800
LOW-DOSE HEPARIN AS A PROPHYLAXIS AGAINST DEEP-VEIN THROMBOSIS AFTER ACUTE STROKE S. T. MCCARTHY D. ROBERTSON†
J. J. TURNER* J. HAWKEY‡ Department of Geriatric Medicine, Oxford Area Health Authority (Teaching) C.
D.
J. MACEY Department of Radiation Physics, Churchill Hospital, Oxford A trial of subcutaneous low-dose heparin in the prevention of deep-vein thrombosis was carried out in elderly patients admitted to hospital after an acute stroke. A statistically significant reduction was observed in deep-vein thrombosis as assessed by isotope leg scanning.
Summary
INTRODUCTION
The control group received no heparin. Both groups received 60 mg of potassium iodide daily for 14 days. 100 aCi of 125Ilabelled fibrinogen was given intravenously at least 4 hours after the first dose of potassium iodide and repeated after 7 days if necessary. Leg scans were performed daily for 14 days. The scan was considered positive if there was a difference of more than 20% between adjacent points on the same leg or corresponding points on opposite legs persisting for 48 hours.’ The leg scans were not performed "blind" since the site of injection of the heparin was usually obvious and it was not considered justifiable to give the control subjects an injection of a placebo. However, only count-rates were recorded at the time of scanning and the subsequent interpretation of these results was done blind by a second doctor who did not know the
patients. The severity of the stroke was assessed according to criteria similar to those of Oxbury et al. Gradings for consciousness and extent of hemiparesis on admission were included. A combined score was then calculated for each patient by adding the grade for consciousness to the sum of the grades for arm and leg weakness and dividing the result by two. (Oxbury et al. showed that the level of consciousness was the most important factor in predicting mortality.) The level of consciousness was graded on a 6-point scale, where 0 normal, and 5 no limb movements in response to pain. The power of each individual limb was graded on a 5-point scale for conscious patients (0 normal, 4 complete paralysis.) =
’
VENOUS thromboembolism is a major and often unrecognised cause of morbidity and mortality in patients after acute strokes. An incidence of deep-vein thrombosis of up to 60% assessed by 1251 fibrinogen leg scanning has been reported.’ In a postmortem study of patients with a stroke admitted to hospital, 15 out of 30 had evidence of pulmonary embolism.2 Low-dose heparin given before operation has become well established as effective prophylaxis against postoperative deep-vein thrombosis.3 In other conditions where low-dose heparin has been given after the episode the results are not so clear. In patients with a fractured neck of femur, this prophylactic effect has not been observed.4 In myocardial infarction the effect has been found by some workers5 and not by others.6 There have been no reports of low-dose heparin in the prevention of deep-vein thrombosis after an acute stroke.
=
=
=
RESULTS
patients were admitted to the trial, 16 in the heparin-treated group and 16 in the control group. The mean age of the control group was 78.2 yr (±7.4) and of the treatment group 78.9 yr (±8.0). There were 11 females in the heparin group and 10 in the control 32
group.
The severity of the strokes in the greater than in the control group:
treatment
group was
Treatment with low-dose subcutaneous
heparin was associated with a significant reduction of positive leg scans from 75% to 12.5% (0.01>P>0.001):
PATIENTS AND METHODS
All patients admitted to the department of geriatric medicine with a diagnosis of stroke within the previous 48 hours were considered for inclusion. Written informed consent was obtained from the patient or next of kin. Patients were not included in the trial if they had: (1) blood in the cerebrospinal fluid (defined as more than 50 red cells per high-power field in tube 3 of a lumbar
puncture); sustained diastolic blood-pressure higher than 120 mm Hg on admission, or grade 3 or 4 hypertensive retinopathy ; (3) a history of active peptic ulceration; (4) a history of subarachnoid haemorrhage; (5) allergy to iodine; (6)a goitre or thyrotoxicosis; (7) a bleeding diathesis; (8) a recent myocardial infarction.
(2)
hours.) 5 patients
in the control group, and 3 in the heparin group died within 28 days-a total mortality of 25%.
a
Patients were ment
In the control group the mean time for scans to become positive was on day 5.6 (±3 -0). (The scan was confirmed as positive only after a rise present for 48
(control)
units of calcium
randomly allocated groups. The
to treatment or non-treat-
treatment
group received 5000
heparin subcutaneously 8-hourly for 14 days.
*Present address: Walton Hospital, Liverpool. †Present address: Parkwood Hospital, Ontario. ‡Present address Nuffield Department of Clinical Medicine, Oxford.
DISCUSSION
We confirm the reported high incidence of deep-vein thrombosis after an acute cerebrovascular accident. Our figure of 75% of patients developing deep-vein thrombosis in the control group is higher than that reported by earlier workers and may be related to the severity of the stroke (60% of the patients had severe hemiparesis) and the advanced age of the patients (mean age 78.2 yr). During the trial there were 8 deaths (25%), 5 in the control group and 3 in the treatment group. No haemorrhagic complications were seen in the patients treated with heparin. In 2 patients in the treatment group there was no evidence of cerebrovascular or other haemorrhage at
necropsy.
801 The trial has shown that subcutaneous calcium in a dosage of 5000 units 8-hourly can safely reduce the high incidence of deep-vein thrombosis after an acute stroke. We are extending the trial to assess the effects of preventing deep-vein thrombosis on the rate of
heparin
mobilisation of patients and
on
the
mortality from pul-
monary emboli. We thank Dr J. M. K. Spalding and Dr A. A. Sharp for their help and advice in setting up the trial, Mr G. J. Draper for advice on statistics, and Dr L. Wollner, Dr R. A. Griffiths, and Dr G. Wilcock for permission to study their patients.
Requests for reprints should be addressed Cowley Road Hospital, Oxford OX4 1XB.
to
S. T.
McCarthy, The
REFERENCES
1. Warlow, C., Ogston, D., Douglas, A. S. Lancet, 1972, i, 1305. 2. Denham, M. J., James, G., Farran, M. Age Ageing, 1973, 2, 207. 3. International Multicentre Trial Lancet, 1975, ii, 45. 4. Morris, G. K., Mitchell, J. R. A. Br. med. J. 1977, i, 535. 5. Warlow, C., Beattie, A. G., Terry, G., Ogston, D., Kenmure, A. C. F., Douglas, A. S. Lancet, 1973, ii, 934. 6. Handley, A. J. ibid. 1972, ii, 623. 7 Kakker, V. V., Nicolaides, A. N., Renny, A. N., Friend, J. T. G., Clarke, M. B. ibid. 1970, i, 540. R. C. D., Grainger, K. iii, 125. 9. Yates, F. JlR. statist. Soc. 1934, suppl. no. 1, p. 217.
8. Oxbury, J. M., Greenhall,
M. R. Br.
med. J. 1975,
Reviews of Books Rational Management of Diabetes HABEEB BACCHUS, M.D., Loma Linda University School of Medicine. Baltimore:
University
Park Press. Lancaster: M.T.P. 1977.
Pp221.$16.50, £11.75. THIS is a well presented, readable, and interesting book that describes the best North American practice in the management of diabetes mellitus. Oral hypoglycaemic agents are dismissed as being of very limited value in the treatment of the maturityonset patient. Most European physicians would claim that sulphonylureas, at least, have a place in the diabetic armamentarium ; but Dr Bacchus presents reasoned arguments for his views, and without one direct reference to the University Group Diabetes Program. This apart, the opinions expressed will in general be familiar to the British reader. Bacchus opts for "split-dose" insulin (a combination of short and intermediate acting preparations given twice daily) in the treatment of most insulin-dependent patients, and he rightly dismisses protamine zinc and ultralente insulins as having no place in the modern treatment of diabetes. This book confirms the impression that American practice is moving away from the oncedaily insulin regimens and that it is now closer to British practice in this respect. The key to the rational management of diabetes is a detailed understanding of intermediary metabolism and its control and the disturbances that are present in diabetes, and almost a third of the book consists of up-to-date and clear reviews of these topics. Almost every chapter begins with a valuable theoretical section. The chapters on acute and long-term complications are outstanding; that on aetiology, and the section on classification and diagnosis, are less satisfactory. The section on the management of the patient undergoing surgery is disappointing and, despite a first-class pathophysiological introductory section, that on the pregnant diabetic is
sketchy. dromes,
There is a useful chapter on hypoglycaemic synpart of which demolishes the fad of "pseudohypogiyca-mia." The chapters on diabetes in childhood and on Perspectives on the Clinician’s Approach to Diabetic Management, are sound and helpful. Bacchus’ strict classification of diabetes into two clearly defined clinical types certainly simplifies treatment but does not allow for the variability of pres-
entation and the occasional overlap between the two extremes of the clinical spectrum. His classification does not recognise the intermediate-onset patient of average weight, who is usually aged 35-55, is not ketotic, does not respond to diet, yet who does not seem to demand immediate treatment with insulin ; but then this is the group of patients for whom sulphonylureas are most commonly used in Britain. Bacchus provides a mass of tables, equations, and formulae to calculate quantities of fluid, electrolytes, and insulin. Formulae like these can serve as guidelines, but in view of the rapidly changing metabolic milieu in the diabetic patient, particularly in ketoacidosis, it would be unwise to follow these instructions too rigidly. This is a very well written and, for the most part, sound review that will be of interest to all physicians concerned with the care of diabetic patients. The index is well prepared and, although a number of the references are old, most important recent publications are noted.
Biological Effects of Microwaves STANISLAW BARANSKI, Institue of Aviation, Warsaw, and PRZECZERSKI, National Research Institute of Mother and Child, Warsaw. Stroudsburg, Pennsylvania: Dowden, Hutchin- 10 son. 1976. Pp. 234.$15.25,/:9.
MYSLAW
IN 1976 it was widely reported that the U.S.A. had complained to the U.S.S.R. about microwave radiation directed at the U.S. Embassy in Moscow. This followed several years of rumour and speculation about the purpose and extent of the irradiation and an alleged high incidence of mysterious illnesses affecting U.S. diplomatic personnel. What made the affair distinctly curious was that, on the figures released by the State Department, the Americans seem to have been protesting
about intermittent exposures that were below the limits of the U.S. exposure standard by a factor of about 300. This bizarre example highlights the very wide range of world opinion about "safe" exposure levels for microwave radiation. One of the most valuable features of this monograph is the authoritative account of and informed comment on the major national exposure standards. These can differ by up to 3 or 4 orders of magnitude, and much of this disparity has come about by the very different safety factors used in deriving permissible exposures from the observed biological effects. In their discussion of this these Polish authors differentiate between three possible approaches: no discernible effect (U.S.S.R.); no change in functional efficiency (Poland, Czeckoslovakia); no irreversible changes (U.S.A., U.K., and other countries). They also point out to people using microwave ovens conforming to the emission limits of the U.S. and of the British Standards Institute would be regarded as being safe under both Polish exposure regulations and those of the U.S.S.R. The authors seem least at home in their selection and treatment of material in the chapters devoted to physics and engineering concepts and to the physical interactions of microwave radiation with tissue. Even so, they make valuable observations about the limitations and oversimplifications involved in mathematical and physical modelling. They are much more fluent and convincing when dealing with experimental biological effects and in discussing epidemiological studies. Their ability to consider documents and research papers in the original languages adds authority to their review of other people’s work. The book seems to have been delayed in translation or publication because consideration of work reported later than 1973 is limited to brief comments in the final chapter. It would have been useful to have had some discussion of medical applications of microwaves (e.g., diathermy) and of the possible synergistic effects when microwaves are used in conjunction with ionising radiations. This is an important book, strongly recommended to anyone interested in microwave bioeffects and hazards. Compared with other monographs on the subject, it is very readable, with the occasional asides and personal views affording valuable in-
sights.
LOW-DOSE HEPARIN AS A PROPHYLAXIS AGAINST DEEP-VEIN THROMBOSIS AFTER ACUTE STROKE S. T. MCCARTHY D. ROBERTSON†
J. J. TURNER* J. HAWKEY‡ Department of Geriatric Medicine, Oxford Area Health Authority (Teaching) C.
D.
J. MACEY Department of Radiation Physics, Churchill Hospital, Oxford A trial of subcutaneous low-dose heparin in the prevention of deep-vein thrombosis was carried out in elderly patients admitted to hospital after an acute stroke. A statistically significant reduction was observed in deep-vein thrombosis as assessed by isotope leg scanning.
Summary
INTRODUCTION
The control group received no heparin. Both groups received 60 mg of potassium iodide daily for 14 days. 100 aCi of 125Ilabelled fibrinogen was given intravenously at least 4 hours after the first dose of potassium iodide and repeated after 7 days if necessary. Leg scans were performed daily for 14 days. The scan was considered positive if there was a difference of more than 20% between adjacent points on the same leg or corresponding points on opposite legs persisting for 48 hours.’ The leg scans were not performed "blind" since the site of injection of the heparin was usually obvious and it was not considered justifiable to give the control subjects an injection of a placebo. However, only count-rates were recorded at the time of scanning and the subsequent interpretation of these results was done blind by a second doctor who did not know the
patients. The severity of the stroke was assessed according to criteria similar to those of Oxbury et al. Gradings for consciousness and extent of hemiparesis on admission were included. A combined score was then calculated for each patient by adding the grade for consciousness to the sum of the grades for arm and leg weakness and dividing the result by two. (Oxbury et al. showed that the level of consciousness was the most important factor in predicting mortality.) The level of consciousness was graded on a 6-point scale, where 0 normal, and 5 no limb movements in response to pain. The power of each individual limb was graded on a 5-point scale for conscious patients (0 normal, 4 complete paralysis.) =
’
VENOUS thromboembolism is a major and often unrecognised cause of morbidity and mortality in patients after acute strokes. An incidence of deep-vein thrombosis of up to 60% assessed by 1251 fibrinogen leg scanning has been reported.’ In a postmortem study of patients with a stroke admitted to hospital, 15 out of 30 had evidence of pulmonary embolism.2 Low-dose heparin given before operation has become well established as effective prophylaxis against postoperative deep-vein thrombosis.3 In other conditions where low-dose heparin has been given after the episode the results are not so clear. In patients with a fractured neck of femur, this prophylactic effect has not been observed.4 In myocardial infarction the effect has been found by some workers5 and not by others.6 There have been no reports of low-dose heparin in the prevention of deep-vein thrombosis after an acute stroke.
=
=
=
RESULTS
patients were admitted to the trial, 16 in the heparin-treated group and 16 in the control group. The mean age of the control group was 78.2 yr (±7.4) and of the treatment group 78.9 yr (±8.0). There were 11 females in the heparin group and 10 in the control 32
group.
The severity of the strokes in the greater than in the control group:
treatment
group was
Treatment with low-dose subcutaneous
heparin was associated with a significant reduction of positive leg scans from 75% to 12.5% (0.01>P>0.001):
PATIENTS AND METHODS
All patients admitted to the department of geriatric medicine with a diagnosis of stroke within the previous 48 hours were considered for inclusion. Written informed consent was obtained from the patient or next of kin. Patients were not included in the trial if they had: (1) blood in the cerebrospinal fluid (defined as more than 50 red cells per high-power field in tube 3 of a lumbar
puncture); sustained diastolic blood-pressure higher than 120 mm Hg on admission, or grade 3 or 4 hypertensive retinopathy ; (3) a history of active peptic ulceration; (4) a history of subarachnoid haemorrhage; (5) allergy to iodine; (6)a goitre or thyrotoxicosis; (7) a bleeding diathesis; (8) a recent myocardial infarction.
(2)
hours.) 5 patients
in the control group, and 3 in the heparin group died within 28 days-a total mortality of 25%.
a
Patients were ment
In the control group the mean time for scans to become positive was on day 5.6 (±3 -0). (The scan was confirmed as positive only after a rise present for 48
(control)
units of calcium
randomly allocated groups. The
to treatment or non-treat-
treatment
group received 5000
heparin subcutaneously 8-hourly for 14 days.
*Present address: Walton Hospital, Liverpool. †Present address: Parkwood Hospital, Ontario. ‡Present address Nuffield Department of Clinical Medicine, Oxford.
DISCUSSION
We confirm the reported high incidence of deep-vein thrombosis after an acute cerebrovascular accident. Our figure of 75% of patients developing deep-vein thrombosis in the control group is higher than that reported by earlier workers and may be related to the severity of the stroke (60% of the patients had severe hemiparesis) and the advanced age of the patients (mean age 78.2 yr). During the trial there were 8 deaths (25%), 5 in the control group and 3 in the treatment group. No haemorrhagic complications were seen in the patients treated with heparin. In 2 patients in the treatment group there was no evidence of cerebrovascular or other haemorrhage at
necropsy.
801 The trial has shown that subcutaneous calcium in a dosage of 5000 units 8-hourly can safely reduce the high incidence of deep-vein thrombosis after an acute stroke. We are extending the trial to assess the effects of preventing deep-vein thrombosis on the rate of
heparin
mobilisation of patients and
on
the
mortality from pul-
monary emboli. We thank Dr J. M. K. Spalding and Dr A. A. Sharp for their help and advice in setting up the trial, Mr G. J. Draper for advice on statistics, and Dr L. Wollner, Dr R. A. Griffiths, and Dr G. Wilcock for permission to study their patients.
Requests for reprints should be addressed Cowley Road Hospital, Oxford OX4 1XB.
to
S. T.
McCarthy, The
REFERENCES
1. Warlow, C., Ogston, D., Douglas, A. S. Lancet, 1972, i, 1305. 2. Denham, M. J., James, G., Farran, M. Age Ageing, 1973, 2, 207. 3. International Multicentre Trial Lancet, 1975, ii, 45. 4. Morris, G. K., Mitchell, J. R. A. Br. med. J. 1977, i, 535. 5. Warlow, C., Beattie, A. G., Terry, G., Ogston, D., Kenmure, A. C. F., Douglas, A. S. Lancet, 1973, ii, 934. 6. Handley, A. J. ibid. 1972, ii, 623. 7 Kakker, V. V., Nicolaides, A. N., Renny, A. N., Friend, J. T. G., Clarke, M. B. ibid. 1970, i, 540. R. C. D., Grainger, K. iii, 125. 9. Yates, F. JlR. statist. Soc. 1934, suppl. no. 1, p. 217.
8. Oxbury, J. M., Greenhall,
M. R. Br.
med. J. 1975,
Reviews of Books Rational Management of Diabetes HABEEB BACCHUS, M.D., Loma Linda University School of Medicine. Baltimore:
University
Park Press. Lancaster: M.T.P. 1977.
Pp221.$16.50, £11.75. THIS is a well presented, readable, and interesting book that describes the best North American practice in the management of diabetes mellitus. Oral hypoglycaemic agents are dismissed as being of very limited value in the treatment of the maturityonset patient. Most European physicians would claim that sulphonylureas, at least, have a place in the diabetic armamentarium ; but Dr Bacchus presents reasoned arguments for his views, and without one direct reference to the University Group Diabetes Program. This apart, the opinions expressed will in general be familiar to the British reader. Bacchus opts for "split-dose" insulin (a combination of short and intermediate acting preparations given twice daily) in the treatment of most insulin-dependent patients, and he rightly dismisses protamine zinc and ultralente insulins as having no place in the modern treatment of diabetes. This book confirms the impression that American practice is moving away from the oncedaily insulin regimens and that it is now closer to British practice in this respect. The key to the rational management of diabetes is a detailed understanding of intermediary metabolism and its control and the disturbances that are present in diabetes, and almost a third of the book consists of up-to-date and clear reviews of these topics. Almost every chapter begins with a valuable theoretical section. The chapters on acute and long-term complications are outstanding; that on aetiology, and the section on classification and diagnosis, are less satisfactory. The section on the management of the patient undergoing surgery is disappointing and, despite a first-class pathophysiological introductory section, that on the pregnant diabetic is
sketchy. dromes,
There is a useful chapter on hypoglycaemic synpart of which demolishes the fad of "pseudohypogiyca-mia." The chapters on diabetes in childhood and on Perspectives on the Clinician’s Approach to Diabetic Management, are sound and helpful. Bacchus’ strict classification of diabetes into two clearly defined clinical types certainly simplifies treatment but does not allow for the variability of pres-
entation and the occasional overlap between the two extremes of the clinical spectrum. His classification does not recognise the intermediate-onset patient of average weight, who is usually aged 35-55, is not ketotic, does not respond to diet, yet who does not seem to demand immediate treatment with insulin ; but then this is the group of patients for whom sulphonylureas are most commonly used in Britain. Bacchus provides a mass of tables, equations, and formulae to calculate quantities of fluid, electrolytes, and insulin. Formulae like these can serve as guidelines, but in view of the rapidly changing metabolic milieu in the diabetic patient, particularly in ketoacidosis, it would be unwise to follow these instructions too rigidly. This is a very well written and, for the most part, sound review that will be of interest to all physicians concerned with the care of diabetic patients. The index is well prepared and, although a number of the references are old, most important recent publications are noted.
Biological Effects of Microwaves STANISLAW BARANSKI, Institue of Aviation, Warsaw, and PRZECZERSKI, National Research Institute of Mother and Child, Warsaw. Stroudsburg, Pennsylvania: Dowden, Hutchin- 10 son. 1976. Pp. 234.$15.25,/:9.
MYSLAW
IN 1976 it was widely reported that the U.S.A. had complained to the U.S.S.R. about microwave radiation directed at the U.S. Embassy in Moscow. This followed several years of rumour and speculation about the purpose and extent of the irradiation and an alleged high incidence of mysterious illnesses affecting U.S. diplomatic personnel. What made the affair distinctly curious was that, on the figures released by the State Department, the Americans seem to have been protesting
about intermittent exposures that were below the limits of the U.S. exposure standard by a factor of about 300. This bizarre example highlights the very wide range of world opinion about "safe" exposure levels for microwave radiation. One of the most valuable features of this monograph is the authoritative account of and informed comment on the major national exposure standards. These can differ by up to 3 or 4 orders of magnitude, and much of this disparity has come about by the very different safety factors used in deriving permissible exposures from the observed biological effects. In their discussion of this these Polish authors differentiate between three possible approaches: no discernible effect (U.S.S.R.); no change in functional efficiency (Poland, Czeckoslovakia); no irreversible changes (U.S.A., U.K., and other countries). They also point out to people using microwave ovens conforming to the emission limits of the U.S. and of the British Standards Institute would be regarded as being safe under both Polish exposure regulations and those of the U.S.S.R. The authors seem least at home in their selection and treatment of material in the chapters devoted to physics and engineering concepts and to the physical interactions of microwave radiation with tissue. Even so, they make valuable observations about the limitations and oversimplifications involved in mathematical and physical modelling. They are much more fluent and convincing when dealing with experimental biological effects and in discussing epidemiological studies. Their ability to consider documents and research papers in the original languages adds authority to their review of other people’s work. The book seems to have been delayed in translation or publication because consideration of work reported later than 1973 is limited to brief comments in the final chapter. It would have been useful to have had some discussion of medical applications of microwaves (e.g., diathermy) and of the possible synergistic effects when microwaves are used in conjunction with ionising radiations. This is an important book, strongly recommended to anyone interested in microwave bioeffects and hazards. Compared with other monographs on the subject, it is very readable, with the occasional asides and personal views affording valuable in-
sights.
