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MASSIVE 'MANDRAX' POISONING
149
Letters
to
the Editor
be translated into " the control of those aspects of the environwhich have a deleterious effect on the health of man ", and the second, an offshoot of the first, into " the control of radiation as it relates to the health of man ". As has been the case with public health, universities throughout the world have been able to associate with both the radiological and environmental varieties a body of knowledge; men and women have been usefully trained in them and contribute to the general welfare by practising the techniques they have learned. The same is true of occupational health, which is perhaps a slightly less objectionable term. In these instances therefore brevity has been gained, not at the cost of clarity, but at the cost of the classical use of English. New expressions-albeit ugly oneshave been coined, and have been shown to fulfil a satisfactory role. But what of " international health " ? I can see no sense in the words themselves. Health (as opposed to health services) is without political limits. It is never described as being intranational or national, so why international ? Does the word " international " in this context have anything to offer which is " not offered by world " or " public " in the same context ? Little help is to be gained from an examination of pro" grammes in international health ", offered by universities-at least in the United States. Some schools of public health have a department or a division of international health, but to judge by their curricula it would seem that they could function just as well under the name " tropical medicine and hygiene ". Obviously the tropics are international and have their own health hazards, but the same can be said of the pall of atmospheric pollution which hangs over Europe. Another, subtly different interpretation for the term " international health ", is when it is applied to the sort of scheme whereby a medical school or one of its departments sets up an exchange programme with a sister institution in a developing country. Guy’s and Johns Hopkins have for years had such a scheme, but to my knowledge this has never been described as international health by either party. Dr. Goodman’s reading-list would suggest that in his view the term connotes epidemiology-with special emphasis on the major pestilences, aspects of the history of medicine, and the development and responsibilities of institutions concerned with world health. Only the last named of these three seems to isolate itself from subjects or disciplines which already have a well-defined existence of their own, yet it has little in common with the various connotations set out above. Can it be that the meaning of " international health " lies wholly in the eyes of the beholder, and that according to his quirks and prejudices it may mean almost anything or nothing at all ? If so let’s do away with it. Department of Epidemiology ment
EARLY DETECTION OF CANCER
SIR,-In his letter1 Mr. Donaldson clarifies the importance of early stage diagnosis " in patients with breast cancer and outlines the likely improvement in prognosis when cancer is caught at a presymptomatic stage. At present there seems to be no single factor, other than the diagnosis of presymptomatic "
breast cancer, which is likely to influence for the better the mortality of this malignancy,2 and we do not hold with the gloomy view disseminated by Professor Brooke.33 When referring to screening procedures for breast cancer we are, however, concerned with Mr. Donaldson’s statement that " Thermography is, I understand, of little use," which, we presume, is based on casual hearsay rather than recorded fact. Some workers are confident that they can diagnose preclinical carcinoma of the breast by thermography alone.4 Other workers, including ourselves, feel that thermography is a useful preliminary screening procedure which has potential but must be used at present in conjunction with clinical examination and
mammography.5 The variation in the tumour form and the state of its cellular such that it is not surprising that thermography, the mechanical measurement of the body’s infra-red emission, has its limitations. Not all early tumours generate enough heat to be distinguished on thermograms. Differing patterns and asymmetry of the superficial mammary venous systems complicate interpretation. Active dysplasias in a breast may give rise to false negative thermograms but in our experience, with the use of repeated examinations (to see whether the thermographic pattern is stable), it is a worth-while preliminary screening procedure which is relatively cheap, easy to perform, entirely free from radiation hazard, and clearly an advance on the fatalistic approach of waiting till a tumour is palpable and in many cases unequivocally disseminated. If thermography could be equated to tumour metabolism-and this does not seem an impossibility-it may even supply an index of the degree of the tumour’s powers to disseminate which would be of clinical use in determining treatment. It seems to us that at present thermography, for detecting asymptomatic breast disease, is a preliminary examination which must be supported by the localising procedures of clinical examination of mammography.6 But it may be that after further experience, and the possible improvements in thermographic apparatus, thermography will become a very important diagnostic tool in all forms of breast disease. Department of Diagnostic Radiology, E. SAMUEL Royal Infirmary, G. B. YOUNG. Edinburgh.
activity is
and Public Health, Yale University School of Medicine, New Haven, Connecticut 06510.
INTERNATIONAL HEALTH Sirenjoyed Dr. Goodman’s elegantly written Personal Book List, presented under the title International Health
(Jan. 4, p. 45). I am, however, disappointed that he did not tilt with his scholarly pen at the title itself, especially in view of his condemnation of brevity when it is gained at the cost of clarity. The word " health " is one of many sinned against in modem medical jargon. The term " public health," which can neatly be expanded into " the health of the public ", is I think a defensible expression, as is " world health "-" the health" of the peoples of the world ". " Environmental health " and radiological health " are wholly indefensible on grammatical grounds, but do at least have the merit of some precision of meaning. The first might 1. Donaldson, M. Lancet, 1968, ii, 1392. 2. Young, G. B. Jl R. Coll. Surg. Edin. 1968, 13, 12. 3. Brooke, B. N. ibid. p. 1289. 4. Wallace, J. D., Dodd, G. D. Radiology, 1968, 91, 679. 5. Samuel, E., Young, G. B. Proceedings of the Boerhaave Conference. Leiden, March, 1968; p. 82. Shawe, G. D. H. ibid, p. 109. Strax, P, Personal communication. Basle, 1968. 6. Samuel, E. Hosp. Med. 1967, 1, 343.
ROY M. ACHESON.
’* ’* ’* This letter has been shown to Dr. Goodman, who writes: That I hold no brief for the phraseInternational Health’ is clear from my reference to it as’those two boring " unimpassioned vocables," ’ but in what other terms would Professor Acheson refer to ’any or all of those activities for the prevention, diagnosis, or treatment of disease which require the combined consideration and effort of more than one country’ 1 ? And the phrase has been in use for more than 90 years."-ED. L. "
MASSIVE ’MANDRAX’ POISONING SIR,-May I comment on the letter from Dr. Wallace and Dr. Allen (Dec. 7, p. 1247) reporting the management by
haemodialysis of a patient poisoned byMandrax’ (diphenhydramine and methaqualone) ? Would it not be advisable in such reports if information were given at least regarding the blood-levels, recovery in dialysate, or clearance of metha1.
Goodman, N. M. International Health Organisations and Their Work; p. 4. London, 1952.
150
qualone for, without such information, readers cannot determine whether dialysis is in fact of any value in this form of poisoning?1 Indeed, apart from circumstantial evidence, notoriously unreliable, there is nothing to indicate that the patient had ingested mandrax. Regional Poisoning Treatment Centre, Ward 3, The Royal Infirmary, HENRY MATTHEW. Edinburgh 3.
EVALUATING DRUG TRIALS UNSEEN SIR,-Doctors whose responsibility it is to advise the pharmaceutical manufacturer on evaluation of new remedies will find themselves in general agreement with your note on the subject last week (p. 109), but some rather important qualifications have been omitted. The double-blind trial is not itself a passport to success in drug evaluation, and in the investigation of new remedies for symptomatic therapy the double-blind trial is often inappropriate. As Cromie2 has stressed, subjective assessment of subjective symptoms should not be scorned. Control of all the variables of weight, age, and sex of the patient leave out of consideration the vital question of the patient’s personality, and, equally important, the attitude of the doctor to his patient and towards the new medicine.3 Bradford Hill reminded us some years ago that the mere use of tests of statistical significance did not ensure that the conclusions reached were correct, and that, if the data were not comparably valid, statistical tests were valueless.4 Controlled trials, statistical significance, and random allocation of treatments have a place in drug evaluation, provided the trial itself is very carefully planned. The computer is surely destined to play a major role in the future practice of medicine, but it will be a sad day if careful clinical observation is replaced by a string of mathematical symbols. The Bayer Products Co.,
Surbiton-upon-Thames, Surrey.
J.
M. MUNGAVIN.
showed practically compiete equipotentiality for signal either spontaneously or in response to various stimuli; these features suggested unrecoverable cerebral function. Supportive therapy and nalorphine injections were continued, but these measures did not result in clinical improvement, and serial electroencephalograms remained unchanged. Shigella sonnei was cultured from the diarrhoeal stools. He
Pampiglione) cerebral
died 65 hours after admission; necropsy showed gross cerebral oedema. The pharmacological action of atropine is well documented, and the total ingested dose in this child was well below toxic amounts. Diphenoxylate hydrochloride is somewhat similar to pethidine in its chemical structure but its metabolism is poorly understood; in our patient it is probable that this drug caused respiratory depression which could not be reversed and ultimately proved fatal. Although respiratory depression is listed amongst the effects of overdosage of lomotil, it seems likely that the dangers are insufficiently known, since the drug is widely prescribed for what is often a mild self-limiting disorder. Indeed, in a double-blind study of 50 children with diarrhoea, Harris and Beveridgefound no clear pattern to suggest that lomotil influences the course of the condition. We thank Prof. 0. Wolff for his
permission
to
report this
patient. Hospital for Sick Children, Great Ormond Street, London W.C.1.
JOHN T. HARRIES MARY ROSSITER.
LYSERGIDE AND CANNABIS AS POSSIBLE TERATOGENS IN MAN letter SIR,-The by Dr. Hecht and his colleagues2 prompts us to describe an infant with a terminal transverse deficit of portions of fingers of the left hand, and syndactyly of the right hand with shortened fingers, whose mother is believed to have been exposed to lysergide and cannabis during pregnancy.
FATAL ’ LOMOTIL ’ POISONING SiR,—The ever-growing list of proprietary medications which are made available to the medical practitioner provide him with a complex and often poorly understood therapeutic armament. The dangers of accidental poisoning with such drugs as salicylates or barbiturates are now well recognised; this is not the case, however, for many of the newer, widely used preparations which may often contain a combination of two or more
drugs.
We briefly report here the death of a 2-year-old boy after the accidental ingestion of ’Lomotil ’ tablets (each tablet contains 2-5 mg. of diphenoxylate hydrochloride and 0-025 mg. of atropine sulphate). For the treatment of a mild diarrhoeal illness lomotil liquid had been prescribed for the patient and lomotil tablets for his mother. 6 hours after accidental ingestion of twelve tablets the patient had been found to be grunting with mild respiratory distress, and this had rapidly progressed during the next 2 hours; respiratory and cardiac arrest had occurred on arrival at a local casualty department and, despite the prompt institution of external cardiac massage, mechanical ventilation, and nalorphine injections, cardiac arrest persisted for 50 minutes. On transfer to this hospital, 12 hours after ingesting the tablets, the patient was hypothermic (temperature 89° F [32°C]), deeply unconscious with fixed dilated pupils, hypotonic, un-
responsive to painful stimuli, and in peripheral circulatory failure; the heart-rate was 120 per minute and the bloodpressure unrecordable. An electroencephalogram (Dr. G. Proudfoot, A. T., Noble, J., Nimmo, J., Brown, S. S., Cameron, J. C. Scott. med. J. 1968, 13, 232. 2. Cromie, B. W. Lancet, 1963, ii, 994. 3. Br. med. J. 1961, i, 43. 4. Bradford Hill, A. Practitioner, 1963, 190, 85. 1.
X-ray of left (L) and right (R) hands of affected newborn. project medially. Note absence of several phalangeal bones. The thumbs
The mother, who had had no previous pregnancies, was 23 years old. The baby, a Caucasian girl, was born, by normal vertex delivery, in June, 1968, 13 days before the expected date of confinement; birth-weight was 5 lb. 3 oz. (2350 g.). The second, third, and fourth fingers of the right hand were webbed and abnormally short. The left hand showed absent nails and shortened fourth and fifth fingers. There was webbing between the second and third toes of the right foot and talipes equinovarus of the left foot. The accompanying figure 1. 2.
Harris, M. J., Beveridge, J. Med. J. Aust. 1965, ii, 921. Hecht, F., Beals, R. K., Lees, M. H., Jolly, H., Roberts, P. Lancet, 1968, ii, 1087.
Letters
to
the Editor
be translated into " the control of those aspects of the environwhich have a deleterious effect on the health of man ", and the second, an offshoot of the first, into " the control of radiation as it relates to the health of man ". As has been the case with public health, universities throughout the world have been able to associate with both the radiological and environmental varieties a body of knowledge; men and women have been usefully trained in them and contribute to the general welfare by practising the techniques they have learned. The same is true of occupational health, which is perhaps a slightly less objectionable term. In these instances therefore brevity has been gained, not at the cost of clarity, but at the cost of the classical use of English. New expressions-albeit ugly oneshave been coined, and have been shown to fulfil a satisfactory role. But what of " international health " ? I can see no sense in the words themselves. Health (as opposed to health services) is without political limits. It is never described as being intranational or national, so why international ? Does the word " international " in this context have anything to offer which is " not offered by world " or " public " in the same context ? Little help is to be gained from an examination of pro" grammes in international health ", offered by universities-at least in the United States. Some schools of public health have a department or a division of international health, but to judge by their curricula it would seem that they could function just as well under the name " tropical medicine and hygiene ". Obviously the tropics are international and have their own health hazards, but the same can be said of the pall of atmospheric pollution which hangs over Europe. Another, subtly different interpretation for the term " international health ", is when it is applied to the sort of scheme whereby a medical school or one of its departments sets up an exchange programme with a sister institution in a developing country. Guy’s and Johns Hopkins have for years had such a scheme, but to my knowledge this has never been described as international health by either party. Dr. Goodman’s reading-list would suggest that in his view the term connotes epidemiology-with special emphasis on the major pestilences, aspects of the history of medicine, and the development and responsibilities of institutions concerned with world health. Only the last named of these three seems to isolate itself from subjects or disciplines which already have a well-defined existence of their own, yet it has little in common with the various connotations set out above. Can it be that the meaning of " international health " lies wholly in the eyes of the beholder, and that according to his quirks and prejudices it may mean almost anything or nothing at all ? If so let’s do away with it. Department of Epidemiology ment
EARLY DETECTION OF CANCER
SIR,-In his letter1 Mr. Donaldson clarifies the importance of early stage diagnosis " in patients with breast cancer and outlines the likely improvement in prognosis when cancer is caught at a presymptomatic stage. At present there seems to be no single factor, other than the diagnosis of presymptomatic "
breast cancer, which is likely to influence for the better the mortality of this malignancy,2 and we do not hold with the gloomy view disseminated by Professor Brooke.33 When referring to screening procedures for breast cancer we are, however, concerned with Mr. Donaldson’s statement that " Thermography is, I understand, of little use," which, we presume, is based on casual hearsay rather than recorded fact. Some workers are confident that they can diagnose preclinical carcinoma of the breast by thermography alone.4 Other workers, including ourselves, feel that thermography is a useful preliminary screening procedure which has potential but must be used at present in conjunction with clinical examination and
mammography.5 The variation in the tumour form and the state of its cellular such that it is not surprising that thermography, the mechanical measurement of the body’s infra-red emission, has its limitations. Not all early tumours generate enough heat to be distinguished on thermograms. Differing patterns and asymmetry of the superficial mammary venous systems complicate interpretation. Active dysplasias in a breast may give rise to false negative thermograms but in our experience, with the use of repeated examinations (to see whether the thermographic pattern is stable), it is a worth-while preliminary screening procedure which is relatively cheap, easy to perform, entirely free from radiation hazard, and clearly an advance on the fatalistic approach of waiting till a tumour is palpable and in many cases unequivocally disseminated. If thermography could be equated to tumour metabolism-and this does not seem an impossibility-it may even supply an index of the degree of the tumour’s powers to disseminate which would be of clinical use in determining treatment. It seems to us that at present thermography, for detecting asymptomatic breast disease, is a preliminary examination which must be supported by the localising procedures of clinical examination of mammography.6 But it may be that after further experience, and the possible improvements in thermographic apparatus, thermography will become a very important diagnostic tool in all forms of breast disease. Department of Diagnostic Radiology, E. SAMUEL Royal Infirmary, G. B. YOUNG. Edinburgh.
activity is
and Public Health, Yale University School of Medicine, New Haven, Connecticut 06510.
INTERNATIONAL HEALTH Sirenjoyed Dr. Goodman’s elegantly written Personal Book List, presented under the title International Health
(Jan. 4, p. 45). I am, however, disappointed that he did not tilt with his scholarly pen at the title itself, especially in view of his condemnation of brevity when it is gained at the cost of clarity. The word " health " is one of many sinned against in modem medical jargon. The term " public health," which can neatly be expanded into " the health of the public ", is I think a defensible expression, as is " world health "-" the health" of the peoples of the world ". " Environmental health " and radiological health " are wholly indefensible on grammatical grounds, but do at least have the merit of some precision of meaning. The first might 1. Donaldson, M. Lancet, 1968, ii, 1392. 2. Young, G. B. Jl R. Coll. Surg. Edin. 1968, 13, 12. 3. Brooke, B. N. ibid. p. 1289. 4. Wallace, J. D., Dodd, G. D. Radiology, 1968, 91, 679. 5. Samuel, E., Young, G. B. Proceedings of the Boerhaave Conference. Leiden, March, 1968; p. 82. Shawe, G. D. H. ibid, p. 109. Strax, P, Personal communication. Basle, 1968. 6. Samuel, E. Hosp. Med. 1967, 1, 343.
ROY M. ACHESON.
’* ’* ’* This letter has been shown to Dr. Goodman, who writes: That I hold no brief for the phraseInternational Health’ is clear from my reference to it as’those two boring " unimpassioned vocables," ’ but in what other terms would Professor Acheson refer to ’any or all of those activities for the prevention, diagnosis, or treatment of disease which require the combined consideration and effort of more than one country’ 1 ? And the phrase has been in use for more than 90 years."-ED. L. "
MASSIVE ’MANDRAX’ POISONING SIR,-May I comment on the letter from Dr. Wallace and Dr. Allen (Dec. 7, p. 1247) reporting the management by
haemodialysis of a patient poisoned byMandrax’ (diphenhydramine and methaqualone) ? Would it not be advisable in such reports if information were given at least regarding the blood-levels, recovery in dialysate, or clearance of metha1.
Goodman, N. M. International Health Organisations and Their Work; p. 4. London, 1952.
150
qualone for, without such information, readers cannot determine whether dialysis is in fact of any value in this form of poisoning?1 Indeed, apart from circumstantial evidence, notoriously unreliable, there is nothing to indicate that the patient had ingested mandrax. Regional Poisoning Treatment Centre, Ward 3, The Royal Infirmary, HENRY MATTHEW. Edinburgh 3.
EVALUATING DRUG TRIALS UNSEEN SIR,-Doctors whose responsibility it is to advise the pharmaceutical manufacturer on evaluation of new remedies will find themselves in general agreement with your note on the subject last week (p. 109), but some rather important qualifications have been omitted. The double-blind trial is not itself a passport to success in drug evaluation, and in the investigation of new remedies for symptomatic therapy the double-blind trial is often inappropriate. As Cromie2 has stressed, subjective assessment of subjective symptoms should not be scorned. Control of all the variables of weight, age, and sex of the patient leave out of consideration the vital question of the patient’s personality, and, equally important, the attitude of the doctor to his patient and towards the new medicine.3 Bradford Hill reminded us some years ago that the mere use of tests of statistical significance did not ensure that the conclusions reached were correct, and that, if the data were not comparably valid, statistical tests were valueless.4 Controlled trials, statistical significance, and random allocation of treatments have a place in drug evaluation, provided the trial itself is very carefully planned. The computer is surely destined to play a major role in the future practice of medicine, but it will be a sad day if careful clinical observation is replaced by a string of mathematical symbols. The Bayer Products Co.,
Surbiton-upon-Thames, Surrey.
J.
M. MUNGAVIN.
showed practically compiete equipotentiality for signal either spontaneously or in response to various stimuli; these features suggested unrecoverable cerebral function. Supportive therapy and nalorphine injections were continued, but these measures did not result in clinical improvement, and serial electroencephalograms remained unchanged. Shigella sonnei was cultured from the diarrhoeal stools. He
Pampiglione) cerebral
died 65 hours after admission; necropsy showed gross cerebral oedema. The pharmacological action of atropine is well documented, and the total ingested dose in this child was well below toxic amounts. Diphenoxylate hydrochloride is somewhat similar to pethidine in its chemical structure but its metabolism is poorly understood; in our patient it is probable that this drug caused respiratory depression which could not be reversed and ultimately proved fatal. Although respiratory depression is listed amongst the effects of overdosage of lomotil, it seems likely that the dangers are insufficiently known, since the drug is widely prescribed for what is often a mild self-limiting disorder. Indeed, in a double-blind study of 50 children with diarrhoea, Harris and Beveridgefound no clear pattern to suggest that lomotil influences the course of the condition. We thank Prof. 0. Wolff for his
permission
to
report this
patient. Hospital for Sick Children, Great Ormond Street, London W.C.1.
JOHN T. HARRIES MARY ROSSITER.
LYSERGIDE AND CANNABIS AS POSSIBLE TERATOGENS IN MAN letter SIR,-The by Dr. Hecht and his colleagues2 prompts us to describe an infant with a terminal transverse deficit of portions of fingers of the left hand, and syndactyly of the right hand with shortened fingers, whose mother is believed to have been exposed to lysergide and cannabis during pregnancy.
FATAL ’ LOMOTIL ’ POISONING SiR,—The ever-growing list of proprietary medications which are made available to the medical practitioner provide him with a complex and often poorly understood therapeutic armament. The dangers of accidental poisoning with such drugs as salicylates or barbiturates are now well recognised; this is not the case, however, for many of the newer, widely used preparations which may often contain a combination of two or more
drugs.
We briefly report here the death of a 2-year-old boy after the accidental ingestion of ’Lomotil ’ tablets (each tablet contains 2-5 mg. of diphenoxylate hydrochloride and 0-025 mg. of atropine sulphate). For the treatment of a mild diarrhoeal illness lomotil liquid had been prescribed for the patient and lomotil tablets for his mother. 6 hours after accidental ingestion of twelve tablets the patient had been found to be grunting with mild respiratory distress, and this had rapidly progressed during the next 2 hours; respiratory and cardiac arrest had occurred on arrival at a local casualty department and, despite the prompt institution of external cardiac massage, mechanical ventilation, and nalorphine injections, cardiac arrest persisted for 50 minutes. On transfer to this hospital, 12 hours after ingesting the tablets, the patient was hypothermic (temperature 89° F [32°C]), deeply unconscious with fixed dilated pupils, hypotonic, un-
responsive to painful stimuli, and in peripheral circulatory failure; the heart-rate was 120 per minute and the bloodpressure unrecordable. An electroencephalogram (Dr. G. Proudfoot, A. T., Noble, J., Nimmo, J., Brown, S. S., Cameron, J. C. Scott. med. J. 1968, 13, 232. 2. Cromie, B. W. Lancet, 1963, ii, 994. 3. Br. med. J. 1961, i, 43. 4. Bradford Hill, A. Practitioner, 1963, 190, 85. 1.
X-ray of left (L) and right (R) hands of affected newborn. project medially. Note absence of several phalangeal bones. The thumbs
The mother, who had had no previous pregnancies, was 23 years old. The baby, a Caucasian girl, was born, by normal vertex delivery, in June, 1968, 13 days before the expected date of confinement; birth-weight was 5 lb. 3 oz. (2350 g.). The second, third, and fourth fingers of the right hand were webbed and abnormally short. The left hand showed absent nails and shortened fourth and fifth fingers. There was webbing between the second and third toes of the right foot and talipes equinovarus of the left foot. The accompanying figure 1. 2.
Harris, M. J., Beveridge, J. Med. J. Aust. 1965, ii, 921. Hecht, F., Beals, R. K., Lees, M. H., Jolly, H., Roberts, P. Lancet, 1968, ii, 1087.