" / would have everie man zorite what he knozoes and no more."—MONTAIGNE

BRITISH JOURNAL OF ANAESTHESIA VOLUME 15, No. 12

DECEMBER 1979

Whilst every effort is made by the publishers and editorial committee to see that no inaccurate or misleading data, opinion or statement appears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contributor or advertiser concerned. Accordingly, the publishers and the editorial committee and their respective employees, officers and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement.

LIVER DYSFUNCTION AFTER REPEATED

Reversible minor changes in liver function are common in the period immediately after operation. The relative contributions of anaesthesia and surgery to these changes cannot be quantified easily in man. However, indirect evidence from animal and human studies suggests that pre-existing liver dysfunction, hypoxia, hypotension and hypercarbia, surgical trauma and interference with liver blood flow, viral hepatitis as well as hepatotoxic effects of anaesthetic and other drugs are important factors. With regard to halogenated volatile anaesthetic agents, a spectrum of hepatotoxicity may be imagined, ranging from chloroform as "worst" to enflurane as "best" with halothane somewhere in between. Hepatotoxicity may be enhanced in animal models by enzyme induction and in the case of halothane by stimulation of the reductive pathway (Van Dyke and Gandolfi, 1976). This mode of metabolism of halothane has been postulated as the mechanism of halothaneassociated hepatitis in man (Cohen et al., 1975). Neither the aetiology nor the frequency of halothane-associated hepatitis has been established in man. However, the condition appears to be rare and frequencies ranging from 1 in 6000 to 1 in 110 000 anaesthetics have been suggested (Inman and Mushin, 1974; Bottinger, Daleri and Hallen, 1976). In addition, the condition is most commonly associated with repeated exposure to halothane at short intervals of time, usually within 4 weeks (Inman and Mushin, 1974; Walton et al., 1976). The liver dysfunction described by these authors included jaundice and a high frequency of fulminant hepatic failure. In addition, various markers of immunological processes, indicating that an immune reaction may be involved in the development of halothane hepatitis, have been found in clinical studies (Walton et al., 1976; Vergani et al., 1978). The most striking

ANAESTHESIA

feature of halothane hepatitis is its sporadic nature and the severity of the liver dysfunction, which is out of all proportion to the anaesthesia and surgical procedure which have preceded its development. There seems little evidence to support the concept of a pyramid of problems—a large number of patients with mild hepatic dysfunction at the base with a few patients at the peak with severe problems (Strunin, 1977). Studies of halothane metabolism in man (Sharp, Trudell and Cohen, 1979) indicate that reductive as well as oxidative metabolism may occur in normal individuals without enzyme induction or hypoxia. If this is so, then it is less likely that the reductive pathway is primarily responsible for liver cell damage, and other mechanisms such as hapten formation leading to an immune response may be necessary. This would fit with the lack of doseresponse and the association of repeated exposure found in cases of unexplained hepatitis associated with halothane (Walton et al., 1976). Against this background, how can we view the prospective study by Fee and his colleagues in the present issue of the Journal ? First, the number of patients studied is small and therefore it is unlikely, except by chance, that the halothane group would include a patient who was likely to develop halothane hepatitis as described above. This has indeed been the case: none of the patients given halothane appears to have come to any harm, or developed jaundice or eosinophilia or other signs of clinical liver dysfunction. All the changes were confined to alterations in enzyme concentrations. Second, most of the patients received their second halothane anaesthetic at more than a 4-week interval and the number of patients receiving more than two exposures to halothane in this period is so small as to make interpretation of the results obtained difficult. A factor

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repeatedly exposing patients to halothane and the possibility of a severe liver reaction occurring. Such hepatitis following enflurane anaesthesia has not been reported in the literature, although there are isolated case reports of minor liver dysfunction. Many anaesthetists would welcome an alternative to halothane for those patients where repeated anaesthesia is required. In the present study care was taken to use halothane-free anaesthetic machines and operating areas during enflurane administration, but this is not a practical proposition for most anaesthetic departments. The cost of the Belfast study both in time and manpower has been immense, whereas the information gathered is limited to simple measurements of some aspects of liver function. Attempting to analyse the results by comparison with other similar studies (McEwan, 1976; Allen and Downing, 1977; Thompson and Friday, 1978) shows that there is considerable disagreement with respect to the effects of halothane. This lends support to the suggestion that assessing liver function after operation by changes in transaminases (or related enzymes) alone is unrewarding (Strunin, 1978). Until the mechanism of liver damage associated with halothane has been elucidated it is unlikely that a specific test will become available. In the meantime, one wonders whether further studies along the lines of Fee and his colleagues can be justified. Leo Strunin REFERENCES

Allen, P. J., and Downing, J. W. (1977). A prospective study of hepatocellulor function after repeated exposure to halothane or enflurane in women undergoing radium therapy for cervical cancer. Br.J. Anaesth., 49, 1035. Bottinger, L. E., Dalen, E., and Kallen, B. (1976). Halothane-induced liver damage: an analysis of the material reported to the Swedish Adverse Drug Reaction Committee 1966-1973. Ada Anaesthesiol. Scand., 20, 40. Cohen, E. N., Trudell, J. R., Edmunds, H. N., and Watson, E. (1975). Urinary metabolites of halothane in man. Anesthesiology, 43, 392.

Inman, W. H. W., and Mushin, W. W. (1974). Jaundice after repeated exposure to halothane: an analysis of reports to the Committee on Safety of Medicines. Br. Med. J., 1, 5. McEwan, J. (1976). Liver function tests following anaesthesia. Br.J. Anaesth., 48, 1065. Sharp, J. H., Trudell, J. R., and Cohen, E. N. (1979). Volatile metabolites and decomposition products of halothane in man. Anesthesiology, 50, 2. Strunin, L. (1977). The Liver and Anaesthesia. London: Saunders. (1978). Halothane hepatitis. Lancet, 2, 468. Thompson, D. S., and Friday, C D . (1978). Changes in liver enzyme values after halothane and enflurane for surgical anaesthesia. South. Med. J., 71, 779.

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adding to this difficulty is the use in some tables of logarithmic transformation of enzyme concentrations. Although this may be correct with regard to the known skewing of the distribution of some enzyme concentrations in the population, it is not normal practice in most laboratories. Therefore, this may lead to confusion if attempting to compare the Belfast figures with those obtained in other centres. The major findings of the Belfast study are contained in tables VI and VII. These ostensibly show an increasing percentage of abnormalities in enzyme concentrations with increasing numbers of exposures to halothane (table VI), whereas there are only minor changes in the patients who received enflurane (table VII). The difference between halothane and enflurane is not unexpected, but the magnitude of the changes seen with halothane needs some further elucidation. On enquiry from the authors it was ascertained that all changes use the first value obtained before the first anaesthetic as a reference point. In addition, it is not necessarily the same patients who show abnormalities after each anaesthetic. Furthermore, in some patients the increased concentrations had not returned to the pre-first anaesthetic concentration before a further anaesthetic was administered. No unethical behaviour is implied, since the results were not available to the anaesthetist concerned. Although all the information is now available analysis has not yet been completed. It is possible, therefore, that the majority of the changes in the halothane group may be confined to a few patients who should be considered in more detail. In particular, those patients whose enzymes had not returned to normal before receiving further halothane are of special interest. It has been suggested by Trowell, Peto and Crampton-Smith, (1975) that transaminase screening before operation would be of value in identifying patients prone to develop halothane hepatitis. The present study may have contributed to the view that such enzyme screening is of little help. Can any conclusions be drawn from the study by Fee and his colleagues ? There were more abnormal changes in enzyme activities associated with halothane than with enflurane. This concurs with animal studies, but would need further confirmation in man as the number of patients studied here is small. Whether the changes associated with halothane are of any relevance is a matter for debate. In the present study they clearly had no effect on the outcome as none of the patients showed any overt signs of liver dysfunction. Nevertheless, there is concern about

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Trowell, J., Peto, R., and Crampton-Smith, A. (1975). Controlled trial of repeated halothane anaesthetics in patients with carcinoma of the uterine cervix treated with radium. Lancet, I, 821. Van Dyke, R. A., and Gandolfi, A. J. (1976). Anaerobic release of fluoride from halothane; relationship to the binding of halothane metabolites to hepatic cellular constituents. Drug Metab. Dispos., 4, 40.

Vergani, D., Tsantoulas, D., Eddleston, A. L. W. F., Davis, M., and Williams, R. (1978). Sensitisation to halothane—altered liver components in severe hepatic necrosis after halothane anaesthesia. Lancet, 2, 801. Walton, B., Simpson, B. R., Strunin, L., Doniach, D., Perrin, J., and Appleyard, A. J. (1976). Unexplained hepatitis following halothane. Br. Med.J., 1, 1171.

ACKNOWLEDGEMENT

Dr A. Angel Dr D. Arthur

Dr T. D. McCubbin Dr P. Mackenzie

Dr J. Barker Dr O. Bastard Professor W. C. Bowman Dr G. H. Bush Dr J. A. Bushman

Professor W. W. Mapleson Dr I. G. Marshall Dr A. H. B. Masson Dr D. Millar Dr D. D. Moir Dr M. Morgan

Professor D. Campbell Dr R. S. J. Clarke Dr P. V. Cole Dr R. S. Cormack Dr K. M. S. Dewar Dr G. Drummond Dr S. A. Feldman Dr P. Foex Professor J. S. Gillespie Dr R. Greenbaum Dr Dr Dr Dr Dr Dr Dr Dr

G. Hall M. Halliday M. Halsey C. Harming J. Henderson K. B. Holloway R. Hughes C. J. Hull

Dr J. Inkster Dr G. Jones Dr C. Jordan Dr Dr Dr Dr Dr Dr Dr Dr

J. Kennedy J. Kerr R. P. Knill-Jones I. McA. Ledingham N. W. Lees A. F. Lever J. Lucke J. Lumley

Dr G. D. Parbrook Dr B. Pleuvry Dr A. Reid Professor J. Reid Dr F. Reynolds Dr C. Richards Professor J. S. Robinson Dr K. Rogers Professor G. Smith Dr W. D. A. Smith Professor M. K. Sykes Dr P. Thompson Dr T. Thorburn Professor J. A. Thornton Dr Tilstone Professor J. Utting Dr J. P. Vance Professor M. Vickers Dr P. G. M. Wallace Dr J. Watkins Dr D. White Professor C. Whitfield Dr J. G. Whitwam Dr T. Wildsmith Dr J. Wilson Mr D. G. Young

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The Editor wishes to acknowledge the help of the following who, in addition to the Editorial Board, provided help with the assessment of manuscripts during 1979.

Liver dysfunction after repeated anaesthesia.

" / would have everie man zorite what he knozoes and no more."—MONTAIGNE BRITISH JOURNAL OF ANAESTHESIA VOLUME 15, No. 12 DECEMBER 1979 Whilst ever...
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