673
Letters
to
the Editor
HALOTHANE, HYPOXIA, AND HEPATITIS SIR,-As correspondence arising out of Professor Sherlock’s paper (Aug. 12, p. 364) indicates, the association between halothane anxsthesia and a liver disorder, sometimes progressing to jaundice and death, is still a matter of controversy among anaesthetists. One suggestion is that a metabolite is the toxic agent, rather than’the halothane molecule itself.’ Since the vast majority of patients anaesthetised with halothane escape this complication it seems reasonable to assume that those affected either produce an unusual toxic metabolite or are unduly susceptible to the effects of a generally produced one. I would like to suggest one possible mechanism. Up to 20% of a halothane "dose" is broken down in the body23 boy enzymes common to all animal species, so animal tissue experiments are qualitatively, if not necessarily quantitatively, relevant.’ The only factor so far found radically to alter halothane metabolism with the production of potentially hepatotoxic metabolites is hypoxia, especially in animals in which hepatic enzymes have been induced.45 Anaesthetists will be quick to deny that patients with post-halothane hepatitis became hypoxic during anaesthesia, though they cannot be sure about the degree of induction of their patients’ enzymes. The bewildering array of inducing agents, including smoking and alcohol, prevent this. In any event the conduct of the anaathesia is not necessarily relevant to the argument because inhalation anxsthetic drugs are not metabolised with any great vigour during administration. Indeed some say that the high levels of these agents in body tissues during clinical anxsthesia inhibit metabolism. Halothane and other halogenated anaesthetic agents seem to be metabolised more quickly after anxsthesia than during it. Serum-bromide concentrations rise for up to 5 days after clinical halothane anaathesia,’ indicating the persistence of both substrate and enzyme activity. Arterial hypoxaemia often occurs after anaesthesia unless preventive measures are taken,8 and minor episodes of postoperative hypoxia must frequently go unnoticed. The widespread method of raising the foot of the bed to treat postoperative hypotension, for example, impairs ventilation of the lung bases by pressure of the abdominal viscera through the diaphragm. Obese patients, who run an increased risk of halothane hepatitis,9 also tend to have ventilatory inadequacy and arterial hypoxaemia postoperatively. Little is known about the arterial supply to or regional distribution within the liver after surgery and anaesthesia. Hepatic oxygenation may not always be fully maintained during this all-important period of halothane metabolism, particularly after an operation at site richly innervated by the autonomic system. Liver function often temporarily deteriorates after apparently uncomplicated anaesthesia, and hypoxia may be a operations under general causative factor. 10 " The rarity of unexpected hepatitis after halothane coupled with the wide variety of hepatic-enzyme-inducing agents to which the patient may be exposed, makes it difficult to test the hypothesis that post-anaesthetic hepatic hypoxia brings about the production of hepatotoxic metabolites by abnormal enzymic degradation of halothane. The detection of potentially 1. Van Dyke, R. A Anesthesiology, 1978, 48, 165. 2 Rehder, K, and others ibid. 1967, 28, 711. 3. Cascorbi, H F., Blake, D.A., Helrich, M. ibid. 1970, 32, 119. 4. McLain, G. W., and others. Annual meeting of American Society of Anesthesiologists, 1977, abstr. p. 481. 5 Andreen, M., Irestedt, L. Paper read at 14th congress of Scandinavian Society of Anæsthesiologists, 1977. 6. Hitt, B. A., and others J Pharmac exp. Ther. 1977, 203, 193. 7. Tinker, J H., Gandolfi, A. J., Van Dyke, R. A. Anesthesiology, 1976, 44, 194. 8 Nunn, J. F, Payne, J. P. Lancet, 1962, ii, 631. 9. Walton, B., and others. Br. med. J. 1976, i, 1171. 10 Dodson, M. E., Richards, T. G. Br. J. Anæsth. 1972, 44, 47 11. Clarke,R.S.,Doggart,J.R.,Lavery, T.ibid. 1976, 48, 119.
toxic metabolites during the post anaesthetic period and the correlation of these findings with hepatic function and clinical progress would be a useful investigation. Raised levels of inorganic fluoride may indicate that reductive rather than oxidative metabolism of halothane has occurred. 12 If this process were shown to account for the hepatotoxicity of halothane what could be done? Should we merely advocate even better standards of postoperative care and even more attention to avoidance of hypoxia? Or should anaesthetists look more critically at inhalational anaesthesia in general, and at the use of halothane in particular, with a view to the eventual substitution of less soluble, and therefore more rapidly eliminated and less readily metabolised agents? St. Bartholomew’s Rochester, Kent
Hospital,
F. E. BENNETTS
SEX AND PROGNOSIS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKÆMIA
SIR,-We were interested to read the letter from Dr Evans colleagues (Sept. 2, p. 522) concerning their results for the treatment of childhood acute lymphoblastic leukxmia (A.L.L.). Our finding (July 15) that girls do substantially better than and
boys on modern treatment is very similar to the results for good prognosis patients in the M.R.C. U.K.A.L.L. trials,with a plateau in the life-table curve for remission duration from about 2 years for girls, whereas boys continue to relapse through the 3rd and 4th year. It is difficult to explain why girls in the Manchester series should have continued to relapse at the same rate as boys. The suggestion that our results are due to failure to take account of the larger proportion of boys with a high initial blast-count is not correct. We had performed a retrospective stratification for initial blast-count but found that the sex difference for duration of complete and haematological remission was independent of this variable (y2 8.16 and 8.48 respectively, P
Letters
to
the Editor
HALOTHANE, HYPOXIA, AND HEPATITIS SIR,-As correspondence arising out of Professor Sherlock’s paper (Aug. 12, p. 364) indicates, the association between halothane anxsthesia and a liver disorder, sometimes progressing to jaundice and death, is still a matter of controversy among anaesthetists. One suggestion is that a metabolite is the toxic agent, rather than’the halothane molecule itself.’ Since the vast majority of patients anaesthetised with halothane escape this complication it seems reasonable to assume that those affected either produce an unusual toxic metabolite or are unduly susceptible to the effects of a generally produced one. I would like to suggest one possible mechanism. Up to 20% of a halothane "dose" is broken down in the body23 boy enzymes common to all animal species, so animal tissue experiments are qualitatively, if not necessarily quantitatively, relevant.’ The only factor so far found radically to alter halothane metabolism with the production of potentially hepatotoxic metabolites is hypoxia, especially in animals in which hepatic enzymes have been induced.45 Anaesthetists will be quick to deny that patients with post-halothane hepatitis became hypoxic during anaesthesia, though they cannot be sure about the degree of induction of their patients’ enzymes. The bewildering array of inducing agents, including smoking and alcohol, prevent this. In any event the conduct of the anaathesia is not necessarily relevant to the argument because inhalation anxsthetic drugs are not metabolised with any great vigour during administration. Indeed some say that the high levels of these agents in body tissues during clinical anxsthesia inhibit metabolism. Halothane and other halogenated anaesthetic agents seem to be metabolised more quickly after anxsthesia than during it. Serum-bromide concentrations rise for up to 5 days after clinical halothane anaathesia,’ indicating the persistence of both substrate and enzyme activity. Arterial hypoxaemia often occurs after anaesthesia unless preventive measures are taken,8 and minor episodes of postoperative hypoxia must frequently go unnoticed. The widespread method of raising the foot of the bed to treat postoperative hypotension, for example, impairs ventilation of the lung bases by pressure of the abdominal viscera through the diaphragm. Obese patients, who run an increased risk of halothane hepatitis,9 also tend to have ventilatory inadequacy and arterial hypoxaemia postoperatively. Little is known about the arterial supply to or regional distribution within the liver after surgery and anaesthesia. Hepatic oxygenation may not always be fully maintained during this all-important period of halothane metabolism, particularly after an operation at site richly innervated by the autonomic system. Liver function often temporarily deteriorates after apparently uncomplicated anaesthesia, and hypoxia may be a operations under general causative factor. 10 " The rarity of unexpected hepatitis after halothane coupled with the wide variety of hepatic-enzyme-inducing agents to which the patient may be exposed, makes it difficult to test the hypothesis that post-anaesthetic hepatic hypoxia brings about the production of hepatotoxic metabolites by abnormal enzymic degradation of halothane. The detection of potentially 1. Van Dyke, R. A Anesthesiology, 1978, 48, 165. 2 Rehder, K, and others ibid. 1967, 28, 711. 3. Cascorbi, H F., Blake, D.A., Helrich, M. ibid. 1970, 32, 119. 4. McLain, G. W., and others. Annual meeting of American Society of Anesthesiologists, 1977, abstr. p. 481. 5 Andreen, M., Irestedt, L. Paper read at 14th congress of Scandinavian Society of Anæsthesiologists, 1977. 6. Hitt, B. A., and others J Pharmac exp. Ther. 1977, 203, 193. 7. Tinker, J H., Gandolfi, A. J., Van Dyke, R. A. Anesthesiology, 1976, 44, 194. 8 Nunn, J. F, Payne, J. P. Lancet, 1962, ii, 631. 9. Walton, B., and others. Br. med. J. 1976, i, 1171. 10 Dodson, M. E., Richards, T. G. Br. J. Anæsth. 1972, 44, 47 11. Clarke,R.S.,Doggart,J.R.,Lavery, T.ibid. 1976, 48, 119.
toxic metabolites during the post anaesthetic period and the correlation of these findings with hepatic function and clinical progress would be a useful investigation. Raised levels of inorganic fluoride may indicate that reductive rather than oxidative metabolism of halothane has occurred. 12 If this process were shown to account for the hepatotoxicity of halothane what could be done? Should we merely advocate even better standards of postoperative care and even more attention to avoidance of hypoxia? Or should anaesthetists look more critically at inhalational anaesthesia in general, and at the use of halothane in particular, with a view to the eventual substitution of less soluble, and therefore more rapidly eliminated and less readily metabolised agents? St. Bartholomew’s Rochester, Kent
Hospital,
F. E. BENNETTS
SEX AND PROGNOSIS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKÆMIA
SIR,-We were interested to read the letter from Dr Evans colleagues (Sept. 2, p. 522) concerning their results for the treatment of childhood acute lymphoblastic leukxmia (A.L.L.). Our finding (July 15) that girls do substantially better than and
boys on modern treatment is very similar to the results for good prognosis patients in the M.R.C. U.K.A.L.L. trials,with a plateau in the life-table curve for remission duration from about 2 years for girls, whereas boys continue to relapse through the 3rd and 4th year. It is difficult to explain why girls in the Manchester series should have continued to relapse at the same rate as boys. The suggestion that our results are due to failure to take account of the larger proportion of boys with a high initial blast-count is not correct. We had performed a retrospective stratification for initial blast-count but found that the sex difference for duration of complete and haematological remission was independent of this variable (y2 8.16 and 8.48 respectively, P
