HEPATOTOXICITY OF VOLATILE ANAESTHETICS

British Journal of Anaesthesia 1993; 70: 339-348

REVIEW ARTICLES

HEPATOTOXICITY OF VOLATILE ANAESTHETICS R. H. ELLIOTT AND L. STRUNIN

(Br. J. Anaesth. 1993; 70: 339-348) KEY WORDS Anaesthetics, volatile: halothane, enflurane, isoflurane. sevoflurane, desflurane. Biotransformation: metabolites. Complications: jaundice. Liver: hepatotoxicity. hypoxia, immune response, metabolism.

the difficulties of reconciling physical properties of substances between anaesthetic action, unwanted effects and biodegradation. Sevoflurane has been available for several years in some countries and desflurane is now undergoing clinical trials [53, 90]. Halothane-associated hepatitis is well documented [23, 32, 83], but new information is available that has relevance for all volatile anaesthetic agents. Therefore, the purpose of this article is to review: the potential direct, metabolic and immunological mechanisms of hepatotoxicity associated with halothane and other volatile anaesthetics; the association of enflurane with liver damage and cross-reactivity with halothane; the potential links between isoflurane, sevoflurane, desflurane and liver damage; and recommendations concerning the investigation of patients who develop unexplained hepatic dysfunction after the use of volatile anaesthetic agents. CLINICAL CONSIDERATIONS

Halothane-associated hepatitis presents as one of two clinical syndromes which occur most commonly in adult patients [8, 75]. Each may develop after uneventful anaesthesia and surgery, with no apparent time—dose relationship. The first syndrome is characterized by moderately increased concentrations of liver transaminases and, sometimes, transient jaundice with low morbidity. It may occur after an initial exposure to halothane and the incidence may be as great as 20% [75]. The second syndrome is uncommon, with an estimated incidence of up to 1:35000 anaesthetics [23,70,95] and is associated with repeated exposure to the drug, often at short intervals, with the development of fulminant hepatic failure with high mortality. The true incidence of these syndromes is uncertain because of a lack of definition of hepatitis, unknown denominators (the total number of patients exposed to halothane) and the failure of many reports to distinguish between the two syndromes. There are many causes of postoperative jaundice and abnormal liver function tests. Viral hepatitis, coexisting liver disease (including latent conditions such as Gilbert's disease), blood transfusion, sepR. H. ELLIOTT*, M.B., B.CH., F.R.CANAES., Leicester Royal Infirmary, Leicester LEI 5WW. L. STRUNIN, M.D., F.R.CANAES.,

F.R.C.P.C, Anaesthetics Unit, The Royal London Hospital,

London El IBB. *Present address, for correspondence: Department of Anaesthesia, Derby Royal Infirmary, London Road, Derby DEI 2UY.

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Postoperative liver dysfunction has been associated with most volatile anaesthetic agents from diethyl ether onwards [23, 64], but in recent years halothane has received the most attention [97]. A direct effect of the drug, or its metabolites, is believed to be responsible in part for halothane-associated hepatitis [8]. In addition, an immune reaction following repeated exposure to halothane may also be responsible for liver damage, particularly in subjects in whom fulminant hepatic failure occurs [97]. Fulminant hepatic failure carries a high mortality [19, 110], but its incidence is very low and it may be avoidable if halothane is never repeated [71]. However, if the mechanism is immunological, it is unlikely that any time interval between exposures may be considered absolutely safe [111], as any exposure could trigger a response, and this raises problems associated with providing vapour-free anaesthetic machines for potentially susceptible patients and pollution of the operating theatre environment. Partly as a result of a perceived threat of litigation in relation to hepatic damage, the use of halothane is declining in many parts of the world [20] and it has even been suggested that the agent is "obsolete" [5,6]. Others have challenged this view, arguing that, as most cases of halothane-associated hepatitis are benign and fulminant hepatic failure is extremely rare, these problems should be viewed in the context of other outcomes, particularly respiratory depression and effects on coronary artery blood flow, that may occur when alternative anaesthetic agents are used [29, 30, 101]. The introduction of enflurane and isoflurane was another reason for the decline in the use of halothane and the potential absence of hepatotoxicity resulting from their lesser metabolism than halothane was an important point in promoting their use [18] as alternatives. However, enflurane has been suspected of causing liver damage and its data sheet in the U.S.A. carries a warning about such damage [28]. Isoflurane was not thought to be hepatotoxic [98], but recent case reports have raised doubts [13, 15, 40]. The search for new volatile anaesthetics has continued, albeit rather slowly, partially because of

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ticaemia, drug reactions, intra- and postoperative hypoxia and hypotension should be excluded before any link with the anaesthetic agent is entertained. In addition, consideration should be given to the surgical procedure so that tissue trauma, surgical misadventure or any physical alteration in liver perfusion is noted. Halothane-associated hepatitis remains an unsatisfactory diagnosis of incomplete exclusion, recently denned [75] as "the appearance of liver damage within 28 days of halothane exposure in a person in whom other known causes of liver disease had been excluded".

METABOLIC AND IMMUNOLOGICAL MECHANISMS

The findings from early animal studies are confusing, as it has proved impossible to mimic fulminant hepatic failure in an animal model. As it became likely that there was more than one process involved in hepatotoxicity associated with volatile anaesthetic agents, attention has focused on direct effects, and on metabolic and immunological models in both animals and humans. Direct effects

Many different animal species have been studied, but the potential for application of the results from these models to humans is unclear, partly because it has not always been possible to avoid hypotension and diminished liver blood flow, which reduce hepatic oxygen availability and further complicate analysis. In addition, there are major differences in the response of the models, depending on the species and experimental conditions. For example, mice do not show hepatotoxicity to halothane [37], but male rats, notably the Fisher 344

strain are very susceptible [38]. As hepatotoxicity is enhanced if the rat is rendered hypoxic [88] and when liver enzymes are induced by agents such as phenobarbitone [67], the most extensively used animal model has been the phenobarbitone enzymeinduced, hypoxic (14% oxygen) rat. Guineapigs develop hepatotoxicity after halothane without phenobarbitone induction or hypoxia [66]; but significant hypotension occurs in this species with small inhaled concentrations of halothane. The hepatotoxicity observed in some rat experiments occurred after single exposure, with some evidence of a dose-response curve [25, 52], and was non-fatal and easily recoverable. All of these features conflict with the clinical observations of halothane-associated hepatitis or fulminant hepatic failure in humans. Recent work has resolved some of this confusion. In an in vivo experiment, 181 Sprague—Dawley rats were divided into four groups [33]. Group one received halothane in 14% oxygen (hypoxia), group two received isoflurane with hypoxia, group three had 25-30 % of their blood volume removed before hypoxia and group four were hypoxic controls. Liver blood flow was measured using radiolabelled microspheres, oxygen availability was calculated and liver histology examined. It was found that an inverse relationship existed between hepatic oxygen availability and the severity of histological lesions. The smallest portal vein flows were in the halothane and blood loss groups; the smallest hepatic arterial flow was in the halothane group, while the greatest hepatic arterial flow was in the blood loss group. It was concluded that the most severe lesions and smallest oxygen availability were associated with halothane, whilst haemorrhage seemed more harmful than isoflurane. Similar results have been obtained from a guineapig model in which animals anaesthetized with halothane or isoflurane were compared with a control group [47]. In both treatment groups, mean arterial pressure was reduced to 50 % of control. In addition to showing differences in cardiac output, hepatic arterial flow was significantly reduced by halothane, but well maintained with isoflurane. Portal blood flow was reduced in both groups compared with control, but was most marked with halothane. The reduction in oxygen availability was 65 % in the halothane group, but only 35% with isoflurane. Similar results were found in a small study in humans [35]. In an in vitro study, isolated hepatocyte monolayers from phenobarbitone and non-phenobarbitone groups of Fisher 344 rats were exposed to either 1.5% halothane or 2% isoflurane at three different oxygen concentrations [93] and aspartate transaminase release at 2 h and 6 h after exposure was taken as an index of cell death. Using multiple regression analyses, it was concluded that hypoxia, halothane and phenobarbitone were each highly significant separate factors for inducing liver damage, but no toxic effect of isoflurane was demonstrated. The mechanism of cell damage in these models may relate to intracellular calcium [34, 83], which is increased by hypoxia [96] and volatile agents [105];

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Viral hepatitis Before the advent of serological markers for the diagnosis of viral hepatitis and other viruses which may damage the liver, such as cytomegalovirus, there was the possibility of confusing hepatitis of viral origin with halothane-associated hepatitis. After the introduction of blood screening for hepatitis B, "non-A, non-B" viruses were the cause of some 90% of cases of post-transfusion hepatitis. Several such viruses have now been identified [117, 118] and serological tests are available (or being developed) for hepatitis C, D and E [60, 62, 87, 119]. Although hepatitis caused by other viruses remains as a clinical diagnosis [117], it seems likely that undetected viral hepatitis can now only be responsible for a small number of cases of halothaneassociated hepatitis. Further evidence for this assumption may be found in the many patients with clinical and serological evidence of a chronic carrier state for viral hepatitis who, when subjected to anaesthesia and surgery, do not develop further hepatic dysfunction. Exceptions to this are patients whose liver function has decompensated before operation; this group appear to do uniformly badly after operation, regardless of anaesthetic agent used. However, the diagnosis in these patients is not usually in doubt [2, 22, 82].

BRITISH JOURNAL OF ANAESTHESIA

HEPATOTOXICITY OF VOLATILE ANAESTHETICS

No hepatotoxicity associated with desflurane has been demonstrated in the relatively few reports so far published [26,44,54]. Metabolic models: animals

Metabolism (biotransformation, biodegradation)

of halothane in humans is at least 20% [85] and possibly as great as 46% [12] of the administered drug, depending on the method of measurement used. This compares with 2-8% of enflurane [12], less than 1 % of isoflurane and 0.02 % of desflurane [114]. Halothane is usually metabolized via oxidative pathways, but no direct link between oxidative metabolites and hepatotoxicity has ever been demonstrated. Halothane may also be metabolized via reductive pathways and this route of metabolism is enhanced under hypoxic conditions. After it was found that reductive metabolites could bind to rat liver microsomes, which contain the cytochrome P450 system [102], it was suggested that, if these microsomal enzymes were pre-induced, hepatotoxicity could result [103]. Much initial work supported this theory; substituting a deuterium atom in place of a hydrogen atom in the halothane molecule slowed the rate of oxidative metabolism, without reducing toxicity [81]; female rats metabolize halothane via the reductive pathway more slowly than males and are less susceptible than males to hepatotoxicity [79]; cimetidine selectively inhibits the reductive pathway of halothane metabolism and partially protects against its toxicity [80]. However, not all studies support the reductive hypothesis. For example, no reductive metabolites of halothane have been shown to be directly hepatotoxic [78]; fasting increases hepatotoxicity but has no effect on metabolism [104]; mice have the same isoenzyme cytochrome P450 as rats, but even when this is induced, hepatotoxicity cannot be provoked by halothane [37]; the guineapig does not metabolize halothane well under reductive conditions, yet develops hepatotoxicity [66]; other drugs, notably enflurane, despite minimal metabolism, induce hepatic lesions in hypoxic rats [104]; tri-iodothyronine (T3) pretreatment decreases cytochrome P450 content and subsequently diminishes halothane metabolism, but rats pretreated with T3 develop increased liver toxicity [113]. Hepatotoxicity was predictable in all these models, again in marked contrast with the problem of unpredictable fulminant hepatic failure in humans. Enzyme induction is a necessary factor in the development of hepatic damage in many animal models. In today's environment, most humans are exposed to many enzyme inducing compounds, including alcohol, drugs both therapeutic and recreational, and industrial and agricultural pollutants. Drugs, including volatile anaesthetics, may also induce their own metabolism [9, 21], but whether or not this is clinically significant is unclear [7]. One study of patients taking enzyme inducing drugs, who underwent anaesthesia and surgery, did not demonstrate postoperative liver dysfunction [39]. However, in another small group of patients who received phenobarbitone before neurosurgical operations, there was evidence of postoperative liver injury and some of these patients also had rash, fever and eosinophilia [76]. Free radicals have been suggested as an aetiological factor in the development of fulminant hepatic failure [74]. This is probably not significant because, although free radicals can be formed under hypoxic

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the latter induce release of intracellular calcium from saponin-treated rat hepatocytes in proportion to their known hepatotoxicity [50]. However, these effects occur with the first exposure, are dose related and predictable, and conflict with the clinical presentation of fulminant hepatic failure. After fulminant hepatic failure has developed in humans, most pathologists have had difficulty in distinguishing differences in hepatic cell morphology caused by alleged halothane-associated hepatitis or viral hepatitis [4, 77, 112]. Electron microscopy has shown that halothane can induce ultrastxucture abnormalities in hepatocytes of patients with normal liver function undergoing abdominal surgery [36], and these changes were not seen in a similar group of patients exposed to isoflurane. However, none of the halothane patients developed overt postoperative liver dysfunction and the relevance of these observations to the development of halothane-associated hepatitis or fulminant hepatic failure remains unclear. An increase in the plasma concentration of alanine (ALT) or aspartate (AST) aminotransferase is often accepted as an index of liver cell damage [115], but ALT and AST may not accurately reflect the extent of hepatic injury and are not specific to the liver [116]. Glutathione-S-transferase (GST) is an enzyme with a plasma half-life of less than 90 min [3] and is distributed primarily in centrilobular hepatocytes [84], in contrast with ALT and AST, which are mainly periportal. Therefore, GST may provide a more sensitive index of hepatocellular damage than the aminotransferases [3], particularly as the lesion induced by halothane is most frequently, but not exclusively, centrilobular [4, 77]. In a study of 71 patients, halothane was compared with isoflurane, using radioimmunoassay of GST as an index of liver damage [1]. It was found that the plasma concentration of GST was increased in 35 % of patients receiving halothane and 70% nitrous oxide in oxygen and in 24% of patients receiving halothane in 100% oxygen, compared with no increase in patients receiving isoflurane and 70% nitrous oxide in oxygen. There were also two distinct peaks of GST, one 3-6 h after halothane, the other 24 h after halothane, suggesting that two different mechanisms are involved, the first being, perhaps, direct damage or from impaired liver blood flow and the second caused by metabolites or an immunological response. A similar study of 70 patients was carried out investigating halothane, enflurane and isoflurane [48]. Abnormal GST concentrations were found in 50 % of patients exposed to halothane, 20 % after enflurane and 11 % after isoflurane. A second peak in GST was again demonstrated in the halothane and enflurane groups, but not in the isoflurane group. With regard to impairment of hepatocellular integrity, it was concluded " isoflurane did not appear to be associated with this effect."

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conditions, oxygen is needed subsequently for lipid peroxidation and cell destruction. Therefore, the radicals can be involved only over a narrow range of small values of oxygen tension, which occur rarely in clinical practice [89]. Immunological mechanisms

Subsequent work [57, 72] has established that antibodies occur only in patients with fulminant hepatic failure associated widi halothane and are present in 70 % of such patients. Antibodies have not been found in patients with liver disease of other aetiology, in patients exposed to halothane without developing fulminant hepatic failure or in normal subjects. Therefore the detection of antibodies could be very useful in the diagnosis of fulminant hepatic failure after halothane. Initially, some criticism [108] was made of this test as it was only performed in one centre, but the results have now been repeated in other laboratories [11,46]. It was also shown that antibodies could develop as early as 4 days after exposure to halothane and may persist for 3 months [46]. The antibody is not directed against a reductive metabolite of halothane, but against an oxidative compound—trifluoroacetyl halide (TFH)—incorporated onto the surface of the hepatocyte [73, 91]. In a study involving two groups of male Sprague— Dawley rats, phenobarbitone was administered for 3 days and then one group was given intraperitoneal halothane, while sesame seed oil was given to the other group by the same route [91]. The rats were killed 4 h later and the liver removed. Using enzymelinked immunosorbent assay (ELISA) and immunoblotting techniques, trifluoroacetyl (TFA) proteins were found in the halothane group, which were present on a liver subcellular fraction having a molecular weight of 54 kDa (kDA = kiloDalton: a measurement of mass, 1 Dalton is equal to onetwelfth the mass of a carbon-12 atom) and localized to the surface microsomal fraction, not the cytosolic

fraction of the cell. The 54-kDa, anti-TFH staining component was subsequently found to be a phenobarbitone-inducible form of cytochrome P450. It should be noted that intraperitoneal administration of volatile anaesthetics may expose the liver to concentrations far in excess of that possible by inhalation. In another study [91], liver biopsies were taken during operation from four patients undergoing halothane anaesthesia and a similar TFA protein (in the range 51-56 kDa) was found in their liver microsomes. It is suggested that TFH is a very reactive compound and that the cytochrome probably traps TFH before it has time to diffuse away and react with other proteins. Therefore, TFA may alter the microsomal liver protein, so that it is recognized as non-self (i.e. a neo-antigen) and an immune response then ensues, leading to liver cell damage, the antibody being an expression of this response. It is not yet clear if a classical cellmediated reaction is also involved. It is now known that serum from patients with fulminant hepatic failure after halothane can contain several protein structures containing the TFA group [55,92] and that there are five main structures recognized—100 kDa, 76 kDa, 59 kDa, 57 kDa and 54 kDa—with varying time courses of expression and deployment in the liver and no other organ [56]. To test for antibodies, serum is first screened by an ELISA for anti-TFA albumin activity. If the result is positive, the specificity of antibody reactivity can be ascertained by testing the ability of trifluoroacetylated lysine to block antibody binding to TFAalbumin in competitive direct ELISA [41]. The specificity of this test has recently been increased and the methodology improved [45, 68]. Liver samples may also be tested for neo-antigen. Genetic basis

It is now clear that all individuals exposed to halothane metabolize halothane to TFA-halide and thereby produce labelled proteins [Kenna JG, Jones RM, personal communication], but why only some patients develop liver damage after halothane anaesthesia (millions of others having been exposed to the drug, many of them repeatedly without apparent ill effect) is still not known. Metabolism of halothane appears to be under genetic influence in both guineapigs [65] and humans [14], and rare reports have appeared claiming halothane hepatitis in patients who were related [42]. An in vitro test has been described which uses rat mixed function oxidases [31] which, when incubated with serum from patients with halothane-associated hepatitis, demonstrate a different degree of lymphocyte toxicity compared with controls. When the families of the patients were also investigated, this test gave a positive result in several family members and it was concluded that there was a genetic susceptibility to halothane-associated hepatitis. The value of this test has not yet been confirmed. Enflurane

Enflurane has been linked to postoperative liver damage [61], but not all authorities are convinced

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In the early case reports of fulminant hepatic failure after halothane anaesthesia, patients often had a history of recent previous exposure to halothane [51]. Auto-antibodies to body tissues (such as liver-kidney microsomes [109], thyroid [109], nucleic contents [69], smooth muscle [69] and mitochondria [86]) and eosinophilia, rash and fever were sometimes present [109]. These features resemble an idiosyncratic drug reaction. As halothane is a small molecule unlikely to be immunoreactive [8], it was postulated that binding of a metabolite of halothane to the liver cytochromes could act as a hapten and induce a hypersensitivity response [102]. It was shown that leucocytes from some patients with fulminant hepatic failure after halothane were sensitized to a cell fraction of liver homogenate from halothane-treated rabbits [107]. Specific circulating IgG antibodies (the presence of which implies prior exposure to the antigen) were found in sera of patients with fulminant hepatic failure after halothane [106] and these antibodies were shown to react with the cell surface of hepatocytes from halothaneexposed rabbits and also to make the hepatocytes more susceptible to antibody-dependent, cellmediated toxicity.

BRITISH JOURNAL OF ANAESTHESIA

HEPATOTOXICITY OF VOLATILE ANAESTHETICS Enflurane

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that enflurane is a causative agent [24, 27], and the mechanism is unclear, as enflurane is metabolized far less than halothane. However, recent work has shown that products of enflurane metabolism can produce TFA-proteins that would be recognized by antibodies from patients with halothane hepatitis [16]. Therefore, a basis exists for "enflurane hepatitis" with cross-sensitization between enflurane and halothane. Indeed, some patients with hepatotoxicity after enflurane had been exposed previously to halothane [61,94]. If metabolism of enflurane is related to its potential to cause postoperative liver dysfunction, then the problem should occur proportionately less frequently with enflurane than with halothane. Isoflurane, sevoflurane and desflurane

There is a common metabolic pathway (fig. 1) involving cytochrome P450, not only for halothane and enflurane, but also for isoflurane and desflurane which can produce similar TFA proteins that could be recognized as neo-antigens [17]. The expression of the neo-antigens should be related to the amount of metabolism of each agent, that is: halothane >

enflurane > isoflurane > desflurane. Sevoflurane is not metabolized via this route. Several case reports have appeared in the literature linking isoflurane [13, 15, 40] and liver damage. Four members of the Anesthetic and Life Support Advisory Committee of the Food and Drug Administration in the U.S.A. reviewed 45 cases of liver damage after isoflurane [98,99]. They concluded that there were only three cases in which "a relationship might have existed" and there were other factors, such as postoperative hypoxia and hypotension, that made a definite link unlikely. The overall conclusion of this review was that "current evidence does not indicate a reasonable likelihood of an association between the use of isoflurane and the occurrence of postoperative hepatic dysfunction". Nevertheless, a potential immunological mechanism for "isoflurane hepatitis" exists (fig. 1) and we suspect that further cases will be reported. In a fatal case of fulminant hepatic failure after anaesthesia with isoflurane [13], the patient had had several previous anaesthetics, although the agents were not described. Unfortunately, no serum was taken from tfiis patient for antibody studies.

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TABLE I. Investigation of a patient with postoperative liver dysfunction [49,100]

Isoflurane is metabolized at least 100-fold less than halothane. If the incidence of fulminant hepatic failure after halothane is 1 in 35000 [83], fulminant hepatic failure caused by isoflurane may only occur in 1 per 3500000 isoflurane anaesthetics—a toxicity considerably less than that of most drugs used today. It remains to be seen if isoflurane can cross-react with halothane or enflurane. As a result of its chemical structure, metabolism of sevoflurane ((CF^H-C-O-CHjF) is unlikely to generate a TFA antigen, although it is metabolized to a similar extent as enflurane, releasing fluoride ions [43]. Hepatotoxicity has been produced in experimental animals, but this may be caused by alterations in liver blood flow [63]. To date there are no clinical reports in humans of fulminant hepatic failure associated with sevoflurane. The molecular structure of desflurane is similar to isoflurane and initial work with enzyme-induced hypoxic rats suggests very low toxicity [26]. Desflurane metabolism may produce TFA-proteins (fig. 1), although it undergoes even less biotransformation than isoflurane [58, 59] and should therefore induce

correspondingly less neo-antigen. Desflurane has now been administered to humans [53, 90], but we are not aware of any TFA protein tests being performed. Investigation of patients with unexplained hepatitis after volatile anaesthetics

In order to avoid designation of patients as "allergic" to volatile anaesthetics, all cases of postoperative hepatitis should be carefully reviewed. Hepatitis may be defined as abnormalities in liver function tests, including the clinical observation of jaundice, occurring in the immediate postoperative period. Using the definition of Neuberger and Williams [71], this would include changes noted up to 28 days after anaesthesia in patients with previously normal liver function. Mild cases of hepatitis show moderate increases in concentrations of transaminases, with minor changes in other enzymes and modest prolongation of the prothrombin time. In patients in whom there is a strong possibility of the development of fulminant hepatic failure, transaminase concentrations in excess of 1000 iu litre"1

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History Information should be sought from the patient, relatives, family doctor and any other attending physicians. Specific questions, as outlined in the examples below, should always be asked before accepting a negative response. Contact history Note any contact with any person with jaundice (or who may have subsequently developed jaundice) in the preceding 6 months. Drug history Note all drugs the patient has taken. In particular: alcohol; barbiturates; chlorpromazine, phenytoin, methyl dopa, chlorpropamide; antibiotics (sulphonamides, nitrofurantoin, rifampicin, isoniazid, cytotoxic agents); hormone contraceptive pills, anabolic steroids; antidepressants (amitripryline); analgesics (paracetamol, salicylates). Lifestyle history Enquire concerning: Occupation; foreign travel; "social risk groups" for viral hepatitis (i.v. drug users, homosexuals, presence of tattoos). Past history Note: Parenteral administration of any blood products; conditions known to have potential hepatic complications (e.g. biliary tract disease, inflammatory bowel disease, autoimmune disease; family or patient history of Gilbert's disease, Wilson's disease, or haemochromatosis; any previous reaction to an anaesthetic by either the patient or a relative (can the anaesthetic records be obtained?). In particular, ask concerning any anaesthetics administered outside a hospital setting (e.g. dental surgery). Anaesthetic chart If possible, this should be reviewed with the anaesthetist concerned and the detailed technique and anaesthetic agents used (including any infusion fluids) recorded. Is evidence of intraoperative hypoxia, systemic hypotension, hypovolaemia or hypercarbia present? Could other volatile agent(s) have been administered? Consider contamination of the circuit, incorrect filling of vaporizer, old anaesthetic machine without vaporizer interlock, etc. Surgical notes Ideally with operating surgeon, note exact operation site, duration and any difficulties encountered. Postoperative course Record onset time of jaundice or other changes in liver function. Exclude: hypotension, hypovolaemia, hypoxia, pyrexia, septicaemia, baematoma, haemolysis, blood transfusion, GI bleed, pancreatitis, hepatic venous thrombosis, cardiac failure, renal failure and pulmonary embolism. Also exclude pregnancy. Clinical examination This should confirm any conditions suggested by the history and record the patient's current status. Investigations Standard liver function tests should be performed serially. Serum amylase. If feasible, a liver biopsy should be considered. Blood cultures should always be performed. Is there evidence of haemolysis or concealed haematoma? Other investigations should be guided by the history and examination. For example, if biliary obstruction, hepatic abscess or tumour are suspected, ultrasound followed by CT scan or magnetic resonance imaging should establish the diagnosis. Every attempt should be made to exclude viral hepatitis. Serological tests are now available for: hepatitis A, B, C, D and E. Other serial viral titres for cytomegalovirus, Epstein—Barr virus (infectious mononucleosis), herpes simplex, Echo, Coxsackie, adenoviruses and HIV should be performed. Antibody screening for volatile anaesthetics. Consult laboratory about storage and transport of samples. If possible, save some urine and plasma samples (deep freeze and clearly identified), for analysis in the future when new tests become available.

HEPATOTOXICITY OF VOLATILE ANAESTHETICS

COMMENT

Is it possible to draw any conclusions regarding the future of volatile anaesthetics, in particular halothane, as a result of this review? Halothane has a pronounced effect on the liver, with evidence of hepatotoxicity not seen to the same extent with other agents currently in use. Although in most instances after an initial exposure the effect appears to be reversible and not clinically significant, it is probable that such disturbance may rarely and unpredictably set the scene for a more dramatic immunological response to a subsequent exposure. Unless there are circumstances in which halothane is indicated specifically, it is now probably impossible to defend an anaesthetist if fulminant hepatic failure follows documented repeated exposure to halothane; indeed, to our knowledge, no such case has reached the courts. However, this view is less relevant for anaesthetists working in situations in which economic factors and availability of trained personnel are primary determinants of clinical practice. In these circumstances, with the exception of diethyl ether, halothane is the cheapest and probably the easiest and safest volatile agent to use and alternatives are not usually available. The small risk of fulminant hepatic failure is more than offset by the rate of unfavourable outcomes after non-anaesthetic causes. What are the implications for other volatile agents ? Essentially by default, isoflurane is the most commonly used volatile agent in North America, and in most other parts of the world where it is available. Anaesthetists appear to have accepted isoflurane as the drug of choice for patients with pre-existing liver disease or in whom repeated exposure is contemplated, although some cost conscious departments have opted for enflurane as an alternative. On the limited evidence available at present, desflurane and sevoflurane appear to have very little potential for hepatotoxicity, but are more expensive than en-

flurane or isoflurane. There is the possibility of cross-sensitization between agents, although the order of response to enflurane and isoflurane, and particularly desflurane, is likely to be much less than halothane. The risk of fulminant hepatic failure after exposure to enflurane, isoflurane or desflurane, after previous exposure to halothane, is probably substantially less than the overall risk associated with anaesthesia and surgery [10], but the strength of this view would be much greater if the immunological hypothesis were proven and the validity of the immunological tests established. In an attempt to answer these questions, a data base of fulminant hepatic failure patients (past and present) is now being instituted at St Mary's Hospital, London (Dr J. G. Kenna or Professor R. M. Jones, Department of Anaesthetics, St Mary's Hospital, London W2 1NY, England; telephone (0)71 725 1681); in the U.S.A., TFA tests are available in Tucson, Arizona (Dr B. R. Brown jr, University of Arizona, Department of Anesthesiology, Health Sciences Center, Tucson AZ 85724, U.S.A.; telephone 602 626 7196). We encourage all anaesthetists to contact these centres for advice as to how and which samples to send for investigation from patients with unexplained hepatitis after use of volatile anaesthetics. In addition to providing better patient care and quantitating the TFA tests, such investigation may prevent repetition of the "halothane controversy". It is worth recalling that, despite case reports of hepatic damage associated with halothane appearing in the literature within a year or two of its introduction into clinical practice, it has taken some 35 years and much acrimonious debate to reach the current consensus on the mechanisms of halothane-associated hepatitis and fulminant hepatic failure. The new volatile agents appear to have low potential for hepatotoxicity, but one would not wish them to be subjected to the same fate as halothane. REFERENCES 1. Allan LG, Howie J, Smith AF, Hussey AJ, Beckett GJ, Hayes JD, Drummond GB. Hepatic glutathione-S-transferase release after halothane anaesthesia: open randomised comparison with isoflurane. Lancet 1987; 1: 771-774. 2. Aranha GV, Greenlee HB. Intra abdominal surgery in patients with advanced cirhosis. Archives of Surgery 1986; 121: 774-778. 3. Beckett GJ, Hayes JD. Plasma glutathione-S-transferase measurements and liver disease in man. Journal of Clinical and Biochemical Nutrition 1987; 2: 1-24. 4. Benjamin SB, Goodman ZD, Ishak KG, Zimmerman HJ, Irey NS. The morphologic spectrum of halothane induced hepatic injury. Analysis of 77 cases. Hepatology 1985; S: 1163-1171. 5. Blogg CE. Halothane and the liver, the problem revisited and made obsolete. British Medical Journal 1986; 292: 1691-1692. 6. Blogg CE. Is halothane obsolete? Two standards of judgement. Anaesthesia 1989; 44: 860-861. 7. Brown BR jr. Anesthesia in Hepatic and Biliary Tract Disease. Philadelphia: FA Davis Co., 1988; 81-82. 8. Brown BR jr, Gandolfi AJ. Adverse effects of volatile anaesthetics. British Journal of Anaesthesia 1987; 59: 14-23. 9. Brown BR jr, SagaJyn AN. Hepatic microsomal enzyme induction by inhalational anesthetics: Mechanism in the rat. Anesthesiology 1974; 40: 152-161. 10. Buck N, Devlin HB, Lunn J. The Report of a Confidential Enquiry into Pcrioperative Deaths. London: Nuffield Provincial Hospitals Trust, 1988.

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and prothrombin times of greater than twice the control are observed. Patients in this category usually feel unwell to a degree out of proportion to their recent operation. In most patients with abnormal liver function tests or postoperative jaundice, the diagnosis can be determined by a careful history, examination of the patient and review of appropriate investigations (table I). Assuming that all reasonable causes of postoperative hepatitis have been excluded, how may the involvement of a volatile anaesthetic agent be established? First, during questioning of the patient and review of the hospital notes and charts, the exact anaesthetic sequence and drugs used should be established and this survey should include any previous exposures. Second, blood and urine samples (and liver biopsy if feasible) should be obtained as soon as possible after the exposure and serially thereafter to identify the presence of TFA antibodies. If such antibodies are identified, the patient should be encouraged to wear a Medic Alert bracelet and informed of the risk of further exposure to any volatile agent.

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