- Email: [email protected]
HALOTHANE
902
unexplained death during exchange transfusion, the variability of transfusion acidosis " is likely to be related to differences in technique, incidental or intentional. Two somewhat neglected aspects of this problem seem worth mentioning. First, the continued patency of the foramen ovale after birth makes it possible for a large, chilled, and biochemically As with
"
unphysiological, "’bolus
" of donor blood to reach the left side of the heart, and hence the coronary arteries and vital centres, unmixed by previous passage through a capillary bed. This danger may be decreased by attention to the position of the umbilical catheter-tip5 and by the slow injection of small volumes of blood; it will not be averted, and may be increased, by the addition of sodium bicarbonate to the donor blood, the immediate effect of which may be to increase intracellular acidosis.6 Second, hypothermia is one of the most common complications of the early exchange transfusion. The infants, often immature, recently delivered, and perhaps ill as a result of rhesus haemolytic disease, are particularly vulnerable to cold; exposure during the transfusion and the injection of chilled blood may further potentiate the " normal " postnatal fall in body temperature. Subnormal temperature, with its influence on cardiac performance tissue perfusion,8 and enzyme function,must exert a powerful effect on the infant’s ability to maintain acid-base homreostasis.lo 11 I suggest that Dr. Barrie has provided ample evidence of the value of routine acid-base studies during exchange transfusions; such a practice, which might mean no more than the estimation of the pH in the first place, would serve to alert the pxdiatrician both to faults in his technique and to the need for appropriate
therapy.
,
Royal Hospital for Sick Children, Bristol.
PETER M. DUNN.
DEXTROSTIX ESTIMATIONS OF BLOOD-SUGAR SIR,-In the past year, there have been several articles in The Lancet on the use of ’Dextrostix ’ to estimate the bloodglucose. Cohen et a1. 12 and Rennie et al. 13 found a good correlation of the dextrostix reading with the blood-glucose. But MacKay et a1.14 commented on observer variations and’the tendency to underestimate the blood-glucose with dextrostix. Alberti et a1.15 also found wide variation of the range of bloodglucose corresponding to any one dextrostix reading, with underestimations of up to 33%. Marks and Dawson 16 question MacKay’s results on the grounds that his blood-glucose method was not specific for true glucose, and further state that they have found a good correlation of the true glucose with the dextrostix values. I have conducted a small study in which I compared true blood-glucose values (’ Autoanalyser ’) with dextrostix. I found that at true glucose values of 90-130 mg. per 100 ml. blood, there is a tendency for dextrostix to underestimate the value by
opinion the correlation of dextrostix values with blood-glucose is too poor to be of value except in
the the differentiation of diabetic from insulin coma. In such circumstances a correct diagnosis could be made immediately and without the possible errors encountered in the use of the urine for immediate diagnosis. Medical Department, Veterans Administration Hospital, SEYMOUR HERSCHBERG. Brooklyn, New York, U.S.A. In my
true
PULMONARY EMBOLISM IN HEALTHY PEOPLE SIR,-Iwas very interested to read Dr. Fleming’s letter (Oct. 2). Over the past 6 years, while dealing with a relatively fit Service population, I had seen only three cases of unheralded pulmonary embolism in previously healthy and active soldiers. All three were males, aged between 25 and 35 years. In August, 1965, however, I admitted to this unit a 34-year-old W.R.A.C. warrant-officer with deep-vein thrombosis and extensive pulmonary embolism. Like the male patients, she had previously been very active, but because.of endometriosis she had been takingEnavid ’ (norethynodrel and mestranol) for 2 months before her embolism. Military Wing, Musgrave Park Hospital, Belfast, 9, D. E. BRADFORD. Northern Ireland.
HALOTHANE SiR,—The revival by your leading article (Sept. 4) of the problem of the hepatotoxicity of halothane prompts us to present here a case-report which, like that of Dr. Howard (Sept. 11), is suggestive of allergic liver damage due to halothane. A 41-year-old man was admitted on Jan. 15, 1964, to the burns unit with severe burns from a gas-oven explosion.
At blood-glucose values of 230 mg. per 100 ml. or more, the error is even greater (40%). At my hospital we use a ’Vacutainer ’ to draw blood, and it is difficult to extract a single drop of blood from the tube. When this is done, the drop does not always completely cover the coated area of the dextrostix. Using a syringe and needle did not, however, greatly facilitate properly covering the area of the test-strip which contained the enzyme. Proper covering of the test-area and exact timing were found difficult under ward conditions and may explain some of the previously recorded differences.
approximately 33%.
5. Dunn, P. M. Archs Dis. Childh. (in the press). 6. Wang, H., Katz, A. L. Circulation Res. 1965, 17, 114. 7. Boyan, C. P. Ann. Surg. 1964, 160, 282. 8. Bond, T. P., Derrick, J. R., Guest, M. M. Archs Surg., Chicago, 1964, 89, 887. 9. Baldwin, E. in Dynamic Aspects of Biochemistry; p. 16. Cambridge, 1963. 10. Gandy, G. M., Adamsons, K., Cunningham, N., Silverman, W. A., James, L. S. J. clin. Invest. 1964, 43, 751. 11. Buetow, K. C., Klein, S.W. Pediatrics, Springfield, 1964, 34, 163. 12. Cohen, S. L., Legg, S., Bird, R. Lancet, 1964, ii, 883. 13. Rennie, I. D. B., Keen, H., Southon, A. ibid. p. 884. 14. MacKay, N., Gordon, A., Neilson, J. McE. ibid. Aug. 7, 1965, p. 269. 15. Alberti, K. G. M. M., Middleton, G. G., Caird, F. I. ibid. Aug. 14,
1965, p. 319. 16. Marks, V., Dawson, A. ibid. Aug. 21, 1965, p. 386.
Liver-function tests in a patient with repeated liver damage due to administration of halothane.
Interrupted line
indicates upper range of normal values.
t s.G.o.T. serum-glutamic-oxaioacetic-transaminase.
possibly
903
9% of his total body-surface had 2nd degree, and 50% of it had 3rd degree, burns. Apart from medical treatment for a duodenal ulcer 9 years previously, he had always been in good health. Treatment of the patient’s burns necessitated general anxsthesia on four occasions as follows: 1. Jan. 28, 1964; thiopentone, d-tubocurarine, nitrous oxide and oxygen, and halothane; duration 90 minutes; 4500 ml. blood, and 1000 ml. serum transfused. 2. Feb. 2, 1964; thiopentone, d-tubocurarine, nitrous oxide and oxygen, and halothane; duration 60 minutes; 2500 ml. blood transfused. 3. Feb. 7, 1964; atropine, nitrous oxide and oxygen, and halothane; duration 240 minutes; 2000 ml. blood transfused. 4. Feb. 28, 1964; atropine, nitrous oxide and oxygen and halothane; duration 150 minutes; 1000 ml. blood transfused. Morphine and hyoscine were given on each occasion for premedication. The blood-pressure was normal during each anaesthesia, and the only immediate complication was a rise in temperature on the first 2 occasions to about 39"C, and on the last 2 to about 38C. 10 days after the 3rd anaesthesia, the patient was jaundiced. The jaundice disappeared during the next week, and there were no subjective complaints and no enlargement of the liver. 2 days after the 4th anaesthesia the patient was jaundiced, and had dark urine and hard pale stools. He had nausea and
venous pressure submits the liver to a state of stagnant anoxia and a centrilobular pattern of hepatic disease is set in train. Anoxssmic anoxia could be expected to produce a similar pattern. Halothane is a powerful cardiorespiratory depressant. With spontaneous ventilation a patient can all too easily reach a state of profound hypotension and anoxaemia. In various operative positions on the table this dangerous situation is accentuated. It seems reasonable to suggest that the combination of lowered alveolar oxygen tension and reduced tissue-oxygen availability could provide the appropriate conditions for liver-failure, according to the degree and duration of exposure. The investigation of a problem of this nature must, of course, cover all other factors (including those which are unrelated to the anxsthetic)-a pre-existing toxaemia or metabolic disorder are obvious ones. It is relevant to recall that the gravest danger of halothane lies in the ease of its administration. F. C. SHELLEY. Cambridge, England.
THE NOTTINGHAM MEDICAL SCHOOL SIR,-It is gratifying to note from your leading article (July 3) that the pattern of medical education is to follow that of North American universities, with the preclinical course leading to a B.sc. degree. This is a progressive step, since doctors in general are narrow in their outlook and education, and when congregated have little other than medical matters was somnolent, but had no other signs of hepatic coma and no about which to talk. Perhaps the paramedical subjects menhepatomegaly. The jaundice reached a maximum value 10 days tioned in your article will be supplemented by others not after the anxsthesia, and thereafter slow spontaneous imconnected with medicine. provement took place. The present training programme of newly qualified doctors The principal liver-function tests are shown in the accomin Britain is inferior to that of their counterparts in North panying figure. The alkaline phosphatase was 6-1mmoles per America. Whilst it is appreciated that teaching hospitals in litre per hour (normal value <2’2) after the third anaesthesia, Britain have insufficient places for all recent graduates, some the after and maximally 7-7 mmoles 5 days 4th, slowly returning of whom do their year’s preregistration training in peripheral to normal values in P/2 months. The prothrombin-time was hospitals, not enough effort is made to give house-officers a reduced to 16% of the normal value after the 4th anesthesia, comprehensive training for general practice. The various units and rose from the 20th day with vitamin-Kl treatment. in a teaching hospital tend to specialise, and it is possible for While in hospital the patient also received penicillin (during a house-officer to have six months’ training in neurosurgery the whole period), diazepam (from Jan. 19 to Feb. 20), and and six months in dermatology, to cite a rather extreme polymyxin (from Jan. 21 to Feb. 20). example. Rotating internships equip a physician far more Thus during a period of 30 days this patient was anxseffectively than do the house-officer posts in Britain. Seminars thetised on 4 occasions, on each of which he was given haloand other postgraduate educational features are also far more thane. After the 3rd anxsthesia there were slight signs, and prominent in North America. after the fourth anaathesia pronounced signs of parenchyFor those doctors who are specialising, rotating programmes matous liver injury which slowly resolved spontaneously. have more to offer than have the static posts in which a registrar Liver biopsy could not be performed because of the bleeding or senior registrar remains with one consultant for periods up tendency and the burns. to several years. Such an arrangement is common in British In this patient allergic hepatic damage was probably caused teaching hospitals, and is stultifying to both consultant and by halothane, and we suggest that halothane should not be registrar. Objective criticism and appraisal are suppressed by administered repeatedly to patients with severe general disthe fear of prejudicing one’s future chances of a consultant post; turbance such as is caused by burns, until the causal relation but this is not so in North America. Rotation through the between halothane and liver damage has been fully elucidated. various units in a teaching hospital, and to the peripheral K. WINKLER. Medical Department III, hospitals, at the registrar and senior-registrar level would P. SEJERSEN. benefit all concerned; would enable the trainee to pick and Department I (surgery and burns unit). choose methods and techniques which he believes are best; H. RASK. Department of Anæsthesiology, would enable doctors from overseas to work in a teaching Municipal Hospital, Copenhagen, Denmark. hospital; and would disseminate knowledge for all the participants. Senior registrars and registrars are loath to vacate SiR,—There have been a number of case-reports of patients teaching-hospital posts because their chances of promotion with liver damage following the administration of halothane. may be reduced if they are working in a peripheral hospital, Many of these reports emphasise the postoperative investigation and consultants tend to encourage an arrangement which of liver function, but no detailed descriptions are given of the ensures that they do not need to impress their ideas and foibles anxsthetic techniques employed. at frequent intervals-and once these are inculcated a registrar Although wide interest is being shown in the alleged hepato- is capable of taking over much of the consultant’s work-load. toxicity of halothane, I wonder whether the techniques of its There should also be greater cooperation between teaching administration are receiving a fair share of attention. This hospitals and developing countries to enable senior registrars suggestion is based upon the belief that the liver may be and registrars to work in such countries, thus lending valuable especially vulnerable to hypoxia because of its dual blood- assistance and increasing their own experience. It is, however, supply from the hepatic artery and portal vein. The mixing of not difficult to understand the reluctance some registrars may these two sources results in the liver being normally exposed to have in applying for such posts, since there may be children a lowered oxygen environment. In certain conditions-for at school, and there is the fear of losing one’s place on the example, in congestive cardiac failure-an increased systemic consultant " ladder ".
unexplained death during exchange transfusion, the variability of transfusion acidosis " is likely to be related to differences in technique, incidental or intentional. Two somewhat neglected aspects of this problem seem worth mentioning. First, the continued patency of the foramen ovale after birth makes it possible for a large, chilled, and biochemically As with
"
unphysiological, "’bolus
" of donor blood to reach the left side of the heart, and hence the coronary arteries and vital centres, unmixed by previous passage through a capillary bed. This danger may be decreased by attention to the position of the umbilical catheter-tip5 and by the slow injection of small volumes of blood; it will not be averted, and may be increased, by the addition of sodium bicarbonate to the donor blood, the immediate effect of which may be to increase intracellular acidosis.6 Second, hypothermia is one of the most common complications of the early exchange transfusion. The infants, often immature, recently delivered, and perhaps ill as a result of rhesus haemolytic disease, are particularly vulnerable to cold; exposure during the transfusion and the injection of chilled blood may further potentiate the " normal " postnatal fall in body temperature. Subnormal temperature, with its influence on cardiac performance tissue perfusion,8 and enzyme function,must exert a powerful effect on the infant’s ability to maintain acid-base homreostasis.lo 11 I suggest that Dr. Barrie has provided ample evidence of the value of routine acid-base studies during exchange transfusions; such a practice, which might mean no more than the estimation of the pH in the first place, would serve to alert the pxdiatrician both to faults in his technique and to the need for appropriate
therapy.
,
Royal Hospital for Sick Children, Bristol.
PETER M. DUNN.
DEXTROSTIX ESTIMATIONS OF BLOOD-SUGAR SIR,-In the past year, there have been several articles in The Lancet on the use of ’Dextrostix ’ to estimate the bloodglucose. Cohen et a1. 12 and Rennie et al. 13 found a good correlation of the dextrostix reading with the blood-glucose. But MacKay et a1.14 commented on observer variations and’the tendency to underestimate the blood-glucose with dextrostix. Alberti et a1.15 also found wide variation of the range of bloodglucose corresponding to any one dextrostix reading, with underestimations of up to 33%. Marks and Dawson 16 question MacKay’s results on the grounds that his blood-glucose method was not specific for true glucose, and further state that they have found a good correlation of the true glucose with the dextrostix values. I have conducted a small study in which I compared true blood-glucose values (’ Autoanalyser ’) with dextrostix. I found that at true glucose values of 90-130 mg. per 100 ml. blood, there is a tendency for dextrostix to underestimate the value by
opinion the correlation of dextrostix values with blood-glucose is too poor to be of value except in
the the differentiation of diabetic from insulin coma. In such circumstances a correct diagnosis could be made immediately and without the possible errors encountered in the use of the urine for immediate diagnosis. Medical Department, Veterans Administration Hospital, SEYMOUR HERSCHBERG. Brooklyn, New York, U.S.A. In my
true
PULMONARY EMBOLISM IN HEALTHY PEOPLE SIR,-Iwas very interested to read Dr. Fleming’s letter (Oct. 2). Over the past 6 years, while dealing with a relatively fit Service population, I had seen only three cases of unheralded pulmonary embolism in previously healthy and active soldiers. All three were males, aged between 25 and 35 years. In August, 1965, however, I admitted to this unit a 34-year-old W.R.A.C. warrant-officer with deep-vein thrombosis and extensive pulmonary embolism. Like the male patients, she had previously been very active, but because.of endometriosis she had been takingEnavid ’ (norethynodrel and mestranol) for 2 months before her embolism. Military Wing, Musgrave Park Hospital, Belfast, 9, D. E. BRADFORD. Northern Ireland.
HALOTHANE SiR,—The revival by your leading article (Sept. 4) of the problem of the hepatotoxicity of halothane prompts us to present here a case-report which, like that of Dr. Howard (Sept. 11), is suggestive of allergic liver damage due to halothane. A 41-year-old man was admitted on Jan. 15, 1964, to the burns unit with severe burns from a gas-oven explosion.
At blood-glucose values of 230 mg. per 100 ml. or more, the error is even greater (40%). At my hospital we use a ’Vacutainer ’ to draw blood, and it is difficult to extract a single drop of blood from the tube. When this is done, the drop does not always completely cover the coated area of the dextrostix. Using a syringe and needle did not, however, greatly facilitate properly covering the area of the test-strip which contained the enzyme. Proper covering of the test-area and exact timing were found difficult under ward conditions and may explain some of the previously recorded differences.
approximately 33%.
5. Dunn, P. M. Archs Dis. Childh. (in the press). 6. Wang, H., Katz, A. L. Circulation Res. 1965, 17, 114. 7. Boyan, C. P. Ann. Surg. 1964, 160, 282. 8. Bond, T. P., Derrick, J. R., Guest, M. M. Archs Surg., Chicago, 1964, 89, 887. 9. Baldwin, E. in Dynamic Aspects of Biochemistry; p. 16. Cambridge, 1963. 10. Gandy, G. M., Adamsons, K., Cunningham, N., Silverman, W. A., James, L. S. J. clin. Invest. 1964, 43, 751. 11. Buetow, K. C., Klein, S.W. Pediatrics, Springfield, 1964, 34, 163. 12. Cohen, S. L., Legg, S., Bird, R. Lancet, 1964, ii, 883. 13. Rennie, I. D. B., Keen, H., Southon, A. ibid. p. 884. 14. MacKay, N., Gordon, A., Neilson, J. McE. ibid. Aug. 7, 1965, p. 269. 15. Alberti, K. G. M. M., Middleton, G. G., Caird, F. I. ibid. Aug. 14,
1965, p. 319. 16. Marks, V., Dawson, A. ibid. Aug. 21, 1965, p. 386.
Liver-function tests in a patient with repeated liver damage due to administration of halothane.
Interrupted line
indicates upper range of normal values.
t s.G.o.T. serum-glutamic-oxaioacetic-transaminase.
possibly
903
9% of his total body-surface had 2nd degree, and 50% of it had 3rd degree, burns. Apart from medical treatment for a duodenal ulcer 9 years previously, he had always been in good health. Treatment of the patient’s burns necessitated general anxsthesia on four occasions as follows: 1. Jan. 28, 1964; thiopentone, d-tubocurarine, nitrous oxide and oxygen, and halothane; duration 90 minutes; 4500 ml. blood, and 1000 ml. serum transfused. 2. Feb. 2, 1964; thiopentone, d-tubocurarine, nitrous oxide and oxygen, and halothane; duration 60 minutes; 2500 ml. blood transfused. 3. Feb. 7, 1964; atropine, nitrous oxide and oxygen, and halothane; duration 240 minutes; 2000 ml. blood transfused. 4. Feb. 28, 1964; atropine, nitrous oxide and oxygen and halothane; duration 150 minutes; 1000 ml. blood transfused. Morphine and hyoscine were given on each occasion for premedication. The blood-pressure was normal during each anaesthesia, and the only immediate complication was a rise in temperature on the first 2 occasions to about 39"C, and on the last 2 to about 38C. 10 days after the 3rd anaesthesia, the patient was jaundiced. The jaundice disappeared during the next week, and there were no subjective complaints and no enlargement of the liver. 2 days after the 4th anaesthesia the patient was jaundiced, and had dark urine and hard pale stools. He had nausea and
venous pressure submits the liver to a state of stagnant anoxia and a centrilobular pattern of hepatic disease is set in train. Anoxssmic anoxia could be expected to produce a similar pattern. Halothane is a powerful cardiorespiratory depressant. With spontaneous ventilation a patient can all too easily reach a state of profound hypotension and anoxaemia. In various operative positions on the table this dangerous situation is accentuated. It seems reasonable to suggest that the combination of lowered alveolar oxygen tension and reduced tissue-oxygen availability could provide the appropriate conditions for liver-failure, according to the degree and duration of exposure. The investigation of a problem of this nature must, of course, cover all other factors (including those which are unrelated to the anxsthetic)-a pre-existing toxaemia or metabolic disorder are obvious ones. It is relevant to recall that the gravest danger of halothane lies in the ease of its administration. F. C. SHELLEY. Cambridge, England.
THE NOTTINGHAM MEDICAL SCHOOL SIR,-It is gratifying to note from your leading article (July 3) that the pattern of medical education is to follow that of North American universities, with the preclinical course leading to a B.sc. degree. This is a progressive step, since doctors in general are narrow in their outlook and education, and when congregated have little other than medical matters was somnolent, but had no other signs of hepatic coma and no about which to talk. Perhaps the paramedical subjects menhepatomegaly. The jaundice reached a maximum value 10 days tioned in your article will be supplemented by others not after the anxsthesia, and thereafter slow spontaneous imconnected with medicine. provement took place. The present training programme of newly qualified doctors The principal liver-function tests are shown in the accomin Britain is inferior to that of their counterparts in North panying figure. The alkaline phosphatase was 6-1mmoles per America. Whilst it is appreciated that teaching hospitals in litre per hour (normal value <2’2) after the third anaesthesia, Britain have insufficient places for all recent graduates, some the after and maximally 7-7 mmoles 5 days 4th, slowly returning of whom do their year’s preregistration training in peripheral to normal values in P/2 months. The prothrombin-time was hospitals, not enough effort is made to give house-officers a reduced to 16% of the normal value after the 4th anesthesia, comprehensive training for general practice. The various units and rose from the 20th day with vitamin-Kl treatment. in a teaching hospital tend to specialise, and it is possible for While in hospital the patient also received penicillin (during a house-officer to have six months’ training in neurosurgery the whole period), diazepam (from Jan. 19 to Feb. 20), and and six months in dermatology, to cite a rather extreme polymyxin (from Jan. 21 to Feb. 20). example. Rotating internships equip a physician far more Thus during a period of 30 days this patient was anxseffectively than do the house-officer posts in Britain. Seminars thetised on 4 occasions, on each of which he was given haloand other postgraduate educational features are also far more thane. After the 3rd anxsthesia there were slight signs, and prominent in North America. after the fourth anaathesia pronounced signs of parenchyFor those doctors who are specialising, rotating programmes matous liver injury which slowly resolved spontaneously. have more to offer than have the static posts in which a registrar Liver biopsy could not be performed because of the bleeding or senior registrar remains with one consultant for periods up tendency and the burns. to several years. Such an arrangement is common in British In this patient allergic hepatic damage was probably caused teaching hospitals, and is stultifying to both consultant and by halothane, and we suggest that halothane should not be registrar. Objective criticism and appraisal are suppressed by administered repeatedly to patients with severe general disthe fear of prejudicing one’s future chances of a consultant post; turbance such as is caused by burns, until the causal relation but this is not so in North America. Rotation through the between halothane and liver damage has been fully elucidated. various units in a teaching hospital, and to the peripheral K. WINKLER. Medical Department III, hospitals, at the registrar and senior-registrar level would P. SEJERSEN. benefit all concerned; would enable the trainee to pick and Department I (surgery and burns unit). choose methods and techniques which he believes are best; H. RASK. Department of Anæsthesiology, would enable doctors from overseas to work in a teaching Municipal Hospital, Copenhagen, Denmark. hospital; and would disseminate knowledge for all the participants. Senior registrars and registrars are loath to vacate SiR,—There have been a number of case-reports of patients teaching-hospital posts because their chances of promotion with liver damage following the administration of halothane. may be reduced if they are working in a peripheral hospital, Many of these reports emphasise the postoperative investigation and consultants tend to encourage an arrangement which of liver function, but no detailed descriptions are given of the ensures that they do not need to impress their ideas and foibles anxsthetic techniques employed. at frequent intervals-and once these are inculcated a registrar Although wide interest is being shown in the alleged hepato- is capable of taking over much of the consultant’s work-load. toxicity of halothane, I wonder whether the techniques of its There should also be greater cooperation between teaching administration are receiving a fair share of attention. This hospitals and developing countries to enable senior registrars suggestion is based upon the belief that the liver may be and registrars to work in such countries, thus lending valuable especially vulnerable to hypoxia because of its dual blood- assistance and increasing their own experience. It is, however, supply from the hepatic artery and portal vein. The mixing of not difficult to understand the reluctance some registrars may these two sources results in the liver being normally exposed to have in applying for such posts, since there may be children a lowered oxygen environment. In certain conditions-for at school, and there is the fear of losing one’s place on the example, in congestive cardiac failure-an increased systemic consultant " ladder ".