponsor, Research Ethics Committees
and for all institutions where research on healthy volun-
teers takes place and have suggested a check list that may
be useful when compiling healthy volunteer consent and
contract forms (Appendix 1). We have also made sugges-
tions regarding compensation for injury. These guide-
lines should be read in conjunction with the Royal
College of Physicians Guidelines on the Practice of Ethics
Committees in Medical Research (1984), edited abstracts of
which appear in Appendix 4.
In this Report we make specific recommendations
about various aspects of research on healthy volunteers.
In many cases we have not provided detailed solutions or
mechanisms for their implementation. For instance, we
recommend that clinical research departments of com-
mercial organisations be subject to external scrutiny, and
that there be a register of approved institutions; but we do
not specify who might take on this responsibility.
Justification for Research on Healthy
Volunteers
Most research into disease is done on patients rather than
on healthy volunteers and is therefore outside the scope of
this Report. Research on healthy volunteers, however, is
required in order to gain knowledge in two main fields.
Physiology and Psychology
Further knowledge of human physiology and psychology
is important in its own right and also because it increases
understanding of disease. Research may be by obser-
vation or experiment. The latter may involve simple
procedures such as measuring heart rate or blood press-
ure before and after exercise, taking blood samples, or
more complex and invasive procedures such as catheteri-
sation of blood vessels or muscle biopsy.
Similarly, psychological research may consist of simple
observations, tests of memory or aptitude, or more
complex experiments sometimes involving stress and
emotion.
Observations on healthy volunteers play an important
part of medical and scientific training.
Drugs and Medicines, Cosmetics and other Substances
New drugs intended for use in man ultimately need to be
tested in man to discover whether they are effective
medicines, because the response to drugs in humans may
be different from that in laboratory animals. Further,
effects on, for example, mood and sleep are difficult to
assess in animals. It is, therefore, essential to discover at
an early stage the dose range, possible side effects and
short-term tolerance of a drug in humans.
It could be argued that it is more ethical to test drugs on
patients who might stand to benefit rather than in healthy
volunteers, but there are advantages in doing initial
(Phase I) studies on healthy volunteers. In healthy per-
sons there is less physiological variation and their re-
sponses are likely to be more uniform. Healthy persons
are often better able to collaborate in more complex
experiments, and the ethical dilemma of starting treat-
ment with an inadequate dose (e.g. in acute infections),
or of stopping or withholding potentially effective treat-
ment does not arise.
In cases where harmful effects of a drug may be
anticipated at therapeutic dose levels it is unethical to use
healthy volunteers. With certain drugs such as those used
for cancer or leukaemia, it is more ethical to undertake
initial studies on patients who may stand to benefit.
Cosmetics and other substances, e.g. domestic washing
powders, used on or by man, may need to be tested on
healthy volunteers and so come within the scope of this
Report. It is useful in this context to refer to the 1982
Report produced by the Committee on Toxicity of the
Department of Health and Social Security, Guidelines for
the Testing of Chemicals for Toxicity.
244 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
Description of a Healthy Volunteer
Although the definition may at first sight appear to be
obvious, we think it important to define what we mean by
a healthy volunteer in the context of research.
A healthy volunteer is an individual who is not known
to suffer any significant illness relevant to the proposed
study, who should be within the ordinary range of body
measurements such as weight, and whose mental state is
such that he is able to understand and give valid consent
to the study.
Although it may be scientifically appropriate to use
patients as control subjects for a condition from which
they do not suffer, they should still be regarded as patients
and not as healthy volunteers. Many patients have a sense
of obligation towards doctors, particularly those respon-
sible for their treatment, that could influence them to take
part in a study which in other circumstances they might
decline. Great care should be taken when recruiting
volunteers from patients in or attending a hospital or
other medical institution, and Ethics Committees should
pay particular attention to this.
On the other hand we see no reason why a volunteer,
who is found incidentally to have an abnormality, such as
congenital displacement of the hip, should be excluded
from a study that is not related to this disorder. However,
a subject in remission from a relapsing condition such as
bronchial asthma cannot be a healthy volunteer for a
study relating to that condition, and should be regarded
as a patient volunteer for studies involving the immune or
respiratory systems. Furthermore, such a subject should
not be enrolled as a healthy volunteer for other studies in
which there is any risk of affecting or precipitating the
condition.
Definition of Risk
Any activity or even inactivity is associated with some
risk, and we accept a concept of minimal risk in healthy
volunteer studies. A risk greater than minimal is not accept-
able in a healthy volunteer study.
In some procedures, studies or experiments, the risk is
so small that it can be ignored. We would equate this with
the sort of risk accepted in everyday life. In medical terms
we include here simple physiological experiments involv-
ing exercise, e.g. on students, procedures such as collect-
ing urine, taking measurements of height and weight, or
a single venous blood sample.
In more complex or invasive physiological and phar-
macological studies it is helpful to consider not only the
seriousness of an adverse effect that might result from a
procedure, but also the probability of it happening. We
therefore use the term 'minimal risk' to cover two types of
situation.
The first is where there is a small chance of a recog-
nised reaction which is itself trivial, e.g. a headache or
feeling of lethargy. The second is where there is a very
remote chance of a serious disability or death.
We regard this second risk to the healthy volunteer as
comparable, for example, to that of flying as a passenger
in a scheduled aircraft.
Before new chemical entries are administered to
healthy volunteers, they are first examined by pharmaco-
logical and toxicological studies in animals. Thus only
substances of low toxicity and so predicted to have low
hazard are given to healthy volunteers. Furthermore, the
experimental design of studies on new drugs requires
them to be administered in low and graded doses, and so
the risk to the volunteer is minimal. In studies of
established drugs, the drug will have been tested in
animal experiments and already administered to many
patients. With many such drugs the risk may be regarded
as minimal, provided that the proper procedures and
adequate safeguards are followed.
The Guidelines of the British Psychological Society
(BPS) state: 'Where it is reasonable to suppose that
research procedures may result in undesirable conse-
quences for participants, psychologists have a responsi-
bility to detect and remove or correct these consequences
including, where relevant, long-term after effects.' While
accepting this responsibility to treat affected subjects, it
would be wrong to take the words 'reasonable to suppose'
as justifying research procedures with more than trivial
risk. The Guidelines of the British Psychological Society
should be consulted whenever psychological research is
undertaken and both we and the BPS believe that experi-
ments that cause more than minimal anxiety, distress,
lowering of self-esteem or long-term harm should be
avoided.
Recruitment and Selection of Volunteers
Volunteers for physiological and other class demonstra-
tions or experiments usually come from within a teaching
department and are normally invited to participate by the
head of the deparrtment or his deputy. Most of these
experiments are for teaching students, and we consider it
reasonable and ethical for students to be recruited in this
way as they have been for a century or more. Class
teaching experiments or demonstrations involving
healthy volunteers should be approved by a Research
Ethics Committee. Once this has been done it is not
necessary for further approval to be sought each time the
same demonstration is repeated, but the decision might
be reviewed at intervals, perhaps every five years.
Recruitment of healthy volunteers for research projects
may involve conscious or subconscious pressures both on
the investigator and the volunteer. For the investigator
there are obvious advantages in ease and availability in
using volunteers within the department, faculty, com-
pany or other organisation. The motives that prompt
people to volunteer are various. They may be scientific or
idealistic but investigators should be aware of and try to
minimise factors such as the desire to please or not
wishing to displease possible patrons, to gain favourable
notice or promotion. Financial incentives in particular
may over-persuade individuals, including students, who
have low incomes, and may promote the 'professional
volunteer'. There should, therefore, be no coercion, overt
or covert, of anyone to volunteer for research, whether
the pressure be financial, for academic or employment
advantage, for job security, or for other reasons. Initial
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 245
recruitment should be through circulars, notices or an-
nouncement to groups and not by individual approach.
The amount of any financial reward should not be stated
on the initial notice.
In the case of a university department, staff of the
department may reasonably be invited to volunteer for
studies, and it is common practice for the clinical pharma-
cology departments of large pharmaceutical companies to
use volunteers from within the company. We consider it
reasonable for these practices to continue under supervi-
sion of Ethics Committees and there may well be advan-
tages to subjects and to research in forming groups of
volunteers who are willing to participate regularly, will be
under particularly close supervision, and who will be
informed to a relatively high level. Psychological experi-
ments are referred to on page 251.
All departments or institutions where research on
healthy volunteers is conducted should keep careful re-
cords and avoid excessive use of any volunteer. It is
difficult to stipulate the maximum amount any individual
should volunteer because of the variety of procedures and
drugs involved, but no person should take part in more
than one study at a time. Account should be taken of
factors such as the total time spent in any one year, the
total exposure to drugs, and the total volume of blood
taken in a year (not normally more than 1.5 litres in men
and 1.0 litre in women).
We recommend that healthy volunteers who partici-
pate in drug trials more than once should be provided by
the investigator with cards or booklets which record
details of the studies in which they took part. If conscien-
tiously completed by the investigator and shown to the
next investigator, such a record would safeguard the
volunteer. The proposal would also apply to the adminis-
tration of radioactive substances for which there are safety
limits. We have considered the desirability of a central
register but think the logistic problems would outweigh
any potential benefits.
The method of recruitment and source of healthy
volunteers should be included in the study protocol
submitted to the Ethics Committees.
In Britain there is a long tradition of investigators
doing research on themselves. We would not wish to
discourage this, but anyone who desires to experiment
upon himself should seek the guidance of the Ethics
Committee before doing so. If any other individual is to
participate, e.g. by administering a drug or test, this also
should be approved by the Ethics Committee.
Special Groups
Special consideration needs to be given to certain groups
of volunteers and some of these are outlined below.
Women
A study which could be harmful to pregnancy should be
avoided in women of child bearing potential, and particu-
lar care should be taken in studies involving radioactivity
in women. Women of childbearing potential should not
normally be accepted as healthy volunteers in initial
pharmacological studies without special consideration by
an Ethics Committee.
Children
In law, individuals below the age of 18 years are regarded
as children or minors. The Family Law Reform Act 1969
states that the consent of a minor who has attained the age
of 16 years to medical treatment is as effective as it would
be if he were of full age and it is, therefore, not essential to
obtain consent from his parent or guardian for a thera-
peutic procedure.
The position regarding younger children was unclear
until the recent House of Lords ruling (Gillick 1985)
which stated that the parental right to determine whether
or not their child below the age of 16 would have medical
treatment terminates if and when the child achieves
sufficient understanding and intelligence to enable him to
understand fully what is proposed.
Therefore, if a child is capable of understanding what is
proposed there is no reason why he cannot give legally
valid consent and authorise medical examination or
treatment. Nevertheless, the Court noted that it would be
'most unusual' for a doctor to treat a child under 16
without the approval of his parent or guardian.
The specific issue of parental consent with regard to
research on a healthy child has not been considered by the
courts but is probably covered by the wider principle that
a minor's capacity to make his own decision depends
upon the minor having sufficient understanding and
intelligence to make that decision and is not to be
determined by reference to any judicially fixed age limit
(Gillick 1985). It is therefore appropriate to consider the
procedure to adopt depending on whether a healthy child
is or is not considered able to give legally valid consent to
a research procedure.
Children competent to give consent
Even if an investigator believes that a child is capable of
giving legally valid consent we advise that the approval of
a parent or guardian should still be obtained before any
research procedure is contemplated on a healthy child
under the age of 16 years, and preferably under the age of
18 years.
Details of the research procedure, including any dis-
comfort involved, should be explained in terms capable of
being understood both by the parent or guardian and by
the child. We advise that the older child, as well as the
parent of guardian, should sign a consent form for more
than trivial procedures. Objection to taking part in a
research procedure either by such a child or his parent or
guardian should always be respected.
Children not competent to give consent
The position of the child who does not have the under-
standing and intelligence to make such a decision is less
clear. The investigator must look to the parent or guard-
ian for consent to proceed but the question arises as to
whether a parent can properly consent in law to his child
246 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
being subjected to a procedure which carries no prospect
of direct benefit and some (if only minimal) risk. The law
is unclear, but the prevailing view appears to be that the
duty of a parent to act in the best interests of the child can
reasonably be interpreted as an obligation not to do
anything clearly against the interests of the child. This
seems sensible to us and we believe that where the
research is for the benefit of children generally, and the
child is incapable of giving legally valid consent, the
investigator can properly rely upon the consent of a
parent or guardian. If, when the parental approval has
been obtained, a child were to object to the procedure
itself, e.g. taking a blood specimen, the investigator and
the parent or guardian should reconsider whether it
would be appropriate for the procedure to be undertaken.
In the past, doubt about the legal position has inhibited
research on children, but the British Paediatric Associ-
ation Guidelines (1980) now accept the need for non-
therapeutic research on children which benefits other
children, although research which could equally well be
done on adults should never be done on children. We
agree with this because research that may add to our basic
biological and psychological knowledge, such as the es-
tablishment of reference ranges, and thereby benefit other
children, can only be done on children.
Pharmacological studies on healthy children should on
the whole be avoided. In the case of a drug to be used in
children, appropriate studies should be done on adults
first unless scientifically valid results can only be obtained
by the inclusion of children.
There must be no financial or other reward either to
the parent or guardian, or to the child, although reim-
bursement of expenses is obviously acceptable.
As in all research on healthy volunteers, projects should
be approved by an Ethics Committee, and when children
are involved particular attention should be paid to the
issues outlined above.
The Elderly
There are some inherent problems in carrying out re-
search in the elderly. For example, it is difficult to
establish the criteria for health in older people and to
determine their mental ability to give valid consent
initially and thereafter to withdraw it if appropriate. Also,
the effects of drugs and their metabolism in the body may
be different in the elderly. However, it may be appropri-
ate to conduct in the elderly physiological or pharmaco-
logical studies relevant to their age providing particular
care is taken to confirm their fitness for the proposed
study. It may be important to study a drug in the elderly
if it is likely to be used as a medicine in this age group.
Pharmacological studies on the elderly who do not need
the drug should on the whole be avoided unless the re-
quired information cannot be obtained from other sources
such as elderly patients or younger healthy volunteers.
The Mentally Handicapped
Special consideration needs to be given to mentally
handicapped subjects, who are not always patients, and
who will frequently not be able to give valid consent. As
with children, studies should not be done in the mentally
handicapped if they could be done in any other group.
Research that is likely to benefit or prevent mental
handicap, and is only possible in mentally handicapped
people, would be ethical provided precautions like those
outlined in the section on 'children' were taken, even
when the subject is adult.
The present legal position would appear to be that a
relative cannot give a legally valid consent on behalf of an
adult who is unable at the time to give consent because of
mental disability. It is prudent in all circumstances for
research proposals to be discussed with the volunteer's
immediate family.
Prisoners
In the past, prisoners in Britain have not normally been
invited to participate as healthy volunteers in research but
we do not consider it inherently unethical to carry out
research on prisoners. There might be a reason to believe
that a certain hormonal, genetic, psychological or other
condition was associated with violence or other pattern of
behaviour likely to lead to criminal action. It would be
reasonable to study such a condition in prisoners as they
constitute a group likely to be relevant to the study. All
the usual safeguards, which include obtaining valid con-
sent, would apply and Ethics Committees might need to
take special advice. Particular care needs to be taken to
avoid coercion in any form including any impression that
inducements such as reduction of sentence or pardon or
other favours could be given. Nevertheless we appreciate
that there is no precise point where a recompense be-
comes an inducement. It should also be appreciated that
for some prisoners the opportunity to contribute positive-
ly to the well-being of society may be of help in re-
establishing self-esteem and therefore in rehabilitation.
Students
Students are likely to volunteer as subjects for research for
various reasons. Sometimes they are motivated by scienti-
fic interest and they may have much to gain in terms of
knowledge and experience from taking part in research
projects. Financial reward may be an added incentive or
even the sole motive. As students are normally young,
healthy, numerous, and have low incomes, they are easily
recruited by university departments and other organisa-
tions. They are, however, particularly vulnerable to
academic, personal and financial pressures. They may
also be tempted to spend more time than is desirable away
from their studies.
Unless the study is educational it is normally undesira-
ble to recruit students who are in close contact with the
investigator, e.g., on his medical teaching 'firm' or in his
class. This is because students are, or may feel, vulner-
able to pressure from someone in a position to influence
their careers, by assessment in an examination or other-
wise. Ethics Committees should be aware of and pay
particular attention to this. When students of an institu-
tion are recruited for other than educational studies, the
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
Dean of that institution or other designated person should
be informed in writing and the student should be aware of
this. The information given should include details of the
research project, the names of those taking part and
which Ethics Committee has approved the study.
Junior Colleagues
It is a time honoured and well-established practice for
junior colleagues to co-operate with their seniors in
research. When the research involves volunteers this may
include doing studies on each other. In this context the
junior colleague is in a vulnerable position, on the one
hand because of overenthusiasm, and on the other be-
cause any lack of eagerness to participate might be
thought to prejudice his future career.
The Ethics Committee should be made aware of the
fact if colleagues are involved as subjects in research.
Other Groups
Volunteers may be recruited from other groups and there
is no reason, for instance, why unemployed people should
not be invited to volunteer for research. Financial re-
wards are likely to be a particular incentive for them,
however, and care needs to be taken that they to not take
part in an excessive number of studies.
Volunteers in the armed or other Services might also be
subject to coercion and this again should be guarded
against. There may, however, be good reasons for re-
cruiting healthy volunteers in the armed forces, e.g. in
experiments designed to help servicemen in action.
Financial and Other Inducements
There is a long tradition that both investigators and
healthy volunteers in research are motivated by the desire
to advance knowledge and help society and this spirit of
altruism is to be admired and encouraged.
Students, particularly in the medical and psychological
sciences, frequently take part in experiments in the course
of their training where the prime object is to enable them
to make their own observations. This we regard as
educational and entirely acceptable.
However, many studies, particularly in pharmacology,
are lengthy and tedious, and may involve urine collec-
tion, multiple venepunctures or other procedures associ-
ated with some discomfort. It is reasonable that
volunteers in this type of research should be paid, over
and above reimbursement of expenses incurred. These
payments are for inconvenience or discomfort and in-
creased payments may be reasonable for procedures
requiring extra care on the part of the subject or involving
more discomfort.
Payments should never be for undergoing risk. Payments
should not be such as to persuade people to volunteer
against their better judgement, nor to induce them to
volunteer more frequently than is advisable for their own
good. While appreciating that any given sum would be
viewed differently by a student or person who is unem-
ployed than by a person in full paid employment we
suggest that payment should range somewhere between
rates equivalent to current student grants and a daily rate
equivalent to the average wage, but time involved and
inconvenience incurred should be taken into consider-
ation. All payments to volunteers should be approved by
the Ethics Committee.
When a volunteer withdraws for medical reasons re-
lated to the study full payments should be made. When
the volunteer leaves the study and exercises his right not
to give a reason or is required to leave for non-compli-
ance, no payment need be made if the consequences of
leaving the study in these circumstances have previously
been explained to him. If a volunteer withdraws for other
reasons, including non-related medical reasons, the in-
vestigator or sponsor should make a proportional pay-
ment.
Some investigators receive personal payment, or mem-
bers of their staff, the department, or laboratory equip-
ment may be funded by a sponsoring company or other
organisations. Any or all these payments should also be
disclosed to the Ethics Committee. This is commented on
in the Royal College of Physicians Report on The Re-
lationship between Physicians and the Pharmaceutical Industry.
(1986, J.Roy.Coll.Physic 20, 235)
Safeguards
It is the responsibility of the investigator to confirm that a
volunteer is healthy. How detailed this confirmation
requires to be depends on the type of study. When using a
volunteer in minor procedures such as a simple physiol-
ogy class demonstration or equivalent research it is
normally adequate to accept the volunteer's assurance
about his health.
A more thorough assessment of the volunteer's health
is required in more complex studies including most
pharmacological studies. When giving consent the volun-
teer should state that as far as he knows he is in sound
physical and mental health and should give details of any
previous medical history. It is advisable to inform the
volunteer's general practitioner and in industry the medi-
cal officer of the company or institution. This is to let a
doctor know that his patient has volunteered for a
particular study and to obtain, if approriate, any past
medical history that could, for instance, increase the risk
of his participation. The volunteer's agreement is re-
quired for this and if he does not agree it would be wise
not to use him. A history of smoking, alcohol or other
drug consumption should be obtained from the volunteer.
He should also be asked if he is taking any medicines,
whether prescribed or not and if he has participated in
any previous studies. Where appropriate the volunteer
should be medically examined and relevant blood or other
tests, e.g. a cardiogram, should be performed. These tests
would normally comprise a blood count and routine
biochemical analysis, but screening for alcohol and other
drugs may sometimes be advisable. If any tests shows an
abnormality that could be associated with an increased
risk for the individual if he participated in the study, the
volunteer should be excluded. Where appropriate, safe-
guards regarding communicable diseases should be taken
to protect the volunteer, the investigator and his staff.
248 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
Further examination and tests may need to be done
after the study. If at any time a significant abnormality is
discovered the volunteer's general practitioner should be
informed. The volunteer should have agreed to this in
advance of the study; and he should also have given
consent if it is the intention or if it is advisable to inform
anyone else, e.g. the medical officer of a company or
other institution.
The volunteer should be provided with a written
account of the study describing simply and clearly what is
involved, including risks that may be incurred and the
probability of their occurrence. The degree of supervision
required and the suitability of premises and equipment
where research takes place should depend on the type of
study and risk involved. The Ethics Committee should
always consider whether a suitably qualified medical
person should supervise and be responsible for a study.
This would be desirable particularly for drug studies and
invasive procedures.
Further safeguards may be required in studies using
drugs that are new chemical entities or new combinations
of established drugs. Where there is any possibility of
serious adverse reactions there should be facilities for full
resuscitation including appropriate drugs, a cardiac defi-
brillator and apparatus for intubation and assisted venti-
lation. The medical and ancillary staff should be trained
and experienced in resuscitation and for some types of
study further medical help and intensive care facilities
should be available within a few minutes.
In some circumstances (see p246) we recommend that
volunteers carry a booklet stating the nature of the study,
any drugs that have been taken, and the name of the
investigator or other appropriate person to contact should
this be necessary. If at any time a healthy volunteer
develops more than a minor reaction the investigator
should stop the study in that individual and consider
whether it is advisable to stop the whole study. As well as
informing the Ethics Committee and the volunteer's
general practitioner the investigator should, where neces-
sary, take appropriate action to safeguard the volunteer's
health.
All laboratories or other places where studies are
performed on healthy volunteers, whether they may be in
university or other academic departments, in NHS hospi-
tals, pharmaceutical companies or contract companies,
should be open to inspection in order to assure all
concerned that high standards are maintained and the
guidelines in this Report are followed. In the case of NHS
hospitals university and other academic departments we
think this inspection could, where necessary, be done by
or on behalf of properly constituted Ethics Committees.
These Committees should consider carefully whether it
might not be advisable for units carrying out substantial
and sustained research on healthy volunteers (particularly
departments investigating drugs under development) to
be inspected.
Clinical research departments of pharmaceutical com-
panies, contract companies and other commercial institu-
tions that perform research on healthy volunteers should
be subject to external scrutiny as they are vunerable to
criticism because of commercial pressures.
We further recommend the establishment of a register
of all commercial institutions approved as maintaining
appropriate standards.
Design and Protocol
Research involving healthy volunteers should conform to
the same ethical standards that apply to all medical
research, as indicated in the Royal College of Physicians
Guidelines on the Practice of Ethics Committees in Medical
Research (1984). There should be an intention to benefit
society by doing research, and also an obligation to
protect subjects of research from harm, and to preserve
their rights. Since healthy volunteers will not benefit
medically from their participation it is particularly im-
portant to respect their autonomy, right of self determi-
nation and safety.
All research on healthy volunteers should be based on
sound scientific principles, should not involve more than
minimal risk and should be conducted or supervised
where necessary by a qualified medical person with the
training and experience appropriate to the particular
study.
Before stating the present position of a healthy volun-
teer in drug studies it is useful to consider the scope and
limitation of the Medicines Act (1968). The Act regulates
medicines, and does not use the term 'healthy volunteer'.
It is concerned with 'medicinal products' administered
for a 'medicinal purpose' (this includes contraception and
anaesthesia) and excludes from its concern any substance
that is administered by or on behalf of a manufacturer
'solely by way of a test for ascertaining what effects it has
when so administered', and 'in circumstances where the
manufacturer has no knowledge of any evidence that
those effects are likely to be beneficial to human beings'.
Therefore the administration of a contraceptive to a
healthy person and the administration of a drug to
prevent heart attacks would both have a 'medicinal
purpose'. The subject would be treated as a patient and
the administration would be regulated by the Medicines
Act. But the administration by (or on behalf of) a
manufacturer of a drug to healthy people to find out what
it does to the blood pressure or blood sugar would not be
controlled by the Act because it is not regarded as the
administration of a medicinal product since there is no
medicinal purpose. Thus the majority of drug studies on
healthy volunteers are excluded from regulation under
the Act. Under the Act, a medicinal product cannot
normally be supplied by a manufacturer for the purposes
of a clinical trial (in patients) unless the manufacturer has
applied to the Licensing Authority for a Clinical Trial
Certificate (CTC) or for exemption from the need to hold
such a Certificate (CTX). In either case submission of
details of laboratory studies in animals (pharmacology,
including studies on absorption, distribution and elimina-
tion, and appropriate studies on safety, including acute
and chronic toxicity and mutagenicity) is usually re-
quired. There are special provisions for investigators to
obtain clearance where they wish to carry out studies on
patients other than on behalf of a manufacturer or other
third party.
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 249
Therefore in the case of almost all healthy volunteer
studies there is currently no statutory requirement for
such prior laboratory work to be done or assessed inde-
pendently, although the common law duty to take proper
care almost certainly imposes an obligation to do such
work, indeed the Association of the British Pharma-
ceutical Industry (ABPI) has advised its members that the
same background work and information should be avail-
able before healthy volunteer studies are undertaken.
We take the same view as the ABPI but recommend a
further safeguard. Although we are aware of problems
caused by delay and of the extra work it will involve, we
recommend that proposals for all drug studies on healthy
volunteers involving new chemical entities and new com-
binations of drugs should be reviewed independently.
This is because Ethics Committees need assurance on the
adequacy and appropriateness of the highly specialised
preclinical laboratory studies both with regard to safety
and potential efficacy, in the assessment of which they
themselves do not usually have the necessary expertise.
The DHSS Medicines Division would appear to be a
suitable organisation to undertake this review, and the
CTX scheme under the Medicines Act (1968) provides a
possible model.
The protocol of any research of any project involving
the use of healthy volunteers should give full details of the
scientific background and the objectives of the study. It
should give the number, age and sex of volunteers
required and how they are to be recruited. It should give
details of how the study is to be performed, where it is to
be done, and where appropriate, the arrangements for
emergency medical care. Volunteers should give valid
consent and should also be told that they may withdraw
from the study at any time without giving a reason. The
protocol should also state what financial arrangements
have been proposed including payment of compensation
to a healthy volunteer in the event of accident, injury or ill
health during the course of or following the study.
If a volunteer drops out of a study, for whatever
reason, the investigator should take reasonable steps to
find out whether harm has come to him as a result of his
participation, e.g. by keeping in touch with the volunteer
for an appropriate time.
Some psychological research involves deception of the
subject and would be invalid were this not so. The
deception that is considered necessary in a study should
not involve the volunteer in any risk, nor should healthy
volunteers be deceived about any possible risk caused by
participation in a psychological research project. Possible
risks are unexpected anxiety or distress, lowering of self
esteem, or any form of long-term psychological or physi-
cal harm. Deception on any aspect that might affect the
subject's willingness to participate is as unacceptable in
psychological as it is in any other kind of research.
Ethics Committees
All research, studies and experiments on healthy volun-
teers must have been approved by an Ethics Committee.
Ethics Committees should be properly constituted and
should follow the 'Guidelines on the Practice of Ethics
Committees in Medical Research' issued by the Royal
College of Physicians in 1984.
Most universities, medical schools and larger hospitals
already have properly constituted Ethics Committees. It
is essential that research at all hospitals, academic institu-
tions, pharmaceutical companies and any other institu-
tions undertaking research on healthy volunteers should
be supervised by such a Committee and that independent
lay and scientific judgement should be available. Some
drug studies on healthy volunteers are done by contract
companies unassociated with universities, hospitals or
pharmaceutical companies. It is important that these
studies should be made subject to the same conditions and
scrutiny.
It is the responsibility of the investigator to ensure that
any proposed research on healthy volunteers is considered
by an Ethics Committee. If a small company or institu-
tion has difficulty in obtaining assessment of its research
by a local or regional Ethics Committee we suggest it
should seek the advice of the Committee on Ethical Issues
in Medicine of the Royal College of Physicians of Lon-
don.
The Ethics Committee should satisfy itself that studies
are scientifically sound because this is an essential ingre-
dient of ethical research. It should also ensure that
volunteers are fully aware of the details, implications and
possible risks of a study and are able to give valid consent.
The Committee should also satisfy itself that there is
adequate provision for compensation independent of
proof of negligence in case of injury or illness arising from
the study. The Committee should be made aware of
payments made not only to healthy volunteers, but also to
the investigator, his staff or department, including grants
for equipment, travel, etc.
In studies involving drugs, the Ethics Committee needs
to ensure that pharmacological and toxicological data
have been properly appraised. New chemical entities and
combinations of drugs pose special problems (see page
250). If the Committee does not have the necessary
expertise to evaluate the scientific merit of proposals it is
advisable to obtain expert advice or co-opt suitably
qualified and informed persons. An Ethics Committee
might also have difficulty in deciding on moral issues
when considering studies involving groups such as prison-
ers, children or the mentally handicapped. Here again the
Committee would be well advised to seek advice or co-opt
a person with special experience of such groups.
Ethics Committees should be informed promptly of any
significant untoward event occurring in the course of a
study, and be consulted about material changes in a
project. They should be told when a project is completed,
and see resultant publications.
It is desirable that Ethics Committees should be made
aware of any significant ethical problems involving re-
search on healthy volunteers that arise in this country and
elsewhere, whether or not they have been reported in the
medical journals or press. Consideration should be given
to the possibility that the Committee on Ethical Issues in
Medicine of the Royal College of Physicians of London
should take responsibility for supplying Ethics Commit-
tees with relevant information that comes its way.
250 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
We understand that the British Psychological Society is
unwilling to accept that psychological experiments should
be scrutinised by Ethics Committees which do not include
at least one properly qualified psychologist as a full
member. While we have some sympathy with their views,
and realise that they accept the general principal of
independent scrutiny of such experiments, we think that
such review should take place in precisely the same way as
for other experiments using healthy volunteers.
Consent, Contract and Liability
By implication a volunteer taking part in an activity
has given consent, but before agreeing to participate in a
research project it is important that the volunteer should
be properly informed and have given valid consent. In the
present state of the law we believe that the investigator's
obligation in this regard is to explain in understandable
terms the nature and purpose of the study and to provide
sufficient information and advice on possible risks to
which the volunteer is exposing himself so as to give
meaning to the volunteer's right to self determination. In
practice this means that the investigator must disclose the
risks he believes, as a matter of professional judgement,
are material to the volunteer's decision on whether to
participate or not, and all other information that might be
considered relevant. Even a remote risk is important to a
healthy person who does not stand to gain any compen-
sating benefit from the study.
As well as being told about possible risk the volunteer
should be aware of other relevant details of the study,
such as its duration and what is required of him, whether
this be taking exercise, drugs, having blood tests or other
procedures. He should also be told whether any intended
procedures will be associated with discomfort and
whether there are any restrictions on, say, driving or
drinking alcohol. He should be assured of confidentiality,
and the financial reward, if any, should be clearly stated.
We recommend that all relevant information about a
project be given to the volunteer in writing, preferably as
a Subject Information Sheet. Ethics Committees should
decide when written information could be dispensed with,
e.g. for trivial studies.
Only when the volunteer has been so fully informed by
the investigator do we believe that the ethical and legal
requirements have been met. Although not essential in
law, it is usual and desirable, except in trivial cases, that a
consent form be signed by the volunteer, and the investi-
gator should state that he has explained the nature of the
investigation to the volunteer. It is useful if the Subject
Information Sheet and the consent form are kept
together.
Having agreed to participate, a volunteer also has a
commitment. He should disclose his full medical history,
comply conscientiously with the protocol, and report any
symptoms that may occur during or after a study. On the
other hand, as already stated (p.250), he should know he
can withdraw from the study at any stage without giving a
reason.
The healthy volunteer will also need to know what his
position is in the event of an accident, injury or the
development of ill health as a result of having taken part
in the research project. The current strict legal position is
that an individual in this situation is only entitled to
compensation if he can show there was negligence on the
part of the investigator, the institution where the study
took place, the sponsor of the research or their respective
staff. (We are aware that the position may change in the
light of the EEC Directive on Product Liability, 1985).
This puts the onus on the volunteer and could make the
investigator an adversary; the volunteer has no legal
redress if he is unable to show negligence. However
carefully a research project has been planned and carried
out, the possibility of an unforeseen event resulting in
injury or ill health and not due to negligence, can never
be eliminated. In the case of research conducted in and
sponsored by universities, National Health Service hospi-
tals, Medical Research Council and other establishments
the healthy volunteer is then dependent on an ex gratia
payment. We believe that universities and other institu-
tions should make binding commitments to provide com-
pensation, because we consider it unacceptable that a
healthy volunteer should have to rely on an ex gratia
payment.
A similar conclusion was arrived at both by the Royal
Commission on Civil Liability and Compensation for
Personal Injury (Cmnd 7054)?the Pearson Report,
March 1978?and by a Ciba Foundation Study Group,
Medical Research: Civil Liability and Compensation for
Personal Injury, 1980. They made, however, rather differ-
ent recommendations.
The Pearson Report recommended 'that any volunteer
for medical research or clinical trials who suffers severe
damage as a result should have a cause of action, on the
basis of strict liability, against the authority to whom he
has consented to make himself available.' (Para. 13.41).
The Ciba Foundation Study Group concluded: 'The
Group has considered the most appropriate means of
compensating participants (or their relatives) for injuries
received as a consequence of medical research. The
Group recognises that injury may occur despite the
exercise of the highest degree of skill and care by the
investigator. It recommends the establishment of a cen-
trally operated Fund to provide compensation on a no-
fault (i.e. insurance) basis.'
We are not in favour of the imposition of strict liability
by legislation because this still retains the need to com-
mence legal proceedings in order to establish responsi-
bility and determine compensation. The Ciba Group
suggested establishing a Fund provided by organisations
such as the Medical Research Council, the universities,
the DHSS, the pharmaceutical industry, the medical
protection societies and private organisations funding
research. We think a no-fault scheme is more attractive
but ultimately impractical in the special case of healthy
volunteers because the problems of funding and adminis-
tration would be unnecessarily burdensome, bearing in
mind the limited number of claims that are likely to arise.
The ABPI recommends the use of a combined consent
and contract form in which the sponsor agrees to pay
compensation independent of proof of negligence in the
event of the volunteer suffering any deterioration in
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 251
health or well being as a result of participating in their
research project, unless there was negligence on the part
of a third party. We agree in the main with the ABPI and
consider this approach should be used generally in re-
search, but we suggest further safeguards for the volun-
teer. We suggest a simple form of contract under which
the sponsoring institution or company agrees to pay
compensation for injury, accident, ill health or death
caused by participation in the research in question.
Normally causation is based on the balance of probabil-
ity. In the case of healthy volunteers the reasonable
inference should be that any unexpected injury or harm
suffered during or shortly after the study is due to
participation in the study. In marginal cases we believe
the benefit of the doubt should be given to the volunteer.
We think it is the responsibility of the institution or
organisation responsible for the research to provide com-
pensation where this is indicated. We advise them to
consider whether they are prepared to cover such an
eventuality out of existing funds or whether to take out an
appropriate insurance policy. Many organisations and
institutions already have third party liability policies that
cover negligence. We recommend that policies be ex-
tended to cover compensation payable under such con-
tracts independent of proof of negligence. The number of
claims is likely to be small and the extra insurance
premium should be acceptable. Where medical research
on healthy volunteers is undertaken by contract compan-
ies on behalf of a pharmaceutical company it should be
made clear whether the sponsor or contract company is
responsible for compensation.
If these suggestions are implemented it is important
that the organisation or institution responsible for com-
pensation be named in the protocol and the contract
form, and that Ethics Committees ensure that this has
been done. In the event of a dispute or difference of
opinion regarding a claim including the issue of negli-
gence by a third party, we advise following the procedure
suggested by the ABPI?that reference be made to an
arbitrator or arbitrators appointed by the President of the
appropriate medical Royal College, the arbitrator having
the power to consult a barrister of 10 years' standing with
regard to any issue of law including the amount of
compensation.
As the law stands, if injury or ill health occurs as a
result of failure to take care by the investigator or anyone
else, the volunteer still has the alternative of pursuing a
claim for negligence. The wording of the contract should
be such that the volunteer would not waive any existing
legal rights he might have against the organisation or
institution or any person involved in the research.
If the contract excludes the right to compensation by
the sponsor where a third party's negligence may have
caused the injury, and if there were a difference of
opinion regarding the issue of negligence, then the volun-
teer would be entitled to ask the Arbitrator to consider
whether there was any evidence to support the sponsor's
case that the injury resulted from a third party's negli-
gence. However, if the Arbitrator decided that there was
such evidence, he could not make any final ruling that the
third party was negligent or bound to compensate the
volunteer because there is no agreement that any dispute
between the third party and the volunteer shall be
determined by Arbitration. The volunteer would have to
commence legal proceedings against the third party and
the delay in resolving whether the third party or the
sponsor should pay compensation might be quite long.
We believe that a healthy volunteer sustaining ill health
or injury as a result of participation in a research project
is entitled to compensation, and also that justice requires
that the parties promoting the research so organise their
affairs that he receives this compensation without delay.
Although it is a complex area involving both insurance
practice and the law we suggest that it is reasonable to
expect the sponsor of research to undertake to pay the
volunteer independent of proof of negligence, even negli-
gence of a third party, such as the investigator. Compen-
sation could than be paid to the volunteer by the sponsor
without delay. Before giving such an undertaking, the
onus would be on the sponsor to protect his right to claim
against the other parties to the research so that if a
payment is made in circumstances where one of those
parties was negligent, the sponsor has a right to recover
the full amount of the payment, or a contribution,
depending upon the facts of the case.
As already stated, we believe it is the responsibility of
Ethics Committees to ensure that adequate arrangements
for compensation have been made before a project involv-
ing healthy volunteers is approved. In the, we hope
unlikely, event of institutions or organisations responsible
for the research either not being able to obtain appropri-
ate insurance cover, or not being prepared to underwrite
compensation themselves, then the future of research on
healthy volunteers might be in jeopardy. If this were to be
the case, thought should be given to the establishment of a
centrally operated fund as suggested by the Ciba Founda-
tion Study Group. The College is not equipped to make a
detailed proposal for such an arrangement but rec-
ommends that it be explored.
Appendix 1 set out the matters that we believe should
be considered for inclusion in the form of contract that
provides evidence of consent and other matters that have
been agreed between the volunteer and the investigator.
Obviously not all these provisions will be relevant to
every type of study, nor can our list be exhaustive given
the infinite number of special situations that might arise.
However, this check-list may be helpful to investigators
wishing to develop a consent form to suit their own
circumstances.
Personal Insurance
It is unlikely that a healthy volunteer would take out a
life, sickness or accident policy in contemplation of taking
part in medical research. It is, however, possible that he
may already have a policy. The advice we have had from
the Association of British Insurers (Life Insurance Coun-
cil) is that an existing policy is unlikely to be affected, but
that it would be prudent for the volunteer to study the
wording of his policy to see whether cover is provided in
respect of accidents arising in connection with research,
or to contact the insurance company for clarification.
252 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
More significantly, when effecting a new life or health
insurance policy the Association has advised that any
intention to participate in medical research should be
disclosed, on the grounds that such participation might
affect the insurer's attitude to accepting the proposal or
fixing the premium.
We note the views of the Association but we think it
unrealistic to expect volunteers to do as suggested, even if
so advised on a consent form. Therefore we recommend
that the Association of British Insurers should take the
broad view and advise its member companies not to treat
an intention to participate in research that has been
passed by an Ethics Committee and is considered to
involve no more than minimal risk as constituting a
material fact that must be disclosed by the healthy
volunteer.
SUMMARY OF RECOMMENDATIONS
Ethical Considerations
I. All research involving healthy volunteers should be
approved by an Ethics Committee (p. 245, 250).
, 2. All studies should be scientifically and ethically justi-
fied (p. 249, 250).
3. Confidentiality of healthy volunteers should be main-
tained (p. 251).
4. The recruitment of some groups, (e.g. students,
i women, children, the elderly, the mentally handicapped,
prisoners), raises scientific and ethical issues which should
v be given special consideration (p. 246-248).
5. If the Ethics Committee does not feel competent to
consider difficult scientific data or difficult ethical issues
(e.g. the use of prisoners) it should seek appropriate
advice or co-opt people with the necessary expertise (p.
250).
6. There shall be no deception that might affect a
volunteer's willingness to participate in research, nor
should there by any deception about the possible risks
involved (p. 250).
7. Relevant information about significant ethical prob-
lems should be supplied to Ethics Committees by a
central body such as the Committee on Ethical Issues in
Medicine of the Royal College of Physicians (p. 250).
Recruitment and Financial Considerations
8. Initial recruitment of healthy volunteers should be via
a notice, or if verbally, through a group approach rather
than to individuals (p. 245, 246).
9. The Ethics Committee should be given full details of
the background, nature and object of the study, how
healthy volunteers are to be recruited and their age and
sex. It should also be informed from which section of the
community it is proposed to recruit them in case this
raises ethical issues (p. 246-248, 250).
10. When students are used as healthy volunteers, the
Dean or designated alternate should be informed in
writing, given details of the students, the project and
which Ethics Committee has approved the study (p. 247).
II. It is normally undesirable to recruit students in close
contact with the investigator, e.g. on his medical teaching
firm or in his class, unless the project is educational (p.
247).
12. There should be no financial inducement or any
coercion that might persuade a volunteer to take part in a
study against his better judgement (p. 245, 248).
13. Any payment to a healthy volunteer should be for
expenses, time, inconvenience or discomfort, and never
for risk. Increased payments may be reasonable for
procedures requiring extra care or involving more dis-
comfort (p. 248).
14. There should be no financial reward when children
are used as healthy volunteers (p. 247).
15. All payments should be declared to the Ethics Com-
mittee; not only those to healthy volunteers, but also
those to the investigator, his staff or his department (p.
248, 251).
Safeguards
16. No study on healthy volunteers should involve more
than minimal risk (p. 245).
17. For most medical research, particularly drug studies,
the investigator responsible should be medically qualified
and with experience appropriate to the study concerned
(p. 249).
18. Any significant untoward event occurring during or
after a study affecting a volunteer should be communi-
cated promptly to the Ethics Committee and the volun-
teer's general practitioner. Appropriate action to
safeguard the volunteer's health should be taken, and the
study should be stopped in that individual (p. 249, 250).
19. If a volunteer drops out of a study, for whatever
reason, the investigator should take reasonable steps to
find out whether harm has come to him as a result of
participation in the study (p. 250).
20. The premises where research takes place should be
appropriate to the type of study and to the risk involved
(p. 249)
21. Where drugs are new chemical entities, or new
combinations of established drugs, and where there is any
risk of serious adverse reactions, there should be facilities
and appropriately trained staff for full resuscitation (p.
249).
22. For some types of study further medical help and
intensive care facilities should be available within a few
minutes (p. 249)
Design, Consent and Contract
23. An investigator should keep full records of all studies
performed and should keep a register of healthy volun-
teers used (p. 245).
24. An investigator should give full details in writing to a
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
healthy volunteer explaining the nature, object and dur-
ation of a study. The volunteer should be informed of any
risk, and told what the study will involve, e.g. number of
blood tests or injections, and whether there are any
restrictions on, e.g. driving or drinking alcohol (p. 249,
251).
25. The volunteer should be asked for permission to
contact his general practitioner, and if appropriate a
company or other medical officer, for details of past
history. Where necessaary, e.g. in the event of any ill
health as a result of the study, there should be further
communication. If this permission is not given it is
advisable not to use the volunteer (p. 248).
26. Having been given appropriate information and
having given his consent the volunteer should sign a
consent form (p. 251).
27. Where appropriate, but particularly before taking
part in any drug trial, a healthy volunteer should be asked
about relevant medical history, which should include
smoking, taking of alcohol, drugs and medicines, and
whether he had participated in previous studies (p. 248).
28. Where appropriate a healthy volunteer should be
medically examined and have relevant blood, urine or
other tests. These may need to be repeated during or after
the study (p. 248).
29. The volunteer should give a commitment to the study
and also report any unexpected or unusual symptoms but
he should have the right to withdraw from the study at
any time without giving a reason (p. 250, 251).
30. Volunteers who participate more than once in drug
trials should be provided with a card or booklet giving
details of studies in which they have participated (p. 246,
249).
31. The Ethics Committee should be informed when a
study has been completed and be supplied with any
relevant publications (p. 250).
Compensation and Insurance
32. The sponsor, whether this be a commercial organis-
ation, university, NHS or other institution, should agree
to pay compensation for injury, accident, ill health or
death caused by participation in a research study without
regard to proof of negligence and without delay. Pro-
vision for arbitration of disagreement should be included
(p. 251-252).
33. Where there is any doubt about causation the benefit
of the doubt should be given to the volunteer (p. 252).
34. Where necessary the sponsor should take out appro-
priate insurance to cover compensation independent of
proof of fault (p. 252).
35. Where ill health in or injury to a healthy volunteer
may be due to negligence by a third party, the sponsor
should compensate the volunteer. The sponsor should
protect his right to claim against other parties in the
research (p. 252).
36. Whether or not they have been notified insurance
companies should honour life and sickness policies of
healthy volunteers affected by participation in research
that has been passed by an Ethics Committee and
considered to involve no more than minimal risk (p. 252-
253).
Standards and General Recommendations
37. The Licensing Authority (Medicines Act, 1968)
should state its view of the role and scope of drug studies
in healthy volunteers in the development of new medi-
cines (p. 244).
38. The laboratory data obtained in animals that are
deemed to justify drug studies involving new chemical
entities and new combinations of drugs should be re-
viewed independently (p. 250).
39. Ethics Committees should be satisfied that there has
been adequate evaluation of background pharmacologi-
cal, toxicological data, etc., in all drug studies, particu-
larly in the case of new chemical entities or combinations,
e.g. by the DHSS. Medicine Division (p. 250).
40. All establishments or laboratories where studies on
healthy volunteers are performed should be open to
inspection in order to assure all concerned that high
standards are maintained and the guidelines in this report
are followed.
Research departments of NHS hospitals, university
and other academic institutions could, where necessary,
be inspected by or on behalf of properly constituted Ethics
Committees. In units where substantial and sustained
research on healthy volunteers is carried out, and particu-
larly in those departments where drugs under develop-
ment are being investigated, Ethics Committees should
consider carefully whether it might not be advisable for
them to be inspected.
Commercial institutions performing research on
healthy volunteers should be subject to independent
scrutiny (p. 249).
41. A register of approved commercial institutions that
perform research on healthy volunteers should be estab-
lished (p. 249).
APPENDICES
Check List for Healthy Volunteer Consent
and Contract Forms
This is a check list and not a specimen consent or contract
form. It is not possible to produce a form that covers all
types of research nor does this check list set out to be
comprehensive.
Consent
Confirmation is required of the fact that:
1. The volunteer is willing to take part in the study and
this should be clearly stated.
2. The investigator has explained the nature and purpose
of the study and has informed the volunteer of any risk to
health that the investigator foresees.
254 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
3. The volunteer has received the Study Information
Sheet describing the essential features of the study which
acts as an aide memoire in relation to attendance, etc.
(Depending upon the type of study involved such a sheet
may be considered unnecessary).
4. The volunteer has been given the opportunity to
question the investigator and has understood the investi-
gator's advice.
5. The volunteer has been told he is free to withdraw
consent at any time without the need to justify that
decision.
Medical Information given by Volunteer prior to
Participation
Confirmation that the volunteer has informed the investi-
gator of:
1. Previous or current participation in healthy volunteer
studies.
2. Significant previous or present illnesses together with
details of consultations with a doctor whether or not they
resulted in treatment.
3. Medicines (whether prescribed or not) being taken or
which have been taken in the recent past (this period can
be defined according to the nature of the study) and that
the volunteer is expecting to take during the course of the
study.
4. History of previous or present use of tobacco, alcohol
and other drugs.
5. The volunteer's readiness to keep the investigator
informed of any additions to the above information.
Authority to Consult the Volunteer's General
Practitioner
Confirmation that the investigator is authorised to consult
the volunteer's general practitioner and that the latter is
authorised to disclose any information concerning the
volunteer's health that he considers relevant to the pend-
ing study.
Continuing Obligations of the Volunteer
Confirmation that the volunteer will:
1. Follow the reasonable instructions of the investigator
and not to do anything that the volunteer knows or might
reasonably suspect will affect the integrity of the study.
2. Inform the investigator of any unexpected symptoms
or deterioration in his health during or immediately
following the study.
3. Not restrict the use to which the study results are put
(including submission to drug regulatory authorities)
provided that any document relating to the Study passed
to a third party does not identify him by name.
Obligations of the Person initiating the Research
Confirmation by the sponsoring institution, company or
other person or body initiating the research or their
respective agents of:
1. Any payment that will be made in consideration of a
volunteer's participation and the terms that have been
agreed regarding payment in the event of withdrawal
from the study.
2. Arrangements made concerning compensation for in-
jury which will include an undertaking by the person or
body initiating the research that compensation will be
paid independent of proof of negligence and without
delay. There should be provision for arbitration in the
event of dispute including the manner of appointment of
the arbitrator and his right to consult a barrister.
3. To provide a simple form of contract giving effect to
the above.
Formalities
1. The volunteer should sign to confirm his consent on
the terms set out but it is not necessary that his signature
be witnessed.
2. The investigator should sign a statement at the bottom
of the document or on a separate attachment confirming
that he has explained the nature, purpose and possible
risks of participation to the volunteer.
3. The person responsible for the payment of compen-
sation (above) or his agent should sign the document. In
some cases it may be more practicable to have the issue of
compensation dealt with in a separate document where
the person supervising the conduct of the study is not
giving the undertaking concerning compensation.
4. The document should be dated.
2. Oral Evidence
The following gave oral evidence and most also submitted
written evidence to the Working Party:
Professor A. W. Asscher, Department of Renal Medi-
cine, University of Wales College of Medicine.
Associate Members' Group of the British Medical Associ-
ation (Miss J. Smith and Mr. C. Valentine)
Association of Provincial Medical Schools (Mr. J. Marr)
Bowring London Ltd. (Mr. M. D. Jones, Divisional
Director)
British Pharmacological Society, Clinical Section (Profes-
sor M. L'E. Orme)
British Psychological Society (Professor A. Gale and Dr.
A. Manstead)
Charterhouse Clinical Research Unit Limited (Dr. S. J.
Warrington, Executive Medical Director)
The Committee of Professors of Clinical Pharmacology
and Therapeutics (Professors C. F. George and D. W.
Vere)
The Faculty of Anaesthetics, Royal College of Surgeons
(Dr. Aileen Adams and Professor J. W. Dundee)
The Faculty of Occupational Medicine, Royal College of
Physicians (Dr. J. F. L. Aldridge)
Health and Safety Executive (Dr. David Gompertz,
Deputy Director Medical Services)
Imperial Chemical Industries PLC (Dr. J. D. Fitzgerald,
Medical Director, Pharmaceuticals Division)
Dr. Gerald Jones, Department of Health and Social
Security, Medicines Division
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 255
Dr. Robert Mahler, MRC Clinical Research Centre,
Northwick Park Hospital
Dr. A. E. M. McLean, Professor of Toxicology, School
of Medicine, University College, London
National Union of Students (Messrs. J. Fallon and P.
Woolas)
Trades Union Congress (Dr. Ronald Owen, Medical
Adviser)
3. Written Evidence
The following gave written evidence to the Working
Party:
The Association of British Insurers, Life Insurance Coun-
cil (Mr. T. H. M. Oppe)
The Association of the British Pharmaceutical Industry
The Association of Medical Advisers in the Pharma-
ceutical Industry (Dr. I. Lennox-Smith)
Dr. L. S. Bernstein: for Clinical Research Physicians of:
Beecham Pharmaceutical Research Division, Glaxo
Group Research Ltd., Imperial Chemical Industries
PLC and The Wellcome Foundation Ltd.
Biomedical Sciences (Dr. E. H. L. Harries)
Professor Ronald Dworkin, University College, Oxford
Huntingdon Research Centre Ltd. (Dr. D. Mansel-
Jones)
Professor June K. Lloyd, Department of Child Health,
St. George's Hospital Medical School
The Medical Research Council
Professor Alan Richens, Department of Pharmacology
and Therapeutics, University of Wales College of
Medicine
The Wellcome Protocol Review Committee (Professor J.
R. Trounce, Chairman)
4. Edited Abstracts of the Royal College of
Physicians Guidelines on the Practice of
Ethics Committees in Medical Research
Because of the importance of Research Ethics Commit-
tees to the protection of research subjects we append some
edited extracts from the Royal College Physicians Guide-
lines on the Practice of Ethics Committees in Medical Research
(1984) to supplement the main text of this report.
The Objectives of Ethics Committees.
The objectives are to facilitate medical research in the
interest of society, to protect subjects of research from
possible harm, to preserve their rights, and to provide
reassurance to the public that this is being done. Commit-
tees also protect research workers from unjustified attack.
Decision
The nature of the decision that the Committee has to
make is largely defined above. But the question of the
extent to which scientific quality, design and conduct
should be considered continues to cause difficulty. It has
been pointed out that badly planned, poorly designed
research that causes inconvenience to subjects and may
carry risk without producing useful or valid results, is
unethical. A Committee should feel free to refuse an
application on grounds of inadequate scientific quality.
Mandatory Review
The institution setting up an Ethics Committee should
provide that all research projects affecting human subjects
come before it. The legitimate concern of the public and
the profession that led to the setting up of Ethics Commit-
tees cannot be satisfied by anything less than mandatory
review.
Definition of Project
Definition of a research project that should be put before
an Ethics committee continues to present difficulties. Any
investigation in man designed to develop or contribute to
knowledge raises ethical issues, though these may some-
times be quite small. Since any such study may involve
subordination of at least the immediate interest of the
individual participant to the objective of the advancement
of knowledge all should be subject to ethical review.
Membership and Appointment of Ethics Committees
Membership should comprise at least:-
(a) Medical: both those occupied chiefly with clinical care
as well as experienced clinical investigators; a general
practitioner should be included whether or not the Com-
mittee reviews projects in general practice.
(b) Nursing: a nurse who is in active practice with
patients.
(c) Lay: i.e. one, or perhaps better, two persons not
trained in or practising any medical or paramedical
discipline.
It is important that the community should have confi-
dence in Ethics Committees and provided that the mem-
bership is seen to be broad and not exclusively medical
and the lay members to be persons of responsibility and
standing who will not be overawed by medical members,
such confidence should be forthcoming.
Experience has shown that lay members, though they
may not grasp some of the niceties of some research
projects (nor do some of the medical members), are
invaluable, particularly on issues of consent and infor-
mation to subjects. A lay member with legal training can
be of great value and his/her role should be a general one,
not simply to answer questions of law.
Both sexes should be represented.
The nominations should be made by a responsible
Authority, District Health Authority, Hospital Commit-
tee or Academic Executive and the Committee will report
to this Authority, though details of its considerations of
applications will be confidential. An established Commit-
tee, knowing its own needs may propose names where this
is appropriate. The appointment of lay members may
need wider consultation than the appointment of pro-
fessional members.
Ethics Committees have no direct sanctions, but in the
event of their discovering that their advice is unheeded or
256 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
that clinical investigations are being conducted without
reference to them, then they should report the facts to the
body that set them up, e.g. an NHS district or hospital
authority or a university board. Plainly, an investigator
who bypasses or ignores the recommendations of a prop-
erly authorised Ethics Committee creates a potentially
serious situation.
Declaration of interest by Committtee members. Just as
applicants should declare an interest, so members of an
Ethics Committee should declare their interests, e.g.
where an application relates to testing a product of a
company to which the member is an adviser.
The complete Report can be obtained from the Royal
College of Physicians.
BIBLIOGRAPHY
1. Association of the British Pharmaceutical Industry
The report of the committee to investigate medical experi-
ments on staff volunteers (1970) (the Stuart-Harris
Report). Updated as: Guidelines for medical experiments
on non-patient volunteers (1984).
2. Association of the British Pharmaceutical Industry
(1985) Guidelines on data needed to support the adminis-
tration of new chemical entities to non-patient volunteers.
3. British Medical Association (1984) The Handbook of
Medical Ethics. British Medical Association.
4. British Paediatric Association (1980) Guidelines to aid
ethical committees considering research involving children.
Archives of Diseases in Children, 55, 75-77.
5. British Psychological Society (1983) Guidelines for the
professional practice of clinical psychology Issued by the
British Psychological Society.
6. Ciba Foundation Study Group (1980) Medical Re-
search: Civil liability and compensation for personal
injury. The Ciba Foundation.
7. DHSS Committee on Toxicity of Chemicals in Food,
Consumer Products and the Environment (1982)
Guidelines for the testing of chemicals for toxicity, Appen-
dix 10: Human Studies. Report on Health and Social
Subjects 27. HMSO.
8. Faculty of Occupational Medicine (1982) Guidance on
ethics for occupational physicians. 2nd edition, Royal
College of Physicians.
9. Family Law Reform Act 1969.
10. General Medical Council (1985) Professional conduct
and discipline: fitness to practice. General Medical
Council.
11. Gillick v. West Norfolk and Wisbech Area Health
Authority and the Department of Health and Social
Security. House of Lords, 1985. 1985 3 All ER 402.
12. Medical Research Council Responsibility in investi-
gations on human subjects. Report of Medical Research
Council 1962-63 (Cmnd 2382).
13. Medicines Act 1968.
14. Medicines (Exemption from Licences) (Special Cases
and Miscellaneous Provisions) Order 1972.
15. Medicines (Exemption from Licences) (Clinical
Trials) Order 1981.
16. World Health Organisation (1982) Proposed inter-
national guidelines for biochemical research involving
human subjects: Geneva CIOMS. (The Declaration of
Helsinki, 1964, revised by the World Medical Associ-
ation, Venice 1983).
17. Report of the Royal Commission on Civil Liability
and Compensation for Personal Injury (Cmnd 7054).
The Pearson Report 1978.
18. Royal College of Physicians (1984) Guidelines on the
practice of ethics committees in medical research. Royal
College of Physicians.
19. Royal College of Physicians (1986) Relationship be-
tween physicians and the pharmaceutical industry. Jour-
nal of the Royal College of Physicians, 20, 235.
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 257
|
PMC005xxxxxx/PMC5371046.txt | Antiviral Strategies and Vaccines
against HTLV III/LAV
A. G. DALGLEISH, BSc, MB, MRCF| FRACR Consultant Medical Oncologist,
Clinical Research Centre, Northwick Park Hospital, Harrow
The Virus, its Origins and Nomenclature
The causative agent of the acquired immune deficiency
syndrome (AIDS) and related conditions was reported in
September 1983 by Barre Sinoussi et al. [1] working in
Montaignier's Laboratory (Pasteur Institute). At that
time there was no evidence that this virus had any causal
role in AIDS or related conditions. It was Robert Gallo
and his colleagues[2] at the National Cancer Institute
(NCI) Washington who first reported (May 1984) the
successful isolation and production in a permanent cell
line of a new retrovirus which induced specific serum
antibodies in the majority of AIDS and AIDS at risk
persons[3]. The causal nature of this new retrovirus was
quickly confirmed by workers in London, who also
confirmed that the French and American isolates were
serologically identical[4].
The first French isolates were known as LAV (lympha-
denopathy virus) or IDAV (immunodeficiency associated
virus). Workers in Gallo's laboratory had previously
isolated the first human retrovirus now shown to be the
causal agent of the adult T cell leukaemia lymphoma
syndrome (ATLL) and this was already known as the
human T cell leukaemia?lymphoma virus?I (HTLV-
I)[5]. A second similar yet different isolate called HTLV-
II has yet to be associated with any specific disease[6].
The French group recognised that 'LAV' and 'IDAV'
were new human retroviruses and that they had a procliv-
ity for T4 + T lymphocytes. They therefore referred to
them as human T cell lymphotrophic viruses. It was not
surprising that Gallo referred to his new isolates as
HTLV-III, the 'L' standing for lymphotrophic as op-
posed to leukaemia or lymphoma. Further isolates report-
ed from San Francisco added to the confusion as they
were called AIDS retroviruses (ARV)[7], The confusion
has recently been compounded with an international
committee declaring the viruses as 'human immunodefi-
ciency viruses' (HIV)[8], This decision is not unanimous,
but in this article I refer to the viruses as HIV if for no
other reason than it is shorter than HTLV III/LAV.
The isolation and establishment of a permanent cell
line was not an easy feat, as the virus is cytopathic for
most host cells. Permanent T4 + leukaemic T cell lines
were eventually used to isolate and produce large quanti-
ties of the virus which could then be used as antigen for
widespread serological screening.
The major 'hold up' in establishing the French isolate
as a causal agent was the inability to establish it in a
permanent cell line. It was initially isolated in a low
producing B cell line and it was not until workers in Prof.
Weiss's laboratory in London established 'LAV' in the
T4 + leukaemic line?CEM that the causative role could
be investigated. The CEM/LAV line was sent back to
Montaignier in March 1984[9],
The availability of the virus in a permanent cell culture
is a prerequisite for investigating antiviral stratagems in
vitro, although it is now possible to 'clone' virus isolates
from primary culture without the establishment of a
permanent cell line.
The Retrovirus Life Cycle
HIV is a retrovirus which means that it is an RNA virus
capable of making double DNA copies of itself which may
then intercalate into the hosts cell genome or remain
within the cytoplasm. Replication is directed by the
enzyme reverse transcriptase (RT) which uses the host's
cell replicative mechanism for replication (Fig. 1). In
order for a virus to enter a cell it must enter through an
appropriate receptor. The presence or absence of this
receptor will establish the host cell range. The virus must
first bind to the appropriate receptor before gaining entry
to the cell as part of the virus receptor complex. Most
retroviruses enter by the endocytic pathway from whence
the virus is 'delivered' to lysosomes which are able to
'uncoat' the virus, thus releasing the infectious core into
the cell. Further replication depends on the RT enzyme
and post-translational events include glycosylation of the
envelope proteins.
Antiviral stratagems may be aimed at any one of these
steps, which may be grouped as follows for possible
therapeutic manipulation:
1. Binding to the receptor;
2. Endocytic pathway;
3. Reverse transcriptase inhibitors;
4. Post translation modification.
The Receptor
Viruses use specific receptors which may only be present
on a very limited number of cells, or they may use a
receptor that is present on a broad range of cells some-
times from many species. The host cell range is often
established by performing plaque assays and/or infectiv-
258 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
Table 1. Therapeutic sites of intervention.
1. Plasma ? complement
2. Neutralising antibody
3. Anti receptor/binding, antibody ? idiotype
4. Drugs affecting the endocytic pathway
NH4C1
Amantadine
(Chloroquine)
(Monensin)
5. Reverse transcriptase inhibitors
HPA-23
Suramin
Phosphonoformate
AZT
? others
6. Cytotoxic T cells
7. Anti-sense RNA variants
ity assays on various cells. As retroviruses do not readily
lend themselves to plaque assay systems[10], alternative
assays have been devised. The simplest is the syncytial
induction assay (Fig. 2) which utilises the ability of
viruses to fuse receptive cells so that giant or multi-
nucleate cells are seen by light microscopy[l 1], Replica-
tion within a cell can be assessed by measuring the reverse
transcriptase levels. Cells may 'fuse' and form syncytia in
the presence of various physical or chemical conditions
other than a virus, and conversely not all cells infected
with retroviruses necessarily form syncytia. In order to
investigate further the viral membrane antigens and the
host cell receptors the ability of viruses to combine
randomly has been usurped in the form of the pseudotype
assay (PT)[ 12,13]. Briefly, a virus which can readily be
used in a quantifiable plaque assay (VSV) is grown
through cells producing the retrovirus under investi-
gation. Some of these viruses will form hybrids, being
VSV cores with retroviral membrane antigens. Non-
hybrid viruses can be 'neutralised' using anti-VSV
monoclonal antibody. Such pseudotypes can. then be
titrated onto various cells, and provided they have recep-
tors for the retroviral antigens they will allow the hybrid
virus to enter the cell, thus enabling the VSV core to
undergo replication which can then be measured quanti-
tatively by applying an overlay of cells suitable for a VSV
plaque assay. Using these assays we were able to show
that most HIV infectable cells were T4 + leukaemic cell
lines[ 13], and that those that were not expressed the T4
antigen. Furthermore, using a range of monoclonal anti-
bodies made against various leukocyte surface antigens
(1) Virus
(2) Virus bound to receptor
(3) Virus/receptor in endosome
(4) 'Released RNA'
(5) Linear DNA
(6) Circular DNA
(7) Proviral (integrated DNA)
(8) Other protein products
(9) Virus budding from cell membrane
Fig. 1. Retrovirus: replication and life cycle.
Replication
GAG
POL
ENV
AWWVWMAAAV
MWW AWWV /WWW
GAG POL ENV
? ? \
Viral genome
Linear DNA
Closed circular
DNA
Proviral DNA
Viral DNA
Primary translation
products
Mature proteins
Fig. 2. Photograph of syncytia or multi-nucleate giant cells
formed by the viral fusion' of JM T4 + cells.
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
obtained from Peter Beverely (ICRF) we were able to
show that all anti-T4 (CD4) monoclonal antibodies were
able to block both the SI and PT assays[13]. We con-
cluded that the T4/CD4 antigen was an essential com-
ponent of the HIV receptor. The possibility that T4 is the
only receptor is exciting as this may lead to a therapeutic
handle against viral replication. Unfortunately, studies
on animal retroviruses have shown us that retroviruses
may learn to use more than one receptor[10]. Our further
studies showed that no other T cell antigen acts as a
component of the receptor (Dalgleish et al., unpublished
observations) and that not all epitopes of T4 block
infection, i.e. OKT4 as well as some other antibodies to
epitopes of T4 in the OKT range do not block infection
(Sattentau et al., submitted).
The definitive experiment to show that T4 is the HIV
receptor would involve the transfection of the cDNA T4
clone into various cell lines that do not normally express
the T4 antigen. The recent cloning of the cDNA of T4 by
Maddon et al. [14] has allowed the construction of a wide
range of cells expressing human T4 antigens. Results of
these studies are in press[15] and show that human cells
expressing T4+ antigen are infectable with HIV. Fur-
thermore it has been shown that T4 and the gp 110-120
envelope antigen of HIV not only bind but also specifi-
cally immunoprecipitate together[16]. What is important
is that no cellular antigen other than T4 is brought down.
These results are exciting in that they suggest that a
specific binding site may be preserved among different
isolates (they all appear to use the T4 antigen as a
receptor) and that further studies may identify this site.
As the sequence of both T4 and many HIV isolates are
now known[14,17] it could be possible to synthesise a
peptide and raise an antibody against this site. This
would clearly be a very important therapeutic strategy,
providing the virus did not learn to use an alternative
receptor.
Post-receptor: the Endocytic Pathway
Following binding to the receptor the virus/receptor
complex has to enter the cell if infection is to take place.
In the case of many viruses this is achieved via the
endocytic pathway[18] (Fig. 3). Fusion of the virus
requires an acidic environment, without which the virus
does not reach the lysosomes and get 'decoated'. Prelimi-
nary data have shown that in keeping with other retrovir-
uses, inhibitors of intracycloplasmic acidification such as
ammonium chloride and amantadine, appear to reduce
the infectability of HIV. The absence of a one viral-
replication cycle assay makes those experiments techni-
cally difficult and therefore difficult to interpret. We have
yet to confirm that carboxylic ionophores such as chloro-
quine and monensin (which inhibit endocytosis in some
animal retrovirus systems) inhibit HIV infection (Dalg-
leish and Marsh, unpublished observations). Further
studies are in progress. In the meantime it may be worth
considering amantadine, or similar compound, in a pilot
therapeutic trial, as it is readily available. A combination
of amantadine with another drug which acts at a different
stage of replication, for example reverse transcriptase
(RT) inhibitors, may be even better.
Reverse Transcriptase Inhibitors
Reverse transcriptase inhibitors may act at different sites
in the enzymatic reaction, as enzyme-binding com-
pounds, template-binding compounds, substrate or prod-
uct analogues, divalent cation binding agents and
miscellaneous compounds[19], A large number of com-
pounds are known to be inhibitory against the RT of
many animal retroviruses[20]. These include (1) suramin
that binds directly to the enzyme and other diasylimida-
zoline derivatives which bind to the template such as
Evans blue and direct yellow 50, adenosine analogues
such as Ara-A, ribavirin, antimoniotungstate, (HPA-23),
pyrazofurin and 5-iodo-2'-deoxy cytidine, thiosemicarba-
zone R (a cation binding agent) and phosphonoformic
acid (PFA).
Following the report that suramin was active against
HTLV-III in vitro[21], we screened a number of suramin
analogues which were found devoid of anti-HIV activity.
We then tested PFA in vitro and found it to be an
extremely active inhibitor of reverse transcriptase at doses
of 100-200 /ig/ml which are readily attainable in vivo (Fig.
4) (Dalgleish et al., unpublished observations). The in
Fig. 3. Endocytosis. 1. virus attached to receptor; 2. virus receptor complex crowd together ('cap') and undergo invagination; 3.
Endosome, where virus undergoes fusion in an acidic environment and is transferred to a lysosome.
260 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
vitro findings that PFA inhibited HIV have since been
confirmed by other workers[22,23], As PFA is licensed
for use against cytomegalovirus (CMV) and appeared to
improve the overall condition of some AIDS patients to
whom it was given for CMV infection, we undertook a
pilot study of PFA in patients with AIDS and AIDS
related conditions, the results of which will be published
shortly (Farthing et al.).
In vivo studies with suramin[24], HPA-23 [25] and
AZT[26] have now been reported. HPA-23 (antimonio-
tungstate) has been given to three patients with AIDS and
one with prodromal symptoms. Although considerable
clinical improvement was reported after a short follow-up
period, the ability to isolate the virus was reduced during
therapy but returned following cessation. A large trial is
at present in progress, although considerable toxicity (to
marrow) and the inability to cross the blood/brain barrier
will limit its further usefulness. Similarly, suramin has
been used on 10 patients with AIDS and ARC. Toxicity
is also a major limitation, although there is some evidence
that this drug is much better tolerated in African patients,
and, again, it is not able to cross the gut or blood/brain
barrier. Viral isolation studies concur with those for
HPA-23. More recently, a new drug known as azido
deoxythymidine (AZT)[26] an analogue of thymidine
(Fig. 5) has been used in vivo. The advantages of a high
therapeutic index, oral administration and easy access
across the blood/brain barrier make this an attractive
therapeutic candidate for long-term administration. A
multi-centre pilot study[26] reports significant improve-
ment in clinical parameters, T4 positive lymphocyte
counts and delayed-type hypersensitivity skin reactions,
as well as a failure to isolate virus from patients given a
high dose of parenteral and oral AZT for six weeks. The
reported short term toxicity was limited to headaches and
leukopenia. Only 19 patients were investigated in this
study which needs to be extended to more patients with
longer treatment and follow-up periods.
Other Drugs
What is exciting about the results seen with AZT is that
similar substitutions in either purines (adenosine, guano-
sine inosine) or pyrimidines (cytidine, thymidine) could
also prevent RT transcription. Therefore a wide variety
of possible compounds may lead to an ideal in vivo, anti-
HIV formulation.
Other drugs have been reported to have potential anti-
HIV activity. Ribavirin, an analogue of guanosine, is
able to inhibit HIV replication in vitro[27] but is unable to
protect against cytopathic effects in vitro and appears to
have no obvious clinical benefit[28],
Dithiocarb (sodium diethyldithiocarbamate) and ino-
sine pranobex (Isoprinosine) also inhibit HIV expression
in infected cells[29]. Both drugs are said to increase the
number of T4 lymphocytes and are used as 'immunomo-
dulators'. The antiviral effect is weak and is thought to
occur at the stage of virus transduction through the
membrane and/or DNA integration in the nucleus. A
novel lipid compound AL 721 has also been claimed to
inhibit HIV replication in vivo by altering the cell mem-
brane cholesterol content[30].
Other parts of the cell cycle may also be susceptible to
interference such as post translation modification e.g.
proteolytic cleavage, glycosylation, acylation and phos-
phorylation (Fig. 1). I am unaware of any clinical studies
of drugs known to affect this end of the pathway.
Tunicamycin is known to interfere with glycosylation and
is at present being studied in vitro.
Time (days)
Fig. 4. The effect of varying doses of PFA on an in vitro
infectivity assay using high virus producing cells (H93) and
very susceptible T4 + cells (JM). These results show that PFA
at a dose of 100 fim/litre and above inhibit viral replication.
3' azido 3' deoxythymidine
Thymidine analogue
HN
CH3
hoch2
Competitive inhibition with thymidine at 1-10/xM in vitro.
These doses do not cause significant immunological
depression or toxicity.
Fig. 5. The structure of AZT showing the similarity with
thymidine with only N3 replacing OH at the 3' position.
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 261
What Determines Infectability?
A number of studies are presently looking at sero-
negative partners of HIV-positive patients. What is sur-
prising is that some patients have had continual exposure
for several years with infected persons and yet remain
sero-negative (IVD Weller et al., unpublished observa-
tions). Nearly all of these patients including sero-negative
haemophiliacs who have had large doses of known infect-
ed blood products, have no evidence of virus detectable
by virus isolation and molecular hybridisation techniques
(E. Miller et al., unpublished observations). It therefore
seems likely that some patients are able to 'deal' with the
virus before it gets a chance to enter the replication cycle.
Human sera have been shown to activate the compliment
pathway against most animal retroviruses[31]. The hu-
man T cell leukaemic-lymphoma virus (HTLV-I) is not
susceptible to destruction by complement[31] and neither
is HIV (Clapham et al., unpublished observations).
It would appear that HTLV-I and HIV may be
infectious because they are not lysed by the plasma.
Clearly it would be interesting to see if there is any
difference in susceptibility to complement between sero-
positive and sero-negative persons.
Neutralising Antibodies (or lack of)
Following infection and replication antibodies are raised
against both core and envelope antigens (Fig. 6). In many
virus systems these antibodies are capable of neutralising
the virus. Whereas patients infected with HTLV-I have
high titres of neutralising antibody[12], patients infected
with HIV have low or absent neutralising antibodies
(NAB), although they may have high titres of non-
neutralising antibodies[12,32]. The small variation in the
low titre of neutralising antibodies does not correlate with
clinical status and is therefore unlikely to have any
protective function. Why then is there no significant
neutralisation present in HIV infected patients? A num-
ber of possibilities exist. The neutralising epitope may be
masked by other epitopes or may be altered by base pair
antibodies against other more prominent epitopes. The
secondary and tertiary structures of antigens may be
altered by base pair changes, far removed linearly from
the binding site regions in other virus systems such as
polio virus[33] where neutralisation may be changed by a
single base pair change up to 300 base pairs away from
the binding site. Similarly, the three dimensional struc-
ture of virus antigens may contain many epitopic sites as
well as binding sites[34] (e.g. influenza virus, see Fig. 7).
Antibodies may therefore detect some epitopes but not
others which may be masked by being recessed, or
masked by antibodies attached to more immunogenic
epitopes (or even that several NABs may be required).
Fig. 6. Immunoprecipitation of HTLV III antigens.
a b
gp 110
p 55
gp 41
p 24
p 19
? Envelope proteins
With a = infected serum
b = normal serum
Fig. 7. Hypothetical illustration showing how an antibody
may be raised against a binding site and not neutralising
epitopes and vice versa, (based on the haemagglutinin antigen of
the influenza virus).
262 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
There is a recent report of a new mechanism for the
neutralisation of enveloped viruses by anti-viral antibody,
whereby binding of a flavi-virus to its receptor does not
preclude neutralisation at the endosomal acid catalysed
fusion step[35]. Clearly, any of these factors could be
present in the case of HIV. Another possibility is that of
antigen misrepresentation by the antigen presenting cell.
HIV is now known to infect monocytes and macrophages
(M-M) many of which bear the CD4 antigen [13, Cla-
pham et al., unpublished observations]. Other viruses
that are able to reside at low levels in M-M also appear to
incite low levels of NAB, i.e. Visna Maedi (VM)[36] and
lactate dehydrogenase virus (LDV)[37], It could be that
M-M is able to alter antigen presentation of various
membrane epitopes or that M-M represent an immunolo-
i gical privileged site for these viruses. It is interesting to
note that these other viruses (VM, LDV) are able to
inflict severe neurological damage (such as demyelina-
tion) on their hosts. Moreover, brain disease now ac-
counts for the major morbidity of HIV infected persons,
ranging from minor neurological dysfunction to severe
pre-senile dementia[38-40]. The reasons for this are not
clear although in the case of HIV infection many poten-
tially susceptible T4 positive mononuclear cells are
present in the brain and some nervous system primary
cells also express CD4.
A useful therapeutic strategy would be to induce NAB
by infecting mice or similar animals. This has now been
done by many groups and although monoclonal ABs to
both core and envelope proteins have been prepared, I
am not aware of any which have significant neutralising
ability. Attempts to change the antigen presentation
using ISCOM techniques have increased the number of
MCABs raised against the envelope proteins but, again,
none have been reported as eliciting neutralisation.
Clearly, other antigen presentation modification tech-
niques should be entertained.
Anti-idiotypes
Knowing that the T4 antigen is the virus receptor
suggests the possibility of raising an anti-virus antibody
by making an anti-idiotype. As the virus binds to T4, the
T4 could be used to make an anti-T4 AB (by immunising
mice); then repeating the technique using the anti-T4 AB
should lead to the production of anti-anti-T4 which could
conceivably be active against the virus (Fig. 8). This is
theoretically an attractive way of raising what would
effectively be a neutralising antibody. However, I am
unaware of any successful NABs raised with this tech-
nique. Recently, Waldmann and his colleagues[41] have
reported that anti-mouse T4 given to mice acts as a
tolerogenic umbrella for the immune system. In other
words mice become tolerant to antigens given under the
cover of anti-mouse T4 antibodies. This has some attrac-
tive speculative appeal for HIV. Idiotypes against HIV
will include anti-T4 ABs, could they therefore allow the
neutralising epitope to be seen as self? Speculation aside,
the use of anti-idiotypes as surrogate antigens has already
been shown to have a role in vaccination against hepatitis
B virus[42] and schistosomiasis[43].
The T Cell Response
The immune system's other arm of defence after B cells
and their antibodies is the T cell system. Unfortunately
the T cell system in HIV infection is severely disturbed.
T4 + cells are destroyed and even those not known to be
infected have impaired function[44], Many retroviruses
have a conserved transmembrane protein called P15E[45]
which is known to be immunosuppressive in some T cell
response assays. Other soluble sustances may be pro-
duced by infected cells which interfere with T cell func-
tion!^]. The clearance of many viruses is dependent on
the activity of virus-specific cytotoxic T lymphocytes
(CTL) restricted by Class II molecules of the major
histocompatibility complex. Indeed, in some animal
model systems, persistent infection occurs if there is an
absence of, or decrease in the production of these
cells[47]. It will be interesting to see if CTL cells are
induced against HIV infected cells and whether or not the
natural killer (NK) cells or lymphokine activated killer
(LAK) cells have any role.
Immunotherapy
The T4 lymphocyte effectively acts as the conductor of
the immunological orchestra[48], and hence there is
probably no more effective way of vandalising the im-
mune system than killing T4 positive cells, which is how
HIV acts in vitro and in vivo. Therefore therapeutic
stratagems designed to replace the body's flagging im-
mune defences have been studied, and, although they
may have an important role to play in the overall
Virus
Anti-ldiotype
\>
Neut. AB
Idiotype
Receptor
Receptor
Virus
Fig. 8. Anti-idiotypes: Two different presentations of the same
theme; antibody to the receptor will itself act as an antigen in its
variable region raising an antibody which should also react with
the virus.
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 263
treatment plan, it is unlikely that immune restoration
alone will succeed while the virus is able to replicate
unhindered.
The numerous immunological abnormalities described
in HIV infection are beyond the scope of this article
[reviewed in 49]. Suffice it to mention however that the
most severe defect appears to involve cellular immunity.
Therapeutic stratagems have therefore focused on the
following potential therapies: interferons, thymic replace-
ment hormones, lymphokines and cytokines, bone mar-
row transplantation, isoprinosine and cimetidine, intra-
venous immunoglobulin therapy and plasmapheresis.
Interferons are known to have a viral function and the
availability of recombinant human interferon has enabled
in vitro and in vivo studies in AIDS patients.
There are two types of interferons: alpha, produced by
leukocytes and fibroblasts and gamma, produced by
lymphocytes and monocytes. Studies in vitro showed that
alpha interferon suppresses the replication of HIV[50], In
vivo studies have unfortunately been disappointing with
the exception of patients with Kaposi's sarcoma (KS). As
vinblastine also has considerable single agent activity
against KS, several centres are now studying combined
therapy using regimes containing alpha interferon and
vinblastine. Clinical trials with gamma-interferon, which
should be theoretically superior to alpha-interferon, were
delayed due to the lack of sufficient material. Preliminary
studies suggest that gamma-interferon may not be as
useful as alpha in the treatment of KS. However numer-
ous centres are intensively studying gamma-interferon in
AIDS and will report in the near future.
Thymic replacement therapies in patients with AIDS
are unfortunately both anecdotal and uninspiring.
Whereas it is easy to overlook the lack of reported clinical
success, it should be noted that numerous different
thymic peptides are now available and some, or a combi-
nation of them, may be useful in some cases. A recent
report that antibodies to thymosin also neutralise HIV
demands further investigational].
Interleukin-2 (IL-2) is a lymphokine which has been
shown to reconstitute deficient in vitro immune re-
sponses]^]. Although IL-2 may improve some immune
responses in vivo, no dramatic response has been reported
from numerous clinical studies. Moreover, it has been
argued that as IL-2 augments the number of T4 + cells it
may in fact be adding fuel to the fire by adding further
infectable cells. Indeed virus production may be 'hotted
up' in vitro by adding fresh T4 + uninfected cells.
Nevertheless IL-2 may yet have a role to play in combi-
nation with other agents such as reverse transcriptase
inhibitors.
Marrow transplants and lymphocyte transfusions have
been performed in a few cases and do not appear to help
the immune status. Again one is adding fresh uninfected
cells to an 'infected' in vivo culture.
Isoprinosine and cimetidine are both able to improve
cellular immunity in vivo with varying degrees of success.
Encouraging results with these agents in melanoma,
systemic lupus erythematosus and rheumatoid arthritis
have led to controlled trials in patients with AIDS and
related conditions, which have yet to be reported.
Intravenous immunoglobulin therapy may have a role
in the management of ill HIV infected patients. It is
unlikely that sufficient neutralising antibody would be
present to have a specific anti-HIV effect. Early trials in
children are said to be encouraging.
Anecdotal experience with plasmapheresis does not
suggest that this will be a useful therapeutic modality in
AIDS.
Whereas there may be some cautious ground for
optimism using some modality in combination, it should
be noted that improvements in in vivo immune function
and clinical status remain curiously uncoordinated in the
majority of trials and reports reviewed.
Vaccines
Studies of the epidemiology of HIV infection suggest that
the only certain barrier to further spread of the disease is a
vaccine.
Previous viral epidemics which have inflicted signifi-
cant mortality and morbity, e.g. paralytic poliomyelitis
and smallpox, have been successfully contained by mass
vaccination. Hepatitis B virus (HBV), the causal agent of
'serum' hepatitis and responsible for the high incidence of
chronic liver disease, and hepatocellular cancer (one of
the most common cancers in some parts of Africa and
Asia), has recently been the target of a successful vacci-
nation programme using antibodies against the envelope
antigen of (HBsAg)[53], The vaccine has been prepared
directly from infected persons by cloning the envelope
gene and, more recently, by preparing an anti-idiotypic
antibody vaccine[42].
The Epstein Barr Virus (EBV) is causally linked with
Burkitt's lymphoma in Africa and nasopharyngeal carci-
noma in Asia. Recently a vaccine, prepared against the
surface antigen (glycoprotein 340), has been shown to
protect against EBV induced lymphomas in cottontop
tamarins[54].
The only retrovirus for which a successful vaccine has
yet been developed is the feline leukaemia virus (FeLV).
This was also the first retrovirus to be identified as being
exogenously transmitted in animals, when Prof. Jarrett
and his colleagues reported the transmissable nature of
lymphosarcoma in cats[55]. He was able to isolate a
retrovirus (FeLV) and showed that infection may be
accompanied by the development of a lymphosarcoma in
some cats, or acquired immunodeficiency (manifested by
wasting and death from opportunistic infections) in
others, while some cats remained asymptomatic[56]. The
development of a vaccine was far from straightforward.
The first prototype, although inducing protective anti-
bodies, did not protect against the development of malig-
nant disease and indeed may have worsened the
outcome[57]. However, the later use of an inactivated
vaccine prepared from a high titre supernatant in such a
way as to preserve the envelope glycoproteins, which was
then combined with an adjuvant, protected against lab-
oratory challenge and natural exposure[58]. This prep-
aration is now commercially available. Although the
successful development of this retrovirus vaccine is en-
couraging, making a vaccine for AIDS is unlikely to be as
264 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
easy because protective neutralising antibodies are not
known to be effectively induced in vivo[32] as they are in
FeLV infected cats.
HIV has now been cloned and many isolates have been
extensively characterised[59]. It is clear that there is
considerable variation in the genes coding for the enve-
lope antigens, and any vaccine would have to depend on
conserved regions. Such regions are being sought in
numerous different isolates from different parts of the
world. In the meantime the envelope gene has been
subcloned and inserted into a vaccinia vector which
readily induces envelope antibodies to the glycoproteins
gp. 110, 120[60,61 ]. Unfortunately these antibodies are
not as yet known to have any neutralising or protective
function. No doubt trials using subunits of the same
protein as well as different proteins alone or in combi-
nation are now in progress.
Another approach which could achieve the same end is
the use of synthetic peptides manufactured from known
base pair sequence information. Sequence peptides, how-
ever, are not necessarily good antigens, as studies on the
tobacco mosaic virus (TMV) have shown[62j. Peptides
having the correct amino acid sequence do not necessarily
have the correct conformation at the region of binding. In
contrast to the relatively stable structure of a protein in
solution, small peptides are thought to exist in a multi-
plicity of transient conformational states in dynamic
equilibrium. The conformation of the binding site may
change to improve structural complementary with the
peptide ligand. X-ray crystallography studies have re-
vealed rotations and translations of aromatic side chains
and expansion of the binding cavity by movement of
various hypervariable loops[62]. Furthermore, the im-
munogenicity of a peptide may be increased by coupling
it with the purified protein derivative of tuberculin (PPD)
in animals presensitised with BCG[63],
Against this background the development of a pro-
cedure for the rapid synthesis of a solid support of a large
number of peptides by Geysin and colleagues[64] has
exciting implications for developing peptides potentially
useful in AIDS. Using this technique he has been able to
develop a neutralising antibody to a putative discontinu-
ous epitope of foot and mouth disease virus[65], Taking
as a template a non-neutralising antigenic epitope (VPI),
peptides of increasing length were synthesised and as-
sayed for antibody binding after addition of each residue,
some of which were /3-alamines to allow structural flexi-
bility. Finally, a neutralising peptide was eventually
obtained. Such a technique could be used against the
binding site of HIV and the T4 molecule.
Vaccine Evaluation
Once a successful vaccine or peptide has been prepared it
will be necessary to establish an evaluation programme
that will document safety and efficacy whilst minimising
the time needed for approval. A primate model has been
developed using the chimpanzee which is susceptible to
HIV infection [for review of vaccine development see 66],
Chimpanzees have already been used successfully to test
HIV vaccines[53], A cheaper primate that was infectable
and had a shorter life cycle would be an advantage, and
one may yet be discovered.
Once satisfactory protection is shown in other primates
human trials would then follow. Initially, trials will need
to investigate immunogenicity safety and protection
against infection; it will be necessary to decide whether or
not volunteers from the AIDS 'at risk' group or others
should be used. Larger scale pilot studies would follow
and then mass vaccination?but for whom? Obviously
those in 'at risk' groups will need to be given the vaccine
but what about the general population? Increasing re-
ports of heterosexual transmission in the West[67,68] and
the epidemic nature of AIDS-like illnesses in Afri-
ca[69,70] could suggest that all sexually active persons be
included in the at risk groups.
Genetic Approaches to Treatment
Following the successful cloning and sequencing of sev-
eral isolates much has been learnt about HIV (Fig. 9).
Initially, it was thought to be very closely related to
HTLV-I in that both are human retroviruses with T cell
trophism for T4 + lymphocytes, and both have standard
retrovirus genomic structure with genes encoding for core
or structural proteins (GAG), reverse transcriptase
(POL) and membrane proteins (ENV) without any
known oncogenes but with the addition of a gene capable
of transactivation (TAT gene) and regulating the rate of
virus replications. Homologous sequences between
HTLV-I and III for the GAG, POL, ENV and TAT
genes have been reported[71]. It is now known that HIV
is a considerably more complicated virus than HTLV-I.
It has at least two extra genes[72,73] (Fig. 9). These are
known as the short open reading (SOR) frame which may
regulate the TAT gene and the open reading frame at the
3 prime end of the virus (3'ORF) which may be respon-
sible for the cytopathogenicity of the virus. This structure
is very similar to that of the Visna-Maedi virus in sheep
and HTLV-III is now regarded as being more akin to the
lenti viruses than to HTLV-I[72, 73],
Recent studies have shown that the TAT gene, which
lies between SOR and ENV, is able to mediate activation
in a trans configuration of the genes linked to HIV long
terminal repeat (LTR) sequences. Biological clones of
HIV with the TAT gene deleted do not replicate until the
TAT gene is restored or by introduction of the TAT III
protein itself[ 74,75].
The gene which may encode the cytopathic potential
for HIV (3'ORF) is under similar investigation. How
then might these genetic Achilles' heels lead to further
therapeutic strategies? The construction of clones encod-
ing genes the wrong way round so that they make mirror
image or anti-sense RNA has been reported in several
systems[76-78]. A recombinant AIDS virus with the
TAT gene reversed (or 3'ORF) is obviously an attractive
theoretical proposition[79]. But could it be given in vivo?
A coupled gene encoding responsiveness to a drug that
could control replication in vivo would be a desirable
addition (e.g. DHFR gene responsive to methotrex-
ate)[80] which would be the minimum control needed to
assuage fears of what recombinant AIDS-viruses might
Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986 265
inflict in vivo. Whereas this approach will be regarded as
scientific fiction for some time, it should not obscure the
tremendous amount of hard scientific fact that has been
accumulated about this virus (viruses) which has allowed
the development of a rational approach to therapeutic
options summarised here.
In spite of the many problems encountered in isolating
and trying to understand HIV there are certainly grounds
for optimism that we will eventually be able to effectively
treat if not to eliminate AIDS and its related conditions.
It cannot be over-emphasised how much of what has
been done in the way of combating the AIDS problem
was only possible because of the strong base of scientific
research covering many disciplines such as animal retro-
virology, immunology, cell and molecular biology, which
were able to be rapidly recruited to identify the causal
agent and subsequently attack this disease. Although
there is no present cure, it should be remembered that the
rate of progress in AIDS research has no historical equal.
Addendum
Since this paper was prepared, one or possibly two new
HIV like viruses have been announced. Montaignier and
colleagues report a virus from West African AIDS
patients which they call LAV-2, whilst Essex and col-
leagues report a virus from healthy Senegalese prostitutes
which they call HTLV-4 and which is claimed to be
apathogenic. Both these viruses have considerable differ-
ences to known strains of HIV and may be more similar
to the T lymphotropic viruses.
Acknowledgements
I would like to thank Professor Robin Weiss, in whose
laboratory some of the quoted work was performed,
and also Paul Clapham, Mark Marsh, Quentin Sattentau
and Peter Beverley with whom we worked on these
projects.
This article is based on a paper read at the Conference on AIDS
held at the Royal College of Physicians in May 1986.
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|
PMC005xxxxxx/PMC5371048.txt | Confidentiality and the Use of Medical
Records for Research
Medical records obey gravitational laws. They accumu-
late in heaps and in retrieval systems; they draw upon
themselves an overlay of legislation and controls. Hippoc-
rates was the first in this field, setting out the confidential
basis of medical practice. A recent contender, the Data
Protection Act, exhibits only a tangential concern for
medicine, responding to quite different social pressures.
Hippocrates could scarcely have imagined the modern
shortening of communications, or the problems that this
would create. In particular, he said nothing on the
conflict between the needs for confidentiality and the
communication of data for research.
May records be used at all for research? May they be
released to other doctors; or to non-doctors? Who de-
cides? Are they to be available only for medical research,
or for non-medical research as well? For health-economic,
health-management and health-finance research? Is the
consent of the patient always required; must he be
informed in advance that his records might be used for
research? What is the position when the patient is dead or
unavailable or incapable of giving consent? Is a refusal to
release information for research and for the health-benefit
of mankind as culpable as an agreement to release it, thus
infringing the individual's right to privacy?
These problems are especially serious for epidemiolog-
ical research which requires large-scale access to records.
This access is precariously vulnerable to legal and bur-
eaucratic measures designed in good faith to supply access
to the subject or to protect confidentiality, but not
necessarily guided by a technical knowledge of research
needs, or a full appreciation of the dependence of im-
proved health care upon enquiries of these kinds.
The legal systems and processes of different countries
generate threats of varying severity. The Hippocratic
precept of secrecy is generally accepted, but different legal
codes (Napeolonic: common law) and different pro-
fessional traditions recognise and accommodate, with
unequal success, the necessary exceptions to the rule. A
group of research workers from several European coun-
tries met under the sponsorship of the EEC to consider
these issues, and their report, The Confidentiality of Medi-
cal Recotds, is now available (Commission of the Euro-
pean Communities, 1984. Report EUR 9471 EN). They
tried first to identify global principles, applicable in any
country; then to devise a general Code of Practice from
which individual countries might derive specific codes for
particular legal and regulatory contexts. Several points of
general interest emerged.
1. Modern reformulations of the Hippocratic rule, such
as the Declaration of Geneva, assert a joint concern for
the good of man as an individual and for the corporate
benefit of mankind. In a competitive world the two
principles sometimes come into conflict. In this field, as in
others, the difficult moral choice is not between good and
evil, but between two principles of equal merit.
2. Appeals to larger principles (contractual agreements,
property rights, and the right to privacy) do not solve the
dilemma. The rules of personal contract demand secrecy,
but the integrity of the society that sanctions and supports
such contracts, demands the broader view. The treatment
of medical records as 'property' invokes the same issue.
The individual's right to 'privacy' also requires excep-
tions in order to protect the society which confers the
right. The Council of Europe demanded in 1950 that
there be . . 'no interference by a public Authority with
the exercise of this right . .' but added '. . except such as
is necessary . . in the interests of national security, public
safety or the economic well-being of the country, for the
prevention of disorder or crime, for the protection of
health or morals, or for the protection of the rights and
freedom of others'. A chill draught on moral ardour!
3. The EEC group concluded that there were no formal
solutions to the dilemma; neither a concern for the
individual nor a concern for mankind may hold absolute
sway over the other. Any strictly enforced legislation on
confidentiality would almost always be harmful in other
ways. For this reason they recommended instead a Code
of Practice, a set of interpretable rules applicable to day-
to-day decisions, but without the direct force of law.
4. Assertions of medical secrecy are often stated in
absolute terms, but are followed by a list of open-ended
exceptions devoid of subsequent regulatory control. The
group questioned the moral force and the practical utility
of such leaky absolutes. They preferred a positive state-
ment of all legitimate uses (including research) to which
medical records might be put, whether at first or second
release; and restriction in these terms.
This retreat from absolutes breached a taboo. The
report did not actually declare that the principle of
Hippocrates was false, but recognised that modern con-
texts sometimes reveal its pragmatic defects. An open
recognition of practical necessities will probably achieve
more than will hard legal regulations, not only for
research and for the benefit of society, but for the effective
protection of confidentiality itself.
E. G. Knox
234 Journal of the Royal College of Physicians of London Vol. 20 No. 4 October 1986
|
PMC005xxxxxx/PMC5371050.txt | Editorial
Who was it who said that travel broadens the mind? Such a fatuous
generalisation; it all depends on what you have in mind when you
travel. The very ease of long distance travel has tended to make it a
trivial pursuit. To our remote forebears every journey was arduous
and needed a toughened body and a determined mind. Celia Fiennes
was a lady of mettle to ride through 17th century England and
produce her extraordinary personal journal. No wonder that Francis
Bacon considered in 1595 that 'Travel in the younger is part of
education; in the older a part of experience.' So what do we make of
our present freedom to visit the world? The hordes of people now
sweeping the skies do not apparently increase the amity of nations. A
week of fish and chips on the Costa Brava transports the body and
leaves the mind at home. Breaking the sound barrier is nothing
compared to breaking the barriers of language and culture. We
seldom stay long enough in another country to appreciate the
problems involved.
Today's doctors certainly do travel. In many specialties visiting the
people concerned rather than just reading about their results has led
to most fruitful international collaboration. Medical students also
travel, usually to exotic places for there elective study. Judging from
their enthusiastic and perceptive accounts their eyes have been
opened to world medicine, a perspective not found in their somewhat
self-regarding medical schools. It is good to think that the College aids
ten students a year to extend their education in this way. The
postgraduate is less fortunate in his travel aims which have to be
geared to furthering his home career. So he learns techniques in
established centres of excellent but does not broaden his mind to
encompass world medical problems. Those that do go to the underde-
veloped countries to help solve local problems give great service to the
community of their choice but may well find that such experience is
detrimental to their career. This reflects badly on their seniors who
stand in judgement.
It would also be naive to consider that the average international
medical congress does anything to foster the concept of medicine as a
global profession. It is very pleasant to get away and meet colleagues
from New York or even Glasgow at a conference in Rio but it gives no
insight into the medical problems of Brazil. The plethora of confer-
ences has lead to the wicked whisper that some physicians are found
more readily in airport lounges than in their departments.
However the ease of international travel has brought the medical
profession closer together in many areas of research and personal
understanding. Hopefully it could support Sir Gordon Wolsten-
holme's concept of world medical action for which he argued most
persuasively in his FitzPatrick lecture (J. Roy. Coll. Phycns, 1985,
p. 17). Most of the time we are busy defending our own corner and see
what we want to see on our journeys. But travel can broaden the well-
intentioned mind.
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 157
|
PMC005xxxxxx/PMC5371051.txt | Book Review
Genetic Biochemical Disorders
by Philip F. Benson and
Anthony H. Fensom. Oxford University Press, 1985. 692
pages. Price ?55.
This is a straightforward, very concise compendium on
inborn errors of metabolism by two authors who have
supervised the Supraregional Laboratory for Genetic
Enzyme Defects. I have found it a useful quick reference
book, but its limitations should be pointed out. There is
no significant overall discussion of the general concepts of
inherited disorders and the ways in which the biochemical
consequences may be harmful, nor of the interaction
between genetic and environmental factors. Neither is it
comprehensive. The reader looking for information on
the renal tubular acidoses, familial periodic paralysis,
pseudohypoparathyroidism, the haemoglobinopathies,
diabetes mellitus and cystic fibrosis, to choose six of the
conditions I used as test cases, will go away empty-
handed. I tried to work out the rationale for what had
been included and what had been left out, without much
success. However, I obtained rapid and excellent infor-
mation on variants of phenylketonuria and glutaric aci-
duria?two of the three relevant conditions which came
my way in clinical practice during the time this review
was gestating. Not surprisingly, it is quite strong on
biochemistry, but it makes no serious attempt to deal with
the 'new genetics', i.e. knowledge obtained from recom-
binant DNA techniques. It is exceedingly well referenced
for the conditions it deals with?over 25 per cent of the
text is occupied by the references. This book is of value as
a lead into many rare conditions which the potential
readership of paediatricians, neurologists, geneticists,
obstetricians, pathologists, medical biochemists and dieti-
cians listed in the preface will occasionally encounter. It
makes no attempt to give the very detailed consideration
of these disorders to be found in Stanbury et al. (The
Metabolic Basis of Inherited Disease) in either the back-
ground, diagnosis or treatment areas. However, the
reader should be able from the reference list to get on to
the right sources rapidly if further details are required.
R. D. Cohen
218 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
|
PMC005xxxxxx/PMC5371052.txt | Physical Disability in 1986 and Beyond
A REPORT OF THE ROYAL COLLEGE OF PHYSICIANS
CONTENTS
Page
INTRODUCTION 161
BACKGROUND
What is Wrong? 162
The Size of the Problem 162
The Principles of Medical Involvement 164
FUTURE EVOLUTION OF DISABILITY SERVICES
The Need for Standards of Care and Audit 165
Basic Criteria for a Disability Service 165
Regional Units 166
District Services 166
Research and Development 168
Organisation and Administration 169
District Advisory Machinery 170
Medical Staffing 170
Education of Medical Students and Postgraduates 171
Timetable 171
Audit Function 172
Costs and Resources 172
GENERIC SERVICES
Disabled Living Centres 173
Housing, Housing Modifications and
Re-Housing 174
The Physically Disabled School Leaver 174
Support Services for Younger Severely
Disabled and Handicapped People 175
Driving for the Disabled 176
Sexual Counselling 176
Head Injury Services 177
Visual Impairment 178
Hearing Impairment 179
Communications Aids 179
Wheelchairs 181
Prosthetics and Orthotics 182
Page
Urinary Continence Services 183
Stoma Care Services 184
Pressure Sores 185
APPENDICES
1. Definitions used throughout the Report 186
2. Prevalence of Physical Disability 186
3. Evaluation of the Services provided by Mary
Marlborough Lodge 186
4. Assessment and Training Facilities for
Re-Learning Driving Skills " 187
5. Communication Aids Centres 188
6. List of Demonstration Centres 188
7. Associations for the Disabled 190
SUMMARY 191
REFERENCES 193
Membership of the College Committee on Disability
Sir Raymond Hoffenberg, KBE, MD (President)
C. B. Wynn Parry, MBE, DM, FRCP (Chairman)
R. Langton Hewer, FRCP (Honorary Secretary)
A. O. Frank, MRCP (UK) (Assistant Honorary
Secretary)
C. J. Earl, MD, FRCP
J. F. Harrison, FRCP
K. S. Holt, MD, FRCP
D. J. Lane, DM, FRCP
D. L. McLellan, FRCP
J. R. A. Mitchell, MD, FRCP
M. D. Warren, MD, FRCP, FFCM
V. Wright, MD, FRCP
TTA. K. Clarke, MRCP (UK)
TJ. R. Hodges, MRCP (UK)
**P. A. Gardner, FFCM
*D. J. Price, FRCGP
D. A. Pyke, CBE, MD, FRCP (Registrar)
D. G. Williams, MD, FRCP (Assistant Registrar)
G. M- G. Tibbs, Hon FRCP (College Secretary)
Miss H. K. Irons (Committee Secretary)
* representative of the Royal College of General Practitioners
** in consultation with the Faculty of Community Medicine
t nominated by the Standing Committee of Members
160 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
INTRODUCTION
The past twenty years have seen major changes in the
pattern of diseases in the Western World. Acute poliomy-
elitis has disappeared, tuberculosis is uncommon, peptic
ulcers rarely require surgery, bacterial infections can
usually be controlled, and the outlook for acute leukaemia
and Hodgkin's disease is much improved.
By contrast, many disabling diseases such as rheuma-
toid arthritis, stroke, multiple sclerosis, Parkinson's dis-
ease and motor neurone disease, remain incurable. Some
of these patients endure much suffering and require
substantial help from the various support services. Dissat-
isfaction with Disability Services in England and Wales
has been expressed both by disabled people and by health
workers. The present Report is written against this
background.
The Royal College of Physicians' Rehabilitation Com-
mittee was established in 1979. It was renamed the
Disability Committee in 1983, thus emphasising that the
problem concerns not only those patients who are likely to
improve (e.g. after head injury or stroke) but also those
whose condition may deteriorate (e.g. rheumatoid arthri-
tis and multiple sclerosis). The Committee felt that it
should produce a document setting out its views as to the
way in which Disability Services in England and Wales
might be developed.
In approaching its task, the Committee felt that it could
not review all aspects of the problem, and that it would be
appropriate to concentrate on the medical aspects of
physical disability (defined in Appendix 1). The Report
considers mainly (but not exclusively) those aspects of
disability that are a responsibility of the NHS as opposed
to, for instance, Social Services. It concentrates on dis-
ability resulting from disorders which are encountered by
physicians and does not deal in detail with disability
resulting from, for example, surgical, orthopaedic, or
psychiatric disorders. The Report analyses particularly
the future role of doctors in the establishment and
operation of Medical Disability Services. The Committee
recognises that there is much overlap with other pro-
fessional groups, especially remedial, nursing, #nd social
work, as well as with other statutory services including
Social Services, Housing, Education and Employment.
We also recognise the important contribution of volun-
tary societies and of disabled people themselves.
We consider that the medical profession has an essen-
tial leadership role in the development of Medical Dis-
ability Services. This role includes the catalysis of local
initiatives and the setting up of services for particular
groups of disabled people. We consider it important that
the medical profession is seen to have a major commit-
ment to the subject of medical disability.
Although the Report concentrates on the physical
aspects of disability, the Committee is keenly aware of the
enormous psychological stresses that are often exper-
ienced by disabled people and their families. The ideas
put forward in this Report concern certain parts of a large
and complex subject. They are not meant to be exclusive,
and should be considered within the total context of
professional endeavour in this field. It is hoped that the
Report will form the basis for constructive discussion and
will assist Regional and District Health Authorities to
review, organise and evaluate Medical Disability Ser-
vices.
The Report is divided into four sections. The first,
entitled 'Background', deals with the evidence that there
are serious shortcomings in the organisation of Disability
Services and also discusses epidemiology and terminol-
ogy. The second, entitled 'Future Evolution of Disability
Services' outlines our recommendations for Regional and
District Services and discusses medical manpower and
administration. The third section deals with 15 specific
areas of disability (e.g. Continence Services, Pressure
Sores and Wheelchairs), which require particular atten-
tion by District and Regional Health Authorities. The
last section includes a summary of the Report's main
recommendations and lists some basic audit standards.
BACKGROUND
What is Wrong?
For many years there has been professional and public
concern about the care given to disabled people. The
response to the recommendations of a number of official
and other reports[l-6] has been inadequate and unsus-
tained[7,8], A survey carried out throughout Great Brit-
ain in 1971 showed that many disabled people who could
be helped by advice, equipment, adaptations and services
were not getting such help[9]. The Chronically Sick and
Disabled Persons Act, 1970, placed an obligation on
Local Authorities to inform themselves of the number of
disabled people and their needs, and to take steps to meet
these needs. Following the activities of the International
Year of Disabled People (1981) there has been increased
understanding of the needs and feelings of disabled
people, who share the same desires, aspirations and rights
as other citizens.
In addition to the national survey mentioned above[9],
there have been many community-based surveys[10] and
in-depth studies and personal accounts published of the
experiences of disabled peoplefl 1,12]. These have in-
cluded accounts of people disabled by rheumatoid arthri-
tis[ 13], multiple sclerosis[14-16], paraplegia[17,18],
strokesf 19-21], , Parkinsonism[22], spina bifida[23,24],
motor neurone disease[25-27], amputations[28,29], can-
cer[30-32], myocardial infarction[33,34], ileostomy and
colostomy[35,36] and incontinence[37].
Certain themes recur throughout the reports and per-
sonal accounts. There are major problems concerning
housing, employment, and the various financial
allowances. There is unevenness of provision between
different Regions and Districts. This was highlighted by
Lady Hamilton in her 1984 Harding Award Address. She
pointed out that there are, for instance, major Regional
differences in medical staffing in rheumatology and neu-
rology. The best staffed Region has six times as many
rheumatologists per head of population as the worst
staffed Region. These reports record a widespread lack of
co-ordination between services which results in frag-
mented help and advice, omissions or duplications of
services, delays in obtaining help, and discontinuity of
help, as the disabled person is referred from one service to
another. Patients with chronic disorders attending for
'follow-up' complain that they are seen by inexperienced
junior doctors who are not familiar with the particular
problems experienced by the patient. A frequent com-
plaint is the inadequate information given to the disabled
person about the nature and expected course of the
underlying condition; about the treatment and the plan of
management of the ensuing disabilities, and about the
opportunities, services and help that are available. Given
sufficient information, a disabled person can choose
certain courses of action and thus retain autonomy. Many
disabled people are concerned about the additional work
and restrictions imposed on the spouses, relatives and
friends looking after them at home. The carers often give
up their jobs, children's contacts and activities become
restricted, social and leisure activities are reduced, extra
costs are incurred, and disturbance at night leads to
physical and mental fatigue.
The picture is not entirely black, and there have been
important initiatives. These include the activities of vol-
untary organisations of all sizes, ranging from the large
national charities to small local groups who together offer
a considerable range of facilities. Various community-
based resources, including the Home Help, Direct Meals,
and Community Nursing Services, make it easier for
severely disabled people to live in their own homes. The
Local Authorities finance adaptations to existing dwell-
ings, and specialised housing has been developed in some
areas. Several agencies provide residential care for se-
verely disabled younger people. Disabled Living Centres
have been established in some areas of the country?
where expert advice is available regarding personal cloth-
ing and equipment for disabled people. Some Districts
operate a Continence and/or a Stoma Care Service.
These various services are provided by a variety of
agencies, including Health, Local Authority, the private
sector, and voluntary services. The result is a patchy
distribution of services, with some areas being very badly
served.
It is clear that Health Authorities can make major
contributions to improving the quality of life for disabled
people. The aim is to enable people with disability to have
access to the various medical services they need, so that
there is the minimum disruption of their lives and
preferred activities. This will involve reviewing local
services, identifying and remedying deficiencies, estab-
lishing collaboration with resources outside the Health
Service, and educating disabled people in safeguarding
their health and avoiding the medical complications of
their condition.
The Size of the Problem
Estimates of the numbers of people with disability in the
population will vary according to the criteria used in
defining disability and its severity, and the intensity of
case-finding. Broadly speaking, in England and Wales,
approximately 10 per cent of the population are physical-
ly disabled (excluding sensory and mental disorders); 20-
30 per cent of these (i.e. 2-3 per cent of the total
population) will be severely or very severely disabled.
The Health District with a population of 250,000 is
therefore likely to contain about 25,000 disabled people,
of whom approximately 6,250 will be severely or very
severely disabled. About 10 per cent of all disabled
persons are aged under 45 years; 30 per cent are between
that age and 64 years, and 60 per cent are 65 years or
older. Overall, more women are disabled than men, but
at ages up to 65, the prevalence rates of disability are
slightly higher in males than in females.
Table 1 gives estimated numbers of people with various
disabilities. Table 2 deals with selected diseases and types
of impairment (for definitions, see Appendix 1). In an
average Health District there will be about 1,810 people
with a wheelchair, about 11,000 persons with regular
162 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
Table 1. Estimated numbers of disabled people and of those who are severely or very severely disabled or handicapped in various
categories in a District with a population of 250,000 people reflecting the national age distribution.
Category
Estimated number in category
Per 10,000 Per 250,000 Per cent
population population severely or very
e.g. typical group e.g. typical severely disabled
practice Health District or handicapped
Estimated number
severely or very
severely disabled
or handicapped in
District
All physically 'disabled' people
National Sample Survey [9]
Local Authority. Surveys [10]
Lambeth Survey [38]
Impaired Hearing
Min. 35 dB HL, at 0.5, 1, 2 &
4 kHz in better ear [39]
Impaired Vision
Less than 6/18 with Snellen
with glasses [40]
Regular Urinary
Incontinence [41]
(Persons aged 15 yrs or more)
Use of Wheelchairs
(See page 68)
670 adults
557
1,150 adults
1,000 adults
52 adults
440
72
16,750 adults
13,925
28,750
25,000 adults
1,300 adults
11,000
1,810
20
30
10
(66-95dB HL)
32
(6/60 or less)
3,350 adults
4,180
4,170
2,500 adults
408 adults
Table 2. Estimated number of persons with major physical disabling conditions and of those who are severely or very severely
disabled or handicapped thereby in a district with a population of 250,000 people reflecting the national age distribution.
Estimated number of
severely or very
severely disabled or
handicapped in District
Based on Harris Survey[9]*
Disabling condition
Osteoarthritis
Rheumatoid arthritis
Ischaemic heart disease
Other heart disease
Respiratory conditions
(excluding cancer of lung)
Stroke (survivors)
Parkinsonism
Multiple Sclerosis
Motor Neurone Disease
Muscular dystrophy
Epilepsy
Paraplegia
Colostomies
Injuries
Head Injuries
Amputations
[42]
[43]
[42]
[43]
[44]
[44]
[44]
[44]
[44]
[44]
[45]
[46]
[46]
Estimated prevalence of
disease/condition
(Various sources)
Per 10,000 population Per 250,000 population
2,900
1,280
250
100
c.700
c.800
55
20
8
1
1
50
16
72,500
32,000
6,250
2,500
17,500
20,000
1,375
500
200
15
15
1,250
400
Major congenital malformations
About 2,500 people per 'District' are treated as
in-patients in hospital each year.
About 675 people per 'District' are treated as in-
patients in hospital each year.
About 30 people per 'District' are referred
annually for the first time to a Limb Centre.
Incidence is about 2 per cent of all live births.
860 all forms and
unspecified arthritis
60
110
115
340
55
80
not known
35
40 (head injuries excluded)
*The Harris Survey deals mainly with physical disability.
urinary incontinence, and 25,000 adults with significant
deafness. The principal causes of severe physical disabil-
ity are neurological disease and arthritis. In the average
Health District there will be 500 people with Parkinson-
ism, of whom 55 will be severely or very severely
disabled. There will be at least 200 patients with multiple
sclerosis and there could be up to 6,000 with rheumatoid
arthritis.
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 153
The- epidemiology of physical disability is discussed at
greater length in Appendix 2 which deals with the
important differences between impairment, disability,
and handicap.
The Principles of Medical Involvement
Historically, rehabilitation of the physically disabled de-
veloped from the speciality of Physical Medicine and
Rehabilitation. This arose largely from the residential
Service Rehabilitation Units in World War II.
Specialists in physical medicine were concerned with
management of chronic disability and with the diagnosis
and management of the rheumatic diseases. In time, the
specialty merged with that of rheumatology and became
known as rheumatology and rehabilitation. With the
expansion of rheumatology in recent years, to become a
sub-specialty of medicine in its own right, its proponents
no longer feel that their work should necessarily be
concerned with the management and rehabilitation of
non-rheumatological disorders. This applies particularly
to disability resulting from neurological disease in which
many rheumatologists have not been trained. However,
many Districts welcome a consultant who can not only
care for patients with rheumatic disorders in the widest
sense (including backache, soft tissue rheumatism, degen-
erative joint disease, and inflammatory arthritis), but also
provide a more general rehabilitation service for chron-
ically disabled people.
England and Wales are almost alone amongst western
countries in having no medical specialty of physical
medicine, or its equivalent. Only a handful of consultants
have a full-time commitment to rehabilitation. In addi-
tion, there are a small number of consultants who have
dual accreditation?usually in rheumatology and re-
habilitation. Some Health Districts do not have any
designated sessions in rehabilitation. It seems probable
that one of the principal reasons for the poor state of
Medical Disability Services in England and Wales is the
fact that there are very few doctors with any formal
professional commitment to the subject. Few have the
experience, time, or responsibility for formulating, pre-
senting, and arguing the case for resources. Planned
investment in the area has been small at both Regional
and District levels.
In the UK there is a well-developed geriatric service
which not only provides for the frequently complicated
medical needs of the elderly, but is also concerned with
their social problems. In many ways it is a Medical
Disability Service for older people. A similar service exists
for children in many parts of the country. However, no
such service exists for the large number of disabled people
aged between 16 and 65 years, who have, to some extent,
become a 'deprived population' with few specific facilities
(e.g. Day Centres) and a paucity of consultants with
specific expertise in the management of their disability
problems.
The Working Party on Rehabilitation Medicine of the
Royal College of Physicians[47] was firmly of the opinion
that 'Rehabilitation is an integral part of total patient
care, and is therefore the concern of all clinicians' and
considered that clinicians, whatever their specialty,
should extend their role and assume at least limited
responsibility for the medical aspects of the rehabilitation
of all patients under their care. However, virtually all
clinicians are fully committed and time has to be found
for them to develop this aspect of medicine. Certainly
there does not seem to be much evidence of major
advances in this particular direction since the Working
Party Report of 1978, and the implications of the recom-
mendations have not, as yet, been explored.
This country, through the NHS, is therefore engaged
in an important, if unplanned, experiment?'Is it poss-
ible to set up an effective care service for the physically
disabled without a substantial specialty of rehabilitation,
or its equivalent?' The view of the medical profession at
the moment appears to be that we should try to do this,
and the remainder of the Report is written on this
assumption.
Terminology (See Appendix 1)
The term 'Rehabilitation' has been used extensively in
the past. Unfortunately, the term lacks any agreed defi-
nition (although a large number have been attempted)
and is widely misunderstood. For example, some people
consider that the term should be confined to the manage-
ment of sequelae of a 'once and for all' insult such as head
injury, or stroke. Others consider that it should include
progressive disorders such as multiple sclerosis and rheu-
matoid arthritis. Historically, rehabilitation has been
linked with rheumatology. This link has now, to a large
extent, been severed. The term "Physical Medicine" is
applied in place of Rehabilitation in some countries. The
term Physiatry is used in North America and the term
Rehabilitation Medicine in Australia.
The terminology used in this Report reflects the
present situation:
1. Services for disabled people are referred to as Disability
Services.
2. Existing consultant posts in rehabilitation or rehabili-
tation medicine are referred to as posts in rehabilitation.
3. The term 'Disability Medicine' is used in this docu-
ment to cover the application of medical and of general
health care services for physically disabled people. The
term is also used in reference to new consultant sessions
that are devoted specifically to the management of disabil-
ity and the co-ordination of Health Care Services for
physically disabled people.
Consultants
The Royal College of Physicians has published reports on
the 'Management of Disabling Chest Diseases'[48] and
on the 'Management of Coronary Heart Disease'[49]. A
Working Party is currently considering the subject of
neurological disability. Rheumatological disability is also
the subject of a Working Party Report, to be published
shortly. By publishing these documents, the College
hopes shortly to be in a position to advise on manpower
and training requirements for each of these specialties?
with particular reference to the management of disability.
164 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
Whatever the details of the final proposal?a substantial
increase in the number of consultant sessions devoted to
disability and its management is likely to be rec-
ommended. This may well involve an increase in the
number of doctors in certain specialties?e.g. neurology,
with some sessions devoted to disability medicine. Some
physical disability falls primarily within the province of
surgeons rather than physicians. For example, orthopae-
dic surgeons are involved with many aspects of disability.
General Practice
The 1978 College Report on Rehabilitation Medicine[47]
recognised the important role of the general practitioner
in the recognition and management of disability. It
commented as follows:
'The great majority of patients, whether suffering from
chronic or temporary physical disability, are living in the
community. The general practitioner, therefore, has a
lynch-pin function of identifying the need for Disability
Services. The general practitioner is likely to be most
effective in helping the disabled patients in his practice if
he is working as a member of a Primary Health Care
Team. The Team needs to have access to, and collabora-
tion with, remedial therapists working in the com-
munity'.
Community Medicine
Community physicians are concerned with the promotion
of health, the prevention of disease and disability, the
assessment of the community's health needs and with the
provision of services to that community and to special
groups within it. They are especially involved with
epidemiology, Health Service planning, and in the joint
planning of services with Local Authorities and voluntary
organisations in respect of child health, young disabled
people, and frail elderly people. They provide the medical
advice to the Social Services, Education, Housing and
other departments of the Local Authorities, and have a
collaborative link with the General Practitioner Services.
Community physicians have an important contribution to
make in developing integrated planning of services, and a
concern that the needs of disabled people are brought to
the attention of the Health Authorities and, as far as
possible, are met.
Occupational Medicine
Occupational physicians have a major responsibility to
prevent disability resulting from accidents or occupation-
al disease. Within the individual workplace, they can
advise on the employment of disabled people. The Man-
power Services Commission is responsible for employ-
ment policy in England and Wales, which includes
providing services to facilitate the employment of disabled
people. One of the resources available is the Employment
Medical Advisory Service, which employs trained occu-
pational physicians to help assess people's suitability for
employment or training, as well as providing medical
advice for the Employment Rehabilitation Centres, and
the Disablement Resettlement Officers, who are respon-
sible for assessment and placement services.
FUTURE EVOLUTION OF DISABILITY SERVICES
The Need for the Setting Up of Standards
of Care and Audit
Before the quality of services for the management of
disability can be judged, standards of care have to be
established. This Report lists some of the services which
need to be provided. Many of these services will be
provided by each District Health Authority, some by one
District on behalf of other Districts, and some by other
agencies. In whichever way these services are provided,
they should be readily available to all disabled people who
require them. Subsequent sections of this Report describe
essential components of the services listed and suggest
simple minimum standards of care. These suggestions
can form the standards against which the provision and
performance of the services can be reviewed. Such re-
views should be carried out periodically in every District
and by each Regional Health Authority. It is particularly
important to listen to the views of disabled people, and of
their spouses or others caring for them at home, about the
provision and use of services. As the services required are
so diverse and are provided by so many authorities, it is
too easy for gaps and unnecessary overlaps to occur. Any
review of the services should seek reports from the various
voluntary organisations representing particular groups of
disabled people.
Basic Criteria for a Disability Service
The remainder of this report outlines our suggestions as
to how Disability Services in England and Wales should
be planned in the future. In making our recommenda-
tions, we have been mindful of the following factors:
1. The urgent need to establish an effective Medical
Disability Service.
2. The importance of taking into account the views of
disabled people and their families.
3. Proposals must be cost-efficient, using existing facilities
where possible.
4. The Service should be based upon the principle that the
management of disability is an integral part of total
patient care and is the responsibility of all clinicians.
5. Certain consultants should have designated responsi-
bility and commitments for services such as Continence,
Stoma Care, the District Head Injury Recovery Service,
and Pressure Sores.
6. There should be a system of internal and external
checks and audit. These should help the service to
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 165
develop in the light of experience and of changing needs.
Plans should be flexible enough to allow for local con-
ditions, whilst at the same time ensuring that a basic
minimum pattern of provision for physically disabled
people is achieved.
7. Regional and District plans should include a timetable
for the development of adequate services, with provision
for review if targets are not achieved.
8. A simple permanent administrative structure should be
set up at both District and Regional level.
Regional Units
We recommend that each Region should have at least one
Unit which would be concerned with certain specific
aspects of disability.
Functions
1. The assessment of severely physically disabled people.
Some severely disabled patients have multiple problems
which require considerable expertise and knowledge re-
lating to a wide variety of techniques and equipment. For
instance, a patient with Duchenne muscular dystrophy
may have as many as 15 different problems, including
difficulty with breathing, difficulty with sitting comfort-
ably because of a severe scoliosis, pain (associated with
skeletal deformity), severe immobility, difficulty with
sleeping (partly due to discomfort) and a wide range of
impaired self-care activities. Such a patient may require a
specially built wheelchair, specialised seating, a moulded
back support, a special bed, and a hoist. In addition, the
relatives and carers will need to be trained in the best
ways of handling the patient. The majority of hospital
physiotherapy and occupational therapy departments are
not equipped to undertake this type of assessment.
A unit catering for patients with severe and multiple
physical disabilities and handicap is Mary Marlborough
Lodge, Oxford, established in 1960. The activities of the
Unit have recently been reviewed and evaluated (see
Appendix 3). This evaluation shows that the Oxford
Region itself generates a substantial number of patients
and that there is a substantial demand for the type of
services offered from far beyond Oxfordshire. It appears
clear from this evaluation and from the experience of
members of the Committee, that facilities of this type
should be widely available throughout the country.
We therefore recommend that each Region should
establish a Unit whose functions would include:
a) The assessment of the severely physically disabled
person?many of whom have multiple handicaps.
b) The provision of appliances, aids and equipment
(including Possum) not readily available from other
centres and some of which may need to be modified or
adapted in the Unit workshops.
c) The training of the disabled person so that he achieves
his maximum potential.
2. The Regional Unit should provide facilities for ortho-
tics (e.g. splints), prosthetics (e.g. artificial limbs), and
difficult wheelchair problems. Some of these functions are
currently provided by the Artificial Limb and Appliance
Centres (ALAC's), and it would seem sensible to incor-
porate these into the Regional Units. This concept was
introduced by the ALAC Review[50], The Unit might
well incorporate a Regional Communication Aids Centre
(see page 179).
3. The Unit could include a Disabled Living Centre (see
page 173) where a wide variety of equipment should be
available for inspection and trial by physically disabled
people, their relatives, and professional workers.
4. It might be possible for the Unit to encompass the
management of certain specific disorders?for example, a
Regional Spinal Injuries facility and/or a Stroke Unit. It
would provide an important service for its own Health
District.
5. The Unit would act as a focus for teaching and training
of professional staff.
6. A major function of the Unit would involve research.
The development and evaluation of the various types of
equipment for disabled people could, and should, take
place in the Unit. The Centres might well become a focus
for the design and modification of wheelchairs and other
equipment.
Siting and Staffing
These Regional Units should be sited in a major centre
and would ideally be linked with a university and a
medical school. The Unit should have facilities for in-
patients and also engineering workshops. There would be
a staff of trained therapists. It is essential to avoid
isolation and in our view the Unit should usually be
situated in the grounds of a District General Hospital
(DGH) to give ready access to a wide variety of medical
specialist skills, and allow for medical 'on call' cover, and
ensure that a close relationship develops with the staff of
the DGH. Rotation of staff in training, both medical and
non-medical, should be arranged. Hostel accommodation
for relatives and for less disabled patients living at a
distance from the Centre, should be available.
We recommend that there should be, at the Regional
Unit, the equivalent of at least two full-time consultants
in disability medicine. The possibility of appointing
consultants with dual accreditation who are still practis-
ing in another specialty, e.g. rheumatology, neurology,
geriatrics or orthopaedics, should be considered.
We consider that these Regional Units are absolutely
essential for the establishment of proper Disability Ser-
vices in England and Wales. The precise way in which
they are established will clearly depend upon local cir-
cumstances, including existing facilities.
District Services
What are the main requirements for Medical Disability
Services within a Health District? We have compiled a
list, which, although not entirely comprehensive, should
form the basis for review and audit. In making our
suggestions we are well aware that there is overlap with
many other organisations, both statutory and non-statu-
tory..These include Social Services, Education, and the
Local Authority.
It is clearly important that the relevant staff, including
the district nurses, in each Health District should be
166 Journal of the Royal College of Physicians of London Vol. 20 No. 3 1 July 1986
adequately trained in the management of disability. The
domiciliary occupational therapists and physiotherapists
are trained to assess the disabled person in his own home.
This service is particularly important.
Generic Services
The Committee has outlined brief criteria for the estab-
lishment of services in 15 particular areas which are
discussed in Section III of the Report. We suggest that all
Health Districts should give consideration to these areas
but in some instances it may be appropriate for certain
facilities to be shared with adjacent Health Districts.
Aids and Equipment Centres.
Housing, Housing Modifications and Re-Housing.
The Physically Disabled School Leaver.
Support Services for Younger Severely Handicapped
People.
Driving for the Disabled.
Sexual Counselling.
Head Injury Services.
Visual Impairment.
Hearing Impairment.
Communication Aids.
Wheelchairs.
Prosthetics and Orthotics.
Urinary Incontinence.
Stoma Care Service.
Pressure Sore Service.
Information about Services for Disabled People
within the Health District
Each Health District should maintain an up-to-date data
base of facilities locally available for disabled people. This
could be accessed using a Ceefax-type system if television
screens were provided in health centres and elsewhere.
This data base should be used to produce a booklet, to be
updated annually, of facilities that are available for
disabled people locally. These lists should include facili-
ties provided not only by the Health Service, but also by
Social Services, voluntary bodies, and other organisa-
tions. This information is needed by disabled people
themselves, and also by doctors and other Health Service
professionals, teachers, social workers, and others. The
lists should include the names and addresses and tele-
phone numbers of local charities and organisations for the
disabled, and advice on how to obtain information about
matters such as wheelchair provision, sexual counselling
and leisure facilities for disabled people.
A list of some of the national organisations and chari-
ties concerned with facilities for disabled people is in-
cluded in Appendix 7 of this Report. More detailed
information can be found in the Directory for the Disabled
(1985) and the Disability Rights Handbook.
Medical Staff
Consultants with Designated Sessions in Disability Medicine
The precise organisation of Disability Services within the
Health District will also depend upon local circum-
stances. A few Health Districts already have a consultant
whose main commitment is to Disability Medicine. How-
ever, the majority do not do so. We make our recommen-
dations on the assumption that it is generally agreed that
individual specialists should supervise the management of
their own disabled patients. It is realised, however, that
this does not always happen at present. In our view, there
should be a number of designated disability sessions in
each Health District. We suggest that, in addition to the
care of his own patients, the consultant would undertake
some, or all, of the following:-
1. Giving advice to consultant colleagues about disability
problems relating to patients under their care.
2. Looking after in-patient facilities for physically dis-
abled people, especially the Young Disabled Unit where
one exists, but also planned short-stay, crisis admission,
holiday relief and terminal care beds.
3. Catalysing the District Health Authority in the pro-
vision of Disability Services. This may involve member-
ship of the District Disability Committee.
4. Being involved in running a number of services
including, for example, continence, splint making, wheel-
chair and stroke disability. In addition, there should be a
commitment to the local Disabled Living Centre.
We regard it as essential that there should be clear-cut
areas of responsibility.
5. Operating a Head Injury Recovery Service. At
present, patients with head injury tend to get admitted
under a number of different consultants in various speci-
alities. We suggest that one consultant in each Health
District should be responsible for implementing the Dis-
trict policy on the management of head injury (see page
177).
6. The consultant(s) would have responsibility for the
training of undergraduates, doctors, nursing and para-
medical staff.
7. As mentioned below, there are important require-
ments for research.
We suggest that there should, initially, be 10-11 disability
sessions per week (the equivalent of one full-time post) in
a Health District and these might be held by two or more
consultants. These consultants, together with the com-
munity physician mentioned below, would be responsible
for the medical input concerned with General Disability
Services, and would, in addition, be responsible for
ensuring that Disability Services in their own particular
discipline were developed.
We have suggested some general guidelines. We wish to
avoid rigid rules, but we consider that the principle of a
substantial number of designated disability sessions held
in each Health District is absolutely essential. These
sessions could be held by consultants from a wide number
of disciplines, including general medicine, rheumatology,
geriatric medicine, neurology, and orthopaedic surgery.
Community Physician
There should be a community physician with designated
responsibility for the development of District Disability
Services. The precise nature and distribution of the
community physician's responsibilities would depend
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 167
upon the medical staffing structure within the Health
District. The responsibilities might include:-
1. Membership of the District and Regional Medical
Disability Advisory Committees.
2. The collection of epidemiological data relating, for
example, to patients suffering with pressure sores, incon-
tinence, head injury, and severe physical dependency.
3. Maintaining a list of severely disabled people within
the Health District who are living at home but are 'at
risk'.
4. Monitoring the inappropriate use of beds within the
Health District. For example, it may be important to
identify patients who are occupying hospital beds for
'social' reasons, or because a long-stay bed cannot be
found.
5. Ensuring that there is an effective District policy for
housing and housing alterations for disabled people. The
person concerned might be responsible for drawing up a
list of priority cases. This work would involve close liaison
with other statutory bodies, notably Housing and Social
Services.
6. Ensuring that the plan for disabled school leavers is
drawn up and implemented (see page 174).
7. Ensuring that a five year plan for Disability Services is
drawn up by the Health District and updated regularly.
8. Compiling annual reports on Disability Services for
the managers and for the District and Regional Disability
Committees, with particular emphasis on cost and effec-
tiveness.
9. Being responsible for running the data base relating to
services for, disabled people and for compiling a booklet
on these services, which would be updated annually.
We see the community physician as having a most
important function in collecting and analysing data,
identifying trends, and acting as a co-ordinator for certain
important clinical groups. We envisage that the com-
munity physician and consultant(s) in medical disability
would work closely together.
General Practitioners
General practitioners have a most important role. The list
of 10,000 people cared for by a group of four or five
principals will include up to 1,000 who are physically
disabled; 200 of these will be severely or very severely
disabled. To function effectively as the primary medical
adviser to disabled people, the general practitioner under-
takes the following:-
1. Defines his patients' problems in physical, psychologi-
cal and social terms. Problem-orientated records can be
helpful.
2. Helps the patient in the management of everyday
maladies to which the disabled population are at least as
prone as the rest of society; the management will often be
modified by the disability.
3. Together with the district nurse and health visitor,
members of the Primary Health Care Team, he provides
information about a wide range of locally available public
and voluntary sources of assistance, advice and support.
4. Helps the disabled person to live with his disability
and his family to support him in doing so.
5. Refers to the social workers, remedial therapists and
other agencies, including voluntary societies working in
the community. He will therefore need to be aware of the
provisions of such services from the National Health
Service, Local Authority, and the voluntary services in
his District.
6. Refers to appropriate consultants, including those
with particular expertise in disability. He would also
make appropriate use of the specific District Disability
Services (e.g. Continence, Stoma Care, etc.)
Research and Development
Disability involves problems that cause much stress and
unhappiness. The costs, both to individuals and to the
State, are very considerable. Many treatment and man-
agement regimes have never been scientifically evaluated
and the task of drawing up criteria for 'model' Disability
Services is seriously hampered by lack of epidemiological
and operational data. There is clearly a need for a
substantial investment in research.
Recent Developments
Developments during the last few years have included the
following:
1. Scientific journals now contain a small but increasing
number of refereed papers relating to disability.
2. The Society for Research in Rehabilitation (SRR) was
started six years ago. The Society is multi-professional,
drawn from a wide variety of disciplines, including
medicine (less than 50 per cent of the Membership are
doctors), the remedial professions, nursing, social work,
psychology, physiology, and engineering. The object of
SRR is to provide a forum for the presentation of
scientific papers relating to causes, prevention, effects
and management of disability.
3. Demonstration Centres.
Twenty-seven Demonstration Centres have been estab-
lished in England and Wales (see Appendix 6) and these
have provided a valuable focus for training and the
development of services.
4. Academic Departments.
There are now two Academic Departments of Rehabili-
tation in the UK (Edinburgh and Southampton).
Future Research
There is an urgent need for the drawing up of validated
audit criteria on which model services could eventually be
based. The establishment of agreed criteria will require
considerable experimentation. The research areas to be
covered are very large, and the following list gives some
examples:-
1. Epidemiology. There is a need for epidemiological
data relating to disability in a number of areas?e.g. head
injury and multiple sclerosis. We need to know the
numbers of people and the costs involved. Community
physicians are well placed to initiate and participate in
this type of research.
2. The development of reliable measures of outcome
168 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
which can be used for clinical audit and research pur-
poses.
3. Research into the natural history and physiology of
recovery.
4. Social implications of disability.
5. Evaluation of equipment, e.g. splints, wheelchairs,
etc.
6. Evaluation of rehabilitation techniques, e.g. assess-
ment of the effectiveness of various types of therapy (new
and old).
7. Evaluation of different ways of providing care, e.g.
home versus hospital for stroke patients. There is also a
need to examine the different ways of improving collabo-
ration between professional staff and between members of
different disciplines.
Implications of Research Needs
More academic units are needed to undertake research
into various aspects of disability. Such units would prob-
ably need to be attached to major hospitals where there is
a steady flow of patients. The proposed Regional Disabil-
ity Units (see page 166) should have an important
function in this regard. Not only would they undertake
research projects, but they would also be concerned with
the training of staff in research methodology. The import-
ance of enthusiastic medical leadership in this field seems
clear.
The Arthritis and Rheumatism Council Research Unit
in Manchester has provided valuable data on the epide-
miology of rheumatic diseases. We consider that more of
these units may be needed and commend particularly the
possibility of establishing research units concerned with
the epidemiology and management of neurological dis-
ability.
Organisation and Administration
We think it unlikely that Disability Services at Regional
and District level will be properly established until a
clear-cut administrative structure is set up. This would
involve committees at both Regional and District levels.
These committees would, amongst other functions, be
concerned with providing an internal audit system for
Disability Services. In making our recommendations, we
have been mindful of four particular points:-
1. The need to avoid unnecessary bureaucracy. The
number of committees should be kept to a minimum and
the membership should be kept as low as is reasonable.
2. The lack of published experience. It is known that
various District advisory bodies already exist. These
operate under a number of different names, including the
District Disability Committee, the Principal User Com-
mittee, and the Health Care Planning Team for Disabil-
ity. To our knowledge, there have been no published
accounts of the workings of these bodies.
3. The fact that a large number of professional bodies,
and individuals, are concerned with providing services.
Within the NHS there are doctors (working in the
hospital and in general practice), nurses and therapists.
Many groups are not part of the NHS, including Social
Services, the Employment Resettlement Service, some
occupational therapists, the Artificial Limb and Appli-
ance Centres, the Department of Housing, and the
Department of Education. All these bodies will need, at
some point, to be involved with various aspects of District
Disability Services.
4. The wish of disabled people themselves to be involved
with discussions relating to the operation of Disability
Services. It will not be easy to satisfy all these require-
ments. Any administrative plans will necessarily be ex-
perimental and subject to modification in the light of
experience.
Each Region and District will need to develop its own
structure. As far as the committee membership is con-
cerned, a number of theoretical options exist:-
1. A membership consisting of doctors only.
2. A multi-professional membership?composed of NHS
employees only (e.g. doctors, therapists, and nurses).
3. The membership could be both multi-professional and
multi-organisational?including representatives of some
or all of the various bodies itemised above?e.g. Social
Services, Housing, etc.
Our suggestion is that Regional Committees should be
multi-professional, but confined to NHS employees. Dis-
trict Committees would probably be multi-professional
and multi-organisational. The lack of co-terminous ad-
ministrative boundaries for, for example, the NHS and
Social Services, is likely to be a significant problem and a
matter which will need to be discussed locally.
Regional Disability Medicine Subcommittee
It is suggested that each Regional Health Authority
should have a Regional Disability Medicine Subcommit-
tee. The Subcommittee would have the following func-
tions:-
1. Being responsible for reviewing supra-District facili-
ties, including the Regional Disability Unit(s).
2. Producing, and updating annually, short and long-
term plans for Regional and supra-District Disability
Services. Realistic targets for the establishment of Re-
gional Disability facilities should be set and the Commit-
tee would be responsible for monitoring these.
3. Reviewing Disability Services in constituent Health
Districts. The Regional Disability Committee would
receive annual reports from each District Disability Com-
mittee. The Committee would also expect to receive
copies of the short and long-term plans for each Health
District.
4. The Regional Disability Committee would produce its
own annual report for the Regional Manager; this would
review the current situation in constituent Health Dis-
tricts, and at Regional level.
It is suggested that the membership of this Committee
might be multi-professional. There would be at least one
representative from each Health District within the Re-
gion. The person concerned would be a member of the
relevant District Disability Committee, and might be its
Chairman. At least one of the full-time consultants in
disability medicine based on the Regional Unit, would be
a member.
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 169
District Advisory Machinery
The District Health Authority will require well thought-
out advice and recommendations on a wide variety of
issues. We suggest that each DHA should have a small
Advisory Disability Committee which would certainly be
multi-disciplinary, and would probably be multi-organi-
sational. It would thus include not only doctors, but also a
social worker and a representative of the nursing and
remedial professions. The Committee would need to
represent both hospital and community interests.
The District Advisory Disability Committee would
draw up an annual report for the District Manager, and
this would be available for the Regional Disability Com-
mittee and for the Regional Manager. It would also draw
up short and long-term plans for the development of
Disability Services within the Health District.
It is important that medical staff locally should develop
a mechanism for the discussion and formulation of its
views. This might be done by a small subcommittee of the
medical staff, which would report to the main Medical
Staff Committee. The committee would include consult-
ants with designated sessions in Disability Medicine and
also the community physician with responsibility for the
development of Disability Services. This committee
would be concerned primarily with the medical aspects of
disability (e.g organisation of stroke care within the
DGH). At least one member of the Medical Disability
Subcommittee would also be a member of the District
Advisory Disability Committee.
The suggested administrative structure is necessarily
experimental. We would strongly encourage Health Dis-
tricts to publish their experience with various types of
committee structure. A national survey of the matter
might be worthwhile. Hopefully, within a short time, the
basis for a nationally applicable administrative structure
will have been established.
Medical Staffing
This section deals with the medical staffing implications
of the recommendations in this Report.
Consultant Staff
Consultants in Disability Medicine working mainly at the
Regional Centre
We have recommended the setting up of Regional Dis-
ability Units and that each Unit should be staffed by the
equivalent of two full-time consultants, whose principal
commitment would be to Disability Medicine. If all the
consultants were to be full-time, then 30-35 full-time
appointments would probably need to be made. How-
ever, if a substantial proportion of the appointees con-
tinue practising in another field (e.g. geriatric medicine
or neurology) then the number required would be great-
er?in order to make up the equivalent of two full-time
posts. There is clearly scope for considerable flexibility. It
should be noted that there are at present only a handful of
posts with a major disability/rehabilitation component,
I
and it is clear that in some cases it will be necessary to
create new posts. ,
Consultants with dual responsibility and accreditation
We recommend that there should be about 10 disability
sessions held in each Health District. We envisage that in
the majority of Health Districts, the sessions would be
divided amongst 2-3 consultants in different specialties.
It is possible that some Health Districts will be able to
identify 'spare' sessions where consultants feel that they
can take on additional responsibilities. However, there
will need to be a significant increase in the number of
consultant posts, many of which will involve dual ac-
creditation (e.g. neurology and disability medicine).
Training of existing consultants in disability skills
Some existing consultants should be asked to take on
designated disability sessions. It is hoped that where
appropriate, the RHA will allow the doctors concerned to
have a substantial period of study leave (perhaps 3-6
months spread over two years) in order to allow him/her
to acquire the requisite skills. Full use should be made of
the Demonstration Centres (see Appendix 6) and special-
ist units. The precise content of the training programme
required will depend upon the experience of the consult-
ant and the particular needs of the Health District.
i
Academic Posts
We have already discussed (page 168) the importance of
research into a wide range of problems involving disabil-
ity. We recommend that there should be an increase in
the. number of academic appointments which concentrate
on Disability Medicine.
Senior Registrars
Full-time Posts
It is, at the moment, unclear as to how many senior
registrar posts will be required in order to achieve the
target of 30-35 full-time consultants in Disability Medi-
cine/Rehabilitation. The number needed will become
clear once Regions have drawn up their plans. In the
short term, it will be necessary to train a number of
doctors at senior registrar level, so that eventually these
consultant posts can be filled. We envisage that some
existing senior registrars in, say, neurology or geriatrics,
may wish to move 'sideways' into Disability Medicine.
Some of the doctors may wish to consider continuing
practising in their primary specialty, whilst allocating the
major part of their time to Disability Medicine. Once the
posts are filled, then the number of replacements required
annually will be small. The posts can be suitable for part-
timers who have domestic responsibilities, but who are of
high' calibre and are otherwise suitably qualified. It is
worth repeating that the short-term aim is to have in post,
within five years, 30-35 consultants working mainly in
Regional Centres whose principal (although not necessar-
170
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
ily exclusive) commitment will be to Disability Medicine.
The wide range of responsibilities listed on page 166
indicates that considerable flexibility in training and
ultimate responsibility is both inevitable and desirable.
% We wish to emphasise the importance that we place on
the consultant posts in Disability Medicine. There will be
considerable clinical and organisational responsibility,
and in addition the Regional Units will have an import-
ant research function (see page 168). It is essential that
? { high quality candidates be recruited.
Dual Training and Accreditation
A substantial number of posts involving dual training and
accreditation should be set up?particularly in neurology,
but also in general medicine, geriatrics and rheumato-
logy. The relevant SAC's should be asked to draw up
training standards as a matter of urgency. In some
instances, there may be proleptic consultant appoint-
ments?the appointee being seconded to appropriate
centres for training in Disability Medicine.
>
Clinical Assistants and Hospital General Practitioner
Sessions
Continuity of care is an essential principle in the manage-
ment of all chronic disorders. We strongly support the
proposition that patients with serious disabling diseases
should be dealt with by doctors who are trained and who
know the patient concerned. Unsupervised follow-up by a
succession of different junior doctors is not good clinical
practice and is generally unacceptable. Clinical assistants
and hospital general practitioners working in out-patient
departments could provide very useful help in the run-
ning of Disability Services. This suggestion should be
tried and evaluated.
Education of Medical Students and
Postgraduates
Any discussion of education and training starts with the
assumption that the management of disability is the
responsibility of all clinical doctors. If this premise is
accepted, then it follows that the subject should be taught
routinely. We consider that in the education of under-
graduates and postgraduates the management of disease
and its consequences should receive similar emphasis as
diagnosis and treatment. Some practical ways in which
this might be implemented include the following:-
1. Disability should be routinely included when a 'case'
is discussed?whether it be on a routine ward round, a
clinical meeting, or a grand round.
2. Examinations should routinely contain questions re-
lating to disability.
3. Disability management should be included in voca-
tional training schemes for general practitioners.
4. Disability and its implications and management
should be discussed in medical textbooks.
Training schedules should include visits to the Re-
gional Disability Centre, a Hospice, a Spinal Injuries
Centre, an ALAC, and one or more Demonstration
Centres. The possibility of attaching undergraduates to a
family, in which there is a disabled person, for the whole
or part of their clinical course, should be considered.
Training should reflect the emphasis being put on the
management of disabled people in the community rather
than in institutions.
Timetable
We are keenly aware of the poor state of Disability
Services in many parts of England and Wales, and that
the recommendations of previous reports (e.g. the Reid
Report on epilepsy[51] and the Tunbridge Report
(1972)[4] have been largely ignored. We think it import-
ant that action on Disability Services be taken in the very
near future, and for this reason we are suggesting a
timetable and a mechanism for ensuring that the Medical
Disability Service is actually set up. In making our
suggestions, we have tried to be realistic and it is fully
appreciated that the recommendations cannot be imple-
mented immediately.
Suggested Timetable
1. July 1986?publication of this Report.
2. End of 1986?the Report should have been read and
digested by relevant organisations and authorities.
3. 1986-1987?We would hope that during these years
Regional and District Medical Advisory Disability ma-
chinery should have been established. By the end of this
time there will be in existence a five-year plan for
Regional and District Disability Services and the siting
for Regional Disability Units should have been identified.
The number of senior registrar training posts required for
future service needs will have been agreed, and the
number of new training posts approved by the relevant
specialist advisory committees of the JCHMT.
4. 1988?In all Health Districts, sessions in Disability
Medicine will have been designated, with the responsibil-
ities for the services outlined in this Report. A sufficient
number of senior registrar training posts approved in
Disability (Rehabilitation) Medicine (many of which are
likely to involve dual approval with another specialty) will
have been established to train the number of senior
registrars required to fill those consultant posts which are
to contain designated Disability Medicine sessions.
5. Early 1990''s?Sessions in Disability Medicine should
by now have been established and filled in all Health
Districts, covering responsibility for the services outlined
in this Report.
A major review of Disability Services in England and
Wales should be taken in the early 1990's to ascertain
whether the targets itemised above have been met. If
there has been no substantial improvement in Medical
Disability Services by the early 1990's, and if no improve-
ment appears likely within the foreseeable future, then
the option of establishing a much larger specialty of
Disability Medicine such as exists in other countries,
should be considered. However, this would almost cer-
tainly be much more expensive than the plan suggested
here. It would probably involve the appointment of at
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 171
least one full-time consultant in disability medicine/
rehabilitation in each Health District.
Audit Function
We have attempted in this Report to draw up some
professional standards for Medical Disability Services.
We have suggested some audit criteria in certain specific
areas (e.g. management of incontinence). It is obviously
important to ensure that the relevant services are actually
established, and the question arises as to how this is to be
achieved.
Much of the responsibility for the provision of services
will fall on Regional and District Managers. However,
they will undoubtedly be under pressure from many other
directions, and in times of financial stringency may find it
difficult to implement the suggestions outlined in this
Report. We think it likely that some form of external
'Watchdog' mechanism will be required to stimulate
Managers and Health Authorities to make sure that
Disability Services are actually established. It may be
these checks should be made by some independent organ-
isation which is not funded by the NHS. A number of
possible organisations exist, including the local Com-
munity Health Councils, the Health Advisory Service,
and The Consumer Association (which has published the
Drug and Therapeutics Bulletin for many years).
It is envisaged that the independent organisation con-
cerned would have access to annual disability reports
produced by District and Regional Health Authorities. In
addition, they should be in a position to undertake their
own checks?e.g. how many Health Districts within the
Region have a trained and designated senior nurse to run
the Continence Service?
The precise way in which the performance of Disability
Services is monitored will require further discussion. We
hope that the monitoring function can be undertaken by
existing organisations. We certainly think it highly desir-
able that a regular review should be undertaken, and
published. We hope that the basic audit standards that
have been suggested in this Report will prove useful as a
basis for the review.
It may be asked why such a special system of review
and audit is required for Disability. We would answer this
question by pointing out that no high quality medical
service has ever been established without a substantial
core of doctors committed to the topic (e.g. geriatrics,
renal failure, spinal injury, mental handicap, etc.). As
indicated earlier in the Report?we are attempting to set
up an effective Medical Disability Service with very few
doctors committed whole-time to the subject. For this
reason, and because of the long history of inaction, we
think that the system of audit and checks that we have
suggested is justified.
Costs and Resources
We recognise that additional expenditure will be involved
in many Regions and Districts if the basic standards of
provision of services and help for people with severe
disabilities, set out in this Report, are to be achieved. The
cost of providing good basic services must, however, be
set against the enormous hidden costs of not providing
them. In many Districts, these concealed costs are being
borne by disabled people themselves or their carers, in
terms of misery, deprivation, loss of access to facilities
enjoyed by the rest of the population, and loss of choice
and autonomy. There are, in addition, direct costs that
fall on their families if they feel obliged to provide
facilities which should be made available to them through
an adequate Disability Service.
We have not carried out a survey to ascertain the level
of present provision. There is no doubt that some Dis-
tricts have good services and some District and Regional
units are pioneers and leaders in the provision of certain
facilities. However, there is evidence, set out at the
beginning of this Report, that there is scope for consider-
able improvement. Without detailed knowledge of ser-
vices currently being provided, it is not possible to
identify what resources are required to implement our
recommendations. For example, the recommendation
that each Region should have at least one Regional
Centre concerned with the assessment of very severely
disabled people, the development of equipment and other
forms of help, and research and training, may require
little action from two or three Regions, some expansion of
an existing Centre or Unit for some Regions, and major
developments in others. Similarly, at District level, the
recommendations concerning consultant sessions in Dis-
ability Medicine, or involvement in a Continence Clinic,
may require no more than revising the contract of a
consultant who is already carrying out the function. In
some instances, however, additional consultant sessions
will be required. Again, the method of funding will have
to be discussed locally. For example?if there is to be a
Disabled Living Centre in each Region?'joint' funding
money may be available. Similarly, where equipment is
not available through the NHS, private companies might
loan samples of such equipment for trial. Voluntary
bodies may be able to raise money for such equipment.
We are well aware that many disabled people require,
and benefit from, 'acute' services and from many techno-
logical advances?e.g. joint replacement and kidney
transplants. It is clear, therefore, that although there may
be some need to transfer resources from the acute to the
chronic sector, this process needs to be done with con-
siderable circumspection. A balance has to be sought, and
this will be helped, the Committee believes, if the present
trend for all specialties to be involved in the management
of disability arising from diseases within their purview, is
further developed, and is backed up by explicit District
and Regional policies.
Additional expenditure will undoubtedly be required,
particularly for the establishment of Regional Centres.
Three areas are currently given priority for funding by
the NHS?mental illness, mental handicap, and the care
of the elderly. We suggest that physical disability should
be a fourth such area.
Our" views on costs may be summarised as follows:-
1. There is clear evidence of major defects in the pro-
vision of medical services for patients with physical
disability (see page 162).
172 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
2. We note the extraordinarily low level of current
investment in medical disability?considering the extent
and size of the problem. We have noted previously that
virtually all other developed countries have substantial
specialties of physical medicine or rehabilitation medicine
incorporating considerable numbers of specialists whose
main professional responsibility is the management of
Medical Disability.
3. Physical disability is expensive, however it is man-
aged. It is obviously important to ensure that money is
spent effectively (e.g. money spent on the prevention and
early treatment of pressure sores may avoid lengthy and
expensive stays in hospital).
4. The Committee recommends that physical disability
should be recognised by the DHSS as an area for top
priority funding.
GENERIC SERVICES
The term Generic Services is used in respect of those
services which are likely to be used by a variety of
disabled patients, but are not necessarily the responsi-
bility of a particular specialty. We have identified fifteen
specific areas. It is recommended that Health Districts
should have a policy on each of these topics. We have
outlined some brief guidelines, and we hope that these
will be helpful to Health Authorities as they draw up and
check their plans for these particular areas. The policy
guidelines have been written on the following principles:
1. There should be agreed professional standards of care
and provision.
2. A system of audit should be established. The audit
criteria should be unambiguous and be based on (1).
3. Clear-cut areas of responsibility should be defined
(e.g. there should be a named consultant in charge of the
District Continence Service).
4. Each Health District should keep records of certain
specific problems (e.g. the number of significant pressure
sores occurring in the District during the year).
5. As far as possible, the costs of each generic service
should be identified and the details published in the
Annual Report of the Health District.
The object of this section is emphatically not to produce
a mini-textbook of Disability Medicine. The purpose is to
demonstrate that it should be possible to set, and achieve,
realistic standards of care in a number of important areas.
Disabled Living Centres (DLCs)
(Previously called Aids and Equipment Centres)
The provision of aids and appliances is one of the most
important activities associated with a District Disability
Service. Aids need to be appropriate both in their func-
tion in the timing of supply. This requires assessment
facilities and an adequate supply procedure. Although
most, if not all, occupational therapy departments, both
in the NHS and in Local Authority Services, do provide
assessment facilities, supply is often very limited and this
may make the assessment irrelevant. There is obviously
no point in recommending an aid if it is not likely to be
provided reasonably quickly. Many Local Authorities
only provide aids associated with a limited range of
activities such as toileting, and there are often large gaps
in what is available. Even when an activity is covered?
the range of products offered may well be limited.
About a dozen DLC's have been opened in this
country. Some Regions (e.g. the South West) do not have
a single Centre. The Centres are usually large rooms (the
size of one or two standard hospital wards) in which a
wide range of equipment is on permanent display. To the
best of our knowledge, no formal evaluation has been
published but experience indicates that they are much
used by both patients and staff. Examples of the kind of
equipment displayed include various types of bed, chairs,
walking aids, and non-statutory electric wheelchairs.
Some Centres include some of the less sophisticated
Possum equipment and British Telecom usually have a
permanent display.
Ideally, all significantly disabled people should live
within easy reach of a Disabled Living Centre. Initially
there should be at least one Centre in each Region. Later,
satellite Centres should be established in each reasonably
sized town. We strongly recommend that adjacent Health
Districts should combine their efforts so that there is a
reasonable scatter of Disabled Living Centres throughout
the country. Rural areas might need to be covered by a
mobile unit.
The Disabled Living Centres would have two principal
functions:-
1. To provide a permanent standing exhibition of a
comprehensive range of aids and equipment with a
supporting information service.
2. To act as an educational centre for staff, volunteers
and patients.
Requirements for Disabled Living Centres
1. To carry as large and representative as possible a
selection of aids and equipment.
2. To ensure that skilled professional advice (e.g. from
nurses, occupational therapists, and physiotherapists) is
available to disabled persons, their relatives and profes-
sionals visiting the Centre.
3. To provide adequate space for assessment, with priva-
cy, of the client with the equipment.
4. To provide information on a wide variety of problems
arising out of disability.
5. To act as a teaching centre for all classes of people
dealing with disability, including such groups as archi-
tects and school teachers.
6. To gather information about the usage of aids and
equipment and feed back information to manufacturers
and other interested parties, including other Disabled
Living Centres.
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 173
Conditions which need to be met when setting up
Disabled Living Centres
1. They must be properly funded with contributions
from both NHS and Local Authority Services, even
where charitable funding is, or was, responsible for the
establishment of the Centre. This activity is well suited
for joint funding.
2. Whoever is appointed to be in charge of the Centre
would need to have a wide experience of disability and its
management. It might be appropriate to appoint a thera-
pist with good managerial skills. Health Authorities
might like to consider the possibility of having a doctor
with designated sessions in the Centre.
3. The therapist appointments should be part of the local
NHS or local Authority manpower establishments to
ensure a proper career structure for the therapist.
4. The Centre could be situated in the grounds of a
hospital, but this need not necessarily be the case and
some successful Centres have been established elsewhere.
An advantage of a hospital site is that staff can be easily
rotated through the Centre. The Centre needs to be
housed in adequate premises with good access and ample
car parking space. There must be sufficient floor space to
allow the display of aids and equipment, and for assess-
ment.
5. A library and information service, including appropri-
ate audio-visual teaching aids must be available. Ulti-
mately, Centres need to be linked together and to be able
to provide information for a computerised data base on
aids, equipment and other aspects of disability.
6. Where it is appropriate that the aid or appliance is
provided from public funds, these should be rapidly
supplied and each Health District must establish with the
appropriate Local Authority or Authorities joint aid
stores which contain stocks of essential items such as
commodes, which can be delivered to the client within 24
hours of being ordered.
Referral to the Centre should be encouraged from any
source, including self referral by disabled people.
Housing, Housing modifications and
Re-housing
The provision of residential accommodation is not pri-
marily an NHS responsibility. However, it is clearly
essential that, when a disabled patient (e.g. after an
amputation or following a stroke) is fit for discharge from
hospital?appropriate accommodation should be avail-
able. Our experience is that a substantial proportion of
hospital beds are currently being occupied inappropriate-
ly by patients who are waiting either for re-housing or for
housing modifications. As in other areas, the problem
involves the need to provide a humane and caring service
that is also related to economics. It seems likely that a
more effective and efficient service could be provided at
little extra cost.[52]
During the last few years there have been important
developments in the housing field, including the setting
up of a considerable amount of warden-supervised ac-
commodation. However, important problems remain,
and these are exacerbated by the complexity of the
administrative system. Many different organisations are
involved, including the Housing Department, Social
Services and the NHS. In many instances, the adminis-
trative boundaries do not coincide. Other problems in-
clude the small stock of appropriate housing for the
disabled, the fact that new houses are still being con-
structed without a downstairs toilet, and long and inap-
propriate delays in effecting housing modifications, such
as the installation of stair-rails and the widening of doors
for wheelchairs.
We think it important that each Health District should
ensure that proper liaison exists between the hospital-
based services (including the occupational therapy de-
partment), Social Services, the Housing Department,
and the Voluntary Housing Associations. Some mechan-
ism must be established which would allow housing
modifications to proceed without prolonged committee
wrangling.
Recommendations
The problems are complex and clearly cannot all be
solved by the NHS. However, the NHS can, and should,
make an important contribution.
We suggest the following:-
1. The Health Authority, Social Services and the Hous-
ing Authority should be represented on a joint committee
(for example, we propose the District Disability Commit-
tee?see page 170), which would be concerned with all
aspects of housing modifications for the disabled. Others
could be co-opted as appropriate, including representa-
tives of voluntary bodies and of disabled people them-
selves.
2. There should be a community physician with specific
responsibility for housing matters (see page 168). He/she
would have specific responsibility for allocating medical
priorities for housing (this would be done after consul-
tation with the appropriate clinician) and for other hous-
ing matters. He/she would probably be a member of the
local Committee (see above) concerned with housing
modifications for the disabled, and would be responsible
for keeping records of the numbers of people with out-
standing housing needs.
The Physically Disabled School Leaver
The problem of the disabled school leaver has been
recognised for many years, but little action has been
taken. The following quotation, taken from a Lancet
annOtation[53], commented:
Handicapped people need sequential care. Yet doc-
tors based in hospitals tend to see their illnesses as
episodic; instead of taking a personal grip on follow-
up, they often leave the patients to organise return
visits. In general, the pre-school leaver and school-
aged person gets adequate continued care, but not
so the school leaver and the young adult. When
these people pass from the care of the Paediatric
Hospital and Paediatric Community Health Ser-
vice, often there is no organisation waiting to take
174 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
over. Handicapped school leavers and young adults
need follow-up services comparable to those that
they had before they left school.
A recent important study was undertaken by a Work-
ing Party set up by the Regional Medical Committee of
the S.E. Thames Regional Health Authority[54] which
set out to investigate the medical needs of the physically
disabled school leaver. It found very little published
information on the subject. It surveyed all the Regional
Health Authorities in England, Scotland and Wales, and
found that the majority of Regional Health Authorities
made no specific provision for, nor were investigating,
this group of patients. It also found in its catchment area
that:-
1. There were inadequate routine medical examinations
for the disabled child, leading to lack of understanding of
his future needs.
2. There was lack of liaison between the School Medical
Services and those services which would be responsible
for the care of the disabled child when he or she left
school; this included the District General Hospital and
the Primary Care Team. There was no adequate arrange-
ment ensuring that the disabled child was referred to the
appropriate discipline for ongoing adult medical care.
The parents commented that there was lack of communi-
cation between them and the medical and caring services
concerning the facilities that were available, such as
appliances, wheelchairs, and finance.
3. Orthotic appliances and wheelchairs were frequently
unsatisfactory.
Recommendations
Our recommendations are based partly on the findings
of the S.E. Thames Working Party which suggested
that a pilot study should be set up to assess the
practical implications of its recommendations, and this
we support.
1. Every Health District should have a written policy on
the subject of the physically disabled school leaver.
2. Each District Health Authority should have a District
Handicap Team for children. This team may be based in
a Child Development Centre or in an out-patient depart-
ment. The leadership of this multi-disciplinary team may
be a consultant paediatrician with special experience in
complex handicap, and/or paediatric neurology, but may
be a community paediatrician.
3. Early in the year before leaving school?the physically
disabled child should be the subject of a case conference at
which there is medical (representing both the paediatric
and adult services), educational, employment and Social
Services representation. Whenever possible, parents
should be encouraged to attend such conferences. The
careers adviser and the DRO would also be involved.
4. At the final school medical examination of physically
disabled school leavers there should be a full clinical
examination and all the various disability problems would
be reviewed. Hopefully?this exercise would be the cul-
mination of a programme which began when the various
disabilities were first recognised. If necessary, there
should be referral to an appropriate consultant or Assess-
ment Centre where the future needs of the disabled school
leaver could be further explored.
5. An accurate Register of disabled school leavers in each
Health District should be compiled, with a senior medical
officer, perhaps the community physician, made respon-
sible for organising and assessing the ongoing care of the
individual disabled school leaver. It is suggested that each
child should remain on the Register for three years.
There should be liaison with the various services, medi-
cal, social, educational and employment.
6. The paediatric team at the District Hospital level
should develop a transfer procedure that would ensure
continuity of care for disabled school leavers who will
require ongoing adult medical care.
7. Appliances and wheelchairs should be checked at
regular intervals by a designated person.
Support Services for Younger Severely
Disabled and Handicapped People
Every district contains an important group of severely
disabled people below retirement age. Cerebral palsy is
the principal cause of the disabilities that date from birth.
Of those that are acquired, the principal causes are
rheumatoid arthritis, multiple sclerosis, stroke, and injur-
ies of the brain and spinal cord. A Royal College of
Physicians' Report (about to be published) will give
details of the epidemiology and discuss many aspects of
the support and care which these people require[55].
In both public and voluntary sectors, there has been a
tendency, until quite recently, to concentrate on the
provision of residential care. It is now recognised that
many people with severe disabilities not only live in the
community, but prefer to do so, provided that adequate
facilities exist. Improved community services have in-
creased disabled people's living options, but much re-
mains to be done[56], A balance has to be maintained
between the desire of many younger people not to be
identified with the 'elderly' and needless duplication of
facilities caused by the rigid segregation into two age-
group categories.
If younger disabled people are to live in their own
homes, then certain criteria need to be met:-
1. The house must be suitable. Necessary requirements
may include fittings and space for wheelchair living, and
for storage of special equipment, wide door-frames, ready
accessibility to shops, post offices and bank, and special
provisions to ensure safety.
2. The support services must be adequate, and when, as
is usual, responsibility falls heavily on one or two carers,
these people must not be subjected to unmanageable
workloads. Provision of 'respite care' facilities is often
crucial, as are day centres, residential homes, and a
variety of hospital-based services.
3. Helping a disabled person to find an occupation and/or
leisure activity is often highly desirable, and is frequently
essential. Day centres and special workshops are a partial
solution, but access to activities in which able-bodied people
participate may be of even greater importance.
4. Changes in the underlying illness and/or disability
may require reassessment of the subject's needs, e.g. a
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
flare-up of multiple sclerosis may suddenly lead to incon-
tinence and inability to walk. Efficient assessment ser-
vices must exist in the Health District.
5. Realistic contingency plans should be prepared in the
event of crises such as the development of intercurrent
illness by disabled people or their principal carers.
Recommendations
1. The Health District should keep an up-to-date list of
the severely disabled people among its population (al-
though it is acknowledged that the methodology for
keeping such lists is yet to be properly developed). We
suggest that this task could be undertaken either by one of
the designated consultants in Disability Medicine, or by
the designated community physician.
2. Support services for the young physically disabled
would be a responsibility of the District Disability Com-
mittee. This Committee would be expected to produce an
annual report for the District Manager. The report would
include matters itemised below (3-6).
3. The stock of houses suitable for disabled people would
be reviewed annually. A similar exercise would be con-
ducted for houses under construction or planned.
4. There should exist, somewhere within or near to the
Health District, some permanent residential accommoda-
tion for the most severely physically disabled patients.
The adequacy, or otherwise, of this would be reviewed
annually.
5. The residential accommodation could include pro-
vision for intermittent planned short-stay, and for coping
with occasional crises. Periods of short-stay can often be
combined with reassessment of existing problems and
active intervention, if appropriate. Some carers are reluc-
tant to allow their dependants to go into residential homes
or hospitals, because they fear that the care will be less
good than that provided at home. For these reasons, it is
essential that the staff involved are present in sufficient
numbers. There must be access to the various skills
represented in a multi-disciplinary team (particularly
including remedial therapists).
6. A Day Centre for younger disabled patients should be
available.
Driving for the Disabled
Car driving is an essential constituent of independence for
many people. The loss of the ability to drive a car can be
one of the most devastating results of illness and injury.
Additionally, the ability to drive a car is often the key
factor in finding and keeping employment.
It is not always recognised that many patients with very
severe disability are still able to drive suitably adapted
vehicles. Thus, some tetraplegics and most paraplegics
can drive. Some stroke patients can also drive. Problems
that virtually preclude driving include severe athetosis,
uncontrolled epilepsy, and hemianopia.
There have recently been considerable advances in
technology which are enabling an increasing number of
disabled people to re-start driving.
The majority of Health Districts do not provide specific
assessment and training facilities for re-learning driving
skills. However, a variety of options are available and
these are listed in Appendix 3.
We recommend that each District Health Authority
should review the local facilities for the assessment and re-
training of patients for driving. We regard it as essential
that each severely disabled patient in whom there is the
slightest possibility of re-starting driving should be able to
be assessed without undue difficulty.
Sexual Counselling
In these days when the media seem to assume that sexual
athleticism is a part of normal personality?it is particu-
larly important that the physically disabled should not be,
or feel, at a total disadvantage. Doctors need to recognise
that the vast majority of people?however badly disabled,
have sexual needs[57].
Sexual dysfunction may occur in disabled people for a
considerable number of different reasons. Particular
problems are likely to be experienced by patients who
have a urinary or supra-pubic catheter, colostomy, mas-
tectomy, or severe facial disfigurement due to burns. The
doctor is frequently in a position to offer helpful advice.
Examples include:-
1. The treatment of depression, which is very common
amongst disabled people, and is an important cause of
impotence.
2. A knowledge of the effects of drugs may be helpful?
particularly those that have an effect on potency.
3. Genetic counselling may be helpful, as some patients
have an unspoken but unwarranted fear that they may
pass on their disease (e.g. multiple sclerosis) to a child.
4. Many patients are anxious about the effect of sexual
intercourse on their disease?this is particularly liable to
occur in patients who have suffered a myocardial infarc-
tion or a stroke. Medical 'permission' to have sex can be
important.
5. Analgesics, given before intercourse, may help
patients with an inflammatory arthropathy. Counselling
about positions, appropriately placed cushions and pil-
lows, may be helpful in relieving discomfort.
6. Orthopaedic operations may be helpful in improving
mobility (e.g. hip replacement in a patient with severe
osteo-arthritis).
Some severely disabled patients are not capable of under-
taking full sexual intercourse and may need advice on
other ways of achieving sexual gratification.
Recommendations
1. Counselling advice should be available by someone
who is knowledgeable both about sexuality and physical
disability. Sometimes advice can be given by the general
practitioner, or the hospital consultant. In other in-
stances, more detailed help may be required, and this can
sometimes be provided by a psychiatrist or psychologist
who has developed an expertise in the subject. SPOD
(Sex and Personal Relationships of the Disabled) is a
voluntary organisation which provides information sheets
and is sometimes able to provide counselling.
176 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
2. Patients who are being looked after in long-term
residential accommodation should be provided with pri-
vacy and the opportunity for sexual contact, if this seems
appropriate. (This provision is frequently not met in
Units for the Younger Physically Disabled.)
3. The management of sexual problems in the physically
disabled should be included in both undergraduate and
postgraduate educational curricula.
Head Injury Services
In our experience, head injury services are frequently not
well organised and there is considerable scope for im-
provement. This is occurring despite the obvious heavy
economic cost, both to the State, and for individuals.
These costs are incurred as a result of a number of factors,
including the use of a considerable number of hospital
beds, heavy use of staff time, and the consequences of
unemployment. There is evidence that some patients are
inappropriately placed. For instance, eight patients with
head injury were found to have been in the acute wards of
a London teaching hospital for up to two and a half years.
Six of these were said to have potential for rehabilitation,
but apparently had nowhere else to go[58].
The majority of Health Districts do not appear to have
developed specific facilities for the management of dis-
abled head injured patients. A similar position exists for
the immediate post-traumatic period, although this mat-
ter is not strictly within the remit of this Report. In some
hospitals, a neurosurgical or neurological opinion cannot
easily be obtained. Head injured patients are frequently
scattered among many different wards, thus making it
difficult for the staff to acquire a reasonable level of
expertise. Research in these circumstances is usually not
possible, and the MRC Working Group[59] suggested
that Assessment and Therapeutic Units should be estab-
lished, where patients from several Districts could attend
during the early months after the acute brain damage.
There seems to be little evidence that Health Districts
have acted on this suggestion, although a successful
experiment, involving the admission of head injured
patients to one unit, has recently been conducted at the
Edinburgh Royal Infirmary[60].
There is some evidence that severe post-traumatic
behaviour disorder can be lastingly improved by beha-
vioural modification techniques[61]. The present position
relating to head injury Disability Services has been
summarised in two recent articles by Gloag[62].
Epidemiology
Field[63] estimated that there are about 7,500 major head
injuries annually in England and Wales (34 per Health
District of 250,000 people). About eight patients per
Health District will be left with a severe permanent
disability. The MRC Group on Stroke and Head In-
jury[59] estimated that 250 persons with head injury per
100,000 population (625 per Health District) are ad-
mitted to hospital annually. This figure corresponds
reasonably well with the figure of 675 given in Table 2.
The prevalence of serious head injury disability is prob-
ably about 150 per 100,000 population (375 per Health
District).
Males outnumber females by about two to one. About
50 per cent of those admitted to hospital are under the age
of 20 years. Road traffic accidents account for 33-37 per
cent of head injured patients admitted to hospital[63].
The data relating to head injury disabilities are, in
general, not of high quality and many are out of date.
The problem is compounded by the changing patterns of
injury resulting from a variety of factors, including seat-
belt legislation. Head injury is an excellent example of a
topic where up-to-date epidemiological information is
required.
The Nature of the Deficits
Closed head injury produces a number of different, and
overlapping, deficits. These may be roughly characterised
as follows:-
1. Cognitive disorders. Patients may experience prob-
lems with learning, language, and memory. In addition,
there may be difficulties with concentration and atten-
tion. These patients are frequently described as being
'poorly motivated'.
2. Emotional difficulties. Irritability is common occur-
ring in 63-71 per cent of cases, in a recent study by
McKinley et al. [64] Mood swings and severe depression
also occur.
3. Behavioural disorders. These include irrational, anti-
social and disinhibited behaviour. A few patients become
violent.
4. A proportion of patients have associated 'physical
defects' including hemiplegia, speech disorders and epi-
lepsy. Some have multiple fractures.
The profound effect of change in personality and mood
on the relatives has become recognised[65]. Families tend
to feel lonely, isolated and under stress for many years. In
addition?there are obvious financial and economic con-
sequences.
Many of these problems do not readily fall within the
province of conventional psychiatry. Nonetheless, psychi-
atrists can have an important role to play. Neuropsycho-
logists are trained in the assessment and management of
many of the problems, but unfortunately very few are
available, and most Health Districts do not have the
benefit of their services.
Some patients with mild/moderate head injuries appear
to recover quickly. However, some have intellectual and
behavioural disorders which are not always recognised.
These patients are in danger of losing their jobs if they
return to work too early. A case can be made out for
ensuring that they have at least one routine neuropsycho-
logical assessment.
Basic Criteria for Head Injury Services within an
Average Health District
1. Every Health District should have a written policy for
the management of head injury?both in the acute and
the recovery phase. This should be updated regularly.
2. Statistics should be kept and reviewed regularly.
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 177
These would include the number of cases, severity, bed
occupancy, and some measure of outcome. An estimate
of head injury costs to the Health District should be made
annually. We suggest that this information should be
available in the annual Report of each Health District.
3. There should be a named consultant in each Health
District who would be in charge of the Head Injury
Recovery Service. He would have allocated sessional time
for this work. It might also be appropriate to identify a
consultant who would 'run' the acute head injury service.
In some instances this job could be undertaken by the
same consultant. Consultants from a variety of disciplines
could be involved in the Recovery Service?including
neurology, neurosurgery, psychiatry, and general medi-
cine.
4. Patients in the acute stage (the first 1-2 weeks) require
intensive nursing and are probably best cared for where
there are other similar patients (e.g. those who are
suffering the effects of an acute stroke).
5. Patients with significant head injury in the recovery
phase (3-30 weeks) should be managed on a ward where
the staff are fully trained. The Health District would
probably not generate sufficient head injured cases to
justify a specific ward dedicated to head injury. We
suggest that these patients might be 'mixed' with patients
who have suffered a stroke and other forms of allied
neurological disability (e.g. multiple sclerosis). Patients
with other disorders could be included in the rehabili-
tation ward?depending on the particular circumstances
of the hospital.
6. Special facilities will probably be required for severe
behavioural and emotional problems. The District Psy-
chiatric Service should be actively involved with this
group. Specific provision should exist for the manage-
ment of noisy and aggressive patients.
7. Follow-up. There should be a system to ensure the
effective follow-up of all patients with a significant head
injury. A register should be kept of such patients. A
clinical psychologist (preferably a neuropsychologist)
would be the appropriate person to supervise the long-
term care of patients with severe residual cognitive
problems.
8. Employment. There should be facilities for the assess-
ment and re-training of head injured patients.
9. Day care. Many patients with severe residual disability
impose an enormous strain on their families. Some form
of day care facilities for this younger group of patients is
required. We do not think that it would be suitable for the
younger patients to be managed in a geriatric day
hospital.
Staff
We consider it essential that there should be a named
consultant in charge of the running and development of
the Head Injury Recovery Service. We also recommend
that a psychologist should be appointed, and he/she
would work closely with the consultant. Other staff will
also need to be recruited and trained. This operation
would include social workers, remedial therapists, and
nursing staff.
Other Comments
Although the scale of the problems posed by head injury
can be predicted from published surveys, there is insuffi-
cient evidence to identify the features that would consti-
tute a model service. The sporadic placement of isolated
patients in wards such as general surgical and general
orthopaedic wards is widely regarded as inappropriate
and has been a very considerable barrier to the conduct of
clinical research in this field. The alternatives of a general
rehabilitation ward in the District Hospital, or a District
head injury ward, or a Supra-District (or Regional) Head
Injury Unit have not yet been evaluated. There is an
urgent need for research into the optimum organisation of
the in-patient care of head injury rehabilitation and also
into the techniques of cognitive and behavioural therapy
employed in such units. It is essential that current Head
Injury Services are evaluated and that a detailed system
of audit is written into the operational policy of all head
injury units.
Many patients are helped by Headway, a voluntary
organisation concerned with the support of head injury
victims and their families. Referral to Headway should be
made in all appropriate cases.
Visual Impairment
We fully appreciate that the medical responsibility for
problems of vision and hearing rests primarily with
clinical departments of ophthalmology and otorhinolar-
yngology. But, as many patients with impaired limb
function also have these problems, we thought it appro-
priate to include short sections on visual impairment and
defective hearing.
Visual impairment is defined as corrected vision of
lower than 6/18. The prevalence of visual handicap was
found to be 520 per 100,000 population[66]. An average
Health District of 250,000 would thus generate about
1,300 visually impaired people. Five per cent occur under
the age of 16; 24 per cent in persons of working age, and
the remainder in elderly and old people. Major causes are
cataract, macular degeneration, diabetic retinopathy,
glaucoma and retinal detachment.
Clearly, each Health District will require a detection
service for preventable and treatable causes of blindness,
such as glaucoma, cataract, and diabetic retinopathy[67].
This would involve the appropriate training of opticians
and general practitioners. It is assumed, also, that each
District will have ophthalmic services for the treatment of
ocular disorders, for example, cataract.
In setting up a District Low Vision Service a close link
will need to be maintained with the Social Services
Department and with the various voluntary bodies. The
suggested basic components include the following:
1. Each Health District should have a written policy.
2. There should be a consultant ophthalmologist with
designated responsibility and sessions for the manage-
ment of visual impairment. This consultant would be
expected to act as a catalyst for the setting up and
operation of the District Low Vision Service.
178 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
3. There would be an optician with designated sessions
for the management of visual impairment.
4. A Low Vision Clinic, to which there would be open
access, including by self-referral. The Clinic would pro-
vide an assessment and follow-up service for patients with
visual handicap (both total and partial blindness), as well
as other visual problems including hemianopia and diplo-
pia. The Clinic staff would be expected to undertake
home assessments and to keep in regular touch with the
patients. They would give advice on simple measures to
overcome visual problems, including those involving
housing, good lighting and the use of contrast. The staff
would be knowledgeable about the various types of
magnifiers and telescopic lenses. Training in various
compensatory techniques, including eccentric fixation for
patients with macular degeneration, should be available.
A supply of equipment should be available for display and
trial by patients.
5. There should be a domiciliary service?so that elderly
and immobile patients can receive advice in their own
homes.
6. There should be a static display of equipment for the
visually handicapped.
Hearing Impairment
Taking an average hearing level of 35 dB or more over
the range 500-4000 Hz in the better hearing ear as
significant impairment, the prevalence of such impair-
ment is around 10 per cent in the adult population of the
UK[39], This figure rises to 75 per cent in those over 70
years old. Significant sensorineural hearing impairment
in the newborn is found in approximately one case per
1000 live births. From these figures it would appear that
hearing impairment is one of the most widespread of all
physical disabilities having a marked effect on the ability
to communicate socially and in the work place.
In most Health Districts, the Hearing Impairment
Service will be organised by the local ENT Department.
The following are some suggested criteria for the setting
up and running of District Services:
1. There should be a written District policy for the
management of hearing impairment.
2. There should be a named consultant with designated
responsibility for hearing assessment and the provision of
services for hearing impairment.
3. A Hearing Assessment Clinic should be held regularly
within the Health District. Ease of access is important,
bearing in mind that much hearing impairment occurs in
elderly people.
4. There should be a fixed site Clinic. This could, if
appropriate, be combined with other Disability Services
such as those concerned with visual impairment. The
Clinic would have several sound-proofed rooms for as-
sessment. There would be a static display of equipment
for the hearing impaired ('environmental aids'), for
example visual doorbells, television listening devices and
telephone amplifiers.
5. Clearly defined links should be established with the
Social Services Department which is empowered to pro-
vide environmental aids.
6. Specific services should be available for the assessment
and management of hearing deficit in small (pre-school)
children. This will require an appropriately trained au-
diological scientist with access to the necessary equip-
ment.
7. The Hearing Assessment Clinic should have facilities
for the management of tinnitus.
8. Domiciliary Services. Many deaf people are living in
residential homes for the elderly. Others are too disabled
to easily attend clinics. There should, therefore, be a
domciliary service for the assessment of hearing impair-
ment and the provision of aids.
9. Each Health District should have a hearing therapist
who would provide support and after-care for deaf people
(for example, running classes and visiting people in their
homes). The duties of the hearing therapist would include
teaching lip-reading and sign language, and giving advice
on environmental aids. The therapist would also be
concerned with the education of institutional (old people's
homes) and hospital staff in ways of communicating with
deaf people.
Communication Aids
In each Health District there are a substantial number of
patients who are unable to communicate in the normal
way. Examples of communication disorders include: cleft
palate, laryngectomy, bulbar involvement in motor neur-
one disease, and writer's cramp. Deafness is considered
elsewhere. Many patients can be helped by electronic, or
other devices termed 'communication aids'. Space-age
technology has had a major influence in this area, and a
large number of devices are available in a rapidly chang-
ing field.
A 1972 figure[68] of 1200 persons with impaired speech
in a population of 250,000 (the size of the average Health
District) is now thought to be an underestimate as a
current review[69] suggests that the average Health Dis-
trict contains 800 persons with severe communication
disorders with a further 1600 with less severe but signifi-
cant problems.
Table 3. Medical diagnoses of 193 patients referred for, and
recommended aids, at the Frenchay Communication Aids
Centre in 1984/5.
Number %
Progressive Neurological Disease?
Motor Neurone Disease, Parkinson's Disease
and Multiple Sclerosis 68 35
Stroke 29 15
Cerebral palsy 29 15
Head injury 23 12
Miscellaneous (Including Laryngectomy and
Glossectomy) 44 23
Communication aids are of particular use to patients
whose language function is intact, but who, for some
reason, cannot speak and/or write. They are not usually
of use to patients with dysphasia, where there is a
disturbance of linguistic ability.
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 179
The main communication systems in use are:
1. Sign and letter systems?e.g. Deaf Alphabet, Maka-
ton, and Amarind.
2. Symbol systems?e.g. Bliss Symbolics (the patient
points to a symbol to represent an expression).
3. Low technology aids to communication?e.g. pointing
boards, pictures and word charts.
4. Medium technology aids?e.g. Canon Communicator
and the Cambridge Lightwriter.
5. High technology aids for communication such as
speech synthesisers and computers.
It is clearly important that patients should not be
supplied with equipment which is inappropriate. Each
patient must be individually assessed and this will involve
an analysis of the precise type of communication defect,
physical, visual and cognitive abilities, as well as his
educational background and the prognosis of the under-
lying disease. The following are the suggested criteria for
an adequate Communication Aids Service.
Recommendations
Assessment
It should be possible for all patients to be assessed by a
speech therapist, and sometimes by other professional
staff, including an occupational therapist, teacher, and
sometimes an engineer.
Equipment
1. A wide range of equipment should be available for trial
purposes.
2. The patient must be able to acquire the requisite
equipment quickly. This is particularly important for
patients with rapidly progressive disorders such as motor
neurone disease.
3. Each patient and his family should be properly in-
structed in the use of the equipment.
4. Most patients require prolonged follow-up to ensure
that their equipment is functioning properly and is the
most suitable and up-to-date device. Different aids may
be needed as the patient's environment or condition
changes.
Hospitals
Sign, letter, and hospital picture boards should be avail-
able in wards and Intensive Care Units where there are
patients with major communication difficulties?for
example, after a tracheostomy. Assessment of each situ-
ation by a speech therapist is desirable.
Regional and District Services
Ideally, all patients should be within a reasonable dis-
tance of a Centre that can provide a Communication Aids
Service. We recommend that each District should have
the ability to undertake simple assessments. More com-
plicated needs would be dealt with at a Regional Centre.
Some Health Districts should consider establishing a
mobile Communication Aids Service for patients in iso-
lated rural areas.
Regional Unit
The Regional Unit should be situated in the speech
therapy department in a major hospital. It would ideally
have links with the university, occupational therapy, and
an engineering department. It should be staffed by two
full-time speech therapists, and there should be some
occupational therapy sessions and appropriate clerical
help. Each Centre would have the capacity to assess
patients with a wide variety of communication disorders,
and have available a wide range of communication aids to
be tried out by each patient. In addition, the Centre
would hold a limited number of aids available for imme-
diate loan (whilst the equipment was being ordered from
the appropriate firm).
Because many patients have to travel a substantial
distance?we recommend that there should be three or
four residential places (some of which could be in hostels)
so that patients could attend the Communication Aids
Centre over a number of days. The Regional Communi-
cation Aids Centre would have an important educational
function and run courses for professional staff.
Services in Individual Health Districts
There should be a small Communication Aids Centre,
offering specific expertise, somewhere within each Health
District. In certain areas it might be possible for this
facility to be shared between Health Districts. This
limited Communication Aids facility would be contained
within a speech therapy department. One of the speech
therapists would be expected to have a sessional commit-
ment to the subject, and there would need to be appropri-
ate cover for sickness and leave. A small amount of
equipment would be held?including the more commonly
used communication aids. The District Communication
Aids Centre should have a close link with the Regional
Centre. At both Regional and District levels, the Com-
munication Aids Centre could be combined with a Dis-
abled Living Centre (see page 173).
Funding
The setting up of a Communication Aids Service will
inevitably involve some expense. It is likely that some
additional staff will be required. Equipment for demon-
stration purposes will need to be provided. We also think
it highly desirable that each Communication Aids Centre
should hold a 'bank' of the more commonly used aids.
These could be loaned out to patients and recalled when
no longer required. Some of the cheaper aids could be
purchased by patients themselves.
Aids may be funded for individual patients by Social
Services, Manpower Services Commission, or the Edu-
catidn Department. More frequently the patient would
qualify for an aid, on consultant prescription, from the
NHS. Each Health District will have to ensure that the
necessary funds for these aids are available. A list of
180 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
Communication Aids Centres in England and Wales is
given in Appendix 5.
Wheelchairs
The provision of wheelchairs is the responsibility of the
Artificial Limb and Appliance Service (ALAC), which is
directly responsible to the DHSS. In Scotland, this
service has been incorporated into the Health Boards. An
enquiry into the future of the ALAC Service has recently
been published[50].
Wheelchairs are provided for people of all ages and
sizes, and for widely disparate patterns of disease and
disability. Data collected during 1973-1976 suggest that
about two thirds of users of wheelchairs are above
retirement age; 5 per cent are in paid employment; 5 per
cent of wheelchairs are privately acquired, and one
person in five will have two or more wheelchairs, with
about 20 per cent requiring non-standard chairs[70].
Figures derived from the Scottish Home and Health
Departmental] indicate that the number of chairs per
1,000 population increased from 1.2 in 1960 to 4.0 in
1970. Recently the Report on ALAC Services in Eng-
land[50] found that 362,000 people have a wheelchair.
Most elderly use a chair once a day; 15 per cent were
totally reliant on the chair, using it on average for 64
hours a week. If these latter figures are accepted, the
average group practice (with a list of 10,000) will have 72
persons with a wheelchair and there will be 1,810 persons
with a wheelchair in each Health District with 250,000
people.
Audit
Fenwick[70] found that 9 per cent of his sample were 'not
very satisfied'. Moreover, the longer a chair was used the
more dissatisfied the user. Delay in the provision of
wheelchairs was unsatisfactory for some people, 22 per
cent waited for more than eight weeks.
The Association for Spina Bifida and Hydrocephalus
told the recent ALAC Review Committee that nine out of
10 of all young people with spina bifida are in wheelchairs
which are unsuitable, needing adjustment or repair. A
representative from Mary Marlborough Lodge told the
Review Committee that 10 per cent of severely disabled
people have wheelchairs which are unsafe or completely
unsuitable. A recent survey in Leeds[72] showed that 77
per cent of hospital wheelchairs were defective; 57 per
cent had tyres which were soft or flat, and 61 per cent had
defective brakes. Similar results were found by Young et
al. [73],
Needs of Wheelchair Users
Wheelchairs are required to fulfil a number of functions,
which include mobility within the home, within the
immediate vicinity of the house including the garden, and
also for longer distances, including travelling to and from
shops and public houses. Many patients need to be able to
travel in a car, and so will require a chair which can fit
into the boot. Comfort is important; some patients are
likely to spend a large proportion of the whole day sitting
in their chair.
A number of patients have particular problems, such
as:
1. Gross trunk instability?necessitating side supports.
2. Scoliosis, requiring a moulded cushion.
3. Hemiplegics, with only one functional arm and leg,
have difficulty propelling the chair themselves.
4. Incontinence.
Common Problems
Experience indicates that problems with the Wheelchair
Service include:
1. Slow provision.
2. Lack of instruction in usage and maintenance.
3. Difficulty with obtaining non-standard wheelchairs; it
can take many months to get an appropriate chair.
4. Some chairs are unsuitable for the needs of the patient.
5. Maintenance of wheelchairs in hospitals seems to be
particularly bad. Common problems include sagging
seats and backs, worn brakes and unsuitable cushions.
6. Non-NHS chairs. There is at the moment, in most
areas of the country, no way of obtaining an unbiased
assessment for a non-NHS chair.
What should be done by Health Districts?
The Wheelchair Service is currently under review but we
feel that some comments are desirable. We suggest that
Health Districts might consider the following actions:
1. Set up a factual review of wheelchairs within the
Health District. Information would need to be collected
relating to the numbers of chairs, and the diseases
encountered. It might be helpful to undertake an 'in
depth' assessment of a sample of wheelchair users?
examining such matters as:
a) How well the various mobility needs are met?e.g.
getting to the shops.
b) General suitability for the patient's needs, e.g. foot
supports, reclining back-rest, etc.
c) How many wheelchairs each patient has, and whether
this number appears to be appropriate.
d) State of maintenance of the chairs.
2. Within the Health District there could be a Wheelchair
Clinic attended by a doctor and an occupational thera-
pist. This Clinic should cater particularly for patients
with severe deformities who are likely to require special
chairs. Advice on non-NHS chairs should also be given at
such a Clinic.
3. Each Health District should ensure that chairs are
maintained, and arrange for all wheelchairs to be re-
viewed at regular intervals?at least twice a year. Within
each hospital there should be a nominated person with
responsibility for the maintenance of hospital wheel-
chairs. The Health District should consider setting up a
small workshop where all but major repairs could be
effected.
4. Health Districts should make some provision for advice
to be given on non-Statutory chairs?particularly electric
chairs for outdoor use.
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 181
Children
Standard wheelchairs do not always fit the patient proper-
ly. Special chairs and modifications are needed in some
cases. Chairs need to be changed frequently?because of
the varying requirements of the growing and developing
child. The wheelchairs are needed for use at home and at
school, and the problems arising from transporting chairs
between home and school should be remembered. The
possibility of holding an occasional Paediatric Wheelchair
Clinic should be considered.
Prosthetics and Orthotics
The term 'prosthesis' is applied to equipment which
replaces a lost part (e.g. an artificial limb). The term
'orthosis' is applied to equipment which can be attached
to the body (e.g. a splint or collar).
Amputations and Prosthetics
The ALAC (Artificial Limb and Appliance Centres)
Review Committee[50] reported that in 1984 there were
51,130 (285 per Health District) lower limb amputees in
England and Wales. There were 11,813 (60 per Health
District) upper limb amputees in England and Wales.
There were approximately 5,000 (28 per Health District)
new amputees each year. The vast majority of patients
had lost limbs as a result of peripheral vascular disease
and 78 per cent of new patients were over the age of 60.
The vast bulk of patients are thus in the older age
group, and they present with multiple problems, which
include cardio-respiratory disease, arthritis, and some-
times the effect of a stroke. Ideally, these patients need the
services of a multi-disciplinary team for the assessment
and management of multifarious disability problems. The
loss of the limb is only one facet of their overall problems.
At present, patients with amputations attend one of the
DHSS Artificial Limb and Appliance Centres (ALAC)
for fitting of the limb. There they are seen by a medical
officer, employed by the DHSS, who acts as an interface
between the surgeon at the hospital and the prosthetist at
ALAC. This service was originally set up in 1945 to
provide limbs for otherwise healthy war veterans, whose
total number was in the order of 45,000. The Service now
has to deal with a much larger number of older patients.
Unfortunately, the training of ALAC medical officers
has not always kept pace with recent advances, and this
criticism has been voiced by the medical officers them-
selves, amongst others. There is also widespread criticism
of the delays in the provision of limbs, and the long
waiting time the patients have to suffer at the ALACs.
Another important aspect is that there seems to be
evidence that British manufacturers have not caught up
with the technical developments in artificial limbs that
have occurred in the USA and in Europe. Also, while
most ALACs are supplied by two or more firms providing
prostheses under contract to the DHSS, there are several
Centres where no choice is available as only one firm is
represented.
Thus, there is considerable evidence that the services
for patients who have sustained the loss of a limb are not,
in general, satisfactory. It seems clear that the ALAC
system requires modernisation. A Working Party was set
up by the Secretary of State to look into the present
ALAC Services and make recommendations, and this
reported in January, 1986. The Report recommends the
establishment of Regional Centres where primary ampu-
tations would be undertaken wherever possible. It also
envisages that the ALAC facilities would be incorporated
into a Regional Disability Centre where a whole range of
disability problems could be catered for (including those
of mobility, communication, continence and special
senses). Prosthetists would work as part of the team at the
hospital and a much wider range of artificial limbs would
be available. In this way, hopefully, the present physical
isolation of ALAC's would be overcome, and the Service
would be largely incorporated into the overall disability
facilities of the Region. These recommendations are very
much in keeping with our own view, which we set out on
Page 166.
Orthotics
Background
The number of orthotic devices (orthoses) is large. The
commonest are special footwear, spinal supports, lower
limb splints and abdominal appliances, e.g. trusses. Less
commonly prescribed orthoses include elastic stockings,
collars, breast prostheses and wigs.
Costs
The costs are apparently unknown, but must be very
considerable. The British Orthopaedic Association
(BOA) Engineering Subcommittee[74] estimated in 1978
that two million orthoses are prescribed commercially
each year. The DHSS does not produce any consumption
figures and Districts do not usually keep detailed figures.
Private contractors supply 97 per cent of orthoses; only
2.5 per cent are supplied by the very few hospital
workshops in existence.
Dissatisfaction with Orthotic Services
Criticisms include:
1. Many orthoses are old-fashioned, ugly and ill-fitting.
2. The supply of orthoses is often slow and erratic?
particularly when the device has to be specially made.
3. Lack of competition. Most Health Authorities deal
with only one, or possibly two, commercial firms for the
supply of equipment. They rely on the orthotist employed
by the firms for advice as to the most suitable equipment.
This orthotist thus becomes partly a salesman and partly
a professional. Clearly, his main allegiance is likely to be
to the company who employs him. So it is difficult for the
patient to obtain independent advice regarding the most
suitable orthosis.
4. There is no incentive for contractors to undertake
research and development?hence the fact that many
devices are clearly out-dated.
182 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
Short-Term Recommendations
Ideally, the whole Service needs to be re-organised. In the
short-term, however, it will be necessary to work with the
system as it exists, however imperfect. Only prescribers
(and patients) can make sufficient demands on the sytem
to ensure that the correct equipment is supplied on time.
This implies particularly that the prescriber (i.e. the
doctor) is properly informed and educated as to what
should be available and provided.
Longer-Term Action
1. The majority of orthoses will be prescribed at District
level and therefore it is clear that Districts themselves
should employ some orthotists. This will mean substan-
tially increasing the salary of orthotists so that the NHS
can compete on equal terms with the private contractors.
Some arrangement with private contractors will have to
be made and proper audit arranged.
2. There should be a proper career structure for orthotists
and prosthetists within the NHS. This will involve the
development of training facilities. Action in this area is
urgently required.
3. There should be Regional (and probably sub-Re-
gional) Orthotic Centres with appropriately equipped
workshops and equipment stores as an integral part of the
Regional Disability Centre. At each major Centre there
should be a display of the principal orthotic devices.
4. The Regional Centres would act as a major focus for
staff training and for research (see below). Health Dis-
tricts at a distance from the Centre might need to
combine in the establishment of smaller satellite Centres
which would be linked organisationally with the main
Centre.
5. A consultant in disability medicine would be in charge
of the Regional Orthotics and Prosthetics Service. He
should be supported by other Health Service profession-
als, including physiotherapists, occupational therapists,
and orthotists.
6. Each Region and District should publish records of the
number and costs of orthoses supplied each year.
7. The DHSS should sponsor research into the develop-
ment of new and improved orthoses, using modern
materials and modular systems. The Regional Disability
Centres, with their university links, would be the ideal
sites for such research.
Urinary Continence Service
Incontinence is defined as a condition in which involun-
tary loss of urine is a social or hygienic problem and is
objectively demonstrable. Thomas et al. [41] estimated
that about 11,000 people (2,000 men and 9,000 women)
could be anticipated to experience some degree of urinary
incontinence in a Health District of 250,000. Of these,
1,000 would be under supervised care, but 10,000 would
not be receiving any services. Incontinence increases with
age. Common causes include prostatic disease in men,
weakness of the pelvic floor in women, multiple sclerosis
and mental subnormality.
The cost of incontinence, both to individuals and the
community, is high. Exton-Smith et al. [75] showed that
incontinence accounted for 25 per cent of nursing time on
a geriatric ward. Frost and Sullivan[76] in 1979 estimated
that the current UK market for incontinence pads and
appliances was in the order of 12 million pounds. Inconti-
nence is often a reason for patients not being accepted
into residential accommodation.
General Principles for the Operation of a District
Continence Service
1. Every Health District should operate a Continence
Service. There should be a written District policy.
2. The Continence Service should be the responsibility of
a designated consultant clinician with a particular interest
and appropriate training in the subject. He would have
one or more designated sessions. The consultant would
frequently be a urologist, but in some cases could come
from another discipline, such as gynaecology or geriat-
rics.
3. Each Health District should employ a full-time nursing
sister as a continence adviser (see below). This person,
together with the consultant, would together be respon-
sible for running the District Continence Service.
4. The District Continence Service should be centred on a
permanent site. This would be manned during working
hours, and telephone enquiries would be welcomed. An
automatic telephone answering service could be in oper-
ation at other times.
5. There should be a regular Continence Clinic in the
Health District?held as often as necessary?perhaps
weekly. This Clinic would have open access and patients
would be able to refer themselves, or could be referred by
any caring agency. The Clinic should be able to advise on
all aspects of incontinence and it should be the focus of
clinical assessment.
6. Each Health District should have a supply of basic
equipment, including catheters, pads, and incontinence
garments. These would usually be held at the permanent
site.
7. There should be a permanent display of incontinence
equipment?at the permanent site. This would include
catheters and protective garments. Links would need to
be forged with the local Disabled Living Centre, which
could also have a static display, if this were felt to be
appropriate.
8. There should be a plentiful supply of literature cover-
ing common topics such as the prevention and manage-
ment of incontinence, and catheter care. This literature
should be widely available?in the Continence Clinic and
elsewhere.
9. There should be training and educational facilities for
professional staff?nurses, doctors, medical students, and
others. These facilities are probably best centred at the
District base.
10. Urological Assessment. Facilities must be available
for the expert assessment of bladder problems, usually by
a urologist. It should be possible to get urodynamic
studies undertaken without difficulty, in order to measure
pressure changes in the bladder and urethra during the
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 183
passage of urine, and urinary flow rates. We envisage
that the urodynamic facilities would be sited in the
District Urological Centre, and they might need to be
shared between two or more Health Districts. Current
evidence is that about six patients per week will require a
urodynamic investigation[77],
11. Surgery. Facilities for urological and gynaecological
surgery will be available in most Health Districts as part
of the routine health service. Facilities for the implanta-
tion of artificial sphincters should be available in a limited
number of Centres, as implantation is a very specialised
technique.
Staffing
Medical
As mentioned above?we are suggesting that there should
be a consultant in each Health District with designated
sessions in the management of incontinence. He would be
responsible for:
1. Organising and running the Service (in conjunction
with the nursing sister).
2. Producing, and updating at regular intervals, plans for
the District Continence Service.
3. Running a regular Continence Clinic in the District
Continence Centre.
Consultant time would need to be available for urodyna-
mic studies.
Clinical Assistant
We suggest that the consultant input could be augmented
by one or two clinical assistant sessions per week?
depending on local needs.
Nursing
The nursing involvement will require a proper structure.
There is now an Association of Continence Advisers with
a particular responsibility for Continence Services. A
high standard of training is now recognised as being
necessary and the English National Board have estab-
lished a Continence course to promote this (ENB Conti-
nence Course 941).
It is suggested that each Health District would employ
a full-time nursing sister (Grade 1) or nursing officer, as a
continence adviser. He/she would supervise the hospital
and community care of incontinent patients. The conti-
nence adviser would work in close collaboration with the
responsible medical staff (particularly the consultant) and
would require support from resource nurses who have
also undertaken some specialist training. A close link
should be established with the Stoma Service in the
Health District.
Other Staff
The help of a secretary and a medical physics technician
would be required (the latter to help with the running of
the urodynamic assessment facilities).
Stoma Care Service
The term 'stoma' in the present context, is applied to any
artificial external opening into one of the abdominal
organs. For practical purposes, the principal stomas are
ileostomy and colostomy for a bowel diversion, and
urinary conduit. Other forms of stoma include gastros-
tomy, jejunostomy, pharyngostomy, and suprapubic uri-
nary catheters.
The number of permanent ileostomies for colitis is
falling. [78] There is a male-female ratio of 1:1.2. The
number of permanent colostomies for rectal cancer has
remained constant?5,510 operations in 1968 to 5,635
operations in 1980, with a male-female ratio of 1.5:1.
Thirty per cent of all stomas are constructed in emerg-
ency situations?ileostomies for acute fulminant ulcer-
ative colitis and a variety of stomas for intestinal
obstruction, trauma, and other causes.
Prevalence data are sparse. Devlin[45] estimated that
there are about 100,000 patients in England and Wales
with a permanent colostomy (i.e. approximately 4-5 per
general practitioner and 400 per average Health District).
The comparable figures for permanent ileostomy is prob-
ably about a tenth of this figure. The number of urinary
conduits per Health District is not known.
Rubin[79] estimated that the average cost of equip-
ment for colostomy patients was ?496. This works out at
about ?200,000 annually for each Health District (assum-
ing 400 patients with a colostomy per Health District).
There will be a smaller sum for patients with other types
of stoma. In addition, there are substantial staffing costs
(mainly nursing and medical).
Present Pattern of Stoma Care
Most stoma care in the United Kingdom is hospital-
based. It has grown up in a haphazard manner, often
with one surgeon showing a specific interest in the
problem, and perhaps having a clinical assistant to help
him run a Stoma Clinic with dedicated nurse involve-
ment. Stoma nurses are generally hospital-based, though
extension of their activities into the community is increas-
ing. Since the early 1970's?Stoma Nurse Training
Centres have provided the ENBCC 216 Clinical Course
in Stoma Care Nursing for registered general nurses,
usually lasting eight weeks, and including the physical,
physiological, psychological and social aspects of stoma
care. Some Centres provide a shorter (eight day) course
on principles of stoma care (ENBCC 980); this course is
available for all qualified nurses.
The improvement in stoma care in the last 8-10 years
has largely been the result of endeavours to train nurses to
give them a greater facility for counselling and to provide
them with reasonable hospital premises. There appears to
be a deficiency in the service?principally in the lack of
continuity that often occurs between the hospital, where
the stoma is created, and the community, where it has to
be rrianaged. The small number of stomas in the average
general practice means that few general practitioners
have any direct knowledge of stoma care and are not
usually in a position to provide detailed advice.
184 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
The voluntary organisations, the Ileostomy Associ-
ation, the Colostomy Welfare Group, and the Ileal
Conduit Association, have provided much support.
Other Background Information
There is widespread recognition of the enormous psycho-
logical consequences of the establishment of a stoma.
Patients require continuing advice about a number of
problems, including types of equipment, irrigation of the
bowel, avoidance of leakage, skin protection, avoidance
of odour, diet, clothing, alcohol intake, and taking of
medication; employment, foreign travel, sexual activity
and pregnancy. A number of complications can occur,
and these need to be dealt with effectively. These compli-
cations include leakage, sore skin and contact dermatitis,
herniation around the stoma, prolapse of the stoma,
depression and impotence. Particular problems are likely
to be encountered by patients who have visual problems,
defective arm function (e.g. after a stroke), and where
there is intellectual deterioration. Considerable expense is
involved in the running of a Stoma Service. Appliances
are expensive and should be used effectively.
Suggested Criteria for the Operation of a District
Stoma Care Service
Our recommendations are very similar to those which we
have made in relation to the District Continence Service.
Indeed, we consider that there is some scope for fusing the
two Services. Certainly, we think that it should be
possible for the two services to use the same building and
probably the same secretarial staff.
The overall objective is that all stoma patients should
have pre- and post-operative counselling, informed and
sympathetic medical and nursing care, and support. The
general practitioner should have an important role. He is
usually the first person to whom the patient turns when
problems arise[80].
1. Every Health District should operate a Stoma Care
Service. There should be a written District policy.
2. There should be a consultant with designated responsi-
bility for the running of the Stoma Care Service. The
consultant will need to give enthusiastic and informed
leadership. He will also need to develop links with other
departments, including psychiatry and dermatology. The
consultant input might need to be augmented by one or
two clinical assistant sessions per week.
3. There should be a full-time stoma care nurse, with the
grade of sister. She, together with the consultant, would
be responsible for the operation of the District Stoma
Care Service. There is probably need for a part-time staff
nurse to provide back-up.
4. The Stoma Care Service should have a permanent
Centre within the Health District (possibly shared with
the District Continence Centre).
5. It will probably be desirable to run a regular Stoma
Clinic?this would be the responsibility of the designated
consultant and the nurse.
6. Within the Stoma Centre there should be a room which
is comfortable, so that the medical staff can sit and
counsel patients and their relatives about stoma care.
There is also need for a room where clinical examinations
can be undertaken, and this room would require sluice
facilities so that patients can be taught how to change
appliances and, for instance, irrigate a colostomy.
7. All patients undergoing elective colostomy or ileostomy
should receive pre-operative counselling. They should be
put in touch with patients in whom the operation has been
satisfactorily completed. In this way, confidence may be
gained.
The Stoma Centre should hold a supply of basic
equipment and have a permanent display (as discussed in
relation to the Continence Service), and also a supply of
literature for lay and professional staff. The Centre would
be used for training and teaching. Careful records should
be kept of the incidence, prevalence, and type of stomas
within the Health District, and this information should be
published in the annual Report of the Health Authority.
There should be a record of equipment used, and of the
costs of running the Service.
Pressure Sores
Pressure sores are life-threatening, unpleasant, socially
undesirable and expensive. It was estimated in 1973 that
hospitals were treating some 60,000 sores annually at a
cost of around 60 million pounds[81], A survey in
Glasgow found that 8.6 per cent of patients in hospital or
community care had tissue damage, from superficial skin
effects to necrosis and cavitation[82]. A review of four
published hospital surveys found the prevalence of press-
ure sores to range from 3 to 8.8 per cent[83]. Thus it
appears that at least 5 per cent of patients in general
hospitals will have one or more sores. A survey of all
patients in the Bath Health District showed a prevalence
of sores in hospital patients of 6.17 per cent compared
with 1.27 per cent for patients in the community[84].
Pressure sores are an increasing problem with age so that
the number of patients at risk will inevitably increase.
Suggested Criteria for Operation of a District Service
The current evidence indicates that pressure sores are
common, frequently preventable and probably are cost-
ing each Health District hundreds of thousands of pounds
each year. On both humanitarian and economic grounds
we recommend that every Health District should have a
properly organised and audited Pressure Sore Prevention
and Treatment Service set up with the following outline
criteria?
1. There should be a written District policy for the
prevention and management of pressure sores.
2. There should be a designated member of the medical
staff in the District General Hospital who should be
knowledgeable about medical aspects of pressure sore
prevention and treatment.
3. There would be a designated senior member of the
nursing staff who would have responsibility for running
the District Pressure Sore Service (in conjunction with the
designated member of medical staff). This person should
be properly trained and informed on all aspects of
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 185
pressure sore prevention and management, and would be
available to advise and train hospital and community
staff. He/she should know about the various types of
weight dispersal cushions and beds.
4. Training. District and ward nurses would be expected
to have training in pressure sore prevention and manage-
ment; this would be one of the responsibilities of the
designated nurse.
5. A regular survey of the incidence and prevalence of
pressure sores, both in the hospital and in the com-
munity, should be undertaken. The annual cost (particu-
larly of admission to hospital) to the Health District
should be calculated and reported in the District annual
Report.
6. Patients at risk of developing pressure sores should be
identified routinely by means of a pressure sore prediction
system, e.g. Norton[85]. There is an argument to be
made for some form of enquiry whenever a major
pressure sore occurs. The subject of pressure sore preven-
tion has been discussed by Scales[86],
7. Plastic surgery help should be available when required.
8. There should be a readily available supply of beds,
mattresses, and weight dispersal cushions. The most
commonly available equipment should be available for
demonstration and trial.
APPENDICES
1. Definitions Used Throughout The Report
Medical Disability Services?This term is used in the
Report in relation to NHS Services that are required in
order to prevent or minimise disability resulting from the
disorders under discussion.
Rehabilitation?The term 'Rehabilitation' has been
used widely for many years and has proved to be virtually
incapable of definition. We have not found it possible to
entirely avoid using this term. However we broadly agree
with the 'Mair Report'[5] which stated:
Rehabilitation is a concept whose meaning varies
from the precise to the vague, according to individ-
ual taste, practice and experience. In the past, it
was frequently taken to mean the application of
physical methods of treatment aimed at restoring
local function and general fitness after disease or
injury. In recent times, a much broader meaning
has been given to the word, which now implies the
whole complicated process of the restoration of
individuals rendered unfit from any cause to a
degree of social and economic independence, within
the limits imposed by any residual restriction of
function. For the purposes of this report, the follow-
ing simple definition was adopted:
Rehabilitation implies the restoration of patients to
their fullest physical, mental and social capability.
2. Prevalence of Physical Disability
Estimates of the prevalence of physical disability and of
the numbers of disabled people in the population vary
according to the criteria used. In an effort to standardise
definitions, the World Health Organisation has intro-
duced a Manual of Classification?the International
Classification of Impairments, Disabilities and Handi-
caps (ICIDH)[87], This classification, based on the work
of Wood[88], distinguishes between impairment, disabil-
ity and handicap as different dimensions of the conse-
quences of disease.
Impairment is defined as any loss or abnormality of
psychological, physiological or anatomical structure or
function; disability as any restriction or lack (resulting
from an impairment) of ability to perform an activity in
the manner or within the range considered normal for a
human being; and handicap as a disadvantage for a given
individual, resulting from an impairment or a disability
that limits or prevents the fulfilment of a role that is
normal (depending on age, sex, and social and cultural
factors) for that individual. The following example illus-
trates the differences between these three definitions:
A building labourer of 40 undergoes a below-knee
amputation as a result of an accident. The term 'impair-
ment' refers to loss of part of the leg. The disability refers
to his inability to walk quickly or to climb ladders. The
handicap refers to the fact that he can no longer under-
take his previous work because of his inability to climb
ladders.
To date, no results have been published of a survey of a
large, defined population which identified impaired, dis-
abled and handicapped people using the definitions and
criteria of the ICIDH. It was necessary, therefore, to
estimate numbers using data from surveys which used
different definitions (Table 1).
3. Evaluation of the Service Provided by
Mary Marlborough Lodge
(Based on a Report to the Oxford Regional Health
Authority; January, 1985, by G. M. Cochrane and G. I.
Hughes).
Mary Marlborough Lodge (MML) was established in
1960 as a Disabled Living Research Unit by the National
Fund for Research into Poliomyelitis and other Crippling
Diseases. In 1964 it was absorbed into the National
Health Service. The Unit was under the direction of Dr.
Philip Nichols from 1964 until his death in 1979. Dr.
George Cochrane was appointed Medical Director in
1980.
The principal function of the Unit is the assessment of
severely disabled persons, and the provision of appropri-
ate equipment, which is not readily available in other
Centres. A wide variety of skills are available, and there is
a comprehensive Workshop.
186 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
A study was undertaken of all new in-patients and out-
patients attending MML during the three month period
September to December 1983. In this period 81 new
patients were seen and 42 (52 per cent) came from outside
the Oxford Regional Health Authority. Patients were
referred from as far away as Cumbria and Cornwall.
Extrapolation of the figures for one year gives 325 new
referrals in a year. Further examination of these figures
shows:
1. The Oxford Regional Health Authority itself generated
a substantial number of patients during this study
period?equivalent to 156 annually.
2. Each year 168 patients will have come from beyond the
Oxford Regional Health Authority catchment area. This
indicates that the need is not being met by the other
Regions.
What Diseases are Involved?
Details of the five principal diseases are given in Table 4.
Table 4. Medical diagnoses of 81 patients seen at MML over a
three month period.
Diagnosis Number %
Cerebral palsy 19 24
Amputees 10 12
Multiple sclerosis 7 10 12
Motor neurone disease 9 11
Spina bifida 7 9
Miscellaneous 26 32
Miscellaneous disorders (none of which comprise more
than 5 per cent of the total) included stroke, muscular
dystrophy, skeletal conditions (e.g. osteoarthritis) and
spinal cord injury.
Principal Problems
Many patients were referred with a mixture of problems;
33 per cent of patients presented with five or more
difficulties. Table 5 gives details of some of the main
problems.
Recommendations Made and Advice Given
In all 412 recommendations were made?the median
number for a single patient being five (range 1-13). Table
6 gives details of some of the recommendations.
Particular Skills Available at MML
The staff are fully trained in the understanding and
management of the problems of patients with multiple
handicap. Particular skills include:
1. The making and fitting of orthoses.
2. Customised seating.
3. Wheelchairs?advising on special types, alterations,
and controls.
Table 5. Patients' problems at MML (% of total).
Problem %
Wheelchairs and seating 58
Pain/weakness/joint contracture 44
Difficulty with transferring 36
Activities of daily living 30
Mobility 26
Psychological 19
Housing 16
Communication/speech 6
Table 6. Recommendations made at MML.
Recommendation Number
Wheelchair/seating 79
Medical 66
Transfer aids 51
Orthoses 27
Exercises, including limb training for amputees 26
Small aids 26
Mobile arm supports 7
4. Special items of equipment for personal care and
recreation.
5. Moulded thermoplastic trunk supports.
6. Design and mounting of special switches for patients
with absent or defective limb control.
7. Mobile arm supports for patients with severe proximal
arm weakness.
8. Gardening for the severely disabled.
Audit
An audit was conducted of the patients who had attended
MML. At follow-up after three months, 90 per cent of
patients remained satisfied with the help that they had
received. More than 80 per cent of the principal pro-
fessional carers were satisfied with the service, infor-
mation, and recommendations made.
4. Assessment and Training Facilities For
Re-learning Driving Skills
Assessment of the possibilities for driving must be carried
out by an expert in this field whose recommendation as to
suitability to drive will be accepted by the Licencing
Authorities. Assessments can be provided by some
branches of the British School of Motoring. If there is no
local school prepared to offer help, enquiries should be
made to the British School of Motoring, Disabled Drivers
Section, 81/87 Hartfells Road, Wimbledon, London
SW19. Assessment and driving instruction courses, and
advice on conversion, are given at the Banstead Place
Mobility Centre, Park Road, Banstead, Surrey, SM73
3LE, who specialise in the difficult case. Enquiries for
driving test and licencing should be addressed to the
Medical Officer, the Medical Advisory Branch, Depart-
ment of Transport, Oldway Centre, Orchard Street,
Swansea. To claim exemption from Road Fund Tax on
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 187
account of disability, enquiries should be addressed to the
DHSS, Department DSB, 7a Warbreck Hill, Blackpool.
The introduction of Mobility Allowance has marked a
considerable advance for disabled patients who cannot
use public transport. The criteria are strict and laid down
in Leaflet L1211/April 1983. They comprise inability or
virtual inability to walk or to make the exertion needed to
walk, creating a serious risk to life or health. The
allowance is ?20 per week, and this may be spent in any
way preferred. Application is made on this form obtained
from the local DHSS Offices and forwarded to the
Mobility Allowance Unit, Norcross, Blackpool, FY5
3TA, to arrange a medical assessment. If an award of
Mobility Allowance has been made, clients are eligible for
the Motability Scheme. The Motability Scheme offers
leasing or hire purchase of a vehicle, or purchase out-
right. Leasing can be a most effective method, for a small
car can be leased for seven years for a down payment of as
little as ?13.00 and the Mobility Allowance assigned to
Motability. There is an annual insurance premium of
?80. All servicing costs and repairs are paid by Motabi-
lity, except the first four new tyres and with a mileage
ceiling of 10,000 miles a year. Outright purchase is
possible on low interest rates, but adaptations duty and
comprehensive insurance must be paid. VAT exemption,
however, is allowed on adaptations at competitive rates.
There is a Disabled Drivers' Insurance Association ad-
dress; 292 Hayle Lane, Edgware, Middlesex. It is well
worth joining the Disabled Drivers Association, which
offers benefits and advice. Its address is: Ash well Thorpe
Hall, Ashwell Thorpe, Norwich. Motability's address is:
Boundary House, 91/93 Charterhouse Street, London
EC1.
Orange Badge Scheme
Most people in receipt of Mobility Allowance will qualify
for the Orange Badge, which allows special parking. This
is issued by the Social Services Department. Application
should be accompanied by a medical report. The system
has been much abused, and the issue of the badge is
strictly controlled.
5. Communication Aids Centres
BRISTOL Assistive Communication Aids Centre,
Speech Therapy Department,
Frenchay Hospital,
Bristol BS16 1LE.
Tel. 0272-565656 Ext. 2140.
LONDON Communication Aids Centre,
(Speech Therapy)
Charing Cross Hospital,
Fulham Palace Road,
London W6.
Tel. 01-7482040.
NEWCASTLE Communication Aids Centre,
Royal Victoria Infirmary,
Queen Victoria Road,
Newcastle-upon-Tyne.
Tel. 0632-325131 Ext. 455.
SANDWELL Communication Aids Centre,
Sandwell Health Authority,
Boulton Road,
West Bromwich,
West Midlands B70 6NN.
Tel. 021-553 0908.
WALES Communication Aids Centre,
Rookwood Hospital,
Fairwater Road, ?
Llandaff,
Cardiff.
Tel. 0222-566281.
LONDON Communication Aids Centre,
Wolfson Centre,
Mecklenburgh Square,
London WC1N 2AT.
' Tel. 01-8377618.
6. List of Demonstration Centres
CENTRE
1. Addenbrooke's Hospital, Hills Road,
Cambridge CB2 2QQ.
2. Crawley District General Hospital, West
Ham Drive, Crawley, Sussex RH11 7DH
and
Horsham Hospital, Hurst Road, Horsham,
Sussex.
3. Derbyshire Royal Infirmary, London Road,
Derby DEI 2QY.
and
Derwent Hospital, Derby, Kings Lodge
Younger Disabled Unit.
CONSULTANT IN CHARGE
Dr J. R. Jenner
Dr J. A. Hicklin
Dr A. Martin
Dr R. Bailey
Dr C. F. Murray Leslie
SPECIALITY
General Rehabilitation
Rheumatology
General Rehabilitation
Geriatric Rehabilitation
Geriatric Rehabilitation
Rheumatology & Rehabilitation
Orthotics & Disability Research
Rehabilitation Engineering &
Disabled Driving Centre
188 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
4. Devonshire Royal Hospital, Buxton,
Derbyshire.
Young Disabled Unit, Withington Hospital,
West Didsbury, Manchester M20 8LR.
Wythenshaw Hospital, Southmoor Road,
Manchester M23 7LT.
5. Garston Manor Medical Rehabilitation
Centre, Garston, Watford, Herts. WD2
7JX.
6. Guy's Hospital, St. Thomas Street, London
SE1 9RT.
7. Medical Rehabilitation Unit, RAF Headley
Court, Leatherhead, Surrey.
8. Kings College Hospital, Denmark Hill,
London SE5.
9. The London Hospital, Whitechapel, London
El IBB.
10. Mary Marlborough Lodge, Nuffield
Orthopaedic Centre, Headington, Oxford
OX3 7LD.
11. Medical Rehabilitation Centre, 152 Camden
Road, London NW1 9HL.
12. Middlesbrough General Hospital, Ayresome
Green Lane, Middlesbrough, Cleveland TS5
5AZ.
13. Norfolk & Norwich Hospital, St. Stephens
Road, Norwich NR1 3SR.
Mundesley Hospital, Mundesley, Norfolk.
St. Michael's Hospital, Aylsham, Norfolk.
14. Pinderfields General Hospital, Aberford
Road, Wakefield, Yorks WF1 4DG.
15. Robert Jones & Agnes Hunt, Orthopaedic
Hospital, Oswestry, Salop SY10 7 AG.
16. Royal East Sussex Hospital, Cambridge
Road, Hastings, Sussex.
17. Royal National Hospital for Rheumatic
Diseases, Upper Borough Walls, Bath, Avon
BA1 1RL.
18. Regional Rehabilitation Unit, Salisbury
General Hospital, Odstock Branch,
Salisbury, Wilts. SP2 OBJ.
19. Westminster Hospital, Dean Ryle Street,
London SW1 2AP.
20. The Wolfson Medical Rehabilitation Centre,
Atkinson Morley's Hospital, Copse Hill,
Wimbledon, London SW20.
21. Fazakerley Hospital, Longmoor Lane,
Liverpool L9 7AL.
22. Royal National Orthopaedic Hospital, 234
Great Portland Street, London SIN 6AD.
Stanmore Branch, Brockley Hill, Stanmore,
Middx. HA7 4LP.
Dr E. P. Copp
Dr P. H. Merry
Dr H. N. Misra
Dr A. P. H. Randle
Dr R. Grahame
Group Captain A. F.
T redre
Dr E. B. D. Hamilton
Mr B. Roper
Dr G. M. Cochrane
Dr F. R. Middleton
Dr J. Fordham
Dr W. G. Wenley
Dr. J. R. Burrows
Dr N. Cardoe
Dr A. A. Burt
Prof. B. T. O'Connor
Mr S. C. Gallennaugh
Dr A. K. Clarke
Dr R. M. Ellis
Prof. D. A. Brewerton
Dr D. G. Jenkins
Dr E. Williams
Dr C. B. Wynn Parry
Rheumatic Disease:
Rehabilitation of Severe
Locomotor Disorders
Arthritis, Stroke and Geriatric
Rehabilitation
General Rehabilitation
Rehabilitation after Trauma
Residential Rehabilitation
Rheumatology
Rehabilitation of Locomotor
Disorders
Orthopaedic Rehabilitation
Rehabilitation of Hand and
Head Injuries
Rheumatology and General
Rehabilitation
Rheumatology: Joint
Replacement Surgery and
Orthopaedic Rehabilitation
The Severely Disabled: Daily
Livine?Rehabilitation Research
Unit
Day Rehabilitation Centre
Rheumatology: Rehabilitation of
Locomotor Disorders
Rehabilitation
Rheumatology Sub-Regional
Service
Neurology
Orthopaedic Rehabilitation
Rheumatology
Orthopaedic Surgery
Joint Replacement Surgery and
associated problems of
rehabilitation
Rheumatology
General Rehabilitation
Rheumatology and
Rehabilitation
Neurological Rehabilitation
Rheumatology and
Rehabilitation; Neurology
Pain
Rheumatological Rehabilitation
Orthopaedic Rehabilitation
Neurological Rehabilitation
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
w
6. List of Demonstration Centres (continued)
CENTRE
23. Royal Devon & Exeter Hospital, Heavitree,
Exeter, Devon.
24. Humberside National Demonstration Centre
in Medical Rehabilitation of the Elderly,
Kingston General Hospital, Beverley Road,
Hull HU3 1UR.
25. Northwick Park Hospital, Watford Road,
Harrow, Middx. HA1 3UJ.
26. Newmarket General Hospital, Exning Road,
Newmarket, Suffolk CB8 7JG.
27. Rehabilitation Unit of Western District of
Leeds, plus Younger Disabled Unit, plus
William Merritt Aids Centre.
Correspondence to: Leeds General
Infirmary, Great George Street, Leeds LSI
3EX. Tel. 0532-4322799.
28. Queen Mary's Hospital, Roehampton,
London SW15 5PN.
29. Rookwood Hospital, Fairwater Road,
Llandaff, Cardiff CF5 2YN.
CONSULTANT IN CHARGE
Dr J. S. Watkins
Dr J. McV Loudon
Dr A. Frank
Dr B. Hazleman
Dr M. Anne Chamberlain
Dr I. H. M. Gurwen
Dr J. C. Chawla
SPECIALITY
Geriatric Medicine and
Rehabilitation in the Elderly
Geriatric Medicine
Childhood and Adult Rheumatic
Disorders. Provision of a Service
to the Health District including
Domiciliary and Coronary
Rehabilitation
Rehabilitation of Rheumatic
Diseases
Rheumatology and
Rehabilitation
Rheumatology and
Rehabilitation
Neurological Rehabilitation
Neurosurgical Rehabilitation
7. Some Useful Addresses from the Disability Rights Handbook
British Sports Association for the Disabled: Hayward
House, Barnard Crescent, Aylesbury, Bucks. HP21
8PP. Tel. 0296-27889.
DEMAND (Design and Manufacture for Disability): 99
Leman Street, London El 8EY. Tel. 01-488 9869.
Disabled Drivers Association: Ashwellthorpe Hall,
Ashwellthorpe, Norwich NR6 1EX. Tel. 050-841
449.
Disability Alliance: 25 Denmark Street, London WC2H
8NJ.
Disabled Living Foundation: 380-384 Harrow Road,
London W9 2HU. Tel. 01-289 6111.
Disablement Income Group: Attlee House, 28
Commercial Street, London El 6LR.
Leonard Cheshire Foundation: 26-29 Maunsel Street,
London SW1P 2QN. Tel. 01-828 1822.
Motability: Boundary House, 91-93 Charterhouse
Street, London EC1 M6BT. Tel. 01-253 1211.
National Bureau for Handicapped Students: 40
Brunswick Square, London WC1N 1AZ. Tel. 01-278
3450/3459.
PHAB: Tavistock House North (2nd Floor), Tavistock
Square, London WC1H 9HX. Tel. 01-388 1693.
John Grooms Association for the Disabled: 10
Gloucester Drive, Finsbury Park, London N4 2LP.
Tel. 01-802 7272.
Radar: 25 Mortimer Street, London WIN 8AB. Tel.
01-637 5400.
REMAP (Rehabilitation Engineering Movement
Advisory Panels): 25 Mortimer Street, London WIN
8AB. Tel. 01-637 5400.
Riding for the Disabled Association: Avenue 'R',
National Agricultural Centre, Kenilworth, Warks.
Tel. 0203-56107.
Royal National Institute for the Blind: 224 Great
Portland Street, London WIN 6AA. Tel. 01-388
1266.
Royal National Institute for the Deaf: 105 Gower
Street, London WC1E 6AH. Tel. 01-387 8033.
SPOD (Sexual and Personal Relationships of the
Disabled): 286 Camden Road, London N7 OBJ. Tel.
01-607 8851/2.
Winged Fellowship Trust Holidays for Disabled People:
Angel House, Pentonville Road, London N1 9XD.
Tel. 01-833 2594.
Note: The Disability Rights Handbook is published each
November, and has a comprehensive list of organisations,
including those for particular conditions. It is available from
the Disability Alliance.
190 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
SUMMARY
This Report puts forward a plan for the management of
physical disability. It recognises that the subject is admin-
istratively complex and that many different organisa-
tions, including Social Services, are involved. The Report
concentrates upon the role of the NHS in general, and
upon the position of physicians in particular.
The Report starts by reviewing some of the evidence
that services for the physically disabled are in many
respects deficient. The evidence includes accounts given
by disabled people themselves, the fact that many patients
are 'followed-up' by inexperienced junior hospital staff,
and the lack of agreed standards of provision in many
areas (see Section 3) such as pressure sores, incontinence,
wheelchairs, and the care of head injured patients. Dis-
abled people between the ages of 15 and 65 are identified
as requiring particular attention (Paediatric and Geriatric
Services probably cater reasonably well for the young and
the old). The 'size' of the problem of physical disability is
examined. For instance, the average Health District (of
250,000 persons) will contain 25,000 physically disabled
people, of whom 6,250 will be severely, or very severely
disabled; and 1,800 will have a wheelchair; 40 per cent of
disabled people are under the age of 65.
The Working Party on Rehabilitation Medicine of the
Royal College of Physicians (1978) was of the opinion
that rehabilitation is an integral part of total patient care,
and is therefore the concern of all clinicians. The implica-
tion of this view is that Medical Disability Services should
be developed without a major specialty of Rehabilitation
or its equivalent, such as exists in most western countries.
The Report explores the practical implications of this
principle in the light of evidence discussed above.
Research (Page 168)
There is a need for a major expansion of research.
Priority areas include epidemiology (particularly of head
injury), the physiology of recovery, and the evaluation of
equipment, rehabilitation techniques, and different ways
of providing care. We recommend particularly the setting
up of units capable of investigating the many problems of
neurological disability. Regional Disability Units should
be important Centres of research.
Regional Services (Page 166)
Some Services will need to be organised at Regional level,
some at District level, and, in other situations, two or
three Health Districts may combine in the setting up of
services. The principles involved are intended to be firm
enough to provide a minimum standard of care, but
sufficiently flexible to allow for local circumstances.
We recommend the setting up of a Regional Disability
Unit in each Region in England and one in Wales. We
agree with the ALAC Review Committee that it would be
sensible to incorporate the functions of the ALACs into
the Regional Disability Units. Each Unit would form
close links with Health Districts in its Region, and would
form an important focus for the development of Regional
Disability Services. The Units would have research and
training functions and would be attached to a major
District General Hospital with, ideally, links with the
medical school and/or university. Each Unit would in-
clude on its staff the equivalent of two full-time consult-
ants in Disability Medicine. The functions that we
envisage for the Unit are as follows:
1. The assessment of severely disabled patients?es-
pecially those with multiple problems.
2. Orthotics, Prosthetics and difficult Wheelchair prob-
lems. Appropriate workshops would be provided.
3. The Unit could include a Disabled Living Centre,
where a wide variety of equipment is available for
inspection and trial.
4. The Regional Communication Aids Centre could be
included.
5. The Unit might incorporate the management of certain
specific clinical disorders, such as spinal injury and/or
stroke disability.
District Services (Page 166)
1. Information. Health Districts should maintain an up-to-
date data base of facilities for the physically disabled
locally. A booklet should be produced annually.
2. Generic services. Certain specific services (e.g. a District
Continence Service) should be provided and minimum
standards should be attained and maintained.
3. Domiciliary Services. Each Health District should ensure
that there are adequate numbers of therapists and district
nurses who are properly trained in the management of
disability. These community workers should collaborate
closely with general practitioners.
4. Medical Staffing.
(a) Consultants. We recommend that in each Health
District there should be 10-11 disability sessions held by
two or more consultants practising in a variety of special-
ities (e.g. general medicine or neurology). Each consult-
ant would have certain specific designated
responsibilities.
(b) Community Physicians. We see an important role for a
community physician who would be involved in collecting
and analysing data and acting as a co-ordinator for
certain clinical groups (particularly the disabled school
leaver). We envisage that the community physician and
consultants with Medical Disability sessions would work
closely together.
(c) General practitioners. The GP has a vital co-ordinating
and supportive function. This role is particularly import-
ant if the principle of maintaining disabled people in the
community, rather than in residential care, is to be
implemented. He should be able to 'plug in' easily to the
wide variety of Disability Services provided within and
outside the District.
Generic Services (Page 173)
The term Generic Services is used in respect of those
services which are likely to be used by a variety of
disabled patients, which are not obviously the responsi-
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 191
bility of a particular specialty. We have identified 15
specific areas:
1. Disabled Living Centres.
2. Housing, Housing Modifications and Re-Housing.
3. The Physically Disabled School Leaver.
4. Support Services for Younger Severely Disabled and
Handicapped People.
5. Driving for the Disabled.
6. Sexual Counselling.
7. Head Injury Services.
8. Visual Impairment.
9. Hearing Impairment.
10. Communication Aids.
11. Wheelchairs.
12. Prosthetics and Orthotics.
13. Urinary Continence Service.
14. Stoma Care Service.
15. Pressure Sores.
For each of the 15 areas we have suggested some basic
professional standards which can be used as a basis for
audit. We anticipate that the establishment of these
Services will make it easier for doctors to care effectively
for disabled patients under their care. Some of the
principles underlying these Generic Services include the
following:
1. There should be a written agreed District policy.
2. There should be a series of simple audit criteria.
3. Areas of defined responsibility should be identified
(e.g. a Consultant in charge of the District Continence
Service).
4. For certain services (e.g. Continence and Stoma Care)
there should be a permanent District site where clinics are
held, equipment is available for trial and inspection, and
where advice can be obtained and training given.
5. A plentiful supply of literature should be available for
patients, relatives and professional staff.
6. Domiciliary facilities should be available for house-
bound patients relating to, for example, visual and
hearing impairment.
7. Certain basic records and statistics should be kept (e.g.
the number of pressure sores, and patients with a signifi-
cant head injury occurring within the Health District).
Medical Staffing (Page 170)
The Committee makes its recommendations on the prin-
ciple that each doctor is responsible for dealing effectively
with the disability problems of patients under his care.
Nonetheless, it is felt that certain defined consultant
sessions in Disability Medicine should be established:
1. Consultant Posts
a) Posts with Disability as the principal component. We
recommend that each Region should have two full-time,
or equivalent, consultants practising in disability medi-
cine. Their main work would be at Regional Disability
Units.
b) Each Health District should have 10-11 consultant
disabiity sessions which would be held by two or more
consultants from a variety of specialties. We anticipate
that these consultants would seek dual accreditation (e.g.
neurology and disability medicine).
c) In each Health District there would be a community
physician with specific responsibility for certain aspects of
Disability Services.
3. Training
A certain number of 'one-off senior registrar training
posts will need to be created in order to achieve a target of
30-35 full-time consultants in disability medicine within
five years. Once these consultant posts have been filled,
then there will need to be a smaller number of permanent
senior registrar posts.
A substantial number of posts involving dual training
are required (e.g. general medicine and disability).
The SAC's are asked to draw up training schedules as a
matter of urgency.
Undergraduate and Postgraduate Education
(Page 171)
The management of disability should be an integral part
of all undergraduate and postgraduate training pro-
grammes. The practical implications of these recommen-
dations include ensuring that examinations include
questions relating to disability, and the inclusion of the
subject in vocational training schemes for general prac-
titioners, and in medical textbooks.
Organisation and Administration (Page 169)
We consider that there should be a formal Committee
structure at both Regional and District levels. Annual
reports would be drawn up by Disability Committees,
and these would be submitted to District and Regional
managers. The Committees would also be expected to
draw up short- and long-term plans.
Timetable (Page 171)
WE suggest a five-year timetable. At the end of this time
the principal recommendations in this Report should
have been implemented. A major review of Disability
Services should be undertaken in the early 1990's.
Audit (Page 172)
This document contains a number of audit standards by
which the quality of Disability Services can be judged.
'Internal' audit would be conducted by District and
Regional managers. 'External' audit would probably
need to be undertaken by some outside body not funded
by the NHS.
Costs and Resources (Page 172)
Because existing patterns of care vary from Region to
Region, no attempt has been made to 'cost' the proposals
outlined in this document. We make the following points:
1. The current level of investment in Medical Disability
Services is low.
2. It is, essential to ensure that money is effectively spent
(e.g. prevention and early treatment of pressure sores
may be cheaper than lengthy stays in hospital).
3. Physical disability should be recognised by the DHSS
as an area for top priority funding.
192 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
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|
PMC005xxxxxx/PMC5371053.txt | Corrigendum
Dr P. G. F. Nixon has pointed out that in the article on
'Incidence and management of arterial injuries from left
heart catheterisation'
in the last issue of the Journal (Vol.
20, p. 126) the authors misquote (their reference 9) a
publication by Dr H. Ikram and Dr P. G. F. Nixon. The
original letter in the Lancet by Drs Ikram and Nixon
referred to the introduction of a needle into the brachial
artery but not to left heart catheterisation.
|
PMC005xxxxxx/PMC5371054.txt | Metabolic Basis of Adverse Drug Reactions
B.K. PARK, BSc, PhD, Wellcome Senior Lecturer,
Department of Pharmacology and Therapeutics, University of Liverpool
The rate of elimination of a lipophilic drug is governed
largely by its rate of metabolism. Therefore, the ability of
an individual to metabolise a particular drug will be an
important determinant of the efficacy (intensity of effect),
the duration of effect and the toxicity of that drug.
Metabolism is usually associated with an increase in
water-solubility of the drug, which in turn leads to an
increase in the rate of either biliary or urinary excretion.
The chemical changes involved usually result in a loss or
diminution of pharmacological activity. Metabolism may
therefore be considered a detoxification process. How-
ever, in certain circumstances, normal metabolic pro-
cesses (biotransformations) may produce a toxic
metabolite. Of particular importance in this context is the
formation of chemically reactive metabolites which are
responsible for various forms of drug toxicity.
Figure 1 shows that both the rate and route of drug
metabolism are important determinants of drug toxicity,
so it is necessary to identify factors that may contribute to
inter-individual variation in drug metabolism and to
characterise metabolites which have toxicological activity.
Inter-individual Variation in Drug Metabolism
Drug metabolism reactions observed in man consist of
phase I reactions (oxidation, reduction and hydrolysis)
and phase II conjugation (Table 1). The enzyme systems
responsible for these biotransformations appear to have
the ability to metabolise an unlimited number of diverse
organic compounds, including drugs. It is thought that
one of the reasons for the versatility of the drug-metabo-
lising enzyme system is that the enzymes exist in multiple
forms which represent different gene productsfl].
Table 1. Drug metabolism reactions observed in man.
Phase I Phase II
Oxidation Acetylation
Reduction Glucuronidation
Sulphation
Hydrolysis Glutathione conjugation
Amino acid conjugation
N,S,0, ? methylation
Population studies have shown that there are large
differences between individuals in their capacity to meta-
bolise drugs and other lipophilic xenobiotics. This inter-
individual variability is due to a number of factors,
centred on the genetic constitution of the individual and
including an array of host factors, such as age, environ-
mental considerations, disease and drugs, which interact
dynamically with each other[2]. All of these factors may,
in theory, partly determine the susceptibility of an indi-
vidual to drug toxicity.
Genetic Variation
Given that the main purpose of drug metabolism is to
convert lipophilic substances into more water-soluble
metabolites and thereby prevent toxicity through accu-
mulation, it is important to recognise individuals who
have a genetically determined inability to perform a
particular biotransformation. Genetic polymorphisms
arise because of the occurrence of mutant alleles in the
population which can influence either the structure or the
amount of enzyme synthesised. t
The two classical examples of polymorphic drug me-
tabolism reactions are acetylation of various drugs and
hydrolysis of succinylcholine. More recently, it has be-
come apparent that certain drug oxidation reactions
exhibit polymorphism.
Succinylcholine produces skeletal muscle relaxation of
short duration because of its very rapid degradation, by
plasma cholinesterase, to succinylmonocholine which is
inactive. About one in 3,000 individuals is extremely
sensitive to succinylcholine, responding to it by prolonged
paralysis, because of an atypical plasma cholinesterase
which hydrolyses the drug at a considerably reduced
rate[3].
The disposition and toxicity of many aromatic amine
and hydrazine compounds are partly determined by the
rate and extent of their N-acetylation. Thus, the capacity
Fig. l. The relationship between drug metabolism and drug
toxicity.
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
195
of individuals to N-acetylate such drugs as isoniazid,
hydralazine, procainamide, dapsone, sulphadimidine,
phenelzine and sulphapyridine is genetically determined.
Quantitative assessments of the rate and extent of acetyla-
tion yield bimodal frequency distributions which separate
'fast' and 'slow' acetylators; 52 per cent of the population
are slow acetylators[4]. Drug acetylation is controlled by
two autosomal alleles at a single gene locus, the trait for
fast acetylation being dominant and that for slow, reces-
sive^].
The clinical implications of acetylator status illustrate
the influence of phenotype on adverse drug reactions.
Differences in acetylator status have marked effects on the
pharmacological and toxicological profiles of a number of
important drugs (Table 2). The neurotoxicities which
Table 2. Adverse reactions associated with slow acetylator
status.
Susceptible
Drug Toxic effect phenotype
Isoniazid Peripheral neuritis Slow
SLE syndrome Slow
Hepatitis Rapid/Slow
Hydralazine SLE syndrome Slow
Procainamide SLE syndrome Slow
Salicylazo- Cyanosis and
sulphapyridine haemolysis Slow
Arylamines Bladder cancer Slow
result from isoniazid, hydralazine- and procainamide-
induced systemic lupus erythematosus and sulphasala-
zine-induced toxicity, illustrate the significance of
acetylator status in clinical medicine[6], These toxicities
are dose-dependent and therefore more common among
slow acetylators, who usually have higher serum concen-
trations of the drug at any time after ingestion, than do
rapid acetylators.
Other disorders for which acetylator status has been
claimed to be a predisposing factor include isoniazid-
induced hepatitis[7,8], arylamine-associated bladder
cancer[9] and haemolysis induced by sulphones and
sulphonamides in glucose-6-phosphate deficiency[10,11].
Analysis of the relationship between the metabolism and
toxicity of some of these compounds is complicated by the
fact that a metabolite is thought to be responsible for the
toxicity.
Acetylator phenotype may partly determine whether or
not an individual is susceptible to drug interactions. For
example, Kutt et al. [12] observed phenytoin intoxication
in approximately 10 per cent of epileptics who took the
drug together with isoniazid. All the patients were slow
acetylators and intoxication could be avoided by simply
reducing the dose of phenytoin.
Although there seems to be common agreement that
acetylator status is an important determinant of an
individual's susceptibility to the toxicity of certain drugs,
the value of acetylator phenotype as a predictor of drug
toxicity remains an open question[13,14]. However, the
distinction made between the two phenotypes is only
semi-quantitative and thus may not be a sufficiently
powerful method to identify those individuals most at
risk.
Until recently pharmacogenetic polymorphisms in
drug oxidation were considered rare, despite the fact that
the majority of lipophilic drugs are metabolised by the
hepatic cytochrome P-450 enzymes, a family of enzymes
with distinct but overlapping substrate specificity. A
number of monogenically controlled polymorphic drug
oxidation reactions have now been discovered. The prin-
ciple biotransformations that have been investigated are
debrisoquine 4-hydroxylation and sparteine oxidation;
independent polymorphisms have been reported for tol-
butamide hydroxylation[15], mephenytoin hydroxyla-
tion[16] and nifedipine oxidation[17].
The formation of the major metabolite of debrisoquine,
4-hydroxydebrisoquine, displays polymorphism in the
British population. Two distinct phenotypes, 'extensive
metabolisers' and 'poor metabolisers', are recognisable;
the 'poor metaboliser' phenotype frequency is an auto-
somal Mendelian recessive character and has a frequency
of 8.9 per cent[18]. Poor metabolisers have grossly im-
paired metabolism and excrete little or no metabolite.
Since the original report that debrisoquine hydroxyla-
tion in man exhibits genetic polymorphism, there has
been much interest in other drug biotransformations
which co-segregate with the defect in debrisoquine 4-
hydroxylase activity and, perhaps more importantly,
whether poor metabolisers are more susceptible to ad-
verse drug reactions (Table 3).
Table 3. Adverse reactions associated with impaired debriso-
quine oxidation.
Drug Adverse reaction
Metoprolol Excessive /3-blockade[21,22]
Nortriptyline Confusional state[35,36]
Phenacetin Methaemoglobinaemia[32]
Phenformin Lactic acidosis[28,29]
Perhexiline Neuropathy and hepatotoxicity[25]
A number of reports have linked adverse reactions to
lipophilic /3-adrenoceptor blockers with impaired ability
to hydroxylate debrisoquine[19,20], Lennard et al. [21,22]
found that plasma metoprolol concentrations and areas
under the plasma concentration-time curve were greater
in poor metabolisers than in normal metabolisers. A
significant correlation was found between debrisoquine
metabolic ratio, metoprolol elimination half-life and per-
centage reduction in exercise-induced tachycardia (24
hours) which was taken as a measure of /3-blockade.
However, Clark et al. [23] found in hypersensitive subjects
no relationship between adverse reactions necessitating
metoprolol withdrawal, and oxidation status.
It^has been tentatively suggested that patients due to
receive lipophilic /3-blockers should first have their drug
oxidation status determined. Jack and Kendall[24] have
questioned the need for this and suggested that subjects at
risk can be detected by measuring pulse rate. Neverthe-
196 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
less, measurement of oxidation status may be of value iri
(a) investigating the mechanism of the adverse reaction,
(b) detecting individuals potentially at risk from the
conventional doses of /3-adrenoceptor blockers and (c)
recognising drugs subject to wide inter-individual vari-
ation in metabolism within the population.
The anti-anginal drug perhexiline is associated with a
number of adverse reactions, the most important of which
are peripheral neuropathy and hepatotoxicity. The drug
is amphiphilic and thus forms stable, non-degradable
complexes with phospholipids which accumulate in cer-
tain cells and thereby produce cytotoxicity.
Shah et al. [25] have suggested that determination of
debrisoquine oxidation status may be of predictive value
in determining perhexiline dosage and in controlling the
neurotoxicity of this drug, the incidence of which appears
to be related to individual half-life[26]. The metabolism
of perhexiline is associated with that of debrisoquine and
poor oxidisers of perhexiline are also poor metabolisers of
debrisoquine[27]. Shah et al. [25] compared a group of
patients who had perhexiline-induced neuropathy with a
control group who had no serious adverse effects on long-
term treatment. The percentage of poor metabolisers of
debrisoquine in the group who had suffered peripheral
neuropathy was about 50 per cent, whereas the propor-
tion of poor metabolisers in the control group was similar
to that expected in a normal, healthy population.
The oral hypoglycaemic agent phenformin has been
withdrawn from use in many countries because of its
association with lactic acidosis. The oxidation of phenfor-
min is thought to be linked with debrisoquine 4-hydroxy-
lation and it has been suggested that phenformin toxicity
might have arisen because of poor metabolism[28]. There
is no direct clinical evidence to support this hypothesis,
although it has been shown that volunteers, phenotyped
as debrisoquine poor metabolisers, given phenformin had
significantly higher blood lactate concentrations than
corresponding extensive metaboliser phenotypes[29].
The analgesic phenacetin is associated with a risk of
renal toxicity and was therefore virtually prohibited in the
UK in 1980. It is converted into paracetamol in the liver
by oxidative de-ethylation. In poor metabolisers of debri-
soquine, the rate of formation of paracetamol is slower
than in extensive metabolisers[30] and phenacetin pro-
duces methaemoglobin in poor metabolisers but not in
extensive metabolisers[31]. It has been suggested that, in
the poor metaboliser, more of the drug is converted into a
toxic metabolite, 2-hydroxyphenetidine, via an alterna-
tive metabolic pathway (de-acetylation and aromatic 2-
hydroxylation) not controlled by the same gene locus
responsible for de-ethylation[32].
The metabolism of tricyclic antidepressants is related to
that of sparteine and dibrisoquine[33,34]. Indeed, it has
been suggested that it is possible to predict steady-state
plasma concentrations from an individual's debrisoquine
metabolic ratio[35]. The poor metaboliser appears to be
at greater risk to nortryptyline-induced vertigo, dizziness
and confusional state[36] but the clinical significance of
this observation has not been defined.
Thus it can be seen that where metabolism is strongly
influenced by a major gene effect, there may be pro-
nounced differences in drug response, and toxicity may
ensue through drug accumulation. Adverse effects are
generally more frequent in the poor metaboliser, but
encainide provides an example of the extensive metabo-
liser possibly being more predisposed, as the metabolites
of the drug are pharmacologically active[37].
In no instance has the determination of phenotype
provided an absolute test for drug toxicity. Indeed, it
would have been naive to suppose that it would. Never-
theless, such information should be useful for detecting
individuals potentially at risk and in the evaluation of the
relationship between the metabolism and toxicity of new
drugs.
Modulation of Drug Metabolism
Numerous factors may alter the capacity of an individual
to metabolise drugs[l,2] and thereby increase the risk of
toxicity because of either drug accumulation or enhanced
rate of formation of a toxic metabolite. In practice, the
most important considerations are age, enzyme induction
and enzyme inhibition.
Age
The incidence of adverse drug reactions in elderly
patients is approximately twice that found in younger
patients. Numerous factors such as multiple disease states
and multi-drug therapy contribute to this difference.
There is, however, an expanding literature of clinical
studies in man which clearly indicate that metabolism of
some drugs is impaired with older age[38]. Therefore the
elderly may be more susceptible to adverse drug re-
actions, especially from drugs with long half-lives.
This point is illustrated by the experience with the anti-
inflammatory drug benoxaprofen (Opren), which was
withdrawn because of adverse effects which were more
severe and frequent in elderly patients[39-41].
The agent was designed with a longer half-life than
other non-steroidal anti-inflammatory drugs, so that it
could be administered once daily, while maintaining a
therapeutic response. However, the rate of metabolism
showed a profound dependence on age, the half-life in
elderly patients being approximately four times longer
than in younger patients[42]. The fatal hepatic and renal
cytotoxicity of benoxaprofen appears to have been related
to the excessive accumulation of the drug.
After paracetamol overdose, children experience rela-
tively mild liver involvement, despite paracetamol serum
concentrations that would be associated with life-threat-
ening hepatotoxicity in adults. Paracetamol toxicity is
due to formation of a toxic reactive metabolite. The lower
incidence of severe toxicity in children may be related to a
greater ability to metabolise paracetamol via non-toxic
pathways[43].
Enzyme Inhibition and Enzyme Induction
The clinical implications of induction and inhibition of
drug metabolism have been reviewed elsewhere[44].
Drug interactions which occur as a result of enzyme
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 197
induction or inhibition are usually produced by drugs
prescribed in doses of 100 mg or more daily. Interactions
involving such changes in enzyme activity are usually of
importance only for drugs with a narrow therapeutic
index such as anticonvulsants, anticoagulants, anti-
arrhythmics and oral contraceptives (Table 4). With these
Table 4. Clinical importance of enzyme induction and enzyme
inhibition.
Enzyme Inducers Enzyme Inhibitors
Substrates
Anti-arrhythmics
Anticoagulants
Anticonvulsants
Oral contraceptives
Tolbutamide
Carbamazepine
Phenobarbitone
Phenytoin
Rifampicin
Cimetidine
Erythromycin
Isoniazid
Sulphaphenazole
drugs, a relatively small alteration in elimination rate
may be associated with a change from a therapeutic to a
toxic response.
For example, co-administration of the H2-antagonist
cimetidine increased warfarin plasma steady-state con-
centration and prolonged prothrombin time to a danger-
ous level[45], More recent work[46] has shown that
cimetidine stereoselectively inhibits the metabolism of R-
warfarin. Phenobarbitone, on the other hand, stimulates
the metabolism of warfarin. Concurrent administration
of phenobarbitone and warfarin produces a change in
steady-state plasma warfarin and anticoagulant effect
within six days[47]. However, after withdrawal of pheno-
barbitone, drug metabolism returns to normal and this
may lead to fatal haemorrhage during continued anti-
coagulant therapy[48].
New drugs thought to be either enzyme inhibitors or
enzyme inducing agents may be screened using model
drug substratesfl]. The time-course of enzyme induction
may be monitored by simply measuring changes in the
disposition of an endogenous compound, 6 /3-hydroxy-
cortisol.
Theoretically, enzyme induction could lead to a selec-
tive increase in toxic metabolite formation. Although
such a mechanism has been demonstrated for carcinogens
and hepatotoxins in sensitive animal test systems[49,50],
there is nO direct evidence for it in man. Furthermore,
White et al. [51] did not find an increased rate of cancer in
patients on long-term anticonvulsant therapy, as might
have been expected if there was enhanced activation of
aromatic hydrocarbons. Animal studies have shown that
toxicity may be reduced by inhibition of paracetamol and
isoniazid reactive metabolite formation with cimetidine,
but this has not been achieved in man[52,53].
Toxic Metabolites
For most drugs metabolism represents a clearance mech-
anism. However, in certain circumstances, a normal
biotransformation may lead to the formation of a toxic
metabolite (Fig.2). Chemically reactive metabolites are
particularly important in this respect because their cova-
lent interaction with biopolymers in vivo might induce
tumorogenicity, cytotoxicity and hypersensitivity[54].
In the process of the chemical induction of a tumour,
binding of that chemical or one of its metabolites to a
biological macromolecule seems to be the initial step.
Good correlations between carcinogenicity and covalent
binding to DNA as target macromolecule rather than
RNA or protein have been observed[55,56]
The liver is the major site of drug metabolism and a
number of drugs, including paracetamol (overdose), ison-
iazid and halothane, are thought to produce hepatotoxi-
city by generating chemically reactive metabolites which
react indiscriminately with vital cellular macromolecules
(reviewed by Timbrell[57]). The relationship between the
toxicity and metabolism of paracetamol has been investi-
gated extensively in both man and experimental ani-
mals[49,58,59].
Paracetamol is largely metabolised via glucuronidation
and sulphation which account for approximately 50 per
cent and 25 per cent of the drug, respectively. In
addition, about 10 per cent of the drug is oxidised to a
chemically reactive metabolite N-acetylbenzoquinone
imine, which is normally detoxified immediately by con-
jugation with glutathione. However, after an overdose
(10-20g) the sulphation and glutathione pathways become
saturated, allowing the chemically reactive metabolite to
arylate essential cell structures[60]. The severity of para-
cetamol-induced cellular necrosis varies in proportion to
the amount of arylation. Administration of N-acetyl-
cysteine may afford protection by providing more glu-
tathione for detoxification of the reactive metabolite[61].
Work on ipomeanol-induced lung disease in animals
provides further convincing evidence for the role of
metabolic activation in chemical-induced tissue in-
jury[50]. In particular, formation of chemically reactive
metabolites in tissues other than liver, may produce
organ-selective toxicity.
Our current understanding of drug hypersensitivity
(allergy) is based on the assumption that drugs form
haptens in vivo. This concept derives from classical
Fig. 2. The role of chemically reactive metabolites in drug
toxicity.
198 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
immunochemical studies[62,63] which showed that low
molecular weight compounds (e.g. drugs) must be linked
by a covalent bond to a macromolecular carrier in order
to elicit an immune response (Fig. 3).
Evidence that drugs produce hypersensitivity in man,
by acting as haptens, came from several groups working
on penicillin allergy[64-66]. Antibodies directed against
antigenic determinants derived from penicillin can be
detected in the majority of patients treated with penicillin.
The sensitising capacity of penicillin can be explained
by the inherent chemical reactivity of the /3-lactam nu-
cleus. However, the question of whether the ultimate
immunogen is formed in vivo from autologous proteins or
is in fact an impurity from the manufacturing process has
not been resolved[67].
Most drugs do not possess direct protein reactivity, and
it is assumed that haptens are formed from chemically
reactive metabolites (Fig. 3). Although this is an attrac-
tive hypothesis, there is no direct experimental evidence
to confirm it. A number of drugs with suspected immuno-
logical adverse effects, such as practolol, procainamide,
chlorpromazine, sulphonamides, ethynyloestradiol, halo-
thane and hydralazine readily form 'reactive metabolites'
in in vitro drug-metabolising systems[68]. It is therefore
possible that such metabolites might form effective (im-
munogenic) haptenated protein conjugates in certain
individuals, especially those with deficient detoxification
mechanisms (e.g. glutathione conjugation).
Conclusion
Individuals show remarkable variation in their ability and
capacity to metabolise drugs. Drug toxicity may occur
because of excessive accumulation of the parent drug or
formation of a toxic (reactive) metabolite. To avoid
adverse reactions, it is important to understand factors
that affect dosage requirements and thus identify, within
the population, individuals susceptible to dose-dependent
drug toxicities.
Drug toxicity may be a function of the route rather
than the rate of drug metabolism. In such circumstances,
toxicity will be partly dependent on the balance between
activation and deactivation pathways. At present it is not
possible to assess an individual's capacity for generating
such toxic metabolites. However, chemical studies of the
in vitro and in vivo metabolism can provide some insight
into the potential toxicity of a particular drug.
A cknowledgements
I should like to thank Professor A. M. Breckenridge for
many helpful discussions.
This article is based on a paper read at the College Regional
Conference in Liverpool in September 1985.
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200 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
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PMC005xxxxxx/PMC5371055.txt | ;?
I
Mayerne and his Successors:
some Huguenot Physicians under the Stuarts
RANDOLPH VIGNE, MA
President, The Huguenot Society of London
Calvinism today has for many a connotation of intolerant
narrowness and rigidity of thought, yet in the late 15th
and early 16th centuries Calvinists, or Huguenots, were
the most intellectually advanced and inventive com-
munity in France. After 1629, with the breaking of
Huguenot power, they were forced on to the defensive as
their community and faith were increasingly threatened
and perhaps the most productive element left France,
either in that early period or in the years around 1685
when 250,000 fled abroad at the Revocation of the Edict
of Nantes, 50,000 of them to Britain.
The successful careers of many of these Huguenot
refugees have been recalled in 1985, the tercentenary
year: their contribution to medicine should also not be
overlooked. There were great names like the Chamber-
lens, Ent, Primrose, the Hameys, Martineaus and many
lesser men whose careers are also representative or of
special interest. Sir Theodore Turquet de Mayerne of the
first category, the Colladons, father and son, and Pierre
Silvestre of the second, have in common their service as
physicians to the Stuarts, from James I to William III,
and their connection with the Royal College of Phys-
icians, of whom all were Fellows or Licentiates, though
only one of them learned his medicine in Britain.
Theodore de Mayerne was born in 1573 in Geneva
where his family had sought refuge the year before. With
an MD from the great Huguenot university of Montpel-
lier, he established himself in Paris in medical practice
and in teaching, becoming a follower of two leading neo-
Paracelsians, Du Chesne (Quercetanus) and Ribit de la
Riviere, both Huguenots. In 1600, through their influ-
ence, he became physician-in-ordinary to the Huguenot-
turned-Catholic King Henri IV, a position he retained
even when the Paris medical faculty, determinedly Galen-
ist and bitterly hostile to his chemical remedies, banned
him from teaching. Like his two fellow Paracelsians, he
was used by the King as a political agent in promoting a
pro-Protestant foreign policy and, after the assassination
of Henri IV, he was, in 1611, brought to England by
James I, to whose court he had already been invited in
1606, after a glowing testimonial from an English noble-
man he had cured in Paris. James had appointed him
physician to the Queen and as such he was made a DM of
Oxford University.
Mayerne's medical practice at the courts of James I
and Charles I brought him great wealth and also lasting
fame, due to the survival of his vast collection of detailed
case notes on his English and, by correspondence, French
patients. In the British Library and the Royal College of
Physicians (which published his Opera in 1703) are to be
found what the medical historian Aikin called in the 18th
century 'the medical annals of the Court of England'.
These records display the meticulous pains he took in
clinical observation, which were as much the reason for
his success and continuing influence, as were his chemical
remedies, involving the use of calomel, iron, mercury and
even antimony.
His early years in England were marred by the death of
the brilliantly promising 18-year-old Henry, Prince of
Wales, whom he was accused of poisoning, and by a
similarly false implication in the death in the Tower of Sir
John Overbury. His account of Prince Henry's illness is
the first written record of a case of typhoid fever, and a
model of its kind.
He retained the King's confidence, despite James's
scornful dismissal of medicine, which Mayerne recorded
in his lengthy memoir on the King's health. James made
use of Mayerne's valuable Huguenot connexions and he
was on a visit to France in 1625 when a stroke caused the
King's death amid an unpleasant wrangle among the
doctors, including William Harvey, and courtiers around
him.
Mayerne returned as Charles's physician and treated
him, his Queen, Henrietta Maria (daughter of his old
master, Henri IV) and all her children, as he did
Charles's sister Elizabeth of Bohemia, the 'Winter
Queen' and her family in England and abroad for 30
years to come.
For Henrietta Maria Mayerne produced a wide range
of cosmetics, for which he has been criticised, but
Mayerne was a dedicated chemist and his interests in-
cluded the making of colouring matter for paints and
enamelling (he introduced the great enamellist Petitot to
Charles's court).
His chemical remedies included the taking of 'steel', in
powdered form, for 'the spleen' or melancholy, pre-
scribed for one of Elizabeth of Bohemia's ladies, as well as
for Dorothy Osborne, who called it 'a drench that would
poison a horse . . .'tis worse than dying by the half!'
Mayerne was socially ambitious, making himself the
Baron D'Aubonne by the purchase of an estate in Swit-
zerland, advancing one of his daughters, Louise, as an
222 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
attendant on Elizabeth of Bohemia, and affiancing
another, Elizabeth, to the young Earl of Huntingdon who
died of smallpox on the eve of the wedding. She mar-
ried?unhappily, wrote Dorothy Osborne?a French no-
bleman, as did her sister Adriana, his youngest and only
child to survive him. The early deaths of both of his sons
were a great grief, again described by Dorothy Osborne,
whose family were the Mayernes' neighbours in Chelsea
in later years.
He had many patients outside the Court, including
Oliver Cromwell, then a young MP suffering from 'a
periodic throbbing pain lasting three hours' and de-
scribed by Mayerne as 'undoubtedly melancholic', and
the wife of Bulstrode Whitelocke, whose doctor's letter
asking his advice may be the first on record from a
'general practitioner' to a 'consultant'.
As a foreigner Mayerne showed less loyalty to Charles
than did Harvey, who followed the King to war while
Mayerne stayed on in London. When the Commons
asked him in 1641 for his views on the necessity of the
Queen's proposed, and rightly suspect, visit to Spa, he
had equivocated, speaking of her 'inward discontent of
mind'. Yet Henrietta Maria continued to rely fully on
him: he had delivered her nine children without a miscar-
riage and had saved two of them, Prince Charles, heir to
the throne and Mary, mother of the future William III, at
the point of death. In 1644 she left the embattled King at
Oxford, for the relative safety of Exeter for the birth of
her last child, Henrietta Anne, later Duchess of Orleans.
Mayerne, though 72 and hugely fat, obeyed the King's
one-line summons to attend her: 'Mayerne: Pour I'amour de
moy alle trouver ma Femme. C.R. ' After the Queen's escape
to France, and Charles's execution, he tried to save the
delicate 14-year-old Princess Elizabeth, leaving, as al-
ways, an exhaustive account of her case. But 'from the
death of her father she fell into a great sorrow whereby all
the ailments from which she suffered were increased' and
she died at Carisbrooke Castle in 1649.
Mayerne found time outside his large practice and
constant attention on the Queen and her children, to help
establish the Apothecaries' Company, drafting its
charter, with the support of the College of Physicians to
which he had been elected the year before. He also wrote
the dedication to James I of the Pharmacopoeia Londinensis
in 1618, and was responsible for much of its contents.
These included Thomas Muffet's Paracelsian medicines,
which he had acquired after Muffet's death. He pub-
lished, after many difficulties, Muffet's great work on
insects (undeservedly less well-known than his daughter
Patience's encounter with a spider famous in every
British nursery).
Having freed the Apothecaries from the Grocers (thus
improving their status) he freed the Distillers from the
Apothecaries, in which action he had a personal interest
as a patentee for 'strong waters' and for making vinegar
'from cider, perry and buck'.
Mayerne's activities sound respectably 'scientific' to
modern ears yet he maintained a continuing interest in
and secret correspondence with Quercetanus and others
on alchemy and was a member of the Fratres Societatis
Rosa Crucis, surprising in one who had prevailed against
all attempts to persuade him to abjure his Protestantism
in France, and who played his part in support of the
Huguenot chapel in the Strand at which he worshippped.
This contradiction can also be seen in his taste for rich
and copious eating (displayed in his posthumously pub-
lished cookery book, Archimagirus Anglo-Gallicus, 1658),
and love of wine, beside the immense pains he took for the
health of his patients and often sound advice on diet.
Though not a refugee in the common sense, Mayerne
had come here because he could not teach and practise the
chemically-based medicine which he and other Hugue-
nots were championing against an inflexible system. He
flowered under English skies, in a way that religious
hostility in France would have made impossible. Both he
and the country that took him in were the gainers. He
died in 1655, aged 82, after drinking bad wine with
friends at a tavern near his old home at Charing Cross,
and was buried at St Martin-in-the-Fields, beside his First
wife, mother, and five of his children. Mayerne's model
case notes, chemically-based drugs, and the institutions
he created lived after him, as did his great wealth, but his
only family descent was through his daughter Adriana,
Marquise de Monpouillan. Her only child married the
brother of that prime eccentric, Charles, first Duke of
Bolton, leaving a numerous posterity. He left his library
to the Royal College of Physicians.
In 1631 Mayerne brought to England a young Gene-
van Huguenot, Jean Colladon, who became an MD of
Cambridge and, after practising briefly at Norwich,
Fig. 1. Sir Theodore de Mayerne.
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 223
married in France in 1637, Ayme de Frotte, daughter of
Mayerne's sister Judith. Colladon, whom Mayerne ad-
dressed in letters as 'Mon Enfantfollowed his uncle and
patron as a Royal physician?to Charles II, first as Prince
of Wales, from 1640, and after the Restoration as King.
Like Mayerne he had patients among the King's en-
emies, too, attending, with Mayerne, John Pym in his
last illness. They both, with others, signed the post mortem
report, designed to show that Pym had died not of an
'Herodian visitation', in all its horror, because of his
sacrilegious opposition to the King, but of an 'impostume
in the bowel'.
Colladon also followed Mayerne as unofficial agent for
the Republic of Geneva at the Court of St James,
retaining, unlike Mayerne, his Genevan nationality until
all hope of being officially appointed by the Sindics of
Geneva had gone. (The premier sindic was his cousin Esaie
Colladon). Both Protector Richard Cromwell and the
restored Charles II urged him to take the post but the
Sindics, always fearful of offending Louis XIV, refused
him politely. In 1655 he had helped transmit the funds?
?38,000?collected throughout England for the Vaudois
survivors of'the late massacre in Piedmont' immortalised
in Milton's greatest sonnet.
While maintaining his Genevan identity, Colladon was
playing a major role in the integration of the Huguenot
community in Britain. He led the petitioners for the
separation of the Church of the Savoy from the mother
church in Threadneedle Street which was resolutely
Calvinist and non-conformist. When Charles II consent-
ed, the new church (a development of Mayerne's Somer-
set House chapel in the Strand) followed the Anglican
liturgy (in French) and accepted the authority of the
Bishop of London. After 1685 other Huguenot congrega-
tions followed the Savoy into the Anglican fold, their
members' descendants abandoning their old Huguenot
churches in the late 18th and early 19th centuries as their
refugee past faded.
Colladon's professional and other activities are a pale
reflection of Mayerne's: a few references in the Verney
papers (in one Tom Verney expresses the impious hope
that the plague then raging 'might touch my chief creditor
Colladon before it yet leaveth'), in Court papers and in a
patent document with Samuel Pepys's unstable, improvi-
dent Huguenot father-in-law, for curing smoking chim-
neys. He became an Honorary Fellow of the Royal
College of Physicians in 1664, was knighted the same year
and remained, as he appeared on the Savoy petition,
physician to the king.
He married off one daughter well in Geneva and the
other to the son of an elder of the Huguenot church in
London. His son-in-law Wickart became a Canon of
Windsor and later Dean of Winchester and chaplain to
the King. His son, Theodore Colladon, a Mayerne on his
mother's side, was already in practice, with his Oxford
DM, when Sir John Colladon died suddenly in 1675,
leaving a handsome estate to his widow, the daughter of
Judith de Frotte, born de Mayerne.
Theodore Colladon's career as a society doctor and
Royal physician maintained the family reputation and
fortune. He was elected an Honorary Fellow of the Royal
College of Physicians in 1685 and was 'constituted a
Fellow by the charter of James II and was admitted as
such at the Comitia Majora Extraordinaria of 12 April
1687', writes Munk. He was knighted by William III in
1700 and married the same year. In 1703 he was present
at William's deathbed, with seven other physicians,
including the President of the College, Sir Thomas
Millington and William's most trusted physician, his
compatriot Dr Govart Bidloo, who was closest to the King
in his dying moments. Curiously, the broadsheet issued
next day omitted the names of both Colladon and Bidloo,
possibly to allay any alarm based on the public dislike of
William's foreign courtiers and servants.
The following year Sir Theodore was appointed phys-
ician to the six-year-old Royal Hospital, Chelsea, and
looked after the old soldier inmates and a host of out-
patients until his death in 1712. Unlike the Huguenot
apothecary to the Hospital, Isaac Gamier, who was
succeeded by his son in the post, Colladon left only a
young widow and ten year old daughter, Ann, later to
marry Charles Montagu, MP, a Nottinghamshire land-
owner. Their son became the Rt. Hon. Frederick Mon-
tagu, a Lord of the Treasury in 1782, and was able to pass
on a family fortune and an equally prodigious Tory
loyalty to Victorian and Edwardian descendants.
Ann Colladon's marriage marks the final integration of
the family into English life, but her mother, Susanne
Maria, Lady Colladon, played her own part in her long
widowhood, as a leading member of the group of Hugue-
nots in high places who administered charitable funds for
the poor and the afflicted among their growing com-
munity. From 1718 the French Hospital, La Providence,
shared the burden, helped at the outset by a generous
subscription from Lady Colladon. She also maintained
the tradition of Royal service that had begun with
Mayerne's appointment by Henri IV in 1600, as sous-
gouvernante to the five daughters of the Prince of Wales,
later George II, at Richmond, after the death of Queen
Anne at last removed the Stuarts from the scene. Lady
Colladon died in 1753.
Pierre Silvestre, the last of the succession of Huguenot
Royal physicians, was a post-Revocation refugee, unlike
Mayerne and the Colladons who were part of the great
Huguenot international with links across Europe but few
remaining connections in France. Silvestre's father was
an advocate at the parlement of Bordeaux and the family
lived at Tonneins on the Garonne, 75 km to the south-
east. After qualifying at Montpellier in 1683, he was sent
to Paris to walk the wards but the Revocation, two years
later, meant the ruin of his career or betrayal of his
family's Protestant faith and he was able to make his
escape to Amsterdam in the company of some German
noblemen. He attracted the attention of the Stadtholder,
William of Orange, and became his physician, ac-
companying him to England and the Glorious Revolution
in 1688. The Duke of Schomberg, William's commander-
in-chief in Ireland, commandeered his services as phys-
ician, but, aged 80, fell in action in the hour of victory at
the Boyne.
Silvestre, who was not on the establishment, was cut
adrift but, returning to England, was offered by William
224 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
a post with the army in Flanders. He accepted instead the
patronage of Ralph, Duke of Montagu, who had been
Charles II's ambassador to Louis XIV, and Silvestre
became one of the large band of Huguenots who came to
serve him in England after the Revocation.
He seems to have been both physician and adviser on
buildings and paintings, and has even, on no evidence,
been suggested as the architect of the very French north
front added to Montagu's Boughton House, near Ketter-
ing in Northamptonshire, before 1700. 'Dr Sylvestre's
Room' is listed in the inventory of the house, made at
Duke Ralph's death in 1709.
Silvestre acquired a large practice in London, becom-
ing a Licentiate of the Royal College of Physicians in
1693, and in 1696, like a number of fellow Huguenot men
of learning, a Fellow of the Royal Society. He was also
appointed a physician to the King but there is no record
of payment, though a pension from his days at the Dutch
court had tided him over after his return from Ireland
without a post.
Montagu put him in charge of his heir, Viscount
Monthermar, on the Grand Tour in 1700, and he made
use of their time in Italy to send two reports and a
collection of 'natural curiosities' (earth, gum, Vesuvius
salt, etc.) to the Royal Society. The second and only
surviving report describes 'the virtuosi I have seen in
Italy and the state of learning there, chiefly as to natural
philosophy and physick'.
It illuminates Silvestre's own eclectic interests and wide
cultivation, as much as it does the scientists he met. His
chief interest and skill was anatomy and his greatest
excitement was expressed at seeing in Genoa a 'wax
carving' of a human body, in natural colour, made by a
lecturer and compatriot, Desnoms, so perfect as to be
indistinguishable from 'a newly embalmed corpse', which
he urged as a marvellous aid to the study of anatomy.
Silvestre had become part of the circle of the brilliant
wit and man of letters, the exiled Catholic nobleman, St
Evremond, who expressed surprise to Montagu that he
had come back from Italy, not 'all upon his Architecture
and Painting' but with the violin sonatas of Corelli. He
did not seem to have suffered as so many Huguenot tutors
did, in charge of wild, philistine young milords on the
Grand Tour, and in 1706 again travelled with Month-
ermer, now married to Marlborough's daughter, in the
Low Countries. He reported to Montagu their difficulties
in getting to see Mothermer's father-in-law, who was
otherwise occupied routing Louis XIV's army at Ramil-
lies.
Silvestre was naturalised in 1705 and thereafter served
on various boards, such as the commissions for naval sick
and aged, and for 'Poor French Proselytes'. He peti-
tioned with others against the inheritance of estates in
France that rightly belonged to refugee heirs, but the
resulting bill was withdrawn when it was shown that those
receiving remittances from their French estates would
suffer. Perhaps his elder brother, who had inherited the
estate at Tonneins, had abjured: their mother came to
England and outlived her son, as did his younger brother
Francis, naturalised in 1707. Madame Susanne Silvestre
made Francis's son, Jean-Baptist Zacharie, her heir,
provided he did not move to France 'or any country
where the Romish religion is predominant'. Perhaps she
feared the influence of his mother, who had been taken
from her Protestant family and put in a convent, until, at
13, she emerged to marry Francis Silvestre, the hope
being that she would be reclaimed. She remained a
Catholic but exemplified both Huguenot stubborness and
longevity by remaining 'd'une bigoterie extreme' until her
death at 93.
Silvestre's double role as physician and man of the arts
continued with his appointment as literary executor to St
Evremond, whose own doctor, Sebastian Le Fevre, MD
(of Rouen), LRCP, had looked after him for 40 of his 42
years in exile. Yet in several letters and in some 'Stances
irregulieres' dedicated to him, Silvestre's great medical
skill, and power to cure by his piercing look, were praised
by St Evremond, who called him 'le docteur aux regards
salutaires
Pierre Des Maizeaux, FRS, who edited St Evremond's
complete works for Silvestre, recalled, in later editions,
his delightful manner and conversation, his gay, healthy,
and laughing countenance, his good taste in music,
painting and the 'beaux arts', and his deep knowledge of
anatomy, medical practice and chemistry.
Silvestre, then living in Frith Street, Soho, among his
fellow Huguenots, died in 1718, his estate passing
through his mother to his nephew, later Sir John Baptist
Silvester, MD (of Leyden), LRCP, FRS, physician to
General Wade in the Low Countries, to The London
Hospital and the French Hospital, La Providence. He
was the father of Sir John Silvester, Bt, FSA, Hon DCL
(Oxon), FRS, Recorder of the City of London. The
baronetcy, under a second patent, survived only a further
generation, through a Carteret nephew. Silvestre's name
now lives only in the letters of St Evremond, which
project him as embodying some of the characteristic
Huguenot virtues he shared with his predecessors,
Mayerne and the Colladons, virtues which, with their
skills, were the contribution the Huguenots made in
return for the asylum given by the British people at their
most tolerant.
This article is absed on a lecture given at the Royal College of
Physicians in December, 1985.
Some Printed Sources
Agnew, Rev David C. A. (1871) Protestant Exiles from France. Edinburgh.
Aikin, John. (1780) Biographical Memoires of Medicine in Great Britain.
London.
Debus, Allen G. (1968) The English Paracelsians. New York.
Debus, Allen G. (1977) The Chemical Philosophy. New York.
Ellis, Henry. (1827) Original Letters Illustrative of English History, Series 2,
Vol III. London.
Gagnebin, Bernard. (1941) 'Un Diplomat Genevois a la Cour d'Angle-
terre au XVIIC Siecle,' Le Mois Suisse, Vol. 26. Geneva.
Gibson, Thomas. (1933) 'A Sketch of the Career of Theodore Turquet
de Mayerne.' Annals of Medical History, Vol. V. New York.
Haag, E. and E. (1858) La France Protestante ou Vies des Protestants Francais,
Vol. VII. Paris.
Hayward, John (ed). (1930), The Letters of St Evremond. London.
Keynes, Geoffrey. (1966) The Life of William Harvey. London.
Kingsley Hart (ed). (1968) The Letters of Dorothy Osborne to Sir William
Temple, 1652-4. London: Folio Society.
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
LeFanu, W. R. (1956) 'Huguenot Refugee Doctors in England'
Proceedings of the Huguenot Society of London, Vol. XIX. London.
Mayerne, Theodore Turquet de. (1703) Opera Medici in quibus continentur
epistolae et observationes, pharmacopoeia, variaeque medicamentorum formulae.
(Ed. Joseph Browne.) London.
Moore, Norman. (1908). The History of the Study of Medicine in the British
Isles. London.
Munk, W. (1878) The Roll of the Royal College of Physicians of London.
London.
The Works of Monsieur de St Evremond made English from the French original,
with the life of the author by Monsieur des Maizeaux FRS. 2nd ed., 1728.
London.
Scouloudi, Irene. (1940) 'Sir Theodore Turquet de Mayerne, Royal
Physician and Writer.' Proceedings of the Huguenot Society of London, Vol.
XVI. London.
Trevor-Roper, Hugh. (1985) 'The Paracelsian Movement.' Renaissance
Essays. London.
|
PMC005xxxxxx/PMC5371056.txt | Medical Disability?A New Look
Thirteen years after the publication of the 'Tonbridge
Report' on Rehabilitation the majority of its recommen-
dations have still not been implemented. Disability Ser-
vices in England and Wales remain in a parlous state and
only a handful of doctors have any professional commit-
ment to the subject. Some people would argue that we
have one of the worst Disability Services in Western
Europe. The point cannot be proved one way or another,
but the potential for improvement is obvious. The publi-
cation of an RCP Report on the subject of Medical
Disability is therefore to be welcomed.
The evidence that Disability Services are in a poor state
is reviewed in the College Report. It includes criticisms
by disabled people themselves, and the fact that in many
cases there are no minimum standards of care. Patients
disabled as a result of head injury are an obvious
example. There is an almost total lack of high quality
epidemiological data, which makes planning difficult,
and many Districts have no policy guidelines and no
organised Rehabilitation Service. Further examples are
given in the recent review of Artificial Limb and Appli-
ance Centre Services which highlights major deficiencies
in the provision of wheelchairs and of artificial limbs. The
picture is, however, not entirely black. Good quality
services now exist in some parts of the country for
disabled children, the elderly disabled, and for patients
with spinal injury. However, disabled people aged be-
tween 15 and 65 are not well provided for and the Report
identifies this group as representing a particular problem.
The need for high quality Disability Services seems
self-evident. In the first place?no civilised country
should allow its disabled members to suffer unnecessary
hardship. In particular, the 'caring professions', which
obviously include medicine, should not connive at the
existence of services which are substandard, even in the
present state of apparent national penury. Secondly, the
cost of disability to the State is considerable, and it is
clearly desirable that maximum use should be made of the
money available.
Why have we ended up with such enormous gaps in
our Disability Services? The question has no simple
answer. One reason is probably that there is no-one 'in
charge'. Indeed, it appears to be true that no high quality
medical service has ever been established without the full-
time commitment of a substantial number of doctors?
renal medicine, spinal injury and geriatrics are obvious
examples. The Working Party on Rehabilitation of the
College (1978) was of the opinion that rehabilitation is the
responsibility of all clinicians. The implication is that we
do not require a large specialty of rehabilitation, or its
equivalent. This new Report explores the implications of
this principle and suggests ways in which a high quality
service might be established.
Reports by themselves never change anything. Cynics
will doubtless anticipate that this Report, like others
before it, will be quietly shelved after some initial enthusi-
astic noises. It is important to ensure that this does not
happen. The Report suggests a system of internal audit
involving District and Regional Managers, and an exter-
nal audit system which would involve outside autono-
mous bodies such as the Consumer Association and/or
the Community Health Councils. Using the professional
audit standards suggested in the Report, these bodies
could become effective. Certainly, nothing will be
achieved without sustained pressure.
How should individual Fellows and Members respond?
What is needed is a group of interested and committed
doctors in each Health District who are keen to make
progress. The first step will be to ensure that the Report is
distributed to administrators, social services, remedial
therapy departments, and other interested bodies. The
second step might be for the group to apply the audit
standards suggested in the Report to their own Health
District. This, after consultation with colleagues, could
form the basis for a Report for the District and Regional
Managers. The opportunity to make progress exists. We
should now grasp it with both hands.
R. Langton Hewer
|
PMC005xxxxxx/PMC5371058.txt | Terminal Care: How can we do Better?
ERIK WILKES, OBE, FRCR FRCGR FRCPsych
Medical Director, St Luke's Nursing Home, Sheffield
In any major organisation it is likely that a majority
perform their duties satisfactorily yet without distinction,
and a minority at each end of the spectrum perform
exceptionally well or exceptionally badly. This also ap-
plies to terminal care, and a recent surveyfl] has attempt-
ed to quantify this quality of performance by interviewing
recently bereaved relatives. These may not be conspicu-
ously reliable or accurate as witnesses, but their opinions
will at least be of interest in their comparative ratings of
doctor and nurse.
The design of the survey mimicked the national pattern
by analysing a sample of two deaths in hospital for each
death at home.
The relatives in a quarter of cases praised with respect
and affection the care given by their GP, although the
hospital nurse, closely followed by the hospital doctor,
were slightly more often praised, in nearly a third of
cases.
But the relatives found fault?sometimes with bitter
criticism and great resentment?with both GP and hospi-
tal too often for our comfort.
The GP in 16 per cent of cases did not seem interested,
did not explain, did not examine, did not visit except on
demand, and the visits were grudging, brief, inadequate
and revolved excessively and improperly around the
repeat prescription that is so often the symbol and token
of second-rate care. Symptom control was often unsatis-
factory despite this eagerness to prescribe and move on.
When the GP was praised, it was because the doctor
seemed to care, to be interested, to respect patient and
relative, to visit regularly and also (when they lived in the
area) to give them their home telephone number in case of
urgent need, to explain things, and to check how well
drugs were working before repeating the prescription.
The hospitals were criticised for their uncaring ap-
proach in a quarter of cases. Doctors or ward sisters were
evasive, information had to be pursued too often by the
relative, it was not often efficiently conveyed, and too
rarely shared adequately among members of the firm so
that different doctors were saying rather different things.
There was also disquiet, not at elderly relatives dying but
becoming, near the end, confused or drowsy strangers as
a result of what the relatives saw as pointless or degrading
overtreatment.
Such complaints point towards the specific problems
that need tackling and, since the hospices look after only
5-10 per cent of deaths, despite their expansion to nearly
100 units, this demands training on a large scale for both
hospital and community.
Training
Fortunately, training is well under way. Various ap-
proaches are being tried. Edinburgh preclinical students
talking with advanced cancer cases, Sheffield students
visiting them in their own homes, and the education of
Belfast students in this fascinating and important sub-
ject[2] are all examples of a general trend. Indeed, the
majority of medical schools not only take more interest in
the care of the dying than 25 years ago, but have a nearby
hospice as a reservoir of patients and teachers who help to
set the local standards of terminal care.
At postgraduate level the situation is less satisfactory.
The demand for a module of hospice training far exceeds
the supply. There are comparatively few registrar posts in
the hospices and only very few general practice vocational
schemes include a hospice module, for all the relevance
and value of such an experience. This will need correcting
over the next decade and it is good, but not good enough,
that some national charities are concerned enough to
consider helping with the funding of some such posts.
The ritualistic lectures held for family doctors at so
many postgraduate centres are usually attended only by
those who do not need to be there. A better idea is to
invite whole practices, receptionists, doctors and attached
nurses, to meetings, perhaps in the local hospice, together
with several neighbouring practices, to discuss their
management of terminal cases at local level, with videos
and a problem-solving approach. This provides some
access at least to the doctors in greatest need.
Meetings of hospital firms or primary health care teams
should discuss regularly the deaths of those under their
care, to see how lessons can be learned and standards
raised.
Postgraduate centres and medical schools should hold
occasional clinico-pathological conferences which start
with the GP describing the patient before the illness,
continue with the hospital doctors describing steps in
diagnosis and the acute treatment, then on to the terminal
hospice care to end with a discussion on the management
of the bereaved relatives' problems. This will accelerate
the integration of hospice expertise with traditional re-
sources that we must achieve.
With ageing relatives, marital breakdown, and looser
family ties generally, it is reassuring to see how hard
families try to cope with a dying relative. This has been
well recognised by the geriatricians[3] but not necessarily
by the system; too often an expensive hospital bed is more
quickly available to a dying patient than incontinence
216 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
pads, a commode or other simple essentials for home
care. Yet home is not always suitable for terminal care
and we know that the needs of the relatives require
admission of the dying patient more often than the needs
of the patient. This makes it clear that the management
and support of the family are as central in terminal care as
the efficient control of symptoms. There needs to be a
more family-centred approach that is not yet well taught
in our medical schools nor easily practised in busy
hospitals. Basic techniques of family therapy need to be
marketed more aggressively to both doctors and nurses,
and to be developed among hospices personnel.
But this broadening of the professional role inevitably
takes the doctor and the nurse beyond the bedside and the
laboratory. Despite the admirable clinical symposia re-
currently held at such centres as St Christopher's, Lon-
don, Michael Sobell House, Oxford and St Colombus',
Edinburgh, we need the clinician to understand some-
thing of leadership, of team-work, of the functioning of
small groups and of the other outside assistance available
for patients within the system ranging from social services
to the voluntary sector. This is partly why management
training for newly-appointed NHS consultants has been
so rapidly developed. It should also be available to senior
colleagues, who may be unhelpfully set in their ways. We
need to remember that most patients seeking the comforts
of fringe medicine have previously been dissatisfied with
conventional medical care of a less than distinguished
quality. Terminal care is thus another area requiring
management skills.
It is impossible in the care of advanced cancer to ignore
the role of the nurse. So far as the patient is concerned,
she may well be a more central figure than the physician.
Training in the schools of nursing has, as with doctors,
greatly improved over the last decade yet is still of
variable quality. This may mean that more senior col-
leagues are less well trained than their juniors, a phenom-
enon not unknown to medicine.
The English National Board runs in some 15 centres
approved full-time six-week courses on the care of the
dying and their family. These improve the confidence and
background of already interested and experienced nurses.
The course explicitly does not claim to produce specialist
nurses yet is routinely misused to that end. We need to
plan for an advanced course to take such experience
further; pilot courses are already being worked out.
Since most major centres now have a hospice within
reach, it has been found of the utmost value to arrange
temporary exchanges of nursing staff between hospice
and acute wards. The hospice staff gets updated, and they
learn again to respect their nursing colleagues from the
local hospital. This mutual respect is also learned by the
visiting hospital nurse and the acute wards become
influenced by the detailed nursing care and the regard for
the emotional and physical welfare of the patient so
characteristic of hospice care.
Case conferences on suitable patients should be held for
both doctors and nurses, although the enthusiasm of the
nurses often makes the occasional doctor appear as a
lonely colleague dedicated more to a sponsored lunch
than to an interdisciplinary meeting of minds.
Attitudes
Advanced cancer is a problem that requires teamwork. It
involves the needs of the patient, the resources of the
family, the therapeutic strategies of the doctor, the bed-
side and management skills of the nurse, the emotional
and spiritual support from social worker and chaplain,
and most important of all, the interplay and fusion of
these elements to produce a strategy agreeable to the
patient. The patient needs to feel actively concerned in his
management rather than a helpless prisoner.
This cannot be helped by the fact that nearly a third of
dying patients have little idea of their real situation. And
basic teamwork is greatly prejudiced when a third of
doctors are unwilling to entrust to capable and exper-
ienced nursing colleagues honest discussions with the
patients about the future. Although lies are rare, evasion
is common, but it is not enough to tell the patient the
truth and let them get on with it. This is a recent and
growing tendency that can be as damaging as uncertain-
ty"
Prognosis should remain uncertain within limits, for
that is the truth of it. Patients should be encouraged to ask
for information they want, but not have it forced upon
them. Someone dying may, early in the illness, feel the
need for less information than is required later on. The
young usually need more information than the old, but
generalisations are to be mistrusted. Relatives are to be
listened to courteously but the plea 'You won't tell him
will you, he couldn't stand it' is often to be translated as
'You won't tell him will you? I don't think I can handle
it'.
Family members may need more time, information
and confidence than their patient. This cannot be deliv-
ered if communication between hospital and GP is unsa-
tisfactory, and family doctors still need to keep an eye on
the local obituary column to see when their hospitalised
patients have died.
Furthermore, a higher priority must be given to im-
proving communication between different hospital col-
leagues, and who told what and when must be clearly
written up in the notes, or juniors will need to play safe,
say nothing, and so unwillingly deprive their patients of
solace and comfort.
But we are at last ceasing to look upon death as our
failure. There is more to the art of medicine than the
production of a tidal wave of unfilled geriatric need. We
are at last beginning to realise that part of the art of
medicine is not to prolong life but independence, for as
long and as comfortably as possible. Survival at all costs is
a false objective: just as a cry for euthanasia is usually a
symptom of inadequate support, a brave inclination not
to be a nuisance, and inadequate symptom control.
Cost-Effectiveness
Many junior doctors and nurses are most critical of their
own achievements in terminal care; their dissatisfaction is
indeed an encouraging feature. However, they have little
idea of how to improve the situation and tend to want to
transfer too many to hospice care, just as their seniors
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 217
transfer the old and confused but keep the young on
active treatment to treat their own needs, despite the
superior family counselling experience of the hospice.
But it is clear that a massive proliferation of hospices is
not the answer. We need hospices for the problem case, to
provide extra support in the home, day care, respite care
and family support or?since 20 per cent of hospice
admissions are social isolates?a new family. Yet most
patients will die on the acute ward or at home. The
hospices need to be sited near schools of medicine and
nursing, in big cities and in retirement areas. They
should not be built in market towns where often the best
of British medicine is to be found and the community
network of support is reasonably intact.
Hospices are expensive. A nurse:patient ratio of 1.5:1
means roughly ?500 per patient-week. Home support
nurses, each costing ?15,000 a year are much more cost-
effective so long as they are able to integrate with the local
district nurses and GPs without mistrust or paranoia
complicating the provision of an additional resource.
Hospice-trained support nurses working similarly in
the local hospitals can influence communication and
symptom control out of all proportion to their cost: but
they need in their turn to be tactful as well as tough, and
to be both accepted and supported.
Day hospitals for hospice-type patients are growing.
They allow relatives to feel more supported, and an eye to
be kept on progress without wasting time on unnecessary
home visits by the doctor. They provide a stimulus and
companionship often more effective than the drugs, a
hairdresser more welcome than the health professional,
and a variety and diversion that help to keep them going.
Such a Day Hospital could look after about 15 patients
each day for five days a week for a cost of less than three
hospice beds.
Yet in our enthusiasm we must remember that the most
cost-effective of all is a well-briefed and involved family, a
well-trained doctor and a caring nurse and, if need be, a
trusted local hospital up the road.
This article is based on a paper read at the Conference on
Advanced Cancer held at the Royal College of Physicians in
December 1985.
References
1. Wilkes, E. (1983) Lancet, 1, 950.
2. Irwin, W. G. (1984) British Medical Journal, 289, 1509, 1604.
3. Isaacs, Bernard, Livingstone, Maureen, Neville, Yvonne. (1972)
Survival of the Unfittest, London: Routledge & Kegan Paul.
|
PMC005xxxxxx/PMC5371059.txt | Reasons for Delay in Permanent Pacemaker
Insertion
A F MACKINTOSH, MD, mrcp*
Consultant Cardiologist
R M BOYLE, mrcp
Lecturer in Cardiology, Killingbeck Hospital, Leeds
International surveys continue to show that the rate of
permanent pacemaker insertion is substantially lower in
the UK than in the USA, West Germany, France and
other countriesfl]. The rate in Britain could be a more
accurate reflection of the need, but it is possible that
British patients are being denied the benefits of pacemak-
er therapy. Patients who should be paced but never are,
cannot be identified easily, but those who do receive a
pacemaker can be assessed for any delay in instituting
pacing and for the reasons underlying that delay.
Patients and Methods
One hundred and one consecutive first implants by the
authors were studied from September 1982 to October
1983. They represent 64 per cent of the first implants at
Killingbeck Hospital in that period and a third of all first
implants in the Yorkshire region. The information con-
cerning each patient was recorded at the time of the
pacemaker procedure. The patient and/or the relatives
were questioned. In nearly all cases the notes of the
referring hospital were available for inspection. Statistical
analysis was by the chi squared test.
Results
Nine patients had no symptoms of a bradycardia prior to
pacemaker insertion. The rest of this report is concerned
with the remaining 92 patients (54 men, 38 women, aged
32-97 years); 64 patients had predominantly atrioventri-
cular block, 27 had predominantly sinoatrial disease, and
one showed a mixed picture.
The time from the onset of symptoms to permanent
pacemaker insertion was more than 10 years in four
patients. Two were women, aged 87 and 92 years at the
time of implantation, who were known to have atrioven-
tricular block. Another was a 62 year old man, with
sinoatrial disease, who was being treated for epilepsy.
The fourth was an 81 year old woman with initially no
clear diagnosis, who was subsequently found to have
sinoatrial disease. Nine patients had been waiting for 3-
10 years: a cardiac arrhythmia had been identified in only
one. More than six months had elapsed between the onset
of symptoms and permanent pacing in 36 patients (39 per
cent).
Increasing age was not associated with a longer delay,
but men were paced quicker than women (Table 1).
Table 1. Distribution of patients by sex and time to pacing.
Men Women
Time to pacing (n = 54) (n = 38)
Less than 31 days 27 9 (p<0.02)
Less than 6 months 39 17 (p<0.01)
There was no significant difference in the delays exper-
ienced by patients referred from hospitals in the two
Leeds (teaching) districts, or those referred from non-
teaching districts (Table 2). Fifteen (56%) patients with
Table 2. Duration of symptoms in teaching and non-teaching
districts (determined by source of referral).
<6 months Total
Teaching districts 25 (68%) 37
Other districts 31 (56%) 55
(p>0.1)
sinoatrial disease waited longer than six months com-
pared with 21 (33%) patients with atrioventricular block,
but this difference was not significant.
The date of the first medical consultation and the first
referral to hospital were recorded. Nine of the 36 patients
whose symptoms started more than six months before
pacemaker insertion did not initially seek medical advice.
Another five were not referred on by their general
practitioner. Thirteen were seen at hospital soon after the
onset of symptoms, but were not paced at that time. The
remaining nine had a combination of delays. Only one of
the 13 patients whose delay occurred after attending
hospital had ambulatory electrocardiographic monitoring
"Correspondence to Dr A F Mackintosh.
220 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
soon after being seen for the first time; it showed a sinus
bradycardia. Four of the 92 patients received anticonvul-
sant therapy prior to pacing and four had a cerebral CAT
scan or an EEG.
Comment
This study demonstrates that a prolonged period of time
may elapse from the onset of symptoms to permanent
pacing. Some delay may be appropriate, especially in
patients with sinoatrial disease; their arrhythmias do not
seem to be associated with excess mortality[2]. Time may
be needed for clarification of the diagnosis or adjustment
of drug therapy. But delays could be dangerous in
patients with atrioventricular block. Without pacing,
complete heart block has a one year mortality of almost 50
per cent[3,4]; the risk is not predictable by the character
of the symptoms or the nature of the ECG findings[4].
More than six months elapsed in a higher proportion of
patients with sinoatrial disease compared to patients with
atrioventricular block; but the difference was not signifi-
cant. A third of the patients with atrioventricular block
waited more than six months. Some of the delays demon-
strated in this study may represent not only an unneces-
sary persistence of symptoms, but also an avoidable risk
to the patient.
The results do not confirm some common assumptions.
The elderly did not wait significantly longer for pacing
than the relatively young, though men did receive a
pacemaker more promptly than women. A mistaken
diagnosis of epilepsy or a series of neurological investi-
gations was rare. Few long delays were solely due to the
general practitioner not referring the patient for a special-
ist opinion. The majority were caused by the patient not
seeking medical aid or by delay once the patient had been
seen at the hospital.
Rickards has suggested that the low rate of pacemaker
implantation in the UK is produced by a shortage of
cardiologists[5]. This study does not support that conclu-
sion. The delays in the two Leeds teaching districts, with
three adult cardiologists in each district, were not signifi-
cantly less than the delays in the non-teaching districts
which possess a maximum of one physician with an
interest in cardiology. In both teaching and non-teaching
hospitals, decisions about further assessment of syncope
and dizziness will be made by general physicians or by the
staff of the accident department. Cardiologists may only
be involved at a later stage. Whatever the cause, the
overall impression of this study is that the hospital service
did not approach these patients with sufficient vigour to
find a remedy for syncope, dizziness and a risk of sudden
death.
References
1. Feruglio, G. A., Rickards, A. F., Steinbach, K, et al. (1983) Pace,
6, A-149.
2. Shaw, D. B., Holman, R. R. and Gowers, J. I. (1980) British
Medical Journal, 280, 139.
3. Friedberg, C. K., Donoso, E. and Stein, W. G. (1964) Annals of the
New York Academy of Sciences, 111, 835.
4. Johansson, B. W. (1966) Acta Medica Scandinavia, suppl 451, 1.
5. Rickards, A. F. (1984) British Medical Journal, 288, 737.
|
PMC005xxxxxx/PMC5371060.txt | Aspergillus Lung Disease
I. }. GORDON, MB, MRCP(UK)
Medical Registrar, Regional Adult Cardiothoracic Unit, Broadgreen Hospital, Liverpool
C. C. EVANS, MD, FRCP
Consultant Physician, Regional Adult Cardiothoracic Unit, Broadgreen and Royal Liverpool
Hospitals
Few general physicians include aspergillus infection in a
differential diagnosis of lung disease as they feel that it is
too much of a rarity. Thus the diagnosis may be
suggested by the bacteriologist from sputum culture, by
the radiologist on detecting a mycetoma on the chest
radiograph or by a bright registrar on finding an asth-
matic with significant eosinophilia. The pathologist can
also be included in this list, especially in cases of broncho-
centric granulomatosis and at autopsy when the diagnosis
of invasive aspergillosis is made more often than in life. In
this review we have summarised the main pulmonary
diseases caused by aspergillus which could be relevant to
the general physician (Table 1). As invasive aspergillosis
Table 1. The major forms of aspergillus lung disease.
Bronchopulmonary aspergillosis (BPA)
Aspergilloma
Extrinsic allergic alveolitis (EAA)
Bronchocentric granulomatosis
Invasive aspergillosis
is one of the atypical pneumonias seen in immunosup-
pressed patients, the fungus has increased its notoriety
recently.
History
The term 'aspergillus' was coined by Micheli, a botanist
and priest, in 1729[ 1 ]. He likened the spore-bearing
heads of the fungus to the aspergillum used in religious
ceremonies to scatter holy water (Latin: aspergere, to
scatter). However, it was over a century later that Sluyter
first described human aspergillus disease in 1847 [2].
Although there are 18 groups with 130 different species of
aspergillus[3], from the point of view of human disease
Aspergillus fumigatus is by far the most important. Other
species which may cause disease in debilitated or
immunosuppressed patients include/I. niger, A.flavus, A.
glaucus and A. terreus. The following discussion therefore
refers mainly to infection with A. fumigatus.
Distribution and Epidemiology
Aspergillus spores are ubiquitous and are the most fre-
quently found fungus in the environment. They have
been recovered from the Antarctic, Sahara Desert[4] and
even from the Skylab spacecraft[5]. They are found in
house dust[6], wet paint[7], cracked dialysis bags[7],
distilled-water bottles[7], ventilation systems[8], tap
water[9], and can even survive in formalin[7]. Numerous
studies have shown the presence of spores in the outside
environment and also in the home[10-14], with increased
concentrations in the winter months. The pathogenicity
of the aspergillus species is enhanced by several factors:
(a) The spores are light, easily dispersed[15], and also
have thick walls; (b) the spores grow most rapidly at 40?C
(limits 12-53?C) while the majority of moulds have
optimum growth below 28?C[16]; (c) the spores of A.
fumigatus are approximately 5 microns[17] which makes
them ideal for lodging and growing in the region of the
terminal bronchioles. The most important predisposing
feature in the host is the presence of underlying disease
such as asthma, old tuberculous cavitation, cystic fibrosis
and altered immunological status. Thus patients with
myeloproliferative disease, lymphoma, carcinoma or on
immunosuppressive therapy are especially at risk of inva-
sive and disseminated aspergillosis. Aspergillus species
may be second only to Candida as a cause of fungal
infections in such patients[18].
Atopy to Aspergillus and Saprophytic Colonisation
The association between asthma and aspergillus lung
disease was first noted in 1925[ 19]. Spores are more often
found in the sputum of asthmatic patients and about 25
per cent of asthmatics have a positive immediate skin test
reaction without other features of broncholpulmonary
aspergillosis (BPA)[ 19-22]. The presence of aspergillus in
the respiratory tract in the absence of direct tissue damage
is sometimes referred to as saprophytic BPA. In addition
to asthma this is "more likely to occur in cystic fibro-
sis^,24], bronchiectasis, chronic bronchitis and ciliary
Correspondence to Dr I. J. Gordon, Chest Laboratory, Broadgreen
Hospital, Thomas Drive, Liverpool L14 3LB.
206 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
dyskinesia syndromes[25], The reasons for this are
thought to be the presence of viscid secretions together
with bronchospasm and ineffectual sputum clearance but
repeated antibiotic and steroid therapy and the presence
of malnutrition may also be important[26]. Positive skin
tests to aspergillus are more commonly seen in these
groups, and up to 58 per cent of patients with cystic
fibrosis have been shown to give a positive skin prick
test[27], In the absence of other features of BPA, the skin
test itself does not warrant any change of management.
Allergic Bronchopulmonary Aspergillosis
Allergic bronchopulmonary aspergillosis was first de-
scribed by Hinson et al. in 1952. They reported eight
cases who had asthma, eosinophilia, aspergillus in the
sputum and pulmonary infiltrates on the chest radio-
graph[28]. At present BPA is probably the commonest
cause of pulmonary eosinophilia in the UK[29] but it is
not known why only 1 per cent of asthmatic sufferers
develop the disease. There have been several reports of
increased exposure to aspergillus in patients who sub-
sequently developed BPA[19,30,31] but this cannot be
shown in the vast majority of cases. One study showed no
increase in the spore counts of aspergillus in the homes
and external environment of 10 patients with BPA[32]
compared to five atopic patients without BPA.
Criteria for Diagnosis
The criteria for diagnosing BPA are not clearly estab-
lished. Many physicians accept the quartet of asthma,
eosinophilia, pulmonary infiltrates on the chest radio-
graph and a positive immediate and delayed skin test
reaction. The presence of raised IgE levels and aspergillus
precipitins are probably only confirmatory, as the range
of IgE levels in asthma is extremely variable and precipi-
tins may be absent in the chronic phase of the disease[33].
Some authorities consider that the presence of proximal
bronchiectasis is the only way of making a definite
diagnosis[34] although bronchography is not without risk
in patients with asthma. At this stage the diagnosis has
been made late in the natural history of the disorder.
Clinical Findings
Asthmatics may develop BPA at any age, although there
is said to be a longer period between the onset of asthma
and the development of BPA in the younger patient[29].
The usual features of an acute exacerbation are worsen-
ing of asthma, malaise and fever, and occasionally expec-
toration of plugs of fungal mycelia[35]. Collapse of a lobe
or even an entire lung may occur due to impaction of a
plug and initially this may suggest a more sinister diag-
nosis. Patients with chronic disease who have developed
bronchiectasis present with the features of any other form
of bronchiectasis. It is for this reason that the diagnosis
should be borne in mind when any asthmatic develops
increasing amounts of purulent sputum. The bronchiec-
tasis in BPA is classically found in the upper lobes and
affects the proximal bronchioles; such proximal lesions
are unusual, as virtually all other forms of bronchiectasis
are distal and more marked in the lower lobes (with the
exception of cystic fibrosis). The end result of chronic
BPA is pulmonary fibrosis and retraction of the upper
lobes, which leads to a mixed obstructive and restrictive
pattern on pulmonary function testing. Cor pulmonale
may develop in such patients.
Laboratory Investigations
Eosinophilia is invariably found, although the level will
be suppressed by oral steroid therapy. Positive sputum
culture only provides corroborative evidence, as it is non-
specific and is seen in saprophytic colonisation and even
in the sputum of normal individuals[36]. One other
drawback is that expectoration of the fungus is often
intermittent. However, the finding of fungal hyphae is
more significant and suggests active growth of aspergillus
in the bronchi. In view of the variability of these findings
the report of a positive sputum culture must not be the
sole criteria for the diagnosis of BPA.
As mentioned previously, positive skin prick tests may
be found in asthmatics without BPA and in patients with
cystic fibrosis. In BPA the immediate skin test is always
positive and a subsequent delayed reaction may occur up
to six hours later in patients who have positive precipitins.
Intradermal skin tests are more sensitive but may induce
an asthmatic attack and should not be routinely used.
The last 10 years have produced significant advances in
the understanding of the immunology of BPA. Most of
the work has been concentrated on the IgE and IgG
classes, although antibodies in most classes have been
reported[37,38]. Radioimmunodiffusion methods have
shown IgG antibodies in nearly all patients with BPA[4],
More recently, total and specific serum IgE have been
found to be significantly elevated with peak values imme-
diately prior to, and during a flare-up of the disease[39-
41]. Oral steroids have been shown to depress the level of
total IgE[39]. It has therefore been suggested that IgE
levels are of value in monitoring disease activity, although
whether predicting an exacerbation leads to a reduced
incidence of irreversible disease and better patient wellbe-
ing is not known.
Aspergillus precipitins are of the IgG class and reflect
either active or recent infection. They can be shown to be
present in up to two-thirds of patients with BPA in
undiluted serum and in 100 per cent if concentrated
serum is used[36], but their presence does not necessarily
reflect disease activity[42]. Precipitins have been demon-
strated in up to 31 per cent of patients with cystic fibrosis
[23] and in 7-18 per cent of asthmatics without
BPA[43,44],
Radiological Changes
The radiographic appearances can be divided into acute
and chronic changes. Acute changes consist of perihilar
infiltrates that may simulate lymphadenopathy, upper
zone tram-lining and infiltration, gloved fingerlike pro-
jections due to mucus impaction and collapse of a lobe or
entire lung[45]. In the chronic phase fibrosis of the upper
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 207
lobes, leading to reduced lung volume and tubular and
ring shadows, may be seen[46].
Treatment
No therapy has been shown to effectively eradicate
aspergillus from the respiratory tract. Antifungals such as
nystatin[47], clotrimazole[48] and natamycin[49] have
been reported as having some success but are not gener-
ally accepted as being useful in treatment. The use of
corticosteroids in the management of BPA is well estab-
lished[50-52]. They probably reduce the antibody re-
sponse to the fungal antigen which is the cause of the
constitutional symptoms and pulmonary infiltration.
Steroids may inhibit growth of aspergillus and they
rapidly reduce the volume of sputum[29], but have not
been shown to be directly fungicidal. The usual starting
dose is 30-40mg of prednisolone daily and this is reduced
according to response. The aim should be to control
symptoms and clear pulmonary infiltrates. A regime has
been proposed in which serial IgE measurements are used
to tailor the prednisolone dose[53]. Inhaled steroids are of
little value in controlling and preventing exacerbations of
BPA[53,54], possibly because the drug cannot penetrate
mucoid plugs to the site of the antigen/antibody reaction.
Additional therapy should include inhaled bronchodi-
lators, physiotherapy to clear plugs and, if necessary,
bronchoscopy to remove viscous plugs which have caused
lung collapse. If there is likely to be considerable exposure
to aspergillus (e.g. farm workers) attempts should be
made to avoid the high concentration of spores found in
mouldy hay and compost heaps.
Aspergilloma
An aspergilloma is a fungal ball developing in a lung
cavity which is poorly drained. The term was first used by
Deve in 1938[55]. Aspergillomata have been found in
patients with BPA[56,57] or may cause BPA[58,59]. The
incidence in the general population is estimated at 0.01-
0.02 per cent[60], and although usually solitary they may
be bilateral or multiple[61, 62].
Aetiology and Pathogenesis
Aspergillomata may form in any preformed cavity but
undoubtedly the commonest antecedent disease is pul-
monary tuberculosis. They have also been reported to
occur in sarcoidosis, bronchial cysts, bronchial carci-
noma, lung abscess cavities, pneumoconiosis, ankylosing
spondylitis, and bullous emphysema[63]. Approximately
25 per cent of patients with an aspergilloma have a
positive history of tuberculosis[64,65] and, surprisingly,
aspergillomata are as common in patients with recent
disease as in those with longstanding healed cavities[66].
The apical regions of the lung are the most frequently
affected, probably because predisposing cavities are more
common in this region. The growth of the fungus is
usually silent, especially in the early phase. The initial
stage is growth of fungal conidiophores on the wall of the
cavity, followed by a growing phase in which a ball is
formed. The final stage is a resting phase in which the
formed aspergilloma may remain quiescent for years.
The possible progressions following the resting phase are:
persistence associated with clinical features, calcification,
degeneration and spontaneous resolution of the cavity,
and development of BPA or, rarely, invasive aspergillo-
sis[63]. The latter is usually confined to immunocompro-
mised patients.
Clinical Features
Patients with aspergilloma may be entirely asymptomatic
and the diagnosis only made from a routine chest radio-
graph. They more usually present with haemoptysis as
the commonest symptom which may be associated with
cough and sputum production. Constitutional symptoms
of fever, malaise and weight loss are sometimes seen,
especially if there is a concomitant BPA. Physical examin-
ation may reveal finger clubbing and reduced percussion
note together with bronchial breathing over the cavity.
Radiological and Laboratory Investigations
The classical radiological finding is of a dense opacity
surrounded by a halo of air (Monod's sign)[55,67]. This
may be seen on the PA radiograph but is more clearly
visualised by tomography. This appearance can also be
produced by a lung abscess, haematoma in a cavity,
neoplasm and hydatid cyst[68]. Occasionally the aspergil-
loma can liquefy and a fluid level may be seen[67]. Since
the fungal ball is not fixed in the cavity it may alter
position and this can be detected by taking several films
with the patient in different positions[69]. Other radio-
graphic features are pleural thickening over the cavity
and lobar contraction. Bronchography has little to offer in
the routine diagnosis of an aspergilloma as there is often
no direct bronchial connection. Interestingly, a metabo-
lite of aspergillus takes up radio-strontium, and isotope
scanning may therefore be useful if the diagnosis is in
doubt[70].
As with other forms of aspergillosis, sputum culture is
too non-specific to be of any value. Immediate skin prick
tests are positive in about 30 per cent of patients[71],
whereas precipitins are found in virtually 100 per
cent[71,72]. Precipitins may be absent if the fungus is
dead, in immunosuppressed individuals[63] or if a fungus
other than A. fumigatus is present[73].
Treatment
Patients who are asymptomatic need no specific manage-
ment but should be reviewed at intervals. The common-
est group are those with recurrent haemoptyses who are
repeatedly admitted to hospital for observation. Usually
the haemoptysis subsides spontaneously but approxi-
mately 5 per cent of patients die from this cause. Attempts
at medical management have met with only limited
su'ccess. These range from nystatin[74], and inhalations
of brilliant green[75], to installation of nystatin and
amphotericin pastes into the cavity. The latter technique
has led to disappearance of the aspergilloma in 50 per cent
208 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
of cases[76], In addition, treatment with natamycin has
been attempted with good results[77] and clotrima-
zole[78] and amphotericin[61] have been used in the peri-
operative period with some success. It is generally agreed
that a large single aspergilloma associated with recurrent
haemoptysis and chronic sputum production should be
excised, providing the general health of the patient is
reasonable[79,80]. The operation of choice is lobar resec-
tion[81], or, for poor risk patients, cavernostomy[82].
The main post-operative complications are empyema and
bronchopleural fistula, and morbidity rates have varied
between 7 per cent[83] and 75 per cent[84], The use of
radiotherapy and bronchial artery embolisation are now
being evaluated. Multiple aspergillomata should be
treated conservatively, as the surgery required to remove
all the lesions is too extensive. Occasionally patients
develop fever, malaise and weight loss, and on some
occasions invasive aspergillosis may occur[85]. Although
steroids do improve the constitutional features and may
be required if there is associated BPA, they also increase
the risk of invasive disease[86,87]. If there is any evidence
to suggest immunodeficiency (malnutrition, alcoholism,
lymphoma, etc.) steroids must be used with extreme
caution but preferably avoided.
Extrinsic Allergic Alveolitis (EAA)
This is a non-specific response to inhaled aspergillus
spores and occurs with many other antigens such as avian
proteins in bird fancier's lung and thermophyllic actino-
mycetes in farmer's lung. Aspergillus spores are es-
pecially plentiful in mouldy hay, compost heaps, straw
and grain[88] and it is from these sources that this form of
aspergillosis is likely to occur. A further source is mouldy
barley which contains A. clavatus, the cause of malt
worker's lung[89]. It is important to note that the site of
the pulmonary response is different in BPA and extrinsic
allergic alveolitis. In BPA the major airways are the site of
the allergic reaction whereas in EAA the lung parenchy-
ma is the primary target.
Clinical Features and Investigations
Symptoms of cough, fever, chest tightness and headache
begin within four hours of exposure to the stimulus and
classically they are noted on return to work after the
weekend. Physical examination reveals upper zone inspi-
ratory crackles and the chest radiograph may show diffuse
pulmonary infiltration. Pulmonary function tests show a
restrictive pattern. All of these findings are non-specific
and are found in other examples of EAA. The diagnosis
will be provided by the history and the finding of
aspergillus precipitins in the serum. A further useful aid is
a delayed response to skin prick testing which is maximal
at 4-6 hours.
Treatment
Treatment consists of avoiding the offending site if it can
be identified. If this is not possible a mask should be
worn. Oral steroids produce rapid improvement but are
not a substitute for avoiding exposure. If the alveolitis is
allowed to persist, pulmonary fibrosis and honeycomb
lung will inevitably occur.
Bronchocentric Granulomatosis
This manifestation of aspergillus lung disease was first
decribed by Liebow in 1973[90], It is a form of vasculitis
and is similar in some respects to Wegener's granuloma-
tosis. The exact incidence is unknown.
Clinical Features[90]
The typical features are productive cough, chest pain,
constitutional disturbance and occasionally haemoptysis.
In contrast to BPA a background of asthma is not
invariable and eosinophilia is not always present. Typical
radiographic features are consolidation, pneumonic infil-
trates, lobar collapse, and nodular or mass densities
which may simulate a tumour. Bronchograms may show
segmental bronchial obstruction and bronchiectasis.
Pathological examination reveals cheesy material in the
lumina of small bronchi and bronchioles, with a foreign
body type of giant cell reaction together with granulomas,
eosinophilic clumps and fungal hyphae. The diagnosis is
usually made following removal of a nodule because of
the possibility of a tumour. Lobar resection has produced
good results in one series, with a symptom-free interval of
up to four years. Oral steroids may produce symptomatic
and radiological improvement although there may be a
recurrence.
Invasive Aspergillosis
Invasive aspergillus lung disease has become important in
recent years with the increasing use of cytotoxic drugs,
and more recently with the advent of the acquired
immune deficiency syndrome. Whereas in BPA colonisa-
tion is confined to the bronchi, with only limited tissue
invasion, in invasive aspergillosis there is extensive in-
volvement of the lung parenchyma which can be shown
histologically. The condition is almost totally confined to
immunosuppressed patients but has been described in a
patient with an aspergilloma who received steroid ther-
apy[87]. Examples of predisposing diseases include: acute
leukaemia, lymphoma, carcinoma, patients on high-dose
steroid and cytotoxic therapy, and diabetes mellitus[3].
Neutropenia favours development of invasive dis-
ease[92,93] which has been recorded in 70 per cent of
patients with neutrophil counts below 0.5 x 109/
litre[94]. In contrast to BPA, other species of aspergillus
are frequently pathogenic and these include A. flavus, A.
glaucus, and A. niger[94], The pathogenesis of invasive
aspergillosis is complex and may involve three mecha-
nisms[95]. First, colonisation of the respiratory tract is
followed by endobronchial proliferation and bronchial
ulceration; this is sometimes referred to as 'aspergillary
bronchitis'. Progression may then proceed to membrane
formation. Invasion of the lung parenchyma can occur at
any stage, producing most commonly a necrotising bron-
chopneumonia, lobar pneumonia or haemorrhagic infarc-
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 209
tion[94]. The second mechanism involves colonisation of
necrotic lung tissue following pulmonary emboli, bac-
terial infection or in pre-existing lung cavities[63]. This
results in abscess formation which may be single or
multiple. This diagnosis is usually only made at autopsy.
Finally, haematogenous spread can occur from such sites
as the gastrointestinal tract or intravenous catheter
lines[63]. This results in multiple miliary micro-abscesses
throughout all organs and is also usually diagnosed at
autopsy.
Diagnosis
The symptoms are usually non-specific and include
cough, wheeze, dyspnoea and fever. The chest radio-
graph is normal in aspergillary bronchitis but in estab-
lished invasive disease there are single or multifocal
nodules up to 3cm in diameter. These may undergo
infarction or cavitation and the appearances at this stage
are of consolidation, which tends to be bilateral[95]. It
should be noted that the radiograph may be normal until
very late in the disease, at which time treatment is
hopeless.
Blood cultures and aspergillus precipitins are unhelp-
ful[96] and sputum culture is only positive in about 30 per
cent of patients[97]. Nasal swabs may be helpful in
predicting the development of pulmonary disease[98]. An
improved diagnostic yield has been shown using serial
immunodiffusion and radioimmunoassay techniques for
detecting aspergillus antibody, but this involves twice-
weekly blood sampling in individuals thought to be at
risk[99]. The ideal method of diagnosis is the detection of
aspergillus antigen[100] and this has been documented in
a few patients[101]. Unfortunately, the methods required
are of unknown sensitivity and are not available to the
majority of clinical laboratories. However, it is likely that
future hopes for the earlier diagnosis of this form of
aspergillosis rest with this method. Bronchoscopy, trans-
bronchial biopsy and bronchoalveolar lavage should be
performed as soon as possible after the onset of respirat-
ory symptoms in any patient at risk of developing asper-
gillosis or any atypical infection. This is of vital
importance especially if pulmonary infiltrates have ap-
peared on X-ray. Once widespread radiological infiltrates
are present the disease has already spread extensively.
The differential diagnosis of invasive aspergillosis in-
cludes Pneumocystis carinii, nocardia, Candida, tubercu-
losis and mycoplasma infections as well as the commoner
bacterial infections.
Treatment
The key to treatment of invasive aspergillosis is to start
therapy as soon as the above investigations have been
done even if there is only a high index of suspicion.
Results of sputum culture and histology of bronchial
biopsy specimens may be confirmatory but should not be
awaited. Patients who are most likely to respond to
therapy are those with disease limited to the lung[102]
and those who have treatment started within 96 hours of
the onset of pulmonary infiltrates[103]. The treatment of
choice is intravenous amphotericin B which may be
required for up to 12 weeks. To obtain an adequate
response a certain degree of host immune-competence is
necessary and it is recommended that, as in bacterial
infection, severely neutropenic patients receive tranfu-
sions of leucocytes from compatible donors[104]. The use
of nystatin and 5-flucytosine by aerosol been reported to
give better results than amphotericin B alone[105].
This article is based on a paper read at the College Conference at
Liverpool in September 1985.
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meth.od.um disposita. Florence.
2. Sluyter, T. (1847) Dissertation.es Inauguri Berlini, p. 14.
3. Raper, K. B. and Fennell, D. I. (1965) The Genus Aspergillus. New
York: Robert E. Krieger.
4. Bardana, E. J. Jr. (1981) CRC Critical Reviews in Clinical and
Laboratory Science, 13, 21.
5. Brockett, R. M., Ferguson, J. K. and Henny, M. R. (1978)
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6. Calvo, M. A., Dronda, M. A. and Castello, R. (1982) Annals of
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7. Rippon, J. W. (1982) Medical mycology: The pathogenic fungi and
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Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
|
PMC005xxxxxx/PMC5371061.txt | Modern Methods of Diagnosis in Liver
Disease
I. T. GILMORE, md, frcp
Consultant Physician, Royal Liverpool Hospital, Liverpool
The advances in the diagnosis and assessment of hepatic
disease in the last 10 years have been considerable, and
have certainly outstripped those in therapy. However, it
is reasonable to expect that this increased understanding
will contribute to more effective treatment in the next
decade.
The concept of a universally applicable 'liver function
test' is no longer adequate, and the information from an
investigation is only as good as the question asked of it.
Some investigations are sensitive to early or mild disease
without giving information as to the cause, while others
are aimed at the underlying aetiology; some aim to give a
global estimate of liver function whereas others are to
detect complications; finally, some are aimed at the
assessment of hepatic architecture, the reversibility of liver
damage and the prognosis.
Assessment of the Cause of Liver Disease
Viral Liver Disease
The greatest recent diagnostic advances have been in
viral hepatitis. Infective hepatitis type A may now be
simply and reliably diagnosed by detection of specific
antibodies of the IgM class. Hepatitis B may usually be
diagnosed by the presence of the virus outer coat,
HBsAg, and it is likely that monoclonal antibodies will
provide yet greater sensitivity than the existing radioim-
munoassays. In the absence of detectable HBsAg, recent
infection will be indicated by the presence of IgM anti-
body to the core antigen (HBcAg) of the intact virus or
Dane particle. Also, the 'e' antigen in serum, a soluble
component of the virus, indicates the presence of virus in
the bloodstream and hence potential infectivity.
A consequence of these more sensitive serological tests,
and in particular the application of molecular hybridisa-
tion techniques to detect integrated sequences of hepatitis
B DNA within hepatocytes, 'is that many cases of chronic
liver disease previously thought to be cryptogenic may be
the result of previous hepatitis B exposure. In a recent
study[l], 52 of 88 patients with cryptogenic chronic liver
disease had HBV DNA sequences detected in the liver,
including 17 of 20 patients with primary hepatocellular
carcinoma.
The diagnosis of non-A, non-B hepatitis remains prob-
lematical; there are probably at least three types and no
reliable serological test, so in practice it remains a
diagnosis of exclusion. However, the delta agent can now
be elevated to the status of hepatitis D[2]. This is an
incomplete RNA virus which utilises HBsAg to become
an infective agent, and is now well described as a cause of
hepatitis supervening in patients who are carriers of
HBsAg. There are serological tests for anti-delta, and
HBsAg carriers who have antibodies to the delta agent
have a higher frequency of abnormal liver function tests
and of active liver disease[3].
Alcoholic Liver Disease
The diagnosis of alcohol as the cause of liver disease
depends on a high index of clinical suspicion. Elevation of
the serum gamma-glutamyl transpeptidase and the eryth-
rocyte mean corpuscular volume are useful laboratory
markers of alcohol abuse, being abnormal in 60-90 per
cent[4], but it should be noted that these may be abnor-
mal in other forms of chronic liver disease and hence have
low specificity. To these blood markers may be added the
mitochondrial fraction of aspartate aminotransferase, m-
AST, which has been recently reported to be reliably
elevated in alcoholics with and without liver damage[5].
Metal Storage Diseases
The early and accurate diagnosis of haemochromatosis
and Wilson's disease is crucial because there are effective
treatments to prevent progression of the hepatic damage.
Haemochromatosis is an autosomal recessive condition
linked to the HLA locus on the short arm of chromosome
6. Relatives of a proband have a very high risk of being
affected if they share the same HLA genotype, although
the particular HLA haplotype varies from family to
family. As a defective gene product has not been identi-
fied, we must rely on indicators of increased iron stores to
pick up affected relatives. In a recent study of early,
asymptomatic cases of haemochromatosis, detected by
screening siblings of known patients, serum ferritin was
the most reliable single biochemical screening test, pick-
ing up 30 of 35 affected, although serum iron and iron
saturation did nearly as well[6]. In Wilson's disease,
depression of plasma caeruloplasmin remains the most
reliable non-invasive indicator, but in high risk subjects
this should be supplemented by serum and urine copper
estimations and by slit-lamp examination for Kayser-
Fleischer rings.
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 201
Detection of Mild Liver Disease
The search for an exquisitely sensitive test of liver
function has been a popular one, as shown by the large
number of potential candidates. Plasma bromsulphtha-
lein (BSP) retention after an intravenous bolus or infusion
has been the most widely used. Its recent relative neglect
is due in part to anxiety over occasional adverse reactions
to BSP and in part to the lack of any direct clinical utility
of such a sensitive test. Indocyanine green clearance
produces similar results, is safer, but expensive. The
clearance of both is influenced by changes in liver blood
flow as well as function.
In the last decade the endogenous concentration of bile
acids in serum has emerged as the 'state of the art'
sensitive liver function test and is also specific for liver
disease[7]. However, the gain in sensitivity over the
aggregate of conventional biochemical liver function tests
is small, so its use is confined to clinical research. Another
highly sensitive biochemical marker of liver dysfunction
under evaluation is plasma glutathione S-transfer-
ase[8,9].
Hepatic imaging methods have been disappointing in
the detection of early or mild diffuse parenchymal liver
disease. In cirrhosis or fatty liver the ultrasound image
may appear unusually 'bright' but this is non-specific.
Density of tissue may be accurately quantitated on CAT
scan; fatty liver is less dense than usual whereas the liver
in haemochromatosis is more dense[10]. These changes
may be useful in following the course of haemochromato-
sis during treatment. Magnetic resonance imaging is
promising because tissue characteristics may be quanti-
tated in ways such as spin relaxation times T1 and T2.
The T1 may be prolonged in cirrhosis[l 1]. However,
there are not yet enough reports on the findings in early
disease.
Quantitative Assessment of Liver Function
While some liver function tests such as serum bile acid
concentration and BSP retention become abnormal early
in the progression of liver disease, others such as plasma
albumin and prothrombin time are well maintained until
severe liver dysfunction develops. This is shown sche-
matically in Fig. 1. It would be useful to have a test which
gives an estimate of functional hepatic mass analogous to
the creatinine clearance in nephrology. However, the
hepatic clearance of substances with high hepatic extrac-
tion depends more on liver blood flow than function[7], so
a substance with low extraction and long half-life time
must be selected. Unconjugated bilirubin clearance
would be suitable in theory, and in fact the plasma
bilirubin concentration correlates well with survival in
conditions as diverse as fulminant hepatic failure and
primary biliary cirrhosis. However, in many instances
many other factors such as haemolysis and cholestasis
contribute to the plasma concentration. The elimination
of galactose has been a popular quantitative liver function
test in Scandinavia[12] but has not been widely adopted
in the UK or USA. The clearance of the drugs antipyrine
and aminopyrine fall progressively with increasing dam-
age to the liver and may be useful. A breath test utilising
14C-aminopyrine in which cumulative breath 14C-C02 is
measured is a simple test for clinical practice, and the
spread of results in patients with differing severity of liver
disease is shown in Fig. 2.
With a conventional "Tcm sulphurcolloid isotope liver
scan, it is possible to get some impression of the efficacy of
hepatic uptake of the radioisotope by its density and
Normal
result
t
Abnormal
result
Decreasing liver function
Fig. 1. Schematic representation of the possible relationships of
liver tests to alterations in liver function.
Fig. 2. Cumulative 2 hour excretion of ,4C-C02 after adminis-
tration of ,4C-aminopyrine to patients with liver disease of
varying severity. (Gilmore, unpublished data.)
% 10.01
9.0-
O 8.0-1
I (severe) II (moderate) III (mild)
Disease severity group
202 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
distribution; in cirrhotic patients there is reduced, patchy
uptake with increased amounts of activity in the spleen
and bone marrow. It is now possible to quantitate this by
a technique known as Single Photon Emission Tomo-
graphy (SPET; Table 1). Following intravenous bolus
injection of a suitable radiopharmaceutical agent such as
I23I-BSP, there is rapid disappearance of activity from
plasma and uptake by the liver (Table 2 and Fig. 3). By
performing serial axial scans in a mode analogous to the
X-ray CT scan, it is possible to make computer recon-
structions of horizontal slices through the liver. The
activity in each slice can be accurately measured and, by
Table 1. Types of radionuclide liver scan.
Target: Kupffer cell, e.g. "Tcm sulphurcolloid
Hepatocyte, e.g. I2T-BSP, "Tcm-HIDA
Mode: Anteroposterior scan
Single photon emission tomography
Table 2. Hepatic uptake of l23I-BSP assessed by SPET in
patients with liver disease of differing severity. (Alstead et al.,
unpublished data.)
Group n % uptake, mean ? SEM
I (severe) 19 36.5 +2.02*
II (moderate) 21 56.7 + 1.75**
III (mild) 20 73.2 + 2.24
*1 v. II, P < 0.002, Mann-Whitney 'U' Test.
**II v. Ill, P < 0.002, Mann-Whitney 'U' Test.
integration of the slices, the liver volume and activity per
unit volume calculated. Such SPET scans can be per-
formed with hepatocye and Kupffer cell imaging agents,
and we have found that uptake of 123I-BSP relates to
disease severity as judged by scoring other multiple
parameters (Fig. 3)[ 13,14],
Detection of Focal Hepatic Disease
This is where the non-invasive hepatic imaging methods
come into their own. Ultrasonography is the cheapest and
most convenient starting point for the assessment of
suspected focal disease, and may detect unsuspected
biliary tract pathology by showing dilated intrahepatic
bile ducts or gallbladder stones. Metastases down to a size
of 1 cm or less may be found, although occasionally
metastases from certain primary sites such as the breast
may not stand out. Also, diffuse infiltrative lesions may
prove more difficult. The outstanding problems with
ultrasonography are its dependence on the skill of the
radiologist, and the marked inter-observer differences.
The clinician cannot interpret the scans himself, whereas
CT scans are more open to general discussion. The CT
scan is particularly useful for suspected vascular lesions,
as intravenous contrast may be administered and the liver
imaged dynamically. It is clearly important to exclude a
haemangioma before a suspected metastasis is biopsied.
For obtaining a tissue diagnosis from small lesions, both
ultrasonography and CT scanning are very useful for
carefully targeting percutaneous biopsies. Most radiolo-
gists find radioisotope scanning less sensitive for picking
up small metastases in the liver, but SPET improves the
Fig. 3. Plasma disappearance and hepatic uptake of intravenoulsy administered ,23I-BSP[14].
Sp.act
Tomographic period
Plasma
mins
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 203
sensitivity considerably. When there is a single focal
defect in the liver and surgical resection is being con-
sidered, hepatic arteriography with late films of the portal
vein is essential.
Histological Assessment
Percutaneous liver biopsy remains an essential part of the
full assessment of most hepatic diseases, but carries an
appreciable morbidity and mortality[15]. Even a mortal-
ity rate of one in 5,000 procedures has to be viewed with
concern. Although the bleeding time of the liver after
biopsy, as viewed through the laparoscope, does not
correlate with the usually measured parameters of clot-
ting[ 16], it is clinical experience that the major bleeding
complications occur in those with disordered haemostasis.
There have been various approaches to making the
procedure safer in these individuals (Table 3). Laparos-
copy is widely used in continental Europe and has the
added advantages of allowing direct inspection of the
liver, before and after biopsy, and targeting biopsies.
However, it is more complex than 'blind' percutaneous
Table 3. Attempts at safer liver biopsy.
Infusion of clotting factors/platelets
Laparoscopic liver biopsy
Operative liver biopsy
Transjugular liver biopsy
Percutaneous 'plugged' biopsy
biopsy, and has not found favour in the UK except in
focal liver disease. Transjugular liver biopsy is theoreti-
cally attractive in those patients with severe coagulopath- ,
ies; the flexible biopsy needle is passed down a catheter
previously inserted into the right jugular vein and posi-
tioned in a wedged position in a branch of the hepatic
vein. It is then advanced into the liver tissue to secure a
sample for histological assessment, and any bleeding
should be back into the venous circulation. During the
procedure, it is convenient to perform hepatic veno-
graphy and hepatic vein wedged pressure measurements
in addition, and multiple samples may be taken from the
patient without extra discomfort. However, like laparos-
copy, the procedure is complex and unlikely to find a
routine clinical place except in a few centres[17]. In
patients with impaired coagulation it is technically much
more straightforward to plug the biopsy site with absorba-
ble gelatin sponge after routine percutaneous biopsy. ^
This has proved safe in our experience of 80 cases[18],
but clearly much larger numbers are required to evaluate
modifications in a technique with a low mortality.
It is the destruction of normal architecture by hepatic
fibrosis that heralds the onset of cirrhosis and portal
hypertension. A serological marker of this fibrogenesis
would be helpful, particularly for following patients
treated with agents aimed at reversing this destruction
when serial liver biopsies are not justified. An encourag-
ing approach is the measurement of the n-terminal
propeptide of collagen III in serum, and there is a
reasonable correlation between serum levels and hepatic
fibrosis as judged by morphometry[19].
Fig. 4. Endotoxaemia in normal subjects and in patients with liver disease[23]. 0 = decompensated cirrhosis, no infection; A =
biliary obstruction or liver failure with sepsis; ? = other liver disease; A = normal controls.
0.5H
c 0.4H
0.3H
0.2-
e
A
0
s
_8_
A
A
Upper limit
Normal
controls
All patients
with liver
disease
Decompensated
cirrhosis without
infection
Biliary obstruction
or liver failure
and gram-ve sepsis
204 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
Diagnosis of Complications in Chronic Liver Disease
, Portal Hypertension
Fibreoptic oesophagoscopy has largely replaced barium
contrast studies in the diagnosis of oesophageal varices. It
may be quite difficult to judge whether or not small
varices are present, particularly in a restless patient, but
this is not usually clinically vital, as the risks of variceal
haemorrhage relate to their size. Gastric varices may be
difficult to see endoscopically, especially in the bleeding
patient, but are even more difficult radiologically.
Patients with portal hypertension may have a gastritis,
and this may be the cause of bleeding rather than the
varices. This is probably the result of mucosal congestion,
and has been termed 'congestive gastropathy'[20].
^ Infection
Spontaneous bacterial peritonitis is a potentially fatal
complication of cirrhosis. It is undesirable to withhold
treatment in a febrile, ill patient until the results of
bacteriological cultures are available, but it is now clear
that the diagnosis is highly likely if the polymorphonu-
clear leucocyte count in ascitic fluid is greater than 250/
mm3[21]. Initial reports that the pH of ascites was a quick
and reliable indicator of spontaneous bacterial peritoni-
tis[22] have not been widely confirmed.
Endotoxaemia is common in patients with cirrhosis and
>. reflects their impaired reticulo-endothelial function and
susceptibility to infection. Assays for circulating endo-
toxin are notoriously fickle, but a new quantitative
chromogenic modification of the standard limulus assay
looks promising[23]. Using this method, most patients
with decompensated cirrhosis have endotoxaemia in the
absence of overt sepsis (Fig. 4).
! Primary Liver Cancer
Alphafetoprotein is the circulating marker of hepatocellu-
lar carcinoma (HCC) most widely used, and the positivity
rate of 50-80 per cent depends in part on whether an
immunodiffusion or radioimmunoassay is used. How-
ever, there are other potential markers that may become
more widely used. B,2-binding protein is detectable,
particularly in the fibrolamellar variant of HCC[24], and
serum ferritin[25] and alphafucosidase[26] seem to have
similar detection rates to alphafetoprotein.
This review is by no means comprehensive and has just
touched on some of the numerous approaches to the
diagnosis and assessment of liver disease. It has also been
biased towards those tests of greatest personal interest.
However, I hope it demonstrates that the clinician has
availed himself of the very best of scientific advances in
the last decade, from magnetic resonance imaging on one
hand to molecular genetics on the other. Perhaps in the
next decade this will be a springboard for developing
more rational and effective therapy.
Acknowledgements
I wish to thank Dr E. Alstead, Dr A. I. Morris, Dr S.
Grimes and Dr M. Critchley for their collaboration in
some of the reported studies, and the Mersey Regional
Health Authority for financial support.
This article is based on a paper read at the College Regional
Conference held at Liverpool in September 1985.
References
1. Brechot, C., Degos, F., Lugassy, C. et al. (1985) New England
Journal of Medicine, 312, 270.
2. Thomas, H. C. (1985) Gut, 26, 1.
3. Arico, S., Aragona, M., Rizzetto, M. et al. (1985) Lancet, 2, 356.
4. Whitehead, T. P., Clarke, C. A. and Whitfield, A. G. W. (1978)
Lancet, 1, 978.
5. Nalpas, B., Vassault, A., Le Gillou, A. et al. (1984) Hepatology, 4,
893.
6. Bassett, M. L., Halliday, J. W., Ferris, R. A. and Powell, L. W.
(1984) Gastroenterology, 87, 628.
7. Gilmore, I. T. and Hofmann, A. F. (1980) Gastroenterology, 78, 177.
8. Bass, N. M., Kirsch, R. E., Tuff, S A. and Saunders, S.J. (1978)
Gastroenterology, 75, 589.
9. Beckett, G. J., Kellett, H. A., Gow, S. M., Hussey, A. J., Hayes,
J. D. and Toft, A. D. (1985) British Medical Journal, 291, 427.
10. Fawcitt, R. A., Forbes, W.St C., Isherwood, I., Morris, A. I.,
Marsh, M. N. and Turnberg, L. A. (1978) Clinical Radiology, 29,
251.
11. Haaga, J. R. (1984) The Radiological Clinics of North America, 22,
879.
12. Tygstrup, N. (1966) Scandinavian Journal of Clinical and Laboratory
Investigation, 18, 118.
13. Alstead, E. M., Morris, A. I., Gilmore, I. T., Grime, J. S. and
Critchley, M. (1984) Gut, 25, A572.
14. Alstead, E. M., Morris, A. I., Gilmore, I. T., Ware, J., Grime, J.
S. and Critchley, M. (1985) Gut, 26, A563.
15. Westaby, D., MacDougall, B. R. and Williams, R. (1980) British
Medical Journal, 281, 1331.
16. Ewe, K (1981) Digestive Diseases and Sciences, 26, 388.
17. Bull, H. J., Gilmore, I. T., Bradley, R. D., Marigold, J. H. and
Thompson, R. P. H. (1983) Gut, 24, 1057.
18. Tobin, M. V. and Gilmore, I. T. (1985) Gut, 26, A1127.
19. Frei, A., Zimmerman, A. and Weigand, K. (1984) Hepatology, 4,
830.
20. McCormack, T. T., Sims, J., Eyre-Brook, I. et al. (1985) Gut, 26,
1226.
21. Hoefs, J. C-, Canawati, H. N., Sapico, F. L., Hopkins, R. R.,
Weiner, J. and Montgomerie, J. Z. (1982) Hepatology, 2, 399.
22. Gitlin, N., Staffer, J. L. and Silvestri, R. C. (1982) Hepatology, 2,
408.
23. Alstead, E. M., Khan, F. J., Morris, A. I., Gilmore, I. T. and
Ware, J. (1984) Journal of Hepatology, 1, S4.
24. Paradinas, F. J., Melia, W. M., Wilkinson, M. L. et al. (1982)
British Medical Journal, 285, 840.
25. Giannoulis, E., Arvanitakis, C., Nikopoulos, A., Doutsos, I. and
Tourkantonis, A. (1984) Digestion, 30, 236.
26. Deugnier, Y., David, V., Brissot, P. et al. (1984) Hepatology, 4, 889.
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 205
|
PMC005xxxxxx/PMC5371063.txt | Book Review
Interferons: Their Impact in Biology and Medicine
edited by
Joyce Taylor-Papadimitriou. Oxford University Press
1985. 148 pages. Price ?20 (hardback), ?10 (paperback).
It is just over a quarter of a century since Isaacs and
Lindenman described the interferons (IFN)?a group of
proteins produced by cells in response to virus infection.
This concept was not immediately accepted, some critics
even suggesting that the material found should really be
called 'misinterpreton'. However, the skilled work of
Isaacs and his colleagues has established beyond doubt
the importance of IFN. These substances are involved in
human immune responses, in growth regulation and
differentiation, and may also affect the growth of malig-
nant tumours. There has been an exponential increase in
the amount of research done in the last few years, much of
it due to the more ready availability of a host of interfer-
ons, and it is one of the most exciting fields of biology at
the present time.
Joyce Taylor-Papadimitriou is to be congratulated on
reflecting this sense of excitement in her book. Clinicians
will, of course, be primarily interested in the role of IFN
in viral infections (presented by Scott), and in malignant
disease (described by Nethersole and Sikora), but they
would be missing one of the most lucid accounts of the
human immune system and the role of interferon if they
do not read Balkwill's chapter on the regulatory role of
IFN in these responses.
The early chapters on the genes of the IFN system and
their expression are somewhat hard going for those not in
the field of molecular biology, but good summaries and
conclusions help to pave the way for understanding later
chapters. It would be an advantage in a future edition to
have an introductory chapter on the different forms of
interferon and their derivation, in order to help the
general reader.
The object of the book is to stimulate thought about
IFN and to help with the institution of new trials. The
chapters are well referenced, and undoubtedly the book
will be of great help to those doing research on IFN.
Wisely, no great claims are made for its clinical efficacy in
either virus diseases or cancer. The editor stresses that
careful, controlled clinical trials will be necessary to find
the role of IFNs in therapy. The number of chapter
authors working in institutions primarily concerned with
cancer research indicates where experimental hopes have
been over the last few years. Nethersole and Sikora have
provided an excellent brief review of the present position
with regard to interferons in malignant disease. There is
no doubt that in a limited number of cancers a beneficial
effect on tumour growth may be seen, and in one very
rare leukaemia, hairy cell leukaemia, it may be that IFN
will establish itself as a treatment of choice. As they
emphasise, however, it is the insight that may be obtained
into tumour cell growth and its regulation that may
produce the greatest benefit from the study of the biology
of IFN.
There is no doubt that in whatever field of medicine
one's interest lies, IFN, but more particularly its biology,
will be increasingly relevant during the next decade. This
book provides a good introduction to the subject and a
basis for further reading.
J. S. Malpas.
194 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
|
PMC005xxxxxx/PMC5371065.txt | Management of Upper Gastro-intestinal
Bleeding in a District General Hospital
M. V. MADDEN, FRCS, Registrar*
G. H. GRIFFITH, FRCS, Consultant Surgeon.
Royal Gwent Hospital, Newport, Gwent
Upper gastro-intestinal bleeding is a common and serious
problem which accounts for approximately 8 per cent of
medical admissions to hospitals in the UK[1], Detailed
results of treatment have been reported from several
academic units in Britain[2,3,4]. However, most patients
with upper gastro-intestinal bleeding are managed in
District General Hospitals and we have therefore exam-
ined our experience to see if it reflects the spectrum of
pathology and the results of treatment found in teaching
hospitals.
Materials and methods
This District General Hospital has 650 beds and serves a
population of 320,000 people. We examined emergency
ward admission records and Hospital Activity Analysis
data for the years 1980 and 1981 to identify patients who
fulfilled Morgan's criteria for the diagnosis of upper
gastro-intestinal bleeding: the patient's history of vomit-
ing blood or clots, or 'coffee grounds' or passage of tarry
black stool or blood confirmed by medical or nursing
staff[5]. We excluded patients not admitted on the day of
referral, to eliminate those referred for elective investi-
gation of anaemia or occult gastro-intestinal bleeding.
Two patients' records could not be traced.
From clinical records we obtained information on drug
or alcohol ingestion, incidental medical problems, pre-
vious upper gastro-intestinal bleeds and the blood press-
ure and haemoglobin level on admission. The initial
clinical diagnosis was recorded, as were endoscopic,
radiological, operative and autopsy diagnoses; when these
conflicted precedence was given to information obtained
at autopsy, operation, endoscopy or barium meal in that
order. Re-bleeding in hospital, operations performed for
bleeding within seven days of admission, operative com-
plications and deaths were noted.
Results
Altogether, 330 patients were admitted of whom 194 were
men (59 per cent) and 136 were women (41 per cent).
Their age distribution is shown in Table 1. The common-
Table 1.
Age of patients (% of total)
Y ears %
<40 14
40-59 27
60-79 44
>80 15
est diagnosis was duodenal ulcer (29 per cent) followed by
gastric ulcer (19 per cent) and gastric erosions (14 per
cent); other diagnoses were much less common (Table 2)
and 16 per cent of patients left hospital or died without a
diagnosis being made.
Table 2.
Final diagnoses
% of patients
Patients % Deaths who died
Duodenal ulcer
Gastric ulcer
Gastric or duodenal erosions
Gastric carcinoma
Oesophageal varices
Mallory-Weiss tear
Oesophagitis
Stomal ulcer
Other diagnoses
No diagnosis made
TOTAL
96 29 7 7
63 19 10 16
46 14 1 2
11 3 7 64
9 3 5 56
17 5 0 0
23 7 0 0
5 2 1 20
7 2 2 30
53 16 17 32
330 100 50
Co-incidental medical problems were recorded if they
might have complicated medical, surgical or anaesthetic
management of bleeding and were present in 36 per cent
of patients. Most of these patients had cardiac or respirat-
ory disease; liver or renal disease was occasionally identi-
fied. Aspirin, non-steroidal anti-inflammatory drugs or
corticosteroids were being used at the time of bleeding by
44 per cent of patients, while in 13 per cent the admitting
doctor indicated that recent alcohol ingestion might have
precipitated bleeding.
*Correspondence to Mr M. V. Madden, Surgical Gastro-enterology
Clinic, Groote Schuur Hospital, Cape Town, 7925 South Africa.
212 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
Previous upper gastrointestinal bleeds had occurred in
86 patients who had bled either once (64 patients), twice
(12), 3 times (3), 4 times (6) or 5 times (1). The death rate
in these patients was 14 per cent, very similar to the 16
per cent death rate in patients who had not bled pre-
viously.
Admission haemoglobin values were obtained for 326
patients: 132 were below 10 g/dL (41 per cent) and 35 of
these were below 7 g/dL (11 per cent). Systolic blood
pressure was below 100 mm Hg, when first recorded in 37
patients (11 per cent). Blood was transfused in 189
patients (57 per cent) who received a mean of 5.7 units.
Endoscopy was performed within 48 hours in 20 per cent
and later during the same admission in a further 46 per
cent, while a barium meal was performed in 11 per cent.
No angiograms were performed to identify sources of
bleeding.
Histamine receptor antagonists were given to 51 per
cent of patients, alkali to 6 per cent and 19 per cent
received both. Neither form of treatment was used in 24
per cent. Operations were performed for bleeding within
7 days of admission in 32 patients (10 per cent) (Table 3).
Table 3.
Indication
Results of surgery
Operation performed Number Deaths
Duodenal ulcer
Gastric ulcer
Gastric erosions
Gastric carcinoma
Oesophageal varices
Stomal ulcer
Aorto-duodenal
fistula
TOTAL
Vagotomy &
pyloroplasty with
under-running of ulcer 9 2
Pyloroplasty with
under-running of ulcer 1 0
Partial gastrectomy 4 2
Partial gastrectomy 8 4
Vagotomy & excision
of ulcer 1 1
Vagotomy &
pyloroplasty 1 0
Under-running of ulcer 2 0
Vagotomy &
pyloroplasty 1 0
Partial gastrectomy 1 1
Laparotomy only 2 2
Vagotomy & under-
running of ulcer 1 0
Direct suture of fistula 1 1
32 13
Three patients underwent reoperation: for re-bleeding
from a duodenal ulcer, for a subphrenic abscess after
gastrectomy with splenectomy for gastric ulcer and for
embolectomy following aorto-duodenal fistula repair: all
three died.
In all, 50 patients died (15 per cent). The causes of
death are shown in Table 4. Thirteen deaths followed
surgery (operative mortality 41 per cent) and a further 14
were ascribed to continued bleeding in patients who did
not have an operation. Deaths were significantly more
common in patients aged 60 or over, in women, in
Table 4.
Causes of death
Total of 50 patients
Number (%) of patients
Number (%)
No operation
Bleeding 14 (28)
Pneumonia 7 (14^
Liver failure 6 (12)
Stroke 3 (g^
Carcinomatosis 2 (4)
Cardiac failure 1 (2)
Limb gangrene 1 (2)
Unknown 3 ^
Total 37 (74)
Following operation
Suture line leak 4 ^
Pneumonia 2 (4)
Cardiac failure 2 (4)
Bleeding varices 2 (4)
Pulmonary embolus 1 (2)
Acute renal failure 1 (2)
Hypovolaemic cardiac arrest 1 (2)
Total 13 (26)
Table 5.
Factors associated with death
Patients dying/Total % dying P (chi2)
Age <60 5/136
Age 60 + 45/194
Men 21/194
Women 29/136
No medical problems 19/210
Medical problems 30/120
Hb 10+ 18/194
Hb <10 30/132
Endoscoped 18/217
Not endoscoped 31/113
No re-bleed 44/303
Re-bleed 8/27
4
23
11
21
9
25
9
23
8
27
15
30
<.001
<.01
<.01
<.01
<.01
<.05
patients with incidental medical problems, those with Hb
below 10 g/dL, in those who had not undergone endos-
copy and in patients who re-bled (Table 5). However, in
each of these categories the group with a higher mortality
rate also had a higher average age, except for patients
undergoing endoscopy whose average age was very simi-
lar to those not endoscoped (60.1 vs 61.2 years).
Discussion
The total of 330 patients admitted during two years
confirms that upper gastro-intestinal bleeding is a com-
mon cause of emergency admission to a District General
Hospital, even assuming that some patients went unde-
tected because the study was retrospective. Using admis-
sion ward records to cross-check the Hospital Activity
Analysis data identified roughly a quarter of the patients
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
traced, so the potential inaccuracy of using HAA data
alone must have been reduced substantially.
Our patients had a mean age of 60.4 years, confirming
that this is largely a disease of the elderly. Allan[3] has
pointed out that the average age of patients with upper
gastro-intestinal bleeding in the UK has risen steadily,
which probably explains why mortality rates have re-
mained static over several decades.
Unchecked bleeding was the commonest cause of death
in our non-operated patients, and was the indication for
surgery in all those who died after an operation. These
two groups accounted for 54 per cent of all deaths, so a
safe and effective way of stopping bleeding in the elderly
should make a major difference to overall mortality. It is
therefore disappointing that reliable endoscopic and phar-
macological methods of controlling bleeding have not yet
been found[6]. However, histamine receptor antagonists
were given to 70 per cent of our patients and this seems to
be a common practice[4] despite the lack of evidence that
they improve survival from upper gastro-intestinal bleed-
ing.
Most of the factors we found to be associated with an
increased death rate were predictable ones: age 60 or
more, associated medical problems, haemoglobin below
10 g/dL and re-bleeding in hospital. Women died more
often than men, probably because they were on average
9.4 years older (66.0 vs 56.6). However, we cannot
explain the higher survival rate of patients who under-
went gastroscopy. It is unlikely that more precise diag-
nosis led to their having better treatment: first, more than
two thirds of endoscopic examinations were performed
over 48 hours after admission, so it would be surprising if
the findings led to life-saving changes in management.
Second, referral for endoscopy was strongly influenced by
the policy of the consultant physician under whom
patients were admitted, so it is possible that enthusiastic
use of endoscopy was accompanied by more aggressive
and successful treatment. Third, routine early endoscopy
has not been shown to influence patient survival[7]
although it seems logical that oesophageal varices, in
particular, should be treated endoscopically once identi-
fied, thus avoiding dangerous surgery in patients with
portal hypertension. Our two patients operated on for
bleeding varices both died because bleeding was not
controlled.
Most patients with upper gastro-intestinal bleeding are
treated in District General Hospitals, so it may be
misleading to deduce national mortality rates from teach-
ing hospital data. We have therefore compared three
series describing teaching hospitals' experiences with our
own, to see if there were differences in the overall death
rate, the operation rate and the operative death rate. We
also compared the proportion of elderly patients in each
series and the causes of bleeding, as these have a major
impact on the likely death rate (Tables 6 and 7).
Allan[3], Berry[4] and Cotton[2] and their co-workers
specify the diagnoses for most or all of their patients, and
the proportions of patients with the three commonest
causes of bleeding (duodenal ulcer, gastric ulcer and
erosions) are similar in all four series. The proportions
bleeding from varices, which are uncommon but have a
Table 6. Causes of bleeding in this series and series from UK
teaching hospitals (%).
This series Allan[3] Berry[4] Cotton[2]
Duodenal ulcer 29
Gastric ulcer 19
Erosions 14
Gastric, carcinoma 3
Varices 3
Mallory-Weiss 5
Oesophagitis 7
Stomal ulcer 2
Other diagnoses 2
No diagnosis 16
30 23 24
19 23 29
17 14 11
2 2
2 2 3
3 1
10 7
1 3
2 3
9 17 15
Table 7. Death rate, operation rate and operative death rate in
this series and in series from UK teaching hospitals.
No of % aged 60 Deaths Operat- Operative
patients or over (%) ions (%) deaths (%)
This 330 59 50 32 13
series (15) (10) (41)
Allan[3] 296* 48 25+ 96+ 9 +
(9) (32) (9)
* *
Berry[4] 125 69 6+ 24+ 3
(5) (19) (13)
Cotton[2] 206* 45 8+ 54+ 6 +
(4) (26) (11)
*patients specified as not having bled from the upper gastro-intestinal
tract have been removed
+ lower operation rates and higher death rates when compared to this
series (chi2, p<0.1)
**lower death rate when compared to this series (Fisher's exact test,
P = 0.04)
high mortality rate, are almost identical. The patients
may therefore be sufficiently similar to allow valid com-
parison. Our results show three clear differences from
each of the teaching hospital series: our overall patient
mortality was higher, the operation rate was lower, and
the post-operative death rate was higher. If the patients in
each series were indeed comparable, our treatment was
less effective, both for patients who had operations and
those who did not, and we have tried to work out why this
was so.
It is disturbing that the commonest cause of death in
patients who were not operated on was unchecked bleed-
ing: these patients may have bled to death because
surgery was used so seldom. Surprisingly, most had not
been referred for a surgical opinion. A reluctance to
operate may also have led to dangerously delayed oper-
ations and contributed to the 41 per cent operative
mortality. The high proportion of our patients aged 60 or
more does not excuse these poor surgical results: we had
fewer elderly patients than in the Oxford study, in which
Berry reported a lower death rate and fewer post-operat-
ive deaths despite a higher rate of recourse to surgery.
Our results are so much worse than those achieved by
others who treat apparently similar patients that a change
in management seems necessary. Potentially avoidable
214 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
deaths appear to have occurred in two situations: first, the
post-operative death rate of 41 per cent was excessive and
second, continued bleeding caused 14 of 37 deaths in
patients who did not have operations. This suggests that
surgical treatment, in the broadest sense, needs improve-
ment but also that more operations to stop bleeding
should be performed. This might be achieved if patients
with haematemesis and melaena were routinely admitted
to a surgical ward.
Admitting bleeding patients directly to a surgical ward
might avoid dangerously delayed operations, and allow
many procedures to be performed on elective surgical
lists, when consultant surgical and anaesthetic cover is
readily available[8]. It should virtually eliminate con-
tinued bleeding as a cause of death. On the other hand,
over a third of our patients had incidental medical
illnesses, usually cardiac or respiratory, which would be
less effectively managed in a surgical unit. Furthermore,
most patients do not actually need operations and would
occupy beds otherwise available for elective surgical
procedures. Perhaps this is why only 4 per cent of UK
hospitals sampled by Thomas[9] admitted patients with
haematemesis and melaena to surgical wards, although
Hegarty and colleagues[8] found that this policy worked
well in a District General Hospital.
Alternatively, Cotton and RussellflO] have suggested
that bleeding patients be nursed in an intensive care unit
for 72 hours after admission. This should ensure early
detection of continued bleeding or re-bleeding, as well as
skilled management of associated illnesses during the
period of maximum risk, but it would be an expensive
way to manage patients who usually turn out not to have
needed intensive care after all.
A third approach has been used by Hunt et al. [11,12]
who have reported a steady improvement in the survival
of patients with bleeding peptic ulcer since the establish-
ment of a haematemesis and melaena unit, which is run
jointly by a gastro-enterologist and a surgeon. This
approach would reduce the use of expensive intensive
care facilities. It should also allow early endoscopic
identification and discharge of low-risk patients (erosions,
oesophagitis or normal endoscopy) as well as careful
monitoring of patients with oesophageal varices, or peptic
ulcers with signs of recent bleeding. We feel that our
results might have been better if management had in-
volved closer co-operation between medical and surgical
teams. A haematemesis and melaena unit, drawing staff
from both sources, should lead to better selection of
patients for surgery, more appropriate timing of oper-
ations, and improved perioperative care as well as earlier
discharge of low-risk patients. Because upper gastro-
intestinal bleeding is a common, dangerous problem in a
District General Hospital it may be worth re-allocating
staff and resources which are already used to care for
these patients to a special unit.
References
1. Johnston, S. J., Jones, P. F., Kyle, J. and Needham C. D. (1973)
British Medical Journal, 3, 655.
2. Cotton, P. B., Rosenberg, M. T., Waldram, R. P. L. and Axon,
A. T. R. (1973) British Medical Journal, 2, 505.
3. Allan, R. and Dykes, P. (1976) Quarterly Journal oj Medicine, 45, 533.
4. Berry, A. R., Collin, J., Dudley, N. E., Frostick, S. P. and
Morris, P. J. (1984) Journal of the Royal College of Surgeons of
Edinburgh, 29, 134.
5. Morgan, A. G., McAdam, W. A. F., Walmsley, G. L., et al. (1977)
British Medical Journal, 2, 237.
6. Editorial (1984). Lancet, 1, 715.
7. Conn, H. O. (1981) New England Journal of Medicine, 304, 967.
8. Hegarty, M. M., Grime, R. T. and Schofield, P. F. (1973) British
Journal of Surgery, 60, 275.
9. Thomas, G. E., Cotton, P. B., Clark, C. G. and Boulos, P. B.
(1980). Journal of the Royal Society of Medicine, 73, 90.
10. Cotton, P. B. and Russell, R. C. G. (1977). British Medical Journal,
1, 37.
11. Hunt, P. S., Korman, M. G., Hansky,J. et al. (1979) British Journal
of Surgery, 66, 633.
12. Hunt, P. S., Hansky,J., Korman, M. G. et al. (1980) Australian and
New Zealand Journal of Surgery, 50, 41.
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986 215
|
PMC005xxxxxx/PMC5371067.txt | Book Review
Principles and Practice of Geriatric Medicine
? edited by M. S.
J. Pathy. John Wiley and Sons, Chichester, 1985. 1336
pages. Price ?62.50.
It has taken me some six months to review this massive
book, reinforcing my admiration of the labour which
must have been involved in its generation. There are now
two major British reference books on geriatric medicine,
this one and Brocklehurst's Textbook of Geriatrics and
Gerontology. Both are too heavy to carry around or for
bedtime reading, so I have dipped into Brocklehurst at
work and Pathy at home during the autumn, looking up
clinical problems I have encountered and topics I have
had to teach. 'Big Brocklehurst', now in its third edition,
is already established as a source. Although a handful of
its authors are also contributors to the new Pathy tome, I
found enough difference between the two books to be glad
to have both.
Pathy (and his 72 contributors) start with introductory
chapters on the basic sociology, biology and psychology of
ageing, but the major part of the book is devoted to the
practical consideration of clinical problems as they affect
the elderly. This is apparent in the emphasis given to
neurological disorders (almost 300 pages) compared to,
for example, the respiratory system (30 pages) or gastro-
intestinal disease (100 pages). The selection of subjects
and their respective allocation of space reflects the prob-
lems posed by the elderly sick, particularly where their
presentation may differ from that seen in younger
patients. As is customary in such large textbooks, the
arrangement of chapters is based on bodily systems, with
additional material on specific topics such as exercise,
pharmacology, sleep disorders, anaesthesia and surgery
in the elderly. While this traditional approach is probably
the most reasonable structure for a reference book, some
shorter introductory texts on geriatric medicine have
successfully adopted a more integrated, problem-orientat-
ed format. Although many of the chapters in Pathy are
eminently readable at a sitting, the book as a whole would
be difficult to plough through from beginning to end.
Towards the end of the book there are chapters on
health care delivery in the UK, Japan and the USA.
These contributions are of broad interest, and since 20 of
the authors come from outside the British Isles the book
should appeal to readers in other countries. It is refresh-
ing to see a chapter on health problems of older people in
the developing world: this is where some two-thirds of the
world's population over 65 years of age will live as we go
into the next century. We can only hope that Bob Geldof
will not retire too early.
With over 60 chapters to choose from, it is customary
for the reviewer to comment on variable standards, but I
will refrain from poaching the curate's egg on this
occasion. However, it is fair to say that this book is
primarily aimed at clinicians, with enough gerontology
included to set the stage for geriatric medicine. The
editing and layout are excellent, the index good, and most
chapters have a useful selection of references. I hope that
Pathy will join Brocklehurst as a standard source in
hospital libraries and departments of geriatric medicine.
Roger Briggs
226 Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
|
PMC005xxxxxx/PMC5371068.txt | Susan Ryland
Susan Ryland, Deputy Editor of the Journal, died on 25th March. These
words are written soon after her tragically early death when the community
of the College is joined with her family in mourning their great loss. Almost
twenty years ago Susan came to the College and started work on the Journal
when its first issue was launched. From that time onwards the complex
organisation of the Journal and College Commentary was in her hands.
That it has run so smoothly is entirely due to Susan's intelligence, diligence
and sheer hard work. There was the secure feeling that as long as she was
there nothing could go far wrong; and nothing did. As befitted a graduate of
Trinity College, Dublin, she had a gift for lucid accurate written English
which she applied to her meticulous editing. Always wanting to increase her
expertise, she learnt to be a skilled sub-editor and could 'page' a journal
with elegance. All her work was measured by her own high standards and,
being unassuming, she was genuinely surprised by praise.
Apart from her heavy editorial responsibilities, she was also Secretary to
the Standing Committe of Members. In the last issue of the Journal the
Committee thanked Susan for 'her unerring efficiency and unending
patience' in her work on 'Training to be a Physician' which she had nursed
from conception to the printed page. This was an accurate tribute to the
way she always did things.
This brief factual account tells little of Susan and of what a pleasure it was
to work with her. She had great charm and courtesy. She looked at the
world with a clear perceptive eye, had an informed love of art and music,
especially opera, disliked pomposity and had compassion for all who
suffered. She never put herself forward but had a dry wit. Her friends knew
her to be a special person and their lives are diminished by her death.
S.M.
Journal of the Royal College of Physicians of London Vol. 20 No. 3 July 1986
159
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PMC005xxxxxx/PMC5371084.txt | I
j
i
(
Towards Rational Drug Therapy in Old Age
The F. E. Williams Lecture 1985
F. I. CAIRD, DM, FRCP
David Cargill Professor of Geriatric Medicine,
Southern General Hospital, Glasgow
University Department of Geriatric Medicine,
Drug therapy can play a major part in the prevention and
relief of the sufferings of old age?the end for which F. E.
Williams endowed the lecture which bears his name?but
is very much a two-edged sword, since injudicious and
irrational therapy may do much more harm than good.
Rational therapy must aim at efficacy with safety, though
these two objectives may at times be incompatible. What
help can we get towards rational drug therapy in old age
from epidemiology, the study of drug kinetics and dyna-
mics, and from official bodies?
Information from Epidemiology
Epidemiology tells us, as might be expected, that the
multiple pathology of the elderly constitutes a standing
temptation to polypharmacy, and that they consume
more drugs than younger people[l-3]; they are respon-
sible for twice the national average drug bill per head[4].
Adverse reactions to drugs (ADRs) increase with age[5-
7] (Fig.l), and some 12 per cent of admissions to geriatric
units are occasioned wholly or partly by ADRs[8]. The
frequency of ADRs may have fallen over the last 20 years
but, at their most recent absolute level, they leave no
place for complacency, and they are still at least twice as
common in the elderly as in the young (Fig.l). The
frequency of ADRs rises with the number of drugs
prescribed; in one study it was 100 per cent if 10 or more
were given[9], and the trend, though not so striking, is
similar in many[10].
ADRs are often attributed to poor patient compliance,
but non-compliance most often leads to under-consump-
tion of drugs. The blame should be taken by the prescrib-
es since multiplicity of drugs has been shown in several
studies to be a most important factor in poor compli-
ancefll]. To simplify the task for the patient must be a
major objective, and should be assisted by deliberate and
repeated teaching and monitoring of the patient's drug-
taking^]. Proper aids to memory, demonstrated as
useful to the patient in question[13], and the proper use of
containers[14], should now be a part of standard practice
both in hospital, in medical wards as widely as is com-
monly now the case in geriatric wards, and in general
practice.
In the longer term there is doubt of the efficacy of
active teaching[15], but at least it can do no harm. In the
last analysis, however, it would be most unwise to
improve compliance before improving prescribing, since
that would mean the disappearance of the patient's last
defence against the doctor.
Symptomatic postural hypotension in elderly hospital
patients is very commonly associated with drug therapy,
and not infrequently with multiple potentially causal
drugs[16]. It is then of little value to decide as to the
precise cause, and in most situations the best thing is to
strike out all drugs. Another approach, particularly useful
on those occasions when one or more of the individual
drugs is essential, is to stop drugs serially and observe the
effects closely. This should allow a decision to be made on
which drug or drugs is a predominant cause, and will
often permit the essential therapy to be continued.
Simplicity of prescribing and the use of as few drugs as
possible are important principles of rational geriatric
clinical pharmacology, which should reduce the frequen-
Fig. 1. Relationship between age and frequency of adverse
reactions to drugs.
<20 30 40 50 60 70 80 +
Age (years)
? ? Seidl [5] USA
* * Hurwitz [6] UK
o o Levy [7] Israel
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 235
cy of adverse reactions and interactions. These principles
should only be set aside if absolutely necessary. Gosney
and Tallis[17] observed 133 adversely interacting combi-
nations of drugs in 6,160 prescriptions for the elderly (2
per cent). Sixty of these 133 were potentially serious, and
67 were avoidable. Clearly, well-established knowledge
was not being correctly applied. A computer program to
assist in the avoidance of these and other ADRs has been
designed[18], and may well prove necessary to reduce the
consequences of the imperfections of human memory.
Meanwhile, much can be achieved by the simple but
arduous process of taking thought.
Single drug therapy may also result in unacceptable
adverse reactions. The frequency of adverse reactions to
flurazepam[19] is low at any age with a small dose, which
is ineffective as a hypnotic, becomes more common in the
elderly with an intermediate dose and rises to totally
unacceptable levels with a dose which is effectively hyp-
notic. Here safety and efficacy are clearly incompatible,
at least in the elderly, and since there are alternative
hypnotics to flurazepam, a rational prescriber would
conclude that this drug should not be given to the elderly.
In the case of nitrazepam, its depressant effects on the
CNS are age-related, and the so-called stimulant effects
are not[20].
It must be questioned whether any benzodiazepine
should be prescribed for the elderly unless there is an
overwhelming requirement. Hypnotics as a whole may be
much less necessary for the elderly than has been thought.
In my wards they have, for the last two years, been
prescribed for fewer than 10 per cent of patients, without
complaint from patients or staff. Indeed, one is driven to
wonder whether they have not been prescribed more to
treat the staff than the patients.
Information from Pharmacokinetics and
Pharmacodynamics
We learn much from pharmacokinetics about the reasons
for the elderly reacting adversely both to individual drugs
and to certain combinations of them. Drug absorption is
little affected by age, and although reductions and delays
in absorption have been described for some drugs[21],
they are of little clinical importance. One important
exception is levodopa with which there is an approximate-
ly three-fold increase in absorption in the elderly[22],
probably due to age-related reduction of gastric dopamine
decarboxylase, and consequent greater availability of
levodopa for absorption. This increase in absorption is
undoubtedly one of the main reasons for the substantially
lower dose of levodopa required for the elderly[23], and
for the place of levodopa as one of the commoner causes of
ADRs in the elderly[8,24].
In the elderly, decrease in pre-systemic elimination by
the liver of lipid soluble drugs with a high hepatic
elimination rate, e.g. propranolol, lignocaine and chlor-
methiazole[25-27] results in increased bio-availability,
which may be a reason for dose reduction in the elderly.
Alterations in drug distribution with age[21] are of
great interest but not very easy to interpret. Age reduces
lean body mass and increases fat mass so that water-
soluble drugs are distributed in a smaller volume and fat-
soluble drugs in a larger volume[28], This effect is of
small magnitude, except with digoxin, when the 30 per
cent reduction in its volume of distribution is probably in
part related to reduced lean body mass[29,30]. This
necessitates a reduction in the loading dose, where a
reduced volume of distribution has its greatest effect.
Altered volume of distribution has an important effect
on the interpretation of changes in the plasma half-life,
which cannot be used alone to provide evidence of
changes in clearance, the most valid measure of elimina-
tion, because clearance is defined as half-life divided by
volume of distribution, so that changes in the latter as
well as in the former may result in changes in clearance.
Properly conducted studies are required, with i.v. as well
as oral dosage, to elucidate the facts with certainty.
Altered protein binding may perhaps be important,
although this is also a confusing subject. Reduced serum
albumin, a common finding in sick but not healthy old
people[31], is clearly important in this connection since
many drugs are bound to albumin, and there is a greater
possibility of interaction between drugs, due to greater
displacement of one by another in the elderly[32].
The most important single kinetic cause of adverse
reactions in the elderly is undoubtedly impaired renal
elimination. This affects drugs eliminated predominantly
by glomerular filtration (digoxin, phenobarbitone, cime-
tidine and procainamide) and those largely eliminated by
tubular secretion (penicillin and aminoglycoside anti-
biotics). Impairment arises because of the magnitude and
regularity of occurrence of reduction in renal function
with age, and the sensitivity of the renal circulation to
extrarenal disturbances in disease.
At all ages the renal clearance of digoxin is related
linearly to clearance of creatinine[8]; the small effect of
the spironolactone-sensitive renal tubular secretion of
digoxin[34] may be ignored in quantitative terms. The
mean digoxin clearance of elderly patients who are given
the drug[33] is only around 40 ml per minute, with values
as low as 10 ml per minute, as against the average normal
glomerular filtration rate in the elderly of 80-90 ml per
minute[35]. The hepatobiliary clearance of digoxin is also
reduced in these patients from the value in young normals
of 50-60 ml/min to around 20 ml/min[33,36], but there is
little clinical evidence that this is of importance.
Any intercurrent factor which produces acute alter-
ations in the glomerular filtration rate, such as the onset
of congestive heart failure or of dehydration, will reduce
digoxin clearance and so increase the risk of toxicity.
Conversely, any factor which increases glomerular filtra-
tion rate, such as the resolution of those conditions
mentioned, will increase digoxin clearance, and render
inadequate a previously adequate dose. The only import-
ant cause of a persistent increase in glomerular filtration
rate above normal at any age is hyperthyroidism[37],
which also increases the volume of distribution by a factor
of 2-3 times[30], probably by increase in muscle Na-K
ATPase[38], of which the volume of distribution may well
be a reflection.
Digoxin provides an excellent example of the effects of
pharmacokinetic knowledge upon rationality of prescrib-
236 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
ing in the elderly. In a study of three loading and one
maintenance dose in three groups, each comprising 7-9
elderly patients with normal renal function[39], the load-
ing doses were 0.75, 0.5 and 0.25 mg, and the mainten-
ance dose 0.25 mg. The time course of the serum
concentrations over five days was calculated from the
fractional absorption of the drug accepted as unaltered in
the elderly[40], estimates of the volume of distribution
and hepatobiliary clearance[30,33], and the previously
demonstrated equivalence of renal digoxin and creatinine
clearances. The agreement between theory and obser-
vation is very close. The three loading dose schedules
result in therapeutic blood levels on days 1, 2, and 4
respectively, without any level approaching the toxic.
The choice of regime can thus depend on a decision on
how fast it is thought necessary to digitalise the patient.
u By contrast, age-related changes in the kinetics of drugs
with predominantly hepatic metabolism are rarely of the
same magnitude and regularity, though statistically sig-
nificant differences may be demonstrable. Surprisingly,
direct measurement in liver biopsy samples has shown
few age-related alterations in the concentration of several
important drug metabolising enzymes in man[41], and
presumably the age-related reduction in liver size and
blood flow is more important[42,43].
Age may affect hepatic oxidative more than conjuga-
tive metabolic pathways[28], and the delayed production
j' and further delayed elimination of active metabolites
produced in the liver may operate to prolong drug action.
The basic genetically determined differences between
individual rates of metabolism of some drugs are pre-
served[44]. There may be differential sex effects, women
being more affected than men[28], and though in the
elderly reduced induction of hepatic enzyme activity has
been shown[45], it is much more difficult to demonstrate
nutritional and other environmental effects, except those
4 ? of cigarette smoking, particularly when the effects may be
due to exposure to noxious agents many years previously.
We know too little of the effects of disease in old age on
drug kinetics, and specific studies should be carried out.
The clearance of Cortisol, which is metabolised by the
same hepatic enzyme system as are many drugs, is much
increased by the chronic infection of pressure sores,
roughly in proportion to their severity; this increase is
abolished by healing of the sores[46]. Chronic infection
may thus lead to a need for greater drug dosage.
Altered pharmacodynamics in the elderly are another
area of great interest but, because of the considerable
difficulties of study in man, have been less investigated.
Almost all that has been studied is the relationship of
plasma concentration to drug effect, which has been
attributed to reduced receptor number or affinity, or to
post-receptor changes. For instance, the heart rate re-
sponse to equivalent concentrations of isoprenaline is
blunted in the elderly[47,48], and beta-blockers are rela-
tively less effective, blood level for blood level[49]. The
failure to demonstrate any effect of age on alpha-adrener-
? ? gic function is one of the few examples of direct measure-
ment of drug effect in man[50].
The increased effect of some benzodiazepines may also
be due to receptor alterations, or to alterations in the
balance of neurotransmitters in the elderly brain, al-
though the effects of any change in the blood/brain
barrier and consequent better penetration of the drug into
the brain have not been investigated. One such example
is the age-related fall in the plasma concentration of
diazepam required to produce abolition of response to
voice but not to pain[51], The psychomotor effects of
nitrazepam are increased in the elderly at equivalent
blood levels[52]. That the effect in both cases may be due
to better penetration into the brain is suggested by the
fact that, in the elderly mouse, cerebral benzodiazepine
receptors are not apparently altered in concentration[53].
The anticoagulant effect of warfarin is increased, owing
to increased sensitivity of hepatic synthesis of clotting
factors[54].
Difficulties with drug therapy and adverse reactions in
the elderly can also be caused by what might be called
conditioning factors. For example, in middle age diuretics
do not cause substantial potassium depletion, but in old
age they often do[55]. This is not due to some peculiarity
in the action of the drugs themselves, but to the known
reduction in potassium intake that occurs with age[56].
Any drug that increases potassium output in the face of a
reduced input must cause potassium depletion. It is often
wrongly and dangerously inferrred that because supple-
mentary potassium is not required with diuretics in
middle age, it is not required at any age.
A second conditioning factor is the effect on tempera-
ture regulation in the elderly of drugs such as phenothia-
zines, which are well up among the causes of hypothermia
in old age; old age itself is associated with a high
prevalence (up to 40 per cent) of abnormalities of tem-
perature regulation[57], A third example is the high
frequency of postural hypotension caused by many drugs.
This is in part a consequence of the age-related impair-
ment of baroreceptor function[58].
The scientific study of drugs in the elderly is at last well
under way. There are now striking examples of age-
related alterations of drug kinetics and dynamics; there is
as yet no very clear set of principles from which useful
predictions may be made about drugs not yet studied in
the elderly. A blanket recommendation to reduce the
doses of all drugs given to the elderly is certainly unwar-
ranted, since no change has been demonstrated in the
handling of several, such as phenytoin[59] and ateno-
lol[60]. Every drug commonly used in the elderly must
have its pharmacology specifically elucidated in the eld-
erly before we can confidently say that our prescribing is
rational. Meanwhile, simple empirical adjustments, such
as in drug numbers and in doses, are required, though
based perforce on only half knowledge. Clearly, drugs
which have already been studied in the elderly are far
preferable to those which have not. There is a consider-
able, but by no means an insuperable, task ahead in this
vital field.
Information from Official Bodies
The Royal College of Physicians' Reportfll] makes a
number of recommendations which are by and large
admirable and open to criticism in detail only. These
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 237
recommendations are, in the case of hospital doctors,
mainly concerned with the responsibility of senior doctors
for proper prescribing, which the report rightly stresses.
Too often this important matter is left to juniors, as a
mere day-to-day question. A thorough and regular review
of drug therapy is rightly suggested (though rather bizar-
rely as occurring 'every 10 days', when most of us work to
a working week), and particularly when the patient leaves
hospital, and is the cornerstone of the proper discharge of
this responsibility. The final decision on drug therapy
should be combined with the beginning of active teaching
of the patient in the days immediately before return
home. The report also stresses the responsibility of gen-
eral practitioners for the supervision of repeat prescrip-
tions, and the limitations of such repeats to a set number.
My main criticism is concentrated on the statement
that the pharmacology of the elderly is not suggested as a
subject for specific study in the undergraduate curricu-
lum, when in the long run nothing will advance ration-
ality of prescribing in the elderly more surely than that it
should be emphasised at the undergraduate level, and
that advantage should be taken of the usefulness of the
facts described as illustrating principles of clinical phar-
macology in one of its most important practical areas. In
Glasgow a considerable proportion of our formal lectur-
ing time in geriatrics is devoted to this topic, and its
importance is stressed at every opportunity during bed-
side teaching.
The second official body is the Committee on Safety of
Medicines. Its criteria with regard to the elderly have
recently been altered. The Committee's definitions of
what constitutes an 'at risk' drug for the elderly are
eminently sensible (Table 1). It is difficult to believe that
Table 1. At risk drugs in the elderly (Licensing Authority
criteria).
1. Low therapeutic index
2. Clearance likely to be reduced
3. Interactions likely with other drugs commonly used by the
elderly
4. Possible kinetic or dynamic effects due to ageing of organs or
common disease processes
5. Membership of therapeutic class with a bad record in the
elderly
any drug will escape its last requirement. The require-
ments for drugs not yet marketed differ from those for
drugs already marketed. For new drugs likely to be a risk
for the elderly there are stringent requirements for testing
in old age, and close monitoring. Thus, what has for
years been immoral and unethical has suddenly become
compulsory. The considerable practical difficulties in
such testing (e.g. exclusion factors can easily become so
numerous that there are virtually no subjects left to study)
should not be allowed to prevent these much-needed
investigations. It is to be hoped that new drugs will be
specifically tested in patients with the conditions for which
they are to be given rather than solely in the fit 'normal
elderly', who may well be very different.
Much more important quantitatively are the require-
ments in respect of drugs already on the market; these are
much less stringent, and there is no monitoring pro-
cedure. This decision may perhaps be due to the apparent
size of the task and the limited resources of the Commit-
tee. A very simple study shows these fears to be unfound-
ed. The study was carried out in November 1984, thus
antedating the DHSS's limited list of drugs for simple
conditions, which in any case is largely irrelevant to the
question. The results of the study err somewhat in
quantitative terms but its principles remain. Those drugs
relevant to the elderly (Table 2) were counted in MIMS,
Table 2. Drugs relevant to the elderly (data sheet study).
Cardioactive drugs (inc. diuretics)
CNS-active drugs (inc. analgesics)
Anti-arthritic drugs (inc. NSAI)
Drugs acting on GI and GU systems with systemic adverse
effects (e.g. anticholinergics, carbenoxolone)
Selected antibiotics (tetracyclines, aminoglycosides)
Anti-diabetic drugs
Cytotoxic drugs used by generalists
and totalled 35 per cent of 1,084 drugs. The pertinent
data sheets in the ABPI's latest data sheet compendium
were studied for any mention of the elderly. It was not
profitable to decide whether the mention was useful and
appropriate or not. Only 27 per cent of drug data sheets
mentioned the elderly. However, with drugs most im-
portant to the elderly, such as psychotropics in the
broadest sense, over half the data sheets already mention
the necessity of care with the elderly (Table 3). The
Table 3. Drugs relevant to the elderly, preparations, and
percentage of preparations in which data sheet mentions the
elderly.
Drug group
Elderly
Number of mentioned (% of
Drugs Preparations preparations)
Digitalis 4 4
Benzodiazepines 18 30
Antidepressants 20 32
Phenothiazines 9 19
Other hypnotics 4 7
Barbiturates 8 21
Analgesics 20 34
Anti-Parkinsonism 12 17
Anti-diabetics 12 29
Other psychotropics 31 46
Other hypotensives 17 24
Diuretics 21 66
NSAI 21 48
Anti-angina 4 19
Anti-arrhythmics 9 13
All other 58 104
Anti-convulsants 8 9
/3-blockers 11 34
Theophylline, etc. 9 23
Anti-histamines 17 51
Sympathomimetics 20 54
100
93
88
74
71
48
48
35
34
33
25
21
19
18
15
14
11
9
9
2
2
238 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
J
i. proportion of hypotensive drug data sheets mentioning
the elderly is far less. The important thing about this
study is that it took one man a week of his spare time, and
one might imagine that rather greater resources might
have managed it in a month. The problem is therefore
? !> much smaller than has been thought, and there is no
reason why a monitoring procedure should not be set up;
Table 2 indicates where the drug companies should be
instructed to look on their data sheets.
v The European Branch of the World Health Organisa-
tion has recently taken a major interest in the problems of
the elderly, and has made a number of useful practical
suggestions with regard to drug therapy. The most
important of these is perhaps a monograph to be pub-
\ lished soon, which details in very simple terms, and
without references, the considerations that are important
to drug therapy in general in the elderly and to specific
therapeutic situations.
These three official bodies have therefore contributed,
each in its own way, to rationality in drug therapy in old
'<? age.
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54. Shepherd, A. N. M., Hewick, D. S., Moreland, T. A. and
Stevenson, I. H. (1977) British Journal of Clinical Pharmacology, 4,
315.
55. Judge, T. G. (1968) Gerontologia Clinica, 10, 102.
56. Judge, T. G., Caird, F. I., Leask, R. G. S. and McLeod, C. C.
(1974) Age and Ageing, 3, 167.
57. Collins, K. J., Exton-Smith, A. N., James, M. H. and Oliver, D.
J. (1980) Age and Ageing, 9, 11.
58. Gribbin, B., Pickering, T. B., Sleight, P. and Peto, R. (1971)
Circulation Research, 29, 424.
59. Lambie, D. C. and Caird, F. I. (1977) Age and Ageing, 6, 133.
60. Rubin, P. C., Scott, P.J. W., McLean, K., Pearson, A., Ross, D.
and Reid, J. L. (1982) British Journal of Clinical Pharmacology, 13,
235.
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 239
|
PMC005xxxxxx/PMC5371085.txt | The Prevalence of Diabetes Mellitus in a
Typical English Community
WENDY GATLING, MB, MRCP(UK), Novo Research Fellow
A. C. HOUSTON, MB, MRCP(UK), Medical Officer (Research)
R. D. HILL, MB, FRCP, Consultant Physician
Poole General Hospital, Longfleet Road, Poole, Dorset
Diabetes mellitus is a chronic medical disorder which,
although eminently treatable, still has a considerable
mortality and morbidity[1,2]. Evidence is now accumu-
lating to suggest that well-controlled diabetics suffer fewer
complications than poorly controlled diabetics[3,4], It is,
therefore, incumbent upon the Health Service to provide
adequate management and follow-up.
There has recently been considerable interest in the
organisation of diabetic care in the UK[5-7], However, to
plan effectively, it is important to know the extent of the
problem in both quantitative and qualitative terms. This
survey identifies the number and type of diabetics in a
well-defined population in the Poole area.
Method
The study population consisted of all the patients regis-
tered with 40 general practitioners working from 10
practices in the Poole district. The geographical area
covered in the survey was divided into two parts. In part
A, a semi-rural area north-west of Poole, all the 28 GPs in
the area were included. In part B, an urban area, 12 GPs
were included, that is only about 25 per cent of all the
GPs in the town of Poole.
During an 18 month surveillance period all the known
diabetics in the study population were identified from the
following sources: (a) a previous diabetic survey[8]; (b)
the Poole Diabetic Register, a computerised record of all
diabetics, listed by GP; (c) diabetic registers held by the
GPs; (d) all the diabetic clinics held in the hospital during
the study period, and (e) repeat prescription requests and
letters in each practice, collected by the GPs' reception-
ists.
A card index file of the names of the diabetics was
maintained in each surgery. All records were scrutinised
to ensure that each patient fulfilled the diagnostic criteria
set by the WHO Expert Committeee on Diabetes Melli-
tus[9]. If they had been treated continuously with insulin
or had had a break of less than one month since diagnosis,
or had suffered a documented episode of diabetic ketoaci-
dosis, the patients were classified as insulin-dependent.
All other patients were classified as non-insulin depen-
dent.
All diabetics were called for review by one observer
(W.G.) as part of another study. When a majority had
been seen in each practice, a count was made of the total
number of people registered with that practice, using the
age/sex register, when available, or the patient record
folders. Thus, for each of the 10 practices a point
prevalence of diabetes mellitus was determined. These
were added together to produce the prevalence for the
study population.
Results
In the study population, 917 diabetics were identified. At
the beginning of the study, the Poole Diabetic Register
and the previous survey[8] had found 604 (65.8 per cent)
diabetics alive and still registered with the 40 GPs.
During the surveillance period a further 313 diabetics
were identified, 248 (27.1 per cent) from the GPs and 65
(7.1 per cent) from the hospital diabetic clinics. The 40
GPs had 90,660 people registered on their lists; 66,542 in
part A, the semi-rural area and 24,118 in part B, the
urban area. Thus, the prevalence of known diabetes
mellitus in the study population is 1.01 per cent. Table 1
Table 1. Age distribution of patients registered with 40 GPs
compared with UK population (1981 Census).
Age No. of patients %
(yr) registered % UK
<5 5,497 6.1 6.1
5?14 12,176 13.4 14.7
15?29 17,961 19.8 22.5
30?44 19,309 21.3 19.5
45?64 20,214 22.3 22.3
65?74 9,204 10.2 9.2
75 and over 6,207 6.8 5.7
Unknown 92 0.1
Total 90,660 100 100
shows the age distribution of the study population and a
comparison with that of the UK. There is a small but
insignificant excess of over 65-year-olds but otherwise the
248 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
age distribution of the study population is comparable
with that of the general population.
t The cumulative frequency with respect to age in the
diabetic patients is shown in Fig. 1, which clearly demon-
strates that more than half the diabetics are aged over 65
years. Table 2 shows the age specific rates for diabetes in
Table 2. Age specific rate for diabetes mellitus in the female and
male populations.
Rate per
Age No. of patients No.of 1,000 study
(yr) registered diabetics population
F M F M F M
<5 2,661 2,836 0 1 0 0.4
5?14 5,694 6,482 6 9 1.1 1.4
15?29 9,199 8,762 34 36 3.7 4.1
30?44 9,973 9,336 50 43 5.0 4.6
45?64 10,474 9,740 105 154 10.0 15.8
65?74 5,169 4,035 128 134 24.8 33.2
75 and over 3,973 2,234 115 102 29.0 45.7
Unknown 47 45
Total 47,190 43,470 438 479
the female and male populations respectively. The rates
are similar in both sexes in the under 45-year-olds, but in
the older age groups the rate is strikingly higher in the
male population. The prevalence of diabetes in the female
population is 0.93 per cent against 1.1 per cent in the
male population.
Of the 917 diabetics identified, 222 (24.2 per cent) were
classified as insulin dependent and 679 (74 per cent) as
non-insulin dependent. There were insufficient data avail-
able to classify the remaining 16 (1.8 per cent) diabetics.
The. type of treatment known for 901 diabetics was diet
alone in 187 (20.4 per cent of the study group), oral
hypoglycaemic agents in 358 (39 per cent) and insulin in
356 (38.8 per cent), of whom 222 were classed as insulin
dependent and 134 as non-insulin dependent diabetics
(NIDDs). The type of diabetes according to age is shown
Table 3. Type of diabetes mellitus in relation to age in 901
diabetics in the survey (excluding 16 unclassified diabetics).
Insulin dependent Non-insulin dependent
Age %in that % in that
(yr) No. age group M/'F No. age group M/F
<10 6 100 1.0 0 0
10?19 32 100 1.3 0 0
20?29 43 90 1.26 5 10 0.3
30?39 40 71 1.35 16 29 0.6
40?49 30 37 1.0 52 63 1.38
50?59 24 19 1.67 101 81 1.25
60?69 21 11 1.1 175 89 1.33
70?79 18 7 0.8 245 93 0.87
80 and over 8 9 0.6 85 91 0.93
Total 222 679
in Table 3. As expected, the proportion of non-insulin
dependent diabetics increases with age.
Discussion
This survey is unusual in that it was population-based
and sought to identify both hospital and GP treated
diabetics. Because of the five different sources used,
ascertainment of all the known diabetics was probably
very high. The fact that over 25 per cent of the diabetics
were picked up through the GP surgeries demonstrates
that a hospital-based survey would have significantly
under-estimated the prevalence of diabetes mellitus. The
surveillance, especially in the GP surgeries, relied heavily
on reviewing repeat prescriptions for insulin, oral hypo-
glycaemic agents and urine testing equipment. A small
number of diabetics treated by diet alone, whose requests
for urine testing equipment may be infrequent, may have
been missed, particularly as some diabetics were found to
have stopped testing their urine altogether. However, the
GPs' own diabetic registers (available in five out of 10
practices) and other sources mentioned earlier were ex-
tremely helpful in identifying these patients.
The population under study was defined as all the
people registered with 40 GPs. It is well known that GP
lists tend to over-estimate the number of patients under
their care because records of deaths and removals may
not be kept up to date. Recent computerisation of all the
records with the local Family Practitioner Committee
(FPC) has reduced this problem to a minimum and the
counts made at each practice were in close agreement
with the FPC numbers for the nearest quarter. However,
it is likely that the prevalence of diabetes mellitus is
slightly higher than the 1.01 per cent determined.
Previous studies on the prevalence of diabetes mellitus
in the UK have been either screening surveys[10], hospi-
tal-based studiesfll] or small-scale community
studies[12,13]. The Edinburgh group[ll] attempted to
identify all the diabetics alive on 1st January 1968, using
the hospital clinic lists as a starting point. Although all the
263 GPs were contacted, no prolonged surveillance in the
surgeries was attempted. They found a prevalence of
diabetes mellitus of 0.63 per cent. However, only 13 per
Age in years
Fig. 1. The cumulative frequency in the 917 diabetics with
respect to increasing age.
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 249
cent of their diabetics were aged 65 years and over
compared with 52.2 per cent in this survey, suggesting
poor ascertainment in the older age groups. In Oxford-
shire, Dornan[12] found a prevalence of diabetes mellitus
of 0.8 per cent, identifying the diabetics principally by a
postal survey. In a large practice in Norfolk (practice list
20,010), Tasker found a prevalence of diabetes mellitus of
1.2 per cent[13]. However, in neither of these two studies
are the diagnostic criteria for diabetes defined.
The higher prevalence of diabetes in men aged 45 years
and over is striking. This may reflect more frequent
diagnosis of diabetes during routine employment and
insurance medicals which men have more commonly than
women. In addition, a higher percentage of male NIDDs
(32.1 per cent) were treated by diet alone, compared to
22.3 per cent of female NIDDs. In 1965 Malins reported
a change in the sex incidence of newly diagnosed diabetics
towards more men being diagnosed[14]. However, the
overall male:female ratio of new attenders was still less
than 1.0.
These figures on the prevalence and type of diabetes
mellitus will be useful in planning adequate facilities for
the management of diabetic patients. An average District
General Hospital in Britain serves a population of
250,000, which will contain approximately 2,530 diabe-
tics. If reasonable diabetic care is to be offered to these
patients, the district health authority must provide facili-
ties for an annual eye and medical examination and
twice-yearly blood sugar and HbAl estimations as a
minimum. Diabetic problems such as pregnancy, serious
retinopathy, nephropathy, painful neuropathy and foot
ulcers require specialist attention. In total, this represents
a large workload. Health authorities, diabetologists and
GPs must make detailed and integrated plans to provide
an efficient workable system.
Summary
A survey was carried out in the Poole area to identify all
the known diabetics under the care of 40 general prac-
titioners. Surveillance in both hospital and general prac-
tice ensured maximal ascertainment. From a study
population of 90,660, whose age distribution was similar
to that of the UK population, 917 diabetics were identi-
fied. The prevalence of diabetes mellitus was 1.01 per
cent. The age-specific rate for diabetes mellitus was
higher in men over 45 years old than in women. Of the
diabetics, 479 (52.2 per cent) were aged 65 years and
over; 222 (24.2 per cent) were classified as insulin-
dependent diabetics, 679 (74 per cent) as non-insulin
dependent and for the remaining 16 (1.8 per cent)
insufficient data were available for classification.
A cknowledgemen ts
Dr Wendy Gatling is a Novo Research Fellow. This
research was supported by Wessex Regional Health
Authority Research Fund, the British Diabetic Associ-
ation and the Bournemouth Lions. Thanks are due to
Professor R. J. Jarrett for his help in preparing the
manuscript, and to all the 40 general practitioners and
their staffs, without whose co-operation the survey would
not have been possible.
References
1. Deckert, T., Poulsen, J. E. and Larsen, M. (1978) Diabetologia, 14,
363.
2. Fuller, J. H., Elford, J., Goldblatt, P. and Adelstein, A. M. (1983)
Diabetologia, 24, 336.
3. Pirart, J. (1978) Diabetes Care, 1, 168, 252.
4. Johnsson, S. (1960) Diabetes, 9, 1.
5. Hill, R. D. (1976) British Medical Journal, 1, 1137.
6. Singh, B. M., Holland, M. R. and Thorn, P. A. (1984) British
Medical Journal, 289, 726.
7. Hayes, T. M. and Harries, J. (1984) ibid., p.728.
8. Houston, A. (1982) In Advances in diabetes epidemiology, pp. 199-206.
Inserm Symposium No. 22 (ed E. Eschwege.) Amsterdam: Elsevier
Biomedical.
9. WHO Expert Committee on Diabetes Mellitus (1980) Second Report.
WHO Tech. Rep. Serv., No. 646.
10. Butterfield, W. J. H. (1964) Proceedings of the Royal Society of Medicine,
57, 196.
11. Falconer, D. S., Duncan, L.J. P. and Smith, C. (1971) Annals of
Human Genetics, 34, 347.
12. Dornan, C., Fowler, G., Mann, J. I., Markus, A. and Thorogood,
M. (1983) Journal of the Royal College of General Practitioners, 33, 151.
13. Tasker, P. R. W. (1984) Practical Diabetes, 1, 21.
14. Malins, J. M., Fitzgerald, M. G. and Wall, M. (1965) Diabetologia,
1, 121.
'
250 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
|
PMC005xxxxxx/PMC5371086.txt | The Influence of Menstrual Status, Body
Weight and Hypothalamic Function on
Nocturnal Respiration in Women
E G. KOPELMAN, MD, MRCP(UK), Lecturer in Metabolism and Endocrinology
M. C. P APPS, MB, MRCP(UK), Senior Registrar in Respiratory Medicine
T. COPE, SRN, Research Nurse, Department of Respiratory Medicine
D. W. EMPEX MB, FRCP, Consultant in Respiratory Medicine
The London Hospital, Whitechapel, London
A disorder of breathing during sleep with episodes of
haemoglobin oxygen desaturation and apnoea has been
described in asymptomatic men of all ages and normal
weight postmenopausal women; an increase in body
weight in either group is associated with a greater fall in
oxygen saturation and an increased frequency of ap-
noea[l,2]. In contrast, obese women with regular men-
strual cycles show a less severe fall in oxygen saturation
during sleep and do not show sleep apnoea[3]. It has been
proposed that the higher plasma progesterone levels in
women with regular menstrual cycles is a protective factor
against the development of sleep-disordered breathing[2],
but, more recently, it has been suggested that sleep-
breathing abnormalities are related to the age rather than
the sex of a patient[4], We have recently reported evi-
dence that the hypothalamus is also important for the
control of nocturnal respiration[3].
We have now investigated the relationship of body
weight and central factors to sleep-breathing patterns in
asymptomatic normal weight and obese postmenopausal
women and six younger women with amenorrhoea and
obesity due to a hypothalamic-pituitary disorder, whose
only complaint was progressive weight gain.
Subjects and Methods
Tables 1 and 2 give details of the subjects studied. The
obese patients were volunteers who had become obese
either as a teenager or during adult life and were attend-
ing the Obesity Clinic; the control group of women were
volunteers from the hospital staff. All of the subjects had
normal thyroid function, were non-smokers and were not
taking any form of medication. They had experienced
regular menstrual cycles until the time of the menopause
which had occurred at least two years prior to study. The
patients with hypothalamic-pituitary disorders (Table 2)
attended the Endocrine Clinic and were characterised by
an insatiable appetite, progressive weight gain and amen-
Table 1. Details of women studied. W/H2 weight (kg)/height2
(m); VC: Vital capacity; FEV: forced expiratory volume in one
second; PEFR: peak flow rate, expressed as a percentage of
predicted normal.
Patient no. 1-9 : postmenopausal normal weight women
? no. 10-15: postmenopausal obese women
? no. 16-21: hypothalamic-pituitary disorders.
Patient Age Weight
no. (yr) (kg) W/H2 VC FEV! PEFR
1 62 67 23 104 98 94
2 50 74 25 94 90 88
3 51 64 22 86 92 95
4 55 67 24 102 96 92
5 65 65 22 111 102 94
6 52 65 24 98 94 98
7 50 65 24 90 88 82
8 55 63 22 85 77 80
9 50 63 24 95 100 89
Mean
? SEM 54 66( ? 1) 23 96 93 90
10 54 96 35 96 93 92
11 60 80 31 107 114 91
12 55 115 46 89 83 91
13 48 96 34 85 92 110
14 53 107 43 80 80 97
15 52 90 32 94 110 96
Mean
? SEM 54 98( ? 6) 37 92 95 96
16 35 104 40 75 75 76
17 44 106 42 84 85 81
18 48 115 44 92 90 104
19 60 106 37 80 85 95
20 30 85 31 95 98 110
21 58 112 44 79 78 81
Mean
? SEM 45 105( ? 4) 40 84 85 91
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 243
Table 2. Details of patients with hypothalamic-pituitary disorders.
Patient Age at
no. diagnosis
Diagnosis
Current treatment
(daily dosage)
16
17
18
19
20
21
23 Craniopharyngioma treated by hypophysectomy and external radiotherapy
38 Hypopituitary after surgery and external radiotherapy for invasive chromophobe
adenoma
48
45
29
57
'Hypothalamic syndrome'?unexplained hyperphagia and somnolence with
hyperprolactinaemia. Normal CT cranial scan, menopause at age 45 years
Acromegaly treated by external radiotherapy. Subsequent pituitary apoplexy and
rapid increase in weight
Hypopituitary following 2nd pregnancy with subsequent rapid weight gain
Progressive weight gain with daytime somnolence. Normal anterior pituitary function.
CT cranial scan suggests a partially empty sella. Menopause at age 46 years
Hydrocortisone (30mg),
thyroxine (200/ig) and
nasal DDAVP (0.2ml)
Hydrocortisone (30mg),
thyroxine (200/xg) and
nasal DDAVP (0.2ml)
Nil
Hydrocortisone (25mg),
thyroxine (150/ig)
Hydrocortisone (30mg),
thyroxine (200fig)
Nil
orrhoea; those patients requiring pituitary hormone re-
placement treatment were taking physiological doses and
no patient was taking an oestrogen preparation. All the
subjects were asymptomatic and none had a past history
of a respiratory disorder. The hypothalamic-pituitary
patients were investigated because of their progressive
weight gain; none of them complained of hypersomno-
lence, severe snoring or extreme tiredness. It was only
after investigation that a history of these complaints was
confirmed by their husbands. Pulmonary function was
assessed using a Wright peak flow-meter and a Vitalo-
graph dry spirometer. Body index was defined as weight
(kg) divided by height in metres2 (normal female range
19-24). We considered patients to be obese if their body
index exceeded a value of 26.
The methods for monitoring respiration during sleep
were identical to those we have previously reported[3].
Obese subjects were studied for two nights but it was only
possible to study the lean subjects for one. Airflow at the
nose and mouth were sensed with a laryngeal micro-
phone, movement of the chest and abdomen was assessed
with inductance bands (Respitrace) which show the
movement of chest and abdomen separately.
Apnoea was defined as a pause in airflow for more than
10 seconds; obstructive apnoea was characterised by
increased respiratory effort with paradoxical collapse of
the chest during inspiration with no airflow due to
obstruction at the pharynx or larynx; central apnoea was
indicated by the absence of airflow with no abdominal or
chest movement and mixed apnoea if there was no
movement early in the episode of apnoea and unsuccess-
ful movement later in the episode[5]. Haemoglobin oxy-
gen saturation (Sa02) was measured with a Hewlett
Packard ear lobe oximeter with the patient in the supine
position. Sleep was staged with an electroencephalogram
(C4Ai), electro-oculogram and submental electromyo-
gram using standard methods. Time to sleep (Ts) was
defined as the time (in minutes) from the start of the study
until the onset of sleep. Time to REM (TREM) was the
time from onset of sleep until REM sleep. The number of
episodes of waking (W) for periods of longer than one
minute was also recorded. One of the investigators
remained at the bedside throughout, noting the subjects'
behaviour, such as snoring or restlessness, and recording
this on the tracing. Timing of the events was also
recorded on the tracing and each tracing was reviewed in
detail and correlated with the stage of sleep. Statistical
analysis was by a Wilcoxon non-parametric test, because
the results were not normally distributed, and Spearman
rank correlation test. Each subject gave fully informed
written consent and the study was approved by the
hospital's ethical committee.
Results
Pulmonary Function Tests (Table 1)
All the patients and controls had normal spirometric
values?that is, between 75 per cent and 125 per cent of
predicted normal.
Sleep Study
Time awake during the night and times for sleep stages I,
II, III/IV, REM and REM latency and the number of
arousals (W) during the night are given in Table 3. The
mean time spent in the stages was not significantly
different between the three groups but only 4 of 9 normal
subjects, 2 of 6 obese and none of the hypothalamic-
pituitary group showed stage III/IV. There was no
significant difference found between the indices of sleep
latency (Ts), TREM, number of arousals and percentage
time of sleep spent in REM sleep. Two of the patients had
numerous apnoeas, one of these (patient 18) had very
poor sleep (90 minutes without REM) and 32 arousals,
the other (patient 19) slept well but with 12 arousals and
only 10 minutes of REM sleep.
Apnoea (Table 4)
Obstructive apnoea was not seen in the normal weight or
obese subjects but three of the hypothalamic-pituitary
patients showed this (cases 16, 18, and 19) and in cases 18
244 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
Table 3. Duration of sleep stage and analysis of sleep pattern in the women studied. Wake T: total time awake during night; Ts: time
from start of study until onset of sleep; TREM: time from onset of sleep until REM sleep; W: number of episodes of waking > 1
minute during night.
Patient no. 1-9: postmenopausal normal weight
? no. 10-15: postmenopausal obese
? no. 16-21: hypothalamic-pituitary disorders.
Patient
no.
Wake T
Sleep stage (min)
I
II
III/IV
REM
Total
sleep
time
(min)
REM/(%)
total
sleep
Ts
TREM
(min) W
Mean
? SEM
121
237
111
14
14
153
187
172
127
126 ?25
118
67
111
51
188
129
45
39
24
6+18
98
101
135
259
183
136
87
165
175
149+ 18
6
9
55
11
55
10
8
42
77
22
14
34
35
33 + 8
273
187
254
407
448
287
122
237
232
272 ?34
20
5
3
10
17
8
11
14
15
11 ?2
105
147
25
5
7
12
5
35
10
39 + 17
47
185
260
290
97
215
175
215
45
170 ?29
10
11
12
13
14
15
Mean
+ SEM
243
246
202
162
142
158
192 + 19
79
48
65
27
21
75
52 ? 10
97
109
117
163
196
172
142 + 17
25
17
11
12
50
32
24.5 ?6
201
174
193
207
271
275
220 + 18
12
9
6
6
18
12
10.5 + 2
94
150
115
15
102
51
8 + 20
85
183
208
175
72
82
134 ?25
16
17
18
19
20
21
Mean
? SEM
56
216
330
149
145
97
165 + 40
45
43
53
79
78
32
55 + 8
273
124
37
159
114
151
143 ?32
33
35
0
10
68
51
33 + 10
351
202
90
248
260
234
231 ?35
9
17
4
26
22
13 + 4
4
17
167
42
21
31
47 + 25
119
134
285
108
230
4
5
32
12
5
3
146 ?42 10
and 19 this was very frequent. In addition, case 19
showed mixed apnoea. The duration of apnoea was
variable, patient 19 showing long apnoea (mean duration
24.5 + 12, range 14-60 sec), patient 18 shorter apnoea
(mean duration 18.2 + 5, range 11-40 sec) and other
patients showing no apnoeas longer than 25 sec.
Haemoglobin Oxygen Saturation (Sa02)
All measurements were made in the supine position and
are given in Table 4. The mean awake saturation did not
differ significantly between the three groups. Oxygen
saturation fell in all subjects on falling asleep but the
mean asleep value was not significantly different between
the three groups. In all subjects except patient 18 (in
whom there was no REM sleep), the minimum oxygen
saturation was seen during REM sleep. The mean mini-
mum saturation value did not differ significantly between
the normal weight and obese subjects but was significant-
ly less in the hypothalamic-pituitary women (P<0.01
versus normals, P< 0.05 versus obese). The lowest values
were seen in the two hypothalamic-pituitary women with
numerous apnoeas (cases 18 and 19) and case 21 in whom
severe desaturation occurred during periodic breathing
without apnoea.
Time spent asleep with Sa02 less than 95 per cent was
similar in the three groups, but the hypothalamic-pitu-
itary group spent significantly longer time with Sa02 less
than 90 per cent (/><0.01). Two of these women had an
oxygen saturation less than 90 per cent for greater than 60
minutes during the night, case 17 without apnoea and
case 19 with apnoea.
There was no significant correlation in the 18 non-
apnoeic women between body index or body weight, and
total sleep time, total REM time, time awake or oxygen
saturations. The narrow distribution of the patients' ages
made it impossible to analyse the effect of age on sleep
and nocturnal oxygen saturation.
Discussion
We have previously reported that premenopausal obese
women have periods of oxygen desaturation but not
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 245
Table 4. Haemoglobin oxygen saturation values (%), number and types of apnoea during sleep in the women studied. Apnoea
index: no. of episodes of apnoea/hours of sleep.
Patient no. 1-9: postmenopausal normal weight
? no. 10-15: postmenopausal obese
? no. 16-21: hypothalamic-pituitary disorders.
Time
Patient Mean Mean Minimum <95%
no. awake asleep asleep (min)
Time Total
<90% no. of
(min) apnoeas
Type of apnoea Apnoea
central obst. mixed index
1
2
3
4
5
6
7
8
9
Mean
+ SEM
94
94
98
95
94
95.5
97
96
98
92
93
97
93
92
94
96
94
98
96 + 0.5 94 + 0.7
91
90
94
85
90
90
95
90
97
91 + 1
all
all
4
207
all
140
0
185
0
0.4
0.1
10
11
12
13
14
15
Mean
+ SEM
94
94
97
97
96
96
92
92
95
96
95
94
96 + 0.6 94 + 0.7
82
84
94
93
94
92
9 + 2
all
all
11
3
7
176
2
0.3
16
17
18
19
20
21
Mean
+ SEM
98
94
97
95
95
93
94
90
93
89
92
90
80
81
87
76
85
72
82
all
63
290
216
all
12
62
3
184
9
17
34
0
277
217
0
4
0
0
97
29
0
4
34
0
180
126
0
4
0
0
0
62
0
4
5.5
186
55
0.7
95 ?0.7 91 +0.8 80 ?2.3
apnoeic episodes during sleep[3]. The fall in oxygen
saturation seen in these women occurs predominantly
during REM sleep and is much less severe than that
reported in obese men of comparable weight[l]. We
found no abnormality of sleep-breathing patterns in
premenopausal women of normal weight, the minimum
oxygen saturation recorded in this group during sleep
being 95 per cent[3]. We now find that normal weight
postmenopausal women show a fall in oxygen saturation
when asleep and in 8 of the 9 women studied, the
minimum Sa02 measured was less than that seen in the
lean premenopausal women. These results are similar to
those reported by Block and colleagues[2]. Our obese
postmenopausal women similarly show lower oxygen
saturation during sleep. An increased amount of fat in the
chest wall and abdomen has the predictable mass loading
effect on the chest and diaphragm and leads to a reduction
in vital capacity, expiratory reserve volume and chest wall
compliance[6,7]. This effect is substantially magnified
when an obese subject lies flat[8,9], but posture alone
does not explain the findings in our patients because all of
the subjects, both obese and normal weight, were studied
only in the supine position. However, the mean awake
and mean asleep oxygen saturation values found in the
postmenopausal obese women are both significantly less
than the values we previously reported in similarly obese
premenopausal women (P<0.01). This finding supports
the hypothesis that increasing age is an important deter-
minant for the development of abnormal sleep-breathing
patterns[4].
Extremely obese subjects show an increased ventilatory
response to hypoxia but a decreased response to hyper-
capnia and this finding may explain the association of
alveolar hypoventilation during sleep at which time cen-
tral respiratory drive is decreased[10,12]. Obstructive
sleep apnoea syndrome is particularly common in obese
men but only a minority of such men develop the obesity-
hypoventilation syndrome (OHS) characterised by hypo-
ventilation, hypercapnia and hypersomnolence[13,14].
An increase of alveolar ventilation is seen in women
during pregnancy and during the luteal phase of the
menstrual cycle and this appears to parallel the increase
in plasma progesterone concentrations^ 5,16]. Some
patients with OHS have been treated successfully with
medroxyprogesterone, which probably has a direct stimu-
latory effect on the central respiratory centre[17]. The
246 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
(
J
(
I
differences in nocturnal oxygen saturation found by us
between the pre- and postmenopausal women support the
concept that plasma progesterone has a protective effect
on the maintenance of oxygen saturation during sleep.
We have previously proposed a relationship between
' hypothalamic function and respiratory control during
sleep[3]. We found that obese premenopausal women
with an absent prolactin response to insulin-induced
hypoglycaemia, a possible marker of abnormal hypotha-
lamic function, showed a significantly greater fall in
oxygen saturation during sleep than equally obese pre-
menopausal women with a normal prolactin response. In
the current study, the six women with proven hypotha-
lamic-pituitary disorders had a greater number of ap-
noeas and lower oxygen saturation than those older
subjects with simple obesity. Insulin tolerance tests were
not considered justifiable in the latter group in view of
their age. This difference cannot be explained by body
weight or body index because these differ little between
the two groups. The results from the women with hypo-
^ , thalamic-pituitary obesity show a variety of disorders of
sleep-breathing, in particular cases 18 and 19 whose
< i sleep-breathing patterns were typical of obstructive sleep
apnoea and case 22 whose oxygen saturation fell to 72 per
cent during REM sleep without apnoea. We consider that
^ centrally mediated relaxation of the larynx during sleep
leading to reversible obstruction may explain the obstruc-
tive apnoea seen in our patients. No evidence of an
obstructive lesion was found in any patient on direct
laryngoscopy; nor was there any narrowing from an
increase in adipose tissue distributed around the larynx,
which has been suggested as a cause of obstructive apnoea
in obese patients[18]. None of these women gave a history
of disturbed sleep, daytime somnolence or lethargy to
suggest such disturbances and the only reason for investi-
gation was the complaint of progressive weight gain
dating from the onset of their illness. The husbands of
cases 18 and 19 confirmed that the patients snored loudly
and were restless during sleep. Despite the heterogeneity
i' of the hypothalamic-pituitary group, the finding that
their breathing during sleep is more disordered than that
of obese women suggests the importance of central factors
for nocturnal respiratory control.
We conclude that a decrease in oxygen saturation and
apnoea occurs in postmenopausal women during sleep
irrespective of body weight but is significantly more
severe in women who become amenorrhoeic at a younger
age as the result of a hypothalamic-pituitary disorder, and
subsequently become extremely obese. These findings,
when considered with previous reports, suggest that the
sex, menstrual status, weight of the patient and hypotha-
lamic function, may individually be important factors
which influence the control of nocturnal breathing.
v
[ Summary
i
We have previously reported that obese women with
i , regular menstrual cycles show a fall in haemoglobin
oxygen saturation when asleep. It has been suggested that
the menstrual cycle, as well as body weight, may influ-
ence sleep-breathing patterns: we have investigated this
by studying respiration during sleep in nine postmeno-
pausal women of normal body weight, six postmenopau-
sal women who were obese and six women who had
become amenorrhoeic and obese following a hypothalam-
ic-pituitary disorder. All of the postmenopausal women
showed a decrease in oxygen saturation during sleep, the
fall being similar between the lean and obese groups. In
comparison, the women with hypothalamic-pituitary dis-
orders showed more disturbed sleep-breathing patterns
with a significantly greater fall in oxygen saturation
(P<0.01 versus lean postmenopausal P<0.05 versus
obese postmenopausal). Three of the hypothalamic-pitu-
itary women had frequent apnoeic episodes during sleep
and one had severe oxygen desaturation unassociated
with apnoea. We conclude that a patient's sex, menstrual
status, body weight and hypothalamic function are indi-
vidually important factors for the control of respiration
during sleep.
Acknowledgements
We thank Dr D. Scott and Dr P. Sheaff, of the Depart-
ment of Clinical Neurophysiology, for their help with the
study, Dr J. P. Monson, consultant endocrinologist, for
permission to study his patients and Miss T. Peterson for
secretarial work.
References
1. Block, A. J., Boysen, P. G., Wynne, J. W. and Hunt L. A. (1979)
New England Journal of Medicine, 300, 513.
2. Block, A. J., Wynne, J. W. and Boysen, P. G. (1980) American
Journal of Medicine, 69, 75.
3. Kopelman, P. G., Apps, M. C. P., Cope, T. and Empey, D. W.
(1983) British Medical Journal, 287, 859.
4. Cattershall, J. R., Claverley, P. M. A., Flenley, D. C. and
Douglas, N. J. (1984) Clinical Science, 67, 34P.
5. Guilleminault, C., Tilkian, A. and Dement, W. C. (1976) Annual
Review of Medicine, 27, 465.
6. Naimark, A. and Cherniack, R. M. (1960) Journal of Applied
Physiology, 15, 377.
7. Sharpe,J. T., Henry, J. P., Sweany, S. K. et al. (1964) Journal of
Applied Physiology, 19, 959.
8. Said, S. I. (1960) Annals of Internal Medicine, 53, 1121.
9. Craig, D. B., Wahba, W. M., Don, H. F. et al. (1971) Journal of
Applied Physiology, 31, 717.
10. Kaufman, B. J., Ferguson, M. H. and Cherniack, R. M. (1959)
Journal of Clinical Investigation, 38, 500.
11. Burki, N. K. and Baker, R. W. (1984) American Review of Respiratory
Disease, 129, 538.
12. Phillipson, E. A. (1978) American Review of Respiratory Disease, 118,
909.
13. Burwell, C. S., Robin, E. D., Whaley, R. D. and Bickelman, A.
G. (1956) American Journal of Medicine, 21, 81.
14. Lopata, M. and Onal, E. (1982) American Review of Respiratory
Disease, 126, 640.
15. Zwillich, C. W., Natalino, M. R., Sutton, F. D. and Weil, J. V.
(1978) Journal of Laboratory and Clinical Medicine, 92, 262.
16. Plass, E. D. and Oberst, F. W. (1938) American Journal of Obstetrics
and Gynaecology, 35, 441.
17. Lyons, H. A. and Huang, C. T. (1968) American Journal of Medicine,
44, 881.
18. Guilleminault, C., Van den Hoed, J. and Mitler, M. (1978) In
Sleep Apnoea Syndromes, pp. 1-12. (ed C. Guilleminault and W. C.
Dement.) New York: Alan R. Liss.
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
247
|
PMC005xxxxxx/PMC5371089.txt | Prospects for New Antibiotics: Keeping One
Step Ahead
DAVID GREENWOOD, DSc, MRCPath
Reader in Microbiology, Department of Microbiology and PHLS Laboratory, University
Hospital, Queen's Medical Centre, Nottingham
L
So many antimicrobial agents are now available to the
physician that it comes as something of a shock to recall
that 50 years ago there were none, save quinine and a
handful of other, generally rather toxic, antiprotozoal and
anthelminthic agentsfl]. So far as antibacterial agents
? ] were concerned, only the antisyphilitic arsenicals, ars-
phenamine (Salvarsan) and neoarsphenamine were avail-
able when Domagk's Prontosil (the activity of which was
later shown to be due to sulphanilamide) burst on the
scene exactly 50 years ago[2]. Since then, the prolifera-
tion of antibacterial agents has advanced to the stage
where an embarras de richesse exists, whereas expansion of
the armamentarium of antiprotozoal, anthelminthic,
antifungal and antiviral agents has progressed extremely
slowly.
/3-Lactam Antibiotics
The astonishing proliferation of antibacterial agents is
nowhere more evident than within the /3-lactam group.
Originally consisting of benzylpenicillin and a few closely
related derivatives, and later widened by the development
of semi-synthetic compounds and by the discovery and
exploitation of the cephalosporins, the group has blos-
\ somed to the extent that over 70 different /3-lactam
derivatives are now in clinical use worldwide, of which 40
?> are on the market in the UK (Table 1). Most of these
compounds are directly derived from 6-aminopenicillanic
acid or 7-aminocephalosporanic acid, but they include
some unusual molecular variants. For example, cefoxitin
carries a methoxy group on the (S-lactam ring, a feature
that confers stability to /3-lactamases; latamoxef also
exhibits this feature and additionally has an oxygen atom
in place of sulphur in the fused ring structure; and the /3-
f ? lactamase inhibitor, clavulanic acid, exhibits a completely
* novel structure that also features oxygen in the fused ring.
j. Present Progress
The most significant recent advance has been the devel-
opment of agents that overcome /3-lactamase mediated
resistance in coliform bacteria. The earliest of these
compounds, cefoxitin and cefuroxime, display striking
enzyme stability, but only moderate intrinsic activity.
More recently, a group of structurally related cephalo-
sporins has appeared in which stability to /3-lactamases is
combined with high intrinsic activity against a wide range
of bacteria. Three of these cephalosporins, cefotaxime,
ceftizoxime and ceftazidime, are available in the UK and
two others, ceftriaxone and cefmenoxime, are on the
market elsewhere; a structurally unrelated /3-lactam
agent, the oxa-cephem, latamoxef, shares similar proper-
ties and is generally considered together with this group.
The appearance of these highly active compounds
undoubtedly represents a useful advance in the treatment
of infection, particularly in those patients prone to sys-
temic infection with Gram-negative rods. Moreover,
these compounds, and in particular cefotaxime and cefti-
zoxime, display outstanding activity against the common
causes of meningitis, including neonatal meningitis, and
this may represent an important area of use. However,
the impressively enhanced activity of these antibiotics
against Gram-negative bacteria has been achieved at the
expense of somewhat reduced antistaphylococcal activity,
and none of these agents possesses useful activity against
Streptococcus faecalis (Table 2); certain species of entero-
bacteria, notably Enterobacter cloacae, readily develop re-
sistance^]. Furthermore, only ceftazidime exhibits
therapeutically useful anti-pseudomonal activity, and
only latamoxef covers adequately for anaerobes of the
Bacteroides fragilis group. Thus, all of these agents possess
notable gaps in their antibacterial spectrum and, indeed,
the amoxycillin/clavulanic acid combination, which em-
braces staphylococci, enterococci and anaerobes, covers a
broader range of organisms.
A few other properties serve to distinguish between the
new cephalosporins; cefotaxime is susceptible to hepatic
enzymes that may reduce its activity in the body, and
latamoxef (as well as cefmenoxime) possesses the methyl-
tetrazole side chain which, in several cephalosporins, is
associated with hypoprothrombinaemia[4]; ceftriaxone
exhibits the unusual property of an extremely long serum
half-life (associated with high protein binding) and is
preferentially excreted in bile.
Future Prospects
Judging from the number of new compounds still being
described in the literature, the scope for developing new
cephalosporins is far from exhausted. However, the most
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 231
L
Table 1. /3-lactam agents in clinical use throughout the world
azidocillin
clometocillin
penethamate hydriodide
(penethacillin)
penimepicycline
nafcillin
oxacillin
dicloxacillin
bacampicillin*
pivampicillin*
talampicillin*
metampicillin
Benzylpenicilhn and its oral and long-acting derivatives
benzylpenicillin*
phenoxymethylpenicillin *
phenethicillin*
penamecillin*
propicillin
Antistaphylococcal penicillins
methicillin*
cloxacillin*
flucloxacillin*
Broad-spectrum penicillins
ampicillin*
amoxycillin*
ciclacillin*
amoxycillin/clavulanate*
epicillin
Antipseudomonal /3-lactam agents
carbenicillin* peperacillin*
ticarcillin* apalcillin
azlocillin* sulbenicillin
mezlocillin* carfecillin*
Oral cephalosporins
cephalexin* cefadroxil*
cephradine* cephaloglycin
cefaclor* cefatrizine
/3-lactamase-susceptible injectable cephalosporins
cephalothin* cephamandole*
cephaloridine* cephacetrile
cephazolin* cefapirin
/3-lactamase-stable cephalosporins
cefuroxime* ceftizoxime*
cefoxitin* ceftriaxone
cefotaxime* cefmenoxime
ceftazidime* cefotetan
* = on the market in the UK; t = strictly an oxa-cephem.
procaine penicillin*
benzathine penicillin*
benethamine penicillin*
clemizole penicillin
hydrabamine penicillin V
diphenicillin
(ancillin)
mecillinam*
pivmecillinam*
hetacillin
fibracillin
penimocycline
carindacillin
cefoperazone
cefsulodin*
pivalexin
cefroxadine
cefazedone
ceftezole
cefotiam
cefmetazole
latamoxeff *
Table 2. Activity in vitro of new cephalosporins against some
common bacterial pathogens, including those commonly in-
criminated in bacterial meningitis. R = resistant.
Minimum inhibitory concentration (/xg/ml)
Organism Cefotaxime Ceftizoxime Ceftazidime Latamoxef
Staph, aureus 2 2 4 8
Sir. faecalis R R R R
Enterobacteria 0.06 0.03 0.12 0.12
Ps. aeruginosa 16 32 2 16
B. fragilis 16 16 16 4
N. meningitidis 0.01 0.01 0.02 0.01
Str. pneumoniae 0.02 0.02 0.2 0.5
H. influenzae 0.01 0.01 0.06 0.06
intriguing innovations concern (3-lactam agents that
exhibit fundamental changes in the central part of the
molecule, rather than simple side chain modifications.
Four compounds have received particular attention: az-
treonam, one of a family of compounds known collec-
tively as monobactams, in which the (3-lactam ring is not
associated with another fused ring system; imipenem, a
carbapenem derivative in which carbon replaces the
sulphur of the thiazolidine ring of penicillins; temocillin,
a penicillin which (like cefoxitin) carries a methoxy group
on the /3-lactam ring; and sulbactam, a penicillanic acid
sulphone which, like clavulanic acid, possesses little in-
trinsic antibacterial activity, but inhibits most bacterial (3-
lactamases.
These four compounds exemplify two diametrically
opposed approaches to antimicrobial chemotherapy: nar-
row-spectrum, targeted therapy (aztreonam, temocillin)
and the ultra-broad spectrum, cure-all approach (imi-
penem, sulbactam/ampicillin) (Table 3). Imipenem, in-
deed, exhibits the broadest antibacterial spectrum of all (3-
lactam antibiotics and combines this spectrum with
impressive intrinsic activity and /3-lactamase stability.
Ironically, however, the compound is rapidly inactivated
in the body by a renal dehydropeptidase and has to be
administered with a dehydropeptidase inhibitor[5],
Quinolones
It is perhaps a tribute to the persistence of the pharma-
ceutical houses that, after years of research effort that
yielded compounds offering little or no improvement over
232 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
Table 3. Comparative activity in vitro of some novel (3-lactam
agents.
Minimum inhibitory concentration (/ig/ml)
Sulbactam/
Organism Aztreonam Temocillin Imipenem ampicillin*
Staph, aureus R
Str. faecalis R
H. influenzae 0.5
Enterobacteria 0.06
Ps. aeruginosa 4.0
B. fragilis R
*expressed as ampicillin activity
R 0.02 2.0
R 2.0 1.0
0.5 0.06 1.0
4.0 0.12 4.0
R 4.0 R
R 0.12 2.0
the parent substance, nalidixic acid, they finally succeed-
ed in devising a derivative that displayed greatly im-
proved spectrum and intrinsic activity. This compound
was norfloxacin, and its discovery has naturally given rise
to a family of closely related compounds, at least one of
which, ciprofloxacin, offers a further improvement in
activity.
The new quinolones, and ciprofloxacin in particular,
display a spectrum of activity rivalling, or even surpass-
ing, that of the new (3-lactam agents (Table 4); they are
Table 4. Comparative activity in vitro of nalidixic acid, norflox-
acin and ciprofloxacin against selected bacterial pathogens.
S/nal = sensitive to nalidixic acid; R/nal = resistant to nalidixic
acid; NT = not tested.
. :
Minimum inhibitory concentration (/ig/ml)
Nalidixic
Organism acid Norfloxacin Ciprofloxacin
Staphylococci 32 1.0 0.5
Streptococci >32 8.0 1.0
Enterobacteria (S/nal) 2.0 0.06 0.02
Enterobacteria (R/nal) 256 0.5 0.25
Ps. aeruginosa 64 0.5 0.25
Bacteroides spp. >32 16 2.0
L. pneumophila NT 0.12 0.06
> M. tuberculosis NT 8.0 1.0
quite well absorbed when administered orally, have a
half-life of 3-4 hours, and are excreted in high concentra-
tion into the urine. These properties suggest a valuable
role for the quinolones in urinary tract infection and
norfloxacin is likely to be marketed solely for this indi-
cation. Manufacturers of other quinolones have their
sights on wider indications, but blood levels are not high
(c. 1-4 /tg/ml, depending on the compound and the dose)
and this may insufficiently exceed the minimal inhibitory
concentration of some organisms, notably staphylococci,
streptococci and Pseudomonas aeruginosa to prevent the
development of quinolone resistance, which emerges
readily. However, on the credit side, these drugs appear
to be extremely well distributed in the body and may be
concentrated within cells[6], factors that may be crucial in
certain infections. Furthermore, parenteral formulations
are becoming available which may provide improved
blood levels when needed.
It is still too early to assess the place of these interesting
compounds; meanwhile, their appearance has provoked
the drug industry into renewed interest in these sub-
stances and yet more derivatives are waiting in the wings.
Other New Antibacterial Agents
Although a trickle of new aminoglycosides continues to
appear (amikacin and netilmicin in the UK, sissomicin
and dibekacin elsewhere), none offers substantial advan-
tages over gentamicin or tobramycin, except in those
units troubled by gentamicin-resistant organisms. Other
new derivatives, such as fortimicin B, and various related
compounds are under development. Little of note has
emerged from the other major antibiotic groups, although
macrolides continue to attract some attention. Josamycin,
a macrolide described over 20 years ago, is being actively
promoted in several countries, but not, as yet, in the UK.
Progress in the development of truly novel antibacterial
agents has been extremely slow and such compounds as
have been described do not appear to represent major
advances. Perhaps the most interesting is the new glyco-
protein, teicoplanin, a distant relative of vancomycin,
with which it shares a similar narrow spectrum; however,
teicoplanin appears considerably more active against
staphylococci and streptococci[7]. Other novel com-
pounds that deserve mention are mupirocin (pseudo-
monic acid) and bicozamycin. Mupirocin is an antibiotic
obtained from Ps. fluorescens which, like teicoplanin,
exhibits a spectrum virtually restricted to Gram-positive
cocci. It is extensively metabolised when administered
systemically, but may be of value in the topical treatment
of staphylococcal and streptococcal skin infections[8] or
for the elimination of staphylococci from nasal carriers. In
contrast, the spectrum of bicozamycin is confined to
enteric Gram-negative bacilli. Even against these organ-
isms the activity is fairly feeble, but oral administration
leads to sufficient concentrations in the lumen of the gut
(the drug is not absorbed) to eliminate enteric pathogens,
and satisfactory trials have been reported in the treat-
ment^] and prophylaxis[10] of traveller's diarrhoea.
Prospects of Non-Antibacterial Agents
In stark contrast to the abundance of therapeutically
useful antibacterial agents, the choice of chemotherapeu-
tic alternatives for non-bacterial infection is severely
limited. Antiviral agents in particular are still in their
infancy, although the appearance of the anti-herpes drug,
acyclovir, has revived hopes of effective antiviral therapy
and a number of interesting compounds are under devel-
opment^ 1].
Progress in antifungal agents has been largely restrict-
ed to the imidazoles. Most of these compounds are
suitable only for topical use, but ketoconazole, which is
well absorbed when administered orally, has proved
useful in systemic mycoses. Recently, attention has
turned to triazoles, one of which, itraconazole, seems
particularly interesting, as experiments in animals sug-
gest that it may be safe and efficacious in aspergil-
losis^].
Journal of the Royal College of Physicians of London Vol. 19 No.4 October 1985 233
Prospects for new antiprotozoal agents are rather
gloomy. Despite the availability for many years of several
excellent anti-malarial agents, the inexorable spread of
resistance, notably resistance to chloroquine in Plasmo-
dium falciparum, has seriously undermined their useful-
ness. Years of endeavour at the Walter Reed Army
Institute of Research in Washington has yielded one
important new antimalarial, mefloquine, but it is feared
that resistance to this drug will also emerge readily[13], A
few other novel antimalarials are under study, one of
which, qinghaosu (artemisinine) has been used as a
herbal remedy in China for centuries[14].
Protozoal diseases such as amoebiasis, giardiasis and
trichomoniasis have yielded to 5-nitroimidazoles (metron-
idazole and its relatives). Resistance has not yet emerged
as a major problem and the therapeutic future of these
drugs thus seems secure. Among other important proto-
zoal infections of man, leishmaniasis still has to be treated
with antimonials and African trypanosomiasis with arsen-
icals. However, two drugs, nifurtimox and benznidazole,
are now available for the previously untreatable Chagas'
disease (South American trypanosomiasis), although both
have toxicity problems.
Chemotherapy of helminthic infections has benefited
from the economic importance of similar diseases in
animals and several important anthelminthic agents have
found their way into medical use via the veterinary route.
Such compounds include the benzimidazoles, thiabenda-
zole and mebendazole (the first really broad-spectrum
agents for intestinal worms) and praziquantel, a major
advance in the treatment of trematode infections, includ-
ing schistosomiasis, and also of tapeworm infections.
This fruitful search for medical anthelminthics among
veterinary products is continuing: another veterinary
benzimidazole derivative, albendazole, is showng prom-
ise in hydatid disease[15], and a new anthelminthic
antibiotic that is active against a wide variety of animal
nematodes (and, curiously, arthropods), ivermectin[16],
appears to be of value in onchocerciasis and other filarial
infections[17].
It is ironic that developments in the treatment of
infections that affect hundreds of millions of people
throughout the Third World should depend on the eco-
nomic importance of animals, but that seems the harsh
reality of the market place. Certainly, what is needed on a
global scale is not yet another new cephalosporin, but
agents active against non-bacterial pathogens.
This article is based on a paper read at the Conference on
Infectious Diseases held at the Royal College of Physicans in
May 1985.
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Greenwood.) London: Bailliere Tindall.
2. Domagk, G. (1935) Deutsche Medizinische Wochenschrift, 61, 250.
3. Sanders, C. C. (1984) Journal of Antimicrobial Chemotherapy, 13, 1.
4. Smith, C. R. and Lipsky, J. J. (1983) Journal of Antimicrobial
Chemotherapy, 11, 496.
5. Kahan, F. M., Kropp, H., Sundelof, J. G. and Birnbaum, J.
(1983) Journal of Antimicrobial Chemotherapy, 12, (Suppl. D,) 1.
6. Easmon, C. S. F. and Crane, J. P (1985) Journal of Clinical Pathology,
38, 442.
7. Williams, A. H. and Griineberg, R. N. (1984) Journal of Antimicro-
bial Chemotherapy, 14, 441.
8. Sutherland, R., Boon, R. J., Griffin, K. E., Masters, P. J.,
Slocombe, B. and White, A. R. (1985) Antimicrobial Agents and
Chemotherapy, 27, 495.
9. Ericsson, C. D., DuPont, H. L., Sullivan, P., Galindo, E., Evans,
D. G. and Evans, D. J. (1983) Annals of Internal Medicine, 98, 20.
10. Ericsson, C. D., DuPont, H. L., Galindo, E. et al. (1985)
Gastroenterology, 88, 473.
11. De Clercq, E. (1985) In The Scientific Basis of Antimicrobial Chemo-
therapy, p. 155. (ed D. Greenwood and F. O'Grady.) Cambridge
University Press.
12. Van Cutsem, J., Van Gervan, F., Van de Ven, M., Borgers, M.
and Janssen, P. (1984) Antimicrobial Agents and Chemotherapy, 26,
527.
13. Peters, W. (1985) In The Scientific Basis of Antimicrobial Chemotherapy,
p.95. (ed D. Greenwood and F. O'Grady.) Cambridge University
Press.
14. Bruce-Chwatt, L. J. (1982) British Medical Journal, 284, 767.
15. Morris, D. L. (1983) Journal of Antimicrobial Chemotherapy, 11, 494.
16. Campbell, W. C., Fisher, M. H., Stapley, E. O., Albers-Schon-
berg, G. and Jacob, T. A. (1983) Science, 221, 823.
17. Aziz, M. A., Diallo, S., Diop, I. M., Lariviere, M. and Porta, M.
(1982) Lancet, 2, 171.
234 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
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PMC005xxxxxx/PMC5371090.txt | Dr Shephard Thomas Taylor
Besides his two important books, described in the next
paragraph, the College has all the surviving papers of Dr
Shephard Thomas Taylor, 1840-1936. His father was a
Norfolk farmer, of Dilham Hall, near Hippisburgh, an
early expert on farming machinery and a skilled carver of
ivory.
y", Dr Taylor kept a diary all his life, in a legible copper-
| plate hand. He was apprenticed to Dr F. Bateman of
Norwich and worked in the Norfolk and Norwich Hospi-
tal, and subsequently went to King's College Hospital in
London. In 1927 and 1930 he published the volumes
describing his medical education, as The Diary of a Norfolk
and Norwich Hospital Student, 1858-1860, and The Diary
of a Medical Student, 1860-1864. They are the best
descriptions of their subject, profusely illustrated with
photographs, and are most amusing. They were complet-
ed by his postgraduate period in Berlin in Reminiscences of
Berlin during the Franco-Prussian War 1870-71; interest-
ing, but written in 'journalese', which he thought proper
for books. This is not in the Library, but is in the London
Library.
He was later on physician to the Norfolk and Norwich,
and the Jenny Lind, Hospitals from about 1880 to 1910,
and Medical Officer of Health, one of his primary
interests: on p.l of the book on his apprenticeship, he
describes how the first thing he did when allotted his room
was to measure it to see if it came up to standard volume
and floor-area (it did not).
As a youth he was interested in a great many things,
became a highly competent botanist, collected epitaphs in
churchyards, got into mischief and never wasted a mo-
ment. While at King's, which was then in Portugal Street
off the Strand, he had lodgings near King's Cross and
occupied himself in 1863 by sketching the iron coal hole
lids in the London pavements. He collected 150 different
designs seen between his lodgings and the hospital, taking
in Portland Place to Gray's Inn Road. This unique
collection of Victoriana was eventually brought to the
attention of the editor of The Ironmonger in 1929. That
journal carried a short account of the work and then
published all the drawings in a pamphlet aptly titled
Opercula, (London coal-hole Plates, sketched by Aesculapius
Junior), a copy of which is in the library.
He left a fair copy of all the lectures he gave at the
Norfolk Students Society, bound in a volume, written in
beautiful handwriting, in the most unfortunate 'literary'
English, and other MS volumes of lists of plants, medical
cases, etc. When he had published the student diaries in
1930 he destroyed all the originals, except the current
volume, probably because they contained notes of the
pretty girls he saw (one survives from the age of 18, and
another at 85!). The last volume, 1895-1926, is so
interesting that it looks as though we lost a heritage as
valuable as Parson Woodforde's diary.
He was a first-class linguist, and read widely in French,
German, Italian, Latin and Greek, with most interesting
comments: e.g. Erasmus' Colloquies 'most delightful read-
ing, abounding in inimitable wit'; 'but a little coarse here
and there, which adds to their attraction, although per-
haps I ought not to say so!'. Of Carlyle's Sartor Resartus,
almost the most revered book of his day, he observed:
'one of the most tedious and exasperating books I have
ever read' (23rd December, 1924); and of Tristram
Shandy, which I for one would include in the top ten
essential books: 'clever and witty, but tedious reading,
being much ado about nothing' (16th September 1924).
He played the cither and taught Edith (?a servant) to play
it: he also taught Katie, the cook, German.
He retired to The Mount, Edgefield, near Holt, added
a large area of woods and cleared the brambles and weeds
with his own hands at 90. It was characteristic of him that
he recorded the exact number of dock plants he dug up
and burned each day. The last volume of the dairy gives a
clear picture of an impressive old man. When the editor
of The Ironmonger went to see him in 1929 he wrote of
hearing 'light and rapid footsteps in the hall' and being
greeted by 'a small elderly gentleman with an almost
imperceptible stoop and a merry twinkle in his eye',
adding that he 'had met a man who was infinitely more
remarkable than his hobby'.
C. E. Newman
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
213
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PMC005xxxxxx/PMC5371091.txt | Editorial
It is easy to make a fairy story from the history of medicine with every
ending happy and conclusive. The sober truth is that the brightest
expectations of a discovery are always dulled by experience. The
dawn of bacteriology was bright enough when bacteria were identified
as specific causes of disease. With the enemy pinpointed, it only
needed a magic bullet to shoot them dead. Years later the bullet of
penicillin was hailed as making lust safe for democracy and sounding
the death knell of venereology as a specialty. The discovery of animal
and insect vectors of human disease was another triumph; kill the
vector and the disease disappears. Yet anopheline mosquitos still fly
and the snails of the Nile positively flourish with the building of the
High Dam at Aswan.
We have learnt the hard way that pathogens are not sitting targets.
They readily counter initially successful attack and, particularly with
viruses, can appear in new pathogenic forms. The disconcerting
ability of P. falciparum to render every therapeutic attack null and void
is pointed out in these pages by Dr Lucas. He rightly stresses the need
for constant surveillance and research if infectious disease is to be
continuously controlled throughout the world. In the same way the
College's report (in the January issue of the Journal) stressed the
present lack of physicians trained in infectous diseases.
It is important that the public should be made aware of these
matters of public health. A false sense of security engendered by past
success may lead to alarming drops in the take-up rates of inoculation
programmes. The public's attitude towards infectious diseases does,
in a long and complicated run, matter in terms of financial provision
for research in the subject and the maintenance of the extensive
laboratory facilities required for the swift detection of new threats and
the adjustment of remedies for the familiar.
It is always difficult to produce a convincing argument for expendi-
ture to face a threat. Publicity likes to comment on a disaster and to
search out why funds have not been available before. Equally,
publicity for an advance in the control of infectious disease can leave
the impression that nothing more needs to be done in that particular
corner of the field, when all may have to be done afresh.
Perhaps it is the huge success of antibiotics that has made us so
complacent in our attitude to infections and somewhat cavalier in our
prescribing. That complacency may well be enhanced by the word-
smiths. 'Hospital gangrene' was, rightly, a fearful term. It certainly
made patients and doctors alike acutely aware of the perils of hospital
admission. However respectable its etymology, nosocomial is far too
bland a term for hospital-based infections. The hospital's contribu-
tion to the population of antibiotic-resistant bacteria is well known.
But our newest hospitals harbour risks in their kitchens and ubiqui-
tous air conditioning. Given the lowered resistance of the patients
they house, hospitals give the best of opportunities to opportunist
infections.
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 201
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PMC005xxxxxx/PMC5371092.txt | Medical Accountability
SIR DOUGLAS BLACK, MD, FRCFj Emeritus Professor of Medicine,
University of Manchester, Past President of the Royal College of Physicians
j ^ The third in the College's new series of one-day symposia
on 'Controversial Issues in Medicine' was held on June
5th under the above title. One speaker, Mrs M. Saunders
from the Public Consultation Unit of the GLC, referred
to the wider social responsibilities of doctors; and within
the title the discussion could certainly have included
examples of this, such as Tudor Hart's concept of the
'community general practitioner', making specific use of
the opportunity given him by a relatively defined popu-
lation within his reach. But in the event, discussion
focused on the accountability of the individual doctor to
his patient. As usual in such discussions, the large
number of episodes in which a reasonable process of care
leads gently to a satisfactory outcome was not given much
prominence; attention was concentrated on the problem
cases in which things go wrong. A bad outcome may of
course be inherent in the clinical situation; it may arise
from a misreading of the complex uncertainties of disease;
it may represent idiosyncracy in the reaction of a patient,
or in the performance of a doctor. More seriously, it can
* arise, as Dr Gwyn Williams pointed out, from 'sloppy
medicine'; this may be the equivalent for the physician of
ham-handed technique for the surgeon, whose disasters,
when they occur, are more likely to be conspicuous.
The initiative for the conference, with support from the
King's Fund, had come from the group 'Action for the
Victims of Medical Accidents', commonly shortened to
AVMA. This group was set up after public interest had
been stimulated in 1980 by the showing of the TV drama
'Minor Complications', by Peter Ransley, now President
of AVMA, who attended the conference. It was appropri-
ate that the first and longest paper should be given by Mr
A. Simanowitz of AVMA. He described cases in which it
was fairly clear that either the treatment given, or
sometimes the withholding of appropriate treatment, had
: ? been the main cause of a patient's deterioration in health.
It had often proved difficult to extract the information
required to obtain redress, and he appealed to doctors to
change their present attitude, which he looked on as
commonly too secretive, towards one of 'frank disclo-
sure'. He was aware that this might carry some cost, both
financial and to reputation; but suggested that our profes-
sion would gain in moral stature by so doing. He
compared the current defence subscriptions paid by
doctors with that paid by solicitors in the UK, which he
quoted as ?1,200 p.a.?still a small sum in comparison
with American rates for doctors. He suggested that
greater openness about clear-cut mishaps might actually
save us from going further along the American road to
very high defence costs; another possibility was a 'no
fault' system. In the brisk discussion that followed, Dr P.
Harvey suggested a role for the specialist societies, which
might set up panels to review treatment given by their
colleagues, perhaps those at some distance. Dr G. H.
Hall suggested that there might be an excess of masochists
and a deficiency of sadists among those doctors likely to
attend this kind of conference. The participation of
administrators in dealing with complaints was criticised,
especially if they tried to prevent discussion between
patients or relatives and the responsible doctor; but Mr
Wall reminded us of the frequent, and indeed statutory,
involvement of the health authority. Miss Katharine
Whitehorn asked if there were anything to be learnt from
the private sector, where perhaps there was less adminis-
tration and more time; but no quantitative answer was
forthcoming, though the private sector was not immune
from mishap. Dr David Sumner pointed out that the
word 'negligence' carried unfortunate overtones for doc-
tors, whereas for lawyers it was simply a term of art; and
Mr Simanowitz agreed it should be 'de-mystified'. It
became clear that in some regions senior doctors were
being given the useful responsibility of assisting the
Regional Medical Officer to deal with complaints.
Next, Dr Peter Reynell gave what I shall describe, in
terms of high praise, as a very physicianly paper on the
importance, and also the problems, of 'information given
to patients'. It was very possible to alarm patients
needlessly by forcing information on them which they did
not want or need; and on at least one occasion he had
been reproached by a widow for doing so. It was worth
consulting the spouse of a patient about how much the
patient should be told. Referring to the Siddaway case,
his own view was that patients should be warned of likely
dangers, but not of remote ones (Mr Simanowitz had also
referred to this case, declaring his conviction that if the
patient had known how the operation would turn out, she
would have refused it; it occurred to me that, if the
surgeon had had equal foresight, he would not have done
it). Because of the great diversity among patients and
their illnesses, Dr Reynell did not favour a 'bill of rights'
for giving information to patients. Of course the doctor
had an ethical (not a legal) obligation to give appropriate
information; but 'appropriate' was not necessarily 'com-
plete', even if that were practically possible. In summary,
what he wanted to see between patient and doctor was 'a
system of trust, not a set of rules'.
Sir John Walton gave a crystalline account of the
mechanisms available to the General Medical Council, in
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 203
dealing with complaints made against doctors, or doctors
convicted in the criminal courts. These are also clearly set
out in the GMC Blue Book, which has recently under-
gone important revision. Questioned as to the part which
patients could play in proceedings relating to the conduct
of doctors, Sir John stated that formal proceedings had to
be initiated with a statutory declaration by the complain-
ant; and thereafter they would be called as witnesses, and
examined and cross-examined, as in a court of law.
Dr A. M. Dawson reminded the meeting that the
object of medical activity was to improve the care of
patients, and for that they were accountable to themselves
and to their colleagues. Litigation was necessary in
certain cases, but its contribution to patient care was
minimal, and might even be negative if it were to
promote unnecessary investigation and defensive medi-
cine generally. That all consultants were equal in status
created the possibility for genuine peer review; and this
should, in his view, be made mandatory, and a condition
of accepting a hospital for training purposes. Over the
past 30 years, the power of medicine to do good had
greatly increased, but so had the possibility of doing
harm, whether by ill-judged action or by failure to take
the correct action. In discussion, the idea of selecting
cases 'with a lesson' was raised; but our President
commended considering cases as they arose, since there
was no case from which nothing could be learned.
In considering the responsibility of doctors towards
their nursing colleagues, Miss E. Winder described the
changing status and responsibility of nurses. While some
retained the traditional attitude of subordination to medi-
cal staff, nurses were really entitled to a role in which,
while certain aspects of their work were still subject to
medical supervision, the area of nursing autonomy, for
example in special care units, was increasing. It was very
important that nurses should acquire these particular
skills while at the same time conserving the basic nursing
responsibility of caring for the patient in the full sense of
the word. In a spirited intervention, Dr Ian Munro
maintained that the duties laid upon us arose from our
moral, ethical and professional responsibility, and should
not require legal enforcement, nor appearance before the
disciplinary mechanisms of the GMC.
Dr B. Pentecost described some of the ways in which
complaints arising in hospital practice could be handled.
The matter could be discussed informally with the
patient, though an administrator should be kept in touch
with this; if the complaint was not satisfactorily dealt with
in this way, it could be made formally in writing to the
health authority, and considered by the Regional Medi-
cal Officer. There was in the background always the
possibility of legal action, but from time to time patients
or relatives would affirm convincingly that they did not
wish to damage a doctor, but were only concerned to
prevent a similar mistake happening to someone else. To
meet this case, the Joint Consultants Committee set up a
few years ago what has been described as a 'second
opinion procedure'. Over the years, this College has been
concerned with about 100 such exercises, in which a
consultant from another region discusses the case both
with the complainant and with the consultant concerned,
with the object of reassuring the complainant, and report-
ing the result to the RMO. In about half the cases, there
has been a fault of communication, which might be in the
manner more than in the actual matter. Some doctors
clearly evaded discussions with patients or relatives. On
the other hand, there were patients with whom communi-
cation was difficult, because they themselves were in a
difficult situation, as members of 'a sensitised family',
e.g. a family with an elderly dependent parent, or a
handicapped child.
Sir Antony Buck, MP, who had chaired the Select
Committee which had recommended additional com-
plaints procedures, to which the 'second opinion pro-
cedure' was the profession's response, said
straightforwardly that what had happened was somewhat
different from what he and his committee had had in
mind.
Certain threads ran through the day's proceedings?
the unpredictability of outcomes; the tendency of doctors
to be less than forthcoming when asked to criticise their
colleagues; the vital importance of communication; and
the public and political feeling that, in spite of the various
mechanisms for handling complaints, some problems
remained. The occasion was educational and not judg-
mental; and I felt that good had been done by bringing
out the range of attitudes as between doctors, lawyers and
pressure groups. Our visitors may have accepted the plea
that some bad outcomes are inevitable, and do not imply
medical shortcomings; we were made aware of the
strength of feeling that we may not yet have done enough
to protect the public, and, indeed, our own profession,
either from isolated scandalous happenings, or from
persistent malpractice.
Occasionally in the past I have had an odd feeling that
in some quarters the flame of love for the patient was
fuelled by hate for the doctor. I did not suffer from a
recurrence of that feeling at this conference. We were
made soberly aware of a very real problem, not perhaps
for the first time; but I came away with the notion that we
should be doing more about it than we are. For example,
I was shaken to hear that the 'second opinion procedure'
may take two to three years to complete?almost as long
as litigation. Even if we do no more than speed up a
procedure which is within our own hands, we shall have
done something useful.
204
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
|
PMC005xxxxxx/PMC5371093.txt | Dr John Radcliffe, Court Physician, and the
Death of Queen Anne
ALEX SAKULA, MD, FRCP
Lately Consultant Physician, Redhill General Hospital, Surrey
Dr John Radcliffe's generosity to the University of
Oxford has ensured that his name remains perpetuated in
such institutions as the Radcliffe Infirmary, the Radcliffe
Observatory, the Radcliffe Camera and the Radcliffe
Library. In addition, his bequests included the Radcliffe
Scholarship and Prize, the Radcliffe Travelling Fellow-
. ships as well as important contributions to University
College, Oxford, the Royal College of Physicians, Lon-
don, and St Bartholomew's Hospital, with all of which he
was associated.
Such philanthropy was made possible by the fortune
which Radcliffe amassed from his highly successful prac-
tice as a London consulting physician. Towards the end
of his life, his estate was valued at more than ?80,000, a
considerable sum in seventeenth century England. Being
a medical adviser to royalty must have contributed to
Radcliffe's reputation as the leading physician in London
society. Yet his relationships with his royal patients were
by no means always harmonious and this was especially
so with Queen Anne.
Doctor John Radcliffe (1652-1714)
John Radcliffe (Fig. 1) was born in 1652 in Wakefield,
Yorkshire, where his father was Governor of the House of
Correction. He went up to University College, Oxford, in
the plague year 1665, graduated BA in 1669 and then
held a Fellowship at Lincoln College from 1670 to 1677.
He read medicine, qualifying BM in 1675 and DM in
1682. From 1675 he practised successfully in Oxford but
in 1680 he decided to move to London[l].
Radcliffe settled in Bow Street, Covent Garden (his
garden backed on to that of the portraitist, Sir Godfrey
Kneller) and soon established himself as one of the
, leading physicians in the capital. On the death of Dr
Richard Lower (1631-91), famed for his pioneer experi-
ments in blood transfusion, Radcliffe took over his prac-
tice. In 1687 Radcliffe was elected FRCP but his relations
with the College of Physicians were troubled and in 1689
he was expelled because he insisted on writing his direc-
tions in Latin, but he was soon readmitted on payment of
a fine. He became a Governor of St Bartholomew's
Hospital in 1690[2].
Radcliffe was no great scholar and made no important
original medical discoveries. His fame lay in his being a
sound practical physician, who inspired confidence in his
patients, numbered amongst whom were Sir Isaac New-
ton, Alexander Pope and Jonathan Swift. They seemed to
enjoy his witty conversation and forthright personality.
Sir Richard Steele wrote of him in The Tatler[3]\
You are not so ignorant as to be a stranger to the
character of Aesculapius as the patron and most suc-
cessful of all who profess the Art of Medicine. But as
most of his operations are owing to a natural sagacity
or impulse, he has very little troubled himself with the
Doctrine of Drugs, but has always given Nature more
room to help herself than any of her learned assistants,
and consequently has done greater wonders than is the
power of the Art to perform, for which reason he is half
Fig. 1. Dr John Radcliffe. (Oil painting from the studio of Sir
Godfrey Kneller, 1712. Courtesy the Treasurer of the Royal
College of Physicians of London.)
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 255
deified by the people and has even been courted by all
the world.
Radcliffe's coffee-house consultations were conducted
at the Bull's Head Tavern. One of his typical prescrip-
tions is his 'Receipt for a Cough'[4].
Take an ounce of Consarve of Roses
An ounce of Sirrup of Clove Gilly Flowers
A teaspoon of Venice Treacle
A teaspoon of Flower of Brimstone.
Take a teaspoon night and morn.
Drink a glass of Milk Water after it and
keep warm all the time you take it.
If consumptive, drink Asses Milk instead of Milk
water.
The advertisement for 'Doctor Radcliffe's Bitter' read:
'Doctor Radcliffe's Royal Tincture or the General Recti-
fier of the Nerves, Head and Stomach. It corrects all
irregularities of the Head and Stomach by hard drinking
or otherwise'[5],
Despite Radcliffe's tendency to be 'perpetually at war
with his professional brethren'[6], the profession must
have held him in high esteem. Dr Richard Mead (1673-
1754) said that Radcliffe '. . . was deservedly at the head
of his profession, on account of his great medical penetra-
tion and experience'[7].
Dr James Monro (1680-1752), in his Harveian Ora-
tion in 1737, described Radcliffe as 'the Aesculapius of
the age'.
With his increasing wealth, Radcliffe acquired estates
in Buckinghamshire, Yorkshire and Northamptonshire
and moved to a fine house in Bloomsbury Square, where
his paintings included some by Rembrandt and Rubens.
He later purchased a house by the river at Hammersmith
and in 1713 a mansion in the village of Carshalton,
Surrey, 12 miles from London (Fig. 2).
Radcliffe never married, although in 1709, in his fifty-
eighth year, he fell in love with a lady much younger than
himself. He was lampooned in The Tatler by Sir Richard
Steele as 'the mourning Aesculapius . . . the languishing
hopeless lover of the divine Hebe, the emblem of youth
and beauty'[8].
In 1695, Radcliffe refused the offer of a baronetcy,
since he had no one to inherit. A confirmed Jacobite and
violent Tory, he was Member of Parliament for Bramber
from 1690 to 1695 and for Buckinghamshire from 1713 to
1714.
Towards the end of his life, Radcliffe transferred his
patients to the younger, brilliant Dr Richard Mead and
also handed over to him the Gold-Headed Cane, which
was to become the emblem of five other royal physicians.
It is now displayed at the Royal College of Physicians of
London[9].
Radcliffe and William III (1650-1702)
In 1689, William III (Fig. 3) became ill with an acute
respiratory complaint. His personal physician was Gott-
fried Bidloo (1649-1713), the eminent Leyden surgeon-
anatomist, who had been persuaded by William of
Orange to accompany him to England in the Glorious
Revolution of 1688[ 10]. The efforts of Bidloo and another
royal physician, Dr Thomas Laurence, not proving suc-
cessful, the King asked that Radcliffe be consulted. A
difference of opinion on the diagnosis ensued, Radcliffe
maintaining that the King was suffering from 'the dis-
tressing symptoms of an asthma, the consequence of the
dregs of the smallpox that had fallen on his lungs'fll].
Fig. 2. Carshalton House, Dr John Radcliffe's Surrey resi-
dence, now St Philomena's Convent School.
Fig. 3. King William III. (Oil painting after Sir Peter Lely,
1677. Courtesy National Portrait Gallery, London).
Fortunately, the patient recovered and, for the next 11
years, Radcliffe remained Physician-in-Ordinary to Wil-
,, liam III.
A further controversy among the physicians arose in
1699 when Queen Mary II was suddenly taken ill. Her
personal physician, Dr Richard Lower and one of Wil-
liam Ill's physicians, Dr Walter Harris (1647-1732)
diagnosed haemorrhagic smallpox, which was confirmed
by Sir Thomas Millington (1628-1703), who was later to
become President of the Royal College of Physicians
1696-1703. At the request of William III, Radcliffe was
called for consultation. He favoured a diagnosis of mea-
sles and openly criticised the treatment which the Queen
I had received. The Queen died a few days later, aged
33[12].
It was said of Radcliffe that . .at first sight of the
prescriptions, without having entered the chamber of the
Royal patient, he exclaimed, with his characteristic rude-
ness, that HM was a dead woman, for it was impossible
to do any good in her case, where remedies had already
been given that were so contrary to the nature of the
j distemper'[13].
Gilbert Burnet, Bishop of Salisbury, no doubt activated
by religious and political bias, wrote thus of Radcliffe:
* ... I will say no more of the physician's part but that
it was universally condemned; so that the Queen's
death was imputed to the unskilfulness and wilfulness
of Dr. Radcliffe, an impious and vicious man, who
hated the Queen much, but vertue and religion more.
He was a professed Jacobite and was by many thought
a very bad physician, but others cried him up in the
highest degree imaginable. He was called for; and it
appeared but too evidently that his opinion was de-
pended on. Other physicians were called when it was
too late[14].
Radcliffe, however, maintained that '. . .he was called
too late and that no remedies that could then be tried had
the least chance of doing her good'[15].
In his dealings with the King, Radcliffe was on occa-
sions too forthright. In 1697, he addressed his Royal
patient in these blunt terms:
Your juices are all vitiated, your whole mass of blood
corrupted, and the nutriment for the most part turned
to water; but, if your Majesty will forbear making long
visits to the Earl of Bradford [where, to tell the truth,
the King was wont to drink very hard], I'll engage to
make you live three or four years longer; but beyond
that time no physic can protect your Majesty's exis-
tence[16].
This was certainly plain speaking. But even more so,
verging on plain rudeness, was the occasion in 1699 when
William III was suffering from cardiac dyspnoea with
marked oedema of the lower limbs and Radcliffe said to
his monarch: 'Why, truly, I would not have your Majes-
ty's two legs for your three Kingdoms'[17],
The King never forgave Radcliffe for this remark and
would not allow him in his presence again, although he
continued to use his prescriptions.
Radcliffe and Queen Anne (1665-1714)
Anne was born in 1665, the daughter of James, Duke of
York (later to be James II) (Fig. 4). At the age of 12, she
suffered a mild attack of smallpox. In 1683, aged 18, she
married Prince George of Denmark and they lived in The
Cockpit at Whitehall Palace (the site of the present 10
Downing Street). In 1686, Radcliffe was appointed Physi-
cian-in-ordinary to HRH Princess Anne of Denmark[18-
20],
Princess Anne had a most tragic obstetric history. In
the course of the 16 years 1684-1700, she endured 17
pregnancies, which terminated in 11 miscarriages, three
stillbirths and three live births, of whom two died under
the age of 18 months (probably from smallpox) and only
one, William, Duke of Gloucester, born in 1689, sur-
vived. The explanation of this sad series of events remains
a matter for speculation. Syphilis[21], rhesus incompati-
bility!^], porphyria[23] and pelvic sepsis (perhaps from
infection by Listeria monocytogenes[24]), have all been
postulated, but there is no convincing proof of any of
these theories.
In 1691, Radcliffe attended the two-year-old Duke of
Gloucester, diagnosed 'an attack of ague' and the patient
recovered. Queen Mary was so delighted that she reward-
ed Radcliffe with 1,000 guineas[25].
In 1695, shortly after one of her miscarriages, Princess
Anne felt unwell and thought she might be pregnant
Fig 4. Queen Anne and William, Duke of Gloucester. (Oil
painting by studio of Sir Godfrey Kneller, ca. 1694. Courtesy
National Portrait Gallery, London.)
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 257
again. She sent a messenger to Radcliffe to attend her at
St James's-. Radcliffe, perhaps too fond of the bottle, was
drinking in a tavern with some friends. He told the
messenger he would come at once but failed to do so. On
the arrival of a second messenger Radcliffe publicly
proclaimed that 'Her Highness' Distemper was nothing
but the Vapours and that she was in as good a state of
health as any Woman breathing could she but give into
the belief of it'[26].
Radcliffe was proved to be correct: the Princess was not
pregnant. But Anne was furious when she heard of
Radcliffe's remarks, dismissed him from her service,
appointed Dr William Gibbons (1647-1728) in his place
and thereafter bore Radcliffe a grudge.
In 1700, the Duke of Gloucester, aged 11, and possibly
hydrocephalic, became seriously ill at Windsor. His
personal physician, Sir Edward Hannes (1667-1710),
together with Dr William Gibbons and Dr Walter Harris,
diagnosed scarlet fever. When the case became desperate,
Anne, despite her aversion to Radcliffe, allowed him to be
consulted. Radcliffe diagnosed smallpox, was openly
critical of Hanne's treatment by bleeding and, protesting
that he had been called too late, exclaimed: 'Then you
have destroyed him and you may finish him, for I will not
prescribe'[27], The young prince died six days later.
In 1702, on the death of William III, Anne became
Queen. She suffered from generalised body pains, la-
belled 'the gout', which were so severe that she needed to
be carried to her coronation. In 1708, fate dealt a further
sad blow: her consort, Prince George of Denmark, an
asthmatic and also a sufferer from 'the gout', became
acutely ill. Queen Anne's favourite physician, Dr John
Arbuthnot (1667-1735) attended him but the patient's
condition worsened. As a last resort, Anne overcame her
antipathy to Radcliffe and permitted him to be consulted.
Yet again, Radcliffe maintained that he had been called
too late; six days later, Prince George died, aged 55.
Queen Anne's health continued to deteriorate. She was
chronically affected by 'the gout' and was attended by her
Physicians-in-Ordinary: Dr Thomas Laurence, Dr Mar-
tin Lister (1638-1711) and Sir David Hamilton (1663?
1721), with Sir John Shadwell (1670-1747) as Physician
Extraordinary. Hamilton became a close friend of the
Queen; as a man-midwife, he understood 'women's
troubles' and considered the Queen's symptoms to be
largely psychosomatic and prescribed Spirit of Milli-
pedes[28]. Anne steadfastly refused to allow Radcliffe to
attend her, but . .he was consulted in all cases of
emergency, and though not admitted as the Queen's
physician, he received large sums for his prescrip-
tions'^].
Queen Anne's Final Illness
At Christmas 1713, the Queen became ill at Windsor,
suffering from fever and painful inflammation of the
inner portion of the right thigh[30-34]. She was attended
by Doctors Laurence, Arbuthnot and Shadwell, Sir Da-
vid Hamilton and Sir Hans Sloane (1660-1753). Laur-
ence and Shadwell diagnosed 'a violent inflammatory
fever' and recommended bleeding. Arbuthnot overruled
them with a diagnosis of 'an ague' and prescribed Jesuit's
bark. Radcliffe was, of course, not asked to attend the
Queen but his analysis of the case is to be found in this
letter to a friend[35]. ;
j
Jan. 5 1714
... I don't doubt but you have heard an account of
her Majesty's illness; and here we are all in the dark as
well as the doctors. At first they said it was ague and
then they gave the Jesuit's bark. She took but three
doses, and that was left off, so that I suppose they found
it no ague, or else she would have taken more or none
at all. Then it was conjectured to be the gout in her
stomach; and now it is thought to be the gout all over
excepting the joints. One of the doctors declared,
because there was no intermission on the second day,
that it was a tertiary postponed. Another, which was
Sir David [Hamilton] declared, now, God be thanked,
her Majesty would certainly be well; and when he was
asked the reason, he told them she had grown deaf, and
that was a sign the bark had taken effect: and at that
time she had taken two doses, and never took but one
afterward. Shadwell was asked how the Queen did, and
he said she would do very well, but the pouls was dure, \
which puzzled all the maids of honour.
The country was led to believe that the Queen would
die; however, she rallied but remained weak and required
to be carried from room to room at Windsor. In February
1714 she was well enough to be transported by coach to
Kensington Palace.
Matters came to a head in the summer of 1714 when
the Queen's illness took a more serious turn. In this, the
final chapter of Queen Anne's long saga of sickness, she
was attended by Doctors Laurence, Shadwell and Ar-
buthnot (Physicians-in-Ordinary); Sir Hans Sloane
(Physician Extraordinary) and Mr Daniel Malthus (Roy-
al Apothecary). Sir Richard Blackmore (1653-1729) and
Dr Richard Mead were also consulted, as well as the
famous 'eye quack', Sir William Read (d. 1715), Oculist-
in-Ordinary to the Queen.
On Wednesday, July 28th, Daniel Malthus reported
'Her appetite was quite lost and her spirits sunk'. On
Thursday, July 29th, the Queen vomited and the follow-
ing day, Friday, July 30th, she suffered two convulsions
and for one hour was 'speechless, motionless and miser-
able'. The Queen would not herself have desired Rad-
cliffe to be called and the Privy Council certainly would
not have wished to offend her sensibilities by so doing.
The queen's friends, however, felt that Radcliffe might
yet help her. Without obtaining anyone's permission, one
of the Ladies of the Bedchamber and the Queen's close
confidante, Lady Abigail Masham, took it upon herself to
send for Radcliffe, who happened to be out of town
staying at his country house in Carshalton, and who was
himself laid up with an attack of 'the gout'. Radcliffe
declined to respond to the call. It was reported later:
'. . . the Duke of Ormonde had in all haste sent Mr.
Lowman with one of the Queen's coaches to Dr. Ratcliffe
(sic) but whether the celebrated Physician thought he
could do no good, or expected to be call'd by an express
258 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
J
order from Council, he excused himself, upon account of
having taken Physic that very day'[36].
On Saturday, July 31st, the Queen's condition wors-
ened and on the following morning she 'ate an inordinate
quantity of black heart cherries', lay back and died[37].
She was aged 49.
A partial autopsy was performed by Dr Thomas Laur-
ence in Kensington Palace on August 2nd but the internal
organs revealed little that was remarkable. The report
was presented to the Privy Council the next day and was
signed by Dr Thomas Laurence, Sir David Hamilton, Dr
John Arbuthnot, Sir John Shadwell and Sir Hans
Sloane[38],
i There was no official announcement of the Queen's
death. Her illness, which had dragged on since December
1713, had given rise to so many false rumours that
'Queen Anne is dead', that on the day before the Queen's
death, Thomas Ford wrote to Jonathan Swift: '. . . I
don't doubt but you have heard the Q is dead . . .
but at present she is alive and much better than could
have been expected'[39],
On the day following the Queen's death, Delaune, the
Whig head of St John's College, Oxford, ordered prayers
for the new monarch 'King George the First' to be said in
morning worship. When the chaplain objected that the
Queen might not yet be dead, he replied: 'Dead? She is as
dead as Julius Caesar'[40],
Queen Anne's death occurred in the midst of consider-
able political turmoil. Dr John Arbuthnot subsequently
wrote to Jonathan Swift: 'My dear mistress' days were
numbered, even in my imagination, and could not exceed
certain limits, but of that small number a great deal was
cut off by the last troublesome scene of the contention
among her servants. I believe sleep was never more
welcome to a weary traveller than death was to
her . . .'[41].
The Last Days of Radcliffe
Immediately the news of the death of the Queen became
generally known, it was put about in London that
Radcliffe had refused orders from the Court that he
should attend the dying Queen. Radcliffe refuted this
accusation[42].
. . . his duty to her Majesty would oblige him to attend
her, had he proper orders for so doing; but he judged as
matters at that juncture stood between him and the
Queen, who had taken an antipathy against him, that
his presence would be of more disservice to her Majesty
than use, and that since her Majesty's case was desper-
ate and her distemper incurable, he could not at all
think it proper to give her any disturbance in her last
moments which were so very near at hand; but rather
an act of duty and compassion to let her Majesty die as
easily as possible.
Among the London populace, feelings began to run
high; they cried for Radcliffe's blood. 'Give us back the
Queen', they chanted. It was even said later of Radcliffe
that '. . .he was alike charged with killing Queen Mary,
whom he did attend in her dying illness?and Queen
Anne, whom he didn't'[43],
Not everyone joined in these charges against Radcliffe.
The Wentworth Papers contain the following letter[44] to
the Earl of Stafford.
July 30 1714
My Lord,
I am informed that when Dr. Ratcliffe (sic) was sent
for to her Majesty in her illness, he announced too
morrow would be time enough to wait on her Majesty,
but the insolence of this expression makes one scruple
the truth of it . . .
However, some of Radcliffe's friends did give credence
to the story. On 5th August 1714 the matter was raised in
Parliament, where Sir John Pakington (1671-1727), an
old friend of Radcliffe, moved '. . . that Radcliffe should
be summoned to this place to be censured for not waiting
upon the Queen when sent for by the Duke of Or-
monde'[45],
Radcliffe being absent and there being no seconder to
the motion, the subject was dropped. Radcliffe was
nevertheless very hurt by Sir John Pakington's action. He
wrote to a friend on August 7th[46]:
... I could not have thought that so old an acquaint-
ance and so good a friend, as Sir John always professed
himself, would have made such a motion against me.
God knows that my will to do her Majesty any service
has ever got the start of my ability, and I have nothing
that gives me greater anxiety than the death of that
glorious Princess.
I must do that justice to the physician that attended
her in her illness, from a sight of the method taken for
her preservation by Dr. Mead, as to declare that
nothing was omitted for her preservation. But the
[political] people about her?the plagues of Egypt fall
on them?put it out of the power of physic to be any
benefit to her.
I know the nature of attending Crowned heads to
their last moments too well, to be fond of waiting upon
them without being sent for by a proper authority. You
have heard of pardons signed for physicians before
sovereigns demise. However, as ill as I was, I would
have went to the Queen in a horse-litter had either her
Majesty or those in Commission next to her command-
ed me so to do.
Writing to Dr Richard Mead, Radcliffe confided that
he had received several anonymous violent letters threat-
ening him with being torn to pieces, should he ever make
his appearance in London.
A gang of 13 toughs planned his assassination, but one
of them thought better of it and divulged the plot to
Radcliffe in the following letter[47]:
Doctor,
Though I am no Friend of yours, but on the contrary,
one that would wish you Destruction in a legal way, for
not preventing the Death of our most Excellent Queen,
when you had it in your Power to save her; yet I have
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 259
such an Aversion to the taking away Men's Lives
unfairly, as to acquaint you, that if you go to meet the
Gentlemen you have appointed to dine with, at the
Greyhound in Croydon, on Thursday next, you will be
most certainly murther'd.
I am one of the Persons engag'd in the Conspiracy
with Twelve more, who are resolved to sacrifice you to
the Ghost of her late Majesty, that cries aloud for your
Blood, therefore, neither stir out of Doors on that Day,
nor any after, nor think of changing your present abode
for your House at Hammersmith, since there, and
everywhere else, we shall be in quest of you.
I am touch'd with Remorse, and give you this
Notice; but take Care of yourself, lest I repent of it, and
give proof for so doing, by having it in my Power to
destroy you, who am,
Your Sworn Enemy,
N.G.
Radcliffe decided it would be safer not to show his face
again in the capital. He remained in Carshalton, where
he became depressed and his health declined. Three
months after the death of Queen Anne, he suffered an
apoplexy while in church, and died on 1st November
1714 aged 62.
A contemporary historian said of Radcliffe[48]:
He was the most eminent Physician England ever
produced. This common Opinion procured him such
vast Practice and consequently Riches and puff'd him
up to that Degree of Surly Pride that he often disdained
to consult with other Physicians; and on many Occa-
sions, refused to attend Persons of the Highest Quali-
ty .. . nay even the late Duke of Gloucester and her
late excellent Majesty Queen Anne on her last Sick-
ness, which was justly resented by all the High-Church
Party . . . However, his last Will and Testament
atoned . . .
Radcliffe may well have been the most successful
physician of his time, but he was certainly a complex
and controversial figure, with a full complement of
both admirers and enemies. Religious and political
differences contributed to the inter-personal tensions in
which he appeared so often to be involved, but it is
possible that his fondness for alcohol may have ac-
counted at times for his apparently intemperate speech
and behaviour.
Radcliffe's approach to his royal patients often
lacked the sensitivity and tact which one would normal-
ly associate with a physician to the court. His maladroit
behaviour and conversation may on occasions have
resulted from pique, but as far as his role in the final
illness and death of Queen Anne is concerned, it would
be unfair to accuse him of lese-majeste.
References
1. British Biography (1766-72) Vol. 8, p. ^46. Dr John Radcliffe.
London: R. Goadby.
2. Dictionary of National Biography (1882) Vol. 16, pp. 572-575. Drjohn
Radcliffe. Oxford: University Press.
3. Steele, Sir Richard (1709) The Taller, No. 44.
4. British Library Add. MSS (Ca. 1690) no. 39289, f. 21. Drjohn
Radcliffe's 'Receipt for a Cough'.
5. Hone, C. R. (1950) The Life of Dr John Radcliffe, p. 71. London:
Faber & Faber.
6. Munk, W. (1878) The Roll of the Royal College of Physicians of London,
Vol. 1, p. 457. London: Royal College of Physicians.
7. Ibid, p. 458.
8. Steele, Sir Richard, op. cit., ref. 3 above. (21st July, 28th July and
13th September 1709).
9. McMichael, W. (1968) The Gold-Headed Cane, pp. 1-55. London:
Royal College of Physicians.
10. Dictionary of National Biography (1882) Vol. 21, pp. 306-325, William
III. Oxford: University Press.
11. McMichael, W., op. cit., ref. 9 above.
10. Strickland, A. and Strickland, E. (1847) Lives of the Queens of
England. Mary II: Vol. 10, p. 239: Vol. 11, p. 1. Anne: Vol. 11, p.
341; Vol. 12, p.l. London: H. Colburn.
13. McMichael, W. (1830) Lives of British Physicians. London: J.
Murray.
14. Burnet, G. (1724) The History of my Own Time. London: T. Ward.
15. McMichael, W., op. cit., ref. 9 above.
16. Ibid.
17. Pittis, W. (1715) Some Memoirs of the Life of John Radcliffe. London:
E. Curll.
18. Dictionary of National Biography (1882) Vol. 1, pp. 441-473. Queen
Anne. Oxford: University Press.
19. Green, D. (1970) Queen Anne. London: Collins.
20. Gregg, E. (1980) Queen Anne, p. 100. London: Routledge & Kegan
Paul.
21. Stevenson, R. S. (1962) Famous Illnesses in History, pp. 213-227.
London: Eyre & Spottiswoode.
22. Anderson, M. (1963) Queen Anne's Children. British Medical
Journal, 1, 684.
23. McAlpine, I. and Hunter, R. (1969) George III and the Mad Business,
pp. 221-222. London: A. Lane.
24. Saxbe, W. B. (1972) Listeria monocytogenes and Queen Anne.
Paediatrics, 49, 97.
25. Green, D., op cit., ref. 19 above, p. 55.
26. British Library Add. MSS. (1695) No. 17677 PP. f.216. L'Hermi-
tage to States. 2/12. April 1695.
27. Nias,J. B. (1918) Dr John Radcliffe, pp. 11-31. Oxford: University
Press.
28. Roberts, P. (ed) (1975) The Diary of Sir David Hamilton 1709-14.
Oxford: University Press.
29. Munk, W., op. cit., ref. 6 above, p. 457.
30. British Library. Sloane MSS (1714) No. 4034. ff. 44 & 46-50.
31. Lavers-Smith, H. (1901) Memoirs of celebrated physicians who
flourished in the reign of Queen Anne. No. 1: Dr. John Radcliffe.
Guy's Hospital Gazette (New Series), 15, 545.
32. Rae, J. (1913) The Deaths of the Kings of England, p. 127. London:
Sherrat & Hughes.
33. Kemble, J. (1933) Idols and Invalids, p. 155. London: Methuen.
34. Yearsley, M. (1935) Le Roi est Mort, p. 136. London: J. Heritage,
Unicorn Press.
35. Cumston, C. G. (1911) Some medical gossip pertaining to the last
illness of Queen Anne of England. New York Medical Journal, 94,
179.
36. Boyer, Abel (1711) The Political State of Great Britain, Vol. 8, p. 90.
London.
37. Nias, J. B., op. cit., ref. 27 above.
38. Public Records Office: Treasury Papers (1716). No. Tl/21. Item
33. (12th March 1716). Autopsy report on Queen Anne.
39. Swift, Jonathan (1935) Letters of Jonathan Swift to Charles Ford, p. 40.
(ed D. N. Smith). Oxford: University Press.
40. Historical Manuscripts Commission (1891) Portland Papers, Vol.
7, p. 198. Letter: Dr William Stratford to Edward Lord Harley,
2nd Aug. 1714. London: HMSO.
41. Swift, Jonathan (1911) Letters, (ed Ball.) Vol. 2, p. 92. London.
42. Pittis, W., op. cit., ref. 17 above.
43. Jeaffreson, J. C. (1860)^4 Book about Doctors, Vol. 1, pp. 134-174.
44. Historical Manuscripts Commission (1883) Wentworth Papers (ed
J.J. Cartwright) Letters 1705-39. London: Wyman.
45. Ibid.
46. Pittis, W., op.cit., ref. 17 above.
47. Ibid.
48. Boyer, Abel, op. cit., ref. 36 above.
260 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
|
PMC005xxxxxx/PMC5371094.txt | Audit Reviewed: Does Feedback on
Performance Change Clinical Behaviour?
M. W. MITCHELL, BA, Research Officer
F. G. R. FOWKES, MB, MRCP(UK), MFCM,* Senior Lecturer in Epidemiology
Department of Epidemiology and Community Medicine, University of Wales College of
Medicine, Heath Park, Cardiff
The purpose of medical audit should be to improve the
effectiveness and efficiency of medical care. An audit that
v simply identifies poor practice, or has the sole objective of
* educating clinicians, may not lead to improvements
which are assured only if the detection of inadequate care
is followed by a change in clinical practice to correct
observed deficiencies. Re-observation of practice may
r then be required to establish whether or not the desired
improvements have taken place.
For an audit to lead directly to improvements in the
effectiveness or efficiency of medical care it is necessary to
(a) observe the practice; (b) set a standard of practice; (c)
compare the observed practice with the standard; (d)
implement change, and (e) re-observe practice. These
actions form a cycle of auditfl] (Fig.l).
Often the cycle is incomplete because no attempt is
made to change clinical practice. It is commonly assumed
that the information produced by audit will naturally lead
to change. In this article we review some past experiences
with feedback of information and consider whether the
evidence supports the assumption that the provision of
information on performance changes clinical behaviour.
Information feedback c^n be divided into two broad
categories?passive and active. Passive feedback consists
of supplying information without any overtly evaluative
material or suggestions for improvement. The infor-
mation is usually relayed to clinicians in the form of
statistics in newsletters or computer printouts. Often the
statistics may be ranked according to the levels pertaining
to the consultants or junior doctors in receipt of the
information.
In contrast, active feedback of information includes
some judgement of the behaviour being studied. The
feedback may be combined with other forms of education
such as seminars or the regular review of medical records
by clinicians in a firm. Clinical guidelines or protocols
may also be provided for clinicians participating in the
feedback process.
Passive Feedback
Many of the trials of passive feedback have taken place in
the USA, and most were concerned with the numbers and
costs of diagnostic tests ordered. In one study designed to
reduce the use of laboratory tests[2], clinicians were
divided into several experimental groups. The 'cost edu-
cation' group received a series of newsletters on cost
containment and a list of charges for commonly used
laboratory tests. The 'cost audit' group received passive
feedback in the form of a weekly computer printout of
tests and charges per patient generated by each clinician.
Another group acted as a control. No change of practice
was recorded in the 'cost education' or control groups.
The 'cost audit' (passive feedback) group surprisingly
increased total test use during the intervention period.
Although education alone and feedback alone had no
effect in reducing the use of diagnostic tests, a group of
clinicians receiving both education and feedback showed
a significant reduction in test usage.
Similar results were obtained in an out-patient clinic in
Baltimore[3], Feedback of haematological, biochemical
and radiological tests ordered on each patient and the
percentage of these tests found to be abnormal produced
no effect on the use of tests over a period of one year.
Indeed, the number of tests per patient increased from
0.7 to 1.5.
"Correspondence to: Dr F. G. R. Fowkes, MRCP(UK), Department of
Community Medicine, University of Edinburgh, Usher Institute, War-
render Park Road, Edinburgh EH9 1DW.
Fig. 1. Cycle of audit.
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 251
Schroeder et al. [4] included rankings of clinicians when
feeding back statistics. They examined variations in the
costs of laboratory tests and drugs used by internists at a
university clinic. Rankings of physicians according to
levels of laboratory and drug use were circulated among
the clinicians, although each was only able to identify
himself or herself on the list. Laboratory and drug
charges were reviewed again, the clinicians being un-
aware that a repeat audit was taking place. In the first
audit, large variations (17-fold) between doctors were
reported for laboratory costs and less so for drug use
(fourfold). Following distribution of the results of the first
audit, there was a 29.2 per cent decrease in laboratory use
but a 6.4 per cent increase in expenditure on drugs. The
greatest reductions were attributable to the high-cost
physicians.
At Flinders Medical Centre in Adelaide, Grivell et
al. [5] also used rankings of medical specialists and identi-
fied them by name. The order used was total diagnostic
costs per bed day incurred by the specialists. (This
ranking was compiled after the complete failure to change
practice by regular feedback to clinicians of their own use
of tests.) The ranking information also had no effect on
the ordering of tests by the specialists.
Passive feedback on aspects of clinical care other than
the use of tests has also had only a limited effect on
utilisation, for example on the use of drugs[6] and on the
process of care for cholecystectomy patients[7]. However,
feedback of tonsillectomy rates to surgeons in Vermont[8]
was associated with a reduction in operating rates over
and above that occurring in the USA as a whole.
Thus, with few exceptions, passive feedback has been
shown in several studies to have almost no effect on
clinical practice.
Active Feedback
In the commonest form of active feedback, information
on the management of patients is provided during regular
reviews of medical records by clinicians in a firm. In one
trial attempting to modify the use of tests by residents in a
hospital in Boston, Martin et al. [11] randomly allocated
24 junior doctors into three groups. The first group
reviewed at weekly intervals the medical records of
patients in their wards; the second group received a
moderate financial incentive if they reduced their use of
tests; the third group acted as a control. During the year
of the study, the group reviewing medical records showed
the greatest decrease in the numbers of laboratory tests
ordered (a reduction of 47 per cent).
A regular audit of medical records in a Birmingham
hospital, however, did not produce a greater reduction in
numbers of tests ordered by clinicians participating in the
audit than by those in a control group[12]. The author
suggested that no substantial change took place because
only emergency medical admissions were reviewed, and
these patients were unlikely to have had many unneces-
sary investigations. Nevertheless the review did lead to
changes in other aspects of care, namely an improvement
in medical recording, a reduction in drugs prescribed on
discharge, and better discharge summaries.
An American hospital study[13] tried to reduce the use
of a wide range of clinical resources by means of feedback
to junior staff during individual tutorials and seminars
held in the wards and out-patient clinics of one medical
department. Average length of stay was reduced by 21
per cent and the cost per admission in the department
rose by only 4.3 per cent per annum compared with an
average growth rate of 14.5 per cent in other depart-
ments. The number of out-patient laboratory tests de-
creased, thus reducing overall patient costs.
Change may be forthcoming if feedback is combined
with general guidelines or specific protocols outlining
recommended modes of practice. Ln a recent study in the
UK (Fowkes, unpublished), surgeons and anaesthetists in
one hospital were issued with the Royal College of
Radiologists' guidelines on the use of pre-operative chest
X-rays. Issuing the guidelines had only a minor effect on
utilisation, but regular feedback to the clinicians on their
own utilisation resulted in a 55 per cent decrease in the
use of pre-operative chest X-rays over a period of one
year (in comparison with no significant change in a
control hospital).
In a Canadian study, the College of Physicians and
Surgeons of Saskatchewan formulated a list of indications
justifying hysterectomy. After hospitals were presented
with data on their numbers of 'justified' and 'unjustified'
hysterectomies according to the College's protocol, the
numbers of 'unjustified' hysterectomies fell mark-
edly [ 14].
As with other methods of active feedback, the provision
of guidelines or protocols is an educational measure
additional to that provided by feedback. Most edu-
cational measures combined with feedback do appear to
have an impact on practice.
Discussion
From the results of studies presented in this review, it
would appear that simply feeding back information on
performance has almost no impact on changing clinical
behaviour. However, feedback combined with other edu-
cational measures would appear to have some success in
changing practice.
It is not surprising that the very act of providing
clinicians with relevant data does not automatically initi-
ate change. Experience of traditional postgraduate educa-
tion would suggest that new knowledge by itself impinges
very little on clinical behaviour. This has also been
demonstrated in studies concerned with the adoption of
innovations: only a few key individuals tend to respond to
new information with some appropriate action[15]. Most
people resist change, being concerned primarily with
maintaining current practices. In the case of clinicians the
picture is further confused by the large amount of infor-
mation with which any individual is constantly presented.
As the amount increases, choosing which pieces of infor-
mation to ignore and which to act upon becomes.increas-
ingly difficult.
In addition to the difficulties in overcoming a natural
resistance to change, the failure of passive feedback may
be due in part to the recipients' perceptions of the
252 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
J
information and of the system for supplying it. A survey
of consultants' opinions of the Scottish Consultant Re-
view of Inpatient Statistics (SCRIPS)[16] showed that 61
per cent thought it was of no value, 44 per cent found it
difficult to understand, 46 per cent thought there was too
long a delay in the provision of data and 64 per cent were
concerned with the extent of errors. However, 82 per cent
said that in future they would like to receive routine data
of some sort. Thus most consultants were not opposed to
the idea of receiving information but they did not approve
of the SCRIPS system. The lack of involvement of
consultants in the planning and provision of data was
probably a major factor contributing to the system's
failure. The system was undoubtedly perceived as an
external review of clinical practice and was counterpro-
ductive in motivating change.
The individuals providing feedback may be crucial to
success in promoting change. Martin et al. [11] thought
that one reason for the success of their weekly chart
reviews in reducing the use of diagnostic tests was that the
reviews were led by senior clinicians whose views were
, respected by junior staff. Eisenberg et al. [17] postulated
that one of the reasons they failed to reduce the inappro-
priate use of tests for lactate dehydrogenase (LDH) in a
hospital was because feedback was provided by junior and
not senior staff in the hospital. They thought that house
officers would be more likely to respond to figures of
authority. Feedback of information must also be directed
to the most appropriate person. Grivell et al. [18] sugges-
ted that a major reason for the lack of effect of feeding-
back data on numbers and costs of tests was because the
feedback was presented to senior staff when in fact the
junior staff ordered tests.
In the UK, one of the most ambitious programmes of
information feedback to consultants was conducted by the
Information Services Division of the Scottish Health
Service in the form of Scottish Consultant Review of
Inpatient Statistics (SCRIPS)[9], Statistical information
on numbers of discharges, diagnoses, ages of patients,
and lengths of stay, was provided regularly to consultants
on patients discharged from their wards. This feedback of
information had almost no effect on clinical practice and
was subsequently withdrawn.
In a more recent experiment in Brent Health Dis-
trict[ 10] consultants were provided with monthly reports
of their use and costs of diagnostic and other services. The
information was also presented intermittently to div-
isions; this allowed consultants to compare their own
firm's performance with that of colleagues. After three
years, there was no evidence to suggest that any consult-
, ant's pattern of work or expenditure had changed mark-
edly.
Restuccia[19] conducted a study in which the persons
providing feedback undertook different roles. The pur-
pose of the feedback was to reduce the number of days in
which patients remained inappropriately in hospital. Cli-
nicians in four hospitals were provided with different
forms of feedback on selected groups of patients. 'Direct'
feedback, in which a nursing officer automatically in-
formed clinicians that patients were in hospital inappro-
priately, resulted in the greatest change in terms of
reduced length of stay and decrease in inappropriate days
in hospital. 'Judgemental' feedback in which the nursing
officer first had to decide whether to inform doctors about
inappropriately located patients, also had a positive effect
on length of stay. 'Indirect' feedback to medically quali-
fied 'advisers', who were then responsible for contacting
the clinicians in charge of patients, proved ineffective as
the 'advisers' appeared unwilling to confront their clinical
colleagues.
The success of active feedback is undoubtedly due to
the combination of feedback with other educational inter-
ventions. The education may not simply provide the logic
for change, but may ensure a more personal environment
between provider and recipient than is the case with
passive feedback. The recipient may feel more involved
and responsive to suggestions for change. Awareness of
peer pressure may also be greater than that provided by
sheets of statistics distributed by colleagues.
Although active feedback may be successful in initiat-
ing change, sustaining this change over a period of time is
a major difficulty. Martin et al. [11] documented a con-
tinuing reduction in use of diagnostic tests for four
months after stopping their weekly chart reviews, but
other studies have not found this to be the case. For
example, Rhyne and Gehlbach[20] combined feedback to
residents on their use of thyroid function tests with an
educational seminar. This reduced use for three months
but, with no further feedback, use then returned to pre-
intervention levels. The stimulus for change has to be
sufficient to sustain change and to overcome the danger of
recipients becoming immune to the stimulus. To sustain
change over a long period of time, active feedback may
have to be accompanied by a variety of educational
interventions or some form of financial incentive or
sanction[10].
In conclusion, there have been relatively few trials of
the effect of feedback on performance in changing clinical
behaviour. Active feedback in its variety of forms appears
to be moderately successful but the lack of appropriate
research design in many studies and the varying enthusi-
asm of researchers and participants make it difficult to
decide on the most appropriate methods of feedback.
Methods used in the future to feed back information on
performance should be implemented on an experimental
basis and should be carried out for a sufficiently long time
to establish that any change is indeed longstanding and
not just a short-term response to a new initiative.
References
1. Fowkes, F.G.R. (1982) Medical Education, 16, 228.
2. Everett, G., de Blois, S., Chang, P. F. and Holets, T. (1983)
Archives of Internal Medicine, 143, 942.
3. Pozen, M. W. and Gloger, H. (1976) Social Science and Medicine, 10,
491.
4. Schroeder, S. A., Kenders, K., Cooper, J. K. and Piemme, T.
(1973) Journal of the American Medical Association, 225, 969.
5. Grivell, A. R., Forgie, H. J., Fraser, C. G. and Berry, M. N.
(1982) Medical Journal of Australia, 2, 326.
6. Brown, C. R. and Uhl, H. S. M. (1970) Journal of the American
Medical Association, 213, 1660.
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 253
L
7. Mitchell, J. H., Hardacre, J. M., Wengel, F.J. and Lohreny, F.
N. (1975) Medical Care, 13, 409.
8. Wennberg, J. E., Blowers, L., Parker, R. and Gittelsohn, A. M.
(1977) Pediatrics, 59, 821.
9. Heasman, M. A. (1970) Scottish Medical Journal, 15, 386.
10. Wickings, I., Coles, J. M., Flux, R. and Howards, L. (1983)
British Medical Journal, 226, 575.
11. Martin, A. R., Wolf, M. A., Thibodeau, A. L., Dzau, V. and
Braunwald, E. (1980) New England Journal of Medicine, 303, 1330.
12. Heath, D. A. (1981) Journal of the Royal College of Physicians of London,
15, 197.
13. Lyle, C. B., Bianchi, R. F., Harris, J. H. and Wood, Z. L. (1979)
Journal of Medical Education, 54, 856.
14. Dyck, F. J., Murphy, F. A., Murphy, J. K. et al. (1977) New
England Journal of Medicine, 296, 1326.
15. Rogers, E. and Shoemaker, F. (1971) Communication of innovations.
New York: Free Press.
16. Parkin, D. M., Clarke, J. A. and Heasman, M. A. (1976) Health
Bulletin, 5, 273.
17. Eisenberg, J. M., Williams, S. V., Garner, L., Viole, R. and
Smits, H. (1977) Medical Care, 15, 915.
18. Grivell, A. R., Forgie, H. J., Fraser, C. G. and Berry, M. N.
(1981) Clinical Chemistry, 27, 1717.
19. Restuccia, J. D. (1982) Medical Care, 20, 46.
20. Rhyne, R. L. and Gehlback, S. H. (1979) Journal of Family Practice,
8, 1003.
|
PMC005xxxxxx/PMC5371095.txt | Gram-Negative Shock: Approaches to
Treatment
MARK A. JACOBSON, MD, Fellow in Infectious Diseases
LOWELL S. YOUNG, MD, Professor of Medicine
Division of Infectious Diseases, Department of Medicine, UCLA School of Medicine and
Center for Health Sciences, Los Angeles, California
Shock (systolic blood pressure less than 90 mm Hg and
signs of tissue hypoperfusion) following Gram-negative
rod bacteraemia represents a medical emergency. For
some groups of patients the mortality has exceeded 80 per
cent despite appropriate antimicrobial therapyfl ,2].
Some physicians might raise the nihilistic view that the
high mortality is but a reflection of the underlying disease
which in turn has been complicated by the onset of severe
hypotension and diminished tissue perfusion. On the
other hand, rather salutary developments have occurred
in the therapy of bacteraemia due to Gram-negative
bacilli[3]. Mortality which, prior to 1970, exceeded 80
per cent in patients with so-called underlying 'rapidly
fatal' diseases is now often less than 25 per cent in a
number of recent studies of antimicrobial therapy[3-5].
The ability to control the underlying disease processes
and the termination of blood-stream infection appear to
be associated with a better prognosis.
There are four subjects, all controversial, that are at
the forefront of any discussion of recent developments in
the management of human bacterial shock. The processes
discussed here relate only to the shock associated with
Gram-negative rod infections. Such a narrow focus is
necessary because of the burgeoning microbiological and
clinical literature on Gram-positive infections and shock,
particularly the well-publicised toxic shock syndrome.
Use of Combinations of Antimicrobial Agents
Literally hundreds of studies of antimicrobial efficacy
have been published in the last 15 years, during which
there appears to have been significant overall improve-
ment in survival from human Gram-negative rod bacter-
aemia. Many of these studies, despite enrolment of large
numbers of cancer patients or critically ill individuals,
have restricted themselves to the therapy of bacteraemic
infections, particularly those complicated by shock. A
retrospective study by Anderson et al. [6] demonstrated
that the use of the synergistic combinations of antimicro-
bials in patients who had developed shock was associated
with a significantly better survival rate than that of
individuals who were treated with non-synergistic combi-
nations of agents. In that study a synergistic combination
was most likely a combination of an aminoglycoside, such
as gentamicin, with a (3-lactam (a cephalosporin or anti-
pseudomonal penicillin). The study involved the individ-
ual testing of actual combinations of antibiotics used
therapeutically against isolates from the infecting organ-
ism of each case studied. Thus a correlation between in
vitro synergism and clinical outcome was demonstrated
but the information obtained did not directly influence
treatment.
One of the problems in studies employing retrospective
correlations is that the data are seldom if ever available
for clinical management of the patient. Indeed, the very
definition of in vitro antimicrobial synergism has varied
considerably and there is no widely accepted methodology
for the performance of such tests. Nonetheless, studies
using several accepted criteria have shown that 40-80 per
cent of combinations of aminoglycosides with /3-lactam
agents result in a synergistic interaction[7]. The use of
synergistic combinations therefore becomes the rationale
for the empiric use of antimicrobial agents.
The results of Anderson's study[6] have not been
confirmed or refuted by any subsequent analysis of
antimicrobial chemotherapy in patients with shock. The
relevance of the nature of antimicrobial therapy to the
outcome of the management of shock should be obvious
to practising clinicians. The controversial studies about
the therapeutic use of steroids as published by
Schumer[8] in man or the therapeutic adjunctive use of
an antiserum against endotoxin by Ziegler et al. [9] give
no detailed analysis of the effect of choice of antimicrobial
therapy on outcome. Indeed, the study by Schumer[8]
makes it very unlikely that synergistic combinations of
antibiotics were ever employed in patients because of the
use of such therapeutic approaches as chloramphenicol
alone or the combination of clindamycin and gentamicin.
Ziegler et al. [9] make no mention of specific antimicrobial
therapy except to indicate that the appropriateness of
treatment was similar in recipients of control and thera-
peutic J-5 antiserum. It is surprising therefore that this
highly important aspect of therapy has not been clearly
detailed in major studies claiming that other forms of
intervention are specifically responsible for a beneficial
therapeutic outcome.
214 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
One can easily imagine how more rapidly effective
bactericidal therapy could influence the outcome of the
^ management of bacterial shock. Death of organisms
might result in enhanced release of endotoxins. This
might make the clinical situation even worse, but it can be
argued that more rapid killing of the responsible bacteria
will terminate the pathogenic process earlier and lead to
greater likelihood of survival. In immunocompromised
patients likely to have a massive inoculum and high grade
i bacteraemia, the rapid killing of organisms must be
accepted as a desirable therapeutic goal which is most
effectively reached by using synergistic combinations of
antimicrobials. Although potent new monotherapeutic
agents have been introduced into clinical practice, such as
, the newer (3-lactam agents (e.g. cefoperazone[10] or
imipenem), the preferred synergistic combination of anti-
microbials is an aminoglycoside with a /3-lactam agent
(e.g. gentamicin or amikacin with piperacillin or azlocil-
lin).
I -
Corticosteroids
The use of steroids in patients with shock due to Gram-
A ? negative bacteraemia has been a focus of controversy for
over 20 years. Many studies of this use of glucocorticoids
have significant methodological problems. Weitzman and
Berger reviewed the English language literature in 1974
and analysed 32 human studies for adherence to eight
standards of clinical trial designfll]. Only 41 per cent of
the studies were prospective, 44 per cent used concurrent
controls, 25 per cent were randomised, and 16 per cent
were double-blind. Most of the studies lacked consistency
in details of steroid administration (e.g. dosage, duration
of therapy, use of a single preparation). The best study
dealing with Gram-negative bacteraemia was by Klas-
tersky et al. [12]. No difference in mortality rates was seen
between patients given placebo and those treated with
betamethasone, 1 mg/kg/day for three days (equivalent to
j - 7 mg/kg/day of methylprednisolone). In 1981, the
Federal Drug Administration (FDA) removed septic
shock from its list of indications for the use of high-dose
methylprednisolone.
The controversy has been kept alive by two further
major reports. The first[8] involved 172 consecutive
- * patients with blood culture-proven septic shock. Higher
doses of glucocorticoids were used than by Klastersky et
al. [12]. Therapy was started at the time of diagnosis. The
mortality rates were significantly different: 10 per cent in
the steroid-treated group and 38 per cent in the placebo
, " group. This study has been criticised for the following
reasons: use of two different steroid preparations (dexa-
methasone and methylprednisolone), failure to use a
uniform antibiotic protocol, use of chloramphenicol alone
during the first phase, lack of data on adjunctive support-
ive measures, and unusually low mortality in the steroid
treated group.
A large body of animal experiments suggests that early
use of steroid therapy prevents the occurrence of the
septic shock syndrome. A recent prospective controlled
unblinded study by Sprung et al. [13] showed that large
corticosteroid doses had a significant effect on reversing
septic shock. Although mortality was unaffected, septic
shock was reversed within 24 hours in 11 of 43 steroid-
treated patients but in none of 16 controls (P< 0.05).
Patients who received corticosteroids within four hours
after onset of shock experienced a significantly higher
incidence of shock reversal than those who were treated
later, but many patients did not receive steroids until
more than 12 hours after onset of shock. Use of large
doses of steroids in shock may delay death, but the
ultimate mortality may be similar in non-steroid treated
subjects. Recovery seems related to ability to improve the
underlying disease, and steroids may 'buy time' for the
patient with a potentially reversible disorder.
There may be a sound physiological basis for empiric
use of steroids. High-dose steroids appear to inhibit the
release of /3-endorphin as well as adrenocorticotrophic
hormone (ACTH) from the pituitary. This may counter
endotoxin stimulation of endorphin release and blunt the
severity of resultant hypotension. Inhibition of comple-
ment-mediated granulocyte aggregation may be another
mechanism of action of high-dose steroids in septic
shock[14]. Endotoxin activates the complement system,
and it has been shown recently that granulocytes aggre-
gate when exposed to activated complement, specifically
C5a[ 15]. When cultured human umbilical vein endotheli-
al cells were exposed to neutrophils activated by C5a, the
neutrophils adhered to the endothelial cells and released
toxic oxygen species which resulted in endothelial cell
damage. Cell damage was inhibited by hydrocortisone.
In another study, the plasma level of methylprednisolone
achieved by a 30 mg/kg dose completely prevented in vitro
complement-mediated granulocyte aggregation[16].
Until further double-blind prospective studies of high-
dose methylprednisolone with controlled antibiotics clari-
fy the clinical value of steroids in septic shock, we favour
restricting administration of a single 30 mg/kg dose of
methylprednisolone to the following patients: those who
are early in the course of presumed Gram-negative
bacteraemia, have suffered hypotension for less than two
hours, and have potentially reversible underlying disease.
In this clinical setting, Sprung et al. showed a significant
superinfection rate attributable to dexamethasone;
patients treated with methylprednisolone did not experi-
ence such increased adverse effects compared to con-
trols[13].
Naloxone
Some researchers have proposed that endorphins play a
major pathogenic role in septic shock. This has logically
led to inquiry about the possible therapeutic effect of
naloxone. Earlier research on endorphins focused on their
role as opiate analogues that function as pain modulators.
Naloxone, a pure opiate antagonist, was shown to block
endorphin analgesia. Endorphins, like exogenous opiates,
produce hypotension, and naloxone can also block this
effect.
Faden and Holaday's animal studies suggest that
naloxone can reverse hypotension in Gram-negative bac-
teraemia[17]. Unanaesthetised rats were given purified
Escherichia coll endotoxin. When the mean blood pressure
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 215
dropped to 65 mm Hg, rats received either a placebo or
naloxone. Naloxone restored mean pressure in rats that
received endotoxin. Naloxone maintained pressure when
given as a continuous infusion, and a dose-response
relationship was shown with maximal effect at 1 mg/kg.
Experiments with levo- and dextrorotatory isomers of
naloxone showed that the effect of naloxone on blood
pressure after endotoxin administration occurred only
with the levo-rotatory form. This stereospecificity sug-
gests that the effect of naxolone is opiate-receptor-mediat-
ed and not due to some other pharmacological effect of
the drug. Increased mean pressure was produced when a
small amount of levo-naloxone was injected into the
cerebral ventricle. There was no effect when the same
amount was given peripherally or when dextro-naloxone
was given intraventricularly. Thus, it appears that the
effect of naloxone in shock is mediated by central nervous
system opiate receptors. Although naloxone increased
mean arterial pressure in the rat endotoxin model, it did
not significantly change survival. Experiments by these
same investigators using the canine endotoxic model
suggest that the primary therapeutic effect of naloxone in
endotoxic shock is to reverse depression of myocardial
contractility[17]. Naloxone, given to pigs two hours after
the induction of Esch. coli septic shock, had only tran-
sient, relatively minor effects on blood pressure[18].
Perhaps the haemodynamic effect of naloxone occurs only
when given early in the course of bacteraemia and not at a
later time.
There are few human studies of naloxone in septic
shock, although several case reports have appeared[19-
21]. Severe septic hypotensive episodes unresponsive to
pressors were dramatically reversed when naloxone was
administered. Doses used ranged from 0.01 to 0.1 mg/kg.
There is one small uncontrolled study[22] in which 13
patients with sustained hypotension, 10 of whom had
sepsis as the aetiology, and all of whom had either oliguria
or impaired mental status, were given intravenous nalox-
one. Pressors, antibiotics, and fluids were continued
unchanged. Four of the 13 were hypoadrenal from either
Addison's disease or chronic steroid administration.
Eight septic patients who were not hypoadrenal had a 45
per cent increase in systolic pressure within minutes of
receiving 0.4-1.2 mg of naloxone. This increase lasted
about 45 minutes (compared with a half-life for naloxone
of about one hour). In two of these patients a second dose
resulted in another increase in blood pressure. The
hypoadrenal patients had no pressor response to nalox-
one.
In the light of these data and the apparent safety of
naloxone, we believe a trial of naloxone therapy can be
justified in cases of septic shock that have been unrespon-
sive to appropriate volume replacement and pressors. In
this situation, we favour giving a 1 mg bolus and
repeating this until hypotension resolves or a maximum
dose of 0.1 mg/kg is reached. Once a clinical response
occurs a 1 mg/hr maintenance infusion is started. While
naloxone appears to have a transient pressor effect in
septic shock and causes minimal adverse effects, clinical
trials are needed to establish its precise efficacy and the
full range of dose response in humans.
Therapeutic Antiserum
Interest in enhancing the protective effect of host anti-
body to bacterial endotoxin was stimulated in part by the
report of McCabe et al. which related different host
antibody titres to the frequency of shock and fatal out-
come in 175 patients with Gram-negative bacter-
aemia[23]. When bacteraemia was first diagnosed or
suspected, serum antibody titres were measured to three
Gram-negative cell-wall antigens: O-specific antigen and
two shared cross-reactive antigens (CA and Re). O
antigen is determined by the polysaccharide component
of the outer membrane and is unique to each bacterial
strain. Re antigen is a shared cross-reactive antigen
associated with core glycolipid. Mutant Re bacteria lack
both the polysaccharide O antigen and the outer core
structures and thus have core glycolipid exposed. Hence,
antibody to Re antigen is essentially antibody to the core
glycolipid common to all Gram-negative bacilli. Shock
and death occurred less frequently only in patients with
elevated titres of anti-Re antibody.
Braude et al., using a mutant form of Esch. coli
designated J-5, have entered the therapeutic arena[24],
J-5 bacteria lack an enzyme required for incorporation of
galactose into cell-wall lipopolysaccharide. This prevents
the" attachment of side chains to core glycolipid. The
exposed core is presumed to be antigenic. Healthy rabbits
vaccinated with killed J-5 Esch. coli developed high levels
of antibody to J-5. Antiserum harvested from these
vaccinated rabbits protected other rabbits from the toxic
effects of injected endotoxin. Bacteraemia neutropenic
rabbits given antiserum had markedly improved survival
compared with controls given non-immune serum.
This group later reported results of a multicentre,
double-blind, randomised, prospective trial of J-5 anti-
serum in patients with Gram-negative bacteraemia[9].
Human J-5 antiserum was obtained from healthy young
men vaccinated with boiled J-5 Esch. coli cells. Control
serum was also obtained from each volunteer before
vaccination. Patients were enrolled if they appeared
septic and had a high probability of Gram-negative
infection. Each participant received one unit of control
serum or antiserum at the time of enrolment. Among
patients with documented Gram-negative infections, the
mortality rate was 22 per cent for those who received
antiserum and 39 per cent for controls (P = 0.01). In the
subgroup with profound shock, the mortality rate was 44
per cent but 77 per cent for controls (P = 0.03).
The fact that antiserum was most effective in non-
neutropenic patients and in those with profound hypoten-
sion supports the hypothesis that antiserum acts by
binding to core glycolipid and blocking its access to host
mediators of shock. J-5 antiserum and active J-5 immu-
nisation have also been shown to be protective against
H. influenzae type b infections in mouse studies[25].
Currently, a major problem is availability of anti-
endotoxin antibodies. Some commercial preparations of
gammaglobulin modified for intravenous use contain
augmented levels of such antibodies, but data on their
efficacy in man are not yet available[26].
The incidence of Gram-negative bacteraemia is now
216 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
estimated to be 70,000-300,000 cases per year[27,28], so
c large amounts of therapeutic antiserum would be needed
if it became a major form of treatment for Gram-negative
septic shock. From a practical standpoint it may be
unrealistic to plan on immunisation and plasma donation
filling such requirements. In addition, current fears about
the safety of blood products in general may limit patient
acceptance. Hence for antiserum to become a practical
treatment, in vitro antibody production is needed. Hu-
> man monoclonal IgG antibody specific for H. influenzae
capsular polysaccharide has been created by fusing hu-
man splenic lymphocytes with a mutant human myeloma
cell line[29]. These monoclonal antibodies are protective
in an animal model of H. influenzae infection. Monoclonal
antibodies to Gram-negative lipopolysaccharide have also
been developed and appear protective in animal models
of infection[30,31]. Perhaps monoclonal antibodies will
be the next major therapy to lower mortality in Gram-
negative septic shock.
This article is based on a paper read by Dr Young at the
?r '? Conference on Infectious Diseases held at the Royal College of
^ Physicians in May 1985.
, References
1. Bryant, R. E., Hood, A. F., Hood, C. E. et al. (1971) Archives of
_ Internal Medicine, 127, 120.
2. McCabe, W. R. and Jackson, G. G. (1962) Archives of Internal
Medicine, 110, 92.
3. Love, L. J., Schimpf, S. C., Schiffer, C. A. et al. (1980) American
, Journal of Medicine, 68, 643.
) , 4. Winston, D. J., Barnes, R. C., Ho, W. G. et al. (1984) American
'' Journal of Medicine, 77, 442.
5. Pizzo, P. A., Commers, J., Cotton, D. et al. (1984) American Journal
of Medicine, 76, 436.
6. Anderson, E. T., Young, L. S., Hewitt, W. L. et al. (1978)
Chemotherapy, 24, 45.
7. Weinstein, R. J., Young, L. S. and Hewitt, W. L. (1975) Journal of
Laboratory and Clinical Medicine, 86, 853.
u
I ,
8. Schumer, W. (1976) Annals of Surgery, 184, 333.
9. Ziegler, E. J., McCutchan, J. A., Fierer, J. et al. (1982) New
England Journal of Medicine, 307, 1225.
10. Boliver, R., Fainstein, V., Elting, L. et al. (1983) Reviews of
Infectious Disease, 5, (Suppl), 181.
11. Weitzman, S. and Berger, S. (1974) Annals of Internal Medicine, 81,
36.
12. Klastersky, J., Cappel, R. and Debusscher, L. (1971) New England
Journal of Medicine, 284, 1248.
13. Sprung, C. L., Caralis, P. V., Marcial, E. H. et al. (1984) New
England Journal of Medicine, 311, 1137.
14. Sheagren, J. N. (1981) New England Journal of Medicine, 305, 456.
15. Jacob, H. S., Craddock, P. R., Hammerschmidt, D. E. el al.
(1980) New England Journal of Medicine, 302, 789.
16. Hammerschmidt, D. E., White, J. G., Craddock, P. R. et al.
(1979) Journal of Clinical Investigation, 63, 798.
17. Faden, A. I. and Holaday, J. W. (1980) Journal of Infectious Disease,
142, 229.
18. Gahhos, F. N., Chiu, R. C., Hinchey, E.J. et al. (1982) Archives of
Surgery, 117, 1053.
19. Swinburn, W. R., Phelan, P. et al. (1982) Lancet, 1, 167.
20. Dirkson, R., Otten, M. H., Wright, D. J. et al. (1980) Lancet, 2,
1360.
21. Tiengo, M. (1980) Lancet, 2, 690.
22. Peters, W. P., Priedman, P. A., Johnson, M. W. et al. (1981)
Lancet, 1, 529.
23. McCabe, W. R., Kreger, B. E. and Johns, M. (1972) New England
Journal of Medicine, 287, 261.
24. Braude, A. I., Ziegler, E. G., McCutchan, J. A. et al. (1981)
American Journal of Medicine, 70, 463.
25. Marks, M. I., Ziegler, E. J., Douglas, H. et al. (1982) Journal of
Clinical Investigation, 69, 742.
26. Roby, R. E. and Collins, M. S. (1984) Proceedings of the 24th
Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstr.
94.
27. Wolff, S. M. (1982) New England Journal of Medicine, 307, 1267.
28. Bryan, C. S., Reynolds, K. L. and Brenner, E. R. (1983) Journal of
Infectious Disease, 5, 629.
29. Hunter, K. W., Hemming, V. G. and Fischer, G. W. (1982)
Lancet, 2, 798.
30. Kim, K. S., Green, D., Cross, A. et al. (1984) Proceedings of the 24th
Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstr.
92.
31. Young, L. S. (1984) American Journal of Medicine, 76, 664.
|
PMC005xxxxxx/PMC5371096.txt | Science in Medicine
The breathtaking advances in the basic sciences in the last
decade have left most clinicians bewildered and with
something of a feeling of hopelessness in their inability to
catch up with and understand current physiology and
biochemistry, let alone immunology and molecular biol-
ogy. Nonetheless, every clinician, whatever his field of
practice, has seen diagnosis and treatment profoundly
altered by the impact of new scientific knowledge on
medicine. We are all aware, for example, that the
practical application of physics has brought new facilities
for imaging, that monoclonal antibodies have been used
for specific immunosuppression and as diagnostic agents,
and that the techniques of molecular biology have led to
the pre-natal diagnosis of inherited disease. No doctor,
therefore, can afford to be out of touch with the advances
in scientific knowledge which are pertinent to medicine. It
could be (and indeed, has been) said that one does not
really need to know the scientific principles underlying
and governing diagnostic procedures, laboratory tests,
and treatment; as long as one can order the appropriate
investigation and choose the correct therapy, understand-
ing need go no further. Not only is this approach
intellectually sterile, it also produces a person blind to the
intricacies, sheer excitement and, indeed, aesthetic values
of current science.
Recognising that there is a need for clinicians to revise
what basic science they remember, and also to be intro-
duced to new facts and hypotheses, the College'began in
1981 a series of conferences entitled 'Science and Medi-
cine'. The second was held in 1983 and the third will take
place on 6th-8th November 1985. Their content ranges
widely, covering obvious fields such as neurobiology, cell
physiology and structure, immunology, the pathogenetic
mechanisms of infectious diseases, and less obvious ones
such as psychology and electronics. Now and again rather
shadowy areas have been explored, such as evolution and
the form it is currently taking.
A very pleasing and, to be frank, unexpected feature of
the two conferences held to date has been the attendance
throughout the whole two and a half days of many of the
basic scientists invited to deliver a lecture. Their reasons
for staying the whole course were the mirror image of
those which brought about the conferences; the scientists
felt a need to learn about the clinical field in which their
own work was being applied.
The College feels that it has fulfilled a need for drawing
together clinicians and basic scientists, and making each
group aware of advances enjoyed by, and problems
facing, the other. Such an association can only be fruitful,
and we must now consider ways in which the College
could be even more instrumental in ensuring that the
dialogue continues.
D. Gwyn Williams
|
PMC005xxxxxx/PMC5371097.txt | The Persistent Challenge of Tropical Parasitic
Infections
The Milroy Lecture 1984
ADETOKUNBO O. LUCAS, MD, FRCFJ FFCM, Director, Special Programme for
Research and Training in Tropical Diseases, World Health Organisation, Geneva, Switzerland
Like Dr Leonard Rogers, Milroy Lecturer for 1907, I
consider my appointment as being 'due to a desire on the
part of this College to recognise the work now being done
in the investigation of tropical diseases'[l]. In choosing
my subject I have been guided by Milroy's suggestions
for the lectureship in which he wrote, 'There is a vast
amount of protracted malaise and suffering, disablement,
or lessened capacity for industrial work, and often, too, of
slow but eventually fatal sickness, in almost every region
of the world. .
In many parts of the tropics, malaria and other parasit-
ic infections remain major causes of disease, death and
disability, killing some, maiming others and, in a variety
of ways, limiting the scale and scope of human endea-
vours and often denying man the full enjoyment of the
fruits of his labour and enterprise. Even where the
diseases have been eliminated or controlled, they con-
tinue to exact a toll by requiring that vigilance be
maintained indefinitely to offset the ever-present risk of
resurgence or re-invasion. These diseases present prob-
lems that confront individuals, communities and govern-
ments in the developing countries of the tropics.
In the efforts to control these infections, the successes in
some places have been as dramatic as were the failures in
others. The overall picture is of the persistence of the
challenge?with the parasites displaying an arrogant defi-
ance to attempts to bring them under control and con-
founding optimistic forecasts that they would fade away.
The challenge posed by these infections can be examined
at three levels: the community, the clinical state and the
cells and tissues.
Community
In extreme cases, the impact of tropical parasitic diseases
can be devastatingly obvious, even determining the
course of history. There is the familiar example of the role
of these diseases in deterring, in fact preventing, Euro-
pean settlement in West Africa[2]. River blindness result-
ing from infection with Onchocerca volvulus caused the
depopulation of large tracts of arable land in Africa[3].
The waxing and waning of epidemics of African sleeping
sickness in endemic foci have had a similar devastating
effect on many communities in Africa[4], Epidemics of
kala-azar in India caused . .a decrease in population of
the affected tracts and the falling out of cultivation of
much land. . .'[1].
It is more difficult to assess the specific contributions of
individual parasitic infections in the typical situation,
where the community is afflicted by a variety of parasitic
and other infectious diseases, often compounded by mal-
nutrition^].
The specific contributions of individual infections can
be teased out by using case-control studies and multiple
regression analyses. The situation is further complicated
by the interactions that occur in cases of concurrent
infections as, for example, the peculiar syndrome of
chronic typhoid infection in association with Schistosoma
mansoni infection[6],
Dr Morrow and his colleagues have devised and tested
a quantitative method for assessing the health impact of
different diseases in less developed countries, based on the
concept of the number of useful days of life lost[7]. This
single index adds the deleterious effects of different
degrees of disability to the losses due to premature death.
Morrow's approach and similar ones require a conceptual
leap to set up a table of equivalence between deaths and
morbidity in clinical cases. One must take this leap in
order to be able to compare the impact of diseases like
malaria, which is a major cause of death in children in the
highly endemic areas, with that of leprosy, which is a
chronic disabling disease.
In order to determine the full impact of these parasitic
infections, it is important to recognise and assess their
indirect effects on the community. Dr Molineaux of
WHO[8] recently reviewed three methods of estimating
the number of deaths caused by malaria in highly en-
demic areas:
(a) Deaths attributed to malaria.
(b) Reduction in death rates on specific anti-malarial
control.
(c) The distribution of the sickle cell gene.
These approaches have yielded estimates that are con-
flicting and internally inconsistent. The number of per-
sons recognised as dying from the classical manifestations
of malaria grossly under-estimates the total mortality due
to this infection. Some of the difference is accounted for
by the indirect mortality caused by the infection. For
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 205
example, Gigioli[9] noted that, following the eradication
of malaria in Guyana (a) the decline in the general
mortality greatly exceeded the fall in mortality specifically
related to malaria; (b) in infants, there was a marked fall
in prematurity, and (c) in adults there was a marked fall
in deaths due to chronic nephritis and chronic respiratory
disease; the decline continued for some 10 years after the
registration of the last death from malaria.
Since Gigioli's observations, the syndrome of nephrosis
in association with Plasmodium malariae infection has been
more clearly defined by studies in Nigeria[10]. Malarial
infection is also associated with immunosuppression, but
it is not clear to what extent this phenomenon aggravates
the morbidity and enhances the mortality of other concur-
rent infections.
Analysis of the distribution of the sickle cell gene gives
the highest estimates of the mortality due to falciparum
malaria. If it is assumed that malaria is the only selective
factor conferring the advantage to AS heterozygotes, then
the high sickling rates of 10-20 per cent in some African
populations suggest that as many as 20 per cent of the
subjects with normal haemoglobin, AA, die of malaria in
childhood.
Onchocerciasis provides another example of the need
to include indirect effects in estimating the impact of
tropical parasitic infections. In a prospective study of
adults (30 or more years old) living in an endemic area of
onchocerciasis, Prost and Vaugeladefl 1] found that the
mortality rate among the blind was four times greater
than among non-blind; such excess mortality would not
normally be attributed to onchocerciasis but it clearly
represents a significant element of the burden of disease.
In addition, there is clinico-pathological evidence of renal
pathology in association with onchocercal infection but
there has been no proper appraisal of the contribution of
this renal complication to morbidity and mortality on a
community basis.
If epidemiologists are having difficulties in assessing
the health impact of these diseases, the methodological
difficulties in assessing the economic impact are even
greater, but social scientists have made brave efforts to
tackle this difficult area[12].
It is well recognised that these diseases have their
maximum impact in the developing countries of the
tropics. This association has misled some to assume that
the more significant association is with development
rather than with the ecological effects of climate. Some
have promulgated the doctrine of spontaneous regression,
suggesting that these diseases would fade away, as they
did in Europe, under the pressure of social and economic
development or in response to broad non-categorical
measures such as personal hygiene and environmental
sanitation. To overlook or underplay the role of climate is
a dangerous over-simplification. After all, there was no
onchocerciasis in Oslo, no sleeping sickness in Siberia,
and no schistosomiasis in Stockholm.
Even though malaria did occur in colder climes, its
incidence was miniscule and its impact trivial compared
with the intensive transmission in the tropical belt,
especially in tropical Africa where it is deeply entrenched.
In England, at its worst malaria was estimated to kill 8
persons per million population per annum; compare this
with the estimated 10-20 per cent of children in Africa
dying of falciparum malaria[13], Not to recognise this
enormous difference in scale would be tantamount to
equating a raging tornado with a storm in a teacup.
Added to the development equation is the fact that man-
made lakes, irrigation schemes and similar agro-engin-
eering projects tend to extend and intensify the
transmission of malaria and schistosomiasis.
Clinical State
The clinical features of malaria and other parasitic infec-
tions have been so well described that this mass of
information tends to obscure our deep ignorance of the
subtle features of the host/parasite relationship. For some
of these infections there is a wide spectrum of clinical
manifestations ranging from asymptomatic or mild cases
at one end to acute life-threatening illness or chronic
crippling disease at the other extreme.
What factors determine the position of the individual
patient in the clinical gradient? For some helminthic
infections the severity of the disease can be correlated
with the number of worms in the particular patient.
Thus, in hookworm infection, there is a correlation
between the load of infection, the intake of dietary iron
and the occurrence of anaemia. In a series of elegant
studies on schistosomiasis, Cheever and his col-
leagues[14] have shown the correlation between the egg
count in the tissues, the number of worms recovered at
autopsy and the severity of the pathological lesions; but
there was still a considerable amount of variation in the
severity of the pathological lesions at each level of inten-
sity. In Schistosoma haematobium infections, there is a
correlation between the load of infection, as measured by
the egg count in the urine, and the lesions shown on
radiological examination. In Ibadan, Nigeria, our find-
ings suggest that in the natural history of this infection
there is a crucial stage of reversible obstructive uropathy;
but as yet there is no clue to the factors that determine the
outcome either in the direction of relief of the obstruction
or of irreversible damage[15].
Similar problems are encountered in the filarial infec-
tions. In lymphatic filariasis, only a proportion of those
infected show lymphoedema. Although some of the im-
munological differences between these types of patients
are being described, we do not know why some patients
develop swollen limbs but others do not. Similarly, in
onchocerciasis there is some correlation between the
severity of the anterior lesions of the eyes and the
intensity of infection as measured by the microfilarial
count, but the risk factors associated with the posterior
lesions have still to be identified.
In 1908, Carlos Chagas made the important discovery
of the parasitic infection that bears his name. He found
the parasite Trypanosoma cruzi in the blood of a two-year-
old girl Berenice[16], In 1961, at the age of 53, Berenice
still showed immunological and parasitological evidence
of the infection but there was no evidence that she had
developed any of the cardiac or gastrointestinal lesions
normally associated with this infection. She died in June /
206 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
1981 at the age of 73 with a form of heart disease but
probably not Chagas' disease. Whereas Berenice lived in
peaceful co-existence with Trypanosoma cruzi for over 70
years, there are countless others infected with the same
organism whose damaged hearts and other organs show
the battle scars of the confrontation between host and
parasite and in whom the infection traces a relentless
downward course of chronic disease and disability, lead-
ing inexorably to premature death. Why the difference?
There are many theories and suppositions as to factors in
the parasite, in the host or in some incompatibility in
their relationship which determine the nature and the
? ? intensity of the struggle as well as its outcome; in most
cases we are still groping in the dark.
?*> Therefore, it is not surprising that the management of
:T? patients tends to be based largely on the stereotyped
approach of killing the parasites with drugs. The current
crude chemotherapeutic approach, with the single-mind-
ed aim of killing the parasites, is associated with the twin
hazards of the toxic effects of the drugs and the reactions
of the host to the decaying mass of the dead parasites. It is
conceivable that if and when we know more about these
subtle relationships, we could devise treatments which
could be more suitably tailored to the needs of individual
patients; we could decide whom to treat, when to treat,
u what drug to use, not merely to kill the parasites, but,
more specifically, to modulate the host/parasite relation-
\ ? ship in favour of the host.
^ New techniques bring the hope that light can soon be
shed on these dark areas. For example, with the use of
i monoclonal antibodies and gene probes, it is now possible
to define more precisely the strains and species of the
parasites of man. In the case of Chagas' disease, studies
are under way to correlate the genetic variations of the
parasite with the clinical epidemiological features of the
disease. Immunological and genetic studies of the host
may also provide useful clues. New imaging techniques
and other non-invasive diagnostic methods should make
it feasible to study the evolution of the pathological lesions
and their response to various types of treatment. With
this new information, we would gain a better understand-
ing of the clinical challenge and this should lead to a more
rational management of infected persons.
Cells and Tissues
New powerful research tools of various basic biomedical
disciplines have led to a major explosion of knowledge of
living cells, their membranes and their constituent organ-
elles. Parasitology has benefited from these advances.
Immunologists, molecular biologists, biochemists and
geneticists are expanding our knowledge of the parasites
and their relationships to their hosts at the level of cells
and tissues. I wish to highlight three important aspects:
host/parasite relationships; vaccine development, and
new drugs.
Host/Parasite Relationships
Except for Entamoeba histolytica which is truly carnivo-
rous, most parasites do not display specific aggression
towards the host. Their activities seem to be directed
towards the achievement of the four cardinal require-
ments of parasitism: to multiply, to emerge from the host,
to find a new host and to infect it.
In the course of these events, damage to the host is
usually incidental, and is, as often as not, due to the
misguided attempts of the host to evict or destroy an
inoffensive but persistent guest, or else to inappropriate
reactions of the host to the dead or dying parasites, their
eggs or other products.
It is fascinating to discover the intimate details of the
mechanisms by which these organisms adapt to parasitic
existence, how they exploit the available resources within
the host and how they protect themselves in what is
clearly a hostile environment. Take, for example, Plasmo-
dium falciparum, whose biology has been intensively
studied since its continuous in vitro culture was
achievedfl 7], It has devised mechanisms for dealing with
the aggressive immune responses of the host. With regard
to humoral immunity, the parasite protects itself by
several mechanisms, some of which are not fully under-
stood. These include antigenic variation and the occur-
rence of changes in the antigenic structure of the parasite
as it switches from one stage to the other. The overall
effect is to present the host with an antigenic 'smoke-
screen' obscuring the most significant antigens that could
provoke protective immunity. Its sequestration in liver
and red cells at crucial stages of its development provides
additional routes of escape from the host's immune
system.
With regard to cellular immunity, the phenomenon
described by Udeinya et al. [18] suggests a mechanism by
which falciparum avoids destruction by the reticulo-
endothelial cells in the spleen and elsewhere. At the stage
when the infected red cells are most clearly recognisable
as foreign elements and the mature schizont is therefore
most susceptible to the scavenging action of the spleen,
the parasite extrudes knobs, covered with a histidine-rich
protein, that specifically adhere to the endothelial cells of
bloodvessels. This sequestration of the mature schizont is
one of the mechanisms by which falciparum malaria
builds up a level of parasitaemia far higher than that
achieved by the freely circulating malarial parasites of
other species.
Drug Resistance
The apparently unlimited capability of falciparum ma-
laria to deal with the challenge of anti-malarial drugs is
remarkable. The parasite has had thousands or even
millions of years to adapt to the immune responses of the
host; in fact, this is a prerequisite of successful parasitism.
But in the short space of a few years, falciparum malaria
has devised metabolic answers to the challenge posed by
practically every anti-malarial drug that has been exten-
sively used. The parasite has developed resistance to
pyrimethamine, proguanil, chloroquine and other 4-
aminoquinolines, to combinations of pyrimethamine and
long-acting sulphonamides, and even to quinine, which is
regarded as a general protoplasmic poison. The success of
falciparum malaria may eventually be traced to mecha-
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 207
nisms permitting it to reorganise its genetic material in a
flexible manner. One may imagine that its genes are not
cast in a solid mould or a rigid template but are construct-
ed out of interchangeable elements that can be fitted and
refitted as in a Meccano set or in Lego.
Vaccine Development
Attempts to develop vaccines against malaria and parasit-
ic diseases have encountered four major problems.
1. Natural infections do not confer a lasting immunity.
2. Parasites possess a wide variety of mechanisms to
evade and/or compromise the host's immune responses.
3. Parasites are large complex organisms as compared
with the viruses and bacteria against which successful
vaccines have been developed.
4. Problems with in vitro culture and the lack of appropri-
ate animal models have made it difficult to manipulate
parasites in the laboratory.
Natural Infections. With most of these parasites, natural
infection confers no immunity or at best an incomplete
protection. Even though most parasitic infections do not
confer sterilising immunity, subsequent attacks may be
clinically less severe; for example, patients recovering
from amoebic liver abscess are unlikely to develop this
complication when reinfected[19]. Falciparum malaria
provides an even more striking example of the way in
which repeated attacks of infection modify the severity of
the clinical manifestations and the outcome of the illness.
In areas of intensive transmission of falciparum malaria
(the so-called holo-endemic areas) adult males and non-
pregnant women become immune to the severe complica-
tions of the infection; in particular they have absolute
immunity to cerebral malaria, even though some compli-
cations tend to occur during pregnancy. Pre-school chil-
dren, pregnant women and foreigners are highly
susceptible and tend to develop fulminating, rapidly
progressive disease[20].
This immunity from cerebral malaria is lifelong, persis-
tent after long absences from the endemic area, and
passively transmitted to the fetus, providing protection
against cerebral malaria during the first few months of
life. The host achieves an accommodation with the
parasite?not total victory but a sort of armed truce.
The knowledge that the adult male inhabitants of holo-
endemic areas can stand up to falciparum malaria was
exploited in the deployment of West African soldiers to
fight in Burma during the Second World War. Falci-
parum malaria provides a convincing case that man is
able to mount some degree of protective immunity to
parasitic infections. The immunity develops slowly and
the protection is not absolute but it is nevertheless
clinically and epidemiologically significant. The response
to malaria is not typical of all parasitic infections; it is but
one example of the many variations of the complex
relationships between man and his endo-parasites.
Evasion of Host Immunity. Parasites evade host immunity
by hiding in safely secluded places in the body of the host,
sometimes finding refuge in the most unexpected places,
e.g. Leishmania organisms in macrophages; hypnozoites
(the dormant phase of P. vivax) in hepatocytes.
Some parasites are able to escape from the host de-
fences by manipulating their antigens. Each developmen-
tal stage of the parasite in man is usually associated with
different sets of antigens. This stage specificity keeps the
parasite one step ahead of the specific immune response of
the host. Antigenic variation is another phenomenon by
which some parasites, notably the blood stages of African
trypanosomiasis and falciparum malaria, escape the host
defences. Schistosome worms adopt antigenic disguise by
acquiring a surface coat of host antigens.
Host Responsiveness. Parasites undermine or compromise
the host's defence mechanisms by various mechanisms.
These include immunosuppression, antibody cleavage,
complement consumption, the formation of circulating
immune complexes, and polyclonal lymphocyte activa-
tion. Some of the parasitic infections provoke clinically
significant immunopathological effects including anaphy-
lactic, cytotoxic and delayed hypersensitivity reactions, as
well as lesions associated with immune complexes. It is
important to identify the antigenic components of the
parasites provoking these undesirable effects so that they
are excluded from the candidate vaccines.
Size and Complexity of Parasites. Parasites are large and
complex organisms. Modern immunological techniques
for purifying and characterising antigens, in particular
monoclonal antibodies, have provided immunologists
with precision tools for dissecting parasite antigens, a
means of separating the wheat from the antigenic chaff.
In Vivo/In Vitro Culture. For many of these parasites there
are no satisfactory animal models. It is also difficult to
extrapolate to man the results obtained from model
parasites in surrogate hosts. In vitro culture techniques
have improved, particularly for the blood stage of falci-
parum malaria, Trypanosoma brucei, and some filarial
worms[21].
Methods are being devised for the production of the
specific antigens in quantities sufficient for laboratory
tests, clinical trials, field trials and eventually for oper-
ational use. Three main approaches are currently being
explored: (a) splicing the parasite gene material into
Escherichia coli; (b) determining the sequence of amino
acids in the reactive sites of the polypeptide chains and
synthesising them, and (c) the use of live carriers, e.g. the
vaccinia virus.
There is now an atmosphere of cautious optimism
about recent steady progress leading to the development
of vaccines against some of the major parasitic diseases of
man. The most exciting progress has been made in the
search for malaria vaccines. Candidate antigens have
been identified for three developmental stages of the
parasite?sporozoite, merozoite and gamete stages. If the
present progress is maintained, clinical trials of a malaria
vaccine may start within the next few years, and others
are likely to follow[22].
208 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
Drug Development
Until recently, the strategy for the development of anti-
parasitic drugs was based on screening natural and
synthetic products; more often than not they were dis-
covered through fortunate accidents. In the case of herbal
remedies, from quinine to Qing-hao-su, we were literally
borrowing a leaf from nature, or perhaps a root or a bark.
We are now moving into the era of the rational develop-
ment of anti-parasitic drugs based on the identification of
leads from comparative biochemistry. The study of the
metabolic pathways of the parasites is revealing likely
targets for therapeutic attack.
(a) Trypanosoma brucei, like other haemoflagellates, is
highly vulnerable to agents that interfere with polyamine
synthesis. This clue led to the screening of specific
inhibitors of ornithine decarboxylase and the identifica-
? tion of di-fluoro-methyl ornithine (DFMO) as a likely
drug for the treatment of African trypanosomiasis[23],
(b) The scavenger pathway utilised by Leishmania organ-
isms instead of de novo purine synthesis led to the testing
of allopurinol and its riboside for the treatment of Leish-
maniasis]^].
(c) Peculiarities of the folate metabolism of the filarial
worms may provide a suitable target for chemotherapeu-
tic attack in filariasis[25].
These new approaches promise the development of
anti-parasitic drugs that are more potent, more selective
and specifically targeted by using lysosomotropic agents
i\ or suicide substrates, or that can achieve special effects,
/ e.g. blocking the receptors on host cells, reducing egg
production in worms, or disrupting the trigger mechan-
ism for antigenic variation. It should then be possible to
banish such notorious poisons as arsenic and antimony
from the pharmacopoeia of tropical medicine.
Conclusions
!, We have three ways of responding to the challenge of
persistent parasitic disease.
r
Biological. The biological responses of the host include a
variety of immunological defence mechanisms, both hu-
moral and cellular. Genetic factors are also important, as
in the case of the high prevalence of the sickle cell gene in
areas of endemic falciparum malaria; there are other
genetic markers, such as glucose-6-phosphate dehydro-
genase deficiency, whose relationships to parasitic infec-
tions are less well defined.
}:
Behavioural. Changes occur as part of the adaptation in
endemic areas, an extreme reaction being the total aban-
donment of areas that are heavily infested with infections
such as onchocerciasis or sleeping sickness.
* V
. Biomedical, or the deliberate fashioning of weapons of
offence and defence against the parasite invaders and
their vectors. In recent years there has been an intensifi-
cation of biomedical research on parasitic diseases and it
is hoped that the discoveries will widen the range and
effectiveness of our armamentarium of anti-parasitic
weapons to include vaccines, drugs with novel properties,
powerful diagnostic methods, and innovative vector con-
trol measures, including biological control.
If these expectations are realised in the coming dec-
ades, if the public health services in the endemic countries
can be equipped with these new weapons, and if their
strategic plans for controlling these diseases can be based
on sound epidemiological analyses with inputs from the
appropriate social sciences, we can confront the persistent
challenge of malaria and other parasitic infections with a
reasonable hope of attaining greater success than in the
past.
References
1. Rogers, L. (1907) British Medical Journal, 1, 427.
2. Schram, R. (1971) History of the Nigerian Health Services. Ibadan:
University Press.
3. World Health Organisation (1966) Technical Report Series,
No.335. Geneva: WHO.
4. De Morais, A. T., Schneider, C. R. and Wright, W. H. (1962)
Tropical Health: A Report on a Study of Needs and Resources, Publication
996. Washington, DC: National Academy of Sciences-National
Research Council.
5. Buck, A. A., Anderson, R. I., Sasaki, T. T. and Kawata, K.
(1970) Health and Disease in the Chad: Epidemiology, culture, and
environment in five villages. Baltimore and London: The Johns
Hopkins Press.
6. Neves, J. and Lobo Martins, N. R. L. (1967) Transactions of the
Royal Society of Tropical Medicine and Hygiene, 61, 541.
7. Ghana Health Assessment Project Team (1981) International Journal
of Epidemiology, 10, 73.
8. Molineaux, L. (1985) Health policy, social policy, and mortality prospects.
(ed J. Vallin and A. Lopez) Liege: Ordina Editions.
9. Gigioli, G. (1972) Bulletin of the World Health Organisation, 46, 181.
10. Gilles, H. M. and Hendrickse, R. G. (1963) British Medical Journal,
2, 27.
11. Prost, A. and Vaugelade, J. (1981) Bulletin of the World Health
Organisation, 59, 773.
12. Rosenfield, P. L., Golladay, F. and Davidson, R. K. (1984) Social
Science and Medicine, 19, 1117.
13. Bruce-Chwatt, L. J. and de Zulueta, J. (1980) The Rise and Fall of
Malaria in Europe. Oxford University Press.
14. Cheever, A. W. (1968) American Journal of Tropical Medicine, 17, 38.
15. Lucas, A. O., Akpom, C. A., Cockshott, W. P. and Bohrer, S. P.
(1969) Annals of the New York Academy of Science, 160, 629.
16. Lewinsohn, R. (1979) Transactions of the Royal Society of Tropical
Medicine and Hygiene, 73, 513.
17. Trager, W. and Jensen, J. B. (1976) Science, 193, 673.
18. Udeinya, I. J., Schmidt, J. A., Aikawa, M., Miller, L. H. and
Green, I. (1981) Science, 213, 444.
19. Sepulveda, B. and Martinez-Palomo, A. (1982) Immunology of
Parasitic Infections, (ed S. Cohen and K. S. Warren.) Oxford:
Blackwell.
20. Gilles, H. M. (1961) West African Medical Journal, 10, 293.
21. Rowe, D. S. and Hirumi, H. (1980) The in vitro Cultivation of
Pathogens of tropical Diseases. Basel: Schwabe.
22. Maddox, J. (1984) Nature, 310, 541.
23. Bacchi, C. J., Nathan, H. C., Hunter, S. H., McCann, P. P. and
Sjoerdsma, A. (1982) Biochemical Pharmacology, 31, 2833.
24. Berens, R. L., Marr, J. J., Nelson, D.J. and Lafon, S. W. (1980)
Biochemical Pharmacology, 29, 2397.
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Parasitology, 66, 428.
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
|
PMC005xxxxxx/PMC5371098.txt | A Profile of Geriatric Rehabilitation Units
KEITH ANDREWS, MD, MRCP(UK), Senior Lecturer
J. C. BROCKLEHURST, MD, MSc, FRCR Professor
Department of Geriatric Medicine, Clinical Science Building, Hope Hospital, Manchester
There are at present about 270 separate departments of
geriatric medicine in the UK, each providing a district
service. This service includes the admission and manage-
ment of elderly people with acute illness, the rehabili-
tation of those with disabilities, the use of day hospitals in
continuing support within the community, and provision
of long-term hospital care when necessary. The actual
delivery of these services varies from one unit to another,
depending on the nature of the available resources, e.g.
whether the beds are in one or more hospitals, and on the
style of practice adopted by the consultant. In 21 per cent
of departments all the functions (acute, rehabilitation and
long-stay) are combined on every ward; in 24 per cent
there are separate acute, rehabilitation and long-stay
wards; while in 38 per cent the acute and rehabilitation
aspects of care are combined in one group of wards but
there are separate long-stay wardsfl]. This article pro-
vides a profile of the rehabilitation wards of those 24 per
cent of geriatric departments in which there are separate
rehabilitation wards. A previous study[l] had identified
52 such departments and 36 of these (69 per cent)
completed a further questionnaire which gave details of
patients admitted and discharged from the rehabilitation
wards during a two-week period (14th-27th March 1983)
together with information about time spent on these
wards by medical staff during the two weeks.
Results
During the two-week period 387 patients were admitted
and 326 discharged from the rehabilitation wards, which
is equivalent to 6.6 admissions and 5.9 discharges per
consultant geriatrician or 0.28 admissions and 0.23 dis-
charges per rehabilitation bed.
Admissions
Table 1 shows the source of the admissions. Two-thirds
were directly from the community and one-fifth by
transfer from other specialties. In many cases, those
admitted from home or residential homes would have
been seen there prior to admission by the consultant or a
deputy on a domiciliary assessment visit. Similar num-
bers of patients (8-10 per cent) were transferred from
orthopaedic wards (principally with fractured neck of
femur) as from medical wards (principally stroke
Table 1. Source of admission of 387 patients admitted to
rehabilitation wards.
Source %
Home 58
Residential home 6
Private rest home 1
Acute geriatric unit 13
Medical 8
Orthopaedic 10
Surgical 3
Not stated 1
patients). The mean age of patients admitted was 80.5
years. Seven per cent of the males and 5 per cent of the
females were aged less than 70 years, and 24 per cent of
the males compared with 30 per cent of the females were
aged 85 years and over. Altogether 103 patients were
male and 284 were female.
Discharges
The mean age of those discharged was slightly lower for
males (76.7 years) than for females (80.6 years), although
a greater proportion of males (15 per cent) than females (8
per cent) were under 70 years of age whereas a greater
proportion of females (29 per cent) than males (13 per
cent) were over 85 years of age. Altogether 58 per cent of
admissions and 52 per cent of discharges were of patients
aged 80 years and over; 110 patients were male and 216
female, showing a slightly higher proportion of males
among those discharged than those admitted.
Diagnostic Categories
The major diagnostic categories are shown in Table 2.
Since it is often difficult to decide on the principal
diagnosis in the elderly, Table 2 shows either the first or
second diagnosis as listed by the respondents.
Stroke was the most common single diagnosis, followed
by arthritis, fracture of the femur, and confusion. It is
surprising, however, that acute medical conditions ac-
counted for 22 per cent of admissions and included an
even larger proportion of those who were discharged. In
19 per cent symptoms, rather than diagnoses, were listed.
240 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
Table 2. Diagnosis on admission and discharges to rehabili-
tation wards.
Diagnosis Admissions Discharges
(No. = 387) (No. = 326)
% %
Stroke 27 20
Other Neurological: 6 8
Parkinsonism 3 5
Myopathy/neuropathy 2 2
Paraplegia 1 1
Acute Medical: 22 28
Cardiac failure 8 9
Respiratory 4 2
Other 10 17
Orthopaedic: 15 7
Fracture femur 11 4
Other fractures 2 1
Amputation 2 2
Psychiatric: 13 4
Dementia/confusion 11 4
Depression 2 <1
Musculoskeletal: 12 11
Osteoarthritis 10 9
Spinal problems 2 2
Peripheral Vascular: 5 4
Peripheral vascular disease 1 2
Skin ulceration 4 2
Other: 2 4
Cancer 1 4
Post-operative 1 <1
Symptoms: 19 9
Debility 5 2
Incontinence 5 1
Balance problems 9 6
k
Length of Stay
The mean length of stay (Table 3) was related particularly
to the places to which the patient was discharged. It was
31 days for those going home, but more than twice that
length of time for those going to residential homes and
long-term care geriatric units. This table also shows that
Table 3. Length of stay related to place of discharge of rehabilitation patients.
Residential Private Long- Died
Length of Home home rest home stay
stay (weeks) 225(69%) 30(9%) 10(3%) 12(3%) 39(12%)
% % % % %
<4 37 7 20 0 35
-6 27 17 30 20 22
-8 17 24 20 30 11
- 10 9 3 10 10 5
- 14 6 17 0 10 11
- 18 2 14 0 0 8
> 18 3 17 20 30 19
Mean length of
stay (days) 31.4 70.8 56.1 81.7 70.2
Mean age (yrs) 78.9 82.5 74.3 83.1 80.1
the 10 patients (3 per cent) discharged to private rest
homes were significantly younger than all the others. The
readier accessibility of home or private rest homes is
shown by the fact that more than 50 per cent of patients
going to either of these were discharged in six weeks or
less.
Follow-up Arrangements
No follow-up was arranged for 38 per cent of the dis-
charged patients. However, 33 per cent continued as day
hospital patients, 20 per cent with review in the out-
patient clinic and for 8 per cent relief admissions were
arranged.
Medical Input
A consultant ward round took place at least once a week
in all but one unit and twice a week in just over half of the
units. The average amount of medical time spent per
patient each week (Table 4) amounted to lj hours; this
included 15 minutes of consultant time?equivalent to
one session a week for a 20-bedded ward.
Table 4. Time spent by medical staff on 34 rehabilitation
wards.
Grade No. of Minutes per bed Equivalent
units with (mean) hours for
grade 20-bed ward
Consultant 33 15 4.9
Senior Registrar 9 18 6.1
Registrar 12 21 6.9
SHO 26 65 21.8
House Officer 4 121 42.0
Other 17 7 2.5
All medical staff 34 96 32.1
Very few pre-registration house officers were involved
in rehabilitation wards, although when they were this was
a full-time equivalent of 42 hours for a 20-bedded unit.
The main day-to-day care was carried out by Senior
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 241
House Officers (in 77 per cent of departments) who spent
an average of 22 hours per week on a 20-bedded ward.
Discussion
About one quarter of the departments of geriatric medi-
cine in the UK have wards that are specially designated as
rehabilitation wards. These are all departments practising
along the traditional lines of progressive patient care with
further wards designated for acute admissions and for
long-stay care. While this is the general pattern of such
units, it is the nature of geriatric provision to be spread
over a number of different hospitals and each of these has
to be used with some degree of flexibility. Thus there is no
absolutely constant pattern of practice. This is clear from
the fact that the designated rehabilitation wards in this
study received almost two-thirds of their patients direct
from the community and only one-third on transfer from
other wards, and the principal diagnosis in one-third of
these cases was an acute medical condition indicating a
need for investigation. These findings suggest that the
wards were not functioning as pure rehabilitation wards
(providing physical therapy after the acute stage has
passed) but rather directly accepting patients whose
breakdown had been precipitated by an acute medical
episode. Thus many of the patients admitted to rehabili-
tation wards required medical treatment and/or investi-
gation as well as physical rehabilitation.
The principal conditions requiring rehabilitation were,
as might be expected, those sub-acute, chronic or com-
plex disabilities such as stroke (27 per cent), fracture of
the femur (11 per cent) and arthritis (10 per cent).
The mean length of stay in rehabilitation wards is
enormously variable, ranging from one month for
patients admitted from home, to two and a half months
for patients transferred from other units. This suggests
that transfer from other units was for complex disabilities
requiring the full skills of a multi-disciplinary team.
Eighty per cent of the workload in these rehabilitation
wards was for the age group in the population which is
expanding most rapidly (i.e those of 75 years and over)
and as many as 11 per cent of females were over the age of
90 years. This has clear implications for priorities in the
development of future resources and emphasises the need
for an increase in the number of therapists and others
working with the elderly[2].
The rehabilitation programme was obviously successful
for the majority of patients, since 69 per cent returned
home and only 3 per cent required a hospital long-stay
ward. Although this might have been due to selection of
those with the most potential for discharge, it must be
recognised that 12 per cent of patients died on the ward
and a further 12 per cent required residential care, either
in social service or private rest homes. The length of stay
of those transferring to social service residential homes
was 71 days?much longer than those going to private
rest homes or to their own homes. While this may partly
indicate increased disability among those going to resi-
dential homes, it is just as likely to indicate a waiting list
for that facility.
Geriatric medicine, especially the rehabilitation com-
ponent, might be expected to require continuous moni-
toring. It is therefore of interest that no follow-up was
arranged for 32 per cent of those discharged, although
about one quarter continued their rehabilitation pro-
gramme in the day hospital. Domiciliary rehabilitation
services were rarely used. The chronicity and complexity
of the patient's management is demonstrated by the fact
that 8 per cent were scheduled for further readmission as
'relief' patients?usually to provide support for caring
relatives.
There is a major medical input into rehabilitation
wards, one session of consultant time and 22 hours of
SHO time being the the norm. From the variety of
patients admitted and the fact that many of them were
suffering from acute medical disorders, it would seem that
these wards are appropriate for general medical training.
This study demonstrated the complexity of geriatric
rehabilitation management in an age group which is
rapidly expanding in number.
Acknowledgements
We are grateful to the King's Fund for financial support,
and to our colleagues who provided the information on
which the study is based.
References
1. Brocklehurst, J. C. and Andrews, K. (1985) Age and Ageing, 14, 1.
2. Andrews, K. and Brocklehurst, J. C. (1984) British Medical Journal,
289, 661.
242 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
|
PMC005xxxxxx/PMC5371099.txt | Progress towards a Malaria Vaccine
S. COHEN, CBE, MD, FRCPath, FRS
Professor of Chemical Pathology, United Medical and Dental Schools, Guy's Hospital, London
The failure of conventional prophylactic measures to
control malaria in tropical and sub-tropical areas of the
developing world has focused attention upon the great
benefits that would accrue from the availability of effec-
tive malarial vaccines. However, some features of ma-
larial immunity, as it develops in its natural hosts
including man, have long cast doubts upon the plausibil-
ity of such a goal. Thus, in areas of sustained malaria
transmission, clinical immunity develops slowly over
perhaps a decade of repeated exposure to infection. In
addition, the immunity achieved is incomplete in the
sense that low levels of parasitaemia are seen intermit-
tently in subjects who are clinically immune. Such obser-
vations have suggested that malaria parasites may be
antigenically diverse so that clinical immunity prevails
only after exposure to a wide spectrum of antigenic
variants. A high degree of variation within a given
plasmodial species could seriously jeopardise attempts to
develop malaria vaccines.
However, certain features of acquired malarial immun-
ity do encourage the hope of vaccine development. For
example, immunoglobulin from immune African adults
effectively clears parasitaemia from infected infants, in-
cluding those resident in geographically remote areas. In
addition, specific immunoglobulins can be shown to
prevent, in vitro, the entry of sporozoites into liver cells
and merozoites into red cells. As anticipated from such
observations, both sporozoites and merozoites, appropri-
ately inactivated, have provided the basis for stage
specific vaccination against various species of experimen-
tal malaria, including Plasmodium falciparum, the cause of
malignant tertian malaria in man. But the large-scale
production and standardisation of such vaccines is not
practical. These difficulties have been circumvented by
two major recent technological developments which have
facilitated the production of vaccines comprising individ-
ual antigenic constituents of malaria parasites. These are
hybridoma technology for production of monoclonal anti-
bodies, and gene cloning which permits the detailed
characterisation and in vitro production of specific plas-
modial polypeptide antigens with potential for inducing
immunity to natural infection. These advances have rev-
olutionised prospects for practical vaccine development.
The Malaria Cycle
More than 100 plasmodial species have been described,
which cause malaria in a wide range of vertebrates and
exhibit narrowly defined host specificity, only four species
being naturally infective for man. Infection is initiated by
the bite of a female anopheline mosquito which inoculates
saliva containing sporozoites. These motile organisms,
11-12 /un long, are rapidly cleared from the circulation
and initiate the tissue stage of primary exo-erythrocytic
(ee) development, which in mammalian malarias is con-
fined to liver parenchymal cells. Exo-erythrocytic forms
become multinucleate and within about 10 days they
rupture to liberate 100-30,000 ee merozoites. In some
species, including P. vivax in man, ee forms may remain
latent for several months before maturation. Blood infec-
tion is initiated by merozoite invasion of red cells. This
involves a sequence of random adherence to the erythro-
cyte, attachment of the apical prominence of the mero-
zoite to a specific red cell receptor and induction of
endocytosis by the red cell. Intracellular growth proceeds
through stages of ring, trophozoite and schizont and
terminates with rupture of infected cells at 24-72 hour
intervals, liberating 10-30 merozoites which initiate a
further cycle of development. The clinical signs and
symptoms of malaria are associated exclusively with
cyclical blood stage development.
After a period of purely asexual multiplication of
erythrocytic parasites, a proportion of newly invaded
merozoites differentiate into male and female gameto- J
cytes. These mature without undergoing cell division
over a period of about 10 days. When ingested into the
mosquito stomach, the male (microgametocyte) under-
goes exflagellation, liberating eight microgametes, and
fertilisation occurs. The zygote differentiates in the wall
of the mosquito gut and sporozoites finally accumulate in
the insect salivary glands to complete the sexual cycle of
development. Current attempts at prophylactic vaccine
development are concentrated on two separate stages of
the parasite, which induce stage-specific immunity.
These comprise the sporozoite and the blood-stage mero-
zoite.
i
Sporozoite Vaccines
Natural sporozoite infection does not lead to acquired
immunity in man or any experimental animal. However,
the inoculation of sporozoites attenuated by irradiation
does induce effective immunity in experimental rodent
and human malarias; this protection is strictly stage
specific and without effect upon the blood-stage of infec-
tion. Sporozoites for vaccine preparation can be isolated
210 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
I
from salivary glands of infected mosquitos by laborious
dissection but a practical vaccine based on such material
cannot be envisaged. The induction of stage-specific
-> clinical immunity by attenuated sporozoites is neverthe-
less of considerable interest and has stimulated attempts
' to identify protective sporozoite antigens.
Monoclonal antibodies secreted by hybridoma cell lines
'recognise' an immunodominant surface antigen, the
y- circumsporozoite (CS) antigen, which occurs in distinct
but analogous forms in several species of plasmodia,
including the human parasites P. falciparum and P.
malariae. The protective nature of the antigen is indicated
by the fact that specific monoclonal antibodies directed
,J, against it are able to neutralise sporozoite infectivity both
in vitro and in vivo.
The molecular structure of CS antigens has been
established in two species by cloning the genes which
control their synthesis. In the case of P. falciparum, the
entire gene was isolated from a genomic DNA library and
, shown to encode a protein, of 412 amino acids, which
includes an unusual central region consisting of 41 tan-
(, dem repeats of a tetrapeptide that constitutes the immun-
odominant portion of the molecule. The simian parasite,
P. knowlesi, has a CS antigen of analogous structure (Fig.
1) with a central segment of repeat sequences of a
dodecapeptide. This peptide has been synthesised and,
after attachment to a carrier protein, used to immunise.
Although the vaccinated animals produced antibody reac-
tive with the CS protein, there are no reports of induced
protection against sporozoite challenge, probably because
an essential component of immunity against exo-erythro-
cytic stages of malaria may be cell-mediated and directed
against parasites developing in hepatic parenchymal cells
(Fig. 2). Thus most mice rendered B-cell deficient by
repeated injection of anti-IgM serum can be successfully
vaccinated with irradiated sporozoites; the failure of these
immunised animals to produce measurable levels of
11, specific antibody indicates that cell-mediated effector
mechanisms have a role in anti-sporozoite immunity.
Effective vaccination may therefore require both the CS
antigen to induce antibody which limits the number of
IK sporozoites entering the liver, and other as yet unidenti-
Tied antigen(s) which induce cell-mediated immunity
against the developing hepatic forms of the parasite.
Blood-Stage Antigens
As the clinical manifestations of malaria are associated
exclusively with the blood-stage of parasite development,
this stage is a prime target for any malaria vaccine.
Immunity to blood-stage infection does develop naturally
after long and repeated exposure to infection and has
been actively induced in experimental malarias by using
isolated erythrocytic merozoites as vaccines. The develop-
ment of more practical and refined vaccines is compli-
C?terminal
N?terminal
Asn
Anchor Charged
Sequence Area
Area of
Degenerate
Repeats?
INTRAMOLECULAR
TANDEM REPEATS
12 (Ala3, Gln3, Gly3,
Pro, Asp, Asn)
Met
Charged
Area
Signal
Sequence
Fig. 1. Diagrammatic representation of the amino acid sequence of the P. knowlesi circumsporozoite protein deduced from the
nucleotide sequence of the gene controlling its synthesis. The central region consisting of 12 tandemly repeated dodecapeptides
constitutes the immunodominant region of the csp protein.
Fig. 2. Immunity to the sporozoite stage of malaria infection
probably requires induction of both antibody to the csp protein,
which limits the number of organisms gaining access to hepatic
parenchymal cells, and cell-mediated immunity which destroys
intracellular exo-erythrocytic schizonts.
L
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 211
cated by the considerable antigenic complexity of the
erythrocytic parasite and the apparent absence of any
immunodominant surface structure as seen in sporo-
zoites. In addition, there is considerable antigenic diversi-
ty of blood-stage plasmodia within a given species.
The phenomenon of antigenic diversity can be illustrat-
ed by the properties of a component found on the surface
of schizont infected red cells in several species of malaria.
This antigen, recognised by monoclonal antibodies, is
synthesised late in the cycle of asexual blood-stage devel-
opment as a high molecular weight protein (about 200
kD) and is localised on the surface of schizont infected
erythrocytes. At the time of rupture of the parasitised red
cell the protein is cleaved to a series of smaller peptides
present on the surface of newly released merozoites. The
protective role of this antigen is shown by the fact that
monoclonal antibodies directed against it inhibit parasite
multiplication in vitro and in vivo; in addition, vaccination
with the antigen confers significant immunity in rodent
malaria. Analysis of the antigen in different isolates of P.
falciparum reveals that it contains a region of invariant
structure while other portions of the molecule vary in
different parasite strains. It is the variable part of the
molecule which seems to be expressed on the red cell
surface and it is this heterogeneity which seems likely to
limit the value of the antigen as a potential vaccine
component.
Fortunately, other protective antigens of blood-stage
parasites appear to have an invariant structure in all
isolates of a given species. One such antigen (150 kD
molecular weight) appears to be lodged in the membrane
of ring-infected red cells during merozoite invasion.
Antibodies reactive with this antigen inhibit parasite
multiplication in vitro. Part of the gene controlling the
synthesis of this antigen has been analysed and found to
code for a series of repeat peptides enclosing a non-
repeating amino acid sequence. This antigen remains
invariant among geographically remote isolates of P.
falciparum and therefore has considerable interest as a
putative vaccine. However, its stability must be estab-
lished by direct testing since another antigen found to be
common to several strains of the simian parasite P.
knowlesi underwent variation when subject to the immune
pressure which followed its use as a vaccine.
Apart from the complication of antigenic plasticity
among malaria parasites, the development of blood-stage |
vaccines may, as suggested above for sporozoites, require
the induction not only of anti-merozoite antibody, but
also of specific cell-mediated immunity active against
intra-erythrocytic parasites (Fig. 3). Specific T-cells reac-
tive with plasmodial antigens are known to stimulate
macrophages to release such parasiticidal agents as tu-
mour necrosis factor and oxygen-derived free radicals I,
which can kill parasites developing within red cells. Such
agents might be most effective when parasitised cells
come in close contact with activated macrophages as
would occur in the splenic circulation; this may explain
the prime importance of the spleen in malarial immunity. >j
The identification of blood-stage plasmodial antigens
reactive with T-cells and able to induce cell-mediated
effector mechanisms against intracellular blood-stage
parasites, may ultimately be mandatory for successful
vaccine development.
Conclusion .
Acquired immunity to malaria is stage and species
specific; it depends in part upon antibodies that block
sporozoite attachment to hepatocytes or inhibit merozoite
invasion of red cells. Additional mechanisms, mediated
by T-cells and macrophages, killing intracellular parasites
through oxidative and other mechanisms, are involved in
the maintenance of immunity. Some forms of experimen-
tal vaccination, including the use of irradiated sporozoites *
and non-viable extracellular blood-stage merozoites, in-
duce effective immunity, but are impractical for mass
human vaccination. The isolation of individual plasmo-
dial antigens is currently being expedited by the use of I
monoclonal antibodies and gene cloning techniques.
Sporozoites of all species have a uniform (but unique)
circumsporozoite protein which has the properties of a
protective antigen. No comparable immunodominant
protective antigen has been identified in blood-stage
parasites, which are antigenically extremely complex.
However, a variety of antigens with protective properties
are being delineated; many of them are associated with
mature schizonts and some appear in a partially degraded
form on the surface of merozoites. This work has led to
the cloning of several genes controlling the synthesis of
protective polypeptide antigens, and is concentrated on
those common to all strains of a given species.
Some immunodominant antigenic peptides of these
antigens have been synthesised and show promise as
components of an ultimately practical and effective vac-
cine against the exo-erythrocytic and erythrocytic stages
of human malaria. The remaining areas of uncertainty in
this endeavour concern the antigenic stability of individ-
Fig. 3. Immunity to the blood-stage of malaria requires the
presentation of antigens by accessory cells (A) to Tjj cells. These
induce B-cells to make antibody which neutralises free merozoites
and also activate macrophages (M<\>) to produce oxidative and other
products, such as tumour necrosis factor, which kill intra-
ervthrocytic parasites.
212 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
I
I
ual protective antigens when subject to immune pressure
?/ following vaccination and the requirement in any vaccine
for T-cell reactive antigenic determinants able to induce
cell-mediated immunity active against intracellular para-
) sites.
r
This article is based on a paper read at the Conference on
Infectious Diseases held at the Royal College of Physicians in
May 1985.
References
The following reviews provide the sources of original work quoted.
1. Allison, A. C. and Eugui, E. M. (1983) Annual Review of Immunol-
ogy, 1, 361.
2. Cohen, S. (ed) (1982) British Medical Bulletin, 38, 115.
3. Cohen, S. and Cross, G. A. M. (eds) (1984) Towards the Immunologi-
cal Control of Human Protozoal Diseases, p.213. London: The Royal
Society.
4. Deans, J. A. and Cohen, S. (1983) Annual Review of Microbiology, 37,
25.
|
PMC005xxxxxx/PMC5371100.txt | The Protean Manifestations of Legionnaires'
Disease
M. A. WOODHEAD, MB, MRCP(UK), Research Registrar
J. T. MACFARLANE, DM, MRCP(UK), Consultant Physician
Department of Thoracic Medicine, City Hospital, Nottingham
The nine years following the dramatic discovery of
Legionnaires' disease (LD) in 1976 has seen a rapid
growth in knowledge about the subject. The explosive
outbreak in the Legionnaires in Philadelphia, the ubiqui-
tous distribution of the organism in moist environments,
its recognition in tourists returning from Mediterranean
holidays, the apparent high mortality and the suggestion
of a unique clinical picture all helped stimulate interest in
the disease.
The recent, severe outbreak of LD in Staffordshire,
with over 160 people affected and at least 34 deaths, has
shown that the disease is capable of presenting, even in
Britain, as a major outbreak as well as the more usual
sporadic, community-acquired cases that we are used to.
Thus doctors everywhere need to be aware of both the
common and and the less usual features of the infection.
The disease is remarkable for the diverse nature of its
clinical features which suggest multi-system involvement.
Not uncommonly respiratory symptoms are minimal
despite the principal pathological manifestation as pneu-
monia. As with any 'new' disease, complications and
unusual features are being reported increasingly often.
We now know there are at least 10 species of legionella
of which one serogroup, of one species, is responsible for
the majority of infections, namely, Legionella pneumophila
serogroup 1. Infection may occur in epidemic form, in
endemic form or as sporadic cases. The disease may be
community-acquired or nosocomial (hospital-acquired).
LD is not uncommon and may account for up to 15 per
cent of all community-acquired pneumonias in both the
USA[1] and Britain[2], although there are regional vari-
ations^].
This article sets out to describe the typical clinical
features of LD and to review the recorded complications
of the condition. Although there is relatively little experi-
ence with infection caused by the other legionella species,
available evidence suggests that the clinical picture is
similar whichever organism is involved and by whichever
means the disease is spread. For the purpose of this
review all forms of the disease will be considered together.
Typical Clinical Features (Table 1)
Two distinct clinical syndromes are recognised. The best
known is the classical pneumonic form of LD. The other
Table 1. Features of Legionnaires' disease.
System
Common Features
Unusual Features
Respiratory Cough, dyspnoea,
chest pain
Progressive consolidation
Slow X-ray resolution
Cardiovascular Relative bradycardia
Neurological
Musculo-
skeletal
Renal
Gastro-
intestinal
Drowsiness
Confusion
Retrograde amnesia
Brain stem features
Myalgia + weakness
Hyponatraemia
Uraemia
Proteinuria +
haematuria
Diarrhoea
Vomiting
Abdominal pain
Abnormal LFTs
Hypoalbuminaemia
Respiratory failure
Pneumothorax
Cavitation
T achyarrhythmias
Myocarditis
Pericarditis + effusion
Endocarditis
Guillain-Barre
Peripheral neuropathy
Meningitis
Rhabdomyolysis
Arthritis
Acute renal failure
Pyelonephritis
Paralytic ileus
Gut perforation
Jaundice
is the non-pneumonic form"known as Pontiac Fever[4],
In addition, asymptomatic seroconversion to legionella
has been recorded[5], but its prevalence is not known.
Legionella Pneumonia
In classical LD the initial, non-specific symptoms of
anorexia, malaise, chills, headaches and myalgia usually
appear after an incubation period of two to 10 days[6].
Although rhinorrhoea and nasal congestion have been
reported[7], symptoms referrable to the upper respiratory
tract are uncommon. Cough, which is initially unproduc-
tive, appears in the first few days in 80-90 per cent of
cases. Sputum production occurs in only 50 per cent and
may be mucoid or purulent. Haemoptysis may occur in
up to one-third of cases at some time in their illness.
Dyspnoea and chest pain, which is often pleuritic, are
found in one- to two-thirds of cases.
224 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
!
I
J
j
Frequently it is the non-respiratory features of the
'j ' illness that attract most attention. Gastrointestinal symp-
\ , toms are common, with diarrhoea in up to 50 per cent,
nausea and vomiting in up to one-third and abdominal
pain in about 20 per cent of patients. Diarrhoea, which
may be the presenting symptom, is usually watery and
not associated with the passage of pus or blood. Involve-
?- > ment of the central nervous system is also common, up to
; , 50 per cent of patients having neurological symptoms.
' Confusion, lethargy and stupor are quite common, hallu-
cinations and agitation being recorded occasionally.
Later in the illness retrograde amnesia is often apparent.
- _ Fever is an almost universal finding. Initial tempera-
ture rise is in a stepwise fashion, very high temperatures
often being reached. Up to 90 per cent of patients will
have a temperature in excess of 38.9?C and up to two-
\ . thirds may have temperatures of over 40?C. Despite the
high fever tachycardia is only present in about one-third
of patients[7]. The relative bradycardia seen in the
majority of patients has been suggested to be characteris-
tic of, though not specific to, LD. Skin rash, unless
related to therapy, is exceptional, but herpes labialis may
^ If occur.
Only about 20 per cent of patients will have classical
signs of pulmonary consolidation, but nearly all will have
focal crepitations and 50 per cent will have rhonchi. The
respiratory rate is usually elevated; 42 per cent had
^ . respiratory rates over 25/minute in the 1976 epidemic[6].
A pleural rub is occasionally noted and pleural effusions
may occur but are seldom clinically detectable.
The abdomen is usually unremarkable and, although
localised tenderness may occur in up to 25 per cent, signs
of peritonism have only been recorded when there is an
adequate alternative explanation such as coincident ap-
pendicitis^].
* Pontiac Fever
Few outbreaks of Pontiac Fever have been reported. They
are usually epidemic and a common source is often
identifiable. Usually there is a 95-100 per cent attack rate
in exposed individuals. The illness is 'flu'-like, with a
short incubation period of 36 hours followed by fever,
chills, headache and myalgia.. Diarrhoea, arthralgia,
. dyspnoea and dry cough may occur. The chest radio-
graph is always normal. The illness is usually self-
limiting, lasting about five days. Complications have not
been recorded. Why legionella infection produces Pontiac
\ Fever in some individuals and pneumonic LD in others is
not known. In one common source outbreak both pat-
l - terns of illness were found[9],
| Laboratory Findings
Leucocytosis is common at presentation with 50-75 per
/ ? cent[6,7,10] of all patients showing a total white cell count
t - of over 10,000/^1 and between one quarter and one half
over 15,000/^tl. The elevated white cell count is due to a
neutrophilia which is usually accompanied by a left shift.
Lymphopenia (< 1,000/yu.l) may occur in one half to two-
thirds of patients[7,l 1], High ESR occurs frequently,
being greater than 60 mm/hour in two-thirds of
patients[6]. Platelet counts are usually normal.
One half to two-thirds of patients are hyponatraemic
(<130 mMol/litre) at presentation. Although in some
cases this may be due to the syndrome of inappropriate
ADH secretion[7], in the majority hypovolaemia appears
to be responsible[12,13]. This may also contribute to the
elevation of serum urea and creatinine found in 50 per
cent of patients[10], frank renal failure being uncommon.
Proteinuria is a common finding and occurs in about half
of all patients; haematuria may also occur in 30-50 per
cent, although it was not noted in any of 65 patients in
one series[7].
Derangement of liver function is also a common find-
ing, 50-75 per cent of patients having elevated liver
enzyme levels. In addition, hypoalbuminaemia occurs in
up to two-thirds[10]. Hypophosphataemia may also be
found in up to half of all cases[7].
Sputum, when present, is usually mucoid and contains
scanty inflammatory cells. Gram staining is unable to
distinguish legionella from normal oropharyngeal com-
mensal organisms.
Pleural fluid usually shows features of an exudate and
may contain large numbers of polymorphonuclear leuco-
cytes.
Radiology
There are no unique radiological features of LD although
it does differ in some respects from other pneumonias.
Consolidation is evident on the chest X-ray at presen-
tation in at least 90 per cent of patients[10]. As with other
pneumonias, involvement of the lower lobes is most
frequent. Consolidation may be patchy or homogeneous,
segmental or lobar. In some cases small well-circum-
scribed areas of shadowing may occur, giving a nodular
appearance[6]. In two-thirds to three-quarters of cases
changes are confined to one lobe, but as many as one-
third may develop bilateral changes[6,14].
Unlike other pneumonias radiographic deterioration is
common in LD. Progression of X-ray changes may be
seen in up to 65 per cent of cases[14,15], occurring over
two to five days. Spread may occur within the same lung
or to the opposite lung and may continue despite appro-
priate antibiotic therapy and clinical evidence of improve-
ment in the patient's general condition.
Pleural effusions are quite common, occurring in one-
to two-thirds of cases[16], more being detected when
lateral decubitus X-rays are routinely performed. Typi-
cally these are small. In a few patients pleural effusion
may precede parenchymal changes by two to seven days.
Muder et al. [17] describe a patient, without parenchymal
consolidation, but with bilateral pleural effusions from
both of which L. micdadei was isolated. Although hilar
gland enlargement is often seen at postmortem[18,19], it
is seldom detected radiologically. Complete lobar collapse
is uncommon[20], but some degree of collapse may be
seen in about one-third of patients[15].
Although in one series 75 per cent of patients showed
radiographic resolution by two months[16], the hallmark
of most series has been the very slow resolution of
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 225
radiographic changes. Radiographic resolution is slower
than for all other pneumonias, with 50 per cent of cases
still showing abnormalities at three months[15], The
series showing relatively rapid resolution of radiographic
changes was of a nosocomial population in whom the
illness was detected very early, with most patients receiv-
ing prompt erythromycin treatment, and may therefore
not be representative. In a number of patients complete
radiological resolution does not occur, linear streaky
opacities remaining in up to one-third and pleural shad-
ows in some.
Complications
Pulmonary
Respiratory insufficiency is common, the majority of
patients requiring supplemental oxygen[6]. Respiratory
failure of sufficient severity to require assisted ventilation
occurs in up to 20 per cent of cases. The mortality in these
patients is very high. Of the patients ventilated in the
Philadelphia epidemic, 68 per cent died[6] and in a study
of nosocomial LD 82 per cent of those ventilated died[7].
In our hospital, of 14 patients ventilated for sporadic,
community-acquired LD, the mortality was only 36 per
cent, suggesting, perhaps, that the prognosis in this group
may be better[21].
Pulmonary cavitation is uncommon, being found in
only 1-4 per cent of cases in most series[10,15,22],
although in one small series from Holland it was recorded
in 20 per cent[23]. Pulmonary cavitation is usually found
in immuno-compromised patients, but may also occur in
the immuno-competent[24,25]. Cavitation occurs within
the area of previous consolidation and more commonly
affects the upper lobes, although other lobes may be
affected[26]. Cavities may be single or multiple, unilater-
al or bilateral[26] and may be complicated by pneumo-
thorax[27,28]. Treatment may be followed by complete
resolution of cavities[29], persisting lung cysts[26], or in a
number of cases, progression to pulmonary fibrosis[25].
In one case cavity formation was followed by total
destruction of the whole lung[27]. In some cases other
pathogens, capable of causing lung necrosis, have been
isolated and may have been responsible for the cavitation.
However, a number of well documented cases have now
been reported in which legionella was the only organism
found. Prolonged carriage of both L. pneumophila]?)^] and
L. pneumophila with L. micdadei[26] has been noted in
patients with cavitary LD, which suggests that prolonged
antibiotic treatment may be necessary in such cases.
Empyema has been reported in association with legionella
infection[31,32], but must be very uncommon.
Relapses of LD over days[26] or months[33] have been
recorded. The former is presumably due to inadequate
antibiotic treatment, but the latter may conceivably be
due to recurrent re-infection.
Destruction of alveolar spaces and healing by fibrosis
are prominent histological features in LD and led to fears
that severe LD might cause persisting lung damage. The
majority of patients make a complete recovery from the
acute illness and although, as already noted, up to one-
third may have persisting radiographic abnormalities,
there is little evidence to suggest that the changes are
functionally significant. A reduction in transfer factor was
noted in nearly 50 per cent of a small group of patients
studied two years after the Philadelphia outbreak[34].
Some of these patients complained of effort dyspnoea, but
whether this was related to the reduced diffusing capacity
is not known. Shaw et al. [35] studied two patients
ventilated during their acute illness. Ten weeks after the
acute episode, lung volumes were normal and transfer
factor was only marginally reduced, despite one patient
having persisting radiographic changes.
Cardiovascular
A relative bradycardia is a common early finding in LD.
Arrhythmias may also occur and are usually supraven-
tricular in origin[7,36,37]. Sudden, unexpected cardiac
arrest has been noted in some series[7,21,38], These
episodes may be secondary to myocardial damage or may
result from involvement of cardioregulatory centres in the
brain stem. Myocardial damage is well documented and
may be part of the generalised muscle necrosis seen in
some patients (see later) or may result from an inflamma-
tory myocarditis. Inflammatory infiltrates have been
shown in the heart at postmortem[39], and L. pneumo-
phila has been demonstrated in myocardium by immuno-
fluorescent methods[40]. Gross[41] described an
otherwise fit 51-year-old woman with typical pulmonary
LD complicated by transient myocardial dysfunction as
shown by electrocardiographic changes and the develop-
ment of congestive cardiac failure. Cardiac specific cre-
atine phosphokinase was elevated and thallium perfusion
scanning showed patchy defects in the myocardium. She
also had evidence of generalised skeletal muscle damage.
Features suggesting myocarditis, in the absence of pneu-
monia, have also been described in three children who
showed seroconversion to L. pneumophila[^2]. Shock may
result from primary myocardial dysfunction or from
peripheral vasomotor collapse. It is uncommon in LD
and is associated with a poor prognosis. Recurrent epi-
sodes of shock, associated with relapses of LD, were
described in one patient[26].
A number of cases of pericarditis, in the absence of
uraemia, have been described in association with LD.
This has been complicated by effusion, which may be
sufficiently large to cause tamponade[37,43-45], or may
just be an incidental finding at postmortem[46]. One
patient, who developed constrictive pericarditis three
months after legionella pneumonia, had received medias-
tinal irradiation for Hodgkin's disease 17 years be-
fore[44]; pericardial fibrosis is a known complication of
mediastinal irradiation[47], L. pneumophila has been iso-
lated from pericardial fluid[37], but has not been docu-
mented within the pericardium itself.
Endocarditis has been reported only once[48]. In this
case prosthetic aortic and mitral valves were infected in
the absence of pneumonia. L. pneumophila was grown
from vegetations after removal of the damaged pros-
theses. The patient made a complete recovery. Infection
of native valves has not been recorded, but one case had
226 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
features very suggestive of endocarditis with persistent
symptoms that resolved only after prolonged, parenteral
erythromycin therapy[45], This case was also remarkable
for the recurrence of pericarditis after seven months.
Two cases of arteriovenous fistula infection with L.
pneumophila following pneumonia have been de-
scribed^], but no other peripheral vascular complica-
tions have been reported. Not surprisingly, deep venous
thrombosis and pulmonary embolus have been noted
' following LD[50,51],
Neurological
A mild and reversible encephalopathy occurs in up to 50
per cent of patients with LD. A number of neurological
complications involving both central and peripheral ner-
vous systems have also been recorded, some of which
appear to be irreversible. The brain stem and cerebellum
are the most frequently involved parts of the central
nervous system. Weir et al. found cerebellar disturbance
in 50 per cent of 27 patients with LD compared with only
5 per cent in non-legionella pneumonia[52]. Typical
* < features include dysarthria, ataxia, gait disturbance and
a " falls, nystagmus and gaze palsies[36,38,51-55]. Legion-
ella infection may cause acute reversible cerebellar dis-
A turbance in children in the absence of pneumonia. Nigro
et al. found serological evidence of legionella infection in
j , 25 per cent of children with acute cerebellar ataxia, all of
whom showed complete recovery[56]. In adults cerebellar
disturbance may persist and be debilitating. One patient
with persisting ataxia had evidence of cerebellar atrophy
on CAT scan three years after the original infection[52].
Features of encephalomyelitis leading to coma, hemi-
paresis or paraparesis have been described in some
cases[36,52,57-60]. Although some recovery has oc-
curred in these cases many of the changes have been
! permanent. Loss of memory for the acute illnesss is
common, but in some cases a permanent defect in short-
term memory may result[36,53]. Other central nervous
abnormalities recorded include epileptic fits[6,58], in one
case in the absence of pneumonia[61], chorea[55], papil-
loedema[62] and isolated cranial nerve palsies[54,59,63].
Two distinct forms of peripheral nervous system in-
volvement have been described. A typical Guillain-Barre
syndrome may occur, with progressive weakness, sensory
loss, areflexia and bulbar involvement[64]. In addition,
there may be a predominantly motor neuropathy with
electrophysiological changes suggestive of an axonal
neuropathy[52]. One reported case showed progression
from isolated weakness of one limb to almost complete
i quadriplegia within 16 hours[65]. Nine months later
i K there had been only minimal improvement. Subclinical
neuropathy may be common. Weir et al. [52] found
evidence of an axonal neuropathy in all six patients
studied, none of whom had symptoms of neuropathy. In
one case the electrophysiological changes were still
present after seven years. Involvement of the peripheral
| nervous system may occur in isolation or with central
nervous system involvement.
The cerebrospinal fluid (CSF) is usually normal unless
signs of meningitis[57,66], encephalomyelitis or Guillain-
Barre syndrome are present. Only one of 10 lumbar
punctures done in the Philadelphia outbreak showed any
CSF abnormality[6], As with other causes of Guillain-
Barre syndrome the CSF abnormality is an isolated
elevation in protein content with no excess of cells. In
meningitis, which is very rare in LD, and encephalomye-
litis, both lymphocyte and neutrophil leucocytosis in the
CSF have been described, in addition to the raised
protein content. Legionella organisms or antigen have
not been detected in the CSF but both have been
demonstrated within the substance of the
brain[58,67,68].
The electro-encephalogram is frequently abnormal but
the changes reported have been non-specific and compati-
ble with toxic damage to the brain[58]. Of 17 CAT scans
performed in patients with LD, 12 were normal, three
showed non-specific changes, one showed ventricular
enlargement[58] and one cerebellar atrophy, as already
described.
Musculoskeletal
Although myalgias and weakness are common symptoms
in LD and mild elevations of muscle enzymes are fre-
quently seen, there is not a close correlation between
symptoms and enzyme levels. A raised serum creatine
phosphokinase (CPK) may occur in up to 78 per cent of
cases compared to only 24 per cent in other pneumo-
nias[69], although there is some evidence that elevated
CPK occurs as frequently in other severe pneumo-
nias[70].
A number of cases of acute rhabdomyolysis have been
described, associated with massive elevation of skeletal
muscle-specific CPK (to more than 400,000 iu/litre in one
case), myoglobinuria and acute renal failure[71-74].
Rhabdomyolysis in the absence of renal failure may also
occur[46]. Myalgia and weakness occurred in the ma-
jority of these cases, but muscle tenderness was noted in
only one[73]. Pathologically extensive rhabdomyonecro-
sis is found with an associated acute inflammatory infil-
trate, but no evidence of vasculitis[4Q], The majority of
patients developing renal failure had CPK levels of more
than 10,000 iu/litre, but in one case the CPK level was
only 3,300 iu/litre[71].
The mechanism of rhabdomyolysis in LD is unknown.
As legionella organisms have not been found in skeletal
muscle, a toxin may be responsible. High fever, a
common feature of LD, may precipitate rhabdomyolysis
on its own and another frequent accompaniment of LD,
hypophosphataemia, may predispose to or be a cause of
rhabdomyolysis[75].
Other than arthralgia, joint manifestations are seldom
seen in LD, but one case of acute arthropathy associated
with LD[76] may have been due to a coincidental onset of
rheumatoid arthritis.
Renal
Frank renal failure, although rare, is a well recognised
complication of LD with a significant influence on out-
come. No cases of acute renal failure were seen in one
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 227
review of 65 nosocomial cases[7], but in a study of
sporadic LD 13 per cent were recorded as requiring
dialysis[77], In the Philadelphia outbreak 14 cases (11 per
cent) were noted to have renal failure with oliguria or
anuria, of whom three required dialysis. The mortality of
these 14 patients was 79 per cent[6].
A number of pathophysiological processes may be
responsible for renal failure in LD. Acute tubular necrosis
is probably the most common cause of the renal fa.il-
ure[78-80] and is usually secondary to hypotension.
Twelve of the 14 patients described above had hypoten-
sion and shock. Nonetheless, renal impairment was noted
in six before the hypotensive episode. Acute renal failure
associated with features suggesting glomerulonephritis
has been recorded[81] and a number of cases of tubulo-
interstitial nephritis has been reported[82], in one case
associated with disseminated intravascular coagu-
lation[80]. Renal failure associated with thrombotic
thrombocytopenic purpura has also been reported in
LD[83], It is not known whether nephritis develops as a
result of direct bacterial invasion of the kidney, as has
been demonstrated at postmortem[18], or is the result of a
circulating toxin. Rhabdomyolysis and myoglobinuria as
a cause of renal failure in LD have already been men-
tioned. In patients recovering from acute renal failure
associated with LD renal function usually returns to
normal, but persisting renal impairment has been report-
ed^].
Legionella infection is a not uncommon cause of
pneumonia in renal transplant recipients and has been
associated with transplant rejection. In one series rejec-
tion necessitating transplant nephrectomy occurred in 50
per cent of legionella infections[7].
In addition to demonstration of the organism of LD in
the kidney at postmortem one case has been reported with
pyelonephritis[85]. However, the exact role of legionella
in this episode is not clear, as another organism was also
present but the tissues were not cultured.
Gastrointestinal
Despite the frequency of gastrointestinal symptoms in
LD, more serious complications related to this system
have seldom been reported. Diarrhoea, so often a pre-
senting feature, usually settles in a few days as the
pneumonia is treated. Occasionally diarrhoea may persist
for several weeks[41] and be associated with histological
features of a non-specific proctitis (Woodhead, unpub-
lished observations). Colonic involvement is further sug-
gested by the occasional reports of paralytic ileus[6,26].
In one case acute peritonitis developed as a result of
multiple caecal perforations[86], Immunofluorescent
staining of the specimen removed at colectomy showed
intact legionellae within the bowel wall. Acute gastric
perforation[18] and acute appendicitis[8] have also been
associated with LD. One case of perirectal abscess has
been reported from which L. pneumophila serogroup 3 and
multiple anaerobic organisms were isolated. The patient
had pneumonia that was also shown to be due to L.
pneumophila serogroup 3[87].
Jaundice is uncommon both in patients with previously
normal liver function[36,41,83,88] and in those with
chronic liver disease[89], Acute liver failure has not been
reported. Legionella organisms have been detected in the
liver at postmortem[90] and one case has been described
of pyrexia of unknown origin associated with hepatic
granulomata (but no pneumonia) and rising antibody
titres to L. pneumophila serogroup 1 [91].
Acute pancreatitis associated with legionella pneu-
monia has been seen in one case in life[92], but has also
been noted at postmortem[18]. The finding of elevated
urinary amylase levels in 16 patients in one series suggests
that asymptomatic damage may be quite common[93].
Reticulo-endothelial
Legionella organisms have been demonstrated in liver,
spleen, bone marrow and lymph nodes at postmor-
tem^,90], Three-quarters of patients showed splenic
enlargement and one quarter of patients showed organ-
isms in the spleen[18]. Clinically detectable splenomegaly
has not been described. Legionella has also been detected
in bone marrow aspirates during life[89]. Pancytopenia
has been noted in LD[18,94] and in one case was
associated with marked reticular fibrosis in the bone
marrow with many free and intracellular organisms[18].
In the Philadelphia outbreak one patient with an isolated
leucopenia and two with thrombocytopenia were not-
ed^]. Thrombocytopenia has been seen in isolation[51],
associated with disseminated intravascular coagu-
lation[61,80] and with thrombotic thrombocytopenic pur-
pura and renal failure[83]. Autoimmune haemolytic
anaemia has been recorded in two cases[6,88], one of
which received steroid therapy. Cold agglutinins are not
usually found in significant titres[7].
Although lymph node enlargement, both within and
outside the thorax, may be common at postmortem,
being found in nearly half of the cases studied[18],
clinically detectable lymphadenopathy is rare.
Miscellaneous
Skin rash in LD is rarely recorded. Erythema multiforme
has been described in a three-year-old boy with legionella
pneumonia[95]. A painful macular erythematous rash,
confined to the lower leg, was described in a 46-year-old
man with LD[96], In addition, a local erythematous
eruption, in one case progressing to pustule formation,
was described in the two cases with infected arteriovenous
fistulae[49].
Retinal changes have been described in one patient
with LD, but these may have been secondary to endocar-
ditis[45].
Comment
The pathogenesis of the widespread effects of legionella
infection is not known. Direct bacterial invasion, circulat-
ing toxins, immunologically mediated damage or a com-
bination of these are the most likely mechanisms. There is
little current evidence for the involvement of an immuno-
logical process. A number of toxins, both exotoxins and a
228 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
weak endotoxin, have been associated with legionel-
lae[97], but these are unlikely to be sufficiently potent to
produce such distant effects.
Dissemination of legionella organisms has been demon-
strated on a number of occasions. The organisms have
been cultured from lung, blood[98,99], brain and
liver[68], pleural[17] and pericardial fluids[37], perirectal
abscess[87] and an excised prosthetic mitral valve[48].
Routine histological stains have revealed organisms in
lung[ 18,40], pleura[32], kidney[32] and brain[58] and,
with immunofluorescent staining, lymph nodes, spleen,
bone marrow[18,89], colon[86], myocardium[40] and
arteriovenous fistulae[49] have also been shown to con-
tain legionella organisms. Of commonly affected tissues
only skeletal muscle, skin, pancreas and cerebrospinal
fluid have so far failed to yield either legionella organisms
or antigen. Clearly, direct spread of the organisms may
occur, but the high frequency of immunosuppressed
patients in the studies so far performed and the rarity of
blood culture isolation suggests that dissemination may
only occur in exceptional circumstances or as an agonal
event. Despite the growth in our knowledge of LD in the
last nine years there remains much to be learnt about this
fascinating disease. Analysis of information from the
Staffordshire outbreak will certainly be of immense inter-
est.
Acknowledgements
We would like to thank Ms P. Heatley and Ms J. Galletti
for typing the manuscript.
This article is based on a paper read by Dr Macfarlane at the
Conference on Infectious Diseases held at the Royal College of
Physicians in May 1985.
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I
230 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
|
PMC005xxxxxx/PMC5371101.txt | Book Review
Microcomputers in Clinical Practice
by D. E. Norris, C. E.
Stilbeck, A. E. Hayworth and D. M. Torpy. John Wiley
and Sons, Chichester, 1985. 159 pages. Price ?7.90.
Physicians who feel inadequate when the conversation in
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providing an admittedly superficial overview of the appli-
cation of computers to medicine, it inevitably deals with
'
\
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ion floppy disc containing demonstration programs, a
statistical package and data handling programs (cost ?35
and available for use on Apple II or lie and Commodore
Pet computers).
Peter A. Emerson
I t
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 217
|
PMC005xxxxxx/PMC5371104.txt | Toxic Shock Syndrome
ROGER FINCH, MB, MRCPath, FRCP*
Consultant and Senior Lecturer in Microbial Diseases
MICHAEL WHITBX MB, FRACR FRCPA, Senior Registrar
The City Hospital, Nottingham
Staphylococcal scarlet fever, recognised in 1927, is char-
acterised by toxaemia, a generalised erythematous rash
and subsequent desquamation. In 1978 Todd et al.[ 1]
described a 'new' disease in children in which fever,
myalgia, erythema and desquamation were associated
with Staph, aureus infection. They coined the term Toxic
Shock Syndrome (TSS). Subsequently this pattern of
disease was described in healthy young women in the
USA. Extensive controlled epidemiological investigations
later identified the association of TSS with menstruation,
tampon usage and the presence of Staph, aureus in the
genital tract.
Epidemiology
Since 1979 more than 2,500 cases of TSS have been
reported in the USA. Of these, 96 per cent have been
females, of whom 95 per cent have been associated with
menstruation and tampon use[2]. The number of cases
reported since 1980 has declined and this is attributable to
a decrease in retrospectively reported cases and possibly
to changes in the pattern of tampon manufacture and
usage, following the publicity associated with this syn-
drome. It is interesting to observe that eight states
contributed more than 60 per cent of cases reported in the
USA[3], This may also reflect differences in population
immunity, prevalence of toxin-producing staphylococci
or, more likely, the intensity of interest and surveillance.
The prevalence of TSS in the USA far exceeds that in
any other country, including Canada. Cases have been
recognised in Western Europe and Australasia, but have
not yet been reported in developing countries. Up to
April 1984, only 88 confirmed or probable cases meeting
the definition of the Center for Disease Control (CDC)
had been identified in the UK. All but 15 were associated
with menstruation. This incidence in the UK is much
lower than that in the USA and may reflect a true lower
frequency, reduced tampon usage or failure to recognise
the syndrome.
Non-menstrual cases account for about 13 per cent of
those reported in the USA[2,4]. The mean age for
menstrual TSS is 22.6 years, 65 per cent of diagnoses
being made in women under 25 years, although only 45
per cent of tampon users are in this age group. Non-
menstrual TSS patients tend to be slightly older, reflect-
ing the greater age distribution of post-partum and post-
surgical cases. Racial differences have been recognised in
the USA, 96 per cent of menstrual cases occurring in
whites, who represent 83 per cent of tampon users[5].
Clinical Features
TSS is a multi-system disease with a wide range of
symptoms and signs. There is at present no specific
laboratory test and diagnosis is based on clinical features.
The criteria of the widely accepted definition, formulated
by the CDC in 1979[6] and subsequently modified to
include orthostatic syncope and patients with staphylo-
coccal bacteraemia[3], are summarised in Table 1.
Menstrual TSS
Prodromal symptoms may occur and include malaise,
myalgia, low grade fever, vomiting, diarrhoea and va-
ginal discharge. However, in many instances the onset is
abrupt, with fever, rigors, myalgia, pharyngitis, conjunc-
tivitis, severe hypotension, vomiting, diarrhoea and gen-
eralised skin rash[7,8]. Headache and abdominal
tenderness may also occur.
The findings on the skin and mucous membranes are
among the most characteristic of the disease. The rash
occurs early and is usually diffuse, erythematous and
blanches on pressure. There may be quite marked
oedema of the face, limbs and perineum. A petechial rash
may also develop in response to thrombocytopenia or
disseminated intravascular coagulation. About 5-10 days
into the illness, a discreet maculo-papular rash may
develop and be mistaken for a drug eruption. Mucosal
abnormalities are common, with conjunctivitis, pharyn-
gitis, 'strawberry tongue' and vaginal hyperaemia. There
may be multiple punctate ulcers of the cervix and vagina.
Desquamation occurs in half the patients 1-2 weeks
after onset of the illness but may be delayed for up to 21
days. It predominantly affects the palms and soles,
especially around the nails, but may be generalised.
Delayed loss of nails and hair may also complicate severe
disease.
Vomiting and effortless watery diarrhoea occur in
"Correspondence to: Dr R. G. Finch, FRCP, Department of Microbial
Diseases, The City Hospital, Nottingham NG8 2FX.
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 * 219
K.
Table 1. Case definition, toxic shock syndrome. (Revised by the Center for Disease Control, 1982.)
Fever
Rash
Desquamation
Hypotension
Multi-system involvement
Gastrointestinal:
Muscular:
Mucous membrane:
Renal:
Hepatic:
Haematological:
CNS:
Other conditions should be excluded
2s 38.9?C (102?F)
Diffuse macular erythroderma
1?2 weeks after onset of illness
Systolic BP <90 mmHg or orthostatic hypotension
>15 mmHg or orthostatic dizziness
Three or more of the following:
vomiting or diarrhoea
severe myalgia or t CPK x 2 normal
vaginal, oropharyngeal or conjunctival hyperaemia
urea or creatinine T x 2 normal or >5 WBC/HPF in urine
total bilirubin, AST, ALT T x 2 normal
platelets < 100 x 109/litre
disorientation or altered consciousness without focal neurology
almost 90 per cent of patients at onset. There is genera-
lised abdominal tenderness, frequently accompanied by
guarding and reduced bowel sounds, but without re-
bound tenderness. Although often severe, these symp-
toms generally subside within 72 hours. Diffuse myalgia
and muscle weakness are common and many patients
complain of exquisite skin and muscle tenderness when
touched or moved. Arthralgia, sterile joint effusions and
low grade synovitis are uncommon.
Hypotension and profound shock are cardinal features
of TSS and may be associated with electrocardiographic
abnormalities such as conduction defects and ischaemic
changes. Acute oliguric renal failure may complicate the
presence of profound hypovolaemic shock. Pulmonary
oedema is common and may be associated with haemop-
tysis or the adult respiratory distress syndrome; head-
ache, confusion, irritability, aggression, hallucinations
and photophobia may be prominent.
The CDC definition was restrictive to provide epidemi-
ological homogeneity in case-controlled studies. Many
patients do not show the full features of this definition.
Such cases are in general milder, and often without
significant fever, erythema and shock[9,10],
Non-Menstrual TSS
TSS has complicated a variety of medical and surgical
conditions in non-menstrual females, males and children,
but is rare under the age of 10 years[2]. The non-
menstrual variant shows the same clinical features as the
menstrual form and is broadly divided into three categor-
ies of staphylococcal infection: (i) associated with abortion
or childbirth in which it may complicate both Caesarean
and vaginal delivery; (ii) associated with cutaneous or
subcutaneous infections including surgical wounds, ab-
scesses, cellulitis, fasciitis, burns and secondarily infected
herpes zoster, and (iii) a smaller heterogeneous group
complicating deep-seated infection such as osteomyelitis,
endocarditis, pneumonia and empyema[5].
Laboratory Findings
A broad range of laboratory abnormalities is recognised
and reflects widespread tissue ischaemia of various organs
rather than the direct effect of a toxin. Frequently
reported abnormalities include neutrophilia, profound
lymphopenia, normochromic normocytic anaemia and
thrombocytopenia. Changes in coagulation include pro-
longed prothrombin and partial thromboplastin time and
may presage disseminated intravascular coagulation[7],
Renal involvement is reflected in oliguria, raised serum
urea and creatinine, trace proteinuria and sterile
pyuria[ll]. Elevated liver enzymes and bilirubin are
common although frank jaundice is rare. Electrolyte
abnormalities may include hyponatraemia, hypokale-
mia, hypophosphataemia and hypocalcaemia which in
part may be secondary to raised calcitonin levels[12].
Elevated creatinine phosphokinase concentrations are
proportional to skeletal muscle involvement.
Cervical and vaginal cultures will yield Staph, aureus in
most menstrual cases [10], while in non-menstrual cases a
focus of sepsis should be sought. Although no specific
diagnostic test for TSS exists, the demonstration of toxin
production by isolates together with a characteristic his-
tory or progression to desquamation is strong evidence for
the diagnosis. The absence of detectable antibody to toxin
in the convalescent phase is also consistent with the
syndrome[13].
Differential Diagnosis
The differential diagnoses vary both with the predomi-
nant organ system involved and geographically. The
variety of differential diagnoses in the UK is listed in
Table 2.
Treatment
i!
The immediate management is directed towards the >'
restoration of circulating blood volume and the mainten-
ance of adequate tissue perfusion. Electrolyte solutions,
colloids or whole blood are appropriate. Large volumes
may be required in combination with vasopressor agents.
Hypoxaemia should be reversed and may require mech-
anical ventilation. The requirements for haemodynamic
monitoring, mechanical ventilation, as well as the arrest
of bleeding by infusing platelets and fresh frozen plasma
can more easily be managed in an intensive care setting.
220 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
Table 2. Differential diagnosis of toxic shock syndrome
Exanthematous conditions
Drug eruptions
Erythema multiforme
Streptococcal scarlet fever
Leptospirosis
Meningococcaemia
Toxic epidermal necrolysis
Staphylococcal scalded skin syndrome
Kawasaki disease
Gastrointestinal conditions
Infectious gastroenteritis
Staphylococcal food poisoning
Miscellaneous conditions
Septic shock
Systemic lupus erythematosus
Pelvic inflammatory disease
Haemolytic-uraemic syndrome
Acute pyelonephritis
f1 Tampons should be removed in menstrual cases. The
value of antiseptic vaginal douches has not been assessed
in a controlled manner. In non-menstrual cases, the focus
of infection should be sought and the need for surgical
debridement or drainage assessed. Antibiotics are indi-
cated to eliminate the source of toxin production and to
prevent recurrent disease; their use probably does not
reduce the duration of the acute illness[9]. As most
' - staphylococci implicated in TSS produce (3-lacta-
mases^ 4], flucloxacillin is an appropriate choice. Dur-
ation of treatment has not been established in controlled
<. trials, although a course of less than 10 days does not
consistently eradicate colonising staphylococci.
The place of corticosteroid therapy is not established,
although anecdotal reports suggest that early adminis-
tration reduces both height and duration of fever,
together with the degree and distribution of erythroderma
- and subsequent desquamation[15].
Once life-threatening complications are controlled, im-
provement is usually rapid, with dissolution of fever
within 72 hours, and the rash and myalgia over the course
of 5-10 days. Laboratory abnormalities similarly return to
normal. Prolonged sequelae are rare, although muscle
weakness, myalgia, impaired memory and concentration
may persist[ 16].
Mortality ranges from 2-13 per cent, but has shown a
progressive fall each year since the description of the
syndrome[2]. This may be attributed to a greater number
of fatal cases reported retrospectively in the early years, or
to the more rapid recognition and treatment of the
l <? condition as physicians have.become aware of the syn-
drome. Death may result from refractory cardiac arrhyth-
mias, adult respiratory distress syndrome, pulmonary
f haemorrhage and disseminated intravascular coagu-
lation.
t v<
Recurrent Disease
TSS has also been characterised by a tendency to recur.
The peak recurrence rate of 65 per cent has fallen[7] with
earlier recognition and more aggressive treatment with
antibiotics. Most recurrences have occurred within two
menstrual periods after the initial attack and are generally
less severe[9]. Recurrence in non-menstrual TSS is rare
because the focus of infection is more readily recognised.
Antibody to the toxin is often absent or in low titre in
those with recurrent TSS and may represent a specific
immune defect.
Pathogenesis and Pathology
The pathogenesis of TSS is not entirely understood but
reflects the interaction between Staph, aureus, a specific
toxin and a non-immune patient. Staphylococcal coloni-
sation of the vagina has been demonstrated in over 85 per
cent of menstrual TSS cases[10]. In controlled and
uncontrolled studies, vaginal colonisation by Staph, aureus
among healthy women varies between 0-17 per cent and
peaks immediately after the onset of menstruation and
post-partum[17]. However, increased adherence of sta-
phylococci to vaginal epithelial cells has not been demon-
strated in either normal persons or TSS patients [18].
Colonisation appears to be higher in women with
contraceptive diaphragms or intrauterine devices, which
suggests that fingers may be a source of these organ-
isms[17]. In both the USA and UK, strains of Staph,
aureus associated with TSS are predominantly ^-lacta-
mase producing and belong to phage group I, especially
types 29 and 52[ 19]. Such strains appear to be more
resistant to inactivation by heavy metals such as arsenic,
cadmium and mercury[20], Lysogenic induction of toxin
production has not been demonstrated[21].
Staphylococci are biologically extremely active and
produce a variety of toxins and virulence factors includ-
ing enzymes. The strains originally isolated by Todd et
al.[ 1] showed variable production of an epidermal toxin
which was subsequently shown to have no aetiological
association with TSS[22]. Later two other candidate
toxins were described. Bergdoll et al. [23] isolated staphy-
lococcal enterotoxin F (SEF) from 91 per cent of 142
strains of Staph, aureus associated with menstrual TSS.
Later this 22,500 dalton protein was renamed toxic shock
toxin (TST). On further purification it was called toxic
shock marker protein (TSMP), as its emetic action in
monkeys was not consistently reproducible. Schleivert et
al. [24] described another toxin?pyrogenic exotoxin C
(PEC)?identified in all 119 strains of Staph, aureus
associated with TSS, since it produced a pyrogenic
response in rabbits. Further immunochemical character-
isation has confirmed that the biologically active moiety
of both SEF and PEC is identical and this has now been
named toxic shock syndrome toxin-1 (TSST-1)[25],
More than 60 per cent of people over 10 years of age
and 88 per cent of individuals over 20 years have
antibodies to TSST-1[26], Bergdoll et al. [13] postulated
an apparently isolated immunodeficiency in TSS patients,
as only 15 per cent develop antibodies to TSST-1 in the
convalescent phase. This finding has been confirmed in
British patients.
The association between toxin production and the
development of pathogenicity is not well understood.
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 221
t
Staph, aureus isolated during the 1950s have been shown
to produce TSST-1 and the prevalence of antibodies in a
general population in 1960 appears similar to that in
1980[27]. Furthermore, 10-50 per cent of Staph, aureus
isolated from the genitalia of healthy females produce
TSST-1 which by extrapolation suggests that between 1-5
per cent of females are at risk of developing TSS.
However, attack rates in the USA have varied between 5-
17/100,000 women[28], considerably lower than the pre-
dicted figure, and therefore other factors must be
involved in the development of the disease. Tampons,
particularly of the high absorbency variety, have been
implicated in several case control studies[29]. Tampons
have been shown to stimulate toxin production to varying
degrees although they do not enhance staphylococcal
growth[30], It has been suggested that tampons absorb
substrates from the vagina, which normally inhibit
staphylococcal growth[31]. Alternatively, aerobic Gram-
negative bacteria may enzymatically degrade the car-
boxy-methylcellulose in tampons, resulting in an
environment rich in carbohydrates and conducive to
staphylococcal growth[32]. Most recently it has been
shown that TSST-1 is a potent inducer of interleukin-1
(endogenous pyrogen) and this may explain many of the
features of TSS[33], However, it must be remembered
that to date TSST-1 has not been identified in the blood
or urine of affected patients.
In general, the pathological findings reflect tissue is-
chaemia secondary to poor perfusion[34]. There is mini-
mal evidence of an inflammatory reaction and no
evidence of bacterial tissue invasion. Acute tubular necro-
sis, pulmonary oedema and haemorrhage and acute fatty
infiltration of the liver are all commonly found. A round
cell infiltrate, together with congestion and oedema of the
myocardium, correlates with clinical evidence of cardiac
involvement.
The only characteristic lesions seen are microscopic
mucosal ulcerations in the cervix and vagina, with tissue
separation occurring below the basal layer. These
changes have also been described in the oesophagus and
bladder and have been attributed to an action of the toxin
and not to tampon damage. Skin biopsies have shown
desquamation below the basal layer in association with a
perivasculitis, but no evidence of immune complex depo-
sition.
Prevention
A number of suggestions for reducing the risks of TSS in
susceptible patients has been made. Most are a logical
extension of our current knowledge of the epidemiology
and pathogenesis of this condition but few have been
proven in controlled studies. Avoidance of tampon use
would eliminate the risk of menstruation-associated dis-
ease but is impractical. Intermittent use might be a
compromise although more realistically high absorbency
tampons might be avoided, unless absolutely necessary.
No information is available on the advantages of more
frequent changing of tampons.
Vaginal colonisation by staphylococci might be de-
creased by the use of applicators rather than fingers for
insertion of tampons. While the frequency of recurrence
is demonstrably reduced by appropriate antibiotic treat-
ment, the potential for re-colonisation with Staph, aureus
remains. Thus patients who have recovered from men-
strual TSS should ideally be advised to discontinue
tampon use, since monitoring of vaginal and cervical
cultures for toxin-producing staphylococci is both insensi-
tive and impractical. However, it should be remembered
that the risk of recurrence is greatest within three months
of an initial attack. Education of both tampon users and
medical staff to recognise early symptoms and signs
remains the cornerstone of management.
The Future
Our understanding of TSS has advanced greatly in a very
short time. Nevertheless, some fundamental questions
remain. As yet, no specific diagnostic test is available and
research in this direction is urgent. Although not a
common condition in the UK, the varied nature of the
clinical manifestations of the syndrome means that TSS
may present to a broad range of clinicians?general
practitioners, surgeons, obstetricians and gynaecologists,
intensive care specialists and psychiatrists as well as
general physicians. The advice of the CDC to physicians
remains true in that a diagnosis of TSS should be
considered 'in all patients with appropriate symptoms
and signs, regardless of the patients' age, sex, race and
menstrual status'.
This article is based on a paper read by Dr Finch at the
Conference on Infectious Diseases held at the Royal College of
Physicians in May 1985.
References
1. Todd, J. K., Ressman, M., Kapral, F. et al. (1978) Lancet, 2, 1116.
2. Reingold, A. L. (1985) Morbidity and Mortality Weekly Report, 33, 19.
3. Reingold, A. L., Hargrett, N. T., Shands, K. N. et al. (1982)
Annals of Internal Medicine, 96, 875.
4. Reingold, A. L., Dan, B. B., Shands, K. N. et al. (1982) Lancet, 1,
1.
5. Irwin, C. E. and Millstein, S. G. (1982) American Journal of Public
Health, 72, 464.
6. Shands, K. N., Schmid, G. P., Dan, B. B. et al. (1980) New England
Journal of Medicine, 303, 1436.
7. Chesney, P. J., Davis, J. P., Purdy, W. K. et al. (1981) Journal of the
American Medical Association, 246, 761.
8. Fisher, R. F., Goodpasture, H. C., Peterie, J. D. et al. (1981)
Annals of Internal Medicine, 94, 156.
9. Davis, J. P., Chesney, P. J. and Ward, P. J. (1980) New England
Journal of Medicine, 303, 1429.
10. Shands, K. N., Schmid, G. P., Dan, B. B. et al. (1980) ibid.,
p. 1436.
11. Chesney, R. W., Chesney, P. J., Davis, J. P. et al. (1981) American
Journal of Medicine, 71, 583.
12. Heimburger, D. C. (1981) Southern Medical Journal, 74, 1265.
13. Bergdoll, M. S., Crass, B. A., Reiser, R. F. et al. (1982) Annals of
Internal Medicine, 96, 969.
14. De Saxe, M., Wienke, A. A., De Azevedo, J. et al. (1982) Annals of
Internal Medicine, 96, 991.
15. Todd, J. K., Ressman, M., Caston, S. A. et al. (1982) Interscience
Conference on Antimicrobial Agents and Chemotherapy, Abstract 368,
p.131.
16. Sahs, A. L., Helms, C. M. and Du Bois, C. (1983) Archives of
Neurology, 40, 414.
17. Guinan, M. E., Dan, B. B., Guidotti, A. L. et al. (1982) Annals of
Internal Medicine, 96, 944.
222 Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985
18. Basscris, H. P., Venezio, F. R., Morlock, B. A. et al. (1981) Journal
:f of Infectious Diseases, 144, 386.
19. Altemier, W. A., Lewis, S. A., Schleivert, P. M. etal. (1982) Annals
of Internal Medicine, 96, 978.
20. Todd, T. K., Franco-Buff, A., Lewellin, D. W. et al. (1984)
Infection and Immunity, 45, 339.
j 21. Kreiswirth, B. N., Lofdahl, S., Betley, M.J. et al. (1983) Nature,
J" 305, 709.
22. Kapral, F. A. (1982) Annals of Internal Medicine, 96, 972.
} 23. Bergdoll, M. S., Cross, B. A., Reiser, R. F. etal. (1981) Lancet, 1,
i, 1017.
24. Schleivert, P. M., Shands, K. N., Dan, B. B. etal. (1981) Journal of
. * Infectious Diseases, 143, 509.
25. Bergdoll, M. S. and Schleivert, P. M. (1984) Lancet, 2, 691.
26. Schleivert, P. M., Osterholm, M. T., Kelly, J. A. et al. (1982)
Annals of Internal Medicine, 96, 937.
27. Vergeront, J. M., Stolz, S. J., Cross, B. A. et al. (198"i) Journal of
Infectious Diseases, 148, 692.
. (
11
28. Osterholm, M. J. and Forfang, J. R. (1982) Journal of Infectious
Diseases, 145, 431.
29. Schlech, W. F., Shands, K. N., Reingold, A. C. etal. (1982)Journal
of the American Medical Association, 248, 835.
30. Lee, A. L. and Cross, B. A. (1983) Proceeding of the American Society
for Microbiology, Abstract B27, 59.
31. Sanders, C. C., Sanders, W. E. and Fragnant, J. E. (1982)
American Journal of Obstetrics and Gynaecology, 142, 977.
32. Tierno, P. M., Hana, B. A. and Davies, M. B. (1983) Lancet, 1,
615.
33. Parsonnet, J., Hickman, R. K., Eardley, D. D. etal. (1985)Journal
of Infectious Diseases, 151, 514.
34. Parvis, A. L., Herwaldt, L. A., Blum, D. et al. (1982) Annals of
Internal Medicine, 96, 852.
35. Larkin, S. M., Williams, D. N., Osterholm, M. T. et al. (1982)
ibid., p.858.
36. Osterholm, M. T., Davis, J. P., Gibson, R. W. etal. (1982)Journal
of Infectious Diseases, 145, 431.
The Great Plague of 1665
Far from the City of London the Rev. Ralph Josselin sat
'? in his vicarage at Earls Colne, Essex, and wrote up his
diary for 28th May 1665 . my personal illness aba-
k, teth, blessed bee God. The plague gott into our land at
Yarmouth and London, 14 dying this weeke.' He was a
bit late with the news for the plague had come from The
Netherlands via Yarmouth to London in November
//' 1664. Indeed in March 1665 there was no Presidential
\ election at the College, its business being disrupted by the
plague, and Sir Edward Alston continued as President.
Things could not have been too bad as on April 15th the
King made his first visit to the College, listened to the
Lumleian lecturer, George Ent, and knighted him on the
< spot. But on May 17th, at the request of the Privy
Council, Comitia discussed measures to be taken against
the plague. This was not too difficult as the measures
recommended were virtually the same as those published
by the College in 1625, 1630 and 1636.
Plague had stalked the land for many years and there
were many statutory and administrative measures to
operate whenever an epidemic threatened. The Plague
Relief Act of 1604 had empowered local authorities to
raise a tax for the relief of distress and to appoint watchers
to ensure that those infected or likely to be infected should
be kept in their houses. Anyone found abroad with an
I * infectious sore was liable to the death penalty as a felon.
Very oddly the powers of this Act were not to be exercised
in the universities of Cambridge and Oxford (the Act has
them in that order), within the precincts of any cathedral
church in England or within the colleges of Eton and
Winchester.
Apart from the watchers, each epidemic saw the ap-
pointment of searchers and bearers, all swearing an oath
?v
A 5
jjr
f >?
of office. The searcher was bound to 'diligently viewe and
search the Corps of all such persons as dureing theis
infectious times shall dye . . He also had to follow
definite rules. 'Yee shall decline, and absent yourselves
from your familys, and allwaies avoide the societye of
people and in your walke shall keepe as far distant from
Men as may be allways carrying in your hands a white
wand by which the people may know you and shunn and
avoide you.' The bearer swore that he would 'beare to the
ground and bury the bodies of all such persons as . . .
shall die of the pestilence . . . carrying them to buriall
alwaies in the nightyme.' He also had to carry a white
wand.
All this organisation could do nothing against the
rapidly increasing epidemic in the City of London. On
12th June 1665, the College, at the request of the Lord
Mayor, nominated eight physicians for a plague service
in the City. Of these, two were chosen, Nathaniel Hodges
and Thomas Witherley, and two volunteered 'upon
principles of honour and conscience', Nicholas Davys and
Edward Deantry. It appears that at least 24 physicians
remained in the City of whom 17 were Fellows of the
College or elected later. Five surgeons and seven apothe-
caries are also known to have stayed to work. By that
autumn five physicians (including Pepys' doctor, Alex-
ander Burnett), and three surgeons were dead. The
College lost its apothecary, William Johnson, but the four
Fellows named above survived.
The long hot dry summer turned the City into a
charnel house; only the watchers and searchers were on
the streets, with the dead carts rumbling through the
night. After the June Comitia the College did not reas-
semble for nine months. An astrologer showed how the
continued on page 254
Journal of the Royal College of Physicians of London Vol. 19 No. 4 October 1985 223
continued from page 223
epidemic was due to the planets and added that the plague
only attacked 'persons of narrow souls and understand-
ings'; 'those of a more refined reason' escaped. Indeed
reason, abetted by money, made many flee the City. A
good many physicians left urgently for the country where
they joined their rich patients. On July 9th Rev. Josselin
wrote 'The plague feares the London. They flie before it
and the country feares all trade with London . . . The
Lord stay his heavy hand.'
The Lord did not stay his heavy hand. During August
and September there was a period of 30 days when over a
thousand died each day in the City. Many churchmen
thought the plague was a punishment from God, as
shown in a book titled God's Terrible Voice; while 'Theo-
logical Queries' contained advice on the ethics of fleeing
the plague or visiting the sick, it also advised the taking of
tobacco in the morning against the infection. Of more
medical importance was the quick reprinting of Dr
Francis Herring's book on the plague which he had
published in 1628, his advice then being the same as that
given officially by the College.
By early winter the worst was over in London. The
plague still ravaged Essex towns. Josselin recorded this,
adding in wonderment 'yett Colne, sinful Colne, is
spared'. But it was not until 1st February 1666 that the
King returned to Whitehall. He made some modest
awards for service during the great plague when he met
his Privy Councillors on May 16th. The College was not
mentioned and only two physicians, Drs Astell and Inard,
neither Fellows of the College, received a piece of in-
scribed plate to the value of ?10. The Council was still
uncertain as to the cessation of the plague, as it continued
to prohibit public burials 'during the time of infection'.
Plague of course did return to London that summer of
1666 but was never severe. More was seen in the country.
In July Josselin wrote 'A very hot season. Plague rageth
at Braintree, Colchester. At London abated . . .'
Of course the whole City of London was to change in
terms of density of population and plague. On Sunday,
2nd September 1666, the first flames of the Great Fire
started to purge the City of infection. The coming of
winter as usual brought the plague to a halt in other
towns. Wrote Josselin: 'Nov. 25. A very wett morning.
The country clear of the plague.'
|
PMC005xxxxxx/PMC5371105.txt | Training to be a Physician
Every year or so the President of the Bristol medical
students' association writes inviting me to set up a stand
at a forthcoming careers fair on becoming a clinical
pharmacologist. 'Certainly not' is my perpetual reply but
I would be pleased to contribute to the hospital medicine
exhibit. So there I have stood with others under the
banner headline 'So you want to be a physician', beneath
which is a disarming list of medical specialties which
grows with each fair and an outline training plan which
has become so out of date that it is reduced to the status of
a sick joke. The questions shower down. 'What are the
chances?' 'How long does it take?' 'Is research neces-
sary?' 'Should I stay in a teaching hospital?' And we
attempt to answer by fact (where it is available), and
opinion (where we have any) and to steer a course
between a realistic view of career chances on the one hand
and not dampening the zeal of those who might well
succeed.
The Standing Committee of Members of this College
has always had matters of training close to its heart. An
initiative was taken by its 1983-84 Chairman to set up the
projects and produce the articles which are collected
together in this issue as 'Training to be a Physician'. This
publication has three main aims and is divided into three
sections. First, it provides some authoritative articles on
the background to training requirements. Second, it
presents some data collected by the SCM in four surveys
of MRCP diploma holders. The third part is a collection
of articles written on each of the sub-specialties of medi-
cine. First reactions might question the need for the
latter. After all we have the JCHMT handbook and
indeed the order of presentation matches it precisely. In
fact these articles are quite different from the entries in
the handbook. They provide the personal views of doctors
within each specialty on the actual requirements for
success, given present manpower constraints and the
popularity of the specialty. Useful questions such as
whether or not an MD is necessary are aired by most
authors and some allow themselves to predict future
trends for the specialty. It is hoped that the publication
will provide some guidance from those in the know, a few
facts and some informed opinion and thus complement
the already existing material.
It must be acknowledged that giving people careers
advice is an extremely hazardous activity. I have seen so
many who have 'done all the right things' and then
become stuck because they appear over-qualified for the
next rung of the ladder or missed the boat by virtue of
age. In fact my advice to those on the lower rungs is to be
careful about paying too much heed to the recommenda-
tions of others. After all, with the conflicting interests of
NHS staffing and training programmes, no one can
clearly predict an individual doctor's likely career course.
Unfortunately, many junior doctors believe that some-
where in the ivory towers of London someone is control-
ling and organising it all. It just is not true. The General
Medical Council wants diversification of interests and
experience at an early stage, but you will have a hard time
explaining to the.appointments committee for a medical
registrar job why you spent six months doing obstetrics
and gynaecology. This misconception has been reinforced
by the enrolment and accreditation system for higher
medical training. Once enrolled, four years later you
become an accredited specialist. But that does not guar-
antee consultant appointment, and what is more, we
learn from the Registrar of the College that accreditation
is not necessary for such an appointment.
The booklet should be judged not as a College policy
document (which it certainly is not) but as a genuine
attempt by a group of individuals to clarify misunder-
standings and set the scene for a career in hospital
medicine. It will become out of date within a single career
span, so some pinches of salt will be needed. Neverthe-
less, it will certainly be available at the next careers fair in
my university.
C.J. C. Roberts
74 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
|
PMC005xxxxxx/PMC5371106.txt | Semantics of Death Certification
STEPHEN LEADBEATTER, MB, Lecturer in Forensic Pathology,
University of Wales College of Medicine, Cardiff
4A man's dying is more the survivors' affair than his
own'fl]. This opinion applies as well to medical certifica-
tion of cause of death as to disposal of property but is not,
apparently, an opinion common among the medical
profession, many of whom regard death certification as a
tedious chore to be delegated to the least qualified
member of the clinical team for completion in whatever
manner he pleases. Such practice, however, may lead to
distress to relatives, inaccurate national statistics and
inappropriate use of resources.
In an early paper on the accuracy of medical certificates
of cause of death Emery[2] drew attention to two possible
sources of error: the wording of a certificate, and the
degree of correlation between clinical opinion and subse-
quent autopsy findings. The second category has been the
subject of several papers [3,4] in recent years and has
occupied the attention of the Working Party of the Royal
College of Physicians and the Royal College of Pathol-
ogists concerned with Medical Aspects of Death Certifica-
tion^]. However, there is little information about the
first category.
This Department has become increasingly concerned
by the wording of causes of death seen on cremation
certificates and requests for autopsies. Subsequent discus-
sion with certifying practitioners has revealed little knowl-
edge or appreciation of the principles of death
certification. This article provides data on the number of
causes of death that are poorly worded and discusses the
possible consequences of such poor semantics.
Current Practice
Issue of the medical certificate of cause of death is the
statutory obligation of the doctor in attendance upon the
deceased during the last illness[6]. Guidance on the
completion of this certificate is printed in the book of
medical certificate forms[7]. Briefly, the cause of death is
recorded in a form recommended by the World Health
Organisation, comprising Part I, which is the sequence of
conditions leading directly to death, and Part II, which
lists other conditions that have contributed to death but
are not related to those listed in Part I. However many
conditions are listed in Part I the last-mentioned should
be the initiating condition of the sequence resulting in
death and should be a cause, not a mode, of death, a
mode being a clinical state which may result from many,
unspecified, causes.
The medical certificate of cause of death is then
transmitted by the qualified informant to the Registrar of
Births and Deaths who must register particulars of the
death as prescribed in the Births, Deaths and Marriages
Regulations, 1968[8]: these particulars include the cause
of death. Unlike the certifying practitioner, who has only
a common law obligation to report a death to H.M.
Coroner, the Registrar of Births and Deaths has a
statutory obligation to report those deaths which fall into
categories prescribed in Regulation 51 of the above
Regulations[8],
H.M. Coroner, after preliminary inquiry, has three
courses of action open to him[9].
(a) If he is satisfied that he has no jurisdiction he issues
Part A of Form 100 ('Pink Form A') informing the
Registrar that no further inquiry is necessary and direct-
ing him to register the cause of death as stated by the
certifying practitioner.
(b) If he is satisfied that he has jurisdiction he may order a
postmortem examination, the results of which may indi-
cate that the death was due to natural causes and that no
inquest is necessary; he then issues Part B of Form 100
('Pink Form B') directing the Registrar to register the
cause of death as stated by the practitioner who per-
formed the postmortem examination.
(c) If he has jurisdiction and is obliged to hold an inquest,
with or without postmortem examination, he will, at the
conclusion of the inquest, issue Form 99 ('Coroner's
Certificate After Inquest') from which the Registrar
registers the cause of death as determined at the inquest.
The causes of death registered by these diverse routes
are transmitted to the Office of Population Censuses and
Surveys where they are coded in accordance with the
International Classification of Diseases[10]. The coders,
who are clerical officers, follow coding rules laid down by
the World Health OrganisationflO], the application of
which reveals the best causal sequence from the infor-
mation contained in Parts I and II. If a sequence cannot
be derived or a certificate indicates that further infor-
mation may be available, a request for clarification is sent
to the certifying practitioner or, for a death in hospital,
the consultant responsible for the care of that patient.
In many cases, however, there is no reply to such a
requestfl 1].
Materials and Method
In a large general hospital the books of Medical Certifi-
cates of Cause of Death completed by clinicians are
retained in the Death Registration Office; a clerical
officer enters other details regarding deaths in a Death
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
129
Register. The counterfoils of death certificates issued by
clinicians from 1979 to 1983 inclusive were scrutinised
after receiving permission from the hospital adminis-
tration. If a cause of death was not completed in the
recommended form it was classified as showing one of the
following inaccuracies:
1. No cause given.
2. Multiple causes given, sequence not clear.
3. Single cause given, relevant details absent.
4. Single cause given, error in layout.
Each cause of death was assigned to only one of these
categories.
Only when an inaccuracy was obvious from a cause of
death as given on a counterfoil was that cause assigned to
a category; in those causes of death where there might be
debate as to whether a condition was causal rather than
contributory, or vice versa, the clinicians' opinions were
respected and those causes were not categorised. Exam-
ples from each category are given in Table 1.
The numbers of causes of death in each category are
given in Table 2. When a cause of death was considered
to contain an inaccuracy the certificate counterfoil was
i
scrutinised to determine whether there was an indication
that further information might be available at a later date;
the Death Register and Autopsy Records were also
scrutinised to determine whether an autopsy had been
requested and performed. This information is given in
Table 3.
Details of those counterfoils which contained no ade-
quate cause of death were noted and the Register of
Deaths Reported to Coroner, held in the Coroner's
Court, was consulted to determine whether these deaths
had been reported , who had reported them and what
course of action had been pursued by H.M. Coroner.
This information is recorded in Table 4.
Discussion
The results indicate that an unacceptably large number of
medical certificates of cause of death are imprecise or
inaccurately completed and that at the time of completion
of many of these certificates the certifying practitioners
are in possession of all the information regarding the
deaths that is, or will be, available. It would appear,
Table 1. Examples of inaccurate death certification.
No cause given
Multiple causes given?sequence Single cause given?relevant Single cause given?error in
not clear detail absent layout
la. Cardiac arrest
lb. ?
lc. ?
II ?
la. Respiratory failure
lb. Cardiac failure
lc. ?
II ?
la. Acute renal failure
lb. ?
lc. ?
II ?
la. Renal failure
lb. Myeloma
lc. Hypertension
II Pelvic peritonitis
la. Myocardial infarction
lb. Polycystic kidneys
lc. Duodenal ulcer
II Duodenal ulcer
la. Bronchopneumonia
lb. Parkinson's disease
lc. Fracture neck of right femur
II Malignant disease
la. Carcinomatosis
lb. ?
lc. ?
II ?
la. Malignant ascites
lb. ?
lc. ?
II ?
la. Carcinoma of lung
lb. ?
lc. ?
II ?
la. Lymphangitis
carcinomatosis
lb. ?
lc. ?
II Carcinoma of stomach
la.
lb.
lc.
II
Septicaemia
Systemic lupus
erythematosus
Steroid therapy
la. Heart failure
lb. C.O.A.D.
lc. Acute chest infection
II ?
la. Intrapulmonary
haemorrhage
lb. Thrombocytopenia
lc. Mycotic septicaemia
II
la. D.I.C.
lb. Bladder Ca.
lc. Aortic aneurysm
II Prostate Ca.
la. Obliterative arteritis
lb. ?
lc. ?
II ?
la. G.I. Haemorrhage
lb. Marrow depression
lc. Cytotoxic therapy
II Ca. breast with lung and
retinal secondary deposits
Table 2. Number of causes of death in eaeh category.
Year
1979
1980
1981
1982
1983
No. of
counterfoils
300
259
454
542
530
No cause given
No. %
52
51
63
52
70
17.3
19.7
13.9
9.6
13.2
Multiple causes Single cause
given?sequence given?relevant
not clear detail absent
No. % No. %
0.3
1.2
1.5
1.1
1.3
15
12
23
23
34
5
4.6
5.1
4.2
6.4
Single cause
given?error in
layout
No. %
12
16
15
31
20
4
6.2
3.3
5.7
3.8
Total
No.
80
82
108
112
131
26.7
31.7
23.8
20.7
24.7
130 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
Table 3. Action taken when cause of death considered to contain an inaccuracy, a?autopsy performed, b?autopsy requested but
not performed, c?counterfoil indicated further information might be available.
Multiple causes Total number of imprecise
given?sequence not Single cause given? Single cause given? causes in which further
Year No cause given clear relevant detail absent error in layout detail potentially available
a b c a b c abc abc No. %
1979 12 6 ? ? ? ? 1? ? 1 ? ? 20 25
1980 38 ? ? ? ? ___ 2 ? ? 13 15.9
1981 441 11? ? ? ?? ? ? 11 10.2
1982 81? 1? ? 2? ? ? 1? 13 11.6
1983 66 ? ? 1 ? ? 2? ? 15 11.5
Table 4. Deaths without stated cause.
1979 1980 1981 1982 1983
Death certificate counterfoils on which no cause of death is 52 51 63 52 70
stated
Number of deaths without stated cause reported to H.M. Coroner 9 7 12 7 7
by certifying practitioner
Number of deaths without stated cause reported to H.M. Coroner 3 2 4 6 3
by Registrar of Births and Deaths
H.M. Coroner's course of action:
'Pink Form A' 11 9 15 10 9
'Pink Form B' 1 ? ? ? ?
Inquest ? ? 13 1
therefore, that these certificates are so completed because
of ignorance of, or failure to apply, the principles of death
certification and not because relevant information is
lacking. Previous research[12] has shown a national
uniformity in death certification practice: there is no
reason to believe practice in this hospital differs from that
elsewhere.
Information contained in medical certificates of cause
of death is important in epidemiological research[13] and
forms the basis of national mortality statistics which may
be concerned in the allocation of resources within the
Health Service. It is important that certifying prac-
titioners complete causes of death in the recommended
form so that data derived therefrom reflect accurately
clinical knowledge and opinion. The causes of death
discussed in this article might not permit this.
The Registrar of Births and Deaths is required by
Regulations to report to H.M. Coroner any death 'the
cause of which appears to be unknown'[8], The infor-
mation upon which the Registrar, a lay person, makes
this decision is that laid before him by the qualified
informant and, therefore, so far as medical data are
concerned, is confined to the cause of death as stated by
the certifying practitioner: an immediate and possibly
distressing consequence of a medical certificate of cause of
death upon which there is no adequate cause of death is
that it may be reported to H.M. Coroner.
It can be seen from Table 4, however, that such
reporting does not occur in the majority of these deaths:
there is a failure of what the Brodrick report[14] described
as 'the long-stop function' of the Registrar in identifying
the unusual death. The explanation of this failure lies in
the wording of many causes of death: to the lay person a
cause of death given as 'la Respiratory failure, lb Cardiac
failure, Ic Acute renal failure, II Liver failure' appears
perfectly adequate in that the deceased has obvious
reason to be deceased; however, there is no cause given
for the failure of the systems.
When the Registrar reports a death because it appears
to be of unknown cause, H.M. Coroner will make
preliminary inquiries but, in law, can only assume juris-
diction if the death is 'a violent or unnatural death or a
sudden death the cause of which is unknown'[9]. In many
of these deaths preliminary inquiry will reveal no violent
or unnatural element: H.M. Coroner may then assume
jurisdiction only if he has reasonable cause to suspect that
the death whose cause is apparently unknown is sudden.
In many cases H.M. Coroner's only course of action is to
complete Part A of Form 100: an anomaly arises in that
the Registrar may, indeed must, report a death whose
cause is inadequately or incorrectly stated but, because
H.M. Coroner cannot assume jurisdiction after prelimi-
nary inquiry, he must register that inadequate or inaccu-
rate cause of death. It can be seen from Table 4 that this is
the course of action followed in most of those deaths
which are actually reported: the conclusion in the Brod-
rick report that '. . . the Coroner's primary function, at
present, is to help to establish the cause of death . . .'[14]
is more idealistic than practicable.
It is obvious that certifying practitioners may cause
unnecessary distress to relatives and unnecessary work for
Registrars, H.M. Coroners, OPCS statisticians and,
indeed, themselves through what are basically simple
semantic errors. It is interesting to speculate what in-
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 131
crease in precision of death certification would be afford-
ed by the implementation of the Brodrick recommenda-
tions^ 4] that a practitioner should have a statutory
obligation to report to H.M. Coroner a death whose
cause he could not certify 'with accuracy and precision'
and that failure to comply with this obligation should be
punishable by a fine.
Failing this, however, the quality of death certification
can be improved only by education; such education, in
the most important statutory obligation of medical prac-
tice, appears perfunctory in many medical schools and no
more thorough in postgraduate training. This deficiency
must be remedied, not only by formal tuition at under-
graduate level, where admittedly the topic appears re-
mote, but also by supervision and example during
provisional registration and beyond.
References
1. Mann, Thomas (1928) The Magic Mountain. London: Martin
Seeker.
2. Emery, J. L. (1962) Proceedings of the Royal Society of Medicine, 55,
738.
3. Waldron, H. A. and Vickerstaff, L. (1977) Intimations of quality:
antemortem and postmortem diagnosis. London: Nuffield Provincial
Hospitals Trust.
4. Cameron, H. M. and McGoogan, E. (1981) Journal of Pathology,
133, 273.
5. The Royal College of Physicians and the Royal College of Pathol-
ogists (1982) Journal of the Royal College of Physicians of London, 16,
205.
6. Births and Deaths Registration Act, 1953. London: HMSO.
7. Forms for Medical Certificates of the Cause of Death (1985)
London: HMSO
8. The Registration of Births, Deaths and Marriages Regulations,
1968. London: HMSO.
9. Knapman, P. A. and Powers, M. J. (1985) The Law and Practice on
Coroners. Chichester: Barry Rose.
10. World Health Organisation (1977) Manual of international statistical
classification of diseases, injuries and causes of death, ninth revision.
Geneva: WHO.
11. Busuttil, A., Kemp, I. W. and Heasman, M. A. (1981) Health
Bulletin, 39, 146.
12. Diehl, A. K. and Gau, D. W. (1982) Journal of Epidemiology and
Community Health, 36, 146.
13. Royal College of Physicians of London (1978) British Medical
Journal, 2, 1063.
14. Brodrick Committee (1971) Report of the Committee on Death Certifica-
tion and Coroners. London: HMSO.
|
PMC005xxxxxx/PMC5371107.txt | Premalignant Disease of the Epidermis _
The Parkes Weber Lecture 1985
RONALD MARKS, mb, frcr FRCPath
Professor of Dermatology, University of Wales College of Medicine, and Honorary Consultant
Dermatologist, University Hospital of Wales, Cardiff
Premalignant disease provokes questions and provides
social challenges. Its occurrence on the skin gives un-
rivalled opportunities for study of the neoplastic process
in vivo. In the past 50 years, many of the aetiological
factors responsible for pre-neoplastic and neoplastic dis-
ease of the epidermis (non-melanoma skin cancer) have
been identified and studied extensively. The most import-
ant of these is ultraviolet radiation (UVR) but the
carcinogenic potential of X-irradiation, chronic heat in-
jury, exposure to soot, pitch and other chemical carcino-
gens, as well as papilloma virus infection, should.not be
forgotten. With this information and with the accessibility
of the target tissue, it should be possible to characterise
accurately the stimulus-response relationship and deter-
mine factors that modulate this relationship.
Because the skin is easy to sample it should also be
possible to track the biochemical and immunological
alterations that take place during the progression from
normal to premalignancy and from there to frank malig-
nancy. Why do some premalignant lesions remain in
status quo for long periods? Why do others regress? What
determines their onward progression? Such questions
have implications for neoplasia in general and explain the
fascination of this group of disorders.
Prevalence
Non-melanoma skin cancer is essentially a preventable
disease yet its frequency in Caucasian populations is
increasing to a frightening degree. It has, for example,
been computed that in 1985 there will be 0.5 million new
patients with non-melanoma skin cancer in the USA.
Robin Marks (a friend but not a relative of mine),
surveying a small town in Victoria, Australia, found that
56.9 per cent of the adult population had at least one solar
keratosis and 2.32 per cent had at least one squamous cell
carcinoma[ 1 ]. In another study by the same group it was
estimated that at least 1,000 patients with non-melanoma
skin cancer presented per week in the State of Victoria[2].
There appears to have been no similar study in the UK
and it may be thought that in our comparatively sunless
climate it would be a rather unproductive exercise.
However, I do not believe this to be the case. Cardiff can
hardly be considered to be exceptionally favoured by the
climate, yet solar keratoses, squamous cell carcinoma and
other forms of skin cancer occupy a not inconsiderable
proportion of our clinic practice. In 1984, 4,540 new
patients were seen in our clinic, of whom 187 (4.1 per
cent) had solar keratoses or Bowen's disease, 29 (0.6 per
cent) had squamous cell carcinoma, and 176 (3.9 per
cent) had basal cell carcinoma. That is, 8.5 per cent of all
new patients had the commoner types of non-melanoma
skin cancer.
Interestingly, this relatively high prevalence in Cardiff
does not seem to be mirrored in all areas. For example, at
St John's Hospital for Diseases of the Skin, London, the
comparable figures for non-melanoma skin cancer in
1981, 1982 and 1983 were 1.1, 0.9 and 1.2 per cent
respectively (Griffiths, personal communication). Of
course, it is difficult to draw firm conclusions on the basis
of these figures, as referral patterns differ between
centres. Nonetheless, the dissimilarity between the inci-
dence in the two centres seems so large that there may
well be genuine differences in the experience of non-
melanoma skin cancer in the two populations served. The
differences may well be due to the comparatively large
number of individuals of Celtic origin in the South Wales
area and the predisposition of this group may not be
entirely due to their light complexions. There is some
evidence that they have a fault in DNA repair after UVR
injury, similar in type but less in degree, to that seen in
xeroderma pigmentosum[3,4]. It is of interest in this
respect to find a higher 'Celticity index' in patients with
malignant melanoma in Massachusetts and Aus-
tralia^^].
Clinico-pathological Considerations
The keratosis is the archetypal premalignant epidermal
lesion. It is often termed solar or actinic keratosis to
denote the usual cause. Solar keratoses are usually scaly
or warty, pink or gray patches on a light-exposed area of
skin. Histologically the keratosis may be identified as an
area in the epidermis in which the basal epidermal cells
show irregular staining, shape and size, particularly as far
as their nuclei are concerned (dysplasia). In addition, the
affected epidermis often demonstrates abnormal differen-
tiation resulting in individual cell keratinization (dyskera-
tosis) or parakeratosis. We have demonstrated that these
lesions have a high rate of epidermal cell production, as
116 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
does the epidermis on which these arise[7]. Bowen's
disease represents one further step towards frank malig-
nancy. Bowen's disease often presents clinically as a
psoriasiform scaling plaque but may also be a warty
nodule. In this condition the abnormal cells are bizarre in
their heterogeneity of size, shape and staining properties
and are present throughout the entire thickness of the
epidermis. When these lesions become frankly malignant
they enlarge and ulcerate. The histological hallmark of
the resulting squamous cell carcinoma is dermal invasion
by the abnormal epithelial cells.
Not all solar keratoses transform to a more 'malignant'
phase but there are only scanty data to characterise the
frequency with which this occurs. Early estimates
suggested that some 20 per cent of keratoses transform to
squamous cell carcinoma[8] but the fact that the former
lesions are so much more common than the latterfl]
suggests that this is not the case. Nonetheless, the dispar-
ity in numbers could be a reflection of the different rates
of growth of the two sorts of lesion and it could be that all
solar keratoses are committed to develop into frankly
neoplastic lesions at some point. To determine whether
this is the case or whether an additional stimulus is
necessary, good long-term studies are required. How-
ever, providing a convincing answer will not be easy
because of the need to remove and examine lesions to
establish the diagnosis. Without good non-invasive diag-
nostic techniques it cannot be certain that any lesion
followed is indeed a solar keratosis, and if it is excised
there is no knowing how it might have behaved.
It may be that some solar keratoses regress and I will
discuss one possible example of this later. Regression of
bronchial metaplasia after stopping smoking has been
described[9] and we are currently involved in determin-
ing whether regular use of a sunscreen to prevent further
damage from ultraviolet radiation can reduce the degree
of dysplasia present.
The Role of Solar Ultraviolet Irradiation
There can be little doubt that solar irradiation is the
major stimulus to the development of non-melanoma skin
cancer. The evidence has been summarised on several
occasions in recent years[10-13] but it is worthwhile
reiterating the main points before proceeding to docu-
ment our own involvement. The most persuasive evi-
dence concerns clinical experience. Black-skinned
individuals are protected from the damage caused by
ultraviolet by the melanin pigment produced by melano-
cytes and subsequently donated to epidermal cells. Non-
melanoma skin cancer is extremely uncommon in this
group of individuals. The converse is also true in that the
lighter the complexion, the higher the incidence of solar
keratoses, squamous cell carcinoma and basal cell carci-
noma. There is also evidence of a dose-effect relationship
as those individuals with outdoor jobs which involve
considerable exposure, to the sun are much more likely to
develop lesions than those who are mostly indoors.
Recently the matter has been highlighted by the wide-
spread use of a form of ultraviolet irradiation in the
treatment of psoriasis (photochemotherapy with long
wave ultraviolet radiation?PUVA). Individuals treated
in this way appear to have a much higher prevalence of
squamous cell carcinoma[14], Another plank in the argu-
ment is that patients with the rare genodermatoses xero-
derma pigmentosum, who often die from some form of
skin cancer, have a defect in a DNA repair mechanism
after damage by UVR[15], As well as the clinical evi-
dence cited above, there is strong experimental evidence,
mostly deriving from the irradiation of mice with ultra-
violet[16].
A Human Model for Photocarcinogenesis
Human skin differs markedly from that of small mam-
mals in its response to UVR. Because of this we felt that
to answer questions relating to solar protection and the
wavelength dependency of photocarcinogenesis it would
be more useful to study man. We noted reports suggest-
ing that enhanced glucose-6-phosphate dehydrogenase
(G6PDH) activity was characteristic of premalignant and
malignant epithelial lesions; in particular, changes were
noted in bronchial mucosal and gastrointestinal lesions
and in a model?the hamster cheek pouch[17-19], We
wondered whether this activity could form the basis of a
marker for premalignant change in human epidermis.
Therefore we decided to study the distribution of this
pentose shunt enzyme activity as well as citric acid cycle
enzyme activities in solar keratoses and squamous cell
carcinoma, and exposed but non-involved skin near the
lesions (paralesional skin), as well as in normally non-
exposed skin. In order to compare the results of our tests
in the different samples examined we used a carefully
standardised sectioning and incubation technique. We
also measured the densities of the formazan reaction
products in the tissues by a densitometric method[20]
using a scanning and integrating microdensitometer. The
results demonstrated a considerable increase in G6PDH
activity in the lesions examined throughout the epidermis
but particularly in the granular cell layer. Paralesional
skin also showed enhanced G6PDH activity in the epider-
mis compared with normally non-exposed skin of the
buttock.
Studies of the succinic dehydrogenase (SDH) activities
also presented us with some interesting results. The SDH
activity was only slightly decreased overall in the epider-
mis but when the various parts of the epidermis were
investigated separately for SDH activity the granular
layer showed a significant decrease in both lesions and
paralesional areas.
As the cytochemical changes (increased G6PDH and
decreased SDH activities) were also present in exposed
but non-involved skin it seemed quite likely that chronic
exposure to ultraviolet radiation was responsible. In order
to confirm this we irradiated 3 cm2 areas on the buttock
skin of five normal healthy volunteer subjects with broad
spectrum ultraviolet (290-400 nm) radiation 10 times in a
14 day period. The dose given was sufficient to keep the
colour of the areas slightly pink and was one to two
'minimal erythema doses'. At the end of the experiment
the treated sites and non-irradiated control sites in the
same, normally non-exposed, area were biopsied. The
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
117
biopsies were studied for G6PDH and SDH activities in
the same standardised manner as outlined above. The
results of this experiment were quite similar to the
findings in patients[21]. After irradiation, the SDH ac-
tivity dropped to 50 per cent of the control value in the
granular cell layer but did not change much overall in the
epidermis. The G6PDH activity increased by about 30
per cent overall in the epidermis and was markedly
increased in the basal and granular cell layers. These
findings suggested to us that we did have the basis of a
model for UVR-induced epidermal change of the type
associated with neoplasia.
The first question that we wanted to ask of the model
concerned the relationship between sunburn and the
cytochemical alterations discussed. Are individuals who
are 'protected' from sunburn by sunscreen agents simi-
larly protected from the epidermal damage caused by
UVR? As the sun-worship cult gains strength, outdoor
activities increase in popularity and holidays in the
Mediterranean sun become ever cheaper, it is important
to know how to reduce the risk of sun-induced skin
cancer. The experiment we designed to obtain this infor-
mation was again in normal human volunteer subjects
and we studied two sunscreen products?one containing
2.5 per cent isoamyl-p-N.N-dimethylaminobenzoate and
the other containing 4 per cent Mexenone[22]. The first is
effective at absorbing UV of wavelengths in the medium
UV wavelength band (UVB), around 290 nm?the wave-
lengths well known to be responsible for causing sun-
burn?and the preparation in which it was formulated
had a sun protection factor of 7 (i.e. a seven times greater
dose of UV is necessary to cause erythema when it is used
than when it is not used). The second preparation has a
broader absorption spectrum and is weakly absorbent in
part of the long wave UV range though it is mainly
effective in the UVB band. The protection factor of this
preparation was approximately 6. Small areas on the
buttocks were irradiated with different doses of UV from
fluorescent tubes. Some areas were 'protected' by one or
other of the sunscreens and others were not. Irradiation
was performed 10 times in a 14 day period and the
irradiated sites, and non-irradiated control sites, were
biopsied 24 hours after the last irradiation. The biopsies
were assayed cytochemically as described previously and,
in addition, portions were incubated in tritiated thymi-
dine for subsequent autoradiography and epidermal la-
belling index determination[23]. Measurements of
epidermal and stratum corneum thickness were also
made.
The preparations were certainly effective in preventing
sunburn erythema, but were less effective in preventing
the objective consequences of UV exposure on the epider-
mis. At the higher doses of UVR (still less than needed to
produce erythema) there was a marked increase in
G6PDH throughout the epidermis and some decrease in
SDH activity. The same was true for the epidermal
thickening and increased thymidine autoradiographic
labelling index usually noted after UVR stimulation of
normal skin in that, despite the absence of clinical
'burning', there were significant UVR induced alter-
ations. Although these changes were most prominent with
the higher doses?there seemed to be a regular dose-effect
relationship?they were also evident with less irradiation.
This dissociation between the clinical sunburn effect and
the objective responses of the epidermis to UVR is a
cause for concern. It suggests that individuals can expose
themselves covered in these sunscreens and not burn, but
nonetheless sustain significant injury to the skin.
One possible explanation for the dissociation between
clinical burning and epidermal damage is that the latter is
at least in part caused by wavelengths not absorbed out by
the sunscreens used. Both sunscreens used absorb maxi-
mally in the 290 nm wave band (the 'erythema' wave
band) and allow through most of the longer wavelengths
of the fluorescent lamps used. Solar radiation certainly
contains the longer UVA wavelengths but this form of
UV radiation has always appeared much less biologically
effective and less attention has been devoted to it in
relation to solar neoplasia. Because of the practical im-
portance of knowing whether UVA was indeed respon-
sible for the changes in our model, we mounted an
experiment employing a monochromator to irradiate the
skin instead of 'broad spectrum' fluorescent lamps. We
chose UVA at approximately 360 nm and used a similar
schedule of treatments on volunteer subjects as described
previously. The energy employed was sufficient to pro-
duce slight tanning at the sites irradiated by the second
week of irradiation. The results demonstrated that similar
cytochemical and cell kinetic alterations take place after
exposure to UVA as take place after irradiation with 290
nm[24]. Manufacturers have now started to include UVA
absorbing chemicals in their sunscreen products. Unfor-
tunately, in most cases their presence is ineffectual, as
they are not as efficient UVA absorbers as the other
substances are UVB absorbers. This suggests that dam-
aging radiation may still reach skin protected from burn-
ing. We do not know the precise relationship of the
cytochemical changes described to the development of
epidermal neoplasia. Indeed, the relationship may be
indirect, their presence only indicating epidermal damage
of the type that eventually leads to skin cancer. We
believe, nonetheless, that the human model we have
described can be used to answer questions concerning the
effects of repeated UVR exposure and attempts to mini-
mise the damage caused by such radiation.
The Antigenic Profile of Non-Melanoma Skin Cancer
Solar keratoses are much more common than squamous
cell carcinomata. A suppressive effect by host immunolo-
gical defences could explain the apparent lack of vigour of
keratoses, and researchers have made special efforts to
identify antigenic differences between normal and neo-
plastic epidermal tissue. The loss of various cell surface
markers and other cytological components of normal
epidermal differentiation as detected by immunolocalisa-
tion procedures has been reported by several groups,
including ourselves.
Abnormalities in the distribution of the intercellular
pemphigus antigen was probably the first such change
recorded[25]. Moragas et al. [26] claimed that there was a
progressive loss of pemphigus antigen with increasing
118 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
dysplasia. Others have also found that solar keratoses
retained this intercellular component, often with reduced
intensity of staining, but that squamous cell carcinomas
showed a marked reduction in the presence of pemphigus
antigen[27]. We demonstrated that short-term incubation
of lesions before examination made the demonstration of
antigen loss very much more obvious[28]. The antigenic
profile of the skin tissues on which neoplastic epidermal
lesions rest has also been studied. The bullous pemphi-
goid antigen of the basement membrane region is also
deficient in squamous cell carcinoma but we found
accentuation of staining in the sub-epidermal region due
to antibodies raised to procollagen[29]. The latter has led
Mitrani and Marks[29] to suggest that the dermal con-
nective tissue synthesis plays a central role in the genesis
of epidermal neoplasia.
Dabelsteen et al. [30] found that oral premalignant
lesions demonstrated loss of blood group substances A
and B but that benign leukoplakic lesions did not. Other
studies have shown that j82 microglobulin is deficient in
epidermal cell surfaces in some lesions, particularly basal
cell carcinoma[31, 32]. Binding experiments with the
lectin concanavallin A reflect the changes registered with
pemphigus antibody?which is not surprising as it seems
that pemphigus antibody and concanavallin A share
binding sites. Beta 2 microglobulin, however, appears
differently distributed over the cell surface. Class 2 mixed
histocompatibility (MHC) antigens are expressed on all
normal epidermal cells but there are relatively few studies
of MHC antigen expression in premalignant and malig-
nant tissue[33]. Our own studies indicate a not dissimilar
picture, as seen with other cell surface markers. There is a
patchy loss of these antigens which is more marked the
more dysplastic the tissue appears. Clearly this group of
cell surface components may be of particular importance,
as they appear to be involved in regulating T-lymphocyte
responses.
Differences in the distribution of keratins between
normal and neoplastic epidermal tissue have also been
documented. Winter et al. [34], using both polyacryla-
mide gel electrophoresis and two-dimensional electro-
phoretic methods, have demonstrated that the larger
molecular weight-keratin peptides are absent from both
experimentally-induced rodent and spontaneously-occur-
ring human squamous cell cancers. A not dissimilar
finding was that of Klein-Szanto et al. [35] who deter-
mined that the keratin fibril organising basic protein
(filaggrin) present in the keratohyalin granules of normal
epidermis was absent from squamous cell carcinoma but
present in keratoacanthomas.
Apart from the potential diagnostic significance of
these various findings, do they yield any biologically
important messages that inform on the nature of the
neoplastic process or can be utilised therapeutically? For
the most part they appear to indicate faulty epidermal
differentiation and faulty membrane synthesis. From the
functional standpoint the loss of cell recognition markers
and cell contacts at the surface has several implications. It
may allow cells to invade and metastasise rather than stay
attached to other cells. It could explain the curious
phenomenon of carcinoma segregans in which groups of
dysplastic epidermal cells appear to grow around other
epidermal structures. Failure of recognition by the im-
mune system of the abnormal cells as 'self' may also
permit an immune response and explain spontaneous
regression. Most of the reported studies have detected an
alteration that is evident in frankly malignant lesions but
only partially expressed in the premalignant lesions
examined. They indicate a stepwise progression and not a
fundamental alteration.
No tumour-specific antigens have yet been detected in
solar keratoses or squamous cell carcinoma.
Evidence of 'Immune Surveillance'
A dense lymphocytic infiltrate beneath a solar keratosis is
a commonly observed histological feature and could be
interpreted as indicating an immune response to the
lesion. In a few lesions the pathological picture simulates
lichen planus in that there is basal cell liquefactive
degeneration and 'colloid body' formation as well as a
heavy infiltrate of lymphocytes sub-epidermally. These
lichenoid keratoses may be examples of the immune
response succeeding in checking the neoplastic process.
We found that 6.1 per cent of 212 solar keratoses
examined retrospectively and 10.7 per cent of 28 kera-
toses examined prospectively demonstrated the distinctive
changes of lichenoid keratosis[36]. Basal cell liquefactive
degenerative change occurred without full-blown 'lichen-
oid change' in some 27.8 per cent of keratoses. Colloid
body formation and apparently apoptotic cells are often
seen in keratoses and may represent a similar type of
individual cell death. We could not identify a specific
pattern of immunoglobulin or complement deposition in
lichenoid keratoses, neither could we identify a particular
morphological feature with which the phenomenon was
associated. Similarly, Tosca et al. [37] could not identify a
particular immunological mechanism for the regression of
keratoacanthoma.
Patients who have had renal transplants and who have
been immunosuppressed for several years to prevent
rejection of the transplanted kidney have a higher preva-
lence of solar keratoses and squamous cell carcinoma than
control populations. Although this is clinically evident in
the UK, it is more of a problem in sunnier climates where
there is already a high prevalence of non-melanoma skin
cancer[38, 39]. A likely explanation for this phenomenon
is that the normal immune 'check mechanisms' are
prevented from acting to suppress UVR-induced neopla-
sia and the onward progression of pre-neoplastic lesions.
A corollary of this hypothesis is that if solar keratoses
could be transplanted to immunologically privileged sites
away from immune influences they would transform and
become more malignant. In order to test this idea we have
transplanted solar keratoses to athymic nude mice and
have been successful in maintaining these lesions for
periods of up to nine months[40]. We removed solar
keratoses from patients, split them in two and examined
half by routine histological methods and transplanted the
other half. The transplanted tissue seemed to retain most
of its own characteristics during its sojourn in the host
site, free of the influence of delayed hypersensitivity. The
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 119
cell kinetic characteristics and the overall morphology of
the transplanted tissue were similar to those of the
original lesion although there was a tendency for the
grafted tissue to be thinner than the original lesion from
which it derived. It was quite obvious that the grafted
lesion retained its human identity. The dysplastic nature
of the epidermis was obvious, as was the solar elastotic
degenerative change in the dermis. Even more convinc-
ing, however, were the antigenic similarities of the grafts
to human epidermis. Involucrin is a component of the
tough protein membrane just inside the plasma mem-
brane of mature human epidermal cells[41]. Antibodies
to this substance reacted with the grafted tissue but not
with neighbouring mouse epidermis. Similarly, anti-
bodies to the mixed histocompatibility complex (anti-
HLA, A, B and C) reacted patchily with the original
lesions and with the grafted lesions early on, but not at all
with older grafts. Interestingly, we have found that there
is an analogy with this state of affairs in cultured epider-
mal cells. After the first days of a subculture the HLA
positivity is lost?to be regained for a short time immedi-
ately after subculturing, but then lost again as the culture
ages (Thomas, Dykes and Marks, in preparation).
We were surprised that there was so little change
overall in the grafted lesions even after periods of nearly
nine months. Not a single transplanted keratosis became
frankly malignant. We have no complete explanation for
this lack of progression but two possibilities should be
considered. The first is that the athymic mouse does
retain some capacity for mounting an immunological
reaction and that this is sufficient to keep the lesions in
check. The second possibility is that solar keratoses
require further UVR stimulation for any frankly neoplas-
tic change to occur.
The epidermal dendritic Langerhans cell, for so long
an annoying puzzle to dermatologists, anatomists and
electron-microscopists, has now been identified as a sort
of macrophage. It has the function of presenting antigen
to T-lymphocytes and is of central importance in the
development of delayed hypersensitivity. In recent years
it has been found that irradiation of the skin with UV
causes the Langerhans cells to disappear[42] and inhibits
the development of delayed hypersensitivity. Whether
this is of importance in allowing the development of
neoplastic epidermal cells in chronically sun damaged
skin is uncertain but clearly it is a possibility. Other work
by Margaret Kripke[43] may also be important. When
UVR-induced tumours in mice are transplanted to other
irradiated mice the tumours are not rejected even though
other types of tumour are. It has been suggested that the
UVR induces a specific immune tolerance to tumours
caused by UVR by inducing suppressor T cells that
interfere with the rejection of the tumours.
It will be evident from the above that the events leading
up to the establishment of a premalignant lesion after
long-continued sun exposure and the subsequent further
development of a squamous cell carcinoma in some cases
are extremely complex. There can be little doubt that the
immune system is involved in several ways but the
relative contribution of each mechanism to the process is
as yet uncertain.
Measurement of the Degree of Epidermal Dysplasia
Methods have been devised for measuring dysplastic
change in bronchial mucosa[9] and have assisted in
detecting an improvement after stopping smoking. If we
possessed a 'dysplasia index' it would be much easier to
assess the effects of drugs and prophylactic measures than
with the present subjective qualitative methods. We have
used two ways of deriving such a dysplasia index[44]. The
first is in reality a semi-quantitative method which em-
ploys 10 cm visual analogue scales. A mark is made on a
10 cm line indicating the severity of the epidermal
change, the left hand end of the line representing no
dysplasia, the right hand end representing the severest
possible dysplastic change. The accuracy of this pro-
cedure is totally dependent on the experience and consis-
tency of the observer, but in our hands can be shown to be
reproducible. ,<
The second method that we have devised utilises image
analysis techniques. Nuclear area and its variability, cell
size, epidermal thickness and irregularity, the degree of
parakeratosis and the number of dyskeratotic cells are all
assessed. The values are weighted arbitrarily and a
dysplastic index is obtained with a complex formula.
Unfortunately, this method is extremely time-consuming,
as at present it takes four man hours per sample. We
believe that some modification of one or other of these
assessment techniques will be helpful in exploring dose-
effect relationships as far as epidermal neoplasia is con-
cerned.
The Social Significance
In countries such as the USA, Australia and South
Africa, non-melanoma skin cancer is now a major public
health problem. Although the various lesions induced by
chronic sun exposure do not often kill, they cause con-
siderable morbidity. Campaigns have been mounted
through the various popular media in those countries to
make the public more aware of the danger of sunbathing
and we must hope that these will be successful. Our
problem in the UK is smaller but rapidly growing in size
because of the increased opportunities for travel and the
growing emphasis on outdoor activities. It would be
prudent to alert the British public to the potential hazards
now.
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10. Van der Leun, J. C. (1984) Photochemistry and Photobiology, 39, 861.
11 ? Epstein, J. H. (1983) Journal of the American Academy of Dermatology,
9, 487.
12. Zayoun, S., Ali, L. A., Shaib,J. and Kurban, A. (1985) Journal of
the American Academy of Dermatology, 12, 522.
13. Holman, C. D. J., Armstrong, B. K., Evans, P. R. et al. (1984)
British Journal of Dermatology, 110, 129.
14. Stern, R. S., Laird, N., Melski, J., Parrish, J. A., Fitzpatrick, T.
B. and Bleich, H. L. (1984) New England Journal of Medicine, 310,
1156.
15. Kraemer, K. H. (1980) In Clinical Dermatology, Vol. 4 (ed. D. J.
Demis, R. L. Dobson and J. McGuire.) New York: Harper &
Row.
16. Blum, H. F. (1959) Carcinogenesis by ultraviolet light. Princeton, New
Jersey: University Press.
17. Ibrahim, K. S., Husain, O. A. N., Bitensky, L. and Chayen., J.
(1983) Journal of Clinical Pathology, 36, 133.
18. Bannasch, P., Benner, U., Hacker, H.J. et al. (1981) Histochemical
Journal, 13, 799.
19. Evans, A. W. (1980) British Journal of Oral Surgery, 18, 3.
20. Pearse, A. D. and Marks, R. (1978) Histochemical Journal, 10, 621.
21. Pearse, A. D. and Marks, R. (1978) Bulletin du Cancer, 65, 351.
22. Pearse, A. D. and Marks, R. (1983) Journal of Investigative Derma-
tology, 80, 191.
23. Shahrad, P. and Marks, R. (1976) British Journal of Dermatology, 94,
7.
24. Pearse, A. D. and Marks, R. (1985) British Journal of Dermatology,
(abstract), 113, 772.
25. Muller, H. K. and Sutherland, R. C. (1971) Nature, 230, 384.
26. Moragas, J. M. de, Winkelmann, R. K. andjordon, R. E. (1970)
Cancer, 25, 1399.
27. Tosca, A., Varelzidis, A., Nicolis, G., Hadzis, J., Stratigos, J.
and Capetanakis, J. (1980) Cancer, 45, 2284.
28. Marks, R., Pearse, A. D., Holt, P.J. A., Mitrani, E. and Nuki,
G. (1978) Les Colloques de I'INSERM, 80, 247.
29. Mitrani, E. and Marks, R. (1982) Archives of Dermatological Research,
274, 21.
30. Dabelsteen, E., Roed-Petersen, B. and Pindborg, J. J. (\975)Acta
pathologica et microbiologica Scandinavica, Sect. A, 83, 292.
31. Mahrle, G., Patyk, H. and Boiling, R. (1982) Archives of Dermatolo-
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32. Turbitt, M. and MacKie, R. M. (1981) British Journal of Derma-
tology, 104, 507.
33. Parmiani, G., Carbone, G., Invernizzi, G. et al. (1979) Immunogen-
etics, 9, 1.
34. Winter, H., Schweizer, J. and Goerttler, K. (1983) Archives of
Dermatological Research, 275, 27.
35. Klein-Szanto, A.J. P., Barr, R. J., Reiners, J. J. and Mamrack,
M. D. (1984) Archives of Pathology and Laboratory Medicine, 108, 888.
36. Tan, C. Y. and Marks, R. (1982)Journal of Investigative Dermatology,
79, 365.
37. Tosca, A., Varelzidis, A., Avgerinou, J., Hatzis, J., Perissios, A.
and Nicolis, G. (1980) Archives of Dermatological Research, 268, 149.
38. Hardie, I. R., Strong, R. W., Hartley, L. C. J., Woodruff, P. W.
H. and Clunie, G.J. A. (1980) Surgery, 87, 177.
39. Koranda, F. C., Dehmel, E. M., Kahn, G. and Penn, I. (1974)
Journal of the American Medical Association, 229, 419.
40. Thomas, S. E., Pearse, A. D. and Marks, R. (1985) European
Journal of Cancer and Clinical Oncology, 21, 1093.
41. Rice, R. H. and Green, H. (1979) Cell, 18, 681.
42. Aberer, W., Schuler, G., Stingl, G. et al. (1981) Journal of
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43. Kripke, M. L. (1981) Advances in Cancer Research, 34, 69.
44. Pearse, A. D., Barton, S. and Marks, R. (1985) British Journal of
Dermatology, (abstract), 113, 786.
|
PMC005xxxxxx/PMC5371108.txt | A Note on Dr Frank Buckland
Fellows may have noticed a blue plaque let into the wall at
the east end of the College garden, recording the fact that
Dr Frank Buckland, Medical Naturalist, lived in a house
on this site from 1863 to 1880.
Buckland, whose given names were Francis Trevelyan,
was born in 1826, the son of William Buckland, a Canon
of Christ Church, Oxford, who later became Dean of
Westminster. William was also a distinguished geologist
and naturalist, and in addition a considerable eccentric.
He once expressed a wish to eat his way through the
whole of the animal kingdom, but had some difficulty
with the bluebottle and the mole.
Frank qualified in medicine from St George's Hospital,
but his only medical practice was a period as Assistant
Surgeon to the 2nd Life Guards. The rest of his life was
devoted to the study of natural history. His special
interest was pisciculture, and in 1867 he was appointed
Inspector of Salmon Fisheries. His numerous publi-
cations included Curiosities of Natural History and books
on pisciculture and fishing.
In 1863 he came to live in Albany Street. My father,
Arthur Clement Cooke, then aged 11, lived nearby. Like
many small boys he was interested in natural history, and
used to go fishing in the Regent's Park canal. There he
collected some specimens of the 10-spined stickleback, a
rare species. My grandfather suggested to Arthur that he
should show them to Frank Buckland down the road.
This he did, and the schoolboy and the eminent naturalist
became firm friends. Frank was not so eccentric as his
father, but delighted in keeping numerous pets of most
unusual species, which were allowed to roam freely in the
house. It must have been a splendid place for a small boy
to visit.
Needless to say my father retained a keen interest in
natural history until his death at 93. When I was a boy we
went to the London Zoo almost every Sunday morning. I
too am fascinated by medicine and the other biological
sciences, and my son is a professional zoologist, all of
which I attribute in some degree to Frank Buckland.
As I walk past the plaque, I have a pleasant awareness
of the continuity of history.
Alexander Cooke
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 145
|
PMC005xxxxxx/PMC5371109.txt | Increased Longevity In Man
(SIR CYRIL CLARKE, kbe, md, frcr frs
Director, (Royal College of Physicians Research Unit '
It is well known that in the UK the proportion of
pensioners to the rest of the population is rapidly rising
and in this article I propose to discuss the old and the very
old, i.e. those over 85 years and especially centenarians.
The reason for my interest is that I believe it is not
sufficiently realised that the old can give important
epidemiological data about what accelerates or retards
ageing and death.
Table 1 shows the nearly ninefold increase in centenar-
ians in 30 years and this must have mainly environmental
Table 1. The number of centenarians in England and Wales,
1951-81. These estimates are taken from the censuses in 1951
and 1961 and the DHSS estimates of centenarian pensioners in
1971 and 1981. (Courtesy Mr A. R. Thatcher, Registrar
General, OPCS.)
Year 1951 1961 1971 1981
Number of centenarians 271 479 1,240 2,410
causes. It could not possibly be due solely to the increase
in population size, nor could the genetic structure of the
population have altered appreciably in this time. So we
should look for environmental factors, of which there are
plenty?antibiotics and other drugs, various caring as-
pects of the NHS, hybridity, the Clean Air Acts, health
education, the 'urge to live', central heating, diet and all
the rest.
All this is well known, but how do these factors rate at
different ages on the way to the century? One clue comes
from examining the sex ratio, shown in Table 2. What is
Table 2. The sex ratio, England and Wales 1981. (Courtesy Mr
A. R. Thatcher, Registrar General, OPCS.)
Age group Female %
25-34 49.6
35-44 49.6
45-54 50.0
55-64 52.0
65-74 56.3
75-84 65.5
85-94 76.7
95-99 84.4
100+ 87.8
so interesting is that women 'take over' only at about
retiring age; they do this to such an extent that by the
time the century is reached only about 15 per cent of these
very old people are males. This could be because there is
some biological basis for increased longevity in women,
but it seems much more likely that it is the males who die
differentially from about the age of retirement onwards.
The survival of the older women is exactly the opposite of
what would be expected on the Darwinian theory of
selection in favour of biological fitness, since this becomes
zero in women after the age of 50?because they then
cannot hand on their genes, whereas men can up to any
age. So there must be causes working against men in
older age groups and these are highly likely to be
environmental factors, for example diseases.
It would be most interesting to see if these sex ratios are
currently different in the different social classes, and to
know the position 20 years ago and what is happening in
other countries. Some readers may know the answers to
these queries, which could indicate changing pressures on
the sex ratio. In passing, if there is now a scourge of
coronary heart disease deaths in males between 40 and 55
one might expect the sex ratio to be affected, but this is
not the case, so I am uncertain how sensitive a marker it
is. However, I obtained some useful information from
two actuaries. They pointed out that 105 boys are born to
100 girls but because the mortality in children and young
adults is higher in boys than in girls the sex ratio at age
25-34 is near unity (49.6). This might be because males
are biologically inferior to females, but, if so, I do not
understand why the sex ratio between 34 and 54 remains
at unity; one would have thought the females should
'nose' ahead during this time, whereas they only start
doing so between ages 55 and 64. A more likely expla-
nation is that trauma is responsible for an increased death
rate in boys and young adults and that between 34 and 54
males are developing but not dying from atheroma to a
greater extent than women. After the age of 55 men start
dying differentially, probably, from cardiovascular dis-
ease, and women 'take over' the sex ratio to an increasing
extent in each decade.
Table 3 gives information about two cohorts, one
between 1876 and 1945 and the other between 1961 and
1980. It will be seen that there is a marked reduction in
mortality and surprisingly this is greatest in the younger
age groups. So when considering factors prolonging life
we have to take the age group into account as well as the
sex ratio in that group.
The fact that each decade is receiving a contribution
from the one before means that there is a cumulative
effect such that there are bound to be more centenarians,
and we need not look for a specific cause at or around the
122 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
v Table 3. Death rates per 1,000. (Courtesy Mr A. R. Thatcher,
Registrar General, OPCS.)
Age 1876-1945 1961-80 Reduction %
85 + 264.5 211.5 20
75-84 127.4 90.2 29
65-74 56.9 37.7 34
55-64 26.1 15.1 42
45-54 13.26 5.70 57
35-44 8.00 1.94 76
25-34 4.85 0.82 83
century (apart perhaps from 'urge' in the 99-year-olds).
The causes of survival will be building up but will be
different in the different decades.
The current trend of increased longevity is described
by what the Americans call 'rectangularisation' of the
population, as shown in Fig.l. In the Stone Age, for
example, only about 12 per cent of the population
reached the age of 50, whereas in 1971 the percentage was
over 90. As a nation, therefore, we are living longer, in
spite of cigarettes, drink, drugs, the dreaded coronary
artery disease and lung cancer. Have we reached the limit
of age? Probably not. The Japanese have reported a
definite example of a man living to 116.
Likely Environmental Factors favouring Survival
Antibiotics and Other Drugs
These are available equally to both sexes at all ages and
may be the principal cause in the reduction of mortality in
the younger age groups where the sex ratio is normal as
mdicated by the decline in tuberculosis and many other
types of infection. But at retirement age and after,
antibiotics will still be as effective in men as in women,
and therefore it is probably not infections which are
killing off the men differentially at 65 years or more.
The NHS and its Facilities
These will tend to prolong life after coronary thrombosis
and strokes, and there is also the improved treatment of
hypertension. The facilities, and the drugs, are available
to both sexes, but I surmise that it is the cardiovascular
diseases which kill off more men than women in the older
age groups, probably because of male life-style in retire-
ment.
Similarly, more men die of cancer, mainly because of
the large number of lung cancer cases (the result of
cigarette smoking) than women. So in the older age
groups this cancer will favour the higher survival rate in
females, at least at the present.
Health Education
This again is available to both sexes but after retirement
men tend to adopt an unhealthy life-style. They run to fat
because of excessive calorie intake and smoke and drink
more than women. Furthermore, they are less active both
mentally and physically?everything is in the bag, so to
speak?whereas most women go on as before, cleaning
the house, cooking the meals, shopping, washing, etc.
There is no retirement for women, so they live longer;
this is my view. Support, showing how women, compared
with men, have kept cardiovascular disease at bay in the
past 80 years, comes from the USA[1],
Hybridity
This is more speculative but it is a likely factor in the
Japanese, where cousin marriages used to be common. A
century ago one tended to marry the girl next door but
with the coming of the internal combustion engine men
became more venturesome and travelled further for their
mates ? so there would be less inbreeding and .more
hybridity and therefore possibly more hardiness. In ani-
mals it holds, for a mule, which is a cross between a mare
and a jack donkey, lives longer than either of its parents.
The Clean Air Acts
These were very important. Pollution (i.e. sulphur diox-
ide and soot) will have affected men in their working life
more than women, often without killing them until later.
Lawther et al. [2] gave bronchitics pocket diaries for the
daily recording of their health, with very simple coding,
and showed that worsening was highly correlated with
smoke and sulphur dioxide levels. With the Clean Air
Acts these findings became of historical interest only.
The story of the Peppered Moth correlates well with the
medical findings. In 1849 the first black mutant appeared
in the Manchester region and by the end of the century 93
per cent of the population was melanic, camouflaged by
the soot and sulphur dioxide, the latter being toxic to the
Fig. 1. 'Rectangularisation': approximate survival curves.
(Courtesy Mr A. R. Thatcher, Registrar General, OPCS.)
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 123
pale coloured lichens. In my home at West Kirby on the
Wirral I have trapped the moth for 25 years and the
proportion of the melanic form has dropped from 93 per
cent to 61 per cent (Fig.2). The probable reason is the
implementation of the Clean Air Acts in the 1960s and
the moth is a good example of evolution in reverse[3].
Central heating
This is the same for both sexes and will not affect the sex
ratio in old age, though it will certainly tend to keep old
people in general alive longer.
'Urge'
The urge to reach the century in the very old may be
strong, particularly in a cricket-loving country, just as
conversely the bereavement syndrome, or the witch-
doctor's curse, may turn faces to the wall. Competitive
urge certainly seems to have physical effects?beating the
four-minute mile is a good example. On the other hand,
racehorses bred for speed run no quicker than they did 50
years ago. Reverting to longevity, the decline in belief in
an after-life may have increased the urge to keep alive in
this one.
Eating and Weight Reduction
Diet is the modern craze and as regards longevity it
receives support from animals. Rats live longer on a low
calorie regime, and exercise, if begun in early life, also
(
)
increases their lifespan. But rats are not men, and what
about the higher animals? I wrote to two experts at the
London Zoo and asked whether their mammals were
living longer than 20 years ago; both said 'yes'. The
longevity improved once the keepers stopped the animals
from having the public's picnic scraps. What better
indictment of human diet could you have? Interestingly,
life appears to be equally prolonged for male and female
mammals. Male animals, of course, have no retirement
age. That really is the core of my argument. In man it is
notoriously difficult to get reliable information on diet; no
one can remember what they had for breakfast yesterday,
but with golden weddings now ten a penny (provided
couples stick together) it might be possible to get useful
information between couples who know each other ex-
tremely well.
The Familial Component in Longevity
There is a general feeling among both laymen and doctors
that a large component of longevity lies in one's genes,
and a number of papers[4-6] have been written on this
theme, mainly from the Johns Hopkins Medical School.
These may be summarised by the statement that there
are not specific genes for longevity but rather the absence
of those that make for premature death, e.g. the sickling
trait. Furthermore, all the papers emphasise the cultural
factors in longevity, and although they do find that long-
lived people tend to have long-lived relatives they are all
somewhat equivocal as to the reason. No one, as far as I
know, has carried out the proper survey to test the genetic
hypothesis for polygenic inheritance. What should be
done is to take male centenarians (the rarer sex) and look
at their brothers and sisters and then do the same with
women. Polygenic inheritance would be indicated if the
males had longer-lived sibs than the females. It is the
same type of work that C. O. Carter[7] did with hyper-
trophic pyloric stenosis. All the surveys that I have seen
go vertically, and these are complicated by the fact that in
looking at the age of the offspring of a centenarian there is
his or her spouse to consider, which is confusing. The sibs
have the same mother and father.
To try and clarify some of these points the RCP
Research Unit is beginning an investigation with both the
Royal Holloway and Bedford New College Sociology
Unit and the Liverpool Institute for Ageing.
First, what sort of people are the very old? Are they
mostly mentally feeble, stone deaf and just waiting for the
end? Some are, and they need to be in institutions, but a
great many are not, particularly if they can be looked
after at home. My namesakes and their colleagues in
Leicester[8] emphasise this particularly, and Dr John
Harrison, on behalf of the College, has investigated
residential care for people with severe physical disabil-
ities. He is all for de-institutionalisation if possible, and
he has an excellent quotation from Gerben Dejong which
I have modified slightly: 'The dignity of risk is what the
movement for independent living is all about. Without
the possibility of failure, the disabled person lacks the true
independence that is the mark of one's humanity?the
right to choose for good or evil'.
Year Total
50
Percentage Carbonaria
60 70 80 90
100
1959
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
1972
1973
1974
1975
1976
1977
1978
1979
1980
1981
1982
1983
283
226
426
840
994
982
478
304
398
480
610
848
207
276
318
313
269
446
490
335
631
637
407
122
689
Fig. 2. Percentage of carbonaria moths 1959-84 at Caldy
and West Kirby. (Courtesy Biological Journal of the Linne-
an Society.)
124 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
In conclusion, I do not think that with the present
environmental evidence we need to concern ourselves
with the inheritance of longevity, except for the single
gene diseases. There is so much that can be put right by
paying attention to the environment. So away with
testing people for those terrible apolipoproteins and let us
concentrate on major factors such as diet, exercise,
obesity and hypertension. If we do I think by the end of
the century part of the College motto, 'life is short', will
no longer be appropriate.
Acknowledgments
I am grateful to Professor George du Boulay and Dr
Leonard Goodwin for their helpful comments about the
longevity in animals at the London Zoo.
This article is based on a paper read at the College Regional
Conference in Liverpool in September 1985.
References
1. Tyler, B. (1985) New England Journal of Medicine, 313, 957.
2. Lawther, P. J., Waller, R. E. and Henderson, Maureen (1970)
Thorax, 25, 172.
3.. Clarke, C. A., Mani, G. S. and Wynne, Goronwy (1985) Biological
Journal of the Linnean Society, 26, 189.
4. Hawkins, Margaret R., Murphy, Edmond A. and Abbey, Helen
(1965) Bulletin of the Johns Hopkins Hospital, 117, 24.
5. Abbott, Margaret H., Murphy, Edmond A., Boiling, David R. and
Abbey, Helen (1974) The Johns Hopkins Medical Journal, 134, 1.
6. Abbott, Margaret H., Abbey, Helen, Boiling, David R. and
Murphy, Edmond A. (1978) American Journal of Medical Genetics, 2,
105.
7. Carter, C. O. (1961) British Medical Bulletin, 17, 251.
8. Clarke, M., Clarke, Susan, Odell, Aileen and Jagger, Carol (1984)
Health Trends, 16, 3.
|
PMC005xxxxxx/PMC5371111.txt | Book Review
Rheumatological Medicine
edited by P. A. Dieppe, M.
Doherty, D. G. MacFarlane and P. J. Maddison. Chur-
chill Livingstone, Edinburgh, London, Melbourne and
New York, 1985. 522 pages. Price ?40.
Nineteen eighty-five is proving to be the year for rheuma-
tological publications. Hard on the heels of new editions
of the two North American tomes ('Hollander' and
'Kelley') and with a further edition of the standard British
work ('Copeman') due out soon, comes this new, medi-
um-sized textbook.
The authors state their aims to be that of filling the gap
between the major reference works and texts written for
students, and also that of setting rheumatology in the
context of general medicine. I believe they have succeed-
ed in both objectives.
The text is divided into six sections, of which I thought
the first (on the structure and function of joints, immuno-
pathology and epidemiology) was quite outstanding. It
provides a reasonably comprehensive account of highly
technical topics in a simple, clear and succinct style which
is a refreshing change from the heavy approach in the
larger textbooks.
The second section deals systematically with the major
rheumatic diseases. This is practical throughout, and has
the ring of experienced clinicians writing with authority.
Section three covers rheumatology and general medicine.
This is perhaps a less satisfactory mix. Systems such as
the skin are discussed in terms of how rheumatic diseases
affect them. It does, however, include a useful problem-
orientated approach to features such as headache and
depression.
The fourth section deals with diseases of bone and of
collagen, and also provides an excellent account of 'soft
tissue rheumatism', including a highly practical approach
to the vague aches for which no pathological diagnosis is
available. Section five is a useful guide to history-taking,
physical examination and laboratory investigations; the
account of regional examination being notable for the
outstanding quality of the illustrations. Section six is an
equally satisfactory review of therapy.
There is a large number of illustrations and, apart from
a few X-rays, these are all line drawings. Most of these
have been prepared with meticulous care and, together
with many well-planned tables, greatly add to the ease of
following the text, and indeed to the pleasure of reading
these well-printed pages. However, the authors might
perhaps have been slightly less rigid about excluding all
clinical photographs. Both nail-fold arteritic lesions (Fig-
ure 4.1) and keratoderma (Figure 5.14) reproduce well in
photographs, while the artist's efforts here do not do
justice to these important signs. When the book is
reprinted it will no doubt be possible to restore the
'triangular ligament' (Figure 9.16) to the correct side of
the wrist. A more serious error is that the subjects in the
second half of the book are indexed as appearing two
pages further on than their actual position in the text.
Despite these criticisms this is an excellent book and a
useful addition to the available texts. It would be a sound
investment for any rheumatology trainee, and a good
reference work for undergraduates.
H. L. F. Currey
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
115
|
PMC005xxxxxx/PMC5371112.txt | Louis Daniel Beauperthuy:
Pioneer in Yellow Fever and Leprosy Research
ALEX SAKULA, MD, FRCP* Emeritus Consultant Physician,
Redhill General Hospital, Surrey
Louis Daniel Beauperthuy's achievements in tropical
medicine have for long been recognised by South Ameri-
can and French medical historians, but in the English-
speaking world his name is virtually unknown. This
article attempts to remedy the apparent British neglect of
a great pioneer of tropical medicine.
Beauperthuy (Fig. 1) was born on 26th August 1807 in
Sainte-Rose, Guadeloupe, a French island possession in
the Caribbean, where his father, Pierre Daniel Beau-
perthuy (1785-1861), who derived from an old French
family in the Perigord, practised as a physician. His
mother, also French, was Marie Laurence Desbonnes
Belasse (1783-1859) and Louis Daniel was the second of
their six childrenfl],
Beauperthuy was educated in France and studied
medicine at l'Ecole de Medecine, Paris, where the Dean
of the Faculty was Mathieu Orfila (1787-1853) and his
teachers included Frangois Magendie (1787-1855). He
attended courses in botany and entomology and devel-
oped a passionate interest in natural history. He was
fascinated by the marvels revealed by the microscope
and, as an extra-curricular activity, attended the course
held by Alfred Donne (1801-78). During his vacations,
while a student, he returned to the Caribbean where
tropical diseases (yellow fever, in particular) were rife. It
was then that the seed of the idea of the transmission by
insects (especially mosquitoes) of human diseases began
to germinate in his mind. In 1837, he qualified MD Paris,
with a thesis entitled 'De la Climatologie'[2] in which he
developed 'la theorie insectile'.
Following qualification, the Musee d'Histoire Natur-
elle, Paris, appointed him in 1837 as 'naturaliste voya-
geur' and during the next four years he explored the basin
of the Orinoco, carried out researches on snakes and
earthquakes and also made important anthropological
observations, sending specimens back to the Paris mu-
seum.
In 1841, during one of his expeditions off Venezuela,
he stopped in the city of Cumana (situated some 300
kilometres east of Caracas) and there he met a Venezu-
elan lady, Ignacia Sanchez Mayz, whom he married in
1842; three children were later born to them. He now
made the important decision not to return to France but
to remain in Cumana. In 1844 he obtained the further
qualification MD Caracas and settled in medical practice
in Gumana, with the intention of devoting his life to
research into tropical disease (Fig. 2).
He remained in Cumana until the last few months of
his life, when he took charge of a leprosy hospital in
British Guiana and it was there, at Bartica, that he died
suddenly, following a stroke, on 3rd September 1871,
aged 64. His grave lies in the Officers' Cemetery of the
British Guiana penal settlement on the River Mazur-
uni[3] (Fig. 3).
*Private correspondence to: Pilgrims Corner, Pilgrims Way, Reigate,
Surrey RH2 9LG.
1. Louis Daniel Beauperthuy. (Oil painting by G. Da
Villadda, in Faculty of Medicine, Rome, Italy. Courtesy
Editions Hervas, Paris.)
146 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
Cholera
Beauperthuy was a medical student when the cholera
epidemic of 1832 hit Paris and he was able to witness the
ravages of this disease. Inl853, he was in Cumana when a
major earthquake seriously damaged that city, a sequel of
which were epidemics of yellow fever, smallpox and
cholera. Beauperthuy was nominated 'Medecin Sani-
y taire', and became responsible for controlling the epidem-
ic. Examining the excreta of the cholera victims, he
detected the motile vibrios which he described in 1855[4].
This was 28 years before Robert Koch definitively isolat-
ed the causative organism of cholera.
Yellow Fever
In the 15 years 1838-53, Beauperthuy had ample oppor-
tunity of studying the manifestations of yellow fever
during outbreaks in Guadeloupe, Caracas, Barcelona
(Venezuela), Cumana and Guiana. He was impressed by
both the manner in which the disease related to the rainy
season as well as by its relative scarcity in the forests, and
he noted a reduction of infection when anti-mosquito
precautions were taken, e.g. the use of smoke and nets.
He came to the conclusion that the mosquito must be the
vector by which the infecting agent of yellow fever was
transmitted, although he conceived that the infecting
agent was particulate decomposing organic matter rather
than a living micro-organism. He became convinced that
it was the striped-legged mosquito ('le moustique a pattes
rayee de blanc'), Stegomyia fasciata (now known as Aed.es
aegypti) which was the variety of mosquito responsible for
the spread of yellow fever[5],
Beauperthuy published his findings in a local journal
Gaceta Oficial de Cumana on 23rd May 1854[6], but an
obscure Venezuelan journal did not circulate widely in
those days. He followed this up with a report in 1856 to
Marie Jean Pierre Flourens (1794-1867), Secretary of the
Academie des Sciences, Paris, entitled 'Recherches sur la
cause du cholera asiatique, sur celle du typhus icteroide et
des fievres des marecages'[7], 'Typhus icteroide' was
yellow fever and 'fievres des marecages' was marsh fever
or malaria. To consider Beauperthuy's theory that 'le
moustique inocule la fievre jaune', the Academie des
Sciences set up a special committee of three eminent
physicians: Etienne Serres (1786-1868), Gabriel Andral
(1797-1876) and Jean Baptiste Boussingault (1801-87)
which gave a favourable report and Beauperthuy's paper
was presented to a meeting of the Academie on 14th April
? 1856 and published later that year in the Comptes Rendus
de VAcademie des Sciences[Q], Beauperthuy's discovery was
subsequently republished in L'Abeille Medicale (1856)[9],
in the Escuela Medica (Caracas, 1875)[ 10] and in 1891 in
the collected Travaux Scientifiques which were published
posthumously, edited by his brother, Pierre Daniel Beau-
perthuy^ 1],
It is important to see Beauperthuy's ideas in the light of
his times, the publication by Louis Pasteur (1822-95) of
his germ theory of disease not appearing until the 1860s.
It is true that Josiah Clark Nott (1807-73) of Mobile,
Alabama, had in 1848 proposed that yellow fever was
caused by 'animalcula', but he used this term to describe
what we would now call micro-organisms[12]. Unfortu-
nately, his 'animalcula' came to be miscontrued as
'insects' and it was thus that the priority for the discovery
of the association of the mosquito with the spread of
yellow'fever has been erroneously ascribed to Nott[13].
Beauperthuy was certainly well in advance of Carlos
Juan Finlay (1833-1915) to whom the discovery of the
role of the mosquito in yellow fever has also been
attributed. Finlay, the son of a Scottish physician who
married a Frenchwoman and emigrated to Cuba, studied
medicine in the USA, qualifying MD Philadelphia, and
then returned to practise in Havana. It was not until
1881, twenty-five years after Beauperthuy, that he pre-
sented his famous paper on the role of the mosquito in
yellow fever.
When the USA occupied Cuba in the Spanish-Ameri-
can War (1898) an American Army Commission on
Yellow Fever in Havana, consisting of Walter Reed
(1851-1902), James Carroll (1854-1907), Jesse William
Lazear (1866-1900) and Aristide Agramonte (1868-1911),
was set up and its report was published in 1901, almost
half a century after Beauperthuy had made his original
crucial observations on the association of yellow fever
with the mosquito, knowledge which was later put to
dramatic and successful use by William Cranford Gorgas
(1854-1920) in his control of yellow fever in Havana and
during the construction of the Panama Canal[14],
Beauperthuy, Yellow Fever and Sir William Osier
Sir William Osier (1849-1919) was aware of the import-
ance of Beauperthuy's contribution to the unravelling of
the mystery of yellow fever. In his "An Address on the
Nation and the Tropics' delivered at the London School
2. Map showing area of Beauperthuy's activities.
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 147
of Tropical Medicine in 1909, Osier presented the follow-
ing version of the yellow fever story:
For centuries there has been a popular belief in the
transmission of disease through mosquitoes and flies,
and in the middle of the nineteenth century that
remarkable clinician and anthropologist, Nott of Mo-
bile, suggested the association between the mosquito
and yellow fever and malaria. A more scientific pres-
entation of the question was made by the French
physician Beauperthuy, an enthusiastic student of the
epidemics in the Spanish Main. But the first clear
demonstration of a mosquito-borne disease was made
by Manson (in 1877) in the case of filariasis. . .
This lecture was published in The Lancet (1909)[ 15]
which in a later issue (1910)[ 16] contained a letter from
Juan Gutteras, Director of Public Health, Cuba, protest-
ing at Osier's omission of Carlos Finlay, to which the
Editor responded:
It is probable that the theories of Beauperthuy had
already been rife amongst the medical men in the West
Indies and on the mainland. Beauperthuy and Finlay
will stand bracketed together. . . It is open to everyone
to examine the respective writings of both Beau-
perthuy and Finlay. Both were original thinkers and
both came to the same conclusion, but Beauperthuy
formulated his opinions earlier;' Finlay coming later
expressed his views more clearly and in a way more in
conformity with modern thinking.
This editorial comment was followed by the following
letter to the Editor:
Sir,
The omission of Dr Finlay's name was a pure
inadvertance for which I am very sorry. His work, of
course, on the subject, has been all important.
I am, Sir, yours faithfully,
Wm. Osier.
Malaria
During his researches into tropical diseases, Beauperthuy
addressed himself also to the problem of malaria and by
1854 considered that, as in yellow fever, the mosquito
(but a different variety from the striped-legged Stego-
myia) was the vector responsible for transmitting this
disease. As early as 1868 he was recommending the use of
mosquito nets as an anti-malarial measure[17].
In this context, it is important to remember that
Beauperthuy's observations were long in advance of the
demonstration by Sir Patrick Manson (1844-1922) of the
role of the mosquito in filariasis sanguinis hominis in
1877; also of Alphonse Laveran (1845-1922) who first
revealed the cycle of Plasmodium malariae in 1880; of
Albert King (1841-1914) who in 1882 favoured the
transmission of malaria by mosquitoes; and of Sir Ronald
Ross (1857-1932) who in 1897 finally provided the scien-
tific proof that was needed.
Leprosy
In 1867, Beauperthuy was placed in charge of the local
lepers in Cumana, which provided an opportunity for
him to make a more careful study of the disease. Lepers
had first been seen in Cumana in 1730 and, as elsewhere
throughout the world, they were considered to be incur-
able and treated as pariahs. Beauperthuy's observations,
however, convinced him that the disease was treatable
and could be controlled. He disposed of the theory that
leprosy was hereditary and concluded that the disease was
contagious, a living agent being responsible for the
infection and its transmission. Shortly afterwards, in
1871, the Norwegian, Gerhard Armauer Hansen (1841-
1912) first demonstrated the leprosy bacillus.
Beauperthuy considered that lepers should be treated
in special isolation hospitals, where their resistance to
infection could be enhanced by improved hygiene and
nutrition. His medicinal treatment was by internal reme-
dies, e.g. mercury bichloride; as external applications he
favoured cashew-nut oil (Thuile d'acajou'), and the
cautery or silver nitrate. On this regime, he was able to
demonstrate beneficial responses which, if not complete
cures, were at least considerably palliative.
The news of Beauperthuy's success with his lepers
reached Robert Bakewell, the acting medical superinten-
dent of the leper asylum in the neighbouring British
colony of Trinidad. Bakewell sent some of his patients to
Cumana and also spent three months in Cumana in 1868,
following which he provided Governor Gordon of Trini-
dad with a favourable report[18,19]. In 1869, Governor
Gordon forwarded Bakewell's report to the Secretary of
3. Postage stamp issued in Venezuela in 1971, to commemorate
the centenary of the death of Beauperthuy.
148 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
State for the Colonies, Lord Buckingham, who in turn
sent it to the Royal College of Physicians.
The Royal College of Physicians had for some time
been taking an interest in leprosy in the West Indies and
in 1863 had constituted a Leprosy Committee, composed
of five Fellows: Arthur Farre (1811-87), George Rees
(1813-89), Edward Greenhow (1814-88), Sir William
Gull (1816-90) and Gavin Milroy (1805-86). This com-
mittee reported in 1867 that leprosy was 'a constitutional
cachexy', was not contagious and therefore special isola-
tion facilities for treatment were not recommended. This,
in fact, remained the official position of the Royal College
of Physicians until, at the Leprosy Conference held in
Berlin in 1897, it was convinced that leprosy was a
contagious disease[20].
On receipt of Bakewell's report in 1869, the Royal
College of Physicians suggested the appointment of 'a
competent and disinterested person to enquire into the
exact evidence of results of Dr Beauperthuy's treat-
ments'. It was not until Bakewell forwarded a second
report in 1870 that the College decided to judge Beau-
l perthuy's claims.
Meanwhile, it had become Beauperthuy's ambition to
pursue his leprosy researches in a hospital adequately
isolated and especially equipped for the purpose. The
authorities in Venezuela would not provide the necessary
funds. Beauperthuy and Bakewell had become friends
and eventually, through Bakewell's contacts in London,
the British government was persuaded to sanction the
creation of a leper hospital in British Guiana and Beau-
perthuy was placed in charge for a period of two years.
There was already in British Guiana a leper asylum at
Mahaica, 50 km from Georgetown. This was visited by
Beauperthuy, who found the cases too advanced and
conditions too crowded for his purpose. Governor Scott of
British Guiana finally assigned the beautiful little island
of Kaow, situated in the river Mazuruni off Bartica,
which lay at the confluence of the rivers Mazuruni,
Cuyuni and Essequibo. The island was well drained and
free of mosquitoes and the hospital, for 60 patients, was
built in pavilion style, one patient per hut. This hospi-
tal?basic and simple?was the first of its kind in the
world to be built exclusively for the study of leprosy.
Beauperthuy arrived in British Guiana in February
1871 and lived in a house at Bartica Grove on the
mainland, opposite the island of Kaow. He immediately
set to work, being joined in July 1871 by Gavin Milroy,
but sadly, two months later, Beauperthuy suffered a
stroke and died on 3rd September 1871.
, The leper hospital at Kaow was later abandoned.
Beauperthuy, Leprosy and Milroy
Following Beauperthuy's death, Milroy continued on his
travels in the West Indies, visiting Jamaica, Barbados,
Antigua and Trinidad, investigating leprosy but also
studying other tropical diseases, especially yaws in Jamai-
ca. On his return to England, his Report on Leprosy and
Yaws in the West Indies (1873)[21 ] contained this vivid
> comment on his visit to the leprosy asylum at Mahaica:
On leaving the building I could not but feel that the
case of the leper at the present time is much like that of
the poor lunatic at the close of the last century: a
hopeless outcast, regarded as a burden and possibly a
danger, to be immured and kept apart with only food
sufficient for his subsistence.
It was this attitude towards the leper which Beau-
perthuy had set out to revolutionise. In his report, Milroy
described Beauperthuy's views on the nature and treat-
ment of leprosy but concluded that Beauperthuy's treat-
ment did not achieve a cure although it did possibly
alleviate the leprosy lesions.
The Royal College of Physicians set up a special
committee to consider Milroy's report, consisting of three
fellows with experience of leprosy in India: John Jackson
(1804-87), William Tilbury Fox (1836-79) and Sir Joseph
Fayrer (1824-1907). They concluded that, to date, no
cure for leprosy had been discovered and that Beauperth-
uy's treatment was not founded on any new principle,
differing from others only in detail. However, they went
on to say:
Great credit is. due to Dr Beauperthuy for re-exciting
the flagging attention of the medical profession to the
possibility of alleviating the condition of leprosy, es-
pecially by improved hygiene and diet and the use of
medicinal tonics.
Their report was accepted by the Royal College of
Physicians and a Lancet leader, commenting on this
verdict, said that the Royal College of Physicians had
'given the profession what was much needed?viz. a
distinct and authoritative decision on the valu,e of the
Beauperthuy plan of treating the leprous'[22].
The archives of the Royal College of Physicians contain
a translated note (which appeared in The Creole News-
paper, Georgetown, 22nd April 1874) by Dr G. F. van
Coppenaal, accompanying a letter forwarded to the Colo-
nial Secretary, Lord Kimberley, in which the writer
castigates Milroy for a too hasty and erroneous assess-
ment of Beauperthuy's treatment of lepers[23].
Beauperthuy's methods were later tried out around the
world (Europe, India, South America) with varying
degrees of success.
Finale
Louis Daniel Beauperthuy was undoubtedly one of that
great band of pioneer medical scientists who, in the
second half of the nineteenth century, addressed them-
selves to unravelling the secrets of tropical disease.
His doctrine of insect-borne diseases and especially his
discovery of the association of the Stegomyia mosquito
with the spread of yellow fever were fundamental obser-
vations on which later investigators could build up more
scientifically our knowledge of the nature and control of
these diseases.
In the case of leprosy, Beauperthuy may not have
discovered a specific cure for the disease, but the enlight-
ened fresh approach he brought to bear on the attitude
towards and the handling of lepers provided inspiration
for other leprosy workers around the world and also
offered fresh hope to the millions of sufferers from that
dread disease.
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 149
Acknowledgements
I should like to express my appreciation of Madame
Rosario Beauperthuy de Benedetti, whose Ecrits de Beau-
parthuy (1985) provides testimony to her efforts, during
the past 25 years, to establish appropriate recognition of
her illustrious ancestor.
References
1. De Benedetti, Rosario Beauperthuy (1985) Ecrits sur Beauperthuy,
Paris: Hervas.
2. Beauperthuy, L. D. (1837) De la Climatologie. MD Thesis. Paris:
Rignoux.
3. Wood, C. A. (1922) Annals of Medical History, 4, 166.
4. Beauperthuy, L. D. (1855) Gaceta Ojicialde Cumana, No. 79, p.350.
5. Tanon, L. (1958) Histoire de la Medecine, Numero special, pp. 37-
43.
6. Beauperthuy, L. D. (1854) Gaceta Oficial de Cumana, No. 57, 23rd
May 1854.
7. Beauperthuy, L. D. (1856) Communication a M. Flourens, Paris.
Cumana, 18th January 1856. (Archives of Academie des Sciences,
Paris.)
8. Beauperthuy, L. D. (1856) Comptes Rendus des Seances de I'Academie
des Sciences, Paris, 42, 692.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19
20,
21
22
23
V
Beauperthuy, L. D. (1856) LAbeille Medicale, 13, 117.
Beauperthuy, L. D. (1875) Escuela Medica (Caracas), No. 10, pp.
139-142. v
Beauperthuy, L. D. (1891) Travaux Scientifiques de Louis Daniel
Beauperthuy. Bordeaux: J. Gonzalez Font.
Singer, C. and Underwood, E. A. (1962) A Short History of
Medicine, 2nd ed. Oxford: Clarendon.
Ackerknecht, E. (1965) The History and Geography of the most important
Diseases, p.58. New York: Hafner.
Scott, H. H. (1939) A History of Tropical Medicine (based on
FitzPatrick Lectures, 1937-38), p.356. London: Arnold. '
Osier, W. (1909) Lancet, 2, 1402.
Guiteras,J. (1910) Lancet,, 1, 1715.
Beauperthuy, L. D. (1868) Letter to Madame Luisa Oriach de
Monagas, Cumana, 5th May 1868.
Bakewell, R. H. (1870) Medical Times & Gazette, 21st May 1870,
p.550.
Bakewell, R. H. (1871) Medical Times & Gazette, 25th Feb 1871,
p.233.
Cooke, A. M. (1972) A History of the Royal College of Physicians,
Vol.3, p.828. Oxford: Clarendon.
Milroy, G. (1873) Report on Leprosy and Yaws in the West Indies.
London: HMSO.
Editorial (1873) Lancet, 2, 339.
Van Coppenaal, G. F. (1874) The Creole Newspaper, 22nd April
1874. (Archives of Royal College of Physicians, London.)
Before the Computer
In the era of computer medicine even we, the elderly
innumerate, know that a byte means information, not
mastication. We are trying to love the data base locked
away on floppy disk. Did Francis Clifton foresee this
when in 1731 he published his 'Tabular Observations
Recommended as the Plainest and Surest Way of Practis-
ing and Improving Physic'? He argued that 'Physic is
only improvable by observation' and added that his
'experiment is attended with no manner of inconvenience
or hazard to the patient'. He created a simple table in
which the left-hand column was for recording the age,
sex, and occupation of the patient with a comment on the
patient's constitution and 'way of life as to eating,
drinking and exercise.' The middle column was for
morbid phenomena, dated by the day of disease and the
calendar date. Then followed a column for remedies and
a final right-hand column headed Eventus which translates
smoothly to outcome. ?
Dr Clifton had a short career, ending in mysterious
disaster. The son of a merchant of Great Yarmouth, he
obtained his MD in the University of Leiden in 1724. He
was known for his love and knowledge of the classics and
published a Latin edition of the works of Hippocrates. He
was so keen on the father of Western medicine that he
wrote a paper attempting to show that Hippocrates had
anticipated Newton's work on gravity and published
proposals for the printing by subscription of 'All the
works of Hippocrates in Latin and Greek, digested in a
new and regular manner'. No one subscribed and the
project flopped.
Clifton's classical learning earned him the friendship of
Sir Hans Sloane who helped him to the Fellowship of the
Royal Society in 1727 and in setting him up in a
fashionable London practice. Cambridge University
awarded him an honorary MD in 1728 and the College
elected him a Fellow a year later. He gave the Gulstonian
Lecture and was appointed physician to the Prince of
Wales.
Then suddenly and inexplicably all went wrong for
Clifton. Leaving his house in Hanover Square, his rich
patients and his influential friends, he set sail in 1734 for
Kingston, Jamaica. There he made a start on writing an
account of the diseases found in the island but some
family disaster seems to have overwhelmed him. On 3rd
May 1736 he wrote to Sloane: 'My misfortunes come so
fast upon me and my brother's provocations were so
frequently repeated that I was hurried in a manner to
death about them'. Indeed he was, for within a few weeks
of writing the letter he died.
150 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
|
PMC005xxxxxx/PMC5371114.txt | ?A
is
Editorial
For long journeys swiftly accomplished jet travel is splendid. But the
splendour lasts only from take-off to landing. Getting to and from the
runway is a tedious complicated process full of unexplained delays
and enough to exasperate a snail. It is all much like the practice of
medicine in hospital. Once with the patient the physician can now
accomplish so much. Working directly on behalf of the patient is the
object of many years of training and the core of the physician's
professional commitment. But how difficult it is to achieve that
modest ambition. Time is frittered away on irrelevancies. A brief
mention of notes and specimens lost, appointments fouled up and
plans upset is enough to trigger off an anxiety state in any hospital
doctor, each one nursing a personal file of such minor horror stories.
As for communication between all sorts of colleagues within and
without the hospital, one might do better with alert pigeons.
This picture of a world that does so much good against the odds is
sad and sour, but, in many places, true. Any patient can give a
graphic account of how he has been affected and so can any member
of staff. The frustrations and irritations are shared. However, critics
have claimed that hospitals are organised solely for the convenience of
consultants, and hospital managers, waving the banner of economy,
have been known to ask consultants to 'generate less clinical activity'.
It looks like a no win situation for doctor and patient alike. After all,
the ultimate economy is to close a hospital and sack the staff.
These personal complaints seem trivial when set against the huge
and international problems of financing health care and the tensions
inherent in deciding clinical priorities. What does matter is that our
National Health Service is the biggest employer of labour in the
country and that the practice of medicine is all about people. Every
little breakdown in day-to-day hospital work means personal irri-
tation that is usually expended by everyone blaming everyone else.
The complex web of human relationships is a vital factor in the
efficiency of a hospital and it is unlikely that every patient will be
treated as a person unless every member of the staff is treated in the
same way.
The concept of health care regulated solely by market forces is
fatally flawed because it omits human values from its equations. It is
precisely that value of each individual's contribution to the care of the
sick that must be seen to be recognised by others. When that is lacking
the morale of a hospital suffers and grievances are nurtured by
sectional interests. Good work for the patient does need mutual
respect for the roles of all concerned. So management for clinicians is
more than distributing an inadequate budget; it concerns the well-
being of all colleagues and an acknowledgement of their worth.
Physicians, with the skills of personal relationships that they should
have for their patients, should be equally good in dealing with
colleagues of all ranks. Meanwhile the Government needs to remem-
ber that virtue is not its own reward and that cash builds morale.
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 73
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PMC005xxxxxx/PMC5371115.txt | (
>?
Incidence and Management of Arterial
Injuries from Left Heart Catheterisation
S. G. CHIVERTON, BM, Senior House Officer
r~
JOHN A. MURIE, MD, FRCS, Clinical Reader in Surgery t
Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headington,
Oxford
A widely varying incidence of peripheral arterial injury
following left heart catheterisation has been reported,
although many studies were performed in the 1960s, well
before the present day dramatic increase in reconstructive
coronary artery surgery[l-4]. The number of patients
being investigated by retrograde arterial techniques has
increased correspondingly and these patients are investi-
gated in an increasing number of medical centres by an
increasing number of cardiologists. The potential for
iatrogenic arterial injury is now greater than ever before.
This study describes a contemporary experience of
peripheral arterial trauma following cardiac catheterisa-
tion in a centre performing more than 500 such examina-
tions annually. The frequency of significant vessel injury
and the nature of such injury is described, along with the
outcome of corrective vascular surgical intervention.
Method
Vascular injuries requiring surgical treatment following
cardiac catheterisation over a five year period (1.1.80 to
31.12.84) were reviewed. Case records and operation
notes were scrutinised to identify possible mechanisms of
injury, operative findings and surgical techniques em-
ployed for vascular repair.
During the study period 2,760 patients underwent left
heart catheterisation in the John Radcliffe Hospital,
Oxford. Cardiac catheterisation was usually performed
percutaneously via the right common femoral artery
using a Seldinger technique. The artery was punctured
with a 16 gauge Pott's needle (Beckton-Dickinson, New
Jersey, USA) and a 0.965 mm Teflon-coated guidewire
introduced, over which cardiac and coronary catheters
were inserted. The catheter most frequently employed
was the No. 8 Fr Cordis pigtail catheter (Cordis, Ux-
bridge, UK). A Cordis catheter sheath that eliminates the
need for repeated insertion of the guidewire has recently
come into common usage. Exercise testing (straight leg
raising) with catheters in situ was used for investigation of
Correspondence to John A. Murie, Esq., MD, FRCS, Clinical Reader in
Surgery, Nuffield Department of Surgery, John Radcliffe Hospital,
Headington, Oxford OX3 9DU.
mitral stenosis. At the conclusion of the procedure hae-
mostasis was effected by firm pressure over the puncture
site for 10 minutes. The majority of patients were given
5,000 units of heparin intravenously during the pro-
cedure and this was not reversed.
In the 5.7 per cent of patients who had significant
occlusive vascular disease of the aorto-iliac segment, left
heart catheterisation was performed via the brachial
artery. The brachial artery, usually on the right side, was
exposed through a short transverse incision at the antecu-
bital fossa and a small longitudinal puncture arteriotomy
made in the vessel. After final withdrawal of the catheters
this arteriotomy was closed either with a purse-string
suture or, more usually, with a few interrupted sutures.
The hand was inspected for signs of ischaemia at the end
of the procedure.
Results
From 2,760 cardiac catheterisation studies performed
during the five year period, nine instances of arterial
trauma requiring surgical intervention were identified.
Catheterisation was followed, therefore, by significant
arterial injury in 0.33 per cent of cases.
Clinical details of the three patients with injury to the
femoral artery are shown in Table 1. In two instances a
local thrombosis with distal limb ischaemia occurred.
Although Fogarty catheter thrombectomy was possible in
one patient, in the other an axillo-femoral graft was
necessary to bypass the damaged segment of common
femoral/external iliac vessels. The third patient under-
went Fogarty catheter extraction of a small plastic intro-
ducer sheath which had become detached in the external
iliac artery. All complications were associated with the
common femoral or external iliac arteries; no significant
puncture trauma was noted in either the superficial
femoral or profunda femoris vessels. All complications
were diagnosed at the time of cardiac catheterisation or
immediately thereafter and all were successfully treated
by surgical intervention. No late complications of trans-
femoral catheterisation were identified.
Table 2 shows the clinical details of the six patients with
126 Journal of the Royal College of Physicians of London Vol. 20 No. 2 .April 1986
Table 1. Complications involving the femoral artery.
Sex
Age
Indication
Complication
Time of
diagnosis
Surgery
Outcome
M
M
73
53
50
constrictive
pericarditis
ischaemic heart
disease
ischaemic heart
disease
thrombosis
thrombosis
introducer sheath
free in arterial
circulation
immediate
immediate
immediate
thrombectomy and
simple arterial
suture
axillo-femoral graft
extraction with
Fogarty catheter:
Dacron patch
good distal
pulses
graft
thrombectomy
at 8 days:
anticoagulation:
good graft
function
good distal
pulses
Table 2. Complications involving the brachial artery.
Sex
M
M
M
F
F
F
Age
Indication
Complication
Time of
diagnosis
Surgery
Outcome
30
53
73
31
33
63
aortic valve
disease
ischaemic heart
disease
ischaemic heart
disease
coarctation of
aorta
aortic valve
disease
mitral valve
disease
thrombosis
thrombosis
thrombosis
thrombosis
thrombosis
haematoma
immediate
immediate
immediate
immediate
immediate
24h
thrombectomy and
simple arterial
suture
thrombectomy and
simple arterial
suture
vein graft
vein patch
vein patch
evacuation of
haematoma
stenosis: vein
graft: late
aneurysm
good distal
pulses
good distal
pulses
good distal
pulses
good distal
pulses
no further
complication
brachial artery trauma. In five cases local thrombosis
with distal limb ischaemia occurred. All were diagnosed
at or soon after catheterisation. Simple thrombectomy
with arterial suture was performed in two patients, one of
whom developed a local stenosis one month later which
was corrected with a saphenous vein graft. One year after
its insertion this graft had become aneurysmal and might
need later surgical correction, but no other problem had
occurred in the limb. The remaining three instances of
thrombosis were treated by Fogarty catheter thrombec-
tomy followed by either a saphenous vein graft (on one
occasion) or by a vein patch graft (on two occasions). In
four of the five patients described, the surgeon noted a
raised intimal flap on the posterior wall of the brachial
artery and it was assumed that such a lesion was involved
in the thrombotic episode. At the time of thrombus
extraction the raised intimal flap was sutured flush with
the undisturbed vessel intima. All surgical procedures
resulted in good distal limb perfusion.
The final patient in Table 2 presented 24 hours after
left heart catheterisation with an expanding haematoma.
This was evacuated and no arterial repair was considered
necessary. The integrity of the vascular supply to the limb
was not in doubt and no false aneurysm has resulted.
Discussion
The reported incidence of peripheral arterial injury fol-
lowing transfemoral left heart catheterisation varies from
almost nil to over 12 per cent[l-3]. The most recent
series, however, suggest that the current incidence is very
low. Hessel et al. in 1981 described 83,000 peripheral
angiograms performed via the femoral artery with an
incidence of arterial injury of only 0.47 per cent[4] while
Davis et al. in 1979 and McMillan and Murie in 1984
reported an incidence of approximately 0.3 per cent
following left heart catheterisation by this route[5,6]. The
incidence of femoral artery trauma requiring surgical
intervention in the present study was only 0.11 per cent.
Studies performed in the 1960s suggested that periph-
eral vascular complications, principally femoral thromb-
osis, are more likely in patients with cardiac valve
diseasefl]. Both aortic incompetence[7] and mitral steno-
sis[8] have been implicated. Perhaps the current low
incidence of femoral artery complications is due to a
relative decrease in recent years in those patients with
valve defects undergoing left heart catheterisation. Car-
diac catheterisation for the assessment of ischaemic heart
disease, on the other hand, has increased.
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 127
Despite the suggestion that anticoagulation may be
associated with a four-fold increase in peripheral arterial
complications[7], no significant bleeding, haematoma or
false aneurysm related to the femoral artery was encoun-
tered in the present study. This differs from the report of
McMillan and Murie in which false aneurysm was the
single most common lesion in the femoral vessel[6].
However, many of their patients underwent left heart
catheterisation while fully anticoagulated with warfarin
on a long-term basis. This is not comparable to tempor-
ary heparinisation of the patient as commonly employed
in the present series.
Despite an early report of only one complication from
388 transbrachial studies by Ikram and Nixon[9], con-
temporary data suggest a much greater incidence, prob-
ably nearer 5 per cent[5,10]. Certainly Brenner and
Couchfll], in a rare prospective study, demonstrated
that 28 per cent of patients developed a diminished or
absent radial pulse after cardiac catheterisation via the
brachial artery. In the present study the incidence of
brachial artery injury requiring formal surgical correction
was 3.8 per cent. Furthermore, most major brachial
artery trauma was manifested by thrombosis and distal
limb ischaemia rather than bleeding, haematoma or false
aneurysm. This agrees with data from other
centres[5,10]. Longitudinal arteriotomies were made in
the brachial artery in the present series. Such wounds
cannot be sutured directly without narrowing the vessel.
Stenosis incurred from this technique may be responsible
for some thrombotic episodes and, on theoretical grounds
at least, a transverse arteriotomy with interrupted suture
closure would be preferable.
Cannulation of the brachial artery is more hazardous
than that of the femoral. However, it should be remem-
bered that the brachial tends, sometimes, to be used when
the aorto-iliac segment is thought to be significantly
diseased, possibly increasing the risk of the transfemoral
approach. It must be appreciated, however, that the vast
majority of peripheral arteriograms are performed via the
femoral atery with retrograde introduction of a catheter
often through a highly diseased aorto-iliac segment.
Indeed, such studies are frequently performed to delin-
eate the extent of aorto-iliac disease itself. Even in these
severely atheromatous vessels the complications due to
catheter passage tend to be minimal, although obstruc-
tion may require the examination to be abandoned[4].
Most complications affect the actual site of puncture of
the femoral artery, where atheroma is rarely gross even in
the presence of serious changes in the iliac vessels.
Although no direct evidence exists that cannulation of a
diseased iliac artery is less hazardous than that of a
normal brachial artery, this may be the case and merits
future investigation.
This study has shown that left heart catheterisation by
the transfemoral approach is attended by very few serious
complications from the vascular standpoint. The trans-
brachial route appears markedly more hazardous and
should be avoided if possible. Nevertheless, vascular
surgical correction of any injury incurred at the time of
catheterisation is likely to be successful, although the
operation itself may not always be simple and should be
undertaken only by a vascular surgeon.
References
1. Lang, E. K. (1963) Radiology, 81, 257.
2. Kottke, B. A., Fairbairn, J. F. and Davis, G. D. (1964) Circulation,
30, 843.
3. Hautz, G. and Amplatz, K. (1968) Surgery, 63, 594.
4. Hessel, S. J., Adams, D. F. and Abrams, H. L. (1981) Radiology,
138, 273.
5. Davis, K., Kennedy, J. W., Kemp, H. G. et al. (1979) Circulation,
59, 1105.
6. McMillan, I. and Murie, J. A. (1984) British Journal of Surgery, 71,
832.
7. Mortensen, J. D. (1967) Circulation, 35, 1118.
8. Kloster, F. E., Bristow, J. D. and Griswold, H. E. (1970) American
Heart Journal, 79, 175.
9. Ikram, H. and Nixon, P. G. (1964) British Medical Journal, 2, 1072.
10. Kitzmiller, J. W., Hertzer, N. R. and Beven, E. G. (1982) Archives
of Surgery, 117, 1066.
11. Brenner, B. J. and Couch, N. P. (1973) American Journal of Surgery,
125,521.
|
PMC005xxxxxx/PMC5371116.txt | Book Review
Practical Geriatric Medicine
edited by A. N. Exton-Smith
and M. E. Weksler. Churchill Livingstone, Edinburgh,
1985. 475 pages. Price ?34.
Doctors in all branches of medicine (save those in paedi-
atrics and obstetrics) now have to deal with an increasing
number of elderly patients and this trend will continue for
the rest of the century. It thus behoves all practising
physicians to have some knowledge and skill in dealing
with the elderly and differentiating disease from dotage if
medical resources are to be used efficiently. This book
aims to fill the gaps in the knowledge of 'Primary care
physicians' (and hopefully surgeons) who may have had
little formal training in geriatric medicine and for whom a
major comprehensive textbook of gerontology would be
inappropriate. The book is planned to be a practical
geriatric vade mecum with a problem-orientated approach.
The multi-author text suffers from the advantages and
disadvantages of being mid-Atlantic (29 authors from the
Americas, 32 from the UK and Ireland and one from the
Antipodes). For example, American enthusiasm provided
chapters on 'Sleep disorders' and 'Gonadal function and
sexual potency in aging men'. However, 15 pages are
devoted to the former subject, compared with eight pages
on 'Transient ischaemic attacks and stroke' and only six
pages on the 'Acutely confused patient', and few British
patients would have access to 'well-trained sleep special-
ists', polysomnographs or facilities for measuring penile
blood pressure. The chapters on 'Diabetes' and 'Renal
disease' give all blood glucose and serum creatinine
values in mg/dl.
The book is divided into three parts. The first is a
general introduction to the assessment of the elderly
patient and outlines some of the functional changes that
accompany the ageing process. There is a useful chapter
on 'The evaluation of the elderly patient for surgery' and
others deal with such problems as 'Cancer' and 'Infec-
tion' in its protean manifestations.
The main part of the book deals with specific systems
such as 'Special sense organs and communication', 'Res-
piratory system' and 'Endocrine disorders'. Chapters
within each section deal with selected common problems
encountered in the elderly, for example 'Parkinsonism',
'Falls' and 'Hearing disorders'. The most useful parts of
these chapters are those describing how illness in the aged
differs from that seen in younger patients. Some infor-
mation seems superfluous; all physicians will know the
typical clinical presentation of myocardial infarction and
the accompanying cardiac enzyme changes but it is
helpful to have details of the atypical presentations of this
condition in older patients. The chapter on 'Small bowel
and pancreas' gives very practical advice as to likely
causes of malabsorption in the elderly and the most
expedient way of confirming the diagnosis. There is much
useful guidance in these chapters but some of the advice is
rather dated; few doctors would recommend subcutane-
ous insulin injection for diabetic coma.
The final part of the book deals with such topics as
rehabilitation (not mentioned in the chapter on stroke)
and public policy for the elderly. There is much of interest
here but I wonder if the general reader (non-geriatrician)
would delve deeply.
The core of this book contains much helpful guidance
for the non-geriatrician on the care of his or her elderly
patients, which would hopefully speed their return to the
community and independent living.
G. M. Wood
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
125
|
PMC005xxxxxx/PMC5371117.txt | Sharing Knowledge and Experience of
Disability
R. S. STEVENS, md, frcp
Formerly Medical Administrator, Kent Postgraduate Medical Centre at Canterbury
M. D. WARREN, md, frcp*
Formerly Professorial Fellow, School of Continuing Education, University of Kent at
Canterbury
The uneven development of rehabilitation services in the
UK is a cause of continuing concernfl]. Major difficulties
arise from the disjointed provision of services[2], the
tunnel vision of members of the professions concerned
[3], inadequate explanation and discussion with the dis-
abled person and failure to involve him or her in the
decisions taken about treatment, and the management of
disability [4,5]. The Open University's course 'The
Handicapped Person in the Community' is a major
attempt to broaden knowledge and understanding be-
tween different professional groups and disabled people
and their families, to suggest a more questioning attitude
towards the roles of 'adviser' and 'helper', and to intro-
duce alternative approaches to the solution of problems
faced by disabled people. We report a current local effort,
jointly organised by the School of Continuing Education
of the University of Kent at Canterbury and the Kent
Postgraduate Medical Centre, which was intended to
bring together doctors, remedial therapists, nurses, social
workers, managers, voluntary workers, disabled people
and their carers so that they could share both their
knowledge and experience.
Planning the Seminars
It was accepted that each group would tend to have their
own perceptions of problems and solutions, and would
have different levels of knowledge about the aetiology,
pathology, natural history and treatment of the under-
lying diseases and disorders, "and of help, aids and
services available to ameliorate some of the effects of the
disabilities. It was hoped that the proposed seminars
would focus on local needs and services against the
background of the most up-to-date knowledge and of
experience gained in other places.
These considerations set the guidelines for the planning
of each seminar and identified the intended audience.
The main doubt about the plan was the feasibility of
presenting knowledge of sufficient interest to the pro-
fessional about his or her own subject, while keeping the
Correspondence and requests for reprints to Dr M. D. Warren, 2
Bridge Down, Bridge, Canterbury CT4 5AZ.
attention and understanding of those who had little
previous knowledge of the subject. Each programme
included invited contributions from doctors, physiothera-
pists, occupational therapists, social workers, and
patients, or officers or members of organisations repre-
senting their interests. Some of the speakers on each
occasion were 'national' leaders in their subject, and
some were from the local services.
Most of the seminars have taken the form of a whole-
day meeting (10 a.m. to 4.30 p.m.) on a weekday, usually
a Friday. Three of the meetings have used one or more
evenings for sessions in addition to taking up a morning
or a whole day.
The essential component in the organisation of the
seminars is the contribution made by the planner of each
seminar. The School, on the advice of the medical
administrator and the clinical tutor (now only the clinical
tutor, since the post of medical administrator was abol-
ished as part of service economies), invited one person to
advise on the construction of the programme and to brief
the chairmen and speakers. This help has been enthusias-
tically and expertly given. Detailed organisation and the
extensive distribution of publicity (including a mention in
the local newspaper) were carried out by the organising
secretary at the School and the medical administrator at
the Centre.
Topics
The topics discussed included groups of diseases, specific
diseases, terminal care, and problems related to medical,
nursing and social work practice such as ethics, coping
with stress, and communicating bad news (Table 1). The
presentation of these last three subjects followed a some-
what different format to that of the others.
Plans are under way for seminars on cancer, AIDS,
diabetes and strokes. The applications for attendance at
the seminar on 'The confused elderly patient' so exceeded
the capacity of the lecture room that arrangements were
subsequently made to replicate the meeting with some
different speakers on each occasion at other postgraduate
medical centres in Kent.
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 133
i
Table 1. Topics discussed at seminars
Seminar j
No. Date Subject and Planner Duration
1 Mar 1982 Ethical problems in the Health Service Dr M. S. Harvey 2 evenings, 1 morning
2 Apr 1982 Parkinsonism Dr M. Hildick-Smith whole day
3 Oct 1982 Hospice care Dr S. R. Kirkham whole day
4 Feb 1983 Communicating bad news Dr C.J. Allison 1 evening, 1 whole day
5 Apr 1983 Arthritis Dr J. Sewell whole day
6 Oct 1983 Hospice?sharing the care Dr S. R. Kirkham whole day
7 Feb 1984 Coping with stress Dr M. S. Harvey 1 evening, 1 morning *
8 Apr 1984 The confused elderly patient Dr R. S Stevens whole day
9 Oct 1984 Asthma Dr A. J. Johnson whole day
10 May 1985 Multiple sclerosis Dr C. I. Roberts whole day
Attendance
The seminars were held at the Kent Postgraduate Medi-
cal Centre at Canterbury which has a lecture room
seating 100 people and is well-equipped with audiovisual
aids. Coffee, lunch and tea were provided in the Centre.
The seminars attracted audiences of 54 to 108 people
from the different interests expected (Table 2). It is
noticeable that apparently few patients attended, al-
though some patients (or disabled persons) were present
as members of the voluntary bodies. A disappointingly
small number of general practitioners attended the semi-
nars on Parkinsonism, coping with stress, the confused
Table 2. Attendance at seminars.
1
Subject Nos. (see Table 1)
4 5* 6 7
10
Doctors (GPs in brackets) 22(17) 19(6) 16(8)
Nurses 14 24 22
Therapists and aides 23 2
Matron/Staff, Nursing,
Residential and Retirement
homes 2 2
Community Care organisers,
Health Visitors and Day Centre
staff 1 6 6
Social Workers and Care
Assistants 1 11
Probation Officers
Members of voluntary bodies 2 10
DHA or CHC 4 4
Teachers and research workers 1 1
Church workers 4
Patients 2
Chiropodists and Opticians
Other, including Counsellors 5
Total 54 102
13
1
25
2
2
2
93
15(8)
12
3
21
5
6
3
3
71
15(10) 15(8)
6 22
18
13
13
17
2
1
3
6
94
19
1
5
72
15(5)
10
4
9
61
31(4) 29(14)
11 18
23
5
16
5
1
2
5
99
3
76
10(6)
10
20
? 7
29
10
108
'Coincided with Update Workshop on Joint Disease
elderly patient, and multiple sclerosis. No remedial thera-
pists attended the seminars on ethical problems, hospice
(sharing the care), or the confused elderly patient. Five of
the seminars attracted more applicants than could be
coped with (the maximum figure was set at 100). The
numbers have remained high throughout the series, and
some people have attended more than one of the semi-
nars.
Evaluation
The high attendance at the seminars is one measure of
success, and by and large the seminars have attracted the
134 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
mixture of professionals and others that was the aim. A
reasonable proportion of each audience was of doctors,
although some meetings attracted only a few GPs, despite
the avoidance of the words 'rehabilitation' or 'chronic' in
the titles of the seminarsfl]. One reason for the sparse
attendance of GPs was that each seminar occupied the
major part of a working day. This was the most con-
venient arrangement for the other intended participants,
but timing is obviously a difficulty in organising multi-
disiplinary meetings. However, it should be noted that
larger numbers of GPs attended the seminars on arthritis
? and asthma, which were arranged in the same way as
some of the seminars they had poorly supported.
Each participant was asked to complete a short ques-
tionnaire about the arrangements, structure, content and
conduct of the seminar. Only a few completed question-
naires were returned and most of these made favourable
comments such as 'all subjects valuable', 'lively useful
v - discussion', 'liked the combined professional/client ap-
proach', 'lot of new knowledge presented', 'very useful
refresher', 'well planned and well chaired', 'please repeat
for more people', 'encouraging to hear about so much
research', and perhaps the final accolade, 'two days
would have been better'
Not all the comments were favourable. One domestic
problem was the inadequacy of toilets for the ladies, who
were in the majority at each seminar. There were criti-
cisms of a few of the speakers and contributions and many
useful suggestions about topics which could have been
included. Only a very few people complained that the
content of the talks was either too technical or too
elementary although some people did find this was so on
occasions and accepted that within limits it was inevitable
at such seminars if so many experts from different
backgrounds were to be attracted. Some participants
would have preferred more small group discussion. This
was considered from time to time by the organisers, but
the construction of the groups, the identification and
> briefing of group-conveners and the time taken up in
reporting back were considered to weigh against this
suggestion. However, it is a feature at the 'follow-up'
local seminars now being carried out on the topic of the
confused elderly patient.
The main question, whether the seminars have im-
proved the care of disabled people in the health districts in
Kent and surrounding areas, cannot be answered direct-
ly. As with all educational activities, it is assumed that
increased understanding and self-confidence, awareness
of other peoples' perspectives on familiar problems,
meeting colleagues on 'neutral' ground and putting faces
to voices and signatures are all means of improving
services. The seminars have certainly been widely ap-
preciated and have introduced well-attended and lively
meetings at the Postgraduate Medical Centre.
Acknowledgements
We are grateful to the planners of the seminars listed in
Table 2, to Dr Stuart Field and Dr Ian Roberts (succes-
sive clinical tutors at the Kent Postgraduate Medical
Centre), to Mrs Joan Thomason (organising secretary,
health and social service courses, School of Continuing
Education) and Mrs Margaret Allen (administrator of the
Postgraduate Medical Centre) for their considerable help
in organising the seminars, and to Mrs Shirley Wood-
ward for typing this report.
References
1. Gloag, D. (1985) British Medical Journal, 290, 1333.
2. Blaxter, M. (1979) Report of the Royal Commission on the National
Health Service. Cmnd 7615. London: HMSO.
3. Brechin, A. and Liddiard, P. (1981) Look at it this way. New
perspectives in rehabilitation. Sevenoaks: Hodder and Stoughton in
association with the Open University Press.
4. Warren, M.D. (1985) International Journal of Rehabilitation Research,
8, 3.
5. The Prince of Wales' Advisory Group on Disability (1985) Living
options. Guidelines for those planning services for people with severe physical
disabilities. London: Prince of Wales' Advisory Group on Disability.
|
PMC005xxxxxx/PMC5371119.txt | Book Review
Searching the medical literature?a guide to printed and on-line
sources
by J. Welch and T. A. King. Chapman & Hall,
London, 1985. 154 pages. Price ?15.
There are over 10,000 medical journals now published
and the number is increasing continuously. Keeping up
to date with medical developments even in one's own
specialty is becoming extremely difficult. The ten or so
journals taken regularly pile up on the desk and it is an
effort to scan the titles, let alone read the articles.
It is against this background that the invitation comes
to give a lecture or write a review about recent develop-
ments in your chosen field. The memory, that imperfect
repository of facts, can recall vague details such as the
Lancet had a useful leader last year or the JRCP (or was it
the BMJ?) had a useful article in '82 (or was it '83?). But
there's always the nagging feeling that out there in the
mass of literature there is an article crucial to the
endeavour.
To assist the profession to search the literature system-
atically there have been for many years indexing and
abstracting services. Print sources for searching the peri-
odical literature have been available since the 1870s. In
recent years these have been supplemented by on-line
data bases which at first could only be accessed by
professional librarians but are now available to be interro-
gated by anybody with a home computer and a modem.
This book is subtitled 'a guide to printed and on-line
sources' and it is the first book written by information
scientists for the general medical reader. Although the
section on print sources is useful, there will be little in it
that is new to those who are regular users of Index Medicus
and Excerpta Medica. The chapter concerned with on-line
sources, however, will be a revelation to most readers,
who are introduced to the services provided by hosts such
as Dialog, DIMDI and Data-Star. Drug information
services are the subject of a separate chapter and there are
further sections on sources of statistical information, the
reference literature and sources of advice for medical
communicators.
The authors have used refreshingly little jargon in
discussing the technology, the data-base overviews show a
similar clarity and the search examples illustrate well the
techniques involved. The overall coverage is comprehen-
sive and the book should prove an extremely useful
reference tool. But useful to whom? Medical librarians
will certainly find it a succinct and well-organised first
point of reference, and as background reading for the
medical profession the book may well clarify some issues.
But the lack of objective evaluation of the services and of
guidance about preferred sources will limit its use for the
doctor who is only an occasional searcher of the medical
literature.
A. M. S. Mason
132 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
|
PMC005xxxxxx/PMC5371120.txt | Education in Peripheral Hospitals:
Missed Opportunities?
J. H. ROSS, MC, MD, FRCP
Retired Physician, Hereford
The hospitals considered in this review are those district
hospitals with heavy commitments in general clinical
subjects, where the senior staff can only specialise to a
lirnited degree, where the 'on-call' duties for any individ-
ual are frequent, and which are distant from the regional
centres. There are, for example, nine such districts in the
West Midlands, with 31 general physicians and 27 gen-
eral surgeons (not more than four of each in each district)
serving 32 per cent of the population of the region (about
5 million). These figures do not include those smaller
districts near teaching centres in which senior staff work
at the centre and the local district hospital, where teach-
ing of students is arranged formally and from which it is
easy to attend central teaching sessions.
It is acknowledged that the younger consultants on the
periphery are nowadays of high calibre. They have often
deliberately chosen to work away from large cities and
have not applied for appointment at teaching hospitals or
regional centres; many of them are possibly better teach-
ers than their colleagues working and specialising in the
centres. What opportunities have they, and should they
have, for continuing their own education, looking after
that of their junior staffs, and for accepting and helping
medical students?
Senior Staff
The 'Terms and Conditions of Service of Hospital Medi-
cal and Dental Staff (England and Wales)' define study
leave as 'for postgraduate purposes approved by the
employing authority, and includes study (usually but not
exclusively or necessarily on a course), research, teach-
ing, examining or taking examinations, visiting clinics
and attending professional conferences'. All these valu-
able activities are to be carried out 'with pay and
expenses, within a maximum of thirty days (including off
duty days falling within the period of leave) in any period
of three years. . .'
Employing authorities have in the past been generous
and have made it possible for consultants to study for
longer periods and in alternative ways, but I have known
study leave, requested for a week to complete the writing
of a paper, refused although this could surely have come
under the heading of 'research' and I doubt if study leave
has often been granted to allow consultants to teach junior
staff or students within their own hospitals. The present
position is not satisfactory, but unfortunately a simple
decision to increase the duration of study leave would not
help much, as the major limiting factor is the increased >
work imposed on colleagues by the absence of one
member of a department of three or four; six weeks'
annual holiday already results in three months of 'one-in- >
two' on-call for the senior staff in a department of three.
Physicians may be able to ask their geriatrician colleagues
to help in such circumstances, but surgeons, obstetricians
and gynaecologists have an inescapable extra burden now
that locum cover is less frequently provided.
However, it would seem to be widely accepted that a
day's absence at a meeting or teaching centre does not
require the granting of study leave: no application for
absence is made, and therefore statistics about consult-
ants' study habits have little meaning. Occasional days
spent informally in a specialist unit, with opportunities
for discussion and individual attention, can be much
more rewarding than attendance at formal courses, meet-
ings or conferences, as can the hours spent in a library \
stimulated by a proposed case presentation, publication
or teaching session.
Time for attendance at regional centres, perhaps a day
fortnightly, and time for teaching junior staff and stu-
dents should be allowed for in the job descriptions and
contracts of consultants in peripheral hospitals. However,
this would require extra staff and so would cost money to
provide them. :
The welcome development of postgraduate centres in
district hospitals in the last 25 years has probably ben-
efited consultants less than general practitioners and
junior medical staff. One often goes out of loyalty to hear
one's colleagues or their visitors speak on subjects of little
relevance to one's own interests. Perhaps the most ben-
eficial activities for consultants in these centres are prep-
aration for teaching sessions or lectures and increased
contact with general practitioners. Visits by specialists
and experts from regional centres are excellent, but are
most valuable without the large audiences which every-
one usually hopes will gather; the visitors should address
small, specifically interested groups with plenty of time I
for discussion and exchange of ideas. The visitors must be
warned that the small size of the audience is an indication ,
of interest rather than lack of it.
Regional associations or clubs, for example thoracic,
urological and endocrine, should have at least one of their
meetings each year at a peripheral hospital, the arrange-
ments being made by a local consultant. l
136 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
Junior Staff
Senior Registrars
There used to be no place for senior registrars in these
hospitals. This was at a time when, throughout their
appointment, they were expected to be learning tech-
niques in their chosen specialty and to be actively en-
gaged in research. Now that periods of general training
are recommended for accreditation, at least for phys-
icians, by the Joint Committee on Higher Medical Train-
ing, both the senior registrars and the local consultants
would benefit from more rotation schemes involving
peripheral hospitals. The former would really meet gen-
eral medicine and take responsibility for its practice
i . .for the population as a whole, small district general
hospitals are more important than the large teaching
hospitals')[l], and the latter would gain specialised infor-
h mation and increase their opportunities to be absent for
learning and teaching. Unfortunately, the family life of
senior registrars often limits their moving far and most
rotation schemes make use of larger district hospitals in
the cities in which the teaching hospitals are situated;
these have larger consultant staffs and the general medical
responsibilities of the senior registrars are reduced.
Registrars and Senior House Officers
This is the staff group which can benefit most from a
peripheral hospital where there is enthusiasm to teach.
There is little to be said which is not already well known.
It is important that junior staff should participate in their
v education; presentation of cases following detailed prep-
aration using a readily accessible and well stocked library
is the most useful activity. The opportunity to learn and
carry out practical procedures is often more available
peripherally but there must be consultant supervision.
Time for further education should be included in job
descriptions.
The clinical tutor should have the responsibility for
seeing that all the hospital departments are providing
adequate teaching for their juniors, outside as well as
within his postgraduate medical centre.
, Teaching for the MRCP and FRCS, given not only by
physicians and surgeons, but also by pathologists, oph-
thalmologists, radiologists and others, is of course essen-
tial but all too often the clinicians have to cancel or fail to
arrange their sessions. These should be arranged well
' \ ahead and adhered to. Bedside teaching should be in-
itiated by a junior who has seen the patient in advance
and discussion groups are also most valuable if initiated
by a juniorHwho has prepared a lecturette on the subject.
Most regions have centrally arranged day courses for
postgraduate degrees but attendance from the periphery
can be difficult, especially in the winter, and the optimum
duration for a course is probably one week.
Pre-Registration House Officers
?
Most house physicians and surgeons enjoy presenting
cases at their departmental meetings and some occasion-
ally attend MRCP or FRCS sessions, but otherwise
attendance at postgraduate centres for lectures and meet-
ings tends to be food-orientated during lunchtime. This is
not surprising after years of formal education. Pre-
registration education and experience should for the most
part take place at the bedside, in the operating theatres
and, morbid though it sounds, in the post-mortem de-
partment.
Medical Students
If, as stated above, there are many good consultant
teachers in the periphery and if clinical practice there is
nearly related to what most students aspire to, then many
opportunities for good undergraduate education are now
being missed.
Present arrangements are very variable. The postgrad-
uate tutor at some teaching hospitals vets a selection of
peripheral hospitals and then makes formal arrangements
for final year student attendance for about four weeks.
The students are attached to medical or surgical firms and
spend most of their time in the wards helping to admit
patients and following their progress. Attendance at
clinics, where pressure of work on the staff makes short-
cuts inevitable, is carefully arranged so that the students
can see an experienced doctor dealing with awkward
problems. These are the ideal arrangements except that
contact with consultants is often confined to 'business'
rounds when much time is spent in discussing adminis-
trative arrangements for the patients. Some of this is no
doubt good for the students but the consultant should
have time to meet the students at regular intervals
entirely for educational purposes and outside the consult-
ant's routine clinical work.
Most student arrangements are in fact more haphazard
than this. Intermittent attachments are arranged by the
regional teaching centre. These may only be for 'lame
ducks' who can be rewarding to help. First year students
may be sent; they get far less benefit from the volume of
patients displayed to them and the informal teaching than
do final year students. The period of attachment may be
only for two weeks or less, which is inadequate and often
treated as a holiday. Arrangements made by the students
themselves during their elective periods may be successful
and more may be learned than during trips to exotic
foreign countries.
One teaching centre surprisingly used to encourage its
students to find their own attachments during their first
year, having only completed an introductory course;
possibly the students did learn as much as they would
have done in their first firms at their teaching hospital but
the peripheral teachers could not spare the time for the
detailed supervision needed at that stage of medical
education.
Medical students should play a part when the firm to
which they are attached is dealing with emergencies. The
drama of emergency admissions and procedures can be a
more potent form of education than any number of
lectures and demonstrations; few of us forget the details of
patients whom we first clerked or had to help in some way
at unsociable hours.
Journal of the Royal College of Physicians of London Vol. 20 No.' 2 April 1986 137
Nurses
The teaching of nurses by consultant staff, especially at
the bedside, has diminished in recent years. Possibly this
is related to limited funds in nursing schools; consultants
are expensive. In addition nursing tutors may believe that
nurses should be taught by nurses and not doctors. It is
sad, however, when carrying out a procedure which one
has done in an orthodox way for many years, to be told by
an assisting student nurse that one's method is not that
taught in the nursing school which was probably demon-
strated there on a video display provided by a drug firm.
The teaching and demonstration of clinical activities
should be done by clinicians, and most consultants would
be happy to help, given time. Their salaries should
include an allowance for this without individual lecture
fees being necessary, and there should be a contractual
obligation to do this work, which would certainly be
appreciated by the students. Postgraduate training for
??<
I
trained nurses has been neglected in most hospitals, and
could also be improved by consultant participation.
Conclusion
Educational opportunities for all staff are being neglected
in peripheral district hospitals. There should be improve- [
ment if all consultant appointments allowed time for j
teaching and learning sessions. The district clinical tutor
should supervise postgraduate education in all depart-
ments.
Acknowledgements
I am grateful to Dr Henry Connor for comments, and to ,
Mrs Belle Rhodes for secretarial work.
I
Reference
1. Hampton, J.R. (1985) Hospital Update, 2, 161.
J
Bold Words
'I would beg any educated person to consider what are
the conditions in which alone animal life can thrive; to
learn, by personal inspection, how far these conditions
are realized for the masses of our population; and to form
for himself a conscientious judgement as to the need for
great, if even almost, revolutionary reforms'. This pas-
sion is unexpected in the annual statistical report of a
Medical Officer of Health. The writer, John Simon, was
an unusual medical officer and the first to be appointed
by the City of London in 1843.
Simon, bred and educated in England, was more
French than English; both his grandfathers and his
mother were French. He started his medical career as a
surgeon, being distinguished in comparative anatomy.
There was no formal training in public health in those
days. Apart from collecting statistics he was all for seeing
for himself and then using figures to buttress the argu-
ments derived from personal observation. He never
ceased to try to impress the administrative bodies to
whom he was responsible and they must have been
influenced by the power of his words.
In his report of 1850 he called the City of London 'this
pestilential heaping of human beings' and 'this uncon-
trolled evil'. The filth and squalor that he had seen but his
masters kept away from created 'mortality enough to
mask the results of all your sanitary progress'. He went
on to say that it was his duty 'to tell you where disease
ravages the people under your charge' and of the injury
that these conditions inflicted on the community.
Simon knew at first hand what environmental disaster
could do to people, apart from specific disease risks. He
wrote: 'Side by side with pestilence there stalks a deadlier
presence; blighting the moral existence of a rising popu-
lation; rendering their hearts hopeless, their acts ruffianly
and incestuous; and scattering, while society averts her
eyes, the retributive seeds of increase for crime, turbu-
lence and pauperism'.
Simon was well aware that the interpretation of epide-
miological statistics is not easy and that apparently
beneficial alterations in environment can have unexpect-
ed results. He and others were concerned by the finding
that death rates in the higher areas around the source of
the river Thames were around 17 per 1,000 per year
whereas in the low marshy areas, both on the north and
south banks of the Thames east of London the death rates
were about 24 per 1,000. It seemed obvious that drainage
of the marshes would eliminate many diseases, particu-
larly malaria, that had been a scourge of the marsh people
for centuries. So the marshes were drained and turned
into fertile land which became the vegetable garden for
London. The Londoners got better food, the farmers got
richer and all things should have been bright and healthy.
But the infant mortality rate did not drop as firmly
anticipated; it rose. Simon went back to see what had
happened. 'It was generally thought' he wrote later, 'that
the infants no longer received any injury from the soil,
climate or malarious influences but that a more fatal
enemy had been introduced by the employment of the
mothers in the fields. On this agricultural employment of
women there follows identically the same results as have
already been traced to result from the employment of
women in manufacture'. The women, working for very
low wages on the newly fertile ground, had to leave their
children with whoever would take them. These minders
fed the children on a mush of sugar, bread and water. To
keep the children quiet opium was frequently used. A new
social evil had come from an apparent improvement of
environment.
138 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
|
PMC005xxxxxx/PMC5371121.txt | Training to be a Physician
COMPILED BY THE STANDING COMMITTEE OF MEMBERS OF
THE ROYAL COLLEGE OF PHYSICIANS j
CONTENTS
Foreword
Page
75
Introduction 76
The Standing Committee of Members 76
Acknowledgements 76
1. Preparing for Consultancy
The College's Role in Postgraduate Education 77
The Role of the Regional Adviser 78
Consultant Appointments Committees 79
Applying for Consultant Appointments 79
General Professional Training 80
Higher Professional Training 82
Part-time Training 84
Should a Doctor learn to Manage? 85
2. Difficult Choices: Inferences from Original Surveys
Survey Method 86
Keeping up to date in (General Internal)
Medicine 87
Research post-MRCP 89
Career Planning with the MRCP(UK) 95
Benefits and Problems of Training Abroad 98
Page
3. Individual Specialties
Accident and Emergency Medicine 100
Cardiology 101
Clinical Genetics 102
Clinical Immunology/Allergy 102
Clinical Pharmacology 103
Communicable and Tropical Diseases 104
Community Medicine 104
Dermatology 105
Endocrinology and Diabetes 106
Gastroenterology 106
General (Internal) Medicine 107
Genito-urinary Medicine 107
Geriatrics 108
Haematology 108
Intensive Care 109
Medical Oncology 109
Neurology and Clinical Neurophysiology 110
Nuclear Medicine 111
Occupational Medicine 111
Paediatrics 112
Rehabilitation Medicine 113
Renal Medicine 113
Respiratory Medicine 113
Rheumatology 114
FOREWORD
The Royal College of Physicians of London was founded
in 1518 through a charter given to Thomas Linacre by
Henry VIII. The King, and the six physicians who
petitioned him to establish the College, were motivated
by the need to regulate the standard of medicine as
practised in London. The maintenance of high standards
of medical practice ? no longer confined to London ?
remains the College's main concern. In part, this booklet
explains how the College achieves this objective. Through
the examination for Membership, which it now shares
with the two Scottish Colleges, selection is made of those
thought worthy to proceed to 'Higher Medical Training',
to become specialists trained in general (internal) medi-
cine or one of its branches. This booklet was designed by
the College's Standing Committee of Members to offer
guidance to those wishing to embark on such training. In
a characteristically thoughtful way, the Committee has
gone well beyond this narrow brief and has included
sections, for instance, that deal with research and the all-
important need to keep up to date in general medicine.
The extraordinary advance of medical science has
introduced complexities into clinical practice that lead
inevitably to specialisation. Necessary as this might be in
some circumstances, many of us share the concern ex-
pressed by Sir William Osier in 1919 about 'the inevitable
tendency to a narrow and perverted vision, in which the
life of the ant-hill is mistaken for the world at large'.
Balance must be sought between the acquisition of broad-
based general medical knowlege and experience and the
high degree of expertise and sophistication derived from
specialisation. At the same time, the pace of scientific
advance is such that physicians find it increasingly diffi-
cult to keep up with new developments. The use of
recombinant DNA technology or nuclear magnetic reso-
nance, for instance, will soon transform clinical practice
and demand increasing effort and application. What this
booklet does not say is that to be a successful physician
you will have to work very hard throughout your pro-
fessional life. To those of you who accept this challenge I
offer the assurance that you will find it overwhelmingly
satisfying.
Raymond Hoffenberg
President, Royal College of Physicians
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
75
INTRODUCTION
At the beginning of his term as Chairman of the Standing
Committee of Members, my predecessor, Dr Martin
Muers, proposed that, each year, the Committee should
take a major interest in a specific topic as well as dealing
with its usual business relating to College affairs. It was
decided to survey the Membership in an attempt to
quantify some of the folklore relating to training for
physicians after the Membership examination. The mid-
dle section of this booklet is an attempt to describe these
results and quantify some of the benefits and problems
associated with postgraduate education, spending time
abroad, and a period of full-time research. The final
survey in this section attempts to describe some character-
istics of 'high-flyers', identify those who are likely to get
into difficulty in their careers and suggest some options
that might be considered in career planning.
The first section complements this by some clear
definitions of the process and requirements for training
and has been written mainly by College Officers. In the
final section we have asked individuals in the sub-
specialties of medicine to provide pen pictures of each
sub-specialty with an emphasis on training requirements
and long-term job prospects.
The booklet contains many personal views and opin-
ions and was designed and edited by members of the
Standing Committee of Members to whom I am person-
ally indebted and grateful for their hard work. It should
not be interpreted as being in any sense an official College
document. It is aimed at physicians who have attained the
Membership, and we hope that it will prove useful to
them in planning a career in medicine. Formal require-
ments in medicine and its sub-specialties are clearly laid
out in the handbook of the Joint Committee on High
Medical Training and the latest edition should be con-
sulted, bearing in mind that the JCHMT encourages
considerable flexibility in training programmes.
John H. Tripp
Chairman (1984-85), Standing
Committee of Members
THE STANDING COMMITTEE OF MEMBERS
The Standing Committee of Members (SCM) is the
forum within the College for representation of the views
of younger physicians. Its 20 members are elected by
postal ballot of the Collegiate Membership. Usually, the
committee has approximately equal numbers of regis-
trars, senior registrars and consultants. The five longest-
serving members retire each year and of the new
members two must be less than 33 years of age and two
must work outside London.
The committee meets every three months to discuss all
matters which affect the interests of Members. Recently
we have considered the problems of part-time training,
and proposals for changing general professional and
higher specialist training. We have commented on many
of the guidelines on consultant appointments which are
sent to Regional Advisers. It has also been possible to
suggest amendments to College publications at draft
stage. Often the SCM has expressed concern over aspects
of medical training and career structure to the College
Council and action has been taken as a result.
The President, Registrar, Treasurer, Assistant Regis-
trar, Linacre Fellow, Hans Sloane Fellow and College
Secretary sit on the SCM and four members of the SCM
sit on the College Council. The views of the committee
are therefore very readily passed on to the decision-
making bodies. Members are informed of our activities
by an article written by an SCM member in the quarterly
College Commentary.
Two Members, one from the general Membership and
usually one from the SCM, are elected to each of the
College specialty committees, where they sit as full
committee members. This provides an important method
of communicating developments in the specialties.
Each year the SCM arranges an open General Meeting
of Members to present reports of its activities and to give
Members an opportunity to raise issues for discussion.
Thereby a chain of representation exists for anyone who
has attained the MRCP diploma.
Clive Roberts
Chairman (1985-1986)
Standing Committee of Members
Acknowledgements
We thank the College Officers and staff for their individ-
ual contributions and the underwriting of this publi-
cation. We are especially grateful to Miss Susan Ryland
for the unerring efficiency and unending patience with
which she has effectively co-ordinated this report. We
gratefully acknowledge the help of many others who have
advised on the contents of scripts.
Our thanks to Dr David Smith, and his student, Hugh
Andrew, for the statistical analysis of the data in the
middle section of the book. We thank also Mr Chris
Ryman and his staff at the College for achieving a very
good response rate for the surveys, while preserving
confidentiality, and the computer data clerks at the
University of Exeter computer unit for successfully de-
coding the questionnaires.
Tawfique Daneshmend, David Honeybourne,
Martin Muers, Andrew Peacock, Clive Roberts
and John Tripp
76 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
I
1. PREPARING FOR CONSULTANCY
The College's Role in Postgraduate
Education
In its approach to education the College aims to provide
up-to-date information and views; it does not arrange
courses designed for the examinations for postgraduate
.^ diplomas. The bulk of the educational programme is
naturally clinical, with an emphasis on the basic scientific
and clinical aspects, but ethical and administrative topics
are not neglected.
The College's educational activities may be described
. . as follows.
'Teach-ins'
Selected topics, e.g. the treatment of heart failure, infec-
tions in immunocompromised hosts, are dealt with in
detail. Each Teach-in is arranged by an expert in the field
, who assembles a panel of expert speakers who not only
deliver their views but form a brains trust for the
audience's questions. The Teach-ins are perhaps the
most didactic of the College's teaching activities, and
although not overtly planned as such, the closest it comes
to teaching specifically for the Membership examination.
An obvious disadvantage of the Teach-ins was that they
were held only in London. Conscious of this, the College
has started to hold Teach-ins outside London.
Conferences
The purpose of conferences is to present advances in
medicine with an emphasis on clinical and basic sciences.
J There are three main types of conference.
Free Ranging. Two conferences are held each year, one in
London, known as the Advanced Medicine Conference,
and another in the provinces. Both cover many unrelated
topics.
Conferences addressing Specific Subjects. Over a period of
anything from one to three days a topic is explored and
discussed in detail. The subjects of these conferences
range from those with wide general appeal, e.g. infec-
tions, hypertension, diabetes mellitus, to those of interest
to a smaller number of doctors, e.g. sports medicine. One
, of these, held every autumn, is a two-day paediatric
conference on either a single or multiple child health
topics. As well as conventional medical subjects, the
College also tries to examine clinical matters in other
dimensions, e.g. diseases in ethnic minorities.
Within this group of conferences one should be singled
out for special mention. This is the biennial conference
\ entitled 'Science and Medicine,' at which basic scientists
eminent in their field present the most recent advances in
their disciplines to an audience of clinicians. The purpose
of this meeting is to inform clinicians of the new thoughts
and findings in the basic sciences which are or will be
influencing their clinical practice.
\ One-Day Meetings. More recently, the College has begun
to hold one-day meetings, under the general heading of
'Issues in Medicine', that are designed to explore subjects
which are controversial or about which there is indecision
in the profession. These meetings are not to forge a
consensus, but are quite simply to stimulate debate. Both
clinical and ethical subjects have been explored, e.g. 'Salt
and Hypertension' and 'Priorities in Medical Care'.
Lectures
Each year the College presents 16 to 18 formal lectures,
most of which are endowed. Until recently all but one
were held in London but now three or four are held in the
regions. The broad subject matter is stipulated in the
endowment of some of these lectures, and their actual
content usually reflects the special interest and experience
of the invited lecturer. The College therefore has only
partial control over the subject matter of these lectures,
and although they usually accompany the conferences
held throughout the year, they are an adjunct to, rather
than an integral part of, the College's educational pro-
gramme. Nonetheless, they present a rich and varied pool
of information and reviews.
The Journal of the Royal College of Physicians
This quarterly Journal presents a wide-ranging review of
medicine for all types of physician. It publishes much
material derived from College conferences and lectures.
Miscellaneous Educational Activities
Some educational activities are not included above. The
College holds courses in French with a medical bent ? a
one-week residential course in France and a series of
weekly lessons held at the College. The possibility of
teaching outside London and of including other lan-
guages is being examined.
The College administers a number of scholarships for
travelling and for undertaking research work for a period
of two to three years.
Although there are no formal curricula for the exami-
nations of the College, there are occasional meetings at
which those interested ? either teachers or candidates ?
are informed of the style of the examinations and the
criteria by which candidates are judged.
Lastly, mindful of the problems posed to certain doc-
tors by the examination for Membership, there is a
counselling service for those who are considered on the
basis of their performance to need advice, and this, of
course, is also available to those who seek help.
In all, the College makes available a continual and
varied diet of educational material which it attempts to
keep topical and comprehensive and which in fact a
physician of any age should Find helpful and stimulating.
D. Gwyn Williams
Assistant Registrar, Royal College of Physicians
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
77
The Role of the Regional Adviser
Regional Adviser posts were made in response to the
effective organisation of the National Health Service on a
regional basis in 1969. As the work gradually increased,
deputies were appointed so that now almost all the
regions have an Adviser and a deputy. These Advisers are
appointed to the regions in England, Wales and Northern
Ireland and there are also Advisers overseas. There are
no such posts in Scotland, which has Royal Colleges in
Edinburgh and Glasgow.
The usual method of appointment is for the Fellows in
each region to elect the deputy Adviser, who succeeds the
Adviser after 2-3 years.
Meetings of Regional Advisers
The Advisers and the deputies meet quarterly at the
College on the morning of Comitia. The meeting is
chaired by the President; the Registrar and the Treasurer
attend. The Censors and Council of the College are
represented. Any Regional Adviser can add to the agenda
any subject that he feels should be discussed. The func-
tion of the meeting is advisory only, though its influence
is considerable.
Liaison with Fellows and Members in the Region
In order to represent the views of the local physicians,
Advisers must keep in close contact with them. In a large
region this can be difficult, so the responsibilities within
the region are often geographically divided between the
two Advisers, one of whom will often come from a non-
teaching district. The Regional Adviser can be consulted
by any Member or Fellow in the region.
Membership of Regional Specialist Sub-committees
The Advisers are ex officio members of the Regional
Specialist Sub-committees, which usually meet twice a
year. The place of the meeting often changes, giving
opportunities for visiting each hospital and district. Al-
though the Advisers are full members of each of the
committees, their main responsibilities are to listen to
problems which concern the College and to try and
interpret College regulations and views. The Advisers
have direct access to the Regional Medical Officers and
officers of the Regional Authority. With the recent reor-
ganisation, Advisers' opinions on regional problems are
sought increasingly often.
Consultant Appointments
The College is concerned with the appointment of con-
sultants in medical specialties and names one of the
members of the appointments committee, who is known
as the College Representative. Before advertisement, the
job description must be approved by the Regional Ad-
viser. It is his responsibility to assess all aspects of the
proposed job, particularly the facilities available and
junior staff support.
Senior Registrar Appointments
In recent years the Advisers have also become involved in
the appointment of senior registrars in medical special-
ties. There is no formal representation of the College on
these statutory committees but most regions ask the
Regional Advisers to nominate a representative. The
Regional Adviser may himself be the representative, but,
more frequently, particularly if the subject is outside his
own sub-specialty, he will nominate another Fellow with-
in the region to represent the College.
Nominations for Fellowships and Distinction Awards
New Fellows are nominated annually, the closing date
being December 1st. Soon afterwards the Advisers re-
ceive the list of nominations for their region. They make
enquiries among the Fellows to determine the support for
these nominations and then transmit their findings to the
College. The Advisers are not involved in the final
decisions.
The College has the role of proposing its Fellows and
Members for Distinction Awards and one of the Advisers
attends the College 'C' Awards Committee. They take
soundings in the region before the meeting of the commit-
tee. They do not attend the higher Awards Committee
but may suggest names.
Professional Training
The Advisers are involved in the assessment of posts for
recognition for general professional training. They are
thus concerned in the approval of senior house officer
posts and of most registrar posts, which must be so
approved before advertisement.
The Advisers maintain a list of recognised posts and
have to make sure that reassessment by a visit takes place
when recognition is about to lapse, usually after approxi-
mately five years. In liaison with the Postgraduate Dean
the Advisers monitor the recommendations of the visiting
team, the visit being organised by the relevant clinical
tutor and local clinicians.
The Advisers are not responsible for approval of posts
for higher medical training, which is organised directly by
the College, though they may be members of a visiting
team.
Other Activities
The Advisers are ex officio members of the Regional
Postgraduate Committee and as such may serve on its
sub-committees. They are frequently concerned with
training facilities for junior staff. They may be asked by
the College to counsel candidates who have difficulty in
obtaining the MRCP and give advice on career pros-
pects.
The Regional Advisers are at times also involved in the
collection 6f information. This has included the on-take
commitment of general physicians, the organisation of
ethical committees and the establishment of registrar
posts.
78 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
Conclusion
The creation of the post of Regional Adviser was intended
to establish a College presence outside London. The fact
that the work and responsibilities have gradually in-
creased shows that the move has been successful. Fellows
and Members of the College, other members of the
medical profession and Health Service administrators
have become increasingly aware of the function and
responsibility of the Royal College of Physicians.
F. D. Rosenthal
Regional Adviser
Consultant Appointments Committees
Appointment of a consultant in the National Health
Service has to follow a set procedure; the appointment
must be advertised, an advisory appointments committee
must be convened, an interview held and a person
selected to be recommended to the Regional Health
Authority.
Before a post can be advertised, several steps have to be
taken. The District Health Authority decides the nature
of the appointment it would like to see made. Whether it
is a new post or a replacement, there may be conflicting
views on its character and on details of the job descrip-
tion. Local medical opinion is likely to be predominant in
making the decisions, but the administration will also
have its say.
When the Authority has decided what it wants, the job
description is submitted to the Regional Adviser of the
College. By an agreement between the Department of
Health and the Colleges, consultant appointments are not
advertised before his approval is given. The Regional
Adviser may take what advice he likes concerning a
proposed appointment. If it is not in his own field of
interest he will probably consult officers of the regional
specialty committee and/or the chairman or secretary of
the College committee. He may ask that certain aspects of
the job description be changed or even disallow the
appointment altogether, although this is fortunately rare.
College committees in the various specialties have
drawn up guidelines to help Regional Advisers assess the
suitability of an appointment, giving general guidance as
to the facilities and resources required for a consultant
appointment in that specialty. These guidelines have
been scrutinised by the Council of the College to make
sure that they are in general harmony with each other and
that, while insisting on essential requirements, they do
not demand so much that the post becomes impossibly
expensive.
When its description has been approved, the job is
advertised in the medical press. A Consultant Advisory
Appointment Committee (AAC) for that job is set up. Its
composition is determined by statute and includes two
representatives from the District Authority, usually doc-
tors from the hospital where the appointment is to be
made, and at least one colleague from the same specialty,
a teaching hospital representative and a College represen-
tative. The College representative, who must come from
outside the NHS region concerned, is almost invariably a
Fellow of the College, usually fairly senior. He or she is
selected from a file held in the College of all Fellows who
have been graded on election to the Fellowship and at
intervals thereafter by the appropriate Regional Adviser
and his deputy and by the chairman and secretary of the
relevant College committee. Most Fellows are regarded
as suitable to represent the College at consultant AACs
but some may be less so, perhaps because, of the limited
nature of their interests. The College tries to ensure that a
wide variety of Fellows represent it at these important
committees.
Methods of short-listing vary; the College representa-
tives should be fully involved in this process. The com-
monest method is for each member of the committee to
mark the candidates and then four or five are invited for
interview.
The College representative is a full member of the
AAC, with neither more nor less power than the others.
He is charged by the College with seeing that the selected
candidate is adequately trained for the appointment but
this does not mean that the candidate must be accredited;
indeed, we specifically ask our representatives to be
flexible on this point. If a candidate is appropriate for the
appointment but lacks some limited aspect of training, for
example proficiency in a technique, the AAC may rec-
ommend that he undertakes further training for a period
of a few weeks or months before taking up his appoint-
ment. The recommendation of the committee is usually
announced to the candidates at the end of the meeting.
The College representative is free to question appli-
cants on all aspects of their application, not merely the
adequacy or otherwise of their specialist experience. He is
asked by the College to emphasise its interest in encour-
aging research and to bring out the candidates' research
contributions.
He has a vote in the committee's decision, but he does
not have a veto. If he is disturbed about a selection he
may report to the College and even, exceptionally, ask the
College to take up his objections with the Regional Health
Authority.
The number and quality of applicants for consultant
appointments varies greatly. Some specialties are less
attractive than others and may attract few and poor
applications and occasionally for this reason no appoint-
ment is made. In other specialties the pressure is intense
and 10-20 high-class applications may be received.
David Pyke
Registrar, Royal College of Physicians
Applying for Consultant Appointments
Members often raise questions about the 'fairness' of
Advisory Appointments Committees for NHS consultant
posts and it was felt appropriate to include a personal
view on a sensible approach to the ordeal of applying for a
permanent job.
The job description for a consultant post will usually
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
79
have been carefully drawn up to suit the present needs of
the department concerned and is strongly influenced by
the other members of that department and other senior
hospital staff. It is likely that others outside the district
consultant body will also have influenced the fine print so
that statements such as 'a special interest would be an
advantage' require further informal investigation. The
department might have very clear ideas as to what that
special interest should be but have been prevented from
making the job description too specific. Similarly, the job
description may have been designed so that it suited a
candidate known to other members of the department,
though again this may have been modified or not be
immediately obvious. Careful, even probing enquiries
may be needed to establish how your prospective col-
leagues envisage your pattern of work and interests, both
so that this discovery is not made at a wasted interview
and to guard against being appointed to a job that is not
as you had expected it to be. A visit to the district will
enable these enquiries to be tactfully made and is an
important initial mutual assessment between applicant
and potential colleagues.
An application, even if on the printed form, should
always be accompanied by a clear statement of why you
want the job, what you hope to contribute to the hospital,
and to stress the appropriateness of your qualifications
and experience. Weighting of your curriculum vitae is
entirely appropriate ? all of your training will not be
equally applicable to the rest of your professional life; for
example, research experience would be given a quite
different emphasis in applications for a teaching hospital
and a DGH post. Word processors are invaluable!
During the period after applying, probably most ap-
propriately after being short-listed, it is important to
allow your future colleagues the opportunity of getting to
know you, at least superficially, and vice versa. The
appointment of a close colleague is one of the most
important professional decisions of a lifetime and has
been likened to marriage without the possibility of div-
orce. It is not in the interests of either party to appoint an
incompatible colleague and while no member of the
committee has a veto (see p.79), a statement by the
department representative that he (or his colleagues)
would find it difficult to work with a particular candidate
would be a high hurdle to jump at the interview. In this
context the question of favouring a local or known
candidate can be put in perspective. 'The devil you know'
is a powerful and applicable argument, having an influ-
ence on the outcome which is often appropriate. In spite
of this it is rare for an advisory appointments committee's
decision to be a foregone conclusion, particularly if the
job has attracted a good field. It is unwise to withdraw
because you know there is a strong local candidate; in the
first place, all is not always as it appears from outside the
district; secondly, strong support in favour of a candidate
from an individual member of the committee who knows
him or her (and will have declared this) is unlikely to have
a dramatic effect on the outcome.
If after your enquiries you decide that you really want
the post and appear to be appropriately qualified, it is
clearly necessary to examine your own strengths and
weaknesses (particularly those which you have inappro-
priately included or omitted from your application). You
will need to be prepared to defend (or alternatively
acknowledge and explain) the latter, hopefully with
suggestions as to how they might be remedied before
taking up the appointment.
At the interview it is rarely the curriculum vitae which
decides the recommendation of the committee. Honesty
and openness are important ? probing questions are
usually probing for a good reason, and it is unusual for
the committee to be deceived. Personality is, as already
mentioned, an important consideration, but you will not
be marked down for an expected degree of nervousness.
Clear statements as to your aims and ambitions in the
new post are valuable ? most committees will wish to feel
that you know where you are going, hopefully with due
attention to the needs and aspirations of your future
colleagues.
Given that more than one candidate with appropriate
qualifications and experience appears at the interview,
factors other than those on the application form will
probably decide the outcome. To complain 'I was much
better qualified for the job' (than the person appointed) is
to a great extent irrelevant; if the appointed candidate
was less well qualified on his curriculum vitae it is
necessary to examine what other qualities he had that you
perhaps lacked at that interview.
It is rare for the recommendation of an AAC to be
unfair and more usual for apparent unfairness to be due
to the committee having given weight to less obvious
attributes of the candidates. The role of the College's
representatives on the Advisory Appointments Commit-
tees is outlined in page 79.
John H. Tripp
General Professional Training
In order to understand the concept of general professional
training it is necessary to consider how the present
pattern of postgraduate medical education has evolved.
Until 1953 there was no obligation for recently quali-
fied doctors to undertake any further training before
being admitted to the Medical Register maintained by the
General Medical Council. It was on the recommendation
of the Goodenough Committee on Medical Schools,
which reported in 1944[1], that the pre-registration year
of internship was introduced. Under the Medical Act of
1950 it was made compulsory for every doctor after
passing his qualifying examination to spend a period as a
resident in an approved hospital before becoming eligible
to proceed to full registration. This provision came into
force on 1st January 1953. In 1964 the Royal College of
Physicians published a Report on Training for Consult-
ants^] which suggested that after becoming fully regis-
tered, those aspiring to a consultant career in a medical
specialty shpuld spend a further three years in general
professional training and four years in the specialty to be
followed.
The report of the Royal Commission on Medical
80
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
Education (the Todd Report, 1968)[3] recommended that
the pre-registration year should be followed by a struc-
tured programme of postgraduate training. The following
pattern was proposed:
1. An intern year, corresponding broadly to the present
pre-registration year, during which the medical graduate
would begin to take responsibility for the management of
patients, would acquire a sound grasp of general clinical
method and would gain confidence, judgement and
understanding under proper guidance in conditions ap-
proved by a university.
, 2. General professional training, lasting about three years
and embracing the present senior house officer and
registrar grades in the hospital service, in which the
young doctor would be given systematic and varied
experience in the general field wherein he hoped to make
his career.
3. After successful completion of general professional
training, further professional training would continue
either on a less intensive basis, merging into the normal
responsibilities of a professional career, or as a period of a
few years' intensive advanced training ? varying in
length in different specialties or branches of medicine ?
which would be designed to bring the most able hospital
doctors more quickly than others to the point where they
might reasonably expect to be considered for consultant
appointments.
4. Continuing education and training for all doctors in
career posts, varying in time, method and intensity, with
the object of keeping them abreast of developments in
their own branch of medicine and in medicine generally.
> - In general these proposals have been adopted and those
applying for enrolment for specialist training are required
to show that they have spent three years in posts con-
sidered suitable for general professional training, during
which time they will have passed the MRCP examin-
ation. However, there have been many problems con-
cerned with this period of general professional training,
particularly with regard to its content and quality, the
educational facilities in different hospitals and increasing
difficulty experienced by trainees in obtaining a suitable
series of posts.
Content of the General Professional Training Period
> The requirements considered to be desirable for general
professional training were defined in the First Report of
the Joint Committee on Higher Medical Training[4]:
General professional training will ordinarily occupy a
? > period of three years after registration. Such training
will be obtained in posts approved for this purpose
providing general medical care, with or without
'special experience and training' in certain specialties.
A proportion of this time may be spent in general
practice under conditions approved for training pur-
poses. Rigidity in training programmes will be avoid-
ed, subject to the suggested restrictions on time to be
spent in certain types of posts. Trainees may rotate,
possibly part time, through other specialties related to
medicine such as clinical pathology, psychiatry and
paediatrics, during general professional training. The
candidate who has completed general professional
training should be 'pluripotential' in the sense that his
training by its nature has not committed him to
continuing in a special branch of medicine.
This definition offers scope for a broad choice of
educational opportunity but difficulties have arisen be-
cause of the limited availability of SHO posts in the more
popular subjects and the tendency of some specialties to
encourage too early an entry to the specialty by their
recruits. An additional factor has been the advent of
vocational training schemes for general practice which
incorporate many posts in the popular specialties and so
limit the availablitity of these posts for others.
Approval of Posts
All junior hospital posts require educational approval if
they are to be filled by doctors in training. Since the
standards required for general professional training by
the Royal College of Physicians and for vocational train-
ing for general practice by the Royal College of General
Practitioners are so similar, a system of joint approval by
both Colleges has been established, hospital visits being
carried out by teams with representatives from each
College.
The Linacre Fellow has a special responsibility for the
approval of posts for general professional training and
through the Training Office of the College, he works
closely with Regional Advisers to ensure that posts are
inspected or reviewed at the appropriate time. Hospitals
are required to submit individual specialty forms in
respect of newly established posts and in respect of any
established posts being re-structured or due for review.
The visiting team normally consists of two physicians
nominated by the Royal College of Physicians, one of
whom is chairman, and a representative of the Royal
College of General Practitioners. The Regional Adviser
of the Royal College of Physicians makes the detailed
arrangements for the visits and is able to provide valuable
information about local conditions.
During visits the team will meet the consultants for a
general discussion about the work of the hospital and will
enquire about the educational facilities and training
programmes. Specific questions will be asked about the
laboratory and radiology services available, and the
Postgraduate Centre and medical library will be visited.
The SHOs and registrars will then be interviewed indi-
vidually and confidentially, when their clinical duties and
weekly teaching activities will be discussed. It is import-
ant for them to understand that it is the posts that are
being assessed and not themselves. The visiting team will
wish to be assured that trainees are only asked to accept
responsibility appropriate for their experience, that their
work is adequately supervised and that they have access
to advice from senior staff whenever necessary. Enquiries
may also be made about the ways in which the work of the
unit concerned is reviewed and assessed and whether any
form of regular audit is undertaken.
The reports of visiting teams are submitted by the
Linacre Fellow to a sub-committee of the College Com-
mittee on General (Internal) Medicine which confirms
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
81
the recommendations. Final approval of posts for general
professional training is granted by Comitia.
Specialist Posts
Difficulties have arisen in the past over the approval for
general professional training of SHO or registrar posts in
specialist departments. This has applied to posts in
departments of cardiology, dermatology and genito-uri-
nary medicine and also to certain paediatric posts. How-
ever, it is recognised that experience in specialist
departments may be beneficial and it is now agreed that it
is on the educational value of the post that its suitability
for approval for general professional training should be
judged. It is recognised that although approval is jointly
granted by the RCP and the RCGP, some specialist posts
may not be suitable for vocational training for general
practice but entirely suitable for those aspiring to a
hospital career.
MRCP(UK) Examination
All those wishing for a career in hospital medicine require
the MRCP which must be obtained before entering
higher professional training as a senior registrar or honor-
ary senior registrar.
Candidates for Part 1 of the examination must have
completed 18 months' training since qualification. No
posts are specifically approved for the MRCP but candi-
dates must have spent 12 months in posts involving the
care of acutely ill medical patients, either adults or
children, and are required to submit evidence that they
have done so.
The immediate objective for individuals completing the
pre-registration year and contemplating a career in a
medical specialty must therefore be a series of good posts
at SHO level, whether arranged individually or as a
rotation, providing experience which will prepare them
for this examination.
Career Advice
During this period of general professional training they
should identify the specialty which they ultimately wish to
follow. Postgraduate Deans and Clinical Tutors are con-
sidered the official sources of career advice and should
have appropriate information available in their offices.
Consultants should always be willing and usually able to
advise their juniors but in practice it seems that most
doctors in training seek information from their immediate
seniors on the training ladder. The serious imbalance
between numbers of training posts and career posts will
eventually be corrected, and an increase in the number of
consultants has long been agreed to be necessary.
The present situation makes it imperative for young
doctors planning a career in hospital medicine to take full
advantage of the posts available for general professional
training, to remain 'pluripotential' for as long as possible
and to take advantage of opportunities which may present
for higher professional training, though not necessarily in
the specialty of their first choice.
References
1. Report of the Interdepartmental Committee on Medical Schools (The Gooden-
ough Committee) (1944) London: HMSO.
2. Royal College of Physicians (1964). Report on Training for Consultants.
3. Report of the Royal Commission on Medical Education, 1965-68 (1968)
London: HMSO.
4. First Report of the Joint Committee on Higher Medical Training,
October 1972.
John Lister
Linacre Fellow, Royal College of Physicians
Higher Professional Training
Training for a specialty in most branches of British
medicine has always been arduous and the ultimate
objective of obtaining a consultant post has often been
difficult to achieve, though in some specialties it is more
difficult than in others.
In some respects this difficulty is a measure of the high
standard and competitive nature of specialist practice in
Britain; in other respects it is a manifestation of an
unsatisfactory career structure which in recent years has
been characterised by a serious imbalance between the
number of training posts and career posts. In most but
not all specialties this imbalance at senior registrar level
has been corrected, the number of senior registrar posts
being closely related to the anticipated vacancies at
consultant level. However, there are still nearly three
times as many registrars as would be required to fill the
vacancies anticipated in the senior registrar grade. The
need to correct this imbalance was emphasised in the
Short Reportfl] which recommended a reduction in the
number of registrars and an increase in the number of
consultants with a shift from a consultant 'led' to a
consultant 'provided' hospital service. Although there has
been a natural concern on the part of consultants that this
may lead to major changes in their work pattern, the
profession has agreed in principle to the proposals,
provided no reduction in junior staff takes place without a
compensatory increase in consultant staff. Progress in this
matter has been disappointingly slow and any registrar
aspiring to a specialist career would be wise at least to
ascertain the career prospects in the specialty which he -
hopes to follow before making any irrevocable commit-
ments.
Joint Committee on Higher Medical Training
(JCHMT)
All those aspiring to a career in a medical specialty must
obtain an appointment as a senior registrar or honorary
senior registrar in a post approved by the JCHMT.
This committee was set up in 1970 as the result of
consultations between the three Royal Colleges of Phys-
icians of Edinburgh, Ireland and London, the Royal
College of ^Physicians and Surgeons of Glasgow and
members of the Association of Professorial Heads of
Academic Departments of Medicine and Paediatrics.
Prior to this, individual Colleges had published training
82 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
programmes in various specialties but it was agreed that
policies on all matters relating to higher training in the
medical specialties could be more satisfactorily deter-
mined by a joint committee on which all the Colleges, the
university departments and the specialist associations
were represented.
The JCHMT now plays an active part in co-ordinating
higher training in all the medical specialties and publishes
a training handbook[2] which may be obtained from the
Training Office of the Royal College of Physicians of
London. This handbook provides valuable information
about the training requirements for each specialty, the
composition of the committee and the names and address-
es of all the Postgraduate Deans in the UK. It points out
that the responsibilities of the committee are 'to formulate
guidelines for training in medical specialties, to approve
posts and training programmes which are suitable for
higher medical training and to grant certificates of ac-
creditation to those who have completed higher medical
training'.
Specialist Advisory Committee (SAC)
It was agreed at an early stage to establish Specialist
Advisory Committees within the parent committee,
which would determine the training programmes for
individual specialties. There are now 19 such SACs with
normally six members each, three being nominated by
the JCHMT on recommendation by the four Royal
Colleges, the other three being nominated by the appro-
priate specialist association. However, there are vari-
ations in the composition of certain SACs, which are
indicated in the Training Handbook.
Every effort is made to ensure that the membership of
SACs is well balanced, with adequate representation of
universities and academic departments, regional phys-
icians and younger consultants. Some regard for geo-
graphical 'spread' is also desirable.
The tenure of membership of SACs is normally four
years and each committee elects its own chairman.
The inspection and re-inspection of senior registrar
posts are carried out by visiting teams set up by the
appropriate SAC. The normal period of approval for
established NHS senior registrar and university lecturer
posts is five years. In the case of certain research posts,
educational approval will be granted on an ad hominem
basis for the tenure of the incumbent concerned.
Enrolment
On appointment to a senior registrar post, trainees should
apply for enrolment for higher training in the specialty or
specialties concerned. Eligibility for enrolment will de-
pend on the required period of general training having
been completed, and any period of post-Membership
training considered suitable for retrospective recognition
towards higher training will be indicated by the SAC.
The maximum period of retrospective recognition that
may be granted is 24 months for single specialty accredit-
ation and 12 months in each subject for dual accredit-
ation.
Enrolment forms may be obtained from Postgraduate
Deans and from the JCHMT office in the College.
Accreditation
Trainees should apply for accreditation towards the end
of their four-year training programme with any period of
retrospective recognition being taken into account. The
forms should be signed by the Postgraduate Dean and
submitted to the JCHMT office.
The granting of accreditation signifies that the trainee
has completed satisfactorily the prescribed period of
' higher training in the specialty or specialties concerned.
However, it is the AAC which determines the suitability
of a candidate for appointment to a specific consultant
post and accreditation is not considered an obligatory
requirement. At the same time it is likely that the
majority of successful applicants will be accredited in the
specialty concerned.
Overseas Experience
The value of overseas experience is recognised by the
JCHMT, but a minimum of two years' training in
approved posts in the UK is required of applicants for
accreditation. Furthermore, it is not always possible to
offer prospective recognition of a proposed period of
overseas training. Trainees are advised to seek the advice
of the JCHMT about such periods of training well in
advance of departure and may also be required to supply
documentation of training acquired overseas when apply-
ing for enrolment or accreditation.
Research Experience
The JCHMT recognises that participation in research
activities forms an important part of training. In the case
of single specialty accreditation, up to two years of
relevant research, not necessarily involving clinical re-
sponsibilities for patients, is accreditable.
Flexibility
The objective of the JCHMT is to improve and maintain
standards of training. Considerable thought and care
have been taken by SACs to ensure that the training
programmes are both comprehensive and relevant to the
specialty. The need to pursue a policy of flexibility in
considering the training of individuals seeking accredit-
ation is well recognised and SACs are constantly remind-
ed of the need to avoid practising rigidity while preaching
flexibility.
Career Guidance
It is hoped that senior registrars will establish good
working and personal relationships with their supervising
consultants who will normally be their main source of
advice. They should be able to advise on matters relating
to the publication of scientific papers and the preparation
of theses and, when the time comes, should be willing to
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
83
advise their senior registrars on their applications for
consultant posts. Advice on the preparation of their
curricula vitae and on interviewing technique may be
helpful at this stage.
Each region has a Senior Registrar Training Commit-
tee which oversees the progress of senior registrars in the
region. The Postgraduate Dean and the College Regional
Adviser are both members of this committee and al-
though reluctant to interfere between senior registrars
and their consultant, they will be available for advice if
necessary.
Finally, although it is not the function of the JCHMT
to offer career advice, the Linacre Fellow, who acts as
Medical Co-ordinator for the JCHMT, will be glad to
respond to any specific queries concerning training pro-
grammes and matters relating to accreditation.
References
1. Social Services Committee (1980-81) Fourth Report: Medical Education.
London: HMSO.
2. Joint Committee on Higher Medical Training (1984) Training
Handbook.
John Lister
Linacre Fellow, Royal College of Physicians
Part-Time Training
Training for a career in hospital medicine is long and
arduous, and occupies the years when most women wish
to have their children. Some will continue to work full-
time with short absences on maternity leave, but others
prefer to spend at least a little time at home with small
children and wish to find part-time work which will
continue their training in medicine.
What is Part-Time Training?
A full-time medical post is one with 10 standard Units of
Medical Time (UMTs) each week, a standard UMT
being a four-hour session between 9 a.m. and 5 p.m. on a
weekday. A part-time post is one with fewer than 10
standard UMTs, even when the on-call commitment
brings the total week to 40, 60 or even 80 hours. There is
a common assumption that all part-time posts are half-
time, but the part-time label applies equally to posts of
eight or nine standard UMTs.
Part-time posts may be approved for postgraduate
training in medical specialties, but must normally be half-
time or more. It is unrealistic to plan a career in hospital
medicine while intending to spend many years working
less than half-time.
Clinical Assistant Posts
Part-time training posts are seldom advertised. Part-time
posts seen in journals are usually clinical assistant posts,
which offer service commitments but no particular train-
ing component. Such posts have the added disadvantage
of being insecure, as there is no long-term contract, and
they may be terminated by health authorities for financial
saving or other reasons at short notice. Such posts may
therefore offer sessions with a continuing clinical commit-
ment to fill a gap when no other medical work is
available, but seldom contribute to training.
Supernumerary Posts
In 1969 the Department of Health published a circular,
HM(69)6, encouraging Regional Health Authorities to
set up special posts for doctors prevented by domestic
commitments from undertaking full-time work. Such
posts were to be supernumerary and personal, ending
when the appointed doctor resigned. The use of this
scheme for different specialties varied greatly, but the
Committees on General Professional Training and High-
er Medical Training did not exclude these posts from
approval for training, provided adequate experience was
obtained. Posts had to provide all the experience which
was required in a full-time post, including emergency and
on-call work, but this could be spread over a longer
period, such as five years for a senior registrar post.
Regional uptake of these posts varied greatly, some
regions, such as Oxford, allocating a specific budget to
part-time training, some Regional Health Authorities
funding fewer posts and some with scarcely any posts.
The problem of obtaining funding of posts has increased ?
with greater financial constraints on health authorities.
At senior registrar level there was the added problem of
manpower planning. A supernumerary post could offer
adequate training and could be funded, but if the special-
ty was already over-subscribed there would be poor
prospects for a consultant post at the end of the training.
The extra post would further increase the number of
senior registrars in that specialty looking for a career post.
In 1979 the Department of Health introduced another
scheme, PM(79)3, under which potential senior registrars
would apply centrally and would be interviewed to con-
sider whether they should be permitted to enter the grade.
If the chosen specialty was already over-subscribed, a
part-time post was unlikely to be approved. Competition
was intended to be no harder but no easier than for full-
time posts. Those who were successful could then go to
the region of their choice with their manpower approval.
Their posts still had to be set up and approved education-
ally, and there was no guarantee of finance being avail- \
able simply because manpower approval had been given.
Some doctors discovered to their cost that manpower
approval, educational approval, and funding were still
not enough; the region had a right to veto an appointment
even when all three had been obtained. This has hap-
pened more than once in one region. x
Part-time posts are not usually set up where there are
already many junior staff in training, therefore the
supernumerary doctor may find little of her time spent in
teaching hospitals. The responsibilities of the post have to
be newly defined as the doctor enters it, which may cause
problems.
Despite these obstacles, some doctors have succeeded i
in completing some of their training part-time and sub-
84
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
sequently obtaining a consultant post. This usually ap-
plies to those who have completed some years full-time
after registration and for whom part-time work filled a
hiatus between two periods of full-time work.
Part-Time Consultant Posts
For those who wish to continue to work part-time,
consultant posts are seldom advertised at fewer than eight
sessions. Some posts are advertised for which doctors
unable to work full-time for personal reasons are invited
to apply. This may improve the opportunities available,
but very few such posts are at present awarded to doctors
who wish to work part-time.
Split Posts
The present PM(79)3 scheme for supernumerary posts is
thought unlikely to continue in the future. An alternative
is the use of split posts. The British Medical Association
offers a bureau to enable a doctor seeking part-time
training in a particular specialty to meet another with an
interest in the same specialty so that they may apply
together for a full-time post which is then split between
them. This scheme has the advantage of the posts being
long established so that responsibilities are clearly defined
and not seen as detracting from other doctors' experience.
The two doctors may apply for posts at any hospital,
including teaching hospitals. There is a rapid decision,
with the usual application, short-list and interview. If
rejection follows, other jobs may be applied for rapidly,
which may be in the same area or even the same hospital.
With supernumerary posts the separate stages may take
months and if rejection follows it may not be possible to
arrange any such part-time post in the same region.
There are some disadvantages to split posts; the two
doctors may not be well matched, and one may handicap
the other's applications. Exceptional co-operation be-
tween the two doctors is necessary because a careful
handover system is required. Needs of the two may
narrow the geographical area in which posts may be
sought. If either wishes to increase the number of sessions
before returning to full-time work this is unlikely to be
permitted. The greatest problems must be the difficulty in
finding a doctor at the same stage of training in the same
specialty, and convincing appointments committees that
two can do the job as well as one, and better than other
applicants.
Choice of Sub-Specialty
The doctor who wishes to complete some training part-
time will always be at some disadvantage in future
applications for posts. It is sensible to study future trends
in staffing in different sub-specialties and avoid those in
which training grades are already providing too many
accredited senior registrars. Often the sub-specialties
already under-subscribed, such as genito-urinary medi-
cine and geriatrics, also have a less demanding emerg-
ency commitment which may allow an earlier return to
lull-time work. Training in internal medicine and the
MRCP are an excellent background for some other
specialties, such as radiology and pathology,^ in which
part-time work may be easier to obtain and full-time work
includes less emergency duty.
For those determined to follow a career in the most
competitive sub-specialties such as cardiology, endocrin-
ology, gastroenterology, respiratory medicine or neurol-
ogy, the decision to work less than full-time should not be
taken lightly. Doctors should discuss with those in the sub-
specialty the prospects for continuing in it after complet-
ing such a post, and should place even greater emphasis
on research and publications and the appropriate higher
degree. The MRCP and accreditation alone will not
guarantee a consultant post against fierce competition.
For those who succeed in walking the tightrope of part-
time training, and in subsequently obtaining a career
post, there are obvious rewards. Being more intimately
involved with one's own children when young and seeing
them every day is the most obvious. It may be possible to
continue an outside interest which otherwise would be lost
in the round of work at home and work in hospital. The
degree of commitment to the chosen career can be no less
for part-timers, and the arrangements for child care must
be just as detailed. Part-time training may be an alterna-
tive, but to be successful it cannot be a soft option.
JEANETTE MEADWAY
Should a Doctor learn to Manage?
Over the last 10 years there have been dramatic changes
in the way the National Health Service is organised and
run. In 1974 hospital management committees respon-
sible for running hospitals were replaced by health au-
thorities responsible for providing health services to a
defined geographical population. To a doctor's tradition-
al one-to-one relationship with patients was added an
explicit responsibility to a community, a defined popu-
lation who might have need of his skills.
New management techniques have been introduced to
attempt to allocate resources more equitably (a formula
for resource allocation), to plan more effectively (the
NHS planning system) and to make authorities more
accountable for their performance (the development of
performance indicators and the introduction of account-
ability reviews). All this has been happening against a
background of a diminution in the amount of money
available for growth in services. Throughout the 1960s 3-
4 per cent more money each year was given to the NHS.
The situation has been very different in the 1980s, when
growth has been near zero. Introduction of the Griffiths'
management structure will further alter NHS adminis-
tration in this decade. As a result of these changes hospital
doctors can no longer, as they often did 10 years ago,
ignore administrative responsibility.
Running the 'Firm'
With increasing demands from patients and dwindling or
static resources, consultants have had to become much
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
85
more concerned with making the best use of what beds,
clinics and theatre sessions are available to them. Clinical
policies have had to be altered, for example the increasing
use of day care. The ordering of investigations and drugs
has had to be critically reviewed. All these activities will
become increasingly important when physicians take on
the responsibility for managing clinical budgets which
will cover all the capital and revenue consequences of
their work. The ability to evaluate clinical policies and the
outcome of care is all part of good postgraduate medical
education, but organisational skills are not yet part of
either the undergraduate or postgraduate curriculum.
Running a Department
In addition to their responsibilities for direct patient care,
an increasing number of physicians run services, such as
a pulmonary function laboratory, ECG department or
nuclear medicine department, that are used by their
colleagues. The manager of a service needs to know about
budgeting, personnel policies, industrial relations pro-
cedures and other administrative matters. Most clinicians
with these responsibilities have gained the requisite skills
in the job. The increasing complexity and importance of
the managerial function has led the Colleges of Radiology
and Pathology to organise seminars on management for
their members. Although most services run by physicians
are smaller in scope and consume considerably less
revenue and capital than pathology and radiology depart-
ments, the time may have come for physicians to adopt a
more formal approach to acquiring management skills.
Involvement in Management in the District
Since 1974 clinical doctors have had a major role to play
in the management of a District Health Authority. The
arrangements were slightly modified as a result of the
1982 reorganisation and major changes occurred in 1985
as a result of the implementation of the Griffiths Report,
which recommended a change from consensus to line
management throughout the NHS.
Each District Health Authority has as a member at
least one consultant nominated by the Regional Health
Authority. The consultant on a District Health Authority ;.
is there as a 'wise man and true'; he does not have the
formal role of representing his colleagues and he brings to
the authority a knowledge of clinical practice.
The appointment of District General Managers, which
started in 1984, will diminish the very powerful role that j
was played by the consultant member of a district man-
agement team. However, a few doctors have been ap-
pointed general managers; they come mainly from
pathology and radiology but include some clinicians. It is
unlikely that many practising physicians will be attracted
to this new role or indeed to the post of unit general
manager in a large acute unit.
The new management arrangements require an input
of advice from doctors and there will continue to be a
medical representative structure through which consult- 1
ants, on behalf of their peers, negotiate with district and
unit managers. Consultants in each district will work out
the arrangements that best serve their purpose but it is
essential that every committee or group is set up with a
clear purpose and that the relationship to other parts of
the management structure is explicit.
\
Conclusion
No consultant can now avoid being involved in adminis-
tration or management. The degree of involvement can
vary and some doctors will expend a considerable amount
of time and energy dealing with these aspects of Health
Service life. To be an effective manager requires learning
how to manage. Although much can be picked up by
doing the job, it is worth while considering participating
in one of the many courses now run for clinicians on
management matters. Details can be obtained from the
Chief Executive of the NHS Training Authority, St
Bartholomew's Court, 18 Christmas Street, Bristol BS1
5BT.
Alastair Mason
2. DIFFICULT CHOICES: INFERENCES FROM ORIGINAL SURVEYS
Survey Method
The need for 'hard data' for aspiring physicians, together
with qualitative guidance, was the reason for the Stand-
ing Committee of Members undertaking this booklet.
The areas chosen for investigation were those of interest
to individual members.
For each of the first three surveys the groups of
Members that were likely to provide the most useful data
for the particular survey were identified by year of
acquisition of MRCP or MRCP(UK) and are described
in each chapter. Members were then randomly selected
from the records held on the College computer and sent
the appropriate survey form. No Member was sent more
than one of these first three surveys, but all were, in
addition, sent the survey concerned with training abroad ,
because we expected the positive response rate to be low.
Members with permanent addresses abroad or who had
qualified abroad and were not practising in this country
were excluded (though in the event a number were
inadvertently included). Reply-paid envelopes with an
identifying number were provided and on receipt the
respondent was recorded as having replied and the ques-
tionnaires were encoded with a unique (consecutive)
number which bore no relation to the identifying num- f
ber. This provided complete confidentiality but allowed
identification of non-respondents before examination of
the responses.
Non-respondents were sent a reminder by the Presi-
dent when the daily returns had dropped to less than ten
86 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
and this produced a further response. Some were sent
back unopened by the Post Office as 'unknown at this
address' and where possible these were re-addressed.
Response rates given in the following chapters are overall
rates, so that rates for those who actually received the
questionnaire are higher by an overall figure of 14 per
cent.
Responses which were narrative in nature were en-
coded by a team drawn from the Standing Committee of
Members and the data were then analysed by the Depart-
ment of Mathematical Statistics at the University of
Exeter, using the SPSS package for survey analysis.
The same basic personal information and information
about MRCP, research and higher degrees was asked for
on three of the questionnaires. There is thus some overlap
of data between the surveys, particularly in relation to
research.
Keeping up to date in General Internal
Medicine
The ease with which doctors keep up to date in general
medicine or paediatrics may depend upon the nature of
their work and the degree of specialisation, and for those
in hospital practice, the size and type of hospital in which
they work. Because there was no clear consensus in the
Standing Committee of Members as to the means avail-
able and their effectiveness in helping doctors keep up to
date in general medicine, we decided to include a survey
on the subject.
The questionnaire was divided into two parts. The first
part asked for general demographic data and the second
part asked about the ways in which doctors keep up to
date in general internal medicine.
The questionnaire was sent to a random sample of
approximately 50 doctors who obtained the MRCP diplo-
ma during each of the years 1968-83; 401 (54 per cent)
out of a possible 744 replied. Our comments are made in
the light of this response rate and for that reason we shall
present the data without attempting any statistical analy-
sis. We have drawn some conclusions, but realise that we
may be dealing with a biased sample of the population
surveyed.
Demography
Sixty-nine (17 per cent) of the sample were female, 90 per
cent were born between 1940 and 1960, and a similar
proportion qualified between 1965 and 1980. We ob-
tained a better response rate from those passing the
MRCP more recently. We have divided the sample into
specialties (Table 1) by asking what constituted the major
proportion of a doctor's time. Therefore if general phys-
icians with a special interest spent the major part of their
time in general internal medicine they were categorised
under general medicine. However, if a specialty such as
cardiology or neurology was the major component, we
have included the doctor under 'medical specialties.'
Haematologists are included with pathologists under
'other medical specialties' even though they have an
increasing clinical commitment. 'Surgically related spe-
Table 1. The proportion of specialties which form the major
part of the doctor's work. 'Medical specialties' includes
neurology, cardiology and renal medicine, etc. where this is
the major or exclusive specialty. Haematology and
microbiology are included under pathology.
Specialty No. ' %
General internal medicine 145 36
Paediatrics 51 12.7
General practice 39 9.6
Geriatric medicine 30 7.5
Medical specialties 55 13.7
Non-medical specialties (including pathology
and radiology) 31 8
Anaesthetics and surgical related specialties 20 5
Psychiatry 113
Other 19 4.5
dairies' includes obstetricians, surgeons and those work-
ing in accident and emergency departments.
Of the 58 (14 per cent) not working in the hospital
service, the majority (39) were in general practice but
others were working in community medicine, occupation-
al health and the pharmaceutical industry. There were 51
paediatricians either based in hospital or in the com-
munity but we have not separated out this or other
specialties.
Figure 1(a) depicts the proportion of hospital grades in
the sample. There was a higher number of consultants
than would be predicted from the sampling frame. The
proportion of different hospitals is shown in Fig. 1(b).
The number of attempts to pass MRCP are depicted in
Fig. 2. Although we have not related this to a future
career in hospital medicine, the proportion of those
working towards, or obtaining, a higher degree was
greater in those requiring less than three attempts at Part
2. An MD or PhD was obtained by 73 men (22 per cent)
and four (6 per cent) women. Of the sample 47 per cent
had done research work appropriate for a higher degree;
45 per cent of these had completed this work but only 19
per cent of the sample had been awarded a degree.
Ways of Keeping up to Date
Meetings
We asked for a graded response (very useful, useful, not
very useful, waste of time, unavailable) to questions
about different types of meeting, and specifically those
meetings which were of use for general internal medicine
and therefore outside the specialist interest of the individ-
ual.
Departmental meetings were considered useful or very
useful by 70 per cent across all grades, but are valued by
fewer who work in smaller District General Hospitals.
Local hospital meetings were useful to 75 per cent of all
grades equally in all types of hospital.
Regional presentations, formal postgraduate lectures
and single local meetings were less useful (to just over 50
per cent) and were appreciated most in large district
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 87
Page 88
general rather than teaching hospitals. Nationally organ-
ised meetings either covering general topics or special
interest were useful to more of the senior doctors. Inter-
national congresses, drug company symposia, local audit
meetings and journal clubs were suggested as additional
useful meetings by 10 per cent of the sample. In response
to a specific question about audit later in the question-
naire, 70 per cent (the majority being junior hospital
staff) thought that audit would be a useful form of
postgraduate education.
Reading Matter
We asked for information about textbooks and various
journals under the same format as for meetings.
Textbooks were still useful to over 65 per cent of the
sample; regular reviews in journal form were more useful
(75 per cent) than in book form (56 per cent). Regular
instructional magazines (e.g. Medicine) were useful to 66
per cent overall, including many no longer in training
grades. Light medical reading and pharmaceutical litera-
ture were of little use.
The British Medical Journal, Lancet and New England
Journal oj Medicine were of use to over 70 per cent; the
latter two being more popular with hospital doctors and
those in specialties requiring MRCP. The Quarterly Jour-
nal of Medicine and the Journal of the Royal College of
Physicians were of use to less than 30 per cent of respon-
dents. Archives of Disease in Childhood was useful to over 90
per cent of paediatricians who also listed the Journal of
Paediatrics and Paediatrics as additional journals. Under
this heading Drug and Therapeutics Bulletin and Prescriber's
Journal were also mentioned by those finding other
journals useful.
The most frequently used meetings and forms of study
are shown in Table 2. This question was answered by
over 90 per cent of the sample who were allowed up to
three preferences.
Fig. 1(a). Different hospital grades of doctor as a percentage of the whole sample (n = 401). The category 'Other Grades' includes
some doctors in non-career posts in the hospital service, general practitioners and others working outside hospitals.
Fig. 1(b). Type of hospital in which 76 per cent of the sample were working. The category of District General Hospital can be
divided further into those with more than six general physicians (13 per cent), four or five general physicians (15 per cent) and three or
less (7 per cent).
Fig. 2. Number of attempts at passing MRCP. D = Parti.
H - Part 2.
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
Table 2. The ten most used forms of study. The proportion of
paediatricians using Archives of Disease in Childhood was greater
than 85 per cent. Ninety per cent responded to this section.
Journal or Meeting No. %
British Medical Journal 235 59
Lancet 137 34
Regular review journal 98 24
New England Journal of Medicine 97 24
Local hospital presentation 70 17
Textbooks and monographs 70 17
Regular instructional magazines 66 16
Other journals 51 13
Department presentations 41 10
Archives of Disease in Childhood 36 9
Table 3. The forms of study (meetings and journals) that
doctors would like to see improved. Only 147 (37 per cent)
replied to this section.
Form of Study or Journal No.
British Medical Journal 58
Journal oj the Royal College of Physicians 50
Regional presentations 48
Formal lectures 41
Material from pharmaceutical companies 45
Local hospital presentations 37
One off local meetings 30
Nationally organised meetings 30
Lancet 25
Department presentations 25
Regular review journals 25
Only 37 per cent replied to the question on areas for
improvement in postgraduate general medical education
(Table 3) and again they were given up to three prefer-
ences. In reply to more specific questions 54 per cent (the
majority being hospital junior staff) felt that the appoint-
ment of a local postgraduate tutor would help. Seventy-
one per cent were in favour of medical audit and 55 per
cent felt that regional meetings organised by the College
were, or would be, helpful. With an eye to future
technology we asked about videos and computer-based
teaching programmes: 53 per cent had access to videos;
37 per cent were keen to receive edited recordings of
lectures or meetings but only half of these would be
prepared to pay for this service. There was less interest in
computers.
Comments
We invited general comments on the topic of postgradu-
ate education. Sixty-six per cent were satisfied with their
local postgraduate library and only 6 per cent expressed
dissatisfaction. The major difficulties that doctors en-
countered were in the lack of time available to keep up to
date (particularly in the case of women doctors) and the
difficulty in attending meetings (particularly those held in
London). Several doctors, predominantly senior regis-
trars in teaching hospitals, felt that the obligatory time
spent in their special interest or specialty prevented them
from keeping up to date adequately in general medicine.
Conclusions
The response rate of 54 per cent is similar to that obtained
in the other surveys. The disproportionate number of
consultants and low number of registrar respondents
suggests that we may have a skewed distribution, as the
proportions were unexpected for the sample which we
surveyed.
The responses to the ways in which people study and
which meetings they find useful are more predictable.
Clearly, most doctors look to a combination of textbooks,
review articles, regular instructional magazines and the
medical weeklies as their major source of written infor-
mation, and this must have implications for the way in
which educational material is presented in the future.
There is a paradox in that while the British Medical
Journal remains popular, it is thought by many to be in
need of improvement. It is salutary that this also applied
to the Journal of the Royal College of Physicians, perhaps
reflecting the small number who found it useful. The
more modern forms of teaching and study need to become
cheaper before they are used more widely.
The appointment of local postgraduate tutors in medi-
cine was supported by just over 50 per cent of respondents
and clearly such an appointee may be helpful in organis-
ing more local meetings including medical audit, local
hospital presentations and local or regional meetings.
Such activities may be especially useful to doctors work-
ing in the smaller district hospitals.
David Carmichael, Pamela Tomlin, Peter Todd
and Martin Muers
Research post-MRCP
Research experience is commonly sought by doctors once
the hurdle of the MRCP examination has been crossed. It
may take the form of full-time work, often for a higher
degree, or part time release during clinical training.
Many have argued that in addition to obtaining new
knowledge, research improves clinical practice by teach-
ing analytical skills so that new or existing medical
developments are assessed critically.
In view of the competitive nature of many of the
general medical specialties, young physicians are fre-
quently advised to undertake research so as to improve
their career prospects. Some consider it mandatory for
progress. However, very little is known about the scale,
nature and value of research carried out after the Mem-
bership examination or of the experiences and attitudes of
doctors. If training is to be improved and appropriate
advice given about the role and place of research, better
information is required.
The aim of this questionnaire was to develop guidance
to improve the research component of post-MRCP train-
ing. Specific objectives included the following: (a) to
investigate the level of research activity undertaken post-
MRCP; (b) to determine the nature and degree of
problems encountered and attitudes towards the value of
research for career development, and (c) to compare the
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 89
results between those likely to advise on research, to have
completed research and to be undertaking research. This
report summarises the main findings; a more detailed
account is in preparation.
Methods
A sample of 596 doctors obtaining Membership of the
Royal College of Physicians in 1972, 1973, 1976, 1977,
1980 and 1981 was randomly selected from the Royal
College of Physicians' computerised register.
Doctors obtaining the Membership in 1978 or earlier
were only included if they had either a current UK
address or qualified in a British medical school. Those
attaining MRCP after 1979 were only included if they
had both a current UK address and qualified at a British
medical school. This procedure was followed in an at-
tempt to exclude those not practising medicine in the UK.
In all, 337 satisfactorily completed questionnaires were
available for analysis, 56 per cent of the total sent.
Results
Characteristics of Respondents
The median age of those replying to the questionnaire
was 35 years, with the majority (87 per cent) aged
between 30 and 40 years. The most frequent years of
qualification were 1970, 1974 and 1978; 76 per cent of
those returning the questionnaire were male. Table 4
Table 4. Frequency of attempts to pass the MRCP
examination (n = 333).
No. of MRCP Part 1 MRCP Part 2
attempts Respondents % Respondents %
1 73 57.5
2 19 24
3 6 14
4 2 3
5 1
6 0.5
shows the numbers of attempts required by the group to
pass the MRCP Parts 1 and 2 examinations. The ma-
jority passed these examinations at the first attempt but,
as might be expected, more candidates had trouble with
the Part 2 than the Part 1 examination.
Research Experience Obtained
Higher Degree. Of those completing the questionnaire, 48
per cent (160) claimed to have done research work
appropriate for a higher degree, 85 per cent of whom
were male. Overall, 54 per cent of the male and 43 per
cent of the female respondents said they had worked for a
higher degree. At the time the questionnaire was distrib-
uted 18 per cent (59) had obtained an MD degree, 4 per
cent (12) a PhD, and 4 per cent (14) an MSc. An MD or
MSc was usually obtained following the MRCP qualifica-
tion but half of the PhDs were obtained before MRCP.
Figure 3 shows the distribution of ages at which
research for the higher degree started in 159 respondents; /
88 per cent began work between the ages of 26 and 34
although a few began when they were older than 40.
Approximately half of those working for higher degrees
spent more than two years doing the necessary research.
As a rough guide, research activities for a higher degree
began four to six years after qualifying as a doctor and
terminated six to nine years after qualification.
There was a wide distribution of ages at which the
degrees were awarded, with a tendency for an MD to be
gained at a greater age than a PhD or MSc (Fig. 4). The
total periods of time taken to obtain MD and PhD degrees
(from the beginning of research to award of the degree)
are shown in Fig. 5. Whereas most candidates finished :J
the MD degree work within four years, 37 per cent took
five or more years.
Information was also obtained on the length of time
taken to write up the research work. The vast majority of
MD and PhD degrees were written up within two years.
Doctors undertaking work towards a higher degree were
more likely to have made fewer attempts to obtain
MRCP. There was, however, no relationship to age at
qualification
Table 5 shows the percentage of doctors undertaking
research for. a higher degree by the year in which they
qualified. There was a tendency for more of those qualify-
Age starting research (years)
Fig. 3. Cumulative frequency distribution of age at which work
for a higher degree started.
90 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
ing after 1968 to carry out research but the trend was not
clear. It must be emphasised that figures for the most
recent cohort sampled (those obtaining MRCP in 1980
Table 5. Percentage undertaking research for a higher degree
by date of qualification.
Doing research for a higher degree
Date of qualification % No.
1968 or before 33 49
1969-71 62 76
1972-3 43 53
1974-6 55 73
After 1977 42 80
and 1981) are probably not yet complete, as some in this
group are still likely to embark on a higher degree.
Major Research Activities since MRCP. Although only 48
per cent had worked for a higher degree, 85 per cent of
those completing the questionnaire said they had under-
taken some form of research work after the Membership
examination (90 per cent of men and 67 per cent of
women). No relationship emerged between research ac-
tivities and the number of attempts required to pass the
MRCP examination. The amount of time spent in
research work is shown in Table 6. Half had done no full-
time research but a fifth had spent more than 500 days in
full-time work. Altogether one-third of researchers had"
spent more than 500 days in total in research work post-
MRCP.
5 -i MSc/other (n = 24)
>42
5 -i PhD (n = 12)
10
5 H
MD (n = 59)
20
25
30 35
Age (years)
40
45
Fig. 4. Distribution of age at which higher degree attained.
15"!
10 H
5 H
0 -J
LjLU
? MD (n = 59)
EH PhD (n = 12)
?
1 234 56789 10
Years
Fig. 5. Distribution of total time spent in obtaining a higher
degree. ? = MD. H PhD.
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
91
Table 6. Time spent undertaking research post-MRCP.
All research Full-time research
No. % No. %
Nil 12 4 136 47
< 100 days 77 27 20 7
100-500 days 105 36 71 25
> 500 days 97 33 61 21
Total 291 100 288 100
One question sought to investigate whether data which
had been collected had ever been presented at a meeting,
written up or published. Table 7 presents the results for
Table 7. Outcome of major research activities started 2-3
years previously by 211 physicians.
No. %
Data collection complete* 187 86
Research written up 163 77
Findings presented out of house 148 70
Results published 148 69
*Of those completing data collection;
76% had published the results
85% had written up the results
74% had presented the results
major research activities commenced between two and
three years previously (211 doctors). More than a quarter
of research work had not seen the light of day and was
neither presented at a meeting, nor written up nor
published. Another objective index of achievement, and
certainly the reward desired by most doctors, is the
number of publications that have been obtained. Fig. 6
shows that 38 per cent of respondents had not published 1
at least one paper as first author and 41 per cent had not
published at least one paper as other author. ,i.
An increasingly important aspect of research in times
of financial stringency is the need to raise resources. Of
those undertaking research 89 per cent (249) had some
form of financial support. Recipients received grants
from pharmaceutical firms (42 per cent), research bodies
(40 per cent), health charities (29 per cent), NHS (27 per (
cent) and other sources (19 per cent). Of those questioned
71 per cent said that they intended to do research in the
future.
j
Problems Encountered
In Undertaking a Higher Degree. Only 138 (43 per cent) of i.
physicians had registered for an MD degree. Of these, 43
per cent had obtained it but 18 per cent had abandoned it. ?<
The final number of failures might be even higher, as
some of those at present working for an MD or writing it
up may yet fail to obtain the degree. This may be
contrasted with the smaller number of PhD and MSc
candidates, none of whom had failed or felt likely to fail to
complete their studies and gain the degree.
Those 25 doctors who had failed or were failing to
obtain an MD degree were invited to list the problems
that they had encountered. These are shown in Table 8.
Table 8. Major problems encountered by 25 physicians in
doing an MD degree.
No.
Lack of resources (40%):
Inadequate financial support 2
Lack of necessary equipment 1
Too few patients 1
Insufficient time to finish 6
Lack of assistance (36%):
Poor supervision 4
No support from seniors 2
Methodological problems 2
Problems with planning 1
Lack of thesis (44%):
Results lost in computer 1
No time to write up work 3
Lost interest in the work 1
Unnecessary due to career advancement 4
Thesis failed by examiners 3
The most common reasons for failure were lack of
resources and finance, inadequate supervision and help
from seniors, and problems at the writing-up stage. Only
three candidates (12 per cent) had been failed by examin-
ers. Very few of those doing PhD or MSc degrees listed
any problems and seemed much more contented with
their research experience than the MD candidates.
In Undertaking Research. Half the doctors involved in
research initiated and undertook the research themselves
Fig. 6. Number of publications as first and 'other' author. ?
= Papers written as first author. I = Papers written as other
author.
50 -i
40 H
? Papers written as first author
n = 337
? Papers written as other author
n = 337
30 H
20 -\
10 H
JZl
0 -1
01 2345678 >9
Number of Publications
92 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
Table 9. Attitudes of 291 physicians undertaking research post-MRCP regarding adequacy of support.
Time Support of Support of Personal
Funding Supervision Allocated seniors employers earnings
More than adequate (%) 10 ^ ^ ^
A J ^ 50 43 54 56 47
< Adequate (%) 53 o
Less than adequate (%) 28 27
Very inadequate (%) 9 13 19 8 19 22
and a third participated as a key member of a research
team. The views of all doctors undertaking research of
any kind post-MRCP were sought regarding the adequa-
cy of funding, supervision, time allocated, support of
seniors and employers, and earnings. Dissatisfaction was
expressed by more than a third in all these areas (Table
9). Many doctors found it hard to ignore patients' needs
- and ward commitments and give the time required for
research work.
Overall, 36 per cent were dissatisfied with their experi-
ence of research and 39 per cent wished they had acted
differently in regard to research work. The most common
unfulfilled wishes were to have done research earlier in
one's career, to have sought a period of full-time re-
search, and to have found a team already active in
research where help and advice would be readily avail-
able. In several cases, the wish to have had some experi-
ence overseas was also mentioned.
Views on the Role of Research
The views of those surveyed on the benefits of doing
research are shown in Table 10; 42 per cent thought
Table 10. Views of 337 physicians on value of research
experience in their specialties.
Definitely Probably No
% % %
Necessary for career
progression 35 23 42
Makes one a 'good'
doctor 13 18 69
Is highly regarded by
consultant appointments
committees 42 38 20
research was not necessary for career progression in their
specialty and only 31 per cent thought such experience
was definitely or probably necessary to be a 'good'
doctor. Those who had done or were doing an MD and
those who had spent more than 100 days in full-time
research were more likely to consider research experience
made one a 'good' doctor compared to those who had
done less research. This view did not apply to those who
had undertaken more than 100 days of part-time re-
search. Eighty per cent thought that consultant appoint-
ments committees regarded research experience as being
important.
Table 11. Views on the necessity of research for career
advancement by year of qualification.
Definitely Probably Not
Year of necessary necessary necessary
qualification % % %
Before 1968 22 28 50
1969-71 30 23 47
1972-3 27 29 44
1974-6 40 25 35
1977 and after 49 14 37
Table 11 presents the views on the importance of
research for career progression among doctors by year of
qualification. A clear trend emerges. Increased import-
ance is placed on research by those qualifying more
recently. Those spending more time in full-time research
were twice as likely to consider that research experience
was important for career advancement than those with
less experience.
Seventy-nine per cent thought that research had helped
their careers and only 6 per cent thought it had been a
hinderance, so that from a practical point of view as a
criterion for promotion, research was thought to be
wholly beneficial. This applied to the group with higher
degrees as well as those without. However, those who had
obtained a higher degree shortly after qualification were
more likely to consider that this had helped their career.
Twenty-four per cent thought that their relative lack of
research experience had hindered their career progress. It
was not surprising to find that those not registered for an
MD thought research was unnecessary for progress and
those working for and having achieved an MD thought it
was necessary. However, those who had abandoned or
were likely to abandon their research projects seemed to
have few regrets and mostly thought that an MD was not
necessary (Table 12).
Table 12. Views on necessity of research experience for career
progression according to MD status.
Not Working Awarded Abandoned
registered at present MD MD
(n = 182) (n = 54) (n = 59) (n = 25)
% % % %
Necessary 21 57 71 12
Probably necessary 25 22 13 32
Unnecessary 54 22 16 56
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
93
Page 94
Discussion
Research after passing the Membership examination
forms an important part in the training of physicians and
yet the experiences of doctors are very mixed. The vast
majority (85 per cent) attempted some form of research,
(90 per cent of men and 67 per cent of women). A third
spent more than 500 days in research work and half
carried out work suitable for a higher degree. Despite this
major personal investment there is considerable dissatis-
faction with research experience and often poor perform-
ance. For example, 40 per cent of physicians had not
published at least one paper as first author or other
author. A quarter had neither published nor presented
the results of research work they had done.
At least one in five MDs are abandoned. One-third of
those obtaining an MD take more than five years to
complete it. More than a third of doctors are dissatisfied
with their experience of research and wished they had
acted differently. Shortage of funding and time, poor
support from seniors and employers, inadequate supervi-
sion and lack of earnings are common complaints. The
majority (80 per cent) of physicians consider that research
experience is highly regarded by consultant appointments
committies and helps their careers. However, two-thirds
do not think it makes them a good doctor. Better advice is
clearly needed if physicians in training are to find re-
search work interesting, enjoyable, productive and pro-
fessionally rewarding. Based on the findings in this study
we suggest the following are considered by those contem-
plating research post-MRCP.
Are you appropriately motivated?
Physicians should consider carefully why they want to do
research. Most doctors seem to have a rather pragmatic
view of research as being useful for one's promotion but
not actually necessary for medical practice. This seems a
recipe for disaster. If research is merely to aid their career
progression it is likely that many will fail to deliver due to
changing circumstances. The result will be a poor experi-
ence of limited benefit.
Are you sufficiently dedicated?
Physicians should be prepared for long-term investment
in research, particularly if an MD degree is sought. Very
few MD submissions are actually failed by examiners.
The vast majority drop out because of lack of resources
and assistance. Perseverance is essential and the support
of others is vital for success.
Are you prepared for funding problems?
Research work is not well paid, and funded inadequately
in more than a third of cases. It is unlikely that the
situation will improve in the future. This is all the more
reason to consider carefully your personal priorities and
how much time you can afford to invest in research work.
This will dictate the form of research possible and which
higher degree, if any, you should* attempt.
h
Have you considered an MSc or PhD? 1
In comparison to an MD, the fewer physicians who
undertake an MSc or PhD are not only more successful
but appear to enjoy the experience more. This may reflect
the fact that these higher degrees are supervised and can
be achieved in a shorter time.
1 /
Can you find a conducive working environment?
Inadequate supervision and support of seniors and em-
ployers is reported by more than a third of researchers.
Finding the right department is essential. Unless you are
incredibly skilled and motivated research cannot be done
just anywhere. Conflicts will certainly arise if there are
excessive patient demands on your time. A good and
caring supervisor is very important.
Ni,
Can you find a full-time research job early in your training?
Doing research full-time not only speeds up the process,
but it appears to be more efficient and effective. Earlier
research experience is recommended by many. Perhaps
the sooner one finds a research post the better after
passing the Membership.
Have you chosen a research area which will help you?
"i\
It is regrettable that so much research never sees the light
of day and is not considered to be valuable in improving
one's ability as a doctor. This must surely reflect both the
choice of research and the manner in which it is carried
out.
Research above all should teach new skills, e.g. critical
appraisal, study design, data collection and processing,
interviewing, computing, analysis, time management,
writing and presentation. Most doctors will not be pro-
fessional researchers, and research experience during
training should be seen as a learning experience rather
than the quest for new knowledge at any cost. Clear
targets should perhaps be set at the start of a research
project, e.g. to submit a paper within 18 months of
starting research.
Have you discussed your proposals with an outside adviser?
It is all too easy to be swayed by an enthusiastic senior,
team or by your own perceptions. There are sometimes
vested interests, e.g. to continue the research programme
of the department, which may not be in your best
interests. The view of an outside adviser could be particu-
larly helpful here. The Postgraduate Dean, Clinical Tu-
tor, College Adviser or a previous consultant could give
you an objective view on your ideas and point out any
unrealistic expectations. It is always a good idea to discuss
your research protocol as widely as possible with clini- '
cians, other researchers, and very importantly a statis-
tician, so as, to avoid unnecessary problems in the
analytical and writing-up stages.
Gordon M. Wood and John C Catford
94 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
Career Planning with the MRCP(UK)
The purpose of this survey was to provide useful guidance
for the aspiring doctor with a recently acquired
MRCP(UK) by describing the characteristics of those
who achieve their career ambitions and comparing them
with those who do not. It is of course accepted that many
people change their ambitions because they develop an
interest in a different specialty or branch of medicine
rather than failing to achieve their original aim. Never-
theless, throughout this chapter the concept of a career
'aim' will be used.
Questionnaires were sent to 951 members who had
received the MRCP by examination between 1966 and
1975. This period was chosen so that most would by now
be in career posts (as indeed they proved to be, with only
32 remaining in training grades). Of those sampled 575
eventually replied. Members were asked personal data
? (age, sex, marital status, etc), their experience of the
MRCP (number of attempts, over what period, etc) and
whether they had obtained a higher degree. The second
part of the questionnaire asked about career aspirations at
certain stages of their training: (a) at registration; (b) at
the time of sitting Part 1 MRCP or MRCP(UK); (c) at
the time of attaining Part 2, and (d) at the start of the
senior registrar job.
Information was requested about their current post,
main specialty and special interests. This was provided by
all respondents. Of the respondents 32 were unable to
give their career aspirations at the time of registration but
only nine were unable to do so at the time of beginning
MRCP. In a third section information was requested
about posts that the Member had done in an attempt to
keep career options open (e.g. an obstetric job with
general practice in mind). Only 100 members had done
such jobs at SHO level and of these approximately one-
third were in obstetrics and one-sixth in paediatrics. At
senior registrar level only 71 had done such posts, mostly
in sub-specialties of adult medicine. In the final section
Members were asked if they could identify and describe
any defects in their career planning.
Demography
This sample is presumed to be reasonably representative
of those obtaining the Membership between 1966 and
1975, there being a 60 per cent overall response rate. The
majority were aged 35-49 years, 81 (14 per cent) were
women and they were slightly younger than the men (40
per cent aged less than 39 compared to 25 per cent of
men), had obtained their qualifying degree at an earlier
age (47 per cent aged less than 23 compared to 23 per cent
men) and had more often obtained Part 2 MRCP before
the age of 28 (42 per cent versus 36 per cent). Only 7 per
cent of the sample had not been married but of the 436
who had been married 158 (36 per cent) were separated or
divorced. At the time of obtaining the diploma 57 per cent
had been married three or more years, 24 per cent five or
more years and 20 per cent were not married until two or
more years after the examination. The remainder mar-
ried at about the time they were sitting the MRCP (22 per
cent). Two hundred and forty-one (47 per cent) had had
children by the time they took the examination. Women
were less likely to have become consultants (57 per cent
compared to 65 per cent for men) and much less likely to
hold academic appointments (4 per cent compared to 11
per cent). A similar number of men and women were
overseas or in non-hospital posts. Nine of 11 individuals
who were still not in permanent posts were women; of
these 8 had been married and 5 of these were divorced.
Marital status did not otherwise appear to have signifi-
cant associations with career status.
Diploma
In common with previous surveys by the College we
found that the majority took Part 1 only once (76 per
cent). A slightly larger number required more than one
attempt at Part 2, only 56 per cent obtaining it at the first
attempt. No less than 43 per cent stated that they passed
both parts at the first sitting. Twenty per cent obtained
Part 2 in the same calendar year that they sat Part 1 for
the first time and 72 per cent had obtained both parts by
the end of the next calendar year. Sex and marital status
had no significant effects on these results.
Career Posts
All but 32 people had career posts, although a slightly
larger number did not regard their present appointments
as permanent; 330 were consultants in the NHS, 57 held
academic appointments of senior lecturer or professor and
34 held consultant or similar academic appointments
overseas. Of the NHS consultants 29 were practising
solely in a sub-specialty, 122 as general physicians, 172 in
allied branches of medicine, 32 in non-medical hospital
specialties and 8 in specialties where it was difficult to
regard the MRCP as being of direct professional value.
Of those practising in allied branches of medicine the
largest group were paediatricians (66).
Higher Degrees and Research
Only 127 individuals (22 per cent) had completed a
higher degree (108 an MD, 14 a PhD and 10 both)
although 294 (51 per cent) claimed to have completed
appropriate research for a higher degree and 3 had work
still in progress. The characteristics of those doing re-
search or obtaining higher degrees are broadly similar.
Table 13 shows that they are less likely to be women,
more likely to be or have been married and may have a
child aged less than three at the time of completing
MRCP. They are also likely to have been successful at the
examination at an earlier age, taking fewer attempts.
There did not appear to be a significant change over the
ten-year period in the number of individuals doing full-
time research or obtaining higher degrees.
Achievement of Career Aims
One simple but crude way of looking at career paths is to
compare the career aim with that actually achieved. For
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 95
Table 13. Social and demographic factors, full-time research
and higher degrees. All figures given as per cent.
Period of full-time
research Higher degree
undertaken obtained
Men
Women
Single
Married
Married and divorced/
separated
Age completed MRCP:
<27
>30
MRCP in single attempts
MRCP in more than 4
attempts in total
Children:
None or < 3 years at
MRCP
3 or more years old at
MRCP
MRCP:
1965-68
1969-72
1973-75
NS not significant
* p<0.05
** p<0.01
***p<0. 001
54
38 **
31
52
57 *
65 **<
39
56
40 * *
56
44 NS
55
53 NS
47
23
15 NS
18
23 NS
22
51 ***
16
25
12 * *
25
12 *
22
22 NS
25
this purpose we made certain generalisations which we
believed to be appropriate although limited in their
applicability to individuals. We arbitrarily divided the
posts according to the following definitions.
Academic. Academic posts and full-time sub-specialists
practising full-time in one of the main-line medical
specialties regarded as highly competitive, e.g. cardiol-
ogy, renal medicine.
Physicians. Consultant physicians with or without a
special interest.
Branches. Consultants in branches of medicine other than
general medicine in which MRCP is mandatory, e.g.
paediatrics, geriatrics, dermatology. , ?-
Non-Physicians. Consultants in specialties in which
MRCP is an advantage but not necessary, e.g. radiology, ^
obstetrics, anaesthetics, psychiatry.
Non-Hospital. Physicians practising outside hospitals in
general practice, community health, pharmaceutical in-
dustry.
Sub-Consultant. Hospital doctors practising below the
grade of consultant. Doctors in training are included in
other appropriate categories.
Overseas. Doctors overseas have generally been considered
separately.
The aim was to put posts in approximate order of
competitive difficulty accepting that there are many
exceptions. It is generally agreed that competition in most ij
of the 'branches' including paediatrics is less fierce than
in general physician posts, though not in all cases. In the
non-hospital group the MRCP is often done because of
individual enthusiasm rather than career requirements or
advantage (for example general practitioners). Table 14
shows the career aims of the group at the time of
completing the MRCP compared to their present posts.
The data can be examined in a number of ways: e.g. of
the 238 whose aim at the time of completing MRCP was a
consultant physician post, 122 have ended up in such a
post although 37 have become academics and 34 are in
other branches of medicine; 33 have gone into non-
hospital medicine including general practice (see below).
The vast majority of current physicians (122) started their
post-MRCP career with that aim though 10 were then t
aiming for academic appointments and 7 considered , J
careers in non-hospital medicine their first choice at that
time. In addition, 27 of these are practising permanently
overseas as physicians.
In contrast, of the 86 'academics' only 34 were aiming
originally at such an appointment and of those practising
in branches of medicine (168) only 110 (and some of the
18 academics) were planning this career at the completion j
of MRCP. ,
An alternative way of looking at the situation is to
examine their specialty interests and Table 15 shows the
Table 14. Comparison of aims at time of passing MRCP and current appointments.
Stated aim at time of completion of MRCP
Present appointment Consultants Consultant Non-
Consultant in other non- hospital
Academics physicians branches physicians doctors Overseas Unknown
(n = 67) (n = 238) (n = 154) (n = 37) (n = 64) (n = 3) (n = 12)
Academic (n = 86) 34 29 18 1 3 ? 1
Consultant physician (n = 122) 10 102 4 0 5 0 1
Consultants in other branches (n = 168) 6 34 110 4 6 0 1
Non-physician consultants (n = 40) 1 6 5 24 20 0 2
Non-hospital doctors (n = 90) 5 31 8 ' 3 41 0 2
Overseas or sub-consultants (n = 51) 5 24 8 5 5 2 2
Unknown (n = 18) 6 9 1 0 0 0 2
96 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
Table 15. Number of physicians in different specialties with comparison of number remaining in the specialty of their choice at the
time of completing MRCP and research experience and higher degree.
Specialty/interests (career posts only)
No.
Achieving aim
at MRCP
% No.
Spent period
in full- Obtained a
time research higher degree
Physicians:
Academic 35 48
NHS (includes full-time specialists) 153 60
General practitioners 69 77
Paediatricians 66 80
Rheumatologists 30 75
Geriatricians 28 63
Dermatologists 20 80
Psychiatrists 15 65
Haematologists 12 92
Clinical pharmacologists 9 ?
Miscellaneous branches where MRCP is necessary 27 60
Miscellaneous branches where MRCP is an advantage 50 73
Miscellaneous branches where MRCP is no apparent
advantage 13 ?
Overseas practice 42 ?
23/48
127/215
40/52
60/75
9/12
5/8
16/21
11/17
11/14
2/2
12/20
24/33
4/8
2/3
82
77
15
33
40
32
40
40
55
100
60
46
62
41
54
39
0
12
7
14
20
27
0
56
15
18
0
17
respondents grouped according to their job description.
Physicians in all specialties practising overseas are in a
separate group. For general physicians those holding
university appointments are separated as 'academics' but
those with a full-time special interest are included with
consultant physicians. In other groups academics and
consultants are included together. After general phys-
icians it is perhaps surprising to find that the next largest
group is general practitioners, with paediatricians a close
third. The second column of Table 15 shows the percent-
age (and numbers) eventually achieving the aim they had
at the time they completed their MRCP. There are 181
individuals who are not in posts which were their aim
when they completed MRCP. Full information is avail-
able on 80 who were planning at that time to be general
physicians (with or without a special interest) and these
are by far the largest group. Of these 80, 18 went into
geriatrics, 13 each into general practice and rheumato-
logy and 5 into clinical pharmacology; 15 went into a
number of other sub-specialties including paediatrics and
dermatology; 2 into psychiatry and 14 into sub-specialties
in which MRCP is either not a standard requirement or
not an obvious advantage.
Taking academic and NHS consultants together, 57
per cent (150/263) of those aiming for a career in general
medicine at the completion of their MRCP obtain career
posts in general medicine and associated sub-specialties.
There is also, however, a significant accretion (38) to the
eventual number of career posts (188) from individuals
who were planning careers in other branches of medicine
at the time of completing MRCP and these represent one-
fifth of all career posts in general medicine. In paediatrics
this accretion is 9 per cent (6 of 66) while in general
practice (42 per cent), rheumatology (70 per cent) and
geriatrics (82 per cent) it is much higher, with most of the
accretion coming from individuals previously aiming for
careers in general medicine. Similar results are seen for
other branches of medicine where MRCP is necessary (55
per cent), where it is an advantage (52 per cent), and
where it is no apparent advantage (69 per cent, note
n= 13). Accretions in the smaller sub-specialties of der-
matology (20 per cent), psychiatry (27 per cent), haema-
tology (8 per cent), or clinical pharmacology (78 per cent)
show a pattern similar to that of general medicine and
paediatrics, with a low accretion rate apart from clinical
pharmacology; but numbers are small and conclusions
must be guarded. Only two of the 42 with career posts
overseas were planning to go overseas at the time of
completion of MRCP so that the accretion rate in this
group is 95 per cent.
Reasons for Change
Very few respondents completed this section of the
questionnaire, which asked for reasons why they had
changed career paths. Dividing the reasons given very
broadly into the three following groups the following data
were obtained: Good Reasons. Described as desirable, e.g.
preferred new career. Bad Reasons. Described as disap-
pointing, e.g. no jobs available in previous career or lack
of necessary experience, etc. Social Reasons. Social, finan-
cial and other linked reasons.
Overall, the good and bad reasons almost exactly
balanced, suggesting that in nearly half the cases where
the career plan had changed this was seen as desirable and
indicated a preference (whether this was the result of
rationalisation or not). The social and financial factors
were significant in only about one-fifth of all the reasons
given. Looking at the large group whose aim was to
become consultant physicians but who changed to a
branch specialty, or even left hospital medicine, reasons
in the 'bad' group outnumber those in the good group by
2:1, while for those now in non-hospital medicine as a
whole who changed careers, good just outnumber bad.
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
97
Similarly, those who were aiming for academic posts at
completion of MRCP but did not achieve them, give
twice as many bad as good reasons and those aiming for
branches of medicine give equal numbers of good reasons
for their changes of career. Social factors appear of
relatively little importance.
Dissatisfaction with Career Ladder
Respondents were asked if they could identify any defects
in their careers which might be responsible for their not
achieving the career path which they would have liked.
Reasons given were divided into the following categories:
(a) blaming the training programme; (b) blaming other
people, e.g. seniors/advisers; (c) lack ofjob opportunities;
(d) health or social reasons; (e) bad planning; (f) appor-
tioning blame to oneself.
One hundred and twenty-eight stated that there had
been a defect in their training and 115 identified a reason.
Of these nearly all (99) blamed 'the system' in one way or
another (training 30; people 40; no jobs 29). Remarkably
few blamed themselves (2), bad planning (7) or health or
social reasons (7).
Experience of MRCP
Members who are at present in academic or full-time
specialist appointments as general physicians were more
likely to obtain the MRCP at a younger age so that the
ratio of this group passing the examination at 27 or less
compared to 30 or more was 2.5:1, for NHS consultant
physicians 1.2:1 and for non-hospital practitioners 0.7:1.
Cause and effect is not established. Similarly, they are
likely to pass the examination after fewer attempts,
though this waiS- not statistically significant.
Research and Degrees
As expected, academics and full-time sub-specialists were
much more likely to have done full-time research (88 per
cent) than NHS consultants (55 per cent); the percentage
of overseas academics (54 per cent) and consultants (42
per cent) was lower than that of their UK counterparts.
The same picture is true for higher degrees (53 per cent of
academics and 22 per cent of consultants having higher
degrees and 39 per cent and 16 per cent respectively of
overseas academics and consultants). Non-hospital phys-
icians were much less likely to have done research (25 per
cent) or have higher degrees (6.2 per cent). It is noticeable
that those who aimed initially for careers in branches of
medicine other than main-stream consultant physician or
paediatrician, etc.; and are now in such posts are much
more likely to have done research and obtained higher
degrees than those who made a decision to go into one of
these branches of medicine at a later date.
Of 244 people aiming to be consultant general phys-
icians at the time of completing the MRCP, 66 got a
higher degree and, of these, 56 (85 per cent) ended up in
consultant or academic physician appointments, with a
further 4 in branches of medicine and 2 overseas. Of the
178 who did not get higher degrees 92 (52 per cent) are in
consultant or academic physician appointments, 30 (17
per cent) in branches of medicine, 21 (12 per cent)
overseas and 30 (17 per cent) in non-hospital medicine.
Conclusions
At the time of completion of MRCP by examination, only
about 50 per cent of Members are planning a career in
academic or NHS general medicine and of these only 57
per cent achieve this ambition. The 'success' rate is much
higher in those who also do a higher degree (85 per cent)
than those who do not (52 per cent). However, only a
minority (39 per cent) of NHS consultant physicians
obtain higher degrees at all. The second most frequent
career aim at the time of completing MRCP (n = 75) is
hospital paediatrics and this was achieved by 80 per cent
of individuals. The other large group is general practice
(n = 52) where a similar proportion (77 per cent) do
become principals in general practice. The other special-
ties with significant numbers can be broadly divided into
those where a decision appears usually to have been made
by the time of completion of MRCP (dermatology,
psychiatry and haematology) and those with a high
accretion rate after MRCP (rheumatology, geriatrics,
clinical pharmacology and the three pooled groups where
MRCP was judged essential, an advantage or no appar-
ent advantage). Nearly all (95 per cent) of those with
career posts overseas made their decision after completing
MRCP.
Those in academic posts were characterised by being
male, taking fewer attempts to obtain the MRCP at an
earlier age and to have done higher degrees and full-time
research.
Many of those who changed career paths did so for
what we characterised as 'good' reasons, i.e. from their
own preference. Those changing from career aims as
general physicians to branches of medicine twice as often
gave 'bad' reasons suggesting that the change had not
been of their own choosing, while those initially aiming
for and achieving career posts in the branches of medicine
were similar to those in general medicine. A large number
of those changing career paths felt that there had been a
defect in their training though nearly all blamed either the
system or senior colleagues and a tiny minority blamed
themselves.
John H. Tripp
Benefits and Problems of Training Abroad
Most doctors in training will have considered spending
some time working abroad. They will be familiar with the
rumour that, on the one hand, the BTA ('Been to
America') qualification is important for career advance-
ment, and on the other that re-entry to the UK career
ladder verges on the impossible. This background led the
Standing Committee of Members to survey College
Members to clarify the benefits and problems of working
abroad for three or more months.
98 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
Method
The survey questionnaire is available from the College
and the author. It was sent with each of the other three
surveys described in this section. This questionnaire was
therefore sent to 744 doctors randomly selected from
those obtaining MRCP between 1968 and 1983; 596
obtaining MRCP in 1972, 1973, 1976, 1977, 1980 and
1981, and 951 obtaining MRCP between 1966 and 1975.
Results
The overall response rate was 55 per cent. Some question-
naires had been sent to College Members living in their
own native country abroad, or who had emigrated from
Britain. These were excluded, leaving 1,192 valid replies
which were analysed.
Most respondents failed to fill in details of their own
post and specialty, presumably because they had already
done so on the accompanying questionnaire. Unfortu-
nately, once the two questionnaires were separated this
^ information became irretrievable.
A total sample of 410 Members who had been abroad
for a period of training was identified and some useful
conclusions can be drawn from the answers they gave.
Of the respondents 34 per cent had been abroad for
more than three months. The most popular countries
were USA (33 per cent), Canada (10 per cent), Australia
(5 per cent) and South Africa (5 per cent). Seventeen per
cent had been to countries within black Africa and of
those Nigeria was the most popular (4 per cent). Nine per
cent had visited countries in mainland Europe and of
these the most popular was France (3 per cent).
The majority (55 per cent) had been to teaching
hospitals similar in standard to those in the UK but 12 per
cent had visited small teaching hospitals and 20 per cent
non-teaching hospitals. Thirteen per cent had been in-
volved in various pursuits from working in full-time
research posts in universities to mountain rescue, ship's
surgeon and the flying doctor service.
Sixty-one per cent left for their period of training
abroad at registrar or senior registrar level and a further 4
per cent were research fellows or lecturers; 20 per cent
were senior house officers and 4 per cent were consult-
ants.
The median time abroad was 18 months, and the
greatest number of people were away for 12-15 months
(28 per cent); 12 per cent had been abroad for two years.
In only 16 per cent was the period abroad a planned
, attachment, but 44 per cent said that they had been
guaranteed a job on their return to Britain; 31 per cent
said that the period abroad was planned at the time of
appointment to a UK post; 84 per cent claimed to have
arranged the visit themselves.
Nineteen per cent found difficulty in gaining employ-
ment on returning to Britain, 20 per cent claimed to have
lost seniority, and 34 per cent had lost financially.
Many different organisations had been used to provide
advice and financial assistance. The following organisa-
v tions were mentioned frequently as providing finance:
Wellcome Foundation, universities, Medical Research
Council, church organisations and related charities, phar-
maceutical companies. Thirteen people had obtained
scholarships for the purpose of travel abroad, but many
obviously relied on funding from the country being
visited. For advice many people stated that their own
consultant or personal friends had been most useful.
Language problems were experienced by 20 per cent,
and 17 per cent said that they had had difficulty integrat-
ing with local practice and consequent problems at work.
Other problems concerned cultural and political differ-
ences of one type or another (18 people). Discrimination
against women was mentioned in particular. Poor facili-
ties (16 people) and unfamiliar standards of practice (7
people) caused problems, and four found themselves
working with colleagues whom they judged as incompe-
tent. Four complained that the work was too hard and ten
had experienced various administrative problems or
problems with accommodation.
Seventy-eight per cent said that they had gained experi-
ence which would not have been available in Britain and
of these 88 per cent believed that that experience had been
useful on return.
Fifty-two per cent felt that they had not contributed
usefully to the development of facilities abroad.
Only 28 per cent had gone abroad primarily for the
purpose of research but 57 per cent had produced publi-
cations from the work abroad and 15 per cent had
achieved a higher degree from research.
One hundred and twelve people said that their time
abroad was not recognised by JCHMT and in 93 cases it
had been. However, it is not clear how many of the
former actually requested such recognition and a large
number had not applied.
Only 2 per cent said that their visit had not been time
well spent. People stated a large number of advantages to
training abroad. Apart from gaining clinical experience
people believed that they had somehow fulfilled them-
selves by going abroad and had developed a better
understanding of world problems (36 people). A number
of people were not ashamed to admit that fun and
sunshine were important aspects of the trip. Some felt
they had gained by meeting people in their own field of
interest (14 people). For many, research facilities and
teaching experience had been made available by their trip
(24 people). Seven people stated that they valued the
experience of seeing medicine run as a financial concern.
Twenty-five people complained that there had been a
failure to recognise the experience abroad as valuable on
return to the UK and 13 mentioned frank prejudice
against them. In nine instances the trip abroad had
apparently caused personal problems and four felt that
their children's education had been disrupted. Three had
felt lonely and ignored abroad and four that loss of
contact with the UK was a worrying problem. Four felt
that they should have received more advice before em-
barking on their trip.
The present grade of 332 respondents was available.
Some comparison between those who had and who had
not been abroad was therefore possible (Table 16). Of
those presently graded consultant 43 per cent who had
been abroad did so at senior registrar level and 29 per
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
99
Table 16. Comparisons of grade in those who had and who
had not undergone some training abroad.
Percentage of total who
had not had
Present Grade trained abroad trained abroad
(n = 226) (n =106)
Academic consultants 5 10
NHS consultants 32 45
General practitioners 12 9
Senior registrars and lecturers 30 15
Registrars 13 10
Others 8 11
Percentage of the grade who
had not had
trained abroad trained abroad No
Academic consultants 50 50 22
NHS consultants 60 40 121
General practitioners 75 25 35
Senior registrars 81 19 83
Registrars 73 27 40
Others 65 35 31
cent at registrar level. Canada and the USA were the
countries visited by 61 per cent of those who had become
consultants. Of the consultants 45 per cent had spent 12-
18 months away but 20 per cent had been away for 18-24
months.
Conclusions
The survey identified a large group of doctors in a range
of specialties and grades who had worked temporarily
abroad. The proportion (34 per cent) was unexpectedly
high. This figure does not appear to have been artificially
inflated by doctors holding the MRCP but not working in
the medical specialties, as 55 per cent of those who had
been away were either academic or NHS consultants and
a further 23 per cent were in hospital training posts. The
data suggest that at present 40-50 per cent of newly
appointed consultants have worked abroad. The majority
of these have done so during their years as registrar or
senior registrar, most having visited Canada or the USA.
The majority had been away for more than one year and
most had found a fruitful research project which had led
to publication, even if that was not the main reason for
going. It seems that a trainee following this type of
programme is unlikely to damage his career.
One clear conclusion is that, despite a number of
problems, very few people regretted their spell abroad.
Practically all had gained valuable experience. There was
a substantial risk of financial loss, including loss of
seniority on return. Nevertheless, it is encouraging that
the JCHMT recognised the period abroad in a substan-
tial proportion of cases. Some people obviously do have
problems gaining employment in the UK on return and
the prejudice against them which some expressed may
indeed have been due to an inappropriate or lengthy
period away from the main stream of medicine.
The effect of the removal on family life is important to
consider before making the upheaval. It had had a
detrimental effect on some children's education, and
separation or changed environment had caused some
marital problems.
A number of people had experienced unhappiness at
their place of work, mostly related to cultural or political
differences but sometimes to inhospitality or incompe-
tence of colleagues. Some found themselves isolated and
lonely. It is obviously important to look carefully at the
local situation which one is planning to enter to ensure
that there are no potential problems.
The overwhelming implication of this survey is that
training abroad is valuable and to be encouraged. It is
fruitful in terms of research and experience but social and
financial safeguards are sometimes neglected, with harm-
ful results. Bona fide training will be credited to one's
career.
Clive Roberts
3. INDIVIDUAL SPECIALTIES
Accident and Emergency (A & E) Medicine
The specialty is now 14 years old and still developing.
The majority of consultants are full-time and come from a
variety of backgrounds. .Of the 170 full-time consultants
in post it must be said that the majority hold the FRCS.
However, a significant proportion hold the MRCP and
often half the patients seen have medical problems. The
growth of the specialty has been restricted by the lack of
suitably trained applicants but with the recent expansion
of the senior registrar grade, consultant expansion is
beginning again. It is anticipated that consultant growth
will continue for the foreseeable future, as many depart-
ments do not have an A & E consultant and very few
indeed have more than one. The Casualty Surgeons'
Association is the professional body which represents and
co-ordinates the specialty and the Emergency Medicine
Research Society provides a forum for the discussion of
research topics.
An A & E consultant is responsible for all the patients
who present to the A & E department. Resuscitation of
the acutely ill and injured takes priority and is seen by
most as the particular forte of this specialty. Management
of cardiac arrest and the multiple injured patient are the
two areas in which the A & E doctor has a great deal to
contribute. Most A & E consultants develop a special
interest, often based on their previous backgrounds, e.g.
hand surgery, if surgically trained, or poisonings if
100 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
medically trained. There are a small number of paediatri-
cally trained A & E consultants who work in paediatric A
& E departments. A feature of A & E medicine is that the
working day is usually unstructured and the variety is
enormous. 'All human life is here' and you can move
from sophisticated resuscitation for a severe cardiac prob-
lem to the treatment of alcoholism or a child with a cut
knee. The requirements are a broad background in both
medical and surgical disciplines and the ability to keep
cool in a crisis. Casualty departments are informal, and
relationships between various specialists and disciplines
are undefined. It is essential to be able to co-operate with
nursing and ambulance staff on an equal level.
Most A & E departments are staffed by senior house
officers and sometimes, it must be said, in inadequate
numbers. The DHSS considers registrar posts in A & E
orthopaedics as posts in A & E. The fact is that these are
orthopaedic training posts and there are only a handful of
pure A & E registrar posts. The specialty is negotiating
with the DHSS to rectify this anomaly and an expansion
of the registrar grade is planned. This will eventually
* allow entry to the specialty at the registrar level. In many
departments for the foreseeable future a consultant will be
the first in line on call after the SHO. What this entails in
terms of emergency call-out depends upon what other
facilities and local arrangements are available at the
hospital concerned. Many A & E consultants become
involved in out-of-hospital rescue work and the higher
training of ambulancemen.
Entry for training in A & E medicine is at present at
senior registrar level and there are about 65 posts avail-
able. No further expansion of the senior registrar grade is
planned for the immediate future. Candidates must have
the FFA, FRCS or MRCP and a broadly-based back-
ground. Many candidates have done a registrar job in A
& E medicine. Once appointed senior registrar, the
training programme is tailored to ensure that those areas
not covered by previous experience are made up. Most
senior registrars therefore spend some time in paediatrics
and intensive care as well as in psychiatry and general
practice. If their training has been predominantly medi-
cal, they spend at least six months in general and
orthopaedic surgery, and if predominantly surgical, vice
versa. It is now possible to take the second part of the
FRCS Edinburgh in A & E medicine and surgery.
Candidates are eligible to sit this examination if they have
been qualified for four years, have either Part 1 of the
Membership, or the primary Fellowship or the primary
FFA of any of the Colleges and have completed 12
months A & E, 12 months' acute general medicine and 12
months' general surgery. Senior registrars may spend
some time abroad during their training and the JCHMT
will recognise appropriate experience.
Accident and Emergency Medicine is expanding and is
now an established specialty. In the past it was thought
that A & E departments should be staffed by one phys-
ician and one surgeon; now the feeling is they should be
staffed by two specialists in A & E medicine. Career
prospects are good.
Anthony Redmond
Cardiology
Consultant posts in this specialty are of two main types:
general physicians with an interest in cardiology, and
pure cardiologists based at regional cardiac centres. Car-
diology has changed with the introduction of echocardio-
graphy, exercise testing and coronary artery bypass
grafting. Coronary angioplasty and intra-coronary
thrombolysis are being evaluated. Non-invasive diagnos-
tic methods, best performed in District General Hospi-
tals, have increased the work of the physician with an
interest in cardiology.
There are slightly more physicians with an interest in
cardiology than pure cardiologists. Anticipated retire-
ments are equally divided between the two, averaging six
a year up to 1995. As in other specialties, those who have
completed four years as senior registrar far exceed the
predicted number of consultant vacancies. Expansion, if
any, is most likely to occur in the post of physician with
an interest in cardiology. In short, present career pros-
pects in cardiology are dismal, with fierce competition for
the vacancies that arise.
Your best chance of becoming a consultant in cardiol-
ogy lies in deciding early in your career, making your
intentions known to your referees and aiming for posts at
well-established centres. General medical experience at
SHO and registrar level is essential. Specialisation tends
to begin at registrar level. A period of research, of a
standard worthy of an MD or PhD, is becoming a
requirement for senior registrar appointments. Great care
is required in selecting a research post. Well-established
departments of cardiology are the best bet. You should be
wary of single-drug projects sponsored by pharmaceutical
firms. The MRC and British Heart Foundation support
research projects in good departments.
There is now a single higher training programme at
senior registrar level. Two years should be spent in a
clinical post as senior registrar in a cardiac centre,
including one year in a centre with cardiac surgery. The
specialist training should include clinical experience in
general cardiology, training in cardiac catheterisation
and angiography, echocardiography, ambulatory moni-
toring, cardiac pacemaking, exercise stress testing, acute
cardiac care, and nuclear cardiology. One year at senior
registrar level should be spent in general medicine and a
further year in a related sub-specialty, e.g. hypertension,
epidemiology, cardiac rehabilitation, clinical pharmacol-
ogy or cardiovascular research.
Paediatric cardiology remains a small sub-specialty
limited to regional centres. An invariable requirement is
paediatric experience in SHO or registrar grades, includ-
ing six months' neonatal paediatrics, six months in
general paediatrics and one year in adult or paediatric
cardiology. Again, a prerequisite for senior registrar
appointments is a doctorate. Senior registrar training
includes some adult cardiology and general paediatrics.
The College has a specialist advisory committee in
cardiology and also a joint cardiology committee (in
collaboration with the Royal College of Surgeons of
England). The College continues to press for an improve-
ment in services for the diagnosis and treatment of heart
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
101
disease. The British Cardiac Society is the main forum for
scientific debate. It has also concerned itself with the
problem of inadequate resources and funding for cardi-
ology, in particular the bottleneck in the career structure
that has resulted in a large number of senior registrars
marking time.
Lawrence Bryson
Clinical Genetics
Clinical genetics is a new and expanding specialty and
few regions at present have adequate clinical genetic
services. It has been recommended that in a region there
should be two full-time clinical geneticists per 2-3 million
population[l] and ideally these should be based in a
Regional Genetic Centre where there are appropriate
supporting staff and associated genetic laboratory ser-
vices. Genetic clinics are held in the Regional Centres
and in 'satellite' clinics in association with local clinicians.
Most clinical geneticists do not have beds but can admit
by arrangement with consultant colleagues.
Genetic conditions can affect all age groups and all
body systems and a broad clinical background is essential.
Day-to-day work is varied and includes diagnosis of
genetic conditions, genetic counselling, ward referrals,
acting as an 'information resource' on genetic matters for
colleagues, liaison with genetic laboratories and clinical
colleagues in investigations and clinical interpretation of
results and in prenatal diagnosis of fetal defects. More
recently, clinical geneticists have been involved in clinical
application of recombinant DNA technology and in re-
search in this exciting field. Teaching of undergraduates,
postgraduates and associated professional groups is an
important aspect of their work.
Entry to the specialty is usually at senior registrar level
and there are six NHS-funded senior registrar posts in the
UK and a small number of ad hominem SR equivalent
posts funded by limited-duration research money. Before
entering the specialty the trainee should have post-
registration general professional training, to include
ideally both paediatrics and general medicine, leading to
the MRCP. An SHO job in obstetrics has been seen as an
advantage by some. A year should have been spent in the
study of basic genetics, either as a postgraduate or during
undergraduate training in the form of an intercalated
BSc. Those SRs without this basic genetic qualification
will be seconded during higher specialist training. As
senior registrar the trainee should gain knowledge of
dysmorphology, biochemical and population genetics,
cytogenetics, DNA technology, the genetics of disorders
of different body systems and genetic counselling tech-
niques. Encouragement is given for research projects
leading to an MD degree. It is recommended that there
should be one consultant clinical geneticist per million
population and, though this target is far from being
achieved, the NHS appears to be moving slowly towards
it. If these hopes are realised, career prospects should be
reasonably good in the medium term. Career prospects
should be good if those regions without clinical genetic
services fund new posts and those with existing services
expand to recommended levels. Trainees for other spe-
cialties may wish to acquire training in genetics, and dual
accreditation may be possible in some cases. The Clinical
Genetics Society, which consists of physicians, scientists
and other professional groups working in the field, meets
twice yearly and contributions and attendance by
younger members are encouraged.
References
1. Clinical Genetics Society (1983) Bulletin of the Eugenics Society, Suppl. 5
Dian Donnai
Clinical Immunology/Allergy
All physicians use the results of immunological investi-
gations in the management of their patients but clinical
immunology has become sufficiently complex to require
specially trained consultant immunologists both in the
laboratory and in clinical care. Clinical immunology as a
separate specialty is proving slow to develop within the
NHS. There are said to be nearly 50 consultants in
immunopathology in the British Isles but many hold
honorary contracts, often with limited service commit-
ments. Many doctors currently practising in this field do
so from an academic base with a major research interest.
Departments of laboratory immunology have developed
in some major hospitals primarily to provide immuno-
diagnostic services. Thus it is not surprising that in recent
years there has been considerable discussion about how
clinical immunology should be developed. Most experts
agree that specialist immunology services are not needed
in every district hospital but that they should be estab-
lished on a sub-regional basis in major medical centres
serving populations of 1-2 million persons. The first need
is for an even distribution throughout the country of
laboratory-based immunologists providing full immuno-
diagnostic services. These consultant immunologists
almost always see referrals on the wards and do out-
patient sessions but the appointment of a specialist phys-
ician in clinical immunology/allergy becomes necessary
when the workload increases. If money were to be made
available for the proper development of this specialty, at
least 25 new consultant posts should appear within the
next few years. The appearance of the acquired immuno-
deficiency syndrome as a major clinical problem makes
this more urgent.
Collaboration with colleagues in the management of
patients is a major attraction of this specialty. Many
members of established medical specialties fear the intru-
sion of yet another expert in the care of their patients.
This fear is not necessary; the shared care of immunologi-
cal problems can be most rewarding for all concerned, not
least the patient. The consultant immunologist is in-
volved ir> the broad spread of medicine without needing to
pretend that he is expert in every aspect. This collabora-
tion should involve consultation on the wards and often
means the development of combined out-patient clinics
102 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
with specialties that see a large number of immunological
problems. However, this does not mean that the clinical
immunologist never has prime responsibility for a
patient's care; for some patients with immunodeficiencies
or certain multi-system immunological disorders it is
natural for the clinical immunologist to become the main
specialist overseeing the management of their illness.
This is particularly the case when special treatments like
plasma exchange are involved.
A further major attraction of this specialty is that the
clinical immunologist also works within the laboratory.
As the close colleague of the laboratory-based immunol-
ogist, he is involved in the planning and interpretation of
investigations, and seeing patients' problems through
from the bedside to the laboratory bench. This requires
comprehensive experience in the laboratory during train-
ing. Clinical immunology also offers many research
opportunities.
At present, training for this discipline is not easy. Clear
guidelines for the training of the laboratory specialist are
already available, and new guidelines for training the
physician in clinical immunology/allergy are currently
being considered by the JCHMT. Meanwhile, physicians
aspiring to this specialty need as basic training at least two
years in posts approved for general medicine, which
should also provide some experience of immunological
disease. Considerable benefit will be gained from a period
in a research post, when knowledge of basic immunology
can be consolidated and research skills developed. After
this comes the move to higher medical training in an
approved post as a senior registrar, which is a little less
certain at present. Any young doctor embarking on the
early part of training for clinical immunology/allergy will
not prejudice his chances in other specialties in which
immunology is important. By the time such a doctor is
ready for his senior registrar post, the future of clinical
immunology will be clearer and posts for specialist train-
ing will have been established.
Timothy Wallington
Clinical Pharmacology
Clinical pharmacology is one of the more recently recog-
nised sub-specialties in medicine, but has previously
existed in one guise or another (materia medica, thera-
peutics). It differs from the established sub-specialties in
not being 'organ-based', having no clear service commit-
ment to offer and, at present, flourishing largely within
an academic environment. These factors may have ham-
pered its development.
In the 1970s the concept of a consultant in clinical
pharmacology in every District General Hospital was
Popular. However, plans for an expansion of the sub-
specialty were shelved by the subsequent adverse econ-
omic climate. Clinical pharmacologists in training were
rarely considered for appointment to consultant posts, as
they could not offer any special service to a clearly defined
group of patients. The writing was on the wall and many
rapidly re-trained in another sub-specialty. A number
have been appointed as physicians with an interest in
diabetes, cardiology, or geriatrics. Some have found a
niche in acute poisoning. While there has been some
expansion of clinical pharmacology posts in medical
schools, there are a mere handful of posts in the NHS.
The present problem is that many a young doctor finds
the subject appealing and is attracted to the idea of
becoming a consultant clinical pharmacologist. Academic
units need good, enthusiastic, young doctors who will
teach and also perform research. There is no shortage of
excellent applicants for research or lecturer posts in
clinical pharmacology. But after a suitable time in such
posts the goal of becoming a consultant clinical pharma-
cologist has often not been realised. Many have then
entered the pharmaceutical industry ? a decision very
few regret.
In the latest review (1983) of manpower in clinical
pharmacology there were six NHS consultant clinical
pharmacologists and 15 NHS consultant physicians with
an interest in the subject. However, it is difficult to
believe that all the latter were appointed as clinical
pharmacologists. In the medical schools there were 54
honorary consultants, though it was not clear how many
were also practising general medicine. There were eight
senior registrar jobs in the sub-specialty and 32 honorary
posts (lecturers and researchers). While only 10 of these
were in their fourth or fifth year, only four or five
consultants were within five years of retirement. The
equations just do not balance. The College is still lobby-
ing for the expansion of clinical pharmacology in the
NHS. However, despite the acknowledged need for
greater influence by clinical pharmacologists on all as-
pects of drugs and therapeutics, the chances of a rapid
improvement in the situation seem slim.
After training in general medicine at SHO and regis-
trar level, the aspirant should obtain a senior registrar
post in general medicine with clinical pharmacology in a
recognised unit. These days it is probably wise to select a
particular organ or system for intensive study, as this
increases the options when applying for consultant posts.
During the senior registrar appointment a knowledge of
methods of investigation of drug action in man should be
acquired, in addition to pharmacokinetics, clinical trial
methodology, statistics and the clinical management of
acute poisoning. Most are best learned by doing one's
own clinical trial(s) or research project(s). Clinical phar-
macologists must be good communicators, so it is import-
ant to acquire high standards of lecturing ability, research
presentation and scientific writing. An MD or PhD is an
essential qualification which is obtained during the senior
registrar appointment, but the trend is towards complet-
ing the work for these while in a research post at registrar
level. When sufficient publications have appeared you
will be eligible for membership of the clinical section of
the British Pharmacological Society. This provides the
principal forum for presentation of scientific research and
professional advancement of the sub-specialty.
Once trained, the clinical pharmacologist should be a
physician, first and foremost. In addition, he should help
develop rational drug prescribing policies within his
hospital or health authority and be a catalyst for research
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
103
projects and clinical trials. He may take on special
responsibility for certain disorders, e.g. hypertension,
epilepsy or acute poisoning. Some may also provide a
service to other physicians and general practitioners on
difficult therapeutic problems, such as drug adverse
effects, drug interactions, and the rationalisation of com-
plicated regimens. A drug information service is now
increasingly provided by hospital pharmacists.
Despite the poor prospects, there are many avenues for
those who are clinical pharmacologists at heart. Very few
senior registrar posts exist for those who are committed to
clinical pharmacology alone. Many senior registrar posts
in general medicine with another sub-specialty as a
primary interest have a period attached to a clinical
pharmacology unit. This is perhaps the best approach, for
I have serious doubts about the value of an accreditation
certificate in clinical pharmacology alone. Other posts
offer triple accreditation, i.e. general medicine, clinical
pharmacology and one other (cardiology, gastroenterol-
ogy, or endocrinology). From these you may apply for
consultant jobs in the sub-specialty, other than clinical
pharmacology, appropriate to your training. Once ap-
pointed consultant you may then develop your interest in
clinical pharmacology. For those who set their sights on
an academic career, there may be slightly better pros-
pects, but remember that present incumbents of chairs of
clinical pharmacology have a remarkably youthful air.
Clive Roberts
Communicable and Tropical Diseases
The specialty of communicable diseases has reached a
crisis of manpower and status. From a position of pre-
eminence at the start of the twentieth century, when
Britain led the world in the management of the classical
infectious diseases, the specialty has dwindled to 44
consultants in communicable diseases and eight consult-
ants in tropical medicine serving the needs of the entire
country. Training is very similar in both fields and many
jobs overlap, so they are here considered together. Most
of the rural isolation hospitals have been closed and
though the remaining Infectious Diseases Units are desig-
nated as regional units, they rarely function as such. As a
result of this contraction of the specialty, district hospital
accommodation for patients with suspected or confirmed
communicable disease is non-existent, while the majority
of districts do not have direct access to the expertise and
advice of a specialist in communicable diseases. This
parlous state of affairs differs markedly from that in other
western countries, in particular North America and
Scandinavia, where every major hospital has the advan-
tage of a specialist in communicable diseases.
The last decade has revealed new problems of infec-
tion; Legionnaires' disease; Campylobacter gastroenter-
itis; Cryptosporidium enteritis; staphylococcal toxic shock
syndrome; new viruses such as parovirus, and the devas-
tating effects of HTLV-3 infection and acquired immuno-
deficiency syndrome; increasing numbers of imported
tropical infections; multiple resistance of bacteria to
commonly used antibiotics. These new problems indicate
the way contemporary infection cuts across the wide field
of medicine, which makes a career in communicable
diseases attractive.
The form and direction of training in a specialty as
diverse as communicable diseases will inevitably define
the ultimate structure of the specialty. To achieve an
equitable distribution of manpower, training must be co-
ordinated centrally and the existing mechanism of the
Specialist Advisory Committee (SAC) of the JCHMT is
ideally placed to oversee this.
What training options are open to the young doctor
wishing to pursue this career? First, he must have a
soundly based training in general medicine to registrar
level and have attained the MRCP(UK). An approved
senior registrar post, or its academic equivalent, in a
recognised Infectious Diseases Unit or academic depart-
ment is then essential. From such a post, and with
guidance from the SAC, it is important for the trainee to
receive training, either directly or by secondment, at
home or abroad (and here the USA has much to com-
mend it), in one of several sub-specialties such as epide-
miology, clinical immunology and tropical medicine.
Those wishing to specialise in tropical medicine will
spend a substantial part of their higher medical training
in a tropical or sub-tropical country. A period of experi-
ence in medical microbiology as part of an MSc or MD
project is to be encouraged and would allow a valuable
insight into the logistics of laboratory medicine and the
interpretation of the investigations performed there. I do
not suggest that the clinical microbiologist will no longer
have a role in the care of infected patients, but propose to
promote the concept of a team approach to clinical
infection.
Communicable and tropical diseases present a great
challenge. The field is as wide as that of a textbook of
general medicine which continues to have new chapters
added to it annually.
Stuart Glover
Community Medicine
Community medicine is concerned with the promotion of
health and the prevention of disease within whole com-
munities. It includes assessment of the health needs of
communities and the planning, delivery and evaluation of
services.
Community medicine complements clinical medicine,
which concerns the health of individuals, by focusing on
the health of populations. Epidemiology is the science
fundamental to the practice of community medicine, and
the skills which must be acquired are population control
of communicable and non-communicable diseases, stat-
istics, computing, health economics, nutrition, social and
public policy, organisational theory, behavioural science,
health education, communication and management.
Community medicine is a new and developing special-
ty founded in 1974 from the interrelated interests of
public health (Medical Officer of Health departments),
104 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
social medicine (university departments) and medical
administration (hospital boards). Every health authority
has a department of community medicine headed by a
District Medical Officer (or Chief Administrative Medi-
cal Officer in Wales and Scotland). Community phys-
icians also work in Regional Health Authorities, Medical
Research Council units, government health departments,
universities, armed forces, the pharmaceutical industry
and other private sector organisations.
Career prospects are good because of the effect of a
cohort of older doctors and premature retirements follow-
ing reorganisations of the Health Service since 1974. In
1984 there were 542 NHS-equivalent consultant posts
and 223 training posts, making it the tenth largest
specialty in Britain out of a total of 54. Within the general
medical specialties only general medicine (1,141) and
paediatrics (573) had greater numbers of consultants.
The provision of community health services normally
falls within the responsibilities of the District Medical
Officer. These can include physiotherapy, speech ther-
apy, chiropody and dietetics, as well as clinical medical
services such as pre-school and school health, occupation-
al health, and family planning services. Community
health doctors who carry out these clinical duties are
known as Clinical Medical Officers and Senior Clinical
Medical Officers. Their training needs are different to
those of community physicians and the development of an
appropriate career structure has been the subject of much
discussion in recent years.
Training for a career in community medicine has many
similarities to that for other specialties but there are some
important differences. First, because the basic sciences of
the specialty have a small place in undergraduate teach-
ing, it is necessary to provide a special academic input
through whole-time study for one year, or part-time over
a longer period. In England and Wales this is undertaken
either by attending a Master of Science (Community
Medicine) course at the London School of Hygiene and
Tropical Medicine or Manchester University, or a part-
time course organised by two groups of university depart-
ments of community medicine (Northern Consortium or
Midlands and South West Consortium).
Second, service training in community medicine pro-
vides experience in a number of topics which relate to
clinical medicine but do not feature to any great extent in
junior hospital posts or general practice vocational train-
ing. Examples would be epidemiological studies, plan-
ning and evaluation of particular services, infectious
disease control, health education and health promotion.
This affects the timing of the specialist qualification, the
examination for Membership of the Faculty of Com-
munity Medicine. The MFCM Part 1 tests the candi-
date's knowledge and understanding of the basic sciences
and should be completed before entry to higher specialist
training. The MFCM Part 2 tests the candidate's ability
to apply these basic skills to community medicine prob-
lems and is usually completed during the holding of a
senior registrar post.
Third, in community medicine there is a single train-
*ng grade covering both registrar and senior registrar
posts. This means that, once appointed, the doctor would
normally stay with the same health authority for the five
years of training. However, rotations with neighbouring
health authorities and short-term attachments to special-
ist units can be arranged.
Many doctors entering community medicine already
have the MRCP. Although it is not a prerequisite,
appointments committees are likely to look favourably on
those applicants with higher degrees and diplomas.
Training requirements can sometimes be varied. Pre-
vious experience is taken into account and those entering
community medicine after many years of clinical medi-
cine could expect a shorter period of training. For those
already in a career post, a specific training programme
with provision for protection of salary can be arranged.
Those wishing to consider a career in community
medicine are encouraged to obtain a copy of the booklet
Community Medicine; training, examination regulations and
syllabus from the Faculty of Community Medicine, Royal
College of Physicians, and to meet the Faculty Adviser for
their region, whose name can also be obtained from the
Faculty of Community Medicine.
John Catford
Dermatology
The specialty in Britain consists of 220 consultants, six
professors and about 120 trainees ? registrars, senior
registrars and academic equivalents. Currently, every
advertised dermatology registrar post attracts 15-20 well-
qualified applicants, i.e. with at least three years' post-
registration general professional training and MRCP.
Teaching centres typically have two or three consultants,
one or two senior registrars and one registrar; any senior
house officers are usually part of general practice training
or a general medical rotation scheme. There are now
increasing numbers of married women training part-time
in dermatology. In District General Hospitals there is one
consultant per 250,000 population; with rare exceptions,
staff below this level are either general practitioner assis-
tants or rotating general practice or general medicine
trainees. The specialty is expanding by an average of four
new consultant posts a year.
Dermatology has adopted the same basic training as
other medical specialties ? a minimum of three years'
post-registration general medical posts and the MRCP,
before entering dermatology at registrar level. It is rec-
ommended that a total of four years is spent in registrar
and senior registrar posts before applying for accredit-
ation. Further clinical training is likely to be needed
before a consultant post is obtained.
Research in the specialty has made considerable pro-
gress in the last 20 years; much can be undertaken with
very little technological back-up. Disease processes and
their treatment can be followed from beginning to end,
and tissue is easily obtained with little inconvenience to
the patient. In addition, treatments known to be toxic
when administered systemically can often be applied
topically with impunity. Many important biological prin-
ciples in fields such as cell kinetics, immunology and
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
105
mediation of inflammatory reactions have been clarified
by dermatology research workers.
There can be few specialties in medicine with as much
variety in everyday practice as dermatology; in any clinic
one may go from examining warts to investigating and
treating systemic disease to removing a tumour. The
majority of dermatologists still treat all the non-acute
general medical problems diagnosed in their department.
Most topical therapy is now based on antagonising known
pathogenic mechanisms. In practice, much of the work
involves the management of eczemas, psoriasis, leg ulcers
and a wide variety of benign, pre-malignant and malig-
nant diseases.
Dermatology is thus an interesting specialty for those
who are physicians by inclination but who also wish to
continue to exercise their surgical skills.
Rodney Dawber
Endrocrinology and Diabetes
Endocrine disorders are uncommon, so there are few
pure endocrinologists except in large referral centres. The
majority of physicians with this special interest look after
patients with diabetes as well and work in District
General Hospitals as general physicians. A consultant
might expect to spend about 40 per cent of his time on
general (internal) medicine, 40-50 per cent on diabetic
services and 10-20 per cent on endocrine diseases. The
services provided countrywide for endocrinology are at
present about right, and have been complemented by the
establishment of the supraregional assay service (SAS) for
hormone measurements. Services for diabetics, however,
are under-developed and it has been recommended that
for each 100,000 of the population there should be one
consultant physician specialising in diabetes. The British
Diabetic Association is actively pressing for the establish-
ment of new consultant posts, particularly in health
districts with no such specialist. The British Endocrine
Society is the forum for scientific presentations in this
field.
The majority of patients referred for an endocrine
opinion will have thyroid disease (around 80 per cent).
The remaining 20 per cent of patients cover the range of
glandular disorders, but reproductive problems are in-
creasing. Collaboration between physicians and
gynaecologists is growing and it is expected that joint
clinics will be set up in many hospitals. Diabetic services
are no longer limited to the clinic and are expanding to
educate patients more effectively and to help general
practitioners manage diabetic patients in their own prac-
tices. With the knowledge that retinopathy is largely
preventable and treatable has come the need to screen
large numbers of patients and refer them on at an early
stage for ophthalmic assessment. Good liaison with other
specialists is essential for adequate management of other
long-term complications of the disease.
Pure endocrinologists in referral centres usually work
with a senior registrar or registrar, and an SHO; there
are often research staff as well. Close working relation-
ships will be established with general and neurological
surgeons, radiotherapists and paediatricians. Diabetolo-
gists in large hospitals may have a consultant colleague
with the same interests and will probably have similar
staffing to the pure endocrinologist but, in addition, on
account of the larger case-load, there may be one or more
clinical assistants. In District General Hospitals there is
seldom more than one consultant to deal with all endo-
crine and diabetic problems. He will usually work with an
SHO and possibly a registrar and clinical assistant as well
as a diabetes liaison nurse.
By virtue of the fact that so much of the work of a
diabetic clinic is basic general medicine and in such large
amounts, a doctor wishing to specialise in this field
should, more than most, have a good general grounding.
Two to three years in busy general hospital practice is
worthwhile, during which the MRCP would normally be
obtained and the grade of registrar achieved. At this
stage, it is conventional to 'go into research,' usually for
two years, and do the groundwork for an MD thesis. This
is 'expected' and as a result it would now be a brave
aspirant who decided not to follow the path. There is no
doubt that endocrinology and diabetes mellitus lend
themselves to research nor that a spell in a laboratory
teaches a realistic approach to the limitations of hormonal
and other assays.
The first real hurdle comes in looking for a senior
registrar post. There are at least four times as many
hopefuls as jobs available at this level. Once into a senior
registrarship, consultancy is usually achieved, although it
may take a further six or more years and several applica-
tions to achieve the goal.
To specialise in endocrinology and diabetes is enjoy-
able. There is the pleasure of looking after large numbers
of different clinical problems. This is why the specialty is
likely to remain popular, creating bottlenecks both at
senior registrar and to a lesser extent at consultant level.
The latter may be eased if new posts in diabetes are
created, but the former seems certain to continue.
Peter Daggett
Gastroenterology
The majority of gastroenterologists in the UK are ap-
pointed as consultant physicians with an interest in the
specialty; a major commitment to general medicine and
involvement in general medical on-take rotas are usually
expected. Nevertheless, the growing demand for special-
ist opinions and diagnostic and therapeutic endoscopies
means that most physician/gastroenterologists spend an
increasing proportion of their time with gastrointestinal
problems. Already there are specialist centres for hepatol-
ogy and gastrointestinal physiology, and the physician
wholly committed to gastroenterology may become more
common. While it is suggested that there should be a
gastroent,erologist for every 150,000 population, that is
unlikely to become a national reality. Private practice is
likely to flourish, particularly since there is payment for
procedures as well as consultations.
106 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
A newly appointed gastroenterologist should be profi-
cient at endoscopy and its therapeutic aspects, including
colonoscopic polypectomy and probably endoscopic
sphincterotomy. He will probably supervise enteral and
parenteral feeding and will be able to manage acute and
chronic liver disease, including bleeding oesophageal
varices. Local circumstances govern the division of work-
load between physicians and surgeons but close collabora-
tion is important, particularly in gastrointestinal bleeding
and inflammatory bowel disease.
Junior staff support for gastroenterologists is similar to
that for other physicians, although contraction of the
registrar grade (to improve overall career prospects)
would change this. Where funding can be obtained, GP
clinical assistants may help with the potentially huge
diagnostic endoscopy workload.
The trainee gastroenterologist will spend about two
years as an SHO in specialties which need not include
i* > gastroenterology. Part 1 and if possible Part 2 MRCP
should be obtained. A registrar post with an interest in
gastroenterology is then appropriate and a rotation with
one year in a District General Hospital and one year in a
teaching centre is ideal. Next, about two years should be
spent in a research unit working towards an MD or PhD
thesis; a number of papers should be published and
attempts made to remain clinically involved while re-
membering that the prime purpose of this period is
research rather than further practical experience. Despite
a completed thesis, attainment of a senior registrar or
lecturer post remains the major obstacle since there are
about four times as many suitably qualified candidates as
there are SR posts available. The unsuccessful have the
opportunity of transferring to radiology or geriatric medi-
cine but these opportunities are unlikely to last indefinite-
Jy-
The SR normally spends one or two years at a district
hospital and two or more years in a teaching hospital
gastroenterology unit. Even then there is no certainty of a
consultant post because many appointments are recent
and there will be few retirement vacancies for some years.
The current expansion rate of the consultant grade will
not absorb the large number of well-trained SRs looking
for consultancies; only a significant expansion at consult-
ant level will lead to an improvement in career prospects.
Alastair Forbes and Anthony Mee
General (Internal) Medicine
General medicine is rarely practised in isolation but
almost always in association with another medical inter-
est. However, training for the general component of most
physicians' work should be carefully planned. Many
specialists are required to take part in on-take rotas and to
deal with out-patient referrals of a mixed nature. To be
an effective consultant receiving emergency cases wide
experience must have been obtained during training
years. Indeed, appointment as a consultant may depend
% on a candidate's ability to demonstrate convincingly his
capability in this situation. It is, therefore, advisable
during the course of one's training to get experience in
many different specialties. Two to three years should be
spent at SHO level in different posts, which is most easily
organised in an established rotation. MRCP should be
taken during this time. At registrar level it is advanta-
geous to rotate between different specialties and between
district and teaching hospitals. Many established ro-
tations exist.
It is very unusual to find a senior registrar post in
general medicine alone; most combine a specialty with
general medicine or include a rotation of specialty experi-
ence in a teaching hospital and general medicine with or
without specialty experience in a district hospital. During
one's time as a registrar it is necessary to decide on a
specialty interest even if the general aspect of a phys-
ician's work is the part one finds most attractive. Experi-
ence in research is essential for a career in general
medicine. It can be gained during the course of a senior
registrar appointment, but the field is now so competitive
that it is advisable to obtain some research experience in
one's chosen specialty between registrar and senior regis-
trar posts.
The career ladder of general medicine is by no means
guaranteed. There is a shortage of 'good' medical SHO
posts and rotations since they are also in demand fcom
prospective GPs, radiologists, haematologists, etc. At
SHO level it is easy to branch out to other fields of
medicine, but at registrar level, especially after a period
of research, it is more difficult to do so. It is therefore
important to take advice about the likelihood of one's
ascending the ladder before becoming a registrar. Having
passed the MRCP it is relatively easy to get a registrar
post but there are far too many registrars for the number
of senior registrar posts and in turn too many senior
registrars for the number of likely consultant posts avail-
able in the next few years. The recommended duration of
senior registrarships is four years but most will spend
much longer in these posts. Although there is no security
of tenure, it is rare for contracts not to be renewed as long
as efforts to secure a consultancy are being made.
The future of the concept of general medicine is
uncertain. On the one hand, most acknowledge that the
practice of modern medicine requires that patients be
seen by the appropriate expert. On the other, many
specialist groups are advising their trainees to ensure that
they are accreditable in general medicine to improve their
chances of obtaining a consultant post.
Edwina Brown
Genito-Urinary Medicine
This specialty in the UK is long established, well organ-
ised and respected worldwide. Departments of genito-
urinary medicine see 600,000 new patients annually, a
threefold rise in 15 years. There are about 230 clinics,
most of which are in the precincts of district general or
teaching hospitals. There are about 110 consultants in the
specialty and they are supported by clinical assistants,
doctors in the training grades, nursing staff and health
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
107
advisers-contact tracers. GU medicine is a growth spe-
cialty and the current prospects for doctors who have
trained appropriately are excellent.
Patients present with a wide variety of clinical con-
ditions and also personal, social and psychiatric prob-
lems. However, the majority of conditions are curable, an
unusual situation relative to other medical specialties,
resulting in a high degree of job satisfaction. GU medi-
cine is largely an out-patient specialty but most depart-
ments have access to in-patient facilities, as well as close
links with many other hospital departments. Most
patients attend direct without first seeking advice from
their own doctor. The spectrum of diseases spread by
sexual activity has continued to increase, with hepatitis
and more recently AIDS providing new epidemiological
problems and interest.
Although the concept of consultant physicians with an
interest in GU disease has been discussed, such a concept
would not seem to be feasible, so the doctor going into
GU medicine must be prepared to leave behind the
excitement of acute medicine and ward work. In addition
to normal teaching duties doctors in this specialty have a
resonsibility for health education of young people, and
requests for help in this respect from various organisa-
tions are increasing.
To enter the specialty a higher diploma is necessary ?
preferably the MRCP but many doctors holding the
MRCOG are attracted to the specialty and are eligible.
Those with the MRCP must have had experience in
gynaecology and those with the MRCOG in general
medicine. During the four years of higher medical train-
ing, experience of dermatology and microbiology are
desirable. The large numbers of patients attending clinics
and the close links with microbiological departments
provide excellent scope for clinical, epidemiological and
microbiological research.
Annual courses in sexually transmitted diseases are
held in London and Liverpool. The Medical Society for
the Study of Venereal Disease meets six times a year
when lectures and original scientific papers are presented.
The society publishes its own journal ? Genitourinary
Medicine, formerly The British Journal of Venereal Diseases.
The good prospects and the different but satisfying
work pattern have attracted many well-qualified doctors
to full- or part-time consultancies in the specialty. Few
regret their choice of career.
Ian Weller
Geriatric Medicine
Geriatric medicine originated from a handful of British
pioneers, dealing mainly with the chronic sick and dis-
abled, at the inception of the NHS. The specialty grew
under the influence of demographic and social changes so
that during the 1970s the number of consultants in
geriatric medicine rose by 50 per cent and there are now
some 500 consultants in the UK, many of whom are
overseas graduates. During recent years there has been a
shift in emphasis towards more acute care; the majority of
consultant posts are still wholly in geriatric medicine, but
>
about a quarter are now combined posts as a general
physician with special responsibility for the elderly. Re-
search and teaching in geriatric medicine have been
encouraged by the establishment of academic depart-
ments in many British medical schools, and there are
currently 14 university chairs in the subject.
In addition to providing general medical care to ill
elderly patients, the geriatrician supervises rehabilitation
and long-stay services for the elderly. Geriatrics remains i
a very wide field of 'general medicine,' with considerable
scope for planning, administrative expertise and liaison
with other disciplines both inside and outside the NHS.
Most geriatricians are responsible for more beds than
their colleagues in other specialties, and often work with
relatively few junior staff. In some services the geriatric
department is run separately from general medicine,
while in others the two are integrated. In either case, good
relationships with other specialties and a satisfactory
division of responsibility for the elderly are essential; this
applies to orthopaedic surgery as well as medicine, and is
particularly important with regard to psychiatric illness in
the elderly, since many health districts have no formal
psychogeriatric service.
The first step towards a career in geriatric medicine is
wide experience in general medicine, including some sub-
specialties (e.g. neurology, cardiology, rheumatology and
rehabilitation). Time spent in fields such as general
practice or psychiatry will not be wasted, and it is wise to
have had some experience in a substantive geriatric post
before committing oneself to a senior registrar appoint-
ment. At that stage, a decision must be made whether to
aim for dual accreditation with general (internal) medi-
cine or in geriatric medicine only: at present, prospects
for either career post are excellent. Clinical experience
and a commitment to care of the elderly outweigh
research experience, higher degrees or publications, at
least for the time being. However, recruitment to the
specialty is improving and there is a trend for well-
qualified physicians to switch to geriatric medicine when
their paths are blocked during training for other special-
ties. Thus it may be advisable to be able to offer either
additional general medical expertise (in the form of dual
accreditation) or additional geriatric expertise (in the
form of a special interest backed up by research) as the
specialty of geriatric medicine becomes more competitive.
The proportion of frail elderly in the population con-
tinues to rise, with serious implications for health services
in general. Geriatric medicine offers a broad based, much
needed and satisfying career, the patlcin of practice
varying greatly from place to place. It is vital to watch
developments in these evolving patterns and to adopt a
flexible strategy during training.
Roger Briggs i
Haematology
Recent advances in the diagnosis and management of
haematological diseases have improved the attraction of a
career in haematology and encouraged stiff competition.
108 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
Opportunities are perhaps better than in other medical
specialties, as haematology is an expanding field. Some
pathology jobs may be re-allocated to haematology and
future expansion of the consultant grade by 10 per cent
per year in the next five years is expected.
;? . District General Hospitals provide 70 per cent of
consultant posts in haematology. These are often single-
handed, and the consultant is expected to be able to
perform and supervise laboratory work, to provide a
service for the rest of the hospital, to have clinical
commitment to out-patients and, in most cases, a small
number of in-patients. There is sub-specialisation in the
regional centres, e.g. haematological oncology, coagu-
lation. In formulating an adequate training programme,
it is important to realise that it is necessary to be
competent clinically-and in the laboratory.
At present, before obtaining a senior registrar job, and
increasingly often a registrar post, the candidate is ex-
_ pected to have the MRCP in addition to general pro-
fessional training. It is desirable, but not essential, to gain
some laboratory experience during this period. MRCP
gives exemption from MRCPath Part 1. To enrol for
MRCPath Part 2, three years of approved higher medical
training are required before the written examination and
five years before the practical. It is also necessary to have
research experience, and even a further degree, e.g. MD
or PhD. General physicians with an interest in haemato-
logy are a dying breed, and MRCPath Part 2 is essential
for a consultant haematologist post.
Some experience of paediatric haematology should be
incorporated in the senior registrar training scheme,
though to sub-specialise in this branch requires general
paediatric training. There are few posts for paediatric
haematologists, and expansion is unlikely.
Consultant posts in blood transfusion are becoming
more popular and require at least two years' experience
in an approved blood transfusion centre and two years of
general haematology experience.
Opportunities for part-time training in haematology do
exist, and, depending on the co-operation of the depart-
ment, may be easier to arrange than in other medical
specialties. However, there are likely to be few part-time
consultant posts available, and there is still a reluctance to
accept part-time training as equivalent to full-time.
Sound advice is to delay part-time training for as long as
possible.
As in other branches of medicine, personality is an
important facet. Haematologists have responsibility to
their laboratory staff and other consultant medical staff as
well as their patients. It is worthwhile gaining some
insight into the managerial role and committee work of
consultants during training.
Angela Robinson
Intensive Care
This is an emerging specialty with few consultant posts
devoted purely to intensive care. However, it is generally
agreed that it is desirable to have physicians experienced
in managing patients with multi-system organ failure.
Most hospitals now have an intensive care (or intensive
therapy) unit. They are usually run by anaesthetists with
nominal cover provided by a physician with an interest in
cardiology or nephrology. In certain units, the physicians
may carry the executive responsibility.
Intensive care of patients requires facilities for mechan-
ical ventilation, acute peritoneal or haemodialysis, hae-
mofiltration, temporary cardiac pacing and invasive
haemodynamic monitoring, apart from continuous moni-
toring of the ECG, EEG or intracranial pressure and total
parenteral nutrition. If an 'intensivist' is to make a real
contribution to patient care he must have received train-
ing in these techniques. The institution and management
of such therapy require a firm grounding in clinical
medicine with a special emphasis on cardiovascular and
renal physiology and pathology.
By its very nature intensive care medicine is a costly
specialty both in terms of staff and equipment (thus often
described as 'expensive care'). The type of patient re-
ferred often depends on the facilities provided by other
specialties in a particular hospital. Although intensive
care medicine can be very satisfying when a moribund
patient is restored to health, the mortality for many
conditions requiring such care remains very high. The
'intensivist' must therefore come to accept that a high
proportion of his patients will not survive.
A recent survey by the College of 168 intensive care
units found anaesthetists in administrative charge, while
patient care remained with the admitting team or was
shared with an anaesthetist in nine out of ten admissions.
Only 14 of 1,031 consultant physicians specified intensive
care as a primary or secondary interest, and for only five
of these was it documented in their contract.
At the present time there is no clear training structure
for this specialty in Britain and the College has not
published guidelines regarding accreditation. The present
view of the Intercollegiate Committee on Intensive Care
is that the influence of physicians should increase in
intensive care units. This committee has suggested that
senior registrars already accredited in internal medicine
and another specialty may wish to gain additional ac-
creditation in intensive care. However, there are as yet no
posts designated or approved for such training.
For those determined to pursue a career in intensive
care medicine, a period in anaesthetics is a must and so
probably is a spell abroad (USA or Scandinavia) where
the specialty is well established.
Dennis Edwards
Medical Oncology
Cancer medicine is an evolving specialty. In the last two
decades, the range and application of cytotoxic drugs has
increased considerably, as has the need for special exper-
tise in their use; in addition to assessment of their efficacy
in particular tumours, there are the problems of the
management of adverse effects and support of the whole
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
109
patient with cancer. Physicians have become increasingly
involved in aspects of the management of malignant
disease other than its medical complications. A sound
understanding of the work of related specialties such as
surgery, radiotherapy and histopathology is essential.
There are at present fewer than 50 consultants in the
specialty, and only 14 are funded by the NHS. Though
most are full-time medical oncologists working in a major
centre, the proportion of physicians with an interest in
medical oncology is increasing from the present level of
about 30 per cent. The need for more consultant posts is
clearly recognised, but overall growth of the specialty has
been slow, with only three new consultant posts a year.
There is an Association of Cancer Physicians, and a
committee advises the College.
A cancer physician typically spends most of his time
treating patients with chemosensitive tumours such as
lymphoma, breast, testis, ovary and small cell carcinoma
of the bronchus. In addition there are a few rarer tumours
in which chemotherapy is important, and a medical
oncologist may also have an interest in a tumour for
which chemotherapy is being developed. Oncologists
increasingly work as part of a team, and multidisciplinary
clinics (with surgeons, haematologists, or chest phys-
icians) may form an important part of this work. Thus an
attraction of the specialty is that it cuts across traditional
specialty boundaries. Some oncologists have developed a
particular interest in cell or molecular biology, or clinical
pharmacology, while others have concentrated on organ-
ising local or multicentre trials. A strong research back-
ground is advisable in view of the rapid pace of change in
this field.
In a teaching hospital, the medical oncologist is usually
part of an academic department. In a District General
Hospital, the oncologist may be part of the division of
medicine or work with radiotherapists in a department of
clinical oncology. The supporting junior staff may be on a
medical or surgical rotation, trainees in radiotherapy, or
clinical research fellows. Entry to the specialty is advised
only after solid general medical experience at SHO and
registrar level. This should be followed by a registrar post
with some experience in oncology and then a period of
research. An MD or PhD is essential. Time spent in a
related discipline such as pathology, haematology or
endocrinology can often be valuable, and the accredit-
ation requirements are flexible to allow for this, but the
crucial training is that in general medicine. If possible,
accreditation should be sought in both general medicine
and medical oncology, and most of the 20 or so SR posts
are in regional or teaching centres. Paediatric oncology is
an even smaller specialty, and trainees would normally
progress through major academic centres.
Medical oncology is a small but exciting new specialty.
There is strong competition for consultant posts because
of the large number of candidates of high calibre and the
small number of new jobs or vacancies. For those who do
not find a suitable niche in oncology, the drug industry or
another medical specialty are possibilities. The less aca-
demically inclined may find a switch to radiotherapy after
MRCP increases their opportunities for obtaining posts
which may arise over the next five years or so, but the
changing nature of clinical practice in oncology must lead
to new posts in cancer medicine in the near future.
Cancer now affects one in four of the population, and i
physicians need to play a much greater role in its
management.
John Green
Neurology and Clinical Neurophysiology
Neurology is a small specialty with a long and prestigious
history, and has always been highly popular and competi-
tive. The training structure and prospects have remained
fairly stable and predictable, and it has been spared the
severe manpower problems of many specialties. There
are approximately 150 consultant neurologists, with no
immediate likelihood of expansion; choice of jobs is, at all
stages, necessarily very limited. There remains a handful
of 'physicians with an interest,' but they are a dying
breed; all new consultant appointments are of full-time
clinical neurologists. In addition, there are a small num-
ber of pure clinical neurophysiologists, mainly based at
large centres, but in many hospitals neurophysiology still
falls within the responsibility of the neurologist.
Neurology appeals to people who particularly enjoy
'bedside' diagnostic medicine and a large amount of
patient contact; basic clinical skills remain of paramount
importance. Neurology is mostly out-patient work, and
the majority of patients are managed without recourse to
specialised investigations. However, there have been
enormous technological advances in the last decade and
neurologists now need to be conversant with a wide range
of investigative techniques. With the growing need for
expensive hardware there is an increasing tendency for
neurologists to be based at a regional centre, usually
attached to a teaching hospital. This will house neuro-
radiology, neurophysiology, neuropathology, and neuro-
psychology, together with in-patient facilities for
neurology and neurosurgery. Liaison with ophthalmol-
ogy, ENT and, of course, general medicine is close. As
well as having sessions at the centre the neurologist will
usually visit one or two regional hospitals each week to see
out-patients and ward referrals. Junior staff in training
are largely based at such centres, where a group of four to
six consultants might have, for instance, one senior
registrar, two registrars and two SHOs. Pre-registration
posts are unusual in neurology. In some areas facilities
are not centralised and a single neurologist may be based
at one large hospital and have some specialist facilities
elsewhere. The vast majority of neurologists do not sub-
specialise although, as neurology encompasses such a
wide spectrum of disease and with the growing appli-
cation of basic medical science, there is ample scope for
special interests.
General professional training may include one year in
clinical neurology, neurosurgery, psychiatry, or research
in related., basic science subjects. Higher professional
training is spent in an approved neurological centre with
an additional recommended year in psychiatry, neurosur-
gery, applied neurophysiology or basic neurological sci-
110 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
ence. The usual course is to spend three to five years as a
medical SHO and registrar while obtaining the MRCP,
then, as an entree into a specialist centre, many aspiring
neurologists become an SHO before going on to be a
neurology registrar, the latter for approximately two
years. Competition is fierce throughout, and particularly
for senior registrar posts. However, the number of senior
registrar and consultant posts is fairly well matched, so
that obtaining a senior registrar appointment almost
guarantees a consultant post elsewhere within four years.
In order to get a senior registrar post it is almost essential
'l to have an MD (or equivalent thesis degree), and this
means at least two years of full-time research, usually
after a neurology registrar appointment. Thus, it is
extremely unusual to become a consultant neurologist in
less than 10-12 years after registration. The importance
of keeping early career options open by making the
general professional phase of training as broad-based as
* - possible cannot be over-emphasised. Alternative career
avenues beyond the stage of neurology registrar are very
limited.
Clinical neurophysiology is a smaller but expanding
specialty with a shortage of adequately trained applicants
to fill senior registrar and consultant posts. The develop-
ment and clinical application of such techniques as
evoked potential studies, ambulatory EEG and specia-
lised muscle recording methods are resulting in expansion
of the number of consultant posts. Newly appointed
consultants have a varied training which usually includes
periods in general medicine, clinical neurology, and as a
senior registrar in clinical neurophysiology; they usually
possess the MRCP and a higher research degree, e.g.
MD in a basic science. Senior registrar posts are limited
to large regional neurology units.
John Hodges
Nuclear Medicine
Nuclear medicine is almost totally a diagnostic specialty
and attracts doctors with a scientific outlook and an
interest in the pathophysiology of disease. The doctor
" 4 whose natural bent is towards the continuing care of the
patient and the development of good doctor-patient rela-
tionships would probably be unfulfilled by a career in
i nuclear medicine.
However, a number of posts exist in which the consult-
ant is for part of his time a clinician with full clinical
responsibility for patients, and for the rest has oversight
of a nuclear medicine diagnostic service. Thus it is
possible to be a physician with a 'special interest' in
nuclear medicine. Because a large proportion of the
results of nuclear medicine investigations are presented as
images, there is a similarity to diagnostic radiology and in
many hospitals a radiologist provides the nuclear medi-
cine diagnostic service. So in parallel with physicians with
a 'special interest' in nuclear medicine there is a growing
number of radiologists with a similar 'special interest.'
? This is an exciting branch of medicine for the doctor
who wishes to be involved in new developments and to
interact closely with clinical specialties. Nuclear medicine
uses as its essential 'tool' pharmaceuticals labelled with
radioactive atoms, and the development of these 'radio-
pharmaceuticals' is a major activity both of the pharma-
ceutical industry and of research organisations. So the
range of applications of nuclear medicine continues to
expand.
A physician wishing to become a consultant in nuclear
medicine will require some special training in basic
sciences in addition to the usual programme for accredit-
ation. This practical and theoretical training in basic
physics, instrumentation, radiochemistry, radiophar-
macy, and radiation dosimetry and protection may be
obtained by attending a block or day-release course or by
obtaining an MSc (Nuclear Medicine).
Unfortunately, it is difficult to assess job prospects. A
handful of new consultant jobs has been established in the
last four years so that there are now about 27 consultant
and five senior registrar posts in nuclear medicine. The
apparently favourable consultant to SR ratio has to be
interpreted with care, as the majority of nuclear medicine
consultants are relatively young, so further expansion of
the specialty remains speculative.
One of the demanding aspects of the subject is its
diversity. The nuclear medicine consultant has to keep up
to date with a much wider field of medicine than do many
of his clinical colleagues. His advice may be sought on a
complex renal problem, then on a cardiological, an
oncological, or an endocrine problem, all in the space of a
few hours.
A nuclear medicine consultant may wish to concentrate
on particular areas. For example, he may carry out
research on bone diseases and the use of radioactive
tracers in their diagnosis and follow-up; another may be
attracted to cardiological work, and so on. He will,
however, remain responsible for providing the general
diagnostic service for which he was employed.
Edward Williams
Occupational Medicine
Occupational medicine is a new and expanding specialty
which is concerned with the effect of work on health and
health on work, and has a major preventive as well as
treatment role. There is now extensive legislation relating
to health and safety at work and this has encouraged the
wider provision of occupational health and safety ser-
vices.
Professional representation is through the Society of
Occupational Medicine which currently has more than
1,700 members, of whom about 900 work full-time. The
Faculty of Occupational Medicine was established in
1978 and now has 1,400 Fellows, Members and Associ-
ates. The age distribution within the Faculty is heavily
skewed towards the 55-65 year old range, so there will be
many job opportunities in the next 15 years.
The primary role is to advise management, trade
unions and workers on all health matters, with the aim of
preventing ill-health and promoting good health. It is a
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
111
clinical and preventive discipline which requires a de-
tailed knowledge of occupational diseases and expertise in
health assessment, rehabilitation and resettlement, occu-
pational toxicology, environmental assessment and con-
trol, the application of epidemiological and statistical
techniques, and much enthusiasm. As industries evolve,
new processes may create new hazards, and perhaps new
occupational diseases, so there is always a challenge.
The problems of different industries ? e.g. aviation,
chemical, mining, steel, National Health Service, retail
? lead to much sub-specialisation. As well as the experi-
ence described, the occupational physician also needs to
acquire administrative and communication skills, as one
day he or she may have to justify the departmental budget
to the tough financial scrutiny of industrial line manage-
ment, and on another speak at a mass meeting of workers
concerned about an unfamiliar hazard and then justify
the recommendations made. The specialty is unusual in
that most posts are outside the NHS, though more are
now being created in it.
Facilities vary, depending on the nature of the indus-
try, but normally include provision for the treatment of
illness and injury at work, for critical health evaluation
and often physiotherapy or rehabilitation services.
A trained occupational physician will be experienced in
industrial chest radiology, pulmonary function assess-
ment, audiometry, toxicology, skin and allergy testing,
and many will develop other skills.
While large industries frequently have well-established
occupational health services, the majority of physicians
may work alone or with perhaps one colleague and a team
of occupational health nurses and part-time GPs. The
effective provision of occupational health care involves
teamwork with other related disciplines such as occupa-
tional hygienists, nurses and safety practitioners. Epide-
miology and research are fundamental to the role:
identification of an occupationally-related health hazard
often involves assessment of the health of the group as
well as of the individual.
Entry to the specialty is normally after the completion
of general professional training, and the MRCP(UK),
though desirable, is not mandatory; currently 60 training
posts are approved. Attendance at an academic course is
possible on a full-time, day or block release, or distance-
learning basis, and while not essential, is strongly rec-
ommended. Most employers are willing to fund training.
Associateship of the Faculty is gained by examination,
and Membership is awarded after satisfactory completion
of training. Once trained, the occupational physician has
many career options, and considerable mobility is poss-
ible at senior levels.
Ewan MacDonald
Paediatrics
Paediatricians are now the second largest group of phys-
icians (after general physicians) who enter higher pro-
fessional training via the MRCP; they are represented
professionally by the British Paediatric Association as well
as by the College. It is a relatively young and growing
specialty with an interest in the care of children both
inside and outside hospitals. A recent recommendation
that Senior Clinical Medical Officers in Child Health
should, in due course, be replaced by consultant paedi-
atricians in community child health will result in a further
major increase in the size of the specialty. As in most
specialties, job prospects are hard to predict, but, at
present, the number of senior registrars is about right or
even low, allowing for the new community posts, the
main hurdle being from registrar to senior registrar
appointment.
Most paediatricians in the country remain generalists,
working in acute medicine with in-patients (95 per cent
emergency admissions), out-patients, in the maternity
unit with the newborn and often also in the community.
Until recently many were single-handed in a district, but
this is now rare and in an increasing number of districts
paediatricians are developing a sub-specialty. A few,
mostly in teaching centres, are full-time sub-specialists in
neonatology, cardiology, oncology, neurology and handi-
cap, nephrology, endocrinology, gastroenterology and
respiratory medicine. Most job descriptions require can-
didates to have had recent experience in working with the
newborn, and this is now the most common sub-specialty
(perhaps soon to be overtaken by community child
health). Compared to departments of adult medicine,
most units are very informal, with no bed allocation,
shared wards and junior staff, absence of white coats and
often considerable camaraderie. Paediatricians are at
present the busiest consultants, in terms of hours of work
and call-out rates, but the rewards in terms of benefit to
patients are considerable. Ability to work with parents
and an understanding of psychology are skills that differ
from those required in general medicine and bring their
own rewards.
Junior staff at SHO level (there are almost no house
physician posts) are on the whole good, being recruited
both from career paediatricians and general practitioner
training schemes, though again the posts are busy and
sometimes stressful. A large number of medical, nursing
and ancillary staff work directly with paediatricians,
including community doctors, paediatric nurses, special
care nurses, physiotherapists, occupational therapists,
speech therapists, psychologists, social workers, teachers
and nursery nurses, so that skills in teamwork and
leadership are important. Training requirements are
clearly laid down, but are fairly flexible in practice. Time
spent in full-time research is undoubtedly valuable, often
providing training in a sub-specialty as well as in re-
search, and will be valued at appointments committees at
senior registrar and consultant level. Higher degrees are
not essential and the Diploma in Child Health is not
necessary for a career in paediatrics. Time spent in
general practice or abroad is valuable, as is a period in
related specialties such as general medicine, obstetrics or
community medicine.
At the final hurdle of a consultant appointments com-
mittee the professional members of the committee will be
at least as interested in the human skills of personal
112 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
relationships with parents and colleagues demonstrated
by the candidate, as in his academic prowess.
Peter Todd and John Tripp
Rehabilitation Medicine
The lack of specialist care for young disabled people is a
notable defect of today's Health Service. In 1972 the
Tonbridge Reportfi] recommended that there should be
a consultant in rehabilitation in every district and, al-
though this is unlikely to become a reality in the near
future, there is a growing appreciation of the need for
specialists in this field and this is slowly being reflected in
advertisements for consultant posts. It is not envisaged
that more than a small minority will practise exclusively
in rehabilitation medicine (RM). Nine out of ten will
have another discipline which may be anything from
orthopaedic surgery to neurology.
There are at present only 18 senior registrar posts
approved for training in RM and the majority are linked
to rheumatology (14 of 18). Approval may be given for
individual posts, however, and it should be possible to
acquire the relevant experience and training at any
Demonstration Centres in Rehabilitation. In view of the
predominance of neurological disease among the severely
handicapped, some experience in this field will be par-
ticularly relevant and may in due course become a
requirement.
There can be few areas of medicine in which there is
such scope for research projects of direct and practical
relevance to patient care. The full potential of new
materials and technology has yet to be realised in the
treatment of disabled people and there are many estab-
lished rehabilitation techniques which would benefit from
rigorous scientific evaluation. The Society for Research
in Rehabilitation holds regular meetings at which such
work can be presented, and the recently formed Medical
Disability Society holds scientific meetings as well as
representing the political interests of those training and
practising in this field.
The consultant practising in RM will have to work
closely with colleagues of all disciplines as well as with the
many other professionals in the health and social services.
Useful qualities to possess would be tact, unlimited
patience and political and managerial skills. The constant
fight for extra resources and facilities for disabled people
is a time-consuming but important part of the job.
Reference
1. Sub-committee of the Standing Medical Advisory Committee (1972)
Rehabilitation. London: HMSO.
Thomas Price
Renal Medicine
Renal medicine is a relatively new specialty, so there will
be virtually no retirements in the near future. It is,
however, still an expanding specialty and many regions
have plans to increase their dialysis facilities. At present,
there appear to be 3-5 new renal medicine consultant
posts a year. There has also been a similar number of new
consultant general physician posts with an interest in
renal medicine at district hospitals with no renal unit.
General medicine is an integral part of renal medicine
because renal problems occur in so many situations and
dialysis and transplant patients have general medical
problems. It is therefore essential to get general medical
experience at SHO level; experience in intensive care at
this stage would also be useful. One's first exposure to
renal medicine usually occurs at SHO level. At registrar
level it is advisable to do a rotation with some general
medicine as well as renal medicine. The other option is to
do a general medical registrar rotation followed by re-
search experience in renal medicine. In either circum-
stance it is advisable to obtain research experience at this
stage, since senior registrar posts are very competitive. It
is very important to look carefully at senior registrar posts
because many are in specialist renal units that give no
general medicine experience.
The main specialist skills obtained during training are
the care of dialysis and transplant patients, the ability to
insert acute dialysis catheters, do renal biopsies and
understand fluid and electrolyte problems. Many aspects
of renal medicine, such as transplantation and the under-
standing of glomerulonephritis, need an understanding of
immunology.
Much of nephrological practice occurs acutely, and
junior staff usually find themselves busier than their
colleagues in other specialties. The acute care of dialysis
patients is also largely done by junior doctors with the
result that there is a disproportionately large number of
SHOs for the size of the specialty. There is a lot of scope
for clinical research so it is important not to be diverted
into a 'dead-end' research post, since they are more
plentiful than senior registrar posts. As pointed out
earlier, however, renal medicine is an expanding special-
ty so the career prospects are slightly better than in some
other specialties.
Edwina Brown
Respiratory Medicine
Respiratory medicine has recently changed radically in
terms of work patterns and staffing, so that now it
represents a most satisfying field of practice both for the
general physician with an interest in the specialty at the
District General Hospital and for the thoracic specialist at
a referral centre.
Most of the consultant posts are of the 'general phys-
ician with an interest in respiratory medicine' type based
at District General Hospitals. Of the 339 consultants now
in post 20 per cent are 'pure' chest physicians and tend to
work in the teaching hospitals. The Royal College of
Physicians and the British Thoracic Society recommend
that there should be one consultant with a substantial
commitment to respiratory medicine per 150,000 popu-
lation, and at least one in each DGH[1],
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
113
Thoracic medicine offers a wide spectrum of disease.
The physician has to be proficient not only in the
assessment and management of acute emergencies, in-
cluding patients in intensive therapy units, but also in the
support and management of patients with chronic or
terminal disease. Currently, less than 5 per cent of beds
are occupied by tuberculous patients and the majority of
the in-patients have obstructive air flow disease, allergic
disorders, chest pains, neoplasia, pleural disease, acute
infections, and the respiratory presentations of systemic
disease.
Although smoking-associated diseases will continue to
dominate the workload into the 21st century, it is likely
that the presentation and management of disease will be
substantially altered by improved knowledge of genetic
and other factors causing susceptibility, and because of
new imaging techniques. A large number of patients are
certain to benefit from the present explosion of knowledge
about the biochemistry and tissue physiology of asthma,
and many young patients with rarer diseases may benefit
from heart/lung transplantation.
Because of the intense competition for senior registrar
posts, the intending thoracic physician would, after ob-
taining the Membership, be well advised to obtain experi-
ence as a registrar both in general and respiratory
medicine before proceeding, most probably, to a research
post leading to a higher degree. At the senior registrar
level he/she would spend two years in general medicine
and two years in respiratory medicine to complete train-
ing and obtain dual accreditation. An approved training
post would offer experience among other things in chest
radiology, including scanning and brochography, fi-
breoptic brochoscopy including lung biopsy, respiratory
intensive care, respiratory physiology and training in
the immunological and allergic aspects of respiratory
disease.
What are the job prospects in respiratory medicine
really like? The most reliable figures are those obtained in
1984 by the British Thoracic Society[2]; for England and
Wales there were 403 consultant posts in 1979, and 64 less
(339) in 1984. There will probably be 11-14 retirements a
year up to 1988, and about 10 a year thereafter. This
number would require about 40 senior registrars to fill 10
jobs a year. In 1970 there were 52 senior registrars
(including honorary posts), and in 1984 there were 86.
Hence in five years' time there may potentially be about
40 time-expired senior registrars. Figures for the current
number of research registrars and their prospects of
obtaining a senior registrar post are published[3]. They
show that about 70 research registrars may be competing
for up to 14 senior registrar posts a year. Clearly, many of
these doctors may have to re-train in a different field
unless there is a substantial expansion of consultant posts
in this specialty, and no reduction in senior registrar
appointments.
In summary, current job prospects in respiratory medi-
cine are rapidly approaching those of the other major
specialties in adult medicine, such as gastroenterology
ind cardiology. The intending thoracic physician should
ilways bear these figures in mind when considering his
;areer choice.
References
1. British Journal of Diseases of the Chest (1984) 78, 303.
2. Citron, K. M., Byfield, S. P., Darbyshire, J. H. and Nunn, A.J.
(1984) Communication at the British Thoracic Society summer
meeting in Brighton, July.
3. Moore-Gillon, J., Peacock, A., Johnstone, I. and Woodcock, A.
(1984) British Medical Journal, 289, 1080.
i
David Honeybourne and Martin Muers
Rheumatology
Despite publicity about the poor opportunities for those
wishing to train in rheumatology, there is little evidence
to suggest that the situation in this specialty is dramatical-
ly worse than in other fields. It is true that the expansion
of the senior registrar (SR) grade that occurred in the
seventies has now gone into reverse and that competition <
for posts at both consultant and SR level is fierce. t
Nonetheless, the expected number of consultant vacan-
cies predicted on the basis of retirements (8-10 p.a.) was .
comfortably exceeded in 1984 and new posts continue to
be advertised in parts of the country where previously few
existed, for example the West Midlands. The British
Society for Rheumatology is monitoring manpower levels
closely and it is hoped that the future number of SR posts
will be limited to about 50. This should approximately
balance the expected number of retirement vacancies and
new posts each year, and should lead to a decrease in the
present array of time-expired SRs.
There is every sign that the rheumatological rat-race
will remain intensely competitive for the foreseeable
future and those contemplating applying for a place in the
starting stalls will need to have had a solid grounding in
general medicine and would be wise to have spent
sufficient time in a research post to achieve a higher
degree before looking for a senior registrar post. Many of
the large rheumatology departments will have a special
research interest and will be able to advise on the funding
and supervision of work in their field. Contrary to the
impression that might be gained from a glance at the
rheumatological journals, not all such research is immun-
ological and there are particularly fascinating develop-
ments in biomechanics, orthopaedics, biochemistry and
metabolism, which are relevant to the rheumatic diseases.
The majority of recent advertisements for consultant
posts have been in rheumatology alone. There is a
continuing demand, however, for those with experience
in rehabilitation medicine and some districts need a
general physician with an interest in rheumatology. It
pays, therefore, to choose a senior registrar post with
care; not all offer dual training with either general
medicine or rehabilitation, which is certainly desirable
when competition is keen.
Although publications are an important component of
a curriculum vitae, teaching skills are also valued and
most districts will welcome some indication that a candi-
date has k/iowledge or experience of administration.
Junior staff are represented on all the various sub-
committees of the BSR.
Despite the recommendation of the Royal College of
114 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
Physicians that there should be one rheumatologist to a
population of 150,000, the rheumatologist in the average
District General Hospital is likely to be single-handed and
may not be well supported by junior staff. Much of the
work, however, is done in out-patients where, in some
districts, there may be clinical assistants to share the load.
Within the hospital the rheumatologist will need to
work closely with colleagues in other disciplines and other
professions. Many patients with rheumatic diseases have
disabling conditions that last a lifetime. To maintain their
health and well-being for many years requires good
organisation and team-work.
Thomas Price
|
PMC005xxxxxx/PMC5371122.txt | Pulmonary Eosinophilia
DUNCAN M. GEDDES, MD, FRCP
Consultant Physician, Brompton and London Chest Hospitals
Pulmonary eosinophilia occurs in a wide range of circum-
stances and many different classifications have been
suggested[l-4]. Recent studies of eosinophil function
have shed much light on the role of this leucocyte in
disease and the pathogenesis of the pulmonary eosinophi-
I lias is therefore easier to understand.
l' * Definitions
The classical definition of pulmonary eosinophilia is the
combination of chest X-ray shadowing with a peripheral
blood eosinophilia; both parts of this definition need
defining. The normal blood eosinophil count increases
during the night and falls in the early morning, is
increased in the presence of atopy which affects up to a
third of the population, and is influenced by a wide range
of drugs and, in particular, is reduced by corticosteroids.
A peripheral blood eosinophilia of > 400/mm3 is usually
considered abnormal but a single lower count does not
exclude an eosinophilic disorder. Most patients with
pulmonary eosinophilia have repeatedly high counts
ranging from 1,000-50,000/mm3 but there is consider-
able day-to-day variability.
There are two difficulties in using chest X-ray shadow-
ing as a part of the definition. In the first place a
considerable eosinophilic infiltrate can exist before it can
be seen on a chest radiograph[5], This is usually proved
by lung biopsy but recently broncho-alveolar lavage has
become popular and is the simplest way of confirming an
eosinophilic infiltrate[6], The second problem involves
the histological nature of the radiographic shadowing. It
is probably best to restrict the diagnosis of pulmonary
eosinophilia (PE) to those conditions in which there is a
predominance of eosinophils in the pulmonary infiltrate,
thus excluding a wide range of miscellaneous lung dis-
orders that happen to have an associated eosinophilia
from time to time, for example, neoplasms, infections,
etc. In clinical practice broncho-alveolar lavage or lung
biopsy are seldom necessary as the clinical patterns are so
characteristic.
A simple diagnostic and aetiological classification of the
pulmonary eosinophilias is given in Table 1.
Eosinophil Properties and Functions[7-9]
The eosinophil has two main functions: cytotoxic and
anti-inflammatory. Its contents, surface receptors and
tissue distribution appear to be adapted to control these
two functions, both of which are normally beneficial to
the host. However, the cytotoxic proteins that are nor-
Table 1. Diagnostic and aetiological classification of the pul-
monary eosinophilias.
True Pulmonary Eosinophilia
Definition: Blood eosinophil count > 400/mm3
Eosinophilic lung infiltrate (lavage/biopsy
only rarely needed)
Causes: Fungi
Drugs
Parasites
Unknown causes: Cryptogenic?vasculitis?granuloma
spectrum
Hyper-eosinophilic syndrome
Secondary Pulmonary Eosinophilia
Definition: Blood eosinophil count > 400/mm3
Chest radiographic shadowing without
eosinophilic infiltrate
Causes: Infections: Pneumonia
Neoplasm: Hodgkin's. Bronchial
carcinoma
Miscellaneous: Sarcoidosis, etc
mally directed against parasites also have the capacity to
damage host tissues and when this happens the eosinophil
has a role in the pathogenesis of disease.
Eosinophil Contents
The eosinophil is a polymorphonuclear leucocyte contain-
ing about 200 granules/cell which stain with acid dyes
(e.g. eosin). There are probably three sub-populations of
these membrane-bound granules which contain a range of
different proteins. The largest granules have a crystalline
core about half of which is made up of major basic protein
(MBP), molecular weight about 10,000 which contains
numerous arginine residues and has an isoelectric point
over 10. This, together with eosinophil cationic protein
(ECP), is cytotoxic to a range of different tissues but
particularly to intact helminths. Other contents of the
granules include the anti-inflammatory enzymes hist-
aminase, acid phosphatase, phospholipase D, arylsulpha-
tase B, eosinophil peroxidase and some lysosomal
hydrolases. These are all capable of degrading various
inflammatory mediators and so modulating immune re-
actions, especially those involving mast cell degranula-
tion.
Surface Receptors
Eosinophil cell surface receptors have been demonstrated
for various complement components and especially C3b
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
139
as well as for IgG and IgE. These receptors influence the
degranulation of the cell in association with various
inflammatory events. In particular, when helminths are
coated with specific antibodies the latter can then link
with eosinophil surface receptors which promote local
degranulation. There are also oestrogen and glucocorti-
coid receptors whose role is less certain.
Tissue Distribution
Eosinophils develop in the bone marrow, circulate briefly
in the peripheral blood and then distribute to the tissues.
For each blood eosinophil there are 100 in the bone
marrow and a further 100 in the tissues. The normal
tissues with a high population of eosinophils are those in
contact with the outside environment, namely, skin, gut
and lungs. The eosinophil is thus ideally placed to patrol
the frontiers against parasites and also to damp down any
uncontrolled immunological fires.
The attraction of eosinophils from the blood to tissues
secondary to parasite entry or inflammatory reactions
depends on a complex interplay of inflammatory and
chemotactic factors. Diapedesis from the capillaries is
aided by various mediators and vasoactive amines which
open intercellular junctions. Thereafter the eosinophil is
attracted by products of mast cells and basophils (eosino-
phil chemotactic factor A, histamine and various lipid
derived factors) as well as by products of other cells
(lymphokines, prostaglandins) and some serum factors
(complement, IgE). Various parasite extracts are also
chemo-attractants.
A number of factors influence the production and
distribution of eosinophils. Lymphocyte-derived products
stimulate the development of eosinophils and their release
from the bone marrow while glucocorticoids inhibit eosin-
ophil chemotaxis as well as enhancing margination and
tissue destruction. The peripheral blood eosinophil count
is increased by exercise and beta-adrenergic blockade and
reduced by stress, menstruation and glucocorticoids. The
influence of these on tissue infiltration and distribution is
less well studied.
Eosinophil Function in Disease
There appear to be three main functions of eosinophils in
disease (Fig. 1).
Helminthotoxic. Eosinophils can kill trichinella, schisto-
somes and their eggs, fasciola, filaria and other parasites
in vitro. The process is probably initiated by binding of
IgG, C3b and IgE to the parasite, with consequent
degranulation of eosinophils. The chief killer proteins are
MBP and ECP.
Modulation of Immediate Hypersensitivity. Many mast cell
mediators are inactivated by eosinophil enzymes. The
precise function of the eosinophil as an anti-inflammatory
cell in immediate hypersensitivity and other forms of
immunological reactions is, however, not yet clear.
Tissue Damage. This may occur in any disease in which
there is an eosinophilic infiltrate and is chiefly due to the
cytotoxic proteins MBP and ECP. The balance between
host benefit and damage is obviously a fine one which is
likely to depend upon the number of eosinophils and how
long they are present. Transient eosinophilic reactions
around parasites are probably wholly beneficial, while
chronic infiltrates secondary to drug, vasculitic disorders
or the hyper-eosinophilic syndrome can cause permanent
damage.
Fig. 1. Eosinophil chemotaxis and function.
Histaminase
Phospholipase D
Arylsulphatase B
etc
Anti-mediators
modulate mast
cell dependent
reactions
140 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
The Pulmonary Eosinophilias (PE)
Fungal Allergy[ 10,11]
Almost all fungal pulmonary eosinophilia is caused by
Aspergillus fumigatus. A few cases are caused by Candida,
penicillium, stemphylium, geotrichum, culvularia and
drechsleria[12] and it is likely that other fungi will be
implicated in the future but these causes are all very rare.
Diagnosis can be suspected from the clinical pattern and
confirmed by skin prick test and serum precipitating
antibodies,to the fungus. Aspergillus may also be found in
the sputum but this is not essential for diagnosis.
Fungi and especially aspergillus favour places that are
warm, wet and dark. The bronchial tree is thus well
suited for colonisation. The probable sequence of events
is immediate hypersensitivity with eosinophilia causing
asthma and tissue inflammation which itself allows deeper
penetration of fungal antigen. Eosinophils are attracted
into the lung in relation to the affected airway, and
fleeting segmental infiltrates are seen on the radiograph.
The antigenic penetration results in precipitating anti-
body formation and immune complex deposition around
the affected airways. The resulting inflammation may
increase airflow obstruction, promote mucous plugging
and eventually damage the airway. Since proximal air-
ways are usually involved, the eventual result is proximal
segmental bronchiectasis. Sometimes a more generalised
pattern of airway damage results in fixed airflow obstruc-
tion together with a generalised thickening of the bron-
chial wall.
A number of different clinical patterns can therefore be
seen.
Simple asthma without pulmonary infiltrates but with an
eosinophilia and evidence of aspergillus allergy. These
patients respond well to standard asthma therapy.
Fleeting segmental eosinophilic pneumonias. The radiogra-
phic shadowing flits from one part of the lung to another,
usually altering over a few days. There is fever, a high
serum IgE and a moderately high eosinophil count
(typically 1,000-3,000/mm3). Systemic corticosteroids
clear the radiograph and the fever within a few days but
chronic steroid treatment may be needed to prevent
progressive pulmonary damage from repeated episodes.
Mucoid impaction. Low-grade fever, malaise and fixed
breathlessness are more common than asthma or pneu-
monic illness in this form. The radiograph shows mucus
impacted in a part of the bronchial tree with a typical
gloved finger or rabbit's ear appearance. However, more
severe mucus plugging can result in the collapse of a lobe,
or even a whole lung. Corticosteroids may resolve the
impaction but bronchoscopic clearance is often needed.
Failure of resolution of mucus impaction causes some
cases of bronchocentric granulomatosis.
Chronic airway damage. Airflow obstruction becomes pro-
gressively fixed as more damage occurs. The radiograph
shows proximal segmental bronchiectasis or more genera-
lised fibrotic shadowing, especially in the upper zones.
Recurrent infections eventually dominate the clinical
picture.
Figure 2 summarises eosinophilic function in this dis-
ease. The inflammatory reaction is based on fungal
colonisation of the airways. The dominant clinical and
radiographic features are therefore due to airway disease
with asthma and segmental infiltrates or mucus impac-
tion. Chronic tissue damage occurs in the airways either
as proximal segmental bronchiectasis or fixed airway
obstruction.
Drugs and Toxins[\3,\^\
Almost any drug in any pharmacological group can cause
pulmonary eosinophilia. Although antibiotics such as
nitrofurantoin^5] and sulphonamides are perhaps best
known and reports of PE with non-steroidal anti-inflam-
matory drugs are common, this probably reflects how
often the drugs are used rather than a special liability to
the adverse effect. The Spanish toxic oil syndrome is
perhaps the best example of a pulmonary eosinophilia due
to an ingested toxin.
The pathogenesis of drug-induced PE has seldom been
studied, so the mechanisms can only be guessed at.
Almost always the drug reaches the lungs via the blood,
so the reaction must be based in the pulmonary blood-
vessels rather than the airways. A wide range of drugs
(usually basic lipophilic amines) are known to accumulate
in the pulmonary circulation[16] and this may be the
initial event. Probably the drug or a metabolite attaches
to the vascular endothelium or modifies it and an allergic
reaction is then centred on that blood-vessel. There, is
commonly an associated rash, presumably due to an
equivalent reaction in the capillaries of the skin. The
pattern of the drug reaction in the lungs is highly
variable, partly due to the size of the blood-vessel on
which the reaction is based and partly to whether the
reaction is focal or diffuse. For example, a reaction based
on a few segmental pulmonary arteries resembles a
pneumonia or pulmonary infarct while one based on
many capillaries resembles a diffuse pneumonitis. If the
Aspergillus etc
Fleeting infiltrates
Segmental lobar
Mucus plug
Collapse
Asthma
Fever
Proximal bronchiectasis
Fibrosis-upper zone
Fig. 2. Pulmonary eosinophilia caused by fungi.
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 141
drug is continued and the inflammatory reaction becomes
chronic, permanent damage occurs, with progressive
interstitial fibrosis, especially at the lung bases.
There are three main clinical patterns.
Pneumonic. Fever, malaise, breathlessness and sometimes
chest pain develop acutely within a few days of starting a
drug. The white count is elevated, with an eosinophilia of
1,000-5,000/mm3, and the radiograph shows alveolar
infiltrates sometimes in a single lobe but more usually
with a patchy distribution. Transient pulmonary infiltra-
tions without symptoms are sometimes seen and may well
be a minor drug reaction analogous to a transient rash.
The illness and radiographic changes improve rapidly on
stopping the drug and recur if it is restarted.
Pulmonary Vasculitis. The clinical picture is similar to the
pneumonic form although pleuritic pain and pleural
effusions may suggest pulmonary infarction. These reac-
tions are somewhat more severe and take longer to resolve
than the simple pneumonic form. Corticosteroids are
sometimes given to speed resolution.
Fibrosing Alveolitis. The best known example is nitrofur-
antoin lung. There may be low-grade fever and malaise
with a slight eosinophilia but usually progressive breath-
lessness is the only symptom. The radiograph shows
diffuse lower zone fibrosis. The amount of resolution
which occurs after stopping the drug depends upon how
long the reaction has lasted. Some degree of permanent
damage is quite usual and corticosteroids may be given to
ensure maximum resolution.
Figure 3 summarises these patterns. The inflammatory
reaction is based on blood-vessels producing a pneumonic
or vasculitic pattern; prolonged inflammation causes
diffuse fibrosis.
Parasitic Pulmonary Eosinophiha\2,17]
Many different helminth infestations can cause PE.
These include nematodes, such as ascaris, strongyloides,
ankylostoma and filaria, and flat worms such as paragoni-
mus and schistosoma.
The details of each life-cycle make exciting reading and
are beyond the scope of this article. Nevertheless, they all
have one event in common, namely the arrival of the
parasite in the lungs, usually via the blood, and its
passage into the alveoli and then to the airways. As the
parasite migrates through the lungs, eosinophilic attack
results in eosinophilic pulmonary infiltrates. The pul-
monary vessels are often damaged while the parasite is
moving into the lungs or when it is being killed, so
haemoptysis is common. Furthermore, a number of
dying parasites may set up a vigorous allergic reaction
with consequent mediator release and asthma. Chronic
damage is probably rare but diffuse fibrosis can follow
microfilarial infection, pulmonary hypertension can fol-
low obliteration of much of the pulmonary circulation by
schistosomes, and paragonimiasis can cause lung cysts
and local fibrosis. Clinical patterns are difficult to classify
due to the large number of different parasites and the fact
that multiple infestations are common.
Fleeting Infiltrates. Transient alveolar shadowing on the
radiograph represents an eosinophilic reaction to the
pulmonary migration of nematodes, and associated
cough, transient haemoptysis, anaemia and weight loss
are common. Spontaneous resolution of the infiltrate is
usual. Peripheral eosinophil counts may be as high as
50,000/mm3 and the serum IgE is usually very high.
Asthma. This form of parasitic pulmonary eosinophilia is
usually caused by microfilariasis due to Wucheria bancrofti
and has become known as tropical pulmonary eosinophi-
lia. Donohugh's[18] diagnostic criteria are (a) residence
in the tropics; (b) asthma; (c) eosinophil count > 2,000/
mm3; (d) positive filarial complement fixation test, and
(e) response to diethylcarbamazine.
This approach remains useful for precise diagnosis
since both asthma and filarial infestation are common and
may co-exist by chance. The chest radiograph usually
shows micronodular shadows although rare patterns in-
clude cavities, pleural effusions and large pneumonic
shadows. Chronic disease causes basal pulmonary fibrosis
or persisting asthma.
Figure 4 summarises the disorders. Pulmonary eosino-
philia due to parasites is caused by their passage through
the lungs with transient shadowing and haemoptysis.
Tropical pulmonary eosinophilia is the particular associ-
ation of asthma and micronodular shadowing caused by
microfilariasis. Chronic damage leads to lung fibrosis
(microfilaria) or pulmonary hypertension (schistosoma).
Cryptogenic Vasculitis?Granuloma Spectrum
The pulmonary eosinophilias of unknown cause present a
spectrum of disorders that vary from the localised 'crypto-
genic pulmonary eosinophilia' to a generalised disease
with vasculitis and granulomata. In pathological terms
three features are present in variable degrees: eosinophilic
infiltrate, granuloma formation and vasculitis. Descrip-
tions of these diseases have depended on the relative
Infiltrates
Non segmental
Fibrosis ?
lower zone
Vasculitis
Fig. 3. Pulmonary eosinophilia caused by drugs.
142 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
amounts of each pathological change, the type of blood-
vessel involved and the organs which have been predomi-
nantly affected. As a result there are a number of quite
confusing classifications. The largest single source of
confusion stems from two early descriptions of pulmonary
eosinophilia with systemic vasculitis. An American paper
in 1951 by Churg and Strauss[19] reported 'allergic
granulomatosis, allergic angiitis and periarteritis nodosa'
and this became known as the Churg-Strauss syndrome,
while a UK paper[20] in 1957 described polyarteritis
nodosa as having two forms, one with and one without
lung involvement and granulomata. As a result, UK texts
have continued to link pulmonary eosinophilia and poly-
arteritis nodosa, while American classifications include
the Churg-Strauss syndrome and reserve the diagnosis of
* polyarteritis nodosa for a necrotising vasculitis of small
and medium sized muscular arteries in which lung in-
volvement and granulomata do not occur. The Ameri-
cans have now won the classification dispute, as shown in
Table 2. The way in which the pulmonary eosinophilias
link up with the systemic vasculitides is shown in Fig 5.
Table 2. Classification of the vasculitides[21]
Systemic necrotising vascu
Hypersensitivity vasculitis
Giant cell arteritis
Granulomatosis:
Polyarteritis nodosa
Allergic granulomatosis
Overlap syndrome
Serum sickness
Henoch-Schonlein purpura
Essential mixed cryoglobulin-
aemia with vasculitis
Vasculitis with primary dis-
eases, e.g. malignancy
Temporal
Takayashu's disease
Wegener's
Lymphomatoid
The pathogenesis of these conditions is unclear. A
number of immunological mechanisms, including im-
mune complex and cell-mediated inflammation, can be
implicated. These all have the capacity to attract eosino-
phils and macrophages and so set up vascular damage
with variable eosinophilic infiltrate and granuloma for-
mation, but the antigen that starts the immune reaction is
usually unknown. The association of allergic granuloma-
tosis with asthma, and often with demonstrable extrinsic
allergens, suggests that an external agent which becomes
associated with blood-vessels or airways may sometimes
be the target, but some unmasked or altered host antigen
is an equal candidate. The association of polyarteritis
nodosa with hepatitis antigen or drugs and the persistent
vasculitis of the Spanish toxic oil syndrome provide good
examples of external trigger agents, but these conditions
are rare. The dominant site of the immune reaction is in
the blood-vessels, although airways can also be involved,
particularly when the histology is predominantly granulo-
matous.
There are two clinical patterns of this disorder.
Cryptogenic Pulmonary Eosinophilia[22\. Fever, weight loss
and low-grade respiratory symptoms are associated with a
very characteristic chest radiograph. There is widespread
alveolar shadowing peripherally and in the upper zones.
The blood eosinophil count is usually greater than 2,000/
mm3 but is occasionally normal, when broncho-alveolar
lavage or biopsy show a predominantly eosinophilic
infiltrate. The response to steroids is rapid, with resolu-
tion of the fever and radiographic shadowing, and there is
subsequent weight gain. Steroid dosage should be re-
duced slowly, as recurrences are quite common, but most
patients are entirely well with no therapy in 1-2 years.
Multi-system disease is not usually apparent clinically
although a few patients progress into the second pattern.
Asthma is present in a significant proportion of patients
but is not universal. Lung biopsy shows an interstitial
eosinophilic infiltrate with only occasional areas of vascu-
litis.
Allergic Angiitis and Granulomatosis[19,20,23], Asthma is
almost always present and may precede the multi-system
disease by many years. Fever, weight loss, radiographic
shadowing and multi-system disease are usually present
at the onset but thereafter the clinical course is highly
variable. The chest radiographic changes include tran-
sient pneumonic infiltrates, nodules which may be mas-
sive and show cavitation; pericardial or pleural effusions
only rarely occur and diffuse interstitial changes have also
been reported. There is a blood eosinophilia at some stage
and the ESR is usually raised. Lung biopsy shows a
vasculitis involving small arteries and veins and a perivas-
cular eosinophilic infiltrate and extravascular granulo-
mata. The lungs may not be the best place to look for
allergic granulomas, liver, spleen or skin often being
better.
Any other organ may be involved, but the skin, central
nervous system and heart are particularly affected while
renal disease is rare. There is usually a good response to
steroids but when these fail azathioprine or cyclophospha-
mide are effective. The original appreciable mortality has
been reduced by cytotoxic drug therapy. A few patients
still die from cardiac failure or infectious complications
(Segmental
Infiltrates
Non segmental
Cough ? blood
Breathless ? asthma
Fever
Pulmonary BP t
Fibrosis
Fig. 4. Pulmonary eosinophilia caused by parasites.
Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986 143
and permanent neurological deficits are quite frequent in
survivors.
Other patterns of disease have been reported under
such titles as eosinophilic pneumonitis, eosinophilic non-
necrotising angiitis, bronchocentric granulomatosis or
necrotising alveolitis. Churg and Strauss[24] have rec-
ommended that all these should be considered part of the
spectrum of a single disease rather than separate entities.
Hyper-eosinophilic Syndrome[25]
This rare condition is quite distinct from the cryptogenic
pulmonary eosinophilias. The eosinophilic infiltrate oc-
curs without any evidence of an inflammatory or allergic
initiating event, there is no vasculitis and no granulomata
are seen. It is therefore unclear why the eosinophils have
infiltrated the tissues and whether they have any ben-
eficial role. It is almost as if there is uncontrolled produc-
tion of eosinophils which therefore accumulate. Although
the clinical course may be prolonged before symptoms
develop, tissue damage eventually occurs, notably in the
heart and central nervous system. Few, if any, progress to
a frank eosinophilia leukaemia. Men are affected nine
times as often as women, usually in the 20-50 age range,
and the disease has a worldwide distribution. It has two
clinical patterns.
Pulmonary Eosinophilia. There are few symptoms, al-
though there is occasionally an associated angio-oedema
and a raised IgE. Allergy is not otherwise seen. The blood
eosinophil count is as high as 50-100,000/mm3. The chest
radiograph shows a non-specific diffuse infiltration.
There is usually a response to corticosteroids with a
reduction in the blood eosinophil count and the pulmon-
ary infiltrate. The prognosis is good unless the heart
becomes involved.
Predominant Cardiac or Central Nervous System Involvement.
The eosinophils in the heart cause a restrictive and
obliterative cardiomyopathy while diffuse brain infil-
tration causes intellectual impairment and more local
deposits may cause focal abnormalities. There is often
complicating thrombo-embolic disease of large and medi-
um bloodvessels. Hydroxyurea and vincristine have been
suggested as logical therapy to reduce the bone marrow
production of eosinophils.
This article is based on a paper read at the College Regional
Conference at Liverpool in September 1985.
References
1. Crofton, J. W., Livingstone, J. L., Oswald, N. C. and Roberts,
A. T. U. (1952) Thorax, 7, 1.
2. Liebow, A. A. and Carrington, C. B. (1969) Medicine, 48, 251.
Bronchopulmonary
eosinophilia
Necrotising
granulomatosis
Bronchocentric
granulomatosis
type 1
Drugs
Fungi
Parasites
Asthma
etc
Bronchocentric
granulomatosis
type 2
Wegener's^
Necrotising \
Sarcoid
. Granuloma
Eosinophilia
Necrotising vasculitis
Fig. 5. The connection between the pulmonary eosinophilias and the systemic vasculitides.
144 Journal of the Royal College of Physicians of London Vol. 20 No. 2 April 1986
3.
4.
5.
6.
7,
8
9,
10
11
12
13
Patterson, R., Irons, J. S., Kelly, J. F. et al. (1974) Journal ofAllergy
and Clinical Immunology, 53, 245.
Schatz, M., Wasserman, S. and Patterson, R. (1982) Archives of
Internal Medicine, 142, 1515. ?
Dejaegher, P., Dervaux, L., Dubois, P. et al. (1983) Chest, 84,
637.
Dejaegher, P. and Demedts, M. (1984) American Review of Respirat-
ory Disease, 129, 631.
Weller, P. F. and Goetzl, E. J. (1980) American Journal of Pathology,
100, 793.
Middleton, E., Reed, C. and Ellis, E. (eds) (1983) Allergy:
Principles and Practice, pp. 701-56. St. Louis: Mosby.
Weller, P. F. (1984) Journal of Allergy and Clinical Immunology, 73, 1.
Hinson, K. F. W., Moon, A. J. and Plummer, N. S. (1952)
Thorax, 7, 317.
Safirstein, B. H., D'Souza, M. F. and Simon, G. (1973) American
Review of Respiratory Disease, 108, 450.
Lahoute, C., Tonnel, A. B., Fournier, E. et al. (1983) Poumon
Coeur, 39, 87.
Cole, P. (1977) Drugs, 13, 422.
Toxic Epidemic Syndrome Study Group (1982) Lancet, 2, 697.
15.
i6;
17.
18.
19.
20.
21,
22.
23
24.
25
Sovijarvi, A. R. A., Lemola, M., Stenius, B. et al. (1977)
Scandinavian Journal of Respiratory Disease, 58, 41.
Brandenberger Brown, E. A. (1974) Drug Metabolism Reviews, 3,
33.
Frazer, R. C. and Pare, J. A. P. (1978) Diagnosis of disease of the
chest, Vol II, pp. 860-80. Philadelphia: Saunders.
Donohugh, D. L. (1963) New England Journal of Medicine, 269,
1357.
Churg, J. and Strauss, L. (1951) American Journal of Pathology, 27,
277.
Rose, G. A. and Spencer, H. (1957) Quarterly Journal of Medicine,
26, 43.
Fauci, A. S., Haynes, B. F. and Katz, P. (1978) Annals of Internal
Medicine, 89, 660.
Carrington, C. B., Addington, W. W., Goff, A. M. et al. (1969)
New England Journal of Medicine, 280, 787.
Chumley, L. C., Harrison, E. G. and DeRemee, R. A. (1977)
Proceedings. Mayo Clinic, 52, 477.
Churg, J. and Strauss, L. (1981) New England Journal of Medicine,
304, 611.
Leading article (1983) Lancet, 1, 1417.
|
PMC005xxxxxx/PMC5371123.txt | Editorial
With alarming regularity patients and relatives recount their distress-
ing experiences in hospital. Left in ignorance of what is happening or
bemused by conflicting statements, they are the victims of psychologi-
cal negligence. Of course it should not happen. No hospital should
ever present as a production line manned by uninterested shift-
workers. Seldom is the individual callous but what is absent is the
corporate demonstration of concern by the many people caring for the
one patient. Care has to be shown to be both continuous and
coherent. This is a difficult matter with a staffing structure that
builds-in ill-defined split responsibilities and short periods of 'duty'.
The patient is the constant feature in a shifting world of professional
visits. He may have to relay information from one professional to
another because they have failed to brief each other. For the patient,
anyone who is ignorant of his condition appears not to care. Alas, the
ignorance can be very real, for the core of the problem lies in the
failure of constant communication between those responsible for care.
Now is the time for an examination of conscience. Have we not all
at some time failed to make intentions clear to house physician and
registrar, or listened to someone's account but not to the patient?
These omissions are the seeds from which grow the major psychologi-
cal disasters for a patient, bereft of knowledge and comfort. More by
individual example than by coherent team effort disasters are rare.
Patients in their gratitude forgive many anxieties that we unwittingly
cause and are benign critics of our performance.
There is happy administrative talk of health care teams. The
question is how to make the care obvious and effective and what
qualities of team spirit are neccessary to achieve this. It is a pity that
much high-level discussion is confined to who should be captain. Too
little thought is given to the integration of team effort for a single
purpose. We are all so used to the idea of a personal one-to-one
relationship with our patient that we do not take kindly to shared
responsibilities or delegation of care to create a united effort. The
daily grind of hospital work blunts our appreciation of the fact that for
the patient every experience is fearful, unpleasant and demeaning,
unless we can soften the blows.
Doctors are beginning to realise that they are not necessarily the
good communicators that they thought they were. Some now advo-
cate a high priority for the teaching and supervision of doctor/patient
communication in undergraduate and post-qualification training.
The idea could well be extended to communication between profes-
sionals. At one level this means the proper transmission of infor-
mation from the person going off duty to the one coming on. Nurses
have a routine for this; junior doctors do not. The other level is the
pooling of information between different types of professional, includ-
ing nurses, laboratory workers and all grades of medical staff.
Strengthening personal communication in hospitals needs that
scarce resource of time. Once found, it will be well spent.
Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986
|
PMC005xxxxxx/PMC5371124.txt | The Gentle Queen
A. G. W. WHITFIELD, cbe, md, frcp
Emeritus Professor of Medicine, University of Birmingham
Assistant Director, Research Unit of the Royal College of Physicians
Princess Adelaide of Saxe-Meiningen must have had
some reservations about leaving the tiny duchy in central
Germany, where she had been born and had lived happily
for all her 26 years, to come to England to marry Prince
^ William Henry, Duke of Clarence, the third son of
^ George III. She had never seen him but knew that he was
more than twice her age, heavily in debt and had had ten
? - illegitimate children by Mrs Dorothea Jordan, the ac-
tress. Moreover, she must have known that she was by no
means the first with whom he had contemplated, and
even proposed, marriage, since his separation from Mrs
Jordan and her subsequent death. She would have been
further discouraged had she heard Canning's speech in
the House of Commons in support of her own and the
Duke's Civil List allowance in which he said, 'Into this
alliance His Royal Highness entered, not for his own
private desire and gratification, but because it was
pressed on him for the purpose of providing for the
succession to the throne'.
However, when she and her mother arrived at Gril-
lon's Hotel in London on the evening of 4th July 1818,
she was doubtless comforted by the kind and warm
welcome afforded to them by the Prince Regent, the
Duke of Clarence and the Earl of Munster, the Duke's
eldest illegitimate son, and from such inauspicious begin-
nings she made a great success of her marriage. Though
not beautiful she spoke excellent English and was calm,
sensible and very kind. She and her husband became
genuinely devoted to each other, the ten Fitzclarence
offspring had a real home at Bushey Park and a good
> mother', and thanks to financial prudence the debts were
discharged. Captain Lord Frederick Fitzclarence, the
third of the illegitimate sons, told Creevey that the
Duchess of Clarence was 'the best and most charming
woman in the world'. In addition she brought about a
marked improvement in the Duke's personality and
behaviour; in 1831 Earl Grey told Creevey that 'her
influence over him as to his manners has been very great
and highly beneficial'.
The Duchess of Clarence only failed in what was
i expected and hoped of her in that she did not produce an
heir to the throne. Her first baby, Charlotte Augusta
Louisa, died within a few hours of birth. Her second
daughter, Elizabeth Georgina Adelaide, was born six
weeks prematurely on 10th December 1820 at St James's
Palace; at first she thrived but on 5th March 1821 died 'in
a convulsive fit'; 'the cause of her death was an entangle-
ment of the bowels'. Later in the same year a twin
pregnancy ended in miscarriage; so, despite the skill and
care of Sir Henry Halford, Sir William Knighton and Sir
Andrew Halliday, it had to be accepted that she was
unlikely to have a successful pregnancy.
When George IV died on 26th June 1830 and the Duke
of Clarence acceded to the throne, Queen Adelaide did
much to guide and control her husband and to give
dignity, charm and respectability to the Court. With such
a wide difference in the ages of the King and Queen it is
not surprising that malicious gossip linked the name of
Fig. 1. Sir Henry Halford, Bart. (From the portrait by Sir
Thomas Lawrence. By kind permission of the Harveian
Librarian of the Royal College of Physicians.)
Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986
63
the Queen with others, particularly Earl Howe, her
Chamberlain, and David Davies, sometimes spelt Davis,
her domestic physician, but there can be no doubt that
Queen Adelaide was the most virtuous and faithful of
wives. David Davies, who is said to have practised
homeopathy, was assistant to one of Queen Adelaide's
previous physicians, obtained the Membership of the
Royal College of Surgeons in 1815 and was granted an
MD Lambeth by the Archbishop of Canterbury in 1836.
He was created a Knight of the Guelphic Order (KCH)
by Queen Victoria shortly after her accession for his
services as King William's and Queen Adelaide's domes-
tic physician for many years.
In 1819 the Queen had had pleurisy and there was a
further attack in 1833. The following year she developed
a cough which was to persist for the remaining 15 years of
her life. She also complained of oppression on her chest
which was relieved to some extent by a long holiday in
Meiningen. On her return, however, her friend Miss
Clitherow wrote, 'She is most miserably thin and has a
sad, wearing cough', and in 1835 Lady Cowper in a letter
to Princess Lieven said, 'I must say she looks very ill'.
Though her household medical man was David Davies
her physician was Halford. He was nearly 70 and The
Lancet wrote, 'He is all tact and nothing else. He is
ignorant of the modern discoveries in pathology and
never employs the modern instruments of diagnosis; he
has never written a line that is worthy of perusal on any
scientific subject'. He certainly never learned to use a
stethoscope and was described by Lord Grey as 'the
damnedest conceited fellow in the world'. Queen Ad-
elaide, though aware of his excellent manners, had no
faith in his abilities. In 1836, therefore, Dr W. F.
Chambers, the fashionable St George's physician, was
asked to see her at Windsor and three weeks later he was
gazetted her Physician in Ordinary. Whether he knew the
nature of the Queen's illness is uncertain but she had
great faith in him, so great that when King William
himself fell ill in 1837 she manipulated affairs so that, to
Halford's great annoyance, Chambers saw the King
before he did despite the fact that he was the King's first
physician. Chambers was immediately appointed Phys-
ician in Ordinary to William IV who conferred upon him
a knighthood of the Guelphic Order (KCH), Chambers
accepting the commandership but declining the knight-
hood.
The Queen's symptoms persisted and though she
remained very active there were occasions when she was
not well enough to fulfil her engagements. However, she
never left the bedside of King William during his last
illness. He had suffered from seasonal asthma for most of
his life but died on 20th June 1837 from cardiac failure
due to aortic stenosis and probably heart block, for
Greville recorded that 'his pulse was down to 30'. After
his death Queen Adelaide returned to Bushey Park,
which had been her home from her marriage until her
husband acceded to the throne in 1830, and Marlborough
House was given to her as a town residence. She gave to
Halford a silver vase inscribed 'To Sir Henry Halford
Bart. GCH. A grateful acknowledgment of his attendance
upon his late Majesty King William IV during his last
illness. A R'. Thereafter, however, Chambers and not
Halford was her first physician.
The first winter of her widowhood she spent at St
Leonard's but there was no improvement in her cough as
her physicians had hoped and they were so concerned
about her condition that they advised that she should
spend the next winter abroad and suggested Madeira.
The Queen Dowager, however, was reluctant to go to
Madeira as it was not British but she agreed to go to
Malta. Queen Victoria put the frigate HMS Hastings
(Captain Francis Loch, RN) at her disposal and she sailed
from Kingstairs on 3rd October 1838, Sir David Davies
being in attendance. Lieutenant-General Sir Henry Bou-
verie was the Governor of Malta at the time and she was
made most welcome, staying at Sant Anton Palace until
April 1839, the rest and warm dry climate appearing to
produce considerable improvement in her condition. The
Queen Dowager was a deeply religious woman and as
there was no Anglican church on the island she gave
?10,000 as a thanksgiving to build St Paul's Cathedral.
The square in which it stands was known as Adelaide
Square until Dom Mintoff became Prime Minister when
he changed its name to Independence Square.
The next winter she stayed in London and, despite a
Fig. 2. Dr W. F. Chambers. (From an engraving in the Royal
College of Physicians.)
64 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986
yJL haemoptysis, attended Queen Victoria's wedding. In
1840 she took a three-year lease of Sudbury Hall in
Derbyshire from Lord Vernon, spending December 1840
and January and the first week of February 1841 there
and returning to London in time to attend the Princess
Royal's christening. While at Sudbury her fellow wor-
shippers at the little church close to the Hall noticed her
cough, and the Queen Dowager's sister, the Duchess of
Saxe-Weimar, told the Duchesse of Dino, Talleyrand's
niece and secretary, 'The Queen Dowager has lost the use
of one of her lungs and that the other was very delicate'.
She returned to Sudbury in September but had a profuse
haemoptysis early in November. Chambers was sum-
moned from London and stayed for three weeks. It was
feared that she would die and she wrote out instructions
for her funeral.
I die in all humility knowing well that we are all alike
before the throne of God, and I request therefore that
my mortal remains be conveyed to the grave without
any pomp or state. They are to be moved to St
George's Chapel, Windsor, where I request to have as
private and quiet a funeral as possible.
I particularly desire not to be laid out in state, and the
funeral to take place by daylight, no procession, the
coffin to be carried by sailors, to the chapel.
All those of my friends and relatives to a limited
number, who wish to attend to do so . . .
I die in peace and wish to be carried to the fount in
peece, and free from the vanities and pomp of this
world.
I request not to be disected nor embalmed and desire to
give as little trouble as possible. I shall die in peace with
the world and full of gratitude for all the kindness that
? was ever shown to me and in full reliance to the mercy
of our Saviour Jesus Christ in whose hands I commit
my Soul.
Miraculously, however, she recovered and was able to
return to Marlborough House on 21st January 1842 but
had to remain indoors until the spring. A further hae-
moptysis, however, occurred later that year.
There are but few traces of the Queen Dowager's
tenancy of Sudbury Hall nearly a century and a half ago.
A remote inn a few miles away is named the Queen
Adelaide and while the Meynell and South Staffordshire
hounds meet there from time to time custom does not
warrant twice-daily opening of the bar! At Sudbury Hall,
now the property of the National Trust, the Queen's
bedroom is beautifully preserved and contains a print of
her and her instructions for her funeral signed and dated
November 1841.
The Queen Dowager faced her illness with remarkable
courage and lack of complaint. She was full of kindness
and nothing prevented her from travelling all over the
country to visit her friends or returning to Meiningen to
see her family and her old home. Whether or not
Chambers was influenced by the inconvenience of his
prolonged detention at Sudbury is uncertain but he
advised her that she should spend the next winter in
Hampshire where he himself had a house?Hordlecliffe,
near Lymington. The Queen Dowager, therefore, rented
Canford House from Lord de Mauley and travelled there
by train in September 1842. After she had been there for
a few weeks she had a cold which provoked an exacerba-
tion of her chest symptoms and led to her return to
Marlborough House in January 1843. She was clearly
deteriorating and in the summer of 1843 was unfit to
attend the marriage of Princess Augusta of Cambridge.
Her next winter home was Witley Court, near Worces-
ter, which she rented from Lord Dudley and Ward. She
spent the winters of 1843-44 and 1844-45 there but these
sojourns in one country house after another were of
course powerless to halt the inexorable advance of her
tuberculosis and she would probably have been wiser to
stay at Bushey Park and Marlborough House. In the
summer of 1844 and again in 1846 she bravely made the
journey to Meiningen without apparent harm and on her
return in 1846 took a three-year lease of Cassiobury, near
Watford, from the Earl of Essex, but she was ill there and
the house proved unsatisfactory, so for the winter of 1847
she went to Madeira. She embarked at Portsmouth in
HMS Howe (Captain Sir John Stirling, RN) on October
9th, sailing two days later. Sir David Davies accompanied
her and she stayed at Funchal until April the following
year but without any benefit to her health.
On her return from Madeira she took a three-year lease
of Bentley Priory, near Stanmore, from the Marquis of
Abercorn and this was her home for the rest of her life
apart from visits to Bushey Park and brief periods at
Woking and Tunbridge Wells. It was widely appreciated
that she could not recover and Queen Victoria and Prince
Albert stayed with her for two days at Bentley Priory and
visited her there on other occasions, as did the Duchess of
Kent, the Duchess of Cambridge, Earl Howe, Prince
George of Cambridge and many of the countless others to
whom she had given friendship and kindness.
In 1848 Chambers suffered a stroke which caused some
dysphasia. He retired from practice and went to live at
Hordlecliffe where he survived until 1855. It appears that
his disability during the last phase of his life was partly
due to anxiety. He was asked to see the Queen Dowager
but begged to decline as he felt the responsiblity would
have been more than he could bear. Richard Bright
replaced him. Chambers had a career of great success and
distinction, having an enormous practice and being Phys-
ician in Ordinary to Queen Victoria and the Duchess of
Kent as well as to King William and Queen Adelaide.
Though he was a Fellow of the College for 36 years, a
Censor, a Councillor and an Elect, he took no prominent
part in College affairs, did not engage in research and
published no original work. Sir David Davies does not
appear to have ever held the College Licence. He died at
Lucca in Italy on 2nd April 1865 at the age of 73 and was
buried at Biarritz.
During the last weeks of her life the Queen Dowager
was confined to bed at Bentley Priory and Bright and
Davies issued bulletins at frequent intervals, often twice a
day. These were inevitably repetitive. She died from a
haemoptysis on 2nd December 1849 and was buried in
accordance with her wishes written in her own hand at
Sudbury Hall eight years earlier. She was generous in
death as in life, leaving 100 legatees, the most touching
being Queen Victoria, to whom she bequeathed the
Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 65
statue by Scoular of her infant daugher, Princess Eliza-
beth of Clarence, which is now at Windsor. Had she
survived, Princess Elizabeth and not Victoria would, of
course, have been Queen. Queen Adelaide was loved and
admired by all who knew her for her kindness, generosity,
?friendship and courage, and for all that she did for her
adopted country and its monarchy. She is often spoken of
as the gentle queen, which is a fitting title but only
embraces one of her many attributes.
Bibliography
British Medical Journal 1865.
Sir James Clark's Diaries.
Directory of Welsh Biography.
Roger Fulford (1973) Royal Dukes. London: Collins.
Mary Hopkirk (1946) Queen Adelaide. London: John Murray
J
Tresham Lever (1957) The Letters of Lady Palmerston. London: John
Murray. i.
List of Fellows and Members of the Royal College of Surgeons 1845.
Sir Henry Luke (1949) An Account and an Appreciation of Malta. London:
Harrap.
Sir Herbert Maxwell (1904) The Creevey Papers. London: John Murray.
William Macmichael (1857) Lives of British Physicians. London: William
Tegg.
Medical Directory 1866.
Medical Register 1845, 1859.
Medical Times and Gazette 1865.
Munk's Roll. j
William Munk (1895) The Life of Sir Henry Halford Bart. London:
Longmans.
Royal Archives, Queen Victoria's Journal.
Lord Sudley (1943) The Lieven Palmerston Correspondence 1828-56. Lon-
don: John Murray.
The Times 1818, 1837, 1838, 1840, 1841, 1847, 1849.
George Whitfield (1983) Beloved Sir fames. Birmingham University.
Philip Ziegler (1971) King William IV. London: Collins.
|
PMC005xxxxxx/PMC5371126.txt | General Internal Medicine
Opinion in the 1970s,gave little support to Mayo's old
claim that one well-trained physician would do better
work for a thousand people than 10 specialists. It was
considered that the mantle of the general physician had
fallen on general practitioners, A & E consultants, geri-
atricians and even professors of clinical medicine. The
growth of relative specialties, fuelled by new technology,
had made serious inroads into the traditional province of
general medicine and there was a large question-mark
over its future. As a result of anxieties expressed from
various quarters, the College set up, in 1979, a working
party to assess the position and future prospects of the
general physician, with particular reference to patient
care, medical education and the economic use of re-
sources. After five meetings it was resolved, in 1982, that
a College committee devoted to the specialty should be
established, and one of its first tasks was to undertake a
fact-finding exercise, with the help of Regional Advisers,
to determine the current role of the general physician.
The results of this enquiry have just been published.
Involvement in the acute emergency take was accepted
as the hallmark of the general physician and replies were
received from 1,031 individuals in 185 districts. In both
teaching and non-teaching hospitals the majority regard-
ed themselves as general physicians with an interest,
although 17 per cent claimed to be pure general phys-
icians. Of those general physicians with an interest, four-
fifths spent more than 40 per cent of their time in general
medicine and this figure was remarkably constant over
the whole range of special interests. All 20 specialties
recognised by the College were represented, with the
majority involved in gastroenterology, respiratory dis-
ease, cardiology and diabetes; 20 per cent had more than
one specialty interest and no less than 36 per cent had
interests not included in their original contracts. The
majority of physicians worked in more than one hospital,
with an acute on-call commitment averaging, in non-
teaching hospitals, one in 4.7 days and in teaching
hospitals one in 6.8 days. Average admissions per take
per day varied from 8.9 in the non-teaching to 4.8 in the
teaching hospitals. In a climate of increasing specialisa-
tion the routine transfer of patients to other units was
expected to be high but, in fact, only 17 per cent of
consultants routinely transferred specific patients to other
departments or other hospitals. Details of firm structure
predictably showed a greater number of senior registrars
in teaching hospitals, with more registrars and senior
house officers in the non-teaching hospitals.
In the intensive care facilities of 178 districts unit
administration fell to anaesthetists in 66 per cent but
continuing patient care remained with the physician or
was shared between the physician and the anaesthetist in
88 per cent, suggesting a satisfactory compromise rather
than competition between anaesthesia and medicine.
These figures suggest that the general physician,
usually with an interest, remains directly responsible for
both immediate and continuing care for the major part of
acute medicine. Of particular interest is the large number
of consultants who developed either interests not included
in their contracts or more than one interest. This under-
lines the frequently expressed view that flexibility should
be maintained in both training and career structures to
enable changes in direction, and also for new specialties,
to be developed in association with general medicine
rather than in isolation. The difference in consultant
acute workload between the teaching and the non-teach-
ing hospitals must have implications for training in the
undergraduate, pre-registration and post-registration
periods and reinforces the view that all District General
Hospitals should, in fact, develop a greater teaching
commitment.
The general physician with an interest will continue to
provide the basis for acute medical services and the
average District General Hospital will require at least five
such consultants. If the physician is to remain generally
based, his acute experience will be diluted if his on-take
commitment falls significantly below one in five. Special
interests covering most of the major specialties will be
required. This may call for the development of new
interests, involvement with more than one and the shar-
ing of specialty expertise across adjacent districts or with
geriatrician colleagues. Involvement of geriatricians in
specialty provision could encourage the College's desire
for integration. The development of technology-based
new specialties should be viewed with caution and possi-
bly assisted by sub-consultant labour substitution. Train-
ing for general medicine should be broad-based and
flexible, with greater exposure to the acute take, es-
pecially at District General Hospitals: we would argue
that two years rather than one should be the requirement
for accreditation. Serious thought needs also to be given
to those areas to which other specialties now lay claim,
such as intensive care, haematology and oncology. In
each case the clinical component must be identified and
quantified and the role and lines of communication
specified to aid the development of interdisciplinary
training programmes.
There is no doubt that the general physician has
responded to the need for change and will remain an
essential component of hospital staffing.
1^-
RjC. King
C. |Davidson
Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986
|
PMC005xxxxxx/PMC5371129.txt | Incidence, Mortality and Prevention of
Infective Endocarditis
SIR RICHARD &AYLISS, kcvo, md, frcp
SIR CYRIL CLARKE, kbe, md, frcp frs
CELIA M. OAKLEY md, frcp
W. SOMERVILLE, md, frcp
A. G. W. WHITFIELD, cbe, md, frcp
SUSAN E. J. YOUNG, mb, mrcp(uk)
Royal College of Physicians Research Unit
Since 1933 the number of deaths in England and Wales,
certified as due to infective endocarditis (IE), has fallen
by about four-fifths[l ,2]. In the pre-antibiotic era the
incidence of the disease was the same as the number of
deaths because IE was then uniformly fatal. Since cura-
tive treatment became available, reported series from the
UK[3-11] and from abroad[12-14], have shown consider-
able differences in mortality and, as the disease is not
notifiable, the incidence is unknown. Oakley[15] has
suggested that it is probably in excess of 1,500 new cases
annually in the UK but Smith et al. [9] report it to be only
16 per million of the population each year in South-East
Scotland, which is about two-thirds of Oakley's estimate.
Certainly IE is still the cause of over 200 deaths each year
in England and Wales[2] and of a severe and dangerous
illness in those who recover.
The purpose of this article is to consider the findings in
a recent study of 582 episodes of IE by the British Cardiac
Society and the Royal College of Physicians Research
Unit and to examine such other relevant evidence as is
available in order to ascertain the current incidence of
and mortality from the disease and to identify any
possible measures by which they might be reduced.
Method
The Survey
All members of the British Cardiac Society were asked,
verbally and by letter, to complete a proforma in respect
of each patient with IE under their care in 1981 and 1982
and to persuade the physicians in their hospital to partici-
pate in the investigation. A similar request was made to
all Fellows and Members of the College through its
Regional Advisers. Microbiologists reporting cases to the
Communicable Disease Surveillance Centre were asked
to encourage the clinician in charge to submit a proforma
in respect of any such patients about whom details had
not already been supplied. The survey was given wide
and repeated publicity in the British Heart Journal, the
British Medical Journal and The Lancet; cardiologists and
physicians were reminded of the project on all suitable
occasions. The proforma asked for the patient's full
name, age, sex and hospital number, the name of the
consultant in charge and the hospital where the patient
was treated, the causal organism and the outcome. It also
required details of any dental, surgical or investigative
procedure, injury or other circumstances that might have
caused the illness, and the nature of any pre-existing
cardiac abnormality and whether or not its presence was
known to the patient or his or her doctor or dentist prior
to the illness. Any areas of uncertainty were clarified by
further correspondence or other contact.
Ofjicial Statistics
The Registrar-General's and Office of Population Cen-
suses and Surveys' (OPCS) Annual Mortality Statistics
for England and Wales were used to obtain the total
population and the number, age and sex of those certified
as dying from IE during each of the 50 years 1933-83.
Other Reported Series
All major series of cases of IE reported during the past
half-century were studied to obtain evidence regarding
total incidence of the disease and changing trends in its
mortality, pathogenesis and microbiology.
Results
From the Survey
Proformas in respect of 582 episodes of IE occurring in
577 patients were received, five patients having a second
episode within the two-year period. The age range was
Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 15
2-87 (mean age 51.4 years); 32 patients were under 20
and all but six of them had congenital heart disease; 163
were over 65 years of age. There was a male preponder-
ance (ratio 2:1). In all, 137 had pre-existing rheumatic
heart disease, 108 congenital heart disease and 145 other
cardiac abnormalities, chiefly mitral valve prolapse and
calcific aortic valve disease. Of these 390 patients, 97 had
had valve replacement and 38 had suffered previous
attacks of IE; 183 patients were not thought to have had
any previous cardiac abnormality.
The aortic valve was the site most frequently affected
(148 patients) and after that the mitral valve (122
patients) and congenital heart lesions (54 patients). In 27
patients both aortic and mitral valves were involved.
The portal of entry of the causal organism, where
known, is summarised in Table 1. Streptococci were
Table 1. Portal of entry for causal organism.
No.
Possibly dental 108
Gastrointestinal tract 24
Genito-urinary tract 25
Respiratory tract 17
Skin 16
i.v. drug abusers 9
Fractures 4
Pregnancy and parturition 3
Nosocomial infections resulting from procedures
involving access to the bloodstream 27
No portal of entry apparent 349
Total 582
responsible in 367 patients, staphylococci in 116, a Gram-
negative bacterium in 15 and Coxiella burnetii in 9. Blood
cultures were negative in 53 patients and in the remainder
IE was caused by a varity of organisms. Factors rendering
patients especially susceptible to IE are shown in Table 2.
Table 3 shows the age, mortality and infecting organism
in the 84 patients with prosthetic valve endocarditis.
Table 2. Factors causing increased risk of IE.
No.
Prosthetic valves 84
Other cardiac surgery 13
Previous IE 38*
i.v. drug abusers 9
Diabetes mellitus 8
Alcoholism 4
Immunosuppression 9
Renal failure and haemodialysis 8
* Includes 9 of the 84 who had undergone valve replacement
Of the 577 patients, 83 (14.4 per cent) died, of whom
32 were female. The mean age of those dying (59.3 years)
was greater than those who recovered (50.0 years). Of
those with staphylococcal infections, 31 per cent died, as
Table 3. Age, mortality and infecting organism in 84 patients
with prosthetic valve endocarditis.
Early* Late
endocarditis endocarditis
Number 11 73
Mean age (yr) 46.9 52.2
Mortality 45% 23.8%
Previous IE ? 11
Organisms!:
Staphylococci:
Coagulase positive ? 15
Coagulase negative 8 10
Viridans streptococci 1 16
Bowel organisms ? 8
Cultures negative 1 10
Negative cultures Coxiella burnetii ? 5
Other organisms 3 10
Valves:
Mitral 3 26
Aortic 5 28
Mitral and aortic 5 10
Other ? 9
*Within 8 weeks of insertion of prosthetic valve
fThree patients' blood grew two organisms
compared with 12 per cent in whom bowel organisms
were responsible and 6 per cent who succumbed to other
streptococcal infections.
Emergency valve replacement was required in 36
patients. The diagnosis of IE was not made until oper-
ation in 4 patients and autopsy in 5.
From Official Mortality Statistics
The total population of England and Wales and the
mortality from IE each year over the period 1933-83 as
reported in the Registrar-General's and OPCS Annual
Mortality Statistics is shown in Fig. 1, the age of those
dying in Fig. 2 and their sex in Fig. 3.
From Other Reported Series
Table 4 shows the period covered by other major reported
series, the number of patients included, the sex ratio,
mortality and causal organism. It also includes the pro-
portion considered to have had previously normal hearts
and the number with prosthetic valves.
Discussion
It was hoped that the joint survey by the British Cardiac
Society and the Royal College of Physicians Research
Unit would provide information regarding the incidence
of the disease, but notification fell very far short of
expectations and it was clear that ascertainment was low.
The total number of proformas received was only slightly
in excess of the known mortality; none was received from
the Republic of Ireland and none from a number of large
hospitals in the UK, while patients reported to the
Communicable Disease Surveillance Centre included
16 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986
many for whom no proformas were forthcoming. More-
over, the low mortality in the 577 patients (14.4 per cent)
suggested under-reporting.
If the mortality among those suffering IE was accurate-
ly known it would be simple to calculate the incidence
from the total population figures. Thus if Hayward's[7]
and Oakley's[15] estimate of 30 per cent was correct, an
incidence of 1,116 cases in England and Wales in 1983
could be assumed, leaving only the undiagnosed and
incorrectly certified deaths excluded. However, Table 4
shows a wide range of mortality (19-46 per cent) in the
other reported series [3-14], Some of this discrepancy is
explained by the evolution of treatment over the years,
particularly in antibiotic therapy and emergency valve
replacement, and some reflects the special interest and
expertise of the authors. However, it also indicates that
none of the series can be accepted as a representative
sample. Smith et al. [9], whose series is probably less
biased and nearer total ascertainment than any other,
suggest an annual incidence of 16 per million of the
population but their mortality was 46 per cent.
The only way, therefore, to ascertain the incidence of
the disease would be to have it made notifiable. This
again would exclude undiagnosed cases and there would
inevitably be some diagnosed cases which were not
notified. It is also doubtful whether the information
obtained would be of sufficient value to justify the work
and expense entailed in collecting it. The number of
undiagnosed cases may be substantial, for it is a disease
notoriously difficult to recognise, as is shown by patients
undiagnosed until operation or autopsy in this and other
series[9,10,15]. Moreover, the traditional purpose of
notification, which never gives reliable absolute numbers,
is to enable local public health doctors to take early action
to prevent spread of disease.
Another possible source of information about incidence
is the Hospital In-Patient Enquiry. This, however, relates
only to a 10 per cent sample of in-patients in National
Health Service hospitals and is therefore unlikely to
provide accurate data.
There is no valid evidence as to whether the incidence
is increasing, decreasing or remaining static[7,12,13,15].
The number of cases reported by Public Health Labora-
tory Service and hospital microbiologists to the Commu-
nicable Disease Surveillance Centre showed an increase
from 298 in 1975 to 488 in 1980 but this probably reflects
improved reporting rather than higher incidence.
The mortality from IE, however, has fallen dramatical-
ly since curative treatment became possible, despite an
increase in the total population of England and Wales of
over nine million during the past half-century (Fig. 1). In
1933 there were 1,256 such deaths in England and Wales
and mortality remained at, or slightly below, this level
until antibiotics became available some ten years later,
Fig. 1. Annual deaths from infective endocarditis and population change, England and Wales, 1933-83.
Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 17
Fig. 2. Annual deaths from infective endocarditis by age group, England and Wales, 1933-83.
Fig. 3. Annual deaths from infective endocarditis by sex, England and Wales, 1933-83.
18 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986
Table 4. Published series of patients with IE
Authors
Years
covered
No. of
patients
Cates and Christie[3] 1945-9
Lerner and Weinstein[12] 1939-59
Cherubin and Neu[13] 1938-67
Hughes and Gauld[4] 1945-64
Shinebourne et al. [5] 1956-65
Hayward[7] 1956-72
Gray[8] 1955-75
Smith et al. [9] 1969-72
Schnurr et al. [10] 1973-6
Pelletier and Petersdorf[14] 1963-72
Moulsdale et al. [11] 1970-9
Lowes et al.[6] 1965-75
Bayliss et al. (present 1981-82
series)
(93
(582
M/F
ratio
Mortality
%
Streptococcal
%
Staphylococcal
%
No. with
Prosthetic previously
valve normal heart
442
100
655
68
93
N.S.
110
78
70
125
88
episodes)
60
577
episodes)
1/1
2/1
1/1
8/9
2/1
N.S.
N.S.
22/17
3/2
96/29
53/35
1.5/1
2/1
44.1
37
19
N.S.
31
31
24
46
34
37
36
20
14.4
94
56
61
59
55
N.S.
53
49
60
32
67
68
63
2
23
14
9
9
N.S.
5
31
27
39
25
9
20
none
N.S.
none
none
1
N.S.
6
13
5
16
20
2
97
0
39
181
18
19
N.S.
5
19
31
35
24
18
183
when deaths from IE were rapidly reduced to 498 in 1948
and 339 in 1953. They remained at about that level for a
decade until the benefits of emergency valve replacement
became evident and the number of deaths fell to 282 in
1968, but for the past decade they have fluctuated
between 189 (1979) and 249 (1974)[1,2]. This failure to
reduce further the number of deaths is due to the
relatively new phenomenon of IE in i.v.-drug abusers
(Tables 1 and 2[8,10,11-15,16-18]), in those with pros-
thetic valves (Tables 2, 3 and 4[8-l 1,14,16,19,20]) and
the increased number of old people in the population who
develop IE on previously normal heart valves and have a
poorer chance of survival than younger subjects (Fig.
2(4,5,8-14,16]).
The benefits of emergency valve replacement are not
wholly attributable to rescuing those in danger from heart
failure but also encompass the eradication of a deeply
entrenched nidus of infection and protection of the kid-
neys from embolic and other damage.
Apart from antibiotic therapy and valve replacement,
the better dental state of the population and antibiotic
prophylaxis to cover dental and surgical procedures and
investigations have doubtless helped to reduce mortality,
and the diminution in rheumatic heart disease has greatly
reduced one group at special risk.
The age and sex of those dying from IE have changed
significantly during the past 50 years[l,2]. In the pre-
antibiotic era about 20 per cent of the deaths occurred in
patients under 20 years of age, but during the past 25
years the number has been above 5 per cent in only one
year and in 1983 only one of the 225 deaths was in this
age group. On the other hand, deaths in the 'over 65s'
have risen from about 8 per cent 50 years ago to one half
of the total during the past decade (Fig. 2). Before
antibiotics there were more female than male deaths but
since treatment became available the reverse has been the
case (Fig. 3). The diminution in rheumatic heart disease,
more common in the female, and the increase, especially
in the male, of congenital bicuspid aortic valves and their
sequel, calcific aortic valve disease, doubtless explain
much of this change[4,5,8-14,16]. The Registrar-Gener-
al's and OPCS Mortality Statistics do not show such a
high male preponderance as that reported by some
authors[5,12,14], another indication that they are de-
scribing selected groups.
Prosthetic v^lve endocarditis carries a high mortality,
45 per cent in early cases and 23.8 per cent in late cases in
this series in which 84 of the 577 patients (15 per cent) had
this type of endocarditis (Table 3). The Communicable
Disease Surveillance Centre found a lower frequency of
endocarditis in those with prosthetic valves (128 cases (5.3
per cent) in 2,432 episodes) but this may reflect failure to
mention such a valve on the laboratory forms[20]. Wilson
et al. [21] reported a higher mortality (86 per cent in early
and 40 per cent in late cases) and 0.98 per cent of the
4,706 who had prosthetic valves inserted at the Mayo
Clinic developed prosthetic valve endocarditis during the
period 1963-74. Masur and Johnson[19] described 48
cases at the New York Hospital-Cornell Medical Centre
during the period 1962-78 during which 1,282 patients
had prosthetic valves implanted. The mortality rate in
early cases was 75 per cent and in late 66 per cent. All
writers have reported an increased proportion of staphy-
lococcal infections, - particularly in early cases[8-
11,14,20,22] and due to Coxiella burnetii in those occur-
ring later. In this series 33 of 84 cases were caused by
staphylococci. Of the 33, all the early cases and 10 of the
25 later cases were caused by coagulase negative species,
which accords with the findings of Masur and John-
son[19] and the Communicable Disease Surveillance
Centre[20],
There is a considerable population at especial risk of IE
(Table 2). Prosthetic valve implantation is the major
hazard but other writers have found a similar susceptibil-
ity in those who have had a previous attack of
IE[13,14,23-25], in i.v.-drug abusers[8,10-15,16,24],
diabetics[5,10,11,13,24,25], those suffering from malig-
nancy^, 11-13,15,25] or leukaemia[ll,13], alcohol-
ics^, 10,24,25], the immunosuppressed[15,23-25] and
those on renal dialysis[8,14,24],
Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 19
Table 1 shows the portal of entry of the causal organism
in the 582 episodes of IE included in the British Cardiac
Society/Royal College of Physicians Research Unit sur-
vey. In 349 no portal of entry was apparent, while in the
remaining 233 a variety of explanations appeared likely;
108 were possibly dental in origin, while 109 arose from
the gastrointestinal tract, the genito-urinary tract, the
respiratory tract, or the skin, or from nosocomial infec-
tion resulting from procedures involving access to the
blood-stream. Smaller numbers were attributable to nar-
cotic addiction, fractures and pregnancy or parturition.
Other writers have reported similar findings[5,9,11-
15,16,23-27],
The success of efforts to reduce the incidence of and
mortality from IE is greatly prejudiced by the fact that in
three-fifths of the patients there is no hint as to how the
causal organism gained access to the blood-stream. Since
Horder's[28] classic paper three-quarters of a century
ago, dental sepsis and dental procedures have been
thought frequently responsible. Cates and Christie[3]
thought the teeth were the culprit in nearly one-quarter of
their 442 patients and it has long been considered neces-
sary to give antibiotic prophylaxis to anyone with known
rheumatic or congenital heart disease to cover any dental
procedure they may undergo. This has not proved as
satisfactory as was hoped. Thousands and thousands of
dental procedures are carried out every day under widely
differing circumstances and the fact that the patient has a
cardiac lesion may be easily forgotten or not known, or
the antibiotic may be incorrectly administered or cor-
rectly administered and ineffectual[25,29]. Recent re-
ports^,6,10,13,14,30] have indicated that a dental source
for the infection is less frequent than hitherto and the
British Cardiac Society/Royal College of Physicians Re-
search Unit survey[25] showed only 11.7 per cent of 544
episodes of IE possibly due to dental procedures and 7.1
per cent possibly due to dental sepsis but of these patients
42.5 per cent were not known to have any pre-existing
heart disease. They recommended prophylactic antibiotic
cover for all those with known cardiac disease as
suggested by the British Society for Antimicrobial
Chemotherapy[31], but stressed the importance of en-
couraging people to seek better routine dental care.
It is even more unrealistic to hope to prevent episodes
of IE of gastrointestinal, genito-urinary, respiratory or
dermal origin or those associated with fractures, preg-
nancy and parturition. Cases so caused are very few,
especially when considered in the light of the enormous
number of surgical and investigative procedures carried
out on the gastrointestinal, genito-urinary and respirat-
ory tracts, the common infections, tumours and other
lesions in these organs and the very frequent breaches of
the skin surface which most people experience, all of
which could act as the portal of entry.
Added to these difficulties is the increasingly recog-
nised fact that in about one-third of cases of IE the
infection appears to attack previously normal hearts. The
scope for effective prophylaxis is therefore limited but the
susceptibility of those with rheumatic or congenital cardi-
ac abnormalities, calcific aortic stenosis, prosthetic
valves, previous other cardiac surgery, previous attacks of
IE, who are immunosuppressed or on dialysis, who are
diabetics or addicted to drugs or alcohol, should be kept
constantly in mind and for these groups antibiotic pro-
phylaxis, as suggested by the British Society for Antimi-
crobial Chemotherapy, should be considered whenever
they are at risk.
Acknowledgements
We are greatly indebted to Fellows and Members of the
College and to members of the British Cardiac Society for
their co-operation and help in this project.
References
1. Registrar-General's Statistical Review of England and Wales 1933- -?
73.
2. Office of Population Censuses and Surveys (1984) Mortality Statistics
1974-83, England and Wales. London: HMSO.
3. Cates, J. E. and Christie, R. V. (1951) Quarterly Journal of Medicine,
20, 93.
4. Hughes, P. and Gauld, W. R. (1966) Quarterly Journal of Medicine,
35, 511.
5. Shinebourne, E. A., Cripps, C. M., Hayward, G. W. and Shooter,
R. A. (1969) British Heart Journal, 31, 536.
6. Lowes, J. A., Hamer, J., Williams, G., Houang, E., Tabaqchali,
S., Shaw, E. W., Hill, I. M. and Rees, G. M. (1980) Lancet, 1,
133.
7 Hayward, G. W. (1973) British Medical Journal, 2, 706, 764.
8. Gray, I. R. (1975) Quarterly Journal of Medicine, 44, 449.
9. Smith, R. H., Radford, D. J., Clark, R. A. and Julian, D. G.
(1976) Thorax, 31, 373.
10. Schnurr, L. P., Ball, A. P., Geddes, A. M., Gray, J. and McGhie,
D. (1977) Quarterly Journal of Medicine, 46, 499.
11. Moulsdale, M. T., Eykyn, S. J. and Phillips, I. (1980) Quarterly
Journal of Medicine, 49, 315.
12. Lerner, P. I. and Weinstein, L. (1966) New England Journal of
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13. Cherubin, C. E. and Neu, H. C. (1971) American Journal of Medicine,
51, 83.
14. Pelletier, L. L. and Petersdorf, R. G. (1977) Medicine (Baltimore),
56, 287.
15. Oakley, C. M. (1980) British Journal of Hospital Medicine, 24, 232.
16. Petersdorf, R. G. and Goldman, P. L. (1979) Journal of Chronic
Diseases, 32, 287.
17. Oram, S. (1981) Clinical Heart Disease. London: Heinemann.
18. Anonymous (1981) British Medical Journal, 282, 677.
19. Masur, H. and Johnson, W. D. (1980) Journal of Thoracic and
Cardiovascular Surgery, 80, 31.
20. Communicable Disease Surveillance Centre, PHLS, unpublished.
21. Wilson, W. R., Jaumin, P. M., Danielson, S. K., Giuliani, E. R.,
Washington, T. A. and Geraci, T. E. (1975) Annals of Internal
Medicine, 82, 751.
22. Oakley, C. M. (1982) British Medical Journal, 284, 995.
23. Gray, I. R. (1981) Journal of the Royal College of Physicians, 15, 173.
24. Bayliss, R. I. S., Clarke, C. A., Oakley, C. M., Somerville, W.,
Whitfield, A. G. W. and Young, S. E. J. (1983) British Heart
Journal, 50, 513. 4
25. Bayliss, R. I. S., Clarke, C. A., Oakley, C. M., Somerville, W.
and Whitfield, A. G. W. (1983) British Heart Journal, 50, 506.
26. Bayliss, R. I. S., Clarke, C. A., Oakley, C. M., Somerville, W.,
Whitfield, A. G. W. and Young, S. E. J. (1984) British Heart
Journal, 51, 339.
27. Klein, R. S., Recco, R. A., Catalano, M. T., Edberg, S. C., a
Casey, J. I. and Steigbigel, N.H. (1977) New England Journal of
Medicine, 297, 800.
28. Horder, T. J. (1909) Quarterly Journal of Medicine, 2, 289.
29. Durack, D. T. and Littler, W. A. (1974) Lancet, 2, 846.
30. Pogrel, M. A. and Welsby, P. D. (1975) British Dental Journal, 139,
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31. Working Party of the British Society for Antimicrobial Chemo-
therapy (1982) Lancet, 2, 1323.
20 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986
|
PMC005xxxxxx/PMC5371130.txt | Modern Methods of Diagnosis of Muscle
Diseases
R. H. T. EDWARDS, MB, FRCP* Professor of Medicine
R. D. GRIFFITHS, MB, MRCP, Senior Lecturer, Department of Medicine
M. HAYWARD, MD, FRCR Consultant Neurophysiologist, Department of Neurological
Science
T. HELLIWELL, MB, MRCPath, Senior Lecturer, Department of Pathology
University of Liverpool, Royal Liverpool Hospital
Muscle diseases are generally considered to be rare and
therefore the province of the specialist. Yet there is no
single specialty in medicine which sees all muscle dis-
eases. At present patients with diseases or complaints
referable to skeletal muscle find their way into the clinics
not only of general physicians and neurologists but also
those of rheumatologists, paediatricians, psychiatrists and
orthopaedic surgeons. This is no surprise because skeletal
muscle represents about 40 per cent (less in the diseases of
muscle which result in wasting) of the body cell mass.
Muscle does therefore reflect disorders in a variety of
other body systems. The more a search is made for
manifestations of disordered structure or function of
muscle the more are changes found in diseases which are
not at first sight classified as muscle diseases. Thus there
are well-recognised changes of muscle structure or func-
tion in endocrine disorders whether or not there is
weakness[l]. Patients with psychogenic weakness or fa-
tigue of the kind which has variously been termed 'effort
syndrome', neurasthenia, Da Costa's syndrome or vaso-
regulatory asthenia[2] may also have altered muscle
mitochondrial function[3] which can result in excessive
intracellular acidosis[4].
Skeletal muscle is not only the biological machine on
which much of life and movement depends but it is also
the tissue capable of the greatest range of alteration in its
overall metabolic rate and most obviously related to the
generation (and absorption) of mechanical forces. Not
surprisingly, the factors that precipitate or aggravate
muscle symptoms are those which pertain to energy
exchanges or mechanical force. The 'machine' cannot be
considered in isolation from its sophisticated control
mechanisms, be they neural or metabolic. Because mus-
cle is also the largest pool of protein in the body, those
factors such as insulin, the sex hormones, prostaglandins
?r amino acids which influence protein metabolism in
general also have an influence on size, structure or
function of muscle.
As yet the diseases of muscle in general and the
inherited, progressive ones in particular (the dystrophies)
tend to be named in 'syndrome' or descriptive terms, for
example 'facioscapulohumeral muscular dystrophy'
(FSH) with little knowledge of the underlying mechanism
or explanation of the distribution of the pathological
process except that the inheritance is clear (dominant in
the case of FSH, see Fig. 1) and important for genetic
counselling. New genetic studies will, it is hoped, help to
explain why there is a high mutation rate in some
muscular dystrophies (i.e. why so many patients have no
family history) and confirm whether patients with the
same clinical appearances have indeed got the same
genetically determined disease. The inverse of this is
whether there is a significant environmental influence on
the course and distribution of the pathological processes,
as suggested in the 'mechanical' hypothesis, to explain
the largely proximal distribution of weakness in most
myopathies[5]. Clearly the identification of the genetic
defect in the dystrophies will have its most immediate and
useful role in carrier detection and antenatal diagnosis[6].
With this background it is our purpose to present new
developments in several fields that help in the diagnosis of
muscle diseases. Some of these have been reviewed
before[7] but this is a new appraisal of practical and cost-
effective techniques we use in a clinical practice involving
the diagnosis and management of paediatric and adult
patients with muscle diseases.
Needle Biopsy
This technique is simple, harmless, rapid, and repeat-
able. It is, in our opinion, now the ethical alternative to
open biopsy for the diagnosis of muscle diseases. Coupled
with histochemistry and electron microscopy it is a power-
ful and cost-effective method of examining muscle for
morphological and biochemical abnormalities with which
there has now been years of experience[8]. The residual
indications for open muscle biopsy are (a) motor point
Correspondence to: Professor R. H. T. Edwards, FRCP.
Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 49
biopsy for end-plate studies in myasthenia gravis, (b) the
search for affected arteries in polyarteritis nodosa, (c) to
obtain large samples of muscle for pharmacological inves-
tigation in suspected malignant hyperthermia or to obtain
samples for isolation of muscle mitochondrial]. Even
here, recent developments in the needle biopsy technique
make it possible to obtain adequate samples for such in
vitro studies (Professor A. Stadthouders, Nijmegen, per-
sonal communication[10]). The most common criticisms
levelled against needle biopsy are of poor orientation of
cross-sections and over-contraction of sarcomere struc-
ture, and of not being sufficiently representative in
heterogeneous (especially focal inflammatory) pathologi-
cal conditions of muscle. These criticisms can now be
countered in practice by orientating the specimen under a
dissecting microscope before freezing and allowing the
specimen for electron microscopy to 'relax' for some
minutes before fixation. The problem of being represen-
tative applies equally to an open biospy which is small in
size in comparison with that of the muscle as a whole and
which is usually more superficially located than a needle
biopsy. This criticism can be countered by taking more
than one needle biopsy through the same 4mm skin
incision from widely separated superficial and deep sites
in the muscle in those patients in whom a focal pathology
is suspected. If this relatively atraumatic approach is
unsuccessful in yielding the information sought, there are
still left the options of repeating needle biopsies at a future
date from another muscle or reverting to open biopsy
from the same or some other muscle.
In general the needle biopsy technique is sufficient to
provide material for diagnosis and research and it is so
valuable a diagnostic tool that it could (should) be carried
out on all patients who are referred for diagnostic electro-
physiology for suspected neuromuscular disease.
Needle biopsy of muscle and histological techniques are
aimed at defining the state of the contractile machine.
Conventional histological procedures demonstrate that
muscle cells respond to damage in only a limited number
of ways: atrophy or damage, adaptation to chronic
mechanical stress by hypertrophy or splitting, and by
invasion (by inflammatory cells) or replacement with fat
and fibrous tissues. Further information on the function
of individual muscle fibres is obtained using frozen tissues
and a variety of staining procedures in order to identify
the activities of individual enzymes. In normal human
muscle three different fibre types can be identified on the
basis of their staining in the myosin ATPase reaction after
pre-incubation at different pHs. Fibres in a given motor
unit are all of one type and normal muscle consists of a
mosaic of the different fibre types. In conditions resulting
in denervation and reinnervation of muscle the mosaic
pattern is lost and groups of fibres of one type are found.
Distinction between fibre types is also important in the
recognition of disorders that predominantly affect a par-
ticular fibre type, e.g. congenital fibre type dispropor-
tion, where the diagnosis is made solely on the presence of
small type 1 fibres, and the large range of disorders
showing selective atrophy of type 2 fibres, e.g. steroid,
hypothyroid and alcoholic myopathies. Other enzyme
stains which are part of the routine armament of the
muscle pathologist include stains for oxidative enzymes
which are useful for displaying the disordered internal
architecture of the fibres seen in many diseases of muscle.
An example is shown in Fig. 2 where pale areas in many
fibres enabled a diagnosis of 'central core disease' to be
made. Of recent interest is the identification of a variety
of metabolic myopathies in which abnormal enzyme
activities can be identified histochemically or biochemi-
cally. The accumulation of substrates may give diagnostic
clues, e.g. in type 2 glycogenosis (lysosomal acid maltase
deficiency) there is increased muscle glycogen and in
carnitine palmitoyltransferase deficiency there is in-
creased lipid. Histochemical methods can also be used to
assess the activities of specific enzymes. The best known
example is that of McArdle's disease (type V glycogeno-
sis) where the absence of myophosphorylase activity can
be readily identified histochemically. Phosphofructokin-
ase deficiency, which presents clinically in a similar way
to McArdle's disease, can also be shown in biopsy
specimens. Mitochondrial myopathies are conditions in
which increased numbers of morphologically abnormal
mitochondria are found in muscle fibres. This is best
appreciated using electron microscopy but histologically a
Muscle Clinic. I?Affected male. ? ? Unaffected male. ??Affected female. O?Unaffected female.
50 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986
characteristic appearance of 'ragged red' fibres is seen on
trichrome staining. Many different clinicopathological
entities have been described which have this appearance
on biopsy and, although they are presumed to be associ-
ated with disordered oxidative metabolism, in only a few
cases have specific enzyme defects been identified, e.g.
cytochrome C oxidase deficiency[11]. Myoadenylate dea-
minase (MAD) is another muscle enzyme whose de-
ficiency may be of clinical significance. MAD deficiency
was initially identified by routine screening of muscle
biopsies[12] by workers who have suggested that de-
ficiency may occur in up to 6 per cent of unselected
biopsies. This has been disputed and experience in the
UK[8,13] shows it to be far less common (<0.1 per cent),
and indeed low levels can be found in other disorders,
including Duchenne dystrophy. Clinically MAD-defi-
cient patients suffer from mild exertional cramps but it is
not clear to what extent these symptoms are related to the
enzyme deficiency. Obviously there is great scope in the
future for unravelling these metabolic myopathies and it
may well prove practical to demonstrate them histologi-
cally as well as biochemically.
The recent revolution in general pathology following
the introduction of immunohistological techniques and
monoclonal antibodies has so far found limited appli-
cation to muscle pathology. Its most significant appli-
cation has been in elucidating the role of immune
complexes and leucocytes in the polymyositis/dermato-
myositis complex?immunoglobulins, complement and
the various subclasses of T lymphocytes can now all be
readily identified in cryostat sections[14,15]. Immunolo-
gical methods for other components of muscle fibres, e.g.
myoglobin, actin, myosin, and intermediate filaments are
of limited diagnostic use except for the identification of
the muscle origin of the various types of rhabdomyosar-
coma. The main intermediate filament of muscle, des-
min, is involved in forming the inclusion bodies of
nemaline myopathy and is also increased in amount in
regenerating cells[ 16].
Electron microscopy (EM) has a limited role in the
diagnosis of muscle disorders. The ultrastructural
changes seen tend to be non-specific and common to
many human muscle disorders. The main use of EM is to
confirm light microscopic findings of, for example, in-
clusion bodies or abnormal mitochondria.
Measurement of Muscle Function
The determination of the force of maximum voluntary
contractions or those elicited by electrical stimulation at
different stimulation frequencies is now seen as valuable
in the assessment of possible drug effects on muscle or to
follow the time course of disease. Measurements with a
hand-held 'myometer' can be a useful adjunct to a
physiotherapist's charting of muscle strengthfl 7,18]. Ser-
ial force measurements can be a useful guide to muscle
breakdown and repair in conditions such as polymyosi-
tis)^]. Electrical stimulation of muscle by an accessible
motor nerve or percutaneously via large pad electrodes
that stimulate the intramuscular nerves allows precise
determination of the forces generated at different fre-
quencies and the relaxation rate[20]. The maximum
relaxation rate, determined as the first differential of the
force signal, is a particularly useful measurement because
it correlates closely with metabolism (determined as the
heat production in the adductor pollicis)[21] both with
ischaemia at rest and with fatiguing muscular activity. It
is of great interest that these tests of muscle function vary
with age, sex and nutritional status of the muscle[22,23]
possibly due to effects of nutrition on the regulation of
intracellular calcium concentration. Better known are the
effects of endocrine disorders on muscle strength and
relaxation rate[24], Ischaemic exercise of forearm mus-
cles followed by venous blood sampling for lactate and
ammonia can be a valuable screening test for distinguish-
ing a glycolytic defect (producing no lactate) from myo-
adenylate deaminase deficiency (producing no ammonia)
with exercise[25],
Electrophysiology
Conventional electrophysiology contributes evidence
based largely on recordings of action potentials that can
help to establish whether the muscle wasting or weakness
is primarily 'neuropathic' or 'myopathic'. Repetitive
nerve stimulation is also a valuable test in the diagnosis of
myasthenia gravis. New techniques involving computer
analysis of the electrical recordings are now providing the
opportunity to analyse the function of individual motor
units.
jrtSfcrVS
Fig. 2. Needle biopsy of skeletal muscle showing features of
'central core disease' in a 16year old male with wasted muscles
since birth (NADH + TR x 375).
Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 51
Electromyographic techniques play an important part
in the diagnosis of neuromuscular diseases and an in-
creasing role in the understanding of the physiology of
normal and abnormal muscle. With the introduction of
special types of recording electrodes many new analytical
techniques have been developed. The core of a single-
fibre electrode (Fig. 3a) is 25 /zm in diameter, comparable
to the diameter of a normal muscle fibre, and the
electrode records selectively a very small number of
fibres. This electrode is widely used to study 'jitter' of
pairs of potentials (Fig. 4), a sensitive index of the
stability of neuromuscular transmission[26J. Neuromus-
cular transmission is disturbed in regenerating poten-
tials^?] as well as in myasthenia gravis. A finding of
abnormally low jitter occurs when muscle fibres are
split[28]. By counting the frequency with which linked
pairs of muscle fibres are recorded on random insertion
into the muscle, the fibre density is measured, an index of
the fine morphology of the muscle, increased in dystro-
phies as well as in denervation[29]. The macro-electrode
(Fig. 3b) is an adaptation of the original single-fibre
electrode in which the proximal part of the shaft is
insulated and the distal part left exposed. A single fibre
potential recorded from the core is used to trigger an
averager and the macro-potential is then averaged be-
tween the exposed tip of the shaft and a remote surface
electrode. The macro-potential is an indicator of the
cross-sectional area of the motor unit[30].
The concentric needle electrode (Fig. 3c) has a core of
150 nm diameter and records motor unit potentials
(MUP) from up to 12 of the closest fibres of an active
motor unit[31]. This electrode remains the standard tool
for diagnostic electromyography. Microprocessors are
starting to make automatic measurement of MUP a
reality in the clinical service department, bringing in-
creased objectivity to the assessment of MUP[32]. In
addition, computer modelling of MUP has given new
understanding of the origin of the MUP and the conduc-
tion of the potentials through the complex ionic environ-
ment of the muscle[33,34]. The interpretation of MUP is
expanding from the empirical associations of parameters
with primary muscle disease or chronic denervation,
established by the pioneers of the subject[35,36], to
include the interpretation of those parameters in terms of
the geometry of the electrical generators.
The interpretation of interference patterns, the com-
plex activity recorded in a muscle at stronger contraction
effort when multiple MUPs are superimposed, requires
automated methods of signal analysis in time or frequen-
cy domains[37,38]. Methods of analysis which were
developed with specifically designed hardware are now
being implemented in general purpose microprocessors,
making them much more readily available for diagnostic
use. Analytical methods which deconvolute the interfer-
ence pattern into its constituent potentials give additonal
insight into the functioning of muscle but require very
considerable computing power and are confined to a few
research laboratories[39].
Magnetic Resonance Spectroscopy in the Study of
Myopathy
This is a new technique which offers much in the
understanding of muscle energy metabolism and chemi-
cal content. A typical 31P MR spectrum of normal muscle
(Fig. 5) shows the key energy metabolites of phosphocrea-
tine (PCr), adenosine triphosphate (ATP) and inorganic
phosphate (Pi). It is now possible to study non-invasively
this high-energy phosphate metabolism along with the
intracellular pH of muscle. This has come about with the
advent of wide-bore magnets and the application of high
resolution magnetic resonance spectroscopy (MRS) using
surface coils. In principle MRS is a method of obtaining
information about the behaviour and content of nuclei in
differing chemical environments through interrogation
with weak radio-frequency pulses.
Pioneering studies of topical 31P MRS in human
muscle metabolism have come from C)xford[40-42),
Philadelphia [43,44], and London[45,46], A recent re-
view[47] discusses this new technology. The first clinical
application of 31P MRS[48] was in a patient with
McArdle's syndrome (myophosphorylase deficiency) in
which lactic acid accumulation during ischaemic exercise
is prevented by the failure of glycogenolysis. It was
possible to show non-invasively the lack of an acid shift in
the intracellular pH which normally occurs with lactic
acid accumulation during ischaemic exercise. Phospho-
fructokinase (PFK) deficiency is a more rare glycolytic
defect which presents with a similar clinical picture as
Fig. 3. Electrodes used for recording from muscle, a?single
fibre electrode; b?macro-electrode; c?concentric needle elec-
trode.
Fig. 4. Pair of single fibres showing jitter.
52 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986
myophosphorylase deficiency. The MRS findings are
strikingly characteristic, with a steady accumulation of a
3lP sugar phosphate resonance during exercise, consistent
with the level of the block in the glycolytic pathway. This
MRS finding initially reported[45] and confirmed[44] in
1982 is illustrated in yet another patient (Fig. 6). The
ability to repeat the measurements non-invasively enables
changes with exercise to be followed (Fig. 7). By studying
the kinetics of the metabolite changes it is possible to
differentiate PFK deficiency from phosphoglyceratekin-
ase deficiency[49].
Patients with mitochondrial myopathies have been
studied[41,47,50]. At rest various abnormalities could be
demonstrated of reduced PCr, high Pi, high calculated
ADP, and in some abnormal intracellular pH. The
kinetics of PCr metabolism, best seen in two patients with
NADH-CoQ reductase deficiency[40] and in a defect in
Pyruvate oxidation[51], show excessive PCr utilisation
with exercise and slowed oxidative recovery. Excessive
intracellular acidosis on exercise has been demonstrated
by MRS in a patient with a post-viral fatigue syn-
drome^].
The question whether a reduced energy state exists in
Fig. 5. Typical 3,P MR spectrum of normal muscle showing
the key energy metabolites of phosphocreatine (PCr), inorganic
phosphate (Pi), and the three resonances of the phosphates of
adenosine triphosphate (A TP). In the lower spectrum from the
calf muscles a noticeable signal (PDi) is seen arising from the
phosphodiesters.
Sugar phosphate
2
*rtw(ui'
22.95
6.25 -/ &
'V^v'Vv Rest
0 min
I i i I i i I i I
10 0 -10-20 PPM
Fig. 6. Changes in energy metabolites with exercise in phospho-
fructokinase deficiency. A large resonance in the phosphomones-
ter region of the spectrum, left of the Pi signal, can be seen and
represents the accumulation of the sugar phosphates before the
enzyme block.
Fig. 7. The energy metabolite changes in a similar study to
Fig. 6, shown plotted as fractions of the total mobile phosphorus
signal. With exercise there is a fall in PCr and rise in Pi but,
due to the trapping of phosphate in glycolytic intermediates, the
rise in Pi is small with a large accumulation of sugar
phosphates. The absence of lactic acid production is shown by
the normal intracellular pH. The slowed metabolite recovery
following exercise is seen.
Time min
Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 53
dystrophic muscle has been studied by MRS, at rest and
with exercise in boys with Duchenne muscular dystro-
phy[52]. The considerable problems of tissue standardisa-
tion, which complicate conventional analysis due to fat
and fibrous tissue derangement of the muscle, have been
addressed by a combination of 'H, 31P MRS and mor-
phometry of needle biopsies. The ATP content was not
reduced in the dystrophic muscle, and was not altered in a
double-blind controlled trial of allopurinol. A lower PCr
and higher Pi content was found indicative of a reduced
phosphorylation potential, yet in a disease characterised
by a massive leak of the enzyme creatine kinase no defect
of intracellular activity of this enzyme could be demon-
strated, with a normal oxidative PCr recovery.
Proton 'H MRS offers exciting possibilities now that
techniques to suppress the dominant water resonance
have been developed[53]. The combination with 31P
MRS[54] allows lactate measurement to be added to the
phosphate metabolite information. The study of urinary
organic acids with 'H and the measurement of carnitine
and acyl-carnitines following carnitine infusion[55] open
up the possibility of studying the disorders of fat metabo-
lism in muscle, which so far by 31P MRS have proved
difficult[56]. The ,3C techniques[57], along with 13C
labelled glucose infusions[58], open up a large field of
study, particularly that of glycolytic metabolism. As
whole-body spectrometers (as in Oxford and shortly in
Liverpool) become available, the study of a myopathy in
relationship to other organ/system involvement will be a
practical but expensive research and possibly diagnostic
opportunity.
Imaging of Skeletal Muscle
It is obvious that a wasted muscle is weak but it is not so
clear whether the muscle, whatever its size, can develop
the force expected of it. What then is the force expected?
It is proportional to the total cross-sectional area of the
actomyosin interactions, which is only approximately
proportional to the cross-section of the muscle as a whole.
Since it is not possible to determine this from surface
measurements (despite attempts to allow for the thickness
of subcutaneous fat) there is interest in the use of modern
imaging techniques, ultrasound (US)[59-61], X-ray com-
puterised tomography (CT)[62] and magnetic resonance
imaging (MRI)[63]. Each has its advantages and limita-
tions but all can not only give an accurate measurement
of the cross-section of the muscle but also an indication of
the composition of the muscle (i.e. whether it has been
replaced with fat or fibrous tissue as typically occurs in
muscular dystrophy[62,64,65]). Radio-nucleide (e.g.
99m pyrophosphate) uptake in skeletal muscle is also a
means of imaging muscle damage as in inflammatory
myopathy[65] and following mechanical damage to
muscle [66].
Conclusions
Several techniques are now becoming available to visua-
lise the structure, electrical properties, contractile capa-
bilities and metabolism in human muscle. As diagnostic
tools not one of them is uniquely sufficient but in
combination they promise rational explanations for the
disorders of muscle structure or function that are current-
ly known in descriptive terms as syndromes. However,
these new opportunities for studying muscle also yield
more descriptive pathological and biochemical diagnoses
(e.g. 'central core disease' or 'mitochondrial myopathy')
which require further analysis.
Accurate (or in practice 'as accurate as possible')
diagnosis is necessary in this class of disease in which
there are important differences in prognosis and inheri-
tance. The new genetics, with the possibility of soon
identifying the abnormal gene in the muscular dystro-
phies, offer an important theoretical and practical tool to
determine the precise genetic diagnosis both antenatally
and for a patient as well as for genetic counselling. It
should also help to resolve the question as to whether
patients with apparently similar clinical appearances have
indeed the same muscle disease. Variation in severity
could be due to environmental (diet or exercise) influ-
ences which might then be explored with possible thera-
peutic benefit. The field of interest in clinical muscle
science is advancing rapidly, with several developments
in basic science and technology, and it is therefore with
guarded optimism that we and others look to a more
promising therapeutic future for this class of diseases for
which there is currently little or no effective treatment.
Acknowledgements
The research which has established many of the new
techniques developed by Professor Edwards' team has
been generously supported by the Wellcome Trust and
the Muscular Dystrophy Group of Great Britain. Gener-
ous support from the Mersey Regional Health Authority
in the form of research grants is also gratefully acknowl-
edged.
This article is based on a paper read at the College Regional
Conference held at Liverpool in September 1985.
References
1. Edwards, R. H. T., Khaleeli, A. A. and Mills, K. R. (1983)
Seminars in Neurology, 3, 294.
2. Newham, D. and Edwards, R. H. T. (1979) Physiotherapy, 65, 52.
3. Mills, K. R. and Edwards, R. H. T. (1983)Journal of the Neurological
Sciences, 58, 73.
4. Arnold, D. L., Bore, P. J., Radda, G. K., Styles, P. and Taylor,
D. J. (1984) Lancet, 1, 1367.
5. Edwards, R. H. T., Newham, D. J., Jones, D. A. and Chapman
S. J. (1984) Lancet, 1, 548.
6. Pearson, P. C. (1985) In Proceedings of the 23rd Symposium of the Society
for the study of inborn errors of metabolism.
7. Edwards, R. H. T. (1984) Muscle and Nerve, 1, 599.
8. Edwards, R. H. T., Round, J. M. and Jones, D. A. (1983) Muscle
and Nerve, 6, 676.
9. Morgan-Hughes, J. A. (1982) In Recent advances in clinical neurology
(ed W. B. Matthews and G. H. Glaser) pp. 1-46. Edinburgh:
Churchill Livingstone.
10. Gohil, K., Jones, D. A. and Edwards, R. H. T. (1981) Clinical
Physiology, 1, 195.
11. DiMauro, S., Mendell, J. R., Sahenk, Z. et al. (1980) Neurology
(N.Y.), 30, 795.
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12. Fishbein, W. N., Armbrustmecher, V. M. and Griffin, J. L.
(1978) Science, 200, 545.
13. Hudgson, P. (1983) Recent Advances in Rheumatology, 3, 117.
14. Isenberg, D. A. (1983) Quarterly Journal of Medicine, L.II, 297.
15. Oxenhandler, R. and Hart, M. N. (1983) Human Pathology, 14,
326.
1?- Thornell, L-E, Eriksson, A. and Edstrom, L. (1983) Cell and Muscle
Motility, 4, 85.
17. Edwards, R. H. T. and McDonnell, M. (1974) Lancet, 2, 757.
18. Scott, O. M., Hyde, S. A., Goddard, C. and Dubowitz, V. (1982)
Muscle and Nerve, 5, 291.
19. Edwards, R. H. T., Wiles, C. M., Round, J. M., Jackson, M.J.
and Young, A. (1979) Muscle and Nerve, 2, 223.
20. Edwards, R. H. T., Young, A., Hosking, G. P. and Jones, D. A.
(1977) Clinical Science and Molecular Medicine, 52, 283.
21. Wiles, C. M. and Edwards, R. H. T. (1982) Clinical Physiology, 2,
485.
22. Lopes, J., Russel, McL. D., Whitwell, J. and Jeejeebhoy, K. N.
(1982) American Journal of Clinical Nutrition, 36, 606.
23. Lenmarken, C., Bergman, T., Larsson, J. and Larson, L-E.
(1985) Clinical Physiology, 5, 243.
24. Edwards, R. H. T., Khaleeli, A. A. and Mills, K. R. (1983)
Seminars in Neurology, 3, 294.
25. Sinkeler, S. P. T., Daanen, H., Wevers, R. A., Oei, T. L., Joosten,
E. M. G. and Binkhorst, R. A. (1985) Muscle and Nerve, 8, 523.
26. Stalberg, E., Ekstedt,J. and Broman, A. (1972) Journal of Neurology,
Neurosurgery and Psychiatry, 37, 540.
27. Schwartz, M. S., Stalberg, E., Schiller, H. H. and Thiele, B.
(1976) Journal of the Neurological Sciences, 27, 303.
28. Ekstedt, J. and Stalberg, E. (1970) Electroencephalography and Clinical
Neurophysiology, 27, 557.
29. Stalberg, E. and Thiele, B. (1975) Journal of Neurology, Neurosurgery
and Psychiatry, 38, 874.
30. Stalberg, E. and Fawcett, P. R. W. (1982) Journal of Neurology,
Neurosurgery and Psychiatry, 45, 870.
31. Thiele, B. and Bohle, A. (1978) Zeitschrift fur EEG-EMG, 9, 125.
32. Stalberg, E. and Antoni, L. (1983) Progress in Clinical Neurophysiology
10, pp. 186-234. (ed J. E. Desmedt.) Basel: Karger.
33. Wani, A. and Guha, S. (1980) Medical and Biological Engineering, 18,
719.
34. Andreassen, S. and Jorgensen, N. (1981) Electroencephalography and
Clinical Neurophysiology, 52, 116S.
35. Kugelberg, E. (1949) Journal of Neurology, Neurosurgery and Psychiatry,
12, 129.
36. Buchthal, F., Guld, C. and Rosenfalck, P. (1959) Acta Physiologica
Scandinavica, 32, 200.
37. Hayward, M. (1977) Journal of the Neurological Sciences, 33, 397.
38. Hayward, M. (1983) Progress in Clinical Neurophysiology, 10, pp. 128-
49. (edj. E. Desmedt.) Basel: Karger.
39. DeLuca, C.J., LeFever, R. S., McCue, M. P. and Xenakis, A. P.
(1982) Journal of Physiology (Lond), 329, 113.
40. Radda, G. K., Bore, P. J., Gadian, D. G. et al. (1982) Nature, 295,
608.
41. Gadian, D. R., Radda, G. K., Ross, B. D. et al. (1981) Lancet, 2,
774.
42. Taylor, D. J., Bore, P. J., Styles, P., Gadian, D. G. and Radda,
G. K. (1983) Molecular Biology and Medicine, 1, 77.
43. Chance, B., Eleff, S., Leigh, J. S. Jr., Sokolow, D. and Sapega, A.
(1981) Proceedings of the National Academy of Sciences USA, 78, 6714.
44. Chance, B., Eleff, S., Bank, W., Leigh, J. S. Jr. and Warnell, R.
(1982) Proceedings of the National Academy of Sciences USA, 79, 7714.
45. Edwards, R. H. T., Dawson, M. J., Wilkie, D. R., Gordon, R. E.
and Shaw, D. (1982) Lancet, 1, 725.
46. Wilkie, D. R., Dawson, M. J., Edwards, R. H. T., Gordon, R. E.
and Shaw, D. (1984), Contractile mechanisms in muscle Vol. II, pp.33-
347. (ed G. H. Pollack and H. Sugied.) New York: Plenum Press.
47. Edwards, R. H. T., Griffiths, R. D. and Cady, E. B. (1985)
Clinical Physiology, 5, 93.
48. Ross, B. D., Radda, G. K., Gadian, D. G., Rocker, G., Esiri, M.
and Falconer-Smith, J. (1981) New England Journal of Medicine, 304,
1338.
49. Dubac, D., Jehenson, P., Fardeau, M., Syrota, A. and Tran Dinh,
S. (1985) Proceedings of the Society of Magnetic Resonance in Medicine,
August 1985, pp.463-464.
50. Arnold, D. L., Taylor, D. J. and Radda, G. K. (1985) Annals of
Neurology, in press.
51. Edwards, R. H. T., Griffiths, R. D., Radda, G. K. and Taylor, D.
T. (1985) Proceedings of the Society of Magnetic Resonance in Medicine.
August 1985, pp..1221-1222.
52. Griffiths, R. D., Cady, E. B., Edwards, R. H. T. and Wilkie, D.
R. (1985) Muscle and Nerve, in press.
53. Williams, S. R., Gadian, D. G., Proctor, E., Sprague, D. B. and
Talbot, D. F. (1985) Journal of Magnetic Resonance in Medicine, in
press.
54. Williams, S. R., Gadian, D. G., Proctor, E., Sprague, D. B. and
Talbot, D. F. (1985) Proceedings of the Society of Magnetic Resonance in
Medicine, August 1985, pp.558-559.
55. lies, R. A., Chalmers, R. A., Jago, J. R. and Williams, S. R.
(1985) ibid., pp.728-729.
56. Griffiths, R. D. and Edwards, R. H. T. (1985) In Subcellular
Pathology: A biochemical approach to organelle damage, (ed T. J. Peters.)
London: Chapman & Hall, in press.
57. Barany, M., Doyle, D. D., Graff, G., Westler, W. M. and
Markley, J. L. (1984) Magnetic Resonance in Medicine, 1, 30.
58. Jue, T., Shulman, G. I., Alger, J. R., Arias-Mendoza, F.,
Rothman, D. L. and Shulman, R. G. (1985) Proceedings of the Society
of Magnetic Resonance in Medicine, August 1985, pp. 6-7.
59. Cady, E. B., Gardener, J. E. and Edwards, R. H. T. (1983)
European Journal of Clinical Investigation, 13, 469.
60. Heckmatt, J. Z., Leeman, S. and Dubowitz, V. (1982) Journal of
Paediatrics, 101, 656.
61. Heckmatt, J. Z., Dubowitz, V. and Leeman, S. (1980) Lancet, 1,
1389.
62. Grindrod, S., Tofts, P. and Edwards, R. H. T. (1983) European
Journal of Clinical Investigation, 13, 465.
63. Weinreb, J. C., Cohen, J. M. and Maravilla, K. R. (1985)
Magnetic Resonance Imaging, 3, 199.
64. Jones, D. A., Round, J. M., Edwards, R. H. T., Grindrod, S. R.
and Tofts, P. S. (1983) Journal of the Neurological Sciences, 60, 307.
65. Bulcke, J. A. L. and Baert, A. L. (1982) Clinical and Radiological
Aspects of Myopathies, New York: Springer.
66. Newham, D. J., Tolfree, S. E. J. and Edwards, R. H. T. (1985)
Clinical Science, 68, 76P.
Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 55
|
PMC005xxxxxx/PMC5371131.txt | The Immunology of Cytomegalovirus Infection
J. G. E .SISSONS, MD, FRCFJ Senior Lecturer in Medicine and Virology, Departments of
Medicine and Virology, Royal Postgraduate Medical School, London
Persistent virus infections are often advanced as possible
causes for diseases of unknown aetiology. This is logical
enough, given the evidence that persistent virus infections
in animals, and in certain specific instances in humans,
may indeed be associated with various chronic diseases.
There are a number of possible strategies for pursuing
research in this area: (a) to look for new viruses in
diseases of unknown aetiology; (b) to ask whether a
particular known virus is associated with a particular
disease; (c) to endeavour to learn as much as possible
about the biology of a given persistent virus, and see what
one learns about its association with disease. Options (a)
and (b) are relatively 'high risk', and while well worth
pursuing, the third option is perhaps safer and will more
predictably yield useful information.
In the last few years we have been studying human
cytomegalovirus (HCMV), attempting to understand
how the virus persists in the normal host, and how
perturbation of this relationship leads to disease.
The Clinical Problem
Primary infection with HCMV in the normal subject is
usually asymptomatic but may be associated with the
syndrome of infectious mononucleosis (about 10 per cent
of infectious mononucleosis is said to be due to HCMV
and associated with a negative monospot test). In
immunosuppressed subjects, however, primary HCMV
infection can produce severe illness, with dissemination
and involvement of lungs, liver, gut, eye and other sites.
In pregnancy, primary maternal infection is more likely
to lead to congenital infection in the neonate than to
reactivation of maternal infectionfl]. Following primary
infection, -the virus persists in the host, as do the other
herpes viruses. In contrast to herpes simplex and varicella
zoster, which establish classical latency in neuronal cells,
it now seems more likely that Epstein-Barr virus (EBV),
and probably HCMV as well, may replicate at low level
for much of the time in the healthy carrier without
producing symptoms. EBV persists in B cells and prob-
ably in oropharyngeal epithelial cells[2] but the exact
site(s) at which HCMV persists in the normal infected
individual is still uncertain. The virus probably persists in
epithelial cells in the salivary gland and in the kidney;
although it is commonly stated that HCMV persists in
lymphocytes and/or macrophages, the hard evidence for
this is lacking. Major reactivation and dissemination may
occur if the host is immunosuppressed. Iatrogenic im-
munosuppression in the context of organ or bone marrow
transplantation has been the most frequent setting for
severe HCMV infection, but HCMV is now also one of
the most frequent causes of morbidity and death in
patients with the acquired immunodeficiency syndrome
(AIDS)[3],
In many ways HCMV is the most enigmatic of the
herpes viruses, and it is partly for this reason that it has
been a 'soft candidate' for implication in diseases of
unknown aetiology. HCMV has been rather speculative-
ly associated with a number of such diseases, from
atherosclerosis to disorders of the central nervous system.
As with other herpes viruses, HCMV is also a candidate
oncogenic virus and has been proposed as a cause of
African Kaposi's sarcoma. These various disease associ-
ations will all remain speculative until more convincing
data emerge, particularly from careful DNA hybridisa-
tion studies.
Virology and Molecular Biology
Some knowledge of the molecular virology of HCMV is
an essential prerequisite to understanding its immunol-
ogy and biology. HCMV is the largest of the human
herpes viruses, with a linear double-stranded DNA gen-
ome of about 235 kilobases (Fig.l). This has the capacity
to code for up to 150 proteins but as yet the precise
number and nature of these proteins is unresolved.
However the complete nucleotide sequence of the virus
will probably be known soon and this will enable much of
the protein structure to be deduced from the primary
sequence. Most work on the molecular biology of the
herpes viruses has been done with herpes simplex, so
more is known about it than about the other herpes
viruses, for which it tends to serve as a prototype.
As with other herpes viruses, synthesis of the virus-
specified proteins occurs in a regulated cascade, expres-
sion of one set of proteins being essential for expression of
the next (Fig.l). The immediate early (IE) proteins are
expressed shortly after the virus infects a cell. Some of
them are 'trans acting factors' that can stimulate tran-
scription of the genes for the virus IE proteins (see below),
and, although this is presumably their true function, they
can also stimulate transcription of inducible cellular
genes[4]. Some of the IE proteins are DNA binding
proteins, and the 'trans' refers to their ability to activate
transcription from transcription units on duplex DNA
other than that on which they themselves are encoded.
The virus early proteins are then expressed: little is
known of their function, but one of them is the virus DNA
40 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986
polymerase. Unlike herpes simplex, HCMV does not
encode its own thymidine kinase, and this explains its lack
of sensitivity to acycloguanosine (Acyclovir). The next
event is replication of the virus DNA, following which the
> virus late proteins are expressed: the late proteins are the
structural proteins of the virus particle. It is important to
emphasise that the IE and early proteins are only ex-
pressed in the infected cell and not in the virion particle
itself, which is particularly pertinent when considering
the specificity of the immune response. Little is known of
the precise molecular events in the host which determine
reactivation of latent virus, or affect the subsequent
transcription of the virus genome, although they are likely
to be of great importance in the pathogenesis of HCMV
infection.
Immunology
The presence of serum antibody is used as a marker of
infection with the herpes viruses (as it is for other viruses)
and thus as evidence for the carriage of latent virus.
Antibody is probably important in neutralising virus in
the fluid phase and perhaps in diminishing the severity of
primary infection. Yet immunoglobulin deficiency is not
associated with particularly severe herpes virus infections,
and reactivation occurs in seropositive subjects despite
the presence of serum antibody. Hence it is generally
assumed that T cell immunity is likely to be of more
importance in controlling these large DNA viruses within
the infected host. Evidence to back this assumption comes
from the considerable body of work on EBV: normal
subjects seropositive for EBV have a high frequency of
memory cytotoxic T cells in their peripheral blood, which
show specificity for EBV-transformed B cells. These T
cells are presumed to play an important role in vivo by
preventing the continued growth of EBV-transformed B
cells[5].
In attempting to understand the immunological control
of HCMV it seems more logical to examine T-cell
responses in the asymptomatic persistently infected host
rather than in patients with symptomatic HCMV infec-
tion in whom such responses are presumably likely to be
defective. In order to determine the nature and specificity
of circulating memory T cells responding to HCMV in
normal seropositive subjects, we used the technique of
secondary in vitro stimulation with antigen and subse-
quent expansion of the responding cells in interleukin-2
(IL-2) dependent culture. IL-2 is a growth factor released
by stimulated T cells which permits the continued growth
of antigen-activated T cells (and is in this sense an
autocrine growth factor); this allows the accumulation of
sufficient T cells for their function to be assessed and also
permits attempts at their cloning[6]. We were especially
interested to see if cytotoxic T cells specific for HCMV
were present, because of the evidence on EBV already
mentioned and because the role of this effector T cell has
been particularly well studied in experimental models of
virus infection[7].
We found that when peripheral blood mononuclear
cells from seropositive subjects were stimulated in vitro
with HCMV antigen, which consisted of virus particles,
the T-cell lines generated were of helper (T4) phenotype
and did not kill HCMV-infected target cells. However, if
HCMV infected fibroblasts were used as the stimulating
antigen, most of the responding T cells were of the T8
phenotype. These T cells were cytotoxic, killing HCMV-
infected fibroblast targets and showing the property of
HLA restriction; i.e. they would only lyse virus-infected
target cells with which they shared class I MHC antigens,
the hallmark of virus-specific cytotoxic T cells. They also
killed cells which had been infected with HCMV for only
six hours[8] (Fig. 2). These experiments suggested that
there were memory T cells in the peripheral blood of
normal seropositive people which were directed predomi-
nantly at the virus early and/or immediate early proteins
which are only expressed in the infected cell and not in the
virus particle itself. In further experiments we found that
such T-cell lines could lyse target cells treated with
phosphonoformate, an inhibitor of the virus DNA poly-
merase which prevents virus DNA replication and expres-
sion of the late proteins (and is now incidentally marketed
as a drug for the treatment of HCMV?Foscarnet). The
experiment provides further evidence that T cells are
directed to those proteins which are only expressed in the
infected cell. In what are probably analogous results, it
has recently been reported that a high proportion of
cytotoxic T cells in mice infected with mouse CMV show
HCMV DNA
11 110 1 235 Kb
Ul Us
? Early proteins
f Late proteins
Fig. 1. Schematic view of genome and protein synthesis of
human cytomegalovirus. The virus has a linear double-stranded
DNA genome divided into long and short unique DNA
sequences (UL and Us) which are each bounded by inverted
repeat sequences. Within the infected cell the proteins specified
by the virus are expressed in three sequential phases, the
immediate early and early proteins are only expressed in the cell,
and virus DNA replication cannot occur until they have been
expressed. Following virus DNA replication the late proteins
are expressed: they are the only proteins actually present in the
virus particle. The times refer to the approximate timing of
expression and progeny virus production in tissue culture.
Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 41
specificity for the immediate early protein of that
virus[9].
T cells with this sort of specificity could obviously
provide a 'surveillance' mechanism for eliminating
HCMV-infected cells before release of progeny virus, but
more work will be needed to determine if this is what
actually happens in vivo. There is work showing that
HCMV-specific cytotoxic T cells may be detected directly
in the peripheral blood of patients (bone marrow trans-
plant recipients) with active HCMV infection, and that
their presence correlates with recovery[10]. However,
one problem with this sort of direct approach, without
secondary stimulation in vitro, is that it is difficult to get
enough cells to analyse their specificity for particular viral
proteins.
The existence of cytotoxic T cells does not necessarily
imply that other T-cell-dependent mechanisms are unim-
portant in host defence. Helper T-cell lines with similar
specificity for the HCMV early proteins can also be
established from normal seropositive subjects, as might
be expected. In addition to providing help for the devel-
opment of other effector T-cell responses, such helper
cells could in theory have an effector function. T cells
mediating delayed hypersensitivity (DH) are important
in resistance to herpes virus infections in experimental
models in micefll]; DH is probably mediated principally
by helper T cells releasing gamma interferon which
activates macrophages at the site. It is difficult to study
DH in human systems because this would have to be done
mainly in vitro, and so far we do not know how important
it is in HCMV, or in any human virus infection.
Non-Specific Immunity
Natural killer (NK) cells are found among peripheral
blood mononuclear cells and are so called for their ability
to kill virus-infected (and tumour) cells without showing
conventional immunological specificity or memory. Their
cytotoxic activity is enhanced by interferons and by
interleukin-2. The extent to which they are primarily of
monocyte or T-cell lineage is uncertain: however, a
proportion of NK cells do have T-cell markers, and the
balance of current evidence favours their being more
related to T cells. There is increasing evidence from
experimental models that NK cells have a role in limiting
the severity of virus infection in the period immediately
following infection, particularly before the development
of specific T-cell immunity; this has been shown better for
mouse CMV infection than for other viruses[12].
We have also looked at the stage at which CMV
infected cells become susceptible to being killed by natu-
ral killer cells. We found that when CMV infected cells
expressed the virus early antigens they became markedly
more susceptible to being killed by NK cells[ 13] (Fig. 3).
The actual target structures recognised by NK cells have
not been defined, but are almost certainly not viral
proteins; it is more likely that NK cells recognise some
normal cell surface component whose expression is modi-
fied or enhanced by the infecting virus[14]. The import-
ance of NK cells in the containment of human virus
infections remains to be determined, although it seems
unlikely that it will be more than adjunctive to that of
specific T-cell immunity.
CMV and Immunosuppression
There is experimental evidence that mouse CMV can
exert immunosuppressive effects by infecting macro-
phages. There is somewhat anecdotal clinical evidence
that HCMV may also produce immunosuppression; it is
said that patients with active HCMV infection are more
prone to infection with other opportunists such as fungi.
50-|
s3 25H
75% HLA Match
.X
JL
75% HLA Match
HLA Mismatch
48 6h
48 6h
48h 6h
j CMV infected targets J ? HSV infected targets | | Uninfected targets
Fig. 2. An example of the specificity of a cytotoxic T-cell line established in response to HCMVfrom a normal seropositive donor,
assessed by release of radioactive chromium from target cells. This T-cell line kills HCMV infected cells, including those which have
only been infected for six hours, but does not kill herpes simplex virus infected cells. Only HLA-matched HCMV-infected cells are
killed.
42 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986
There have been more concrete reports of monocytes
from patients with primary HCMV infection having a
reduced ability to support the lectin-induced proliferation
of human peripheral blood T cells[ 15]. We have exam-
ined possible mechanisms by which HCMV might pro-
duce such effects, by infecting monocytes with HCMV in
vitro; these HCMV-infected monocytes were no longer
able to produce interleukin-1 (IL-1) activity[16], IL-1 is
required as a second signal for T-cell activation during
antigen presentation, and has an increasingly recognised
number of other biological activities[17], Further experi-
ments showed that this loss of IL-1 activity was due to the
release of an inhibitor of IL-1 from the virus-infected
cells, abrogating the action of IL-1 on the responding
cells[ 16] (Fig. 4). This IL-1 inhibitor appears to be a
normal cellular protein whose release is induced by the
virus. Despite this clear biological consequence of
HCMV infection, the infected monocytes show no evi-
dence of virus replication and there is little or no expres-
sion of viral proteins, so the molecular mechanism of the
effect remains uncertain.
The whole question of the extent to which HCMV
infects immunocompetent cells (lymphocytes and macro-
phages) is controversial. It seems clear that normal
resting lymphocytes and monocytes/macrophages do not
replicate the virus but there are reports that expression of
the CMV major IE protein occurs in a small proportion
(a few per cent) of peripheral blood mononuclear cells,
following their infection in vitro[ 18]. It is possible that
such limited expression of virus proteins could have
functional consequences, for instance by virtue of the
'trans acting' factors discussed above. However, it is
important to emphasise that there is no firm evidence as
yet that any of these cells are a normal site of latency for
HCMV.
In addition to these possible effects on macrophages,
there is one report that HCMV can also act as a
polyclonal B cell activator[19]. If confirmed it would be of
considerable interest.
Implications for Therapy
In the absence, at least until very recently, of effective
specific chemotherapy, there have been several alterna-
100-1
PBL
Adhered 2h
@ 37?
Nylon wool
column
IFNa 1000u ml"1
18h @ 37?
6h 51Cr release assay
(J
50 A
?I r~
Uninf IEA
I -?? ? ?
Fig. 3. Natural killer (NK) cells were prepared from peripheral blood lymphocytes (PBL) as shown on the left, using a interferon
(IFNa) to enhance their killing capacity. Their ability to kill HCMV-infected cells was then assessed in a chromium release assay.
HCM V-infected cells became more susceptible to being killed by NK cells at the stage when the virus early proteins or antigens (EA)
were expressed. Uninf = uninfected; IEA = immediate early antigen; LA = late antigen.
o
x
It
u 3
CO
a
3 8
c
n ?
<D 03
? C
s is
?? E
>
-C
X
12 3 4
Time (days)
Fig. 4. HCMV abolishes the production of interleukin-1 (IL-
1) activity from normal human monocytes. IL-1 activity was
constitutively produced by normal monocytes maintained in
culture for 1-4 days (A). Production of IL-1 was not affected
by infection of the monocytes with heat-inactivated HCMV
(O), but was abrogated by infection with live virus (See
text forfurther details. Uninf = uninfected; Con A - concanavi-
lin A; AH = heat inactivated.
Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 43
tive approaches to the treatment of HCMV infection on
which an understanding of the immunology of HCMV
has some bearing. There has been considerable interest in
the prophylactic and therapeutic use of human immuno-
globulin containing antibody to HCMV. There is some
evidence that its prophylactic administration to seronega-
tive bone-marrow transplant recipients lessens the fre-
quency and severity of primary HCMV infection in this
susceptible population[20]. It has also been used for the
treatment of HCMV disease but without conclusive
evidence of its efficacy. Indeed, as severe HCMV disease,
from reactivation, may occur in the presence of serum
antibody, it would be surprising if administration of
further antibody were particularly effective.
There have also been attempts to develop HCMV
vaccines. The 'vaccines' reported to date are derived
from HCMV isolates that have been passaged in tissue
culture and are used as live vaccines; it should be
emphasised that there is no marker for determining
attenuation in such viruses. They have been administered
to susceptible seronegative subjects before renal trans-
plantation but there is no conclusive evidence that they
prevent infection with wild type HCMV[21]. There are
theoretical objections to the use of live persistent virus
vaccines that will presumably persist for life in the
recipient and could conceivably have oncogenic potential.
Therefore sub-unit vaccines (devoid of virus genetic
material) seem a more attractive possibility, but their
development demands a knowledge of which HCMV
proteins are the relevant antigens. Finally, we do not
know how effective any such vaccines are in inducing
effector T-cell immunity, or indeed whether this matters
for conferring immunity to primary infection.
The best prospect for effective treatment for HCMV
will almost certainly come from specific chemotherapy,
and there are promising new antiviral agents such as the
nucleoside analogue 9-( 1,3 dihydroxy-2-propoxy-methyl)
guanine (DHPG). What is becoming clear, however,
especially from the experience of treating patients with
AIDS who have active HCMV disease, is that even
specific chemotherapy is likely to be of limited value in
the absence of an effective immune response. In these
patients the HCMV disease is likely to recrudesce as soon
as chemotherapy is stopped, emphasising the importance
of intact T-cell immunity in containing virus replication
at local sites and preventing dissemination. Using inter-
leukin-2, attempts have been made to restore T-cell
responses to HCMV in AIDS patients, but although IL-2
may improve their T-cell responses in vitro, it has not yet
proved effective as an 'immunomodulator' in vivo[22\.
There is clearly still much to be learned, particularly in
molecular terms, about the relationship between HCMV
and the persistently infected human host. New knowledge
should tell us how HCMV produces the diseases we
already suspect it of causing, and may perhaps reveal
other hitherto unsuspected pathogenetic effects, as well as
providing further basic information on the fascinating
problem of virus persistence.
Acknowledgements
The work described above was carried out by Doctors L.
K. Borysiewicz, B. D. Rodgers, and D. M. Scott, and
with the aid of grants from the MRC and Wellcome
Trust. J. G. P. Sissons is a Wellcome Trust Senior
Lecturer.
This article is based on a paper read at the Conference on
Infectious Diseases held at the Royal College of Physicians in
May 1985. ?
References
1. Stagno, S., Pass, R. F., Dworsky, M. E. et al. (1982) New England
Journal of Medicine, 306, 945.
2. Sixby, J. W., Nedrud, J. G., Raalo-Traub, N., Hanes, R. A. and
Pagano, J. S. (1984) New England Journal of Medicine, 310, 1225.
3. Hirsch, M. S., Schooley, R. T., Ho, D. D. and Kaplan, J. C.
(1984) Review of Infectious Diseases, 6, 726.
4. Everett, R. D. (1984) The Embo Journal, 3, 3135.
5. Rickinson, A. B., Yao, Q. Y. and Wallace, L. E. (1985) British
Medical Bulletin, 41, 75.
6. Smith, K. A. and Ruscetti, F. W. (1981) Advances in Immunology,
31, 137.
7. Zinkernagal, R. M. and Doherty, P. C. (1979) Advances in
Immunology, 27, 52.
8. Borysiewicz, L. K., Morris, S., Page, J. D. and Sissons, J. G. P.
(1983) European Journal of Immunology, 13, 804.
9. Reddehase, M. J., Keil, G. M. and Koszinowski, U. H. (1984)
European Journal of Immunology, 1, 56.
10. Quinnan, G. V., Kirmani, N., Esber, E. et al. (1981) Journal of
Immunology, 126, 2036.
11. Nash, A. A. (1985) British Medical Bulletin, 41, 41.
12. Bukowski, J. F., Warner, J. F., Dennert, G. and Welsh, R. M.
(1985) Journal of Experimental Medicine, 161, 40.
13. Borysiewicz, L. K., Rogers, S., Morris, S., Graham, S. and
Sissons, J. G. P. (1985) Journal of Immunology, 134, 2695.
14. Borysiewicz, L. K., Graham, S. and Sissons, J. G. P. (1984)
Immunobiology, 167, 182.
15. Carney, W. P. and Hirsch, M. S. (1981) Journal of Infectious
Diseases, 144, 47.
16. Rodgers, B. C., Scott, D. M., Mundin, J. and Sissons, J. G. P.
(1985) Journal of Virology, 54, in press.
17. Dinarello, C. A. (1984) Review of Infectious Diseases, 6, 51.
18. Rice, G. P. A., Schrier, R. D. and Oldstone, M. B. A. (1984)
Proceedings of the National Academy of Sciences, 81, 6134.
19. Hutt-Fletcher, L. M., Balachandran, N. and Elkins, M. H.
? (1983) Journal of Experimental Medicine, 158, 2171.
20. Winston, D. J., Pollard, R. B., Ho, W. G. et al. (1982) Annals of
Internal Medicine, 97, 11.
21. Plotkin, S. A., Friedman, H. M., Fleisher, G. R. et al. (1984)
Lancet, 2, 528.
22. Rook, A. H., Masur, H., Land, C. et al. (1983) Journal of Clinical
Investigation, 72, 398.
44 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986
|
PMC005xxxxxx/PMC5371132.txt | An Epidemiological Assessment of Neonatal
Screening for Dislocation of the Hip
IAN'LECK, MB, PhD, DSc, FRCP, FFCM
Professor of Community Medicine, University of Manchester
Screening for congenital dislocation of the hip was re-
cently described in The Lancet as 'a mess'fl]. This article
attempts to assess the deficiencies of screening by measur-
ing it against the main criteria that any population-wide
screening programme should meet. These criteria are
that the disorder to be detected should be important and
of known natural history and be best treated early, before
the usual clinical time of presentation; the screening test
should be accurate and safe, the treatment should be
effective and its indications agreed; and both test and
treatment should be practicable and worth the cost. In
this article the term 'dislocation of the hip' (DH) will be
used of cases in which the femoral head is either totally
outside the acetabulum (luxation) or only in partial
contact with it (subluxation); and the screening pro-
cedures considered will be those undertaken to detect
neonates who, if untreated, would present clinically with
DH on one or both sides when they began to walk.
Importance of DH
Importance depends on frequency, severity and duration.
As to frequency, records made before the introduction of
screening suggest that, without it, DH would become
clinically apparent in early childhood in 0.8-1.6 per 1,000
children born in Scandinavia, North America and the
UK (the regions where most of the available data on
screening originated). Much higher figures have been
reported for Amerindian, Japanese and Lapp communi-
ties whose methods of cradling or clothing infants tend to
keep their hips extended and adducted (Fig. 1, left side).
Severity is more difficult to quantify, but a DH that is
severe enough to produce clinical signs in the infant or
toddler will tend, if untreated, to lead to the formation of
a false acetabulum, to degenerative changes, and to the
knee joint problems and other consequences of limping
caused by the affected leg being shorter than the other.
The duration of these problems in the untreated is of
course life-long.
The dislocated hip may be even more important than
these facts would suggest, since the cases that present in
early childhood may be only the tip of an iceberg. The
number of children with hips in which the signs of
subluxation, laxity or other dysplasia can be elicited at
birth greatly exceeds one per 1,000, and although many
of these hips may become normal later, it is widely
assumed that an 'unknown number . . . persist as dys-
piasia or subluxation into adult life and ultimately be-
come painful due to the development of secondary osteo-
arthritis'^].
DISLOCATION
reported in persons not
screened neonatally
NEONATAL INSTABILITY
reported on screening
100
80-
60-
40-
20-
10
8
6-j
4
2-\
11
0.8-1
7 (Cree-Ojibwa amerindians)
. 5 (Navajo amerindians)
O 9
AA 8, 10 (Australia)
om 6, 2
?A 4, 3
A 37 (Brittany)
O## 46, 23, 42
? A 11, 43 (New Zealand)
? 38 & 39
? A 16.35
O# 36. 41
OO 28, 45
A 46
A 33
A A 15, 20 (New Zealand)
? ? 22, 34
OB 29, 11
O# A A A 47, 24, 8, 17, 40 (Australia)
OO* 30, 31, 25
OA 49, if
O 44
100
-80
-60
-40
20
-10
-8
-6
-4
-2
to,
Fig. 1. Prevalence per 1, 000 (logarithmic scale) of clinically
diagnosed dislocation of the hip(s) in populations not studied
neonatally, and of neonatal instability of hip(s) in screened
populations. Screened hips have been assumed to exhibit insta-
bility if the published data were consistent with their being
clinically dislocated or dislocatable. (Numbers show where
sources appear in the list of references.)
O = UK
# = Scandinavia (excluding predominantly Lapp series)
A = North America (excluding predominantly Amerindian
series)
? = Japan
A = Other
56 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986
J
Natural History of DH
Epidemiological data suggest that DH has the natural
history shown in Fig. 2 [ 13]. Most of the risk factors fall
into two groups, one associated with decreases in the
resistance of the hip to dislocation and the other with
external constraints. The risk factors affecting resistance
include shallowness of the acetabulum and a generalised
laxity of connective tissue (both of which are reported to
be relatively common in children with DH and their
relatives) and the female genotype (which may make
joints liable to become lax under the influence of ovarian
hormones). The risk factors that may owe their effects to
external constraints include at least three in which these
constraints are likely to be prenatal (oligohydramnios,
primigravidity?when the uterus is 'tighter' than sub-
sequently?and breech presentation), one which may
operate before and/or after birth (birth around the coldest
time of year, which is when both women in late preg-
nancy and newborn infants are most likely to be well
wrapped up), and one with postnatal effects (membership
?f an ethnic group in which infants' legs are kept
i extended and adducted; the prevalence of DH has fallen
sharply in Japanese communities in which this practice
has been abandonedf 11 ]).
Most of the above risk factors that are likely to act
prenatally appear to apply both to neonatal instability of
the hips as detected by screening tests and to established
DH in unscreened toddlers[14]. For this reason and
because it seems inherently more likely that a hip which is
dislocated or dislocatable at birth will remain abnormal
than that a stable hip will become so, it is generally
v assumed that the unstable hip of the neonate and the
dislocated hip of the toddler are early and late stages of
the same process?although the fact that neonatal insta-
bility is almost always treated when found means that we
have little direct evidence as to what happens if it is not.
Two points, however, are well established from studies
of children who have been screened for dislocated and
dislocatable hips at birth. The first is that the prevalence
of these abnormalities in screened neonates tends to be
much higher than the prevalence of recognised DH in
toddlers who were not screened at birth (Fig. 1). Second,
most of the reports of screened populations (Fig. 1) make
reference to children in whom hip abnormalities were not
detected and treated as a result of screening but who were
later diagnosed as having DH. In Fig. 3 the proportions
of children in this category are plotted against the propor-
tions in the same series in whom screening led to treat-
ment. Like an earlier analysis reported by Parkin[51],
Fig. 3 reveals no association between the frequency with
which neonatal instability is treated and the prevalence of
cases presenting late?suggesting that screening pro-
grammes with a high yield of cases of instability have in
general had no more success than those with a low yield in
picking up infants at risk of lasting dislocation. However,
the prevalence of late cases in nearly three-quarters of the
screening studies was below the lower limit of the range
for unscreened populations, even though the figures for
late cases in some of these studies included children whose
hips only appeared unstable a few months after birth and
might never have progressed to established DH in early
childhood.
This evidence that treating neonatal instability pre-
vents some cases of DH in early childhood provides
further support for the view that these two conditions are
early and late stages of the same process. However, the
higher prevalence of neonatal instability in the screened
than of childhood DH in the unscreened indicates that
most cases of the former do not progress to the latter if left
untreated. Presumably the cases most likely to progress
are the most unstable and those in which there is most
interference with hip flexion and abduction during infan-
cy.
There is probably more than one explanation for the
finding that hips that appear stable in the neonate
Fig. 2. Suggested natural history of 'congenital' hip dislocation.
Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 57
sometimes manifest DH later. Sometimes abnormalities
are present at birth which standard screening tests do not
detect?notably irreducible dislocation?or which are
missed because the observer is inexperienced; but there
are also well-documented cases on record in which hips
that an experienced examiner had found to be clinically
stable at birth showed increasingly obvious dysplasia on
radiological follow-up and eventually became dislocat-
ed^].
In picturing the natural history of DH, we should
therefore envisage some cases as developing de novo after
birth, perhaps as a result of postnatal constraints interact-
ing with a genetic predisposition in the way portrayed by
the interrupted line in Fig. 2. One component of the
genetic predisposition in these cases may be acetabular
shallowness, to which the parents of children with estab-
lished DH seem to be more predisposed than parents
whose children's hips were unstable at birth[53].
It is not possible to estimate how many cases of DH
involve hips that were stable at birth, although the data
shown in Fig. 3 (which are confined to populations of
European origin) could be interpreted as suggesting that
careful neonatal screening can detect instability in a
substantial majority of the 0.8-1.6/1000 infants in such
populations who would develop DH if unscreened.
In the higher-risk communities (e.g. in Japan) in which
infants' legs are kept extended and adducted, we should
expect screening to be less sensitive if such postnatal
constraints can indeed lead to DH in initially stable hips.
This expectation is borne out by a report that, in a series
of Japanese infants of whom 2.7 per cent had DH
according to a one-year follow-up, less than one-fifth of
this 2.7 per cent had shown signs of instability one week
after birth[27].
Best Time for Treatment of DH
The question whether DH is best treated earlier than the
time at which unscreened cases present ignores the
neonates whose hips are unstable at birth but would
stabilise later even if not treated, and focuses our atten-
tion on those who, without treatment, would present with
clinical DH as toddlers. If splinting in abduction, the
recommended early treatment, is effective, they must
clearly stand to benefit by receiving this treatment, partly
because otherwise their hips will become more abnormal,
and also because neonatal treatment is less radical than
the alternative later treatment, probably carries less risk
of ischaemic necrosis of the femoral head (the main
hazard of later treatment)[51], and comes at a time when
it is likely to have less impact on the physical and
psychosocial development of the child and on family life.
Accuracy of Neonatal Screening for DH
Although radiographic and clinical methods have both
been advocated for neonatal screening, radiography can-
not really be regarded as suitable for general use, given its
hazards and the fact that the head of the femur and much
of the pelvis are not yet ossified. The most widely used
clinical procedure has two parts. The first is the Ortolani
test of abducting the flexed thigh, which is designed to
enable the already dislocated hip to be detected by
causing the femoral head to slip into the acetabulum,
when a 'clunk' should be felt or heard. The second part,
introduced by Barlow to identify unstable hips which the
Ortolani test misses because they are not already dislocat-
ed, is to see whether dislocation followed by reduction can
be detected if one presses first on the lesser trochanter and
then on the greater while holding the thigh in 90? of
flexion and 45? of abduction.
It is debatable how accurately these signs pick out
unstable hips. Some workers[49,54] have argued that the
other clicks and grating sensations which these ma-
noeuvres sometimes cause should also be accepted as
evidence of instability, although this view is not generally
held[l,55]. However, it seems beyond debate that these
tests for dislocation and dislocatability are far from
accurate in identifying future cases of established DH,
given that the latter are far less common than are positive
tests (Fig. 1) and sometimes arise in infants in whom the
tests were negative (Fig. 3). The figures which these
results yield for the standard indices of accuracy?sensi-
tivity, specificity, and predictive value of a positive test?
are of course very variable, because of the wide variations
in the frequency both of positive tests and of 'false
negatives' (negative tests in infants who are later found to
have DH). Table 1 shows estimates of accuracy for what
may be regarded as the best available recent English data,
based on prolonged follow-up of a large series of Bristol
infants screened by a teaching unit with particular exper-
? CO
.<2 -C
"O t
E ^
O o
-5 ?
? O
^ CO
= 3-
CD
CD <U
? "5
S ro
CD g
*- T3
3.0-
2.0-
1.0-
0.8-
0.6-
0.4-
0.3-
0.2-
0.1 -
0.08-
0.06-
P = 0.044
? 5? 035
Infants treated for neonatal hip joint instability
(per 1000 births)
Fig. 3. Prevalence of infants in screened British, Scandina-
vian, North American and Australasian populations who were
not treated for neonatal instability of the hip but in whom DH
was diagnosed later, plotted against proportions of infants who
were so treated (logarithmic scales). Cases described as being of
dysplasia alone have been excluded. (Numbers show where
sources appear in the list of references.)
58 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986
Table 1. Indices of accuracy yielded by a series of 23,002
screened Bristol children[48], given the assumption that DH
occurs in 1.25/1,000 unscreened children (midpoint of range for
non-Lapp populations of European origin in Fig. 1).
Screening test result
Total
Positive Negative
Prognosis if not treated:
Dislocation 19 10 29
No dislocation 426 22,547 22,973
Total 445 22,557 23,002
Sensitivity = ||= 66%
Specificity = 22973 = 98
Odds against developing established dislocation, given a positive test
result, = 19:426 = 1:22.
tise in this field[48,55], The most disappointing of these
figures is the estimate that even in such a favourable
setting the test yields as many as 22 false positive results
for every one true positive. The reason for this figure
being so large when sensitivity and specificity are as high
as 66 per cent and 98 per cent respectively is the relatively
low prevalence of DH; with a test of this accuracy the
number of true positive results will only exceed the
number of false positives for conditions affecting over 2.9
per cent of subjects.
Safety of Neonatal Screening for DH
It has been suggested that one of the manipulations
involved in screening?the manoeuvre described by Bar-
low for seeing whether the hip can be dislocated?may
itself render some hip joints less stable[42]. Although this
hypothesis has received very little attention, it should
perhaps be borne in mind as a possible reason why there
have been screened series in which the reported preva-
lence of late-diagnosed cases of DH (Fig. 2), and even the
proportions of all infants undergoing surgical operations
for DH[9,30,49], exceeded the overall prevalence of DH
in unscreened populations. A rigorous test of the hypoth-
esis that screening (perhaps when inexpertly performed)
can be harmful would be to screen but not treat a group of
neonates so that they and an unscreened group could be
compared for the subsequent prevalence of DH; but this
would raise ethical problems.
Indications for Treating Neonatal Hip Joint
Instability
The clinician who accepts both the possible benefits of
early treatment and the limitations of early screening for
DH faces a major problem. Should every neonate in
whom the results of screening appear positive be immedi-
ately subjected to some form of splinting in abduction,
even though most of these neonates would not develop
DH even if left untreated; or should the numbers treated
unnecessarily be reduced by restricting splinting to those
whose hips are still abnormal at some later date, even
though the latter children may by this time be harder to
treat?
Not surprisingly, there is no agreed answer to this
question. In 1981, Parkin[51] pointed out that different
authorities had recommended policies of (a) immediate
treatment of all cases with evidence of instability; (b) a
few weeks' observation of all cases followed by treatment
of those remaining abnormal; and (c) a combined ap-
proach whereby those in whom screening provides evi-
dence of spontaneous dislocation are treated immediately
while those whose hips only appear dislocatable are
observed for a few weeks and then treated if the abnor-
mality persists. More recent papers indicate that the first
two of these policies still have their advocates among
experienced British workers[9,48].
Disagreement about the indications for treatment is
also implicit in the above-quoted debate about the clinical
signs that should be treated as evidence of instability.
Even among the minority who accept as evidence not only
signs that the hip is or can be dislocated but also other
clicks and grating sensations, there are some who splint
hips on the basis of such evidence alone[54] while others
do no more initially in cases with the latter signs only than
follow them up, splinting at a later stage those that then
prove to be dislocated, dislocatable, or radiologically
abnormal[49].
Effectiveness of Treatment of Neonatal Hip Joint
Instability
The treatment of neonatal instability of the hip joint has
been advocated as a measure for preventing osteoarthro-
sis^] as well as established dislocation of the hip. It is
unlikely that we shall be able to evaluate its effectiveness
against osteoarthrosis, much the commoner condition,
until data based on follow-up of screened and unscreened
populations for several decades become available. Even
the success of neonatal treatment in preventing estab-
lished dislocation of the hip cannot be fully evaluated,
since there appear to have been no randomised clinical
trials. The most that published data enable one to do (and
this applies in a small number of studies only) is to
examine the overall frequency of significant residual
abnormalities in screened populations, including cases
both in children given early treatment for instability and
in other children.
Table 2 shows the proportions of children in these
studies whose residual abnormalities were apparently
considered significant enough to be submitted to surgical
operations. As will be clear from the final column of the
table, it is questionable whether each figure relates to
precisely the same surgical procedures: the procedures
included in the Aberdeen statistics for operative treat-
ment were not specified, and the papers from Edinburgh
and Uppsala made no mention of adductor tenotomies.
The most informative sets of results appear to be the two
from England. Neither of these suggests that neonatal
screening and treatment are highly effective: in the
Mansfield series the proportion requiring surgery was
Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986 59
Table 2. Frequency of surgery for DH in screened populations.
Place
Proportion undergoing surgery
(per 1000 total population)
Population
size
Splinted
as
neonate
Not
splinted
as
neonate
Total
(No. in
brackets)
Nature of surgery (No.)
Uppsala, Sweden[23]
Aberdeen, Scotland[28]
Edinburgh, Scotland[29]
Aberdeen, Scotland[9]
Bristol, England[48]
Mansfield, England[49]
11,868
71,169*
31,961
53,033
23,002
7,864
0.25 0.42 0.67(8) Open reduction (2), closed
reduction (6)
0.11 1.10 1.21(86) 'In-patient operative
treatment'
0.22 0.13 .0.35(11) Surgical reduction (9),
excision of limbus only (1),
derotation osteotomy (1)
0.19 1.64 1.83(97) 'Operated on'
0.22 0.43 0.65(15) 'Open surgery' (7),
adductor tenotomy (8)
0.25 1.14 1.40(11) Adductor tenotomy ( +open
reduction in 1)
'Estimated number remaining through follow-up period.
close to what might have been expected in the absence of
screening, and even the proportion for Bristol (the centre
of expertise from which the figures in Table 1 also came)
only seems to have been halved by the screening pro-
gramme. However, these findings may reflect more
discredit on the screening procedure than on the treat-
ment: in both the English series and in three of the others
a substantial majority of the operations were carried out
in children who had not been selected for splinting when
originally screened.
The different types of abduction splints have not been
compared here because epidemiological data on their
relative merits are lacking. However, the keeping of
infants with unstable hips in double nappies, which has
been advocated as an alternative to the use of special
splints, seems to emerge as particularly ineffective from a
recent report; when splinting was replaced by double
nappies in Southampton, the percentage of cases respond-
ing to treatment among those diagnosed by screening fell
from 92 to 55[56].
Table 3. Health care costs of screening and not screening a population of 100,000 with a distribution like that estimated for the
Bristol population in Tables 1 and 2, given unit costs based on British Columbia experience in 1981?2[57].
Type of care
Number of recipients
Cost (Canadian
for each
recipient
for total population
Requirements if screening is omitted
Surgical treatment
Requirements if screening is practised
Screening
Splinting
Surgical treatment
125
100,000
1,935
65
Ratio of costs with screening to costs without screening = |' = 0-97:1
9,133
1.90
167
9,133
1,141,625
190,000
323,145
593,645
106,790
Practicability of Providing Screening and Treatment
for Neonatal Hip Joint Instability
For a screening programme to be practicable, it must
have both the ability to reach those for whom it is
intended and the resources to screen and, where neces-
sary, treat them. These conditions are readily attainable
by screening for DH in countries such as Britain where
almost all births occur in hospitals, so that the neonates to
be screened form a captive population, and staff are
available who can be trained to carry out the screening.
Cost of Providing Screening and Treatment for
Neonatal Hip Joint Instability
Estimates of the current financial costs of screening and
splinting for neonatal instability and of surgical treatment
for established DH in the UK are not readily available,
but figures have been published for British Columbia in
1981?82[57 ] which can be used to make an approximate
60 Journal of the Royal College of Physicians of London Vol. 20 No. 1 January 1986
J
assessment of the relative health service costs of screening
and not screening. When these figures are applied to the
Bristol-based statistics in Tables 1 and 2, screening
emerges as marginally more economical (Table 3).
More than half the estimated health care costs associ-
ated with screening are attributable to surgical treatment
of children in whom early splinting either failed or was
not carried out. However, the British Columbia workers
assumed that the cost of surgical treatment per case for
these groups was the same as for unscreened children with
DH. If, as is possible, the former tended to require less
treatment than the latter, or if the accuracy of screening
or the effectiveness of splinting in early infancy were to
improve, the financial advantages of screening could
increase considerably. The converse is, of course, equally
true.
To try to quantify and compare the costs for infants
and their families which policies of screening and not
screening incur would involve many other aspects of life
besides money. It could be that the two policies are as
finely balanced in respect of these costs as in respect of the
costs of health care; the main difference between the two
policies in both cases may be that, with screening as
compared to without, the costs are shared between many
more individuals.
Conclusions
There seem to be four main problem areas in the field of
neonatal screening and treatment for hip joint instability
as currently practised.
1. False Positives. Most of the screened cases in which
unstable hips are reported are 'false positives', at least in
the sense that they would not present later with estab-
lished DH if untreated. Although it is widely believed that
these false positives have a predisposition to osteoarthro-
sis, which may be reduced by treating the neonatal
instability, this hypothesis has not been tested epidemio-
logically. It is therefore at least possible that several
infants? more than ten in many areas?suffer unneces-
sary splinting for every one who benefits from this
procedure.
2. False Negatives. The prevalence of 'false negatives'
(cases in which a hip that appeared stable when screened
!s later reported to be dislocated) in screened populations
varies widely, but averages about half as much as the
prevalence of DH in unscreened populations. In other
words, the number of false negative results yielded by
screening tests seems to be of the same order as the
number of true positives. It is not known how often in
these false negative cases instability is present but missed
at birth and how often it develops later.
3- Treatment Policies. There are at least three questions
about treatment on which experts differ. First, should the
mdications for treatment include abnormal physical signs
short of those accepted as manifestations of dislocation
and dislocatability? Second, should treatment be started
nnmediately in all in whom the relevant signs (however
defined) are observed, or postponed for a few weeks and
confined to those in whom signs persist? Third, what type
of splint should be used?
4. Outcome of Early Treatment. Although there are some
screened populations in which established DH is substan-
tially less common than in the unscreened, there are
others in which it is so common as to raise the possibility
that, at least in some hands, one or more of the pro-
cedures involved in screening may actually increase
prevalence. The example of Bristol shows that, even at a
centre of expertise, screening may do no more than halve
the frequency of established DH and have negligible
effects on health care costs.
It should be noted that there are unanswered questions
in all these four areas. Some of the more important of
these questions?whether unstable hips other than those
which would progress to established DH benefit from
splinting in early infancy, and whether screening pro-
cedures can themselves predispose to DH?may be ex-
tremely hard to answer, the former because very long
follow-up would be needed and the latter because of the
ethical problem mentioned when the safety of screening
was discussed. However, it should be possible to set up
randomised clinical trials which would answer ethically
and relatively quickly the three questions listed under
'treatment policies'. These trials should be designed to
enable the costs and benefits of current neonatal screen-
ing and treatment policies to be compared as comprehen-
sively as possible. The costs and benefits of the best of
these policies should then be compared with those of the
policies of screening later in infancy and of not screening
but treating DH when it presents clinically. Whether
screening is justified will remain an open question until
this is done.
This article is based on a paper read at the Screening Conference
held at the Royal College of Physicians in December 1984.
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