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PROBLEMS OF MULTIPLE INHALATION ANAESTHETICS
Br. J. Anaesth. (1981), 53, 63S
PROBLEMS OF MULTIPLE INHALATION ANAESTHETICS
J. W. In a survey of 10 000 unselected patients presenting for anaesthesia, Fee and colleagues (1978) found that 47% had previous exposure to one general anaesthetic, 22% to two anaesthetics and as many as 15% to at least three. As might be expected, the frequency of previous exposure to anaesthetics increased with the age of the patient, reaching about 100% in septuagenarians. Thus, one of the problems of repeat anaesthetics may be a result of the age of the patient having the second or third anaesthetic. Many operations are more common in the elderly but, provided the time interval between administrations is greater than 6 weeks, there is no reason to believe that the risk involved is any greater than on the first exposure. The only possible exception would be the patient recovering from long-term toxic effects of a previous anaesthetic such as hepatitis after chloroform or high-output renal failure after methoxyflurane. Apart from its potential role in "halothane hepatitis", -there is no evidence to suggest that a previous exposure to an inhalation agent sensitizes the patient to a subsequent administration, such as occurs with some i.v, anaesthetic agents. PROBLEMS
The main problem of multiple inhalation anaesthetics is the sequelae of the repeated administrations of the halogens, halothane and, to a lesser extent, enflurane. The early halogenated compounds have been abandoned almost completely as have the flammable ethers (diethyl, divinyl, ethyl vinyl, methyl propyl and fluoroxene). No problems were reported following the repeat administration of these agents, but this does not mean that there were none. At their peak of popularity it was assumed that inhalation agents were excreted unchanged and if any complications occurred after operation, a cause other than the anaesthetic agent would have been sought. Even after 1964, when
J. W. DUNDEE, M.D., PH.D.,F.F.A.R.C.S., M.R.C.P.,Department of Anaesthetics, The Queen's University of Belfast, Northern Ireland. 0007-0912/81/130063--05 $01.00
DUNDEE
van Dyke demonstrated conclusively the metabolism of several volatile anaesthetics, there was no suggestion that the metabolites were toxic (Cohen and van Dyke, 1977). We know now that chloroform is metabolized via free-radicle reactive intermediates which are responsible for its hepatotoxicity. A survey of cases called "delayed chloroform poisoning" may well reveal a number of repeat administrations, but it is not likely that such a survey is possible. A similar situation may also apply to fluoroxene. It is worth noting that the prolonged administration of both methoxyflurane and enflurane can cause delayed renal toxicity if the concentrations of inorganic fluoride reach a nephrotoxic threshold (Cousins and Mazze, 1973; Cousins et al., 1974). Doubtless this effect would be cumulative if there were a short interval between the repeated administrations. This would be similar to the effect of two nephrotoxic drugs administered concurrently. HALOTHANE
The potential hepatotoxic effect of halothane is the' real clinical problem. This possibility has been debated widely and although most authorities recognize that it is an uncommon but reasonably well-proven clinical entity (Brown, 1979), some disagree (Bruce, 1979). It is instructive to trace the history of reporting and investigation of this emotive topic.
Surveys The American National Halothane study (Bunker et al., 1969) is the best known early survey, in which a number of co-operating institutions pooled data on the frequency of postoperative liver failure in almost 1 million patients. It is the largest investigation of this type on an anaesthetic topic. The National Halothane Study is sometimes misunderstood or quoted wrongly. It must be pointed out that it dealt only with the frequency of massive hepatic necrosis, which was calculated to be 1.02 in 10000 administrations, similar to the ©
Macmillan Publishers Ltd 1981
64S
overall frequency of this entity. Furthermore, it did not concentrate on repeated administrations, although cases of hepatitis following a second or subsequent exposure to halothane had been reported (Dykes, 1970). Subsequently, data have been obtained from five other sources. Initially these were individual case reports (too numerous to list) of jaundice which seemed to be undisputedly related to a single or multiple administration of halothane. Second, there have been a number of controlled retrospective surveys, some of which are listed in table I. Different workers have taken different criteria for including patients with liver damage, but this must depend on information available. The results of these retrospective surveys have not given conclusive results (table I). However, one recent study by Bottinger, Dalen and Hallen (1976) is of interest. As many as 82% of the affected patients had multiple exposures. The distribution of halothane hepatitis differed from that of viral hepatitis: liver injury following halothane was commonest in middle-aged obese females, while viral hepatitis occurred in the young. The frequency of unexplained jaundice following the administration of halothane appeared to be increasing in Sweden. Reports Third, the U.K. Committee on Safety of Medicines produced two analyses of reports of jaundice submitted to them (Inman and Mushin, 1974; 1978). The 1974 paper, which was derived from 130 reports of jaundice occurring after anaesthesia with halothane, showed "a significant relationship between the number of exposures to this anaesthetic and the rapidity with which jaundice develops after exposure". They considered that "this provided strong evidence of a cause-effect relationship between the use of halothane and jaundice". Of the 114 patients with complete anaesthetic histories, 82% had been exposed more than once; of those exposed, 80% had been anaesthetized with halothane more than once within 28 days. At the same time the Medical Assessor to the Committee on Safety of Medicines sent a memorandum to doctors in the United Kingdom stating that there was a greater risk of jaundice when halothane was given repeatedly within a period of a few weeks, than following a single exposure (Mansell Jones, 1974).
BRITISH JOURNAL OF ANAESTHESIA The second paper of Inman and Mushin (1978), which was derived from 170 reports of jaundice following halothane, compared the relationship between multiple exposures to halothane and jaundice and between the number of exposures and the rapidity with which jaundice develops. When combined with the previous report, it provided complete anaesthetic histories of 251 patients, 82% of whom had been exposed to halothane more than once and of these patients, 75% had been exposed more than once in 28 days. Altogether 46% of the jaundiced patients died. This form of report has been widely criticized by anaesthetists, but surely its failings are all the result of inadequate reporting. Hepatitis survey Fourth, there has been one large well-designed prospective study of 203 patients who actually developed hepatitis after halothane (Walton et al., 1976). No cause could be found in 76 of these and halothane was presumed to be the causative factor. Hepatitis in 95% of these followed multiple exposure to halothane with repeated exposure within 4 weeks in 55% of patients. These authors concluded that, although halothane may cause hepatitis, such a complication is rare. They felt that, possibly, obese women with a tendency to organspecific autoimmunity may be more at risk. Prospective studies There are few controlled prospective trials. Trowell, Peto and Crampton-Smith (1975) described eight patients with carcinoma of the uterus who developed jaundice with hepatocellular damage following three or four repeat administrations of halothane over a period of 3-7 weeks. Two of these died and necropsy showed massive .hepatic necrosis. This prompted a prospective study of 39 patients using a single liver function test, serum alanine aminotransferase (ALT or SGPT). This was abnormal in four of 18 patients receiving halothane and in none of 21 controls, the difference being significant at the 0.02% level. In a larger study, Wright and colleagues (1975) showed that patients who have had a previous exposure to halothane within a period of 1 year, if given a further halothane anaesthetic are more likely to have abnormal serum aspartate aminotransferase (AST or SGOT) concentrations than a control group receiving another appropriate anaesthetic agent (other than methoxyflurane)
65S
PROBLEMS OF MULTIPLE INHALATION-ANAESTHETICS TABLE 1. Retrospective surveys-elinical hepatic damage : controlled study
Criterion
Author Dawson and others (1963) Allen and Metcalf (1964) Mushin and others (1964) Henderson and Gordon (1964) Dykes and others (1965)
Halothane 3: 749
Unexplained deterioration; no surgical cause Unexplained complications Abnormal tests; no surgical cause Bilirubinaemia> 1.5 mg dl " 1 Acute parenchymatous disease
using a halothane-free apparatus. In contrast, McEwan (1976) and Allen and Downing (1977) failed to show any abnormal effects from halothane. The most recent prospective study is that of Fee and his colleagues (1979), who investigated the frequency and severity of changes in enzymatic liver function in comparable series of patients anaesthetized with thiopentone-nitrous oxidehalothane and thiopentone-nitrous oxideenflurane. Because of the unavailability of enflurane when it was started (in 1976) this was not a randomly controlled study and no direct comparisons were made between the frequency of changes with these two inhalation agents. Studies were carried out on patients having standard urological or gynaecological operations (McIlroy et aI., 1979) and care was taken to ensure that the anaesthetic equipment used was not contaminated with other agents. Patients were seen on the 2nd-3rd and 13th-15th days after operation and liver function tests undertaken. The results were compared with similar tests carried out before the first administration of anaesthesia. A standard serum was analysed with each batch of estimations to determine the variability of the method and increases of more than three standard deviations of the method were considered to be abnormal. This study, which extended over 3 years, involved 63 patients having two or more administrations of halothane and 66 receiving two or more
Others
0: 16: 88: 8:
4: 925
13 024 15747 21 461 14685
0: 7160 14: 6123 113: 26 850 10: 32238
administrations of enflurane. There was a greater frequency of increased enzymatic activity following repeat administrations of halothane than following enflurane. In table II it may be seen that the average alanine amino transferase (ALT) and gamma glutamyl transpeptidase (GGT) concentrations were increased to a significant degree following the second administration of halothane. There was no change in the eosinophil count and no significant morbidity after operation in either series. These patients were often seriously ill and requiring radiotherapy for the treatment of tumours, but an analysis failed to reveal any correlation between the presence of malignancy or radiotherapy and the occurrence of enzymatic evidence of hepatic dysfunction. However, changes in ALT, GGT and lactate dehydrogenase occurred more frequently in obese patients receiving halothane. While many of these subjects had enzymatic evidence of anicteric hepatitis, no patient became jaundiced-in either series. When a patient had enzymatic evidence of anicteric hepatitis following the second administration, this occurred generally in subsequent administrations. There was a higher frequency of changes when the interval between administrations was 6 weeks or less (table III). The value of changes in serum GGT as evidence of liver dysfunction has been criticized by Ellis, Worthy and Goldberg (1979) on the grounds of
TABLEII. Average ALT and GGT values in the sample obtained before the first operation (preop.) and on days 3-5 and 13-15 following
repealed administrations of halothane.
ALT No. of anaesthetic
Preop.
Days 3-5
Days 13-15
Preop.
Days 3-5
Days 13-15
1 2 3 4
18.8 18.9 16.1 15.2
28.3 27.3 59.9 59.0
23.1 28.3 18.4 29.1 *
12.3 12.4 9.7 10.1
13.3 17.9* 26.6* 34.3*
13.2 24.1 * 20.3* 20.1*
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BRITISH JOURNAL OF ANAESTHESIA
TABLE III. Frequency of abnormal concentrations of gamma glutamyl transpeptidase (GGDfoliowing repeated halothane and enfiurane anaesthesia, related to the interval between anaesthetics
Interval between first and second anaesthetic (weeks) 1--6
7-12 13-17 18-30
Halothane 8/16 3/17 3/13 5/17
(50%) (18%) (23%) (30%)
Enflurane 4/16 (25%) 1/10 (10%) 3/16 (19%) 4/24(17%)
non-specificity. However, most studies used more than one test or showed enzyme changes after halothane which did not occur with other agents. On the basis of these prospective studies it would appear that anicteric hepatitis can follow the repeat administration of halothane and although the frequency is very low (estimated at 1 in 7000-10 000) (Brown, 1979; Cousins, 1980) it does appear to be something of clinical importance. HALOTHANE METABOLISM
There are three major urinary metabolites of halothane (Cohen et aI., 1975), which is broken down in the liver by both oxidative (Van Dyke and Gandolfi, 1976) and reductive (Widger, Gandolfi and Van Dyke, 1976) pathways. In his review Cohen pointed out that the covalent binding of the trifluoroacetyl group to ethanolamine and the conjugation of halothane with glutathione indicate the production of potentially destructive reactive intermediates. Such volatile metabolites (CF 3CH 2Cl and CF 2CHCl) have been described by Sharp, Trudell and Cohen (1979), with the non-volatile CF 2CBrCI with closed-circuit techniques. The current concensus of opinion supports the view that halothane-induced liver dysfunction is caused by its potentially hepatotoxic reductive metabolites (Cousins et aI., 1978, 1979; Brown, 1979; Cousins, 1980). The ability to produce an animal model of halothane hepatotoxicity (McLain, Sipes and Brown, 1979) has shown the potential role of tissue hypoxia, with reduced hepatic blood flow, in directing the metabolism of halothane along its reductive hepatotoxic pathway. The binding of reactive intermediates of halothane to cytochrome P-450 is increased in the presence of hypoxia. Phenobarbitone-induced stimulation of hepatic drug-metabolizing enzymes may enhance the dangers of hypoxia (Ross, Daggy and Cardell, 1979).
PROPHYLAXIS
Factors capable of influencing the occurrence of liver changes following repeated administrations of halothane include: (1) obesity; (2) hypoxaemia; (3) short interval between administrations; (4) enzyme induction. Many workers have drawn attention to obesity as being important and this may well be related to tissue hypoxia with reductive breakdown of halothane in fat. Some workers place the dangerous interval between administrations as being up to 4 weeks, but perhaps care should be taken to avoid further exposure within a period of 3 months. It may be difficult to detect patients in whom enzymes are induced, but where this is know halothane should be avoided completely. In this, and similar studies, the patients were mostly elderly. It is unlikely that the same frequency of anicteric hepatitis will be found in the young. Not only may there be different methods of metabolizing drugs in the young, but also better reparative processes. In the light of these factors it is worth reanalysing the data from the study of Fee and his colleagues (1979). If one excludes obese patients and those with an interval of less than 6 weeks between administrations, then enzyme changes occurred no more frequently with halothane than with enflurane. Halothane is a very versatile inhalation agent and one needs to put the situation with regard to the rare complications of halothane hepatitis into perspective. It is undoubtedly a very rare phenomenon, although anicteric hepatitis may occur more frequently than was believed. Where an alternative exists, the repeated use of halothane should be avoided in obese subjects, particularly if they are known to have enzyme induction. Steps should be taken to avoid tissue hypoxia in such patients. Perhaps we should continue inhalation of oxygen for longer periods following operation in obese patients who have been given halothane, particularly for the second or subsequent time within a short period. It was once recommended that glucose be given before chloroform to minimize its hepatotoxicity. Although its efficacy was never evaluated, the concept is attractive. We may yet find a mixture of amino acids which could be infused prophylactically before halothane and reduce its hepatotoxicity, similar to the therapeutic value of providing additional sulphydryl
PROBLEMS OF MULTIPLE INHALATION ANAESTHETICS groups for the liver from methionine or acetyl cysteine and cysteamine in paracetamol overdosage. REFERENCES
Allen, H. L., and Metcalf, D. W. (1964). A search for halothane liver complications. Anesth. Analg, (Cleve.), 43, 159. Allen, P. J., and Downing, J. W. (1977). A prospective study of hepatocellular function after repeated exposures to halothane or enflurane in women undergoing radium therapy for cervical cancer. Br. J. Anaesth., 49, 1035. Bottinger, L. E., Dalen, E., and Hallen, B. (1976). Halothaneinduced liver damage: an analysis of the material reported to the Swedish adverse drug reaction committee 1966-1973. Acta Anaesthesiol. Scand., 20, 40. Brown, B. R. ir (1979). Halothane hepatitis is a reasonably well-proved clinical entity; in Controversy in Anesthesiology (ed. J. E. Eckenhoff), p. 31. Philadelphia, London, Toronto: W. B. Saunders. Bruce, D. L. (1979). Halothane and hepatitis: a direct relationship; in Controversy in Anesthesiology (ed. J. E. Eckenhoff), p. 38. Philadelphia, London, Toronto: W. B. Saunders. Bunker, J. P., Forrest, W. H., Mosteller, F., and Vandam, L. D. (1969). The National Halothane Study. Washington D.C.: U.S. Government Printing Office. Cohen,E. N., Trudell,J. R., Edmunds, H. N., and Watson, E. (1975). Urinary metabolites of halothane in man. Anesthesiology, 43, 392. - - Van Dyke, R. A. (1977). In Metabolism of Volatile Anaesthetics, p. 2. Sydney: Addison-Wesley. Cousins, M. J. (1980). Halothane hepatitis: what's new? Drugs, 19, 1. - - Gourlay, G. K., Sharp, J. H., Adams, J. F., Hall, P., O'Brien, P., and Haynes, W. D. (1978). Halothane hepatitis. Lancet, 2, 1197. - - Mazze, R. I. (1973). Methoxyflurane nephrotoxicity. A study of dose-response in man. J. A. M. A., 225, 1611. - - - - ~osek, J. C., Hitt, B. A., and Lover, F. V. (1974). The etiology of methoxyflurane nephrotoxicity. J. Pharmacol. Exp. Ther., 190, 530. - - Sharp, J. H., Gourlay, G. K., Adams, J. F., Haynes, W. D. G., and Whitehead, R. (1979). Hepatotoxicity and halothane metabolism in an animal model with application for human toxicity. Anaesth. lntens. Care, 7, 9. Dawson, B., Jones, R. R., Schnelle, N., Hartridge, V. B., Paulson, J. A., Adson, M. A., and Summerskill, W. H. J. (1963). Halothane and ether anesthesia in gallbladder and bile duct surgery. A retrospective study into mortality and hepatobiliary complications. Anesth. Analg. (Cleve.), 42, 759. Dykes, M. H. M. (1970). Hepatotoxicity of anesthetic agents; in Anesthesia and the Liver (ed. M. H. M. Dykes). Internat, Anesthesiol. cu«, 8, 241. - - Walzer, S. G., Slater, E. M., Gibson, J. M., and 'Ellis, D. S. (1965). Acute parenchymatous hepatic disease following general anesthesia. Clinical appraisal of hepatotoxicity following administration of halothane. J. A. M. A., 193,339. Ellis, G., Worthy, E., and Goldberg, D. M. (1979). Lack of value of serum gamma-glutamyl transferase in the diagnosis of heparebiliary disease. Clin. Biochem., 12, 142. Fee, J. P. H., Black, G. W., Dundee, J. W., Mcilroy, P. D. A., Johnston, H. M. L., Johnston, S. B., Black, I. H. c.,
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McNeill, H. G., Neill, D. W., Doggart, J. R., Merrett, J. D., McDonald, J. R., Bradley, D. S. G., Haire, M., and McMillan, S. A. (1979). A prospective study of liver enzyme and other changes following repeat administration of halothane and enfiurane. Br. J. Anaesth., 51, 1113. - - McDonald, J. R., Dundee, J. W., and Clarke, R. S. J. (1978).Frequency of previous anaesthesia in an anaesthetic patient population. Br. J. Anaesth., 50, 917. Henderson, J. C., and Gordon, R. A. (1964). The incidence of postoperative jaundice with special reference to halothane. Can. Anaesth. Soc. J., 11, 453. 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. - - - - (1978). Jaundice after repeated exposure to halothane: a further analysis of reports to the Committee on Safety of Medicines. Br. Med. J., 2, 1455. McEwan, J. (1976). Liver function tests following anaesthesia. Br. J. Anaesth., 48, 1065. McIlroy, P. D. A., Fee, J. P. H., Dundee, J. W., Black, G. W., Doggart, J. R., Johnston, H. M. L., Haire, M., and Neill, D. W. (1979). Methodology of a prospective study of changes in liver enzyme concentrations following repeat anaesthetics. Br. J. Anaesth., 51, 1125. McLain, G. E., Sipes, I. G., and Brown, B. R. (1979). An .animal model of halothane hepatotoxicity: roles of enzyme induction and hypoxia. Anesthesiology, 51, 321. Mansell Jones, D. (1974). Circular letter from the Committee on Safety of Medicines CSM/S/121. 3 January. Mushin, W. W.,Rosen, M.,i3owen, D'-J., lmdCampbell, H. (1964). Halothane and liver dysfunction. A retrospective study. Br. Med. J., 2, 329. Ross, W. T., Daggy, B. P., and Cardell, R. R. jr (1979). Hepatic necrosis caused by halothane and hypoxia in phenobarbital-treated rats. Anesthesiology, 51, 327. Sharp, J. H., Trudell, J. R., and Cohen, E. N. (1979). Volatile' metabolites and decomposition products of halothane in man. Anesthesiology, 50, 2. 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, 1,821. 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. Dis., 4, 40. 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. Widger, L. A., Gandolfi, A. J., and Van Dyke, R. A. (1976). Hypoxia and halothane metabolism in vivo: release of inorganic fluoride and halothane metabolites binding to cellular constituents. Anesthesiology, 44, 197. Wright, R., Chisholm, M., Lloyd, B., Edwards, J. C., Eade, D. E., Hawksley,M., Moles, T. M., and Gardner,M. J. (1975). Controlled prospective study of the effect of liver function of multiple exposure to halothane. Lancet, 1, 821.
PROBLEMS OF MULTIPLE INHALATION ANAESTHETICS
J. W. In a survey of 10 000 unselected patients presenting for anaesthesia, Fee and colleagues (1978) found that 47% had previous exposure to one general anaesthetic, 22% to two anaesthetics and as many as 15% to at least three. As might be expected, the frequency of previous exposure to anaesthetics increased with the age of the patient, reaching about 100% in septuagenarians. Thus, one of the problems of repeat anaesthetics may be a result of the age of the patient having the second or third anaesthetic. Many operations are more common in the elderly but, provided the time interval between administrations is greater than 6 weeks, there is no reason to believe that the risk involved is any greater than on the first exposure. The only possible exception would be the patient recovering from long-term toxic effects of a previous anaesthetic such as hepatitis after chloroform or high-output renal failure after methoxyflurane. Apart from its potential role in "halothane hepatitis", -there is no evidence to suggest that a previous exposure to an inhalation agent sensitizes the patient to a subsequent administration, such as occurs with some i.v, anaesthetic agents. PROBLEMS
The main problem of multiple inhalation anaesthetics is the sequelae of the repeated administrations of the halogens, halothane and, to a lesser extent, enflurane. The early halogenated compounds have been abandoned almost completely as have the flammable ethers (diethyl, divinyl, ethyl vinyl, methyl propyl and fluoroxene). No problems were reported following the repeat administration of these agents, but this does not mean that there were none. At their peak of popularity it was assumed that inhalation agents were excreted unchanged and if any complications occurred after operation, a cause other than the anaesthetic agent would have been sought. Even after 1964, when
J. W. DUNDEE, M.D., PH.D.,F.F.A.R.C.S., M.R.C.P.,Department of Anaesthetics, The Queen's University of Belfast, Northern Ireland. 0007-0912/81/130063--05 $01.00
DUNDEE
van Dyke demonstrated conclusively the metabolism of several volatile anaesthetics, there was no suggestion that the metabolites were toxic (Cohen and van Dyke, 1977). We know now that chloroform is metabolized via free-radicle reactive intermediates which are responsible for its hepatotoxicity. A survey of cases called "delayed chloroform poisoning" may well reveal a number of repeat administrations, but it is not likely that such a survey is possible. A similar situation may also apply to fluoroxene. It is worth noting that the prolonged administration of both methoxyflurane and enflurane can cause delayed renal toxicity if the concentrations of inorganic fluoride reach a nephrotoxic threshold (Cousins and Mazze, 1973; Cousins et al., 1974). Doubtless this effect would be cumulative if there were a short interval between the repeated administrations. This would be similar to the effect of two nephrotoxic drugs administered concurrently. HALOTHANE
The potential hepatotoxic effect of halothane is the' real clinical problem. This possibility has been debated widely and although most authorities recognize that it is an uncommon but reasonably well-proven clinical entity (Brown, 1979), some disagree (Bruce, 1979). It is instructive to trace the history of reporting and investigation of this emotive topic.
Surveys The American National Halothane study (Bunker et al., 1969) is the best known early survey, in which a number of co-operating institutions pooled data on the frequency of postoperative liver failure in almost 1 million patients. It is the largest investigation of this type on an anaesthetic topic. The National Halothane Study is sometimes misunderstood or quoted wrongly. It must be pointed out that it dealt only with the frequency of massive hepatic necrosis, which was calculated to be 1.02 in 10000 administrations, similar to the ©
Macmillan Publishers Ltd 1981
64S
overall frequency of this entity. Furthermore, it did not concentrate on repeated administrations, although cases of hepatitis following a second or subsequent exposure to halothane had been reported (Dykes, 1970). Subsequently, data have been obtained from five other sources. Initially these were individual case reports (too numerous to list) of jaundice which seemed to be undisputedly related to a single or multiple administration of halothane. Second, there have been a number of controlled retrospective surveys, some of which are listed in table I. Different workers have taken different criteria for including patients with liver damage, but this must depend on information available. The results of these retrospective surveys have not given conclusive results (table I). However, one recent study by Bottinger, Dalen and Hallen (1976) is of interest. As many as 82% of the affected patients had multiple exposures. The distribution of halothane hepatitis differed from that of viral hepatitis: liver injury following halothane was commonest in middle-aged obese females, while viral hepatitis occurred in the young. The frequency of unexplained jaundice following the administration of halothane appeared to be increasing in Sweden. Reports Third, the U.K. Committee on Safety of Medicines produced two analyses of reports of jaundice submitted to them (Inman and Mushin, 1974; 1978). The 1974 paper, which was derived from 130 reports of jaundice occurring after anaesthesia with halothane, showed "a significant relationship between the number of exposures to this anaesthetic and the rapidity with which jaundice develops after exposure". They considered that "this provided strong evidence of a cause-effect relationship between the use of halothane and jaundice". Of the 114 patients with complete anaesthetic histories, 82% had been exposed more than once; of those exposed, 80% had been anaesthetized with halothane more than once within 28 days. At the same time the Medical Assessor to the Committee on Safety of Medicines sent a memorandum to doctors in the United Kingdom stating that there was a greater risk of jaundice when halothane was given repeatedly within a period of a few weeks, than following a single exposure (Mansell Jones, 1974).
BRITISH JOURNAL OF ANAESTHESIA The second paper of Inman and Mushin (1978), which was derived from 170 reports of jaundice following halothane, compared the relationship between multiple exposures to halothane and jaundice and between the number of exposures and the rapidity with which jaundice develops. When combined with the previous report, it provided complete anaesthetic histories of 251 patients, 82% of whom had been exposed to halothane more than once and of these patients, 75% had been exposed more than once in 28 days. Altogether 46% of the jaundiced patients died. This form of report has been widely criticized by anaesthetists, but surely its failings are all the result of inadequate reporting. Hepatitis survey Fourth, there has been one large well-designed prospective study of 203 patients who actually developed hepatitis after halothane (Walton et al., 1976). No cause could be found in 76 of these and halothane was presumed to be the causative factor. Hepatitis in 95% of these followed multiple exposure to halothane with repeated exposure within 4 weeks in 55% of patients. These authors concluded that, although halothane may cause hepatitis, such a complication is rare. They felt that, possibly, obese women with a tendency to organspecific autoimmunity may be more at risk. Prospective studies There are few controlled prospective trials. Trowell, Peto and Crampton-Smith (1975) described eight patients with carcinoma of the uterus who developed jaundice with hepatocellular damage following three or four repeat administrations of halothane over a period of 3-7 weeks. Two of these died and necropsy showed massive .hepatic necrosis. This prompted a prospective study of 39 patients using a single liver function test, serum alanine aminotransferase (ALT or SGPT). This was abnormal in four of 18 patients receiving halothane and in none of 21 controls, the difference being significant at the 0.02% level. In a larger study, Wright and colleagues (1975) showed that patients who have had a previous exposure to halothane within a period of 1 year, if given a further halothane anaesthetic are more likely to have abnormal serum aspartate aminotransferase (AST or SGOT) concentrations than a control group receiving another appropriate anaesthetic agent (other than methoxyflurane)
65S
PROBLEMS OF MULTIPLE INHALATION-ANAESTHETICS TABLE 1. Retrospective surveys-elinical hepatic damage : controlled study
Criterion
Author Dawson and others (1963) Allen and Metcalf (1964) Mushin and others (1964) Henderson and Gordon (1964) Dykes and others (1965)
Halothane 3: 749
Unexplained deterioration; no surgical cause Unexplained complications Abnormal tests; no surgical cause Bilirubinaemia> 1.5 mg dl " 1 Acute parenchymatous disease
using a halothane-free apparatus. In contrast, McEwan (1976) and Allen and Downing (1977) failed to show any abnormal effects from halothane. The most recent prospective study is that of Fee and his colleagues (1979), who investigated the frequency and severity of changes in enzymatic liver function in comparable series of patients anaesthetized with thiopentone-nitrous oxidehalothane and thiopentone-nitrous oxideenflurane. Because of the unavailability of enflurane when it was started (in 1976) this was not a randomly controlled study and no direct comparisons were made between the frequency of changes with these two inhalation agents. Studies were carried out on patients having standard urological or gynaecological operations (McIlroy et aI., 1979) and care was taken to ensure that the anaesthetic equipment used was not contaminated with other agents. Patients were seen on the 2nd-3rd and 13th-15th days after operation and liver function tests undertaken. The results were compared with similar tests carried out before the first administration of anaesthesia. A standard serum was analysed with each batch of estimations to determine the variability of the method and increases of more than three standard deviations of the method were considered to be abnormal. This study, which extended over 3 years, involved 63 patients having two or more administrations of halothane and 66 receiving two or more
Others
0: 16: 88: 8:
4: 925
13 024 15747 21 461 14685
0: 7160 14: 6123 113: 26 850 10: 32238
administrations of enflurane. There was a greater frequency of increased enzymatic activity following repeat administrations of halothane than following enflurane. In table II it may be seen that the average alanine amino transferase (ALT) and gamma glutamyl transpeptidase (GGT) concentrations were increased to a significant degree following the second administration of halothane. There was no change in the eosinophil count and no significant morbidity after operation in either series. These patients were often seriously ill and requiring radiotherapy for the treatment of tumours, but an analysis failed to reveal any correlation between the presence of malignancy or radiotherapy and the occurrence of enzymatic evidence of hepatic dysfunction. However, changes in ALT, GGT and lactate dehydrogenase occurred more frequently in obese patients receiving halothane. While many of these subjects had enzymatic evidence of anicteric hepatitis, no patient became jaundiced-in either series. When a patient had enzymatic evidence of anicteric hepatitis following the second administration, this occurred generally in subsequent administrations. There was a higher frequency of changes when the interval between administrations was 6 weeks or less (table III). The value of changes in serum GGT as evidence of liver dysfunction has been criticized by Ellis, Worthy and Goldberg (1979) on the grounds of
TABLEII. Average ALT and GGT values in the sample obtained before the first operation (preop.) and on days 3-5 and 13-15 following
repealed administrations of halothane.
ALT No. of anaesthetic
Preop.
Days 3-5
Days 13-15
Preop.
Days 3-5
Days 13-15
1 2 3 4
18.8 18.9 16.1 15.2
28.3 27.3 59.9 59.0
23.1 28.3 18.4 29.1 *
12.3 12.4 9.7 10.1
13.3 17.9* 26.6* 34.3*
13.2 24.1 * 20.3* 20.1*
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TABLE III. Frequency of abnormal concentrations of gamma glutamyl transpeptidase (GGDfoliowing repeated halothane and enfiurane anaesthesia, related to the interval between anaesthetics
Interval between first and second anaesthetic (weeks) 1--6
7-12 13-17 18-30
Halothane 8/16 3/17 3/13 5/17
(50%) (18%) (23%) (30%)
Enflurane 4/16 (25%) 1/10 (10%) 3/16 (19%) 4/24(17%)
non-specificity. However, most studies used more than one test or showed enzyme changes after halothane which did not occur with other agents. On the basis of these prospective studies it would appear that anicteric hepatitis can follow the repeat administration of halothane and although the frequency is very low (estimated at 1 in 7000-10 000) (Brown, 1979; Cousins, 1980) it does appear to be something of clinical importance. HALOTHANE METABOLISM
There are three major urinary metabolites of halothane (Cohen et aI., 1975), which is broken down in the liver by both oxidative (Van Dyke and Gandolfi, 1976) and reductive (Widger, Gandolfi and Van Dyke, 1976) pathways. In his review Cohen pointed out that the covalent binding of the trifluoroacetyl group to ethanolamine and the conjugation of halothane with glutathione indicate the production of potentially destructive reactive intermediates. Such volatile metabolites (CF 3CH 2Cl and CF 2CHCl) have been described by Sharp, Trudell and Cohen (1979), with the non-volatile CF 2CBrCI with closed-circuit techniques. The current concensus of opinion supports the view that halothane-induced liver dysfunction is caused by its potentially hepatotoxic reductive metabolites (Cousins et aI., 1978, 1979; Brown, 1979; Cousins, 1980). The ability to produce an animal model of halothane hepatotoxicity (McLain, Sipes and Brown, 1979) has shown the potential role of tissue hypoxia, with reduced hepatic blood flow, in directing the metabolism of halothane along its reductive hepatotoxic pathway. The binding of reactive intermediates of halothane to cytochrome P-450 is increased in the presence of hypoxia. Phenobarbitone-induced stimulation of hepatic drug-metabolizing enzymes may enhance the dangers of hypoxia (Ross, Daggy and Cardell, 1979).
PROPHYLAXIS
Factors capable of influencing the occurrence of liver changes following repeated administrations of halothane include: (1) obesity; (2) hypoxaemia; (3) short interval between administrations; (4) enzyme induction. Many workers have drawn attention to obesity as being important and this may well be related to tissue hypoxia with reductive breakdown of halothane in fat. Some workers place the dangerous interval between administrations as being up to 4 weeks, but perhaps care should be taken to avoid further exposure within a period of 3 months. It may be difficult to detect patients in whom enzymes are induced, but where this is know halothane should be avoided completely. In this, and similar studies, the patients were mostly elderly. It is unlikely that the same frequency of anicteric hepatitis will be found in the young. Not only may there be different methods of metabolizing drugs in the young, but also better reparative processes. In the light of these factors it is worth reanalysing the data from the study of Fee and his colleagues (1979). If one excludes obese patients and those with an interval of less than 6 weeks between administrations, then enzyme changes occurred no more frequently with halothane than with enflurane. Halothane is a very versatile inhalation agent and one needs to put the situation with regard to the rare complications of halothane hepatitis into perspective. It is undoubtedly a very rare phenomenon, although anicteric hepatitis may occur more frequently than was believed. Where an alternative exists, the repeated use of halothane should be avoided in obese subjects, particularly if they are known to have enzyme induction. Steps should be taken to avoid tissue hypoxia in such patients. Perhaps we should continue inhalation of oxygen for longer periods following operation in obese patients who have been given halothane, particularly for the second or subsequent time within a short period. It was once recommended that glucose be given before chloroform to minimize its hepatotoxicity. Although its efficacy was never evaluated, the concept is attractive. We may yet find a mixture of amino acids which could be infused prophylactically before halothane and reduce its hepatotoxicity, similar to the therapeutic value of providing additional sulphydryl
PROBLEMS OF MULTIPLE INHALATION ANAESTHETICS groups for the liver from methionine or acetyl cysteine and cysteamine in paracetamol overdosage. REFERENCES
Allen, H. L., and Metcalf, D. W. (1964). A search for halothane liver complications. Anesth. Analg, (Cleve.), 43, 159. Allen, P. J., and Downing, J. W. (1977). A prospective study of hepatocellular function after repeated exposures to halothane or enflurane in women undergoing radium therapy for cervical cancer. Br. J. Anaesth., 49, 1035. Bottinger, L. E., Dalen, E., and Hallen, B. (1976). Halothaneinduced liver damage: an analysis of the material reported to the Swedish adverse drug reaction committee 1966-1973. Acta Anaesthesiol. Scand., 20, 40. Brown, B. R. ir (1979). Halothane hepatitis is a reasonably well-proved clinical entity; in Controversy in Anesthesiology (ed. J. E. Eckenhoff), p. 31. Philadelphia, London, Toronto: W. B. Saunders. Bruce, D. L. (1979). Halothane and hepatitis: a direct relationship; in Controversy in Anesthesiology (ed. J. E. Eckenhoff), p. 38. Philadelphia, London, Toronto: W. B. Saunders. Bunker, J. P., Forrest, W. H., Mosteller, F., and Vandam, L. D. (1969). The National Halothane Study. Washington D.C.: U.S. Government Printing Office. Cohen,E. N., Trudell,J. R., Edmunds, H. N., and Watson, E. (1975). Urinary metabolites of halothane in man. Anesthesiology, 43, 392. - - Van Dyke, R. A. (1977). In Metabolism of Volatile Anaesthetics, p. 2. Sydney: Addison-Wesley. Cousins, M. J. (1980). Halothane hepatitis: what's new? Drugs, 19, 1. - - Gourlay, G. K., Sharp, J. H., Adams, J. F., Hall, P., O'Brien, P., and Haynes, W. D. (1978). Halothane hepatitis. Lancet, 2, 1197. - - Mazze, R. I. (1973). Methoxyflurane nephrotoxicity. A study of dose-response in man. J. A. M. A., 225, 1611. - - - - ~osek, J. C., Hitt, B. A., and Lover, F. V. (1974). The etiology of methoxyflurane nephrotoxicity. J. Pharmacol. Exp. Ther., 190, 530. - - Sharp, J. H., Gourlay, G. K., Adams, J. F., Haynes, W. D. G., and Whitehead, R. (1979). Hepatotoxicity and halothane metabolism in an animal model with application for human toxicity. Anaesth. lntens. Care, 7, 9. Dawson, B., Jones, R. R., Schnelle, N., Hartridge, V. B., Paulson, J. A., Adson, M. A., and Summerskill, W. H. J. (1963). Halothane and ether anesthesia in gallbladder and bile duct surgery. A retrospective study into mortality and hepatobiliary complications. Anesth. Analg. (Cleve.), 42, 759. Dykes, M. H. M. (1970). Hepatotoxicity of anesthetic agents; in Anesthesia and the Liver (ed. M. H. M. Dykes). Internat, Anesthesiol. cu«, 8, 241. - - Walzer, S. G., Slater, E. M., Gibson, J. M., and 'Ellis, D. S. (1965). Acute parenchymatous hepatic disease following general anesthesia. Clinical appraisal of hepatotoxicity following administration of halothane. J. A. M. A., 193,339. Ellis, G., Worthy, E., and Goldberg, D. M. (1979). Lack of value of serum gamma-glutamyl transferase in the diagnosis of heparebiliary disease. Clin. Biochem., 12, 142. Fee, J. P. H., Black, G. W., Dundee, J. W., Mcilroy, P. D. A., Johnston, H. M. L., Johnston, S. B., Black, I. H. c.,
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McNeill, H. G., Neill, D. W., Doggart, J. R., Merrett, J. D., McDonald, J. R., Bradley, D. S. G., Haire, M., and McMillan, S. A. (1979). A prospective study of liver enzyme and other changes following repeat administration of halothane and enfiurane. Br. J. Anaesth., 51, 1113. - - McDonald, J. R., Dundee, J. W., and Clarke, R. S. J. (1978).Frequency of previous anaesthesia in an anaesthetic patient population. Br. J. Anaesth., 50, 917. Henderson, J. C., and Gordon, R. A. (1964). The incidence of postoperative jaundice with special reference to halothane. Can. Anaesth. Soc. J., 11, 453. 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. - - - - (1978). Jaundice after repeated exposure to halothane: a further analysis of reports to the Committee on Safety of Medicines. Br. Med. J., 2, 1455. McEwan, J. (1976). Liver function tests following anaesthesia. Br. J. Anaesth., 48, 1065. McIlroy, P. D. A., Fee, J. P. H., Dundee, J. W., Black, G. W., Doggart, J. R., Johnston, H. M. L., Haire, M., and Neill, D. W. (1979). Methodology of a prospective study of changes in liver enzyme concentrations following repeat anaesthetics. Br. J. Anaesth., 51, 1125. McLain, G. E., Sipes, I. G., and Brown, B. R. (1979). An .animal model of halothane hepatotoxicity: roles of enzyme induction and hypoxia. Anesthesiology, 51, 321. Mansell Jones, D. (1974). Circular letter from the Committee on Safety of Medicines CSM/S/121. 3 January. Mushin, W. W.,Rosen, M.,i3owen, D'-J., lmdCampbell, H. (1964). Halothane and liver dysfunction. A retrospective study. Br. Med. J., 2, 329. Ross, W. T., Daggy, B. P., and Cardell, R. R. jr (1979). Hepatic necrosis caused by halothane and hypoxia in phenobarbital-treated rats. Anesthesiology, 51, 327. Sharp, J. H., Trudell, J. R., and Cohen, E. N. (1979). Volatile' metabolites and decomposition products of halothane in man. Anesthesiology, 50, 2. 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, 1,821. 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. Dis., 4, 40. 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. Widger, L. A., Gandolfi, A. J., and Van Dyke, R. A. (1976). Hypoxia and halothane metabolism in vivo: release of inorganic fluoride and halothane metabolites binding to cellular constituents. Anesthesiology, 44, 197. Wright, R., Chisholm, M., Lloyd, B., Edwards, J. C., Eade, D. E., Hawksley,M., Moles, T. M., and Gardner,M. J. (1975). Controlled prospective study of the effect of liver function of multiple exposure to halothane. Lancet, 1, 821.