The Organ Toxicity of Inhaled Anesthetics

Organ toxicity is rare in patients exposed to inhaled anesthetics, but it is of particular clinical concern because its occurrence is highly unpredictable and because it may result in severe, potentially life-threatening hepatic and/or renal damage. Although all inhaled anesthetics are small and lipid-soluble molecules that share the common property of interaction with the anesthetic target site(s) within the brain, they differ markedly with respect to their intrinsic toxicities. This was first recognized soon after the first modern clinical descriptions of general anesthesia in the 1850s. "Delayed death" poisoning, which eventually was attributed to severe hepatotoxicity and/or nephrotoxicity, was observed in patients anesthetized with chloroform [1] but not in patients given ether [2]. Severe liver damage has also been documented in patients anesthetized with trichloroethylene, divinyl ether, and tribromoethanol [2], which now are obsolete as anesthetics. The clinical use of methoxyflurane has been discontinued because of many case reports of rare but severe hepatotoxicity [2] and because of dose-dependent nephrotoxicity [3]. Of the inhaled anesthetics in use currently, halothane causes rare but severe hepatotoxicity [2,4]. Hepatitis has also been reported in patients exposed to enflurane and isoflurane, but is much rarer than hepatitis after exposure to halothane [4]. At least in part, this is probably why many anesthesiologists now use isoflurane or enflurane, not halothane, as the inhaled anesthetic of choice in adults. (During the first 6 mo of 1994, halothane was used in less than 20% of procedures involving use of an inhaled anesthetic in the United Kingdom.) The means by which inhaled anesthetics cause organ toxicity in experimental animals and man have been investigated intensively over the last 3 yr or so, and many of the mechanisms involved have now been defined at the cellular and molecular level. The toxicities are not attributable to the compounds per se, but rather to metabolites produced by cytochrome P-450-mediated biotransformations. The purpose of this review is to summarize the information provided by this research, using illustrative examples, and to highlight the important role played by cytochrome P-450-mediated metabolism. Both hepatotoxicity and nephrotoxicity may arise because of generation of cytotoxic metabolites in the target organ, as exemplified by chloroform and by the many animal models of halothane-induced liver damage (see Section 1). In addition, hepatitis may arise via immune responses to metabolite-modified hepatic protein antigens, as in the case of halothane (see Section 2), while nephrotoxicity may occur because of metabolic liberation of inorganic fluoride, as has been shown for methoxyflurane (see Section 3). An additional mechanism of nephrotoxicity, termed the "beta-lyase pathway," is believed to be responsible for the nephrotoxicity of trichloroethylene and has been described in rats given high doses of a metabolite of halothane (see Section 4). These various mechanisms are summarized in Table 1. The potential for toxicity of sevoflurane is discussed in light of this information (see Section 5).Table 1: Mechanisms of Organ Toxicity of Inhaled Anesthetics1. The Direct Organ Toxicity of Reactive Metabolites Chloroform The renal and hepatic dysfunction caused by chloroform is now viewed as a classic example of toxicity caused by metabolic bioactivation in the target organ. Nonetheless, chloroform was commonly used in general anesthesia in the late 19th century and in the early part of this century, and the experience gained during this time showed that overt "delayed chloroform toxicity" was infrequent [1,2]. The typical clinical features included a relatively prompt onset after anesthetic administration (48 to 72 h), centrizonal hepatic necrosis, renal proximal tubular necrosis, and renal and hepatic fatty infiltration [2]. Studies performed using experimental animals have implicated bioactivation of chloroform in the liver and kidneys to a highly reactive metabolite, which binds covalently to cellular macromolecules (proteins and lipids), in the mechanism of toxicity [5]. The process of bioactivation is catalyzed by cytochrome P-450 isoenzymes [5]. The toxic metabolite has not been identified directly because of its chemical reactivity. However, experiments in which the metabolite was generated in vitro and trapped by addition of cysteine or glutathione led to its identification as phosgene [6]Figure 1. The mechanisms of cellular toxicity of phosgene are likely to be complex and have not been defined in detail.Figure 1: Metabolic bioactivation of chloroform. Unstable metabolites are enclosed within brackets. P450 = cytochrome P-450.Animal Models of Liver Damage Due to Halothane Two patterns of halothane-induced liver injury have been defined in humans. Mild hepatic damage, which results in modest and transient increases in serum transaminase levels, is relatively common in patients exposed to halothane (incidence about 1 in 4) [7-9]. This liver injury, which presumably is attributable to temporary and minor derangement of hepatocellular integrity, resolves uneventfully and does not pose a clinical problem. This may be contrasted with the severe form of halothane-induced liver injury, termed "halothane hepatitis," which is rare and unpredictable (estimated incidence between 1 in 3000 and 1 in 30,000) but commonly leads to massive hepatocellular necrosis and large elevations in serum transaminase levels and jaundice, and may result in death due to liver failure [10,11]. This remains an important clinical issue because of the continuing (albeit decreasing) use of halothane. The problem of halothane hepatitis has led to many investigations of the metabolism and toxicity of halothane in experimental animals. Metabolism of halothane occurs predominantly in the liver. It is catalyzed by cytochromes P-450, and distinct oxidative and reductive pathways have been identified [4,12-15]Figure 2. Experiments performed using microsomal fractions, prepared from livers of animals treated with various enzyme-inducing agents, have indicated that halothane can be metabolized by at least two cytochrome P-450 isozymes (CYP2B and CYP2E1) [16,17]. The isoenzyme(s) that catalyze this process in humans have not yet been but are likely to metabolism is animals are exposed to halothane at and is the of metabolism of the in humans during anesthesia metabolism is at Both pathways via reactive metabolites and pathways have been implicated in animal models of halothane The various animal models and the mechanisms of toxicity have been discussed in and are summarized in Table Metabolic bioactivation of Models of Halothane or of animal models probably the form of liver injury caused by halothane in humans. The likely is the which does not of animals with enzyme-inducing or and which toxicity caused by oxidative metabolites The animal models not to be directly to the severe form of halothane-induced liver damage produced in patients halothane this is to arise via immune mechanisms (see 2. Halothane Hepatitis with halothane hepatitis a of features that that the toxicity via mechanisms and that are not by patients with the form of halothane-induced liver These of levels of immune and to patients with halothane hepatitis have been exposed to halothane many and the time to onset of is to the between anesthetics, as is the of the liver injury the patients cellular and immune to halothane-induced hepatic in vitro with in of livers from but not in of livers from In addition, to the of from livers of and rats The immune to halothane-induced is to patients with halothane It is not in patients with liver than halothane in not or in patients with hepatitis have anesthesia with halothane that the have been shown to be to cytotoxic in vitro in the of the and These that the immune is involved in the mechanism of liver damage in patients in of the of the have been of the important is have been in The halothane-induced are in livers of and exposed to halothane in in from livers of humans and in exposed to halothane in vitro of from rats has shown that the are relatively liver and are predominantly in and have shown that the are predominantly in the and are also the Two distinct of halothane-induced have been of can be by and of The can be by but not by and to be It that antigens, halothane-induced that have a and are by the relatively during The by are that molecular of and by oxidative metabolism of halothane to which binds covalently to the via This of to the in livers of rats Experiments using livers from rats that with enzyme-inducing agents, and given halothane, have that metabolism of halothane by the cytochrome P-450 is responsible for generation of also been implicated in the mechanism of generation of the of identified by of was to be rats treated with halothane in of halothane and has been shown to oxidative metabolism of halothane to but of the by have been from livers of of by and/or by has shown that they to of that have been identified and by of the a role in metabolism of halothane. are highly that within the of the and are to be cytochrome are of the it is that of the occurs in this and is a relatively This is by that generation is a process that occurs with a of 6 and that the are = of the the from the to the via the This occur because results in of the features of the that within the The of the identified by remains to be by from with Halothane by by the various halothane-induced is of from patients with halothane hepatitis to or of the that can be by These are to patients with halothane hepatitis and their is of The have shown that the that the features of the protein In addition, using hepatic of the as have shown that of to the It is likely that are that arise because the covalently cause a of to the the in general be by which that the features recognized are in patterns of have been observed in various The for this are as is its of the to the of identified by but not by have not been and of the target However, experiments using a of have that this of is an important target of the halothane-induced immune in patients with halothane hepatitis An additional of has shown that of from patients with halothane hepatitis that with at least the to an protein The of are markedly than the of to the Nonetheless, using may be of to a of hepatic antigens, which are distinct from the described have been by in from patients with halothane hepatitis These not in from not the which that their is to the immune to halothane metabolite-modified In vitro have that may to the process of hepatic damage The mechanism of halothane-induced liver damage that is by the experimental summarized is in liver injury in of the in vitro and/or cellular issue that has yet to be is why an small of patients an immune to the halothane-induced and liver damage. It that all halothane to and the in levels of generated due to levels of hepatic and/or the target in of the to the immune in of the by the immune and/or in are likely to be be at least in part, by between protein and to protein why to animal models of halothane-induced liver damage have been mechanism of halothane by and injury has been observed in rats with to and anesthetized with halothane, enflurane, or isoflurane at and also in rats exposed to anesthetics after with However, the hepatic injury produced in has been to cellular not toxic of reactive metabolites enflurane or isoflurane has the potential to hepatotoxicity in humans has not been of hepatitis in patients anesthetized with enflurane have been described The incidence of this is (estimated at less than 1 in of has that patients with enflurane hepatitis clinical features that are to described in patients with halothane hepatitis In addition, case reports of patients are to halothane and enflurane have been as have a of hepatitis of an anesthetic of enflurane is metabolized in humans Halothane is metabolized to a and isoflurane is metabolized to a Metabolism of enflurane and isoflurane is catalyzed by hepatic and via reactive which covalently to hepatic to metabolite-modified In common with halothane, the metabolite from isoflurane is believed to be the The metabolite from enflurane to be Metabolic bioactivation of enflurane and = cytochrome P-450 = = by of microsomal from livers of rats treated with enflurane or isoflurane have shown that the metabolite-modified from enflurane and isoflurane are from the protein from halothane and are recognized by in from patients with halothane hepatitis This that enflurane and isoflurane have the potential to hepatotoxicity in humans via immune mechanisms to described for halothane hepatitis and the that mechanisms may be responsible for the rare liver injury described in patients given anesthetics. the showed that the levels of metabolite-modified much in livers from rats than in livers from animals treated with doses of halothane and in livers of rats treated with isoflurane the incidence of hepatitis caused by halothane is markedly than the incidence of liver damage caused by enflurane or isoflurane, this the that the of the anesthetics is to their of metabolic bioactivation to reactive metabolites that covalently to hepatic This is it is with the of toxicity of enflurane and isoflurane in but has yet to be that enflurane and isoflurane cause liver damage via immune from patients with the toxicities that metabolite-modified hepatic protein antigens, by with halothane this to be Due to use of methoxyflurane was discontinued because of rare but severe hepatotoxicity [2] and because of the occurrence of dose-dependent nephrotoxicity This anesthetic metabolism in humans in and in experimental animals which has been attributed to a of metabolism of the by hepatic cytochrome Studies in vitro using hepatic microsomal have shown that metabolism of methoxyflurane is catalyzed predominantly by and to a by cytochrome P-450 isozymes and of the results in of of inorganic and in of and metabolites and is to via reactive that have the potential to covalently to and Although of metabolites of methoxyflurane to macromolecules has not been a metabolic has that an of an anesthetic of the within the Metabolic bioactivation of mechanisms by which methoxyflurane causes liver damage in humans have not been This is an rare by clinical and features that of halothane hepatitis [2]. In of the liver damage may occur in humans via immune to discussed for halothane, enflurane, and toxicity of reactive metabolites be The renal injury caused by methoxyflurane is by renal failure with serum and investigations have that the of renal damage is to the of methoxyflurane to The nephrotoxicity of methoxyflurane has been attributed to toxicity of inorganic This is because inorganic has been shown to directly renal and because of to in humans after methoxyflurane anesthesia have been shown to cause renal in rats a between of serum inorganic levels, and the of nephrotoxicity has been The of nephrotoxicity It is that to as and is the of all and that this results in of to of various metabolic pathways In addition, the by which its in the binds to a which and increases the of This in protein and leads to the of in the of of the late and The of remains defined but the protein is as are Studies in the used to the of that their after but the mechanism Although of does not it that the of which is for and are but their in the may be to as because the by and clinical have indicated that the serum of fluoride, which renal damage occurs in is about and that levels are after anesthesia with methoxyflurane for than anesthetic However, it be that markedly levels of serum inorganic can be for to in patients anesthetized with methoxyflurane This is due to the of the a has in addition to metabolized by hepatic cytochrome methoxyflurane is metabolized in vitro by renal cytochrome renal metabolism to the mechanism of nephrotoxicity of by to high levels of inorganic or to generation of toxic reactive metabolites within renal tubular It is by means that the of serum inorganic is for anesthetics than methoxyflurane enflurane, isoflurane, and which are much less are from the and are not for renal cytochrome Inhaled of inorganic in patients are and not nephrotoxicity This is because of halothane metabolism of the via the reductive which occurs to a during anesthesia in humans. Although metabolism of enflurane and isoflurane the of metabolism of the compounds is levels of inorganic not the after anesthesia with agents, and renal damage does not occur levels of inorganic that have been after enflurane anesthesia in patients treated with the which is a of However, patients of overt nephrotoxicity This have been because the patients high levels of serum inorganic for a of time and the anesthesia was discontinued and/or because enflurane renal metabolism with methoxyflurane levels of inorganic that have also been observed in patients given isoflurane for during or as a in the not overt renal damage. These that of levels of inorganic in be used as a of the potential of anesthetics. It is to that the levels of inorganic observed in markedly than the in patients anesthesia with isoflurane This that of metabolism of the anesthetic occurs in patients exposed to isoflurane for via the In addition to its many in the trichloroethylene was used as an anesthetic in the United and in anesthetized with trichloroethylene may rare hepatotoxicity and/or nephrotoxicity [2], as may exposed to the and trichloroethylene The hepatotoxicity is by clinical and features that are to described for chloroform hepatotoxicity and has been attributed to toxicity caused by reactive metabolites of trichloroethylene [2]. The mechanisms the renal toxicity are of experiments using experimental animals have implicated a complex of termed the "beta-lyase pathway," which generation of toxic within the The features of the are in The is to which glutathione This is an that occurs in the liver and is catalyzed by glutathione The glutathione is from the liver the and/or and to the cysteine which is in the liver by the to a Both the cysteine and the are to the via the and are proximal tubular by The is from the proximal tubular the of the renal and in the or within the tubular by renal to the cysteine the cysteine is within the proximal tubular by the cysteine to an This to and highly reactive a or a that cellular to glutathione and protein and cause nephrotoxicity In addition, the may with and have been shown to using the Metabolic bioactivation of trichloroethylene via the cysteine = = = renal cysteine = has been identified as a metabolite of trichloroethylene in the renal failure by proximal tubular necrosis has been in rats treated with or and that this is due to metabolism via the has been of of the glutathione to the cysteine of rats with which was shown to the as was of animals with of renal and cysteine treated with the which be by cysteine not nephrotoxicity the nephrotoxicity produced in rats treated with or has been shown to occur in the of the proximal which with the of of reactive metabolites of the compounds The organ of the toxicity is attributable to of the cysteine renal proximal tubular and also the high of the and within Halothane In the of halothane is to This has been in anesthetic after exposure of patients to halothane in and is used as a In addition, has been in from patients It is that this via glutathione of that via 2. This is in to and has been shown to metabolism via the to reactive metabolites that are and Metabolic bioactivation of via the cysteine = treated with in to dose-dependent This was by of protein and of serum and severe in the in the proximal The of toxicity was observed rats treated with the glutathione of experiments performed using a that and cytotoxic in The was by an of and by the and was not observed the in the of an of that not be metabolized by cysteine was shown to in of and to be in as defined by also results in this cysteine that not not It has been that this is attributable to in the chemical of metabolites produced by bioactivation of and It is likely that can be to highly reactive or that can with but that this occur for These the that patients anesthetized with halothane in or anesthetic nephrotoxicity and/or However, toxicities have not been described in Toxicity via the is markedly the levels of reactive potentially metabolites produced in patients via the are the of The of halothane that is to during halothane anesthesia is small the of the anesthesia is using the of an inhaled of halothane that is as the has not been this is likely to be small the reductive of metabolism of halothane occurs in patients to a may be less toxic in humans than in experimental animals because of in of or of the that the and/or metabolic In this it is that the of cysteine in is than the of the in Metabolism and Toxicity Two metabolites of sevoflurane have been These are inorganic and a that with the the to the of Metabolism of sevoflurane is catalyzed by cytochrome P-450 and the is shown in this of the of the Studies in vitro and in have shown that metabolism of sevoflurane in humans is catalyzed by cytochrome P-450 and occurs predominantly in the liver of of sevoflurane by cytochrome P-450 has been in but this is to the of metabolism of sevoflurane by hepatic cytochrome P-450 or methoxyflurane by renal cytochrome P-450 Metabolism and of = cytochrome P-450 = = has been shown to be a for hepatic cytochrome P-450 and to be metabolized in vitro in the of liver microsomal However, the of metabolism that occurs in in anesthetized patients is at and is to the of metabolism of enflurane This is because the anesthetic has a In levels of sevoflurane are and of the occurs anesthesia is discontinued The that nephrotoxicity occur in patients anesthetized with sevoflurane because of metabolic liberation of levels of inorganic has been investigated intensively and is discussed in this it is that levels of inorganic that are in patients anesthesia with sevoflurane but that this does not to result in clinical or nephrotoxicity This is probably attributable to the of sevoflurane and/or to its relatively of metabolism by renal cytochrome of its sevoflurane is anesthesia is high levels of inorganic are for a relatively of time This may be contrasted with the of and of methoxyflurane the of metabolism of sevoflurane by cytochrome P-450 is and markedly less than the of renal metabolism of generation of high levels of inorganic in renal tubular not be to occur in patients anesthetized with sevoflurane of liver injury in patients anesthetized with sevoflurane have been reported in the liver injury has many causes it is early to that sevoflurane can hepatotoxicity in humans. reports that mechanisms of liver injury to be investigated and In of the experience gained while the of anesthetics, the high of metabolism of sevoflurane by hepatic cytochrome P-450 is of this does not to generation of reactive metabolites However, experiments with experimental animals have indicated that sevoflurane its metabolites are directly as have in vitro with liver Although liver damage was in in which anesthetized with sevoflurane the of produced was of which that the liver damage as a of doses of have been reported to cause of the in in and also to cause in liver in vitro and However, toxic doses the of in patients anesthetized with sevoflurane by of cause hepatic injury in humans via as described for halothane. of toxicity is that the anesthetic bioactivation to reactive that covalently to hepatic (see Section This because metabolism of the is not to via reactive metabolites covalently metabolites not be in livers of rats anesthetized for with anesthetic using a It be that the highly that have been used to protein from halothane, enflurane, and isoflurane have not yet been used to this In addition, serum from patients with liver injury have not been for the of to metabolite-modified protein using the used to halothane hepatitis (see Section are important that to be investigated in the of The is the commonly used to to a of sevoflurane that is in of the anesthetic as a from the at levels of about 1 as in the is a ether and is also produced sevoflurane is in the of as are levels of termed and of sevoflurane to has been shown to occur during clinical anesthesia in of sevoflurane by the or results in of in the anesthetic that may a of with and with Studies by showed that high doses of to rats after exposure for 1 and that animals that and necrosis of renal and reported that rats of renal tubular necrosis 1 after exposure to for 3 at The observed in markedly the of and the of exposure These in renal from relatively the observed in animals exposed to at and the observed after markedly less severe than the observed after 1 Severe nephrotoxicity was not observed the to the by the that high doses of the rats of was and in rats exposed for and in the of to of renal and to this with the observed In a reported in renal and in clinical in rats exposed to at of and as as presumably for the toxic reported in this with in the investigations of In of various the that cause renal injury in humans anesthesia with sevoflurane is of Although sevoflurane has been used in in in overt nephrotoxicity, the experience gained using is much Nonetheless, it be that the and clinical to have not produced of clinical or organ toxicity in patients anesthetized with sevoflurane for using is that a problem in humans at the during the issue of the potential nephrotoxicity of toxicity be in in to the of renal and to the mechanisms of renal The toxicity arise via the cysteine which has been described for many compounds and metabolite of and trichloroethylene, as discussed so, this be In the of the use of toxicity in the to the of in humans is highly at In addition, clinical investigations to be in mechanism of nephrotoxicity of = glutathione The experience gained while the organ toxicities of a of used anesthetics, with the of toxicity of the in use currently, means that anesthetics be to of potentially toxic compounds clinical in this sevoflurane with the anesthetics at of metabolism by hepatic cytochrome P-450 may not have This is because the of metabolism of sevoflurane in patients in is due to its and because metabolism is not to via reactive of liver injury in patients have been described The clinical experience gained with halothane, enflurane, and isoflurane has shown that of of organ toxicity in the can be of be to sevoflurane can cause rare hepatotoxicity in and investigations of potential mechanisms of toxicity be of the of of sevoflurane metabolite-modified hepatic protein be of and be of protein in animals given anesthetic doses of sevoflurane that this does not have the potential to This be a sevoflurane with halothane, enflurane, and the of sevoflurane to the ether termed a remains to be of are produced anesthesia with sevoflurane is using that a as to toxicity have that the of generated in may be to the of toxicity of the and have the that nephrotoxicity may However, the clinical to have not of renal in patients anesthetized with sevoflurane using The markedly of renal cysteine in as with may to this that the nephrotoxicity is a of bioactivation of via the investigations are These of the mechanisms by which can cause renal in the of the of the and of mechanisms to toxicity during anesthesia in humans.