Isoflurane liver

Halothane (boiling point BP] 50 °C), enfhirane (BP 56 °C), isoflurane (BP 48 °C), and the obsolete methoxyflu-rane (BP 104 °C) have to be vaporized by special devices. Part of the administered halothane is converted into hepatotoxic metabolites (B). Liver damage may result from halothane anesthesia. With a single exposure, the risk involved is unpredictable however, there is a correlation with the frequency of exposure and the shortness of the interval between successive exposures. 

The metabolism of enflurane and sevoflurane results in the formation of fluoride ion. However, in contrast to the rarely used volatile anesthetic methoxyflurane, renal fluoride levels do not reach toxic levels under normal circumstances. In addition, sevoflurane is degraded by contact with the carbon dioxide absorbent in anesthesia machines, yielding a vinyl ether called "compound A," which can cause renal damage if high concentrations are absorbed. (See Do We Really Need Another Inhaled Anesthetic ) Seventy percent of the absorbed methoxyflurane is metabolized by the liver, and the released fluoride ions can produce nephrotoxicity. In terms of the extent of hepatic metabolism, the rank order for the inhaled anesthetics is methoxyflurane > halothane > enflurane > sevoflurane > isoflurane > desflurane > nitrous oxide (Table 25-2). Nitrous oxide is not metabolized by human tissues. However, bacteria in the gastrointestinal tract may be able to break down the nitrous oxide molecule. 

Anesthesia is achieved rapidly and smoothly with sevoflurane, and recovery is more rapid than with isoflurane. However, sevoflurane is chemically unstable when exposed to carbon dioxide absorbents in anesthesia machines, degrading to an olefinic compound (fluoromethyl-2,2-difluoro-l-[trifluoromethyl]vinyl ether, also known as compound A) that is potentially nephrotoxic. In addition, sevoflurane is metabolized by the liver to release fluoride ions, raising concerns about potential renal damage. 

In the 1980s two more anaesthetics came into use enflurane and isoflurane. These were not metabolised by the liver to the same extent, 2% in the case of enflurane, and only 0.2% of isoflurane. Enflurane was introduced into clinical use in 1981, but isoflurane was delayed because some research appeared to show that it caused liver cancer in mice. This research was repeated by others and shown to be wrong and isoflurane came into general use in 1984. What operating theatre personnel did not like was its off-putting smell. Were there health risks associated with the new anaesthetics A statistical analysis of the side-effects experienced by 17,201 patients on whom they were used was compared with the effects experienced by a similar group on whom halothane had been used. Patients on the newer anaesthetics were more likely to suffer a heart attack and, with isoflurane, palpitations were more common. However, there was no increased risk of the patient dying. 

Most recorded cases of liver disorders occurred after either repeated exposure (38) or prolonged exposure (39) to halothane. In one case, hepatitis developed 3 weeks after a single halothane anesthetic in a 37-year-old renal transplant recipient who had previously been exposed to isoflurane (40) this report suggests that previous exposure to isoflurane may predispose to subsequent halothane toxicity. 

Hepatic damage related to isoflurane anesthesia has very occasionally been described (9,10), including one report of hepatic necrosis and death (11). Hepatitis or hepatocellular injury has been described with all current volatile anesthetics. Among these, halothane-associated hepatitis has been best characterized and is probably caused by an immune reaction induced by hepatocyte proteins that have been covalently trifluoroacetylated by the trifluoro-acetyl metabolite of halothane. The reactive acyl-halide metabolite of trifluoroacetic acid can trifluoroacetylate liver proteins, resulting in immune-mediated hepatic necrosis (12). However, isoflurane biotransformation to trifluoroacetate is less than 0.2%, compared with 15-20% for halothane. 

An obese 35-year-old diabetic woman developed isoflurane-induced hepatotoxicity (15). She had had four previous halothane anesthetics, the last two of which were associated with jaundice. She made a full recovery and during a subsequent anesthetic received an infusion of propofol. Unfortunately, trifluoroacetic acid antibody titers were not performed. Liver function does not appear to have been severely affected peak alanine transaminase activity was 1410 IU/1. 

A 76-year-old woman with previous exposure to isoflurane 3 years earlier underwent an above-knee amputation for a liposarcoma using isoflurane anesthesia. On day 3 postoperatively she became febrile and confused. Bacterial cultures later showed Staphylococcus aureus in the sputum and Escherichia coli in the urine. Associated hypotension for 2 hours resolved with inotropic support and here renal function remained normal. On day 6 she became jaundiced and developed further hypotension. Despite intensive care treatment she died on day 7. An autopsy showed centrilobular necrosis consistent with drug-induced hepatitis. All liver serology was negative. 

Njoku DB, Shrestha S, Soloway R, Duray PR, Tsokos M, Abu-Asab MS, Pohl LR, West AB. Subcellular localization of trifluoroacetylated liver proteins in association with hepatitis following isoflurane. Anesthesiology 2002 96(3) 757-61. 

Thus, the evidence suggests that sevoflurane is as safe as isoflurane in low-flow anesthesia with respect to liver dysfunction. 

Modem inhalation anesthetics are fluoiinated to reduce flammabihty. Initially, these inhaled agents were believed to be biochemically inert. Over the past 30 years, however, research findings have demonstrated that not only are inhaled anesthetics metabolized in vivo [27], but their metabolites are also responsible for both acute and chronic toxicities [28,29]. Therefore, the use of some anesthetics has been discontinued, including methoxyflurane because of its nephrotoxicity and other anesthetics are more selectively used, e.g. halothane due to a rare incidence of liver toxicity. Studies have also provided the impetus to develop new agents - isoflurane and desflurane - with properties that lower their toxic potential. The result has been improved safety, but there is room for further improvement as our insight into toxicological mechanisms expands. 

Inhalation anaesthetics are either gases or volatile liquids. Apart from nitrous oxide, which is still widely used, earlier inhalation anaesthetics are no longer used. Ether is not suitable because it is explosive and irritant to the respiratory tract. Chloroform cannot be used because it is toxic to the liver. Inhalation anaesthetics currently in use are the volatile liquids halothane (since 1956) and more recently isoflurane, desflurane and sevoflurane and nitrous oxide gas. 

Isoflurane, desflurane and sevoflurane have superseded halothane. None of them is as potent as halothane, but they are less likely to cause liver toxicity. Isoflurane is widely used. Its main adverse effects are that it can cause myocardial ischaemia in patients with heart disease and it depresses respiration. 

Isoflurane is a respiratory depressant (71). At concentrations which are associated with suigical levels of anesthesia, there is little or no depression of myocardial function. In experimental animals, isoflurane is the safest of the oral clinical agents (72). Cardiac output is maintained despite a decrease in stroke volume. This is usually because of an increase in heart rate. The decrease in blood pressure can be used to produce "deliberate hypotension" necessary for some intracranial procedures (73). This agent produces less sensitization of the human heart to epinephrine relative to the other inhaled anesthetics. Isoflurane potentiates the action of neuromuscular blockers and when used alone can produce sufficient muscle relaxation (74). Of all the inhaled agents currently in use, isoflurane is metabolized to the least extent (75). Unlike halothane, isoflurane does not appear to produce liver injury and unlike medioxyflurane, isoflurane is not associated with renal toxicity. 

Cardiovascular effects Most inhaled anesthetics decrease arterial blood pressure moderately. Enflurane and halothane are myocardial depressants that decrease cardiac output, while isoflurane causes peripheral vasodilation. Nitrous oxide is less likely to lower blood pressure than are other inhaled anesthetics. Blood flow to the liver and kidney is decreased by most inhaled agents. Halothane may sensitize the myocardium to the arrhythmogenic effects of catecholamines. 

Halothane also can produce another form of hepatotoxicity. This is a self-limiting hepatic dysfunction characterized by elevated liver transaminase enzymes, which probably results from impaired oxygenation of the hepatocytes during exposure to this anesthetic. Isoflurane and enflurane also have been reported to produce a similar elevation of liver enzymes, although to a lesser extent than halothane. 

These substances are metabolized in the liver and to a lesser extent in the kidneys and lungs. Metabolism is higher with halothane (20-46%), followed by enflurane (2.4-8.5%), sevoflurane (2.5-3.3%), isoflurane (0.2%) and desflurane (0.02%). So their determinations are intended to find drugs, not metabolites. The following concentrations in blood have been found in deaths related with these substances (Table 7). 

Njoko D, Laster MJ, Gong DH, Eger El II, Reed GF, Martin JL. Biotransformation of halothane, enflurane, isoflurane, and desflurane to trifluoroacetylated liver proteins Association between protein acylation and hepatic injury. Anesth Analg 1997 84 173-178. 

Peiris LJ, Agrawal A, Morris JE, Basnyat PS. Isoflurane hepatitis-induced liver failure a case report. J Clin Anesth 2012 24 477-9. 

Chloroform was fast acting and nonflammable, but also had two serious limitations. The first was that it caused liver injury in many patients. The second was that a small fraction of patients given chloroform developed lethal disturbances of the electrical conduction system in the heart, leading to sudden death. Fortunately, ether and chloroform have long since been replaced by safer drugs. Three that were popular at the time of your surgery were halothane (the one you received), enflurane, and isoflurane (see Figure 4.12 for structures). None is nearly as lipid soluble as ether, but halothane is nonetheless nearly twice as soluble as isoflurane enflurane has an intermediate solubility. 

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