The inhaled anesthetics were initially considered biochemically inert. Toxicity after administration was poorly explained, although it is now clear that the metabolites of the inhalational anesthetics are responsible for acute and chronic toxicities, which are predictable and dose related.
Two distinct types of hepatotoxicity are associated with halothane use. The first is a mild dysfunction that develops in approximately 20% of exposed patients. Patients often are asymptomatic but exhibit modestly elevated serum aminotransferase concentrations within a few days of anesthetic exposure. Recovery is complete.22 In contrast, a life-threatening hepatitis occurs in approximately 1 in 10,000 exposed patients and produces fatal massive hepatic necrosis in 1 in 35,000 patients.48 Because the histologic findings of massive hepatocellular necrosis are indistinguishable from many of the causes of viral hepatitis,52 differentiating halothane hepatitis from other causes of hepatitis in the postoperative period is difficult without definitive serologic studies. Jaundice, which is common after anesthesia and surgery, usually results from factors such as preexisting liver disease, blood transfusion, sepsis, or other causes of hepatitis. Thus, halothane hepatitis is a diagnosis of exclusion or inclusion based on the chemical history.
Several studies report an association between multiple exposures to halothane and subsequent development of hepatitis.37,51,56 In one study, 95% of cases of halothane hepatitis occurred after repeat exposures, 55% of which involved reexposure within 4 weeks.56 Under these circumstances, hepatic dysfunction usually is more severe, and the latency before clinical presentation usually is shorter than when the syndrome develops after initial exposure to halothane.51
Obesity is a risk factor commonly implicated in halothane hepatotoxicity.1,53 Increased fat stores may act as a “reservoir” for halothane, with slow and prolonged release into the circulation and subsequent increase in production of potentially hepatotoxic metabolites.
Most cases of halothane hepatitis occur in middle-aged patients, with women having twice the risk.22 Genetic factors may play a role in some patients, as indicated by a report of this syndrome in three pairs of related Mexican women.21
Halothane is the most extensively metabolized inhalational anesthetic. Approximately 20% of the absorbed anesthetic undergoes oxidative metabolism, principally by CYP2E1 in the liver, to trifluoroacetic acid. Reduction to trifluorochloroethane and difluorochloroethylene is a minor route of halothane metabolism that requires the absence of oxygen and the presence of an electron donor (Fig. 68–3). These volatile metabolites are free radicals, which may directly produce acute hepatic toxicity by irreversibly binding to and destroying hepatocellular structures. Alternatively, by acting as haptens, they may trigger an immune-mediated hypersensitivity response.41,54 The high percentage of patients with halothane hepatitis who had recent reexposure is most consistent with the latter mechanism in which the first exposure primes the development of antibodies to a haptenized protein.22
Reductive metabolism of halothane results in the formation of a reactive metabolite that may directly bind macromolecules and create neoantigens or undergo further metabolism to trifluorochloroethane and difluorochloroethylene. CYP = cytochrome P450.
The use of halothane for inhalational anesthesia has markedly decreased in North America with the widespread availability of newer, safer halogenated anesthetics. Halothane is still widely used in some countries because it is inexpensive and provides a smooth induction of anesthesia.
Isoflurane and desflurane are pungent gases that can be airway irritants. Isoflurane, desflurane, and sevoflurane all appear to have low hepatotoxic potential. An immune form of hepatitis has been reported with all anesthetics except sevoflurane. Cross-sensitivity may exist, such that prior exposure to one anesthetic triggers hepatotoxicity upon subsequent exposure to a different anesthetic.
The kidneys are the only other organ at risk for toxicity from modern inhalational anesthetics. Methoxyflurane is an anesthetic that was introduced in 1962. By 1966, it was linked to the development of vasopressin-resistant polyuric renal insufficiency (nephrogenic diabetes insipidus) in 16 of 94 patients receiving prolonged methoxyflurane anesthesia for abdominal surgery13 (Chap. 19). Polyuria was associated with a negative fluid balance, elevations of serum sodium and urea nitrogen concentrations, osmolality, and a fixed urinary osmolality approximating that of serum. Kidney abnormalities lasted from 10 to 20 days in most patients but persisted for more than one year in three patients. Subsequent studies demonstrated that kidney toxicity was caused by inorganic fluoride (F–) released during biotransformation of methoxyflurane.50 The risk of toxicity was highly correlated with both the total dose of methoxyflurane (concentration times duration) and the peak serum F– concentration.12 The nephrotoxic serum F– concentration is 50 to 60 μmol/L.12 The factors that enhance biotransformation such as obesity and enzyme induction also increase the risk of toxicity. Although the precise mechanism by which fluoride produces its toxic effect on the kidneys is not clear, one hypothesis is that fluoride inhibits adenylate cyclase, thereby interfering with the normal action of antidiuretic hormone on the distal convoluted tubules.
Although methoxyflurane is no longer used, lessons learned regarding its toxicity are applied when evaluating the nephrotoxic potential of other fluorinated anesthetics. Of the currently used anesthetics (halothane, isoflurane, desflurane, sevoflurane), only sevoflurane undergoes biotransformation by defluorination.
Approximately 5% of sevoflurane is metabolized. This process occasionally results in sufficient serum F– concentrations to produce transient decreases in urine-concentrating ability.24 However, clinically evident renal impairment almost never occurs with use of sevoflurane.18 In volunteer studies, exposure to sevoflurane that resulted in high serum fluoride concentrations did not result in any urine-concentrating defects. In patients with chronic kidney disease (CKD), the risk of postoperative kidney dysfunction is believed to be worse with exposure to inhalational anesthetics. However, studies demonstrate that deterioration of kidney function does not occur after exposure to desflurane and isoflurane,31 possibly because intrarenal fluoride concentrations are more important than serum fluoride concentrations in the development of nephrotoxicity.
Sevoflurane reacts with the alkali within carbon dioxide absorbers to produce several degradation products, including a vinyl ether called compound A (CF2C(CF3)OCH2F). Compound A causes renal tubular necrosis in rats, especially at the corticomedullary junction.23,55 The extent of nephrotoxicity is determined by both the concentration of compound A and the duration of exposure. Compound A is also conjugated, and its breakdown products are nephrotoxic.
Extensive clinical experience with several million patients who were exposed to sevoflurane and 4000 closely studied volunteers failed to demonstrate nephrotoxicity.31 Higher concentrations of compound A are generated during low-flow anesthesia, use of high concentrations of sevoflurane, and increased temperature conditions. A high fresh-gas flow rate dilutes the concentration of compound A. Concern that higher compound A concentrations are generated when a low fresh-gas flow rate (eg, <2 L/min) is used in a closed circuit led to the current sevoflurane package labeling, which warns against fresh-gas flow rates below 2 L/min in a circle absorber system.30
Some controversy exists regarding the safety of low-flow sevoflurane anesthesia. Although there have been no clinical reports of sevoflurane-induced nephrotoxicity as measured by changes in blood urea nitrogen (BUN), serum creatinine, or creatinine clearance, clinical data demonstrate transient nephrotoxicity when more subtle measurements of glomerular and tubular function are used.16,18,20 For example, when young, healthy patients without underlying kidney disease were anesthetized with low-flow sevoflurane for a mean of 6.7 hours, transient but statistically significant increases in urinary glucose and protein excretion were documented without any changes in BUN, creatinine, or creatinine clearance.20 The clinical significance of such transient abnormalities in kidney function is uncertain. Regardless, it seems prudent to avoid the practice of low-flow sevoflurane in patients with CKD until clinical data document safety. Newer carbon dioxide absorbents that are free of strong alkali are now available to decrease generation of compound A.