[Inhalation anesthesia with halogenated hydrocarbons: value of isoflurane].

The halogenated hydrocarbons halothane, enflurane and isoflurane are used extensively. Like every other anaesthetic, these inhaled agents are not devoid of side effects, most of which are undesirable. This review summarises the similarities and differences between the actions of these vapours.

Halothane hepatitis: a case report.

This report describes a patient who required 12 anaesthetics over a period of 25 yr. Halothane was used on at least five occasions. The first documented halothane anaesthetic was followed by jaundice.

The effects of volatile anesthetics on Ca++ mobilization in rat hepatocytes.

This study provides direct evidence that in hepatocytes, intracellular Ca++ is released from internal stores by halothane, enflurane, and isoflurane. Hepatocytes isolated from rat livers were used fresh or treated with saponin and then incubated in 45Ca++ media. The uptake of 45Ca++ by hepatocytes was maximal following 13-16 min of incubation (untreated or saponin-treated) and the effects of various agents on the release of 45Ca++ was studied following maximal loading.

[Protective effect of calcium channel blockers on the liver against halothane hepatitis in rats].

This study examined whether nifedipine or flunarizine, calcium channel blockers, could protect the liver against halothane hepatotoxicity in rats. Six groups of 102 enzyme-induced male Sprague-Dawley rats were studied. Group N1 and N2 rats received nifedipine 20 micrograms and 100 micrograms.

Fatty acid lessens halothane's inhibition of energy metabolism in isolated hepatocytes.

This study has examined whether adverse halothane effects on liver-cell energy metabolism are influenced by the availability of alternate substrates for energy-generating reactions. Halogenated volatile anesthetics affect both energy supply and energy demand in tissues, and cellular energy deficits have been implicated in anesthetic hepatotoxicity. Using hepatocytes isolated from fed rats either pretreated with phenobarbital or not treated (+PB or -PB cells, respectively), we studied the cellular energetic effects of providing fatty acid (oleic acid) along with glucose as substrate(s) for energy metabolism, while exposing the cells to 0%-2% halothane.

Halothane and hepatitis. Incidence, predisposing factors and exposure guidelines.

Despite early controversy, it is now recognised that halothane anaesthesia may be followed by abnormalities of liver function. The resulting hepatitis may take 1 of 2 forms: in type I, there is a minor degree of disturbance of liver function shown by increased serum transaminases or glutathione-S-transferase in up to 25 to 30% of patients; subsequent re-exposure to halothane is not necessarily associated with evidence of liver damage. In contrast, type II hepatitis is often associated with massive liver cell necrosis, frequently leading to fulminant hepatic failure.

Age and gender influence halothane-associated hepatotoxicity in strain 13 guinea pigs.

The factors of age and gender, which have been linked to development of fulminant halothane hepatitis in humans, were evaluated in a guinea pig model of acute halothane-associated hepatotoxicity. Since nitrous oxide is commonly coadministered with halothane and has been shown to exacerbate halothane-associated liver injury in rats; this combination of anesthetics was also evaluated in guinea pigs. Male and female strain 13 guinea pigs (300-1000 g) were exposed to 1% v/v halothane and 39% O2 for 4 h with a balance of either 60% N2 or 60% N2O.

Preoperative cimetidine does not prevent subclinical halothane hepatotoxicity in man.

To assess the influence of pretreatment with cimetidine on changes in hepatocellular integrity after halothane anaesthesia, 53 patients were allocated randomly to receive either cimetidine 1600 mg orally or placebo tablets before anaesthesia. Plasma concentrations of glutathione S-transferase (GST) were measured as an index of hepatic damage. Data from 45 patients were available for analysis.

The pathology of halothane hepatotoxicity in a guinea-pig model: a comparison with human halothane hepatitis.

The pathology of halothane hepatotoxicity is described in detail in a guinea-pig model. Twenty-two of 40 guinea-pigs developed liver damage after exposure to 1% halothane in 21% O2 for 4 h. The other 18 animals showed no evidence of hepatic injury.

Metabolism of halothane in obese Fischer 344 rats.

Halothane is metabolized by an oxidative pathway to stable, nonvolatile end products, trifluoroacetic acid (TFAA) and bromide (Br-), and by reductive pathways to Br-and inorganic fluoride (F-). There is evidence that both oxidatively and reductively formed intermediates may produce hepatotoxicity, although the exact etiology of the fulminant hepatic necrosis seen in humans is unproven. Obese patients receiving volatile anesthetics exhibit higher serum anesthetic metabolite concentrations than do normal-weight patients, and thus might be at greater risk of hepatotoxicity because of higher concentrations of reactive intermediates from halothane metabolism.

Occupational exposure to anaesthetics: liver injury, microsomal enzyme induction and preventive aspects.

Apart from a risk excess of liver disease among operating theatre personnel and of spontaneous abortion in women exposed during pregnancy, no definitive conclusion has been drawn as regards health impairment among anaesthesiology staff. Hepatotoxicity has been detected in experimental and epidemiological studies, suggesting a close relationship between liver disease and anaesthetics, particularly halogenated hydrocarbons (halothane and isoflurane) and nitrous oxide. The liver microsomal enzyme system has received particular attention in order to clarify the mechanism involved in anaesthetics hepatotoxicity and an increased microsomal enzyme activity has been observed in experimental conditions and in humans (both patients treated with anaesthetic mixture and anaesthesiology staff).

The role of oxidative biotransformation of halothane in the guinea pig model of halothane-associated hepatotoxicity.

The role of the oxidative pathway of halothane biotransformation in mediating the hepatotoxicity of halothane in the guinea pig was examined by utilizing the deuterated form of halothane (d-halothane), which is resistant to oxidative metabolism. Male outbred Hartley guinea pigs were exposed to either 1% v/v halothane or d-halothane, FIO2 = 0.21, for 4 h.

[Protective effects of ulinastatin on hepatic oxygen metabolism during halothane anesthesia in the presence of graded hypoxic hypoxemia].

Hepatic oxygen metabolism and the hepatic energy charge were assessed in mongrel dogs receiving 40,000 U.kg-1 of ulinastatin intra-portally during 2 MAC halothane anesthesia combined with graded hypoxic hypoxemia (21-6% oxygen) for the purpose of evaluating the role of ulinastatin in protecting the liver against the deprivation of the hepatic energy charge resulting in halothane-induced hepatotoxicity. Hepatic blood flow was measured using electromagnetic flowmetry; hepatic oxygen delivery and consumption were calculated from measured hepatic blood flow and oxygen content in hepatic arterial, portal venous and hepatic venous blood.

Effects of halothane and hypoxia on hepatic oxygen metabolism in the dog.

Hepatic oxygen delivery and consumption were assessed in mongrel dogs receiving 2MAC of halothane combined with graded hypoxic hypoxemia (21-8% oxygen). Hepatic blood flow was measured using electromagnetic flowmetry; hepatic oxygen delivery and consumption were calculated from measured hepatic blood flow and oxygen content in hepatic arterial, portal venous and hepatic venous blood. In hypoxia-halothane group, total hepatic blood flow decreased at mild hypoxia (15% O2) from control value, but recovered to control level at moderate hypoxia (10% O2), then again decreased at 8% O2.

Hepatotoxicity and inhalation anesthetics: views in the era of isoflurane.

The halogenated inhalation anesthetics continue to be an important group of drugs in current anesthesia practice. The purpose of this article is to discuss current concepts of the mechanisms of halothane-induced hepatotoxicity and to attempt to answer the question: Do all halogenated inhalation anesthetics share halothane's propensity to hepatotoxicity?

Risk factors for halothane hepatitis.

Helothane hepatitis is a rare but sometimes fatal complication of halothane anaesthesia. Examination of case reports has pointed to a number of risk factors. Studies in animals and humans in the laboratory have provided evidence of a complex multifactorial basis for halothane hepatotoxicity, with the following factors playing a part: genetic predisposition; metabolism of halothane; repeated halothane anaesthetics; female sex; age of patient; intrahepatic hypoxia; and enzyme induction.

Enflurane metabolism produces covalently bound liver adducts recognized by antibodies from patients with halothane hepatitis.

The existence of a rare syndrome of "enflurane hepatitis" similar to that described for halothane and of a cross-sensitization between halothane and enflurane has been controversial, largely due to equivocal clinical case reports and a lack of a plausible molecular mechanism for the hepatotoxicity. The present study suggests a possible hypersensitivity basis for enflurane hepatitis and the apparent cross-sensitization between halothane and enflurane involving covalently bound liver microsomal adducts. Immunoblotting studies have revealed that antibodies in the sera of six patients with halothane hepatitis recognize liver microsomal antigens of Mr = 100,000, or both 100,000 and 76,000, formed in rats treated with enflurane or halothane.

Altered hepatic calcium homeostasis in guinea pigs with halothane-induced hepatotoxicity.

Exposure of guinea pigs to 1% halothane in air for 4 hr resulted in extensive centrizonal hepatic necrosis in 70% of animals examined 2 to 3 days later. In contrast, confluent hepatic necrotic lesions were not present in animals studied 24 hr after halothane exposure; only microvascular fatty change of hepatocytes with occasional necrotic cells was observed at that time (in 84% of animals). This delayed onset of lesion development afforded the opportunity to study microsomal membrane composition and indices of Ca++ homeostasis before and after the onset of halothane-induced hepatic necrosis.

Hepatic protection from chemical injury by isoflurane.

Isoflurane inhibits oxidative metabolism of halothane. Because hepatotoxicity of chemicals may be associated with their metabolism, whether isoflurane can protect the liver against chemical injury was investigated. Hepatic injury was produced in female F344 rats by a 30-minute exposure to 250 ppm of carbon tetrachloride.

Comparison of covalent binding from halothane metabolism in hepatic microsomes from phenobarbital-induced and hyperthyroid rats.

1. Hepatic microsomal suspensions from rats pretreated with saline, phenobarbital or triiodothyronine were incubated with 14C-halothane under aerobic and anerobic conditions. 2.

Halothane-induced liver injury as a consequence of enhanced microsomal lipid peroxidation in guinea pigs.

We investigated the role of microsomal lipid peroxidation in halothane hepatotoxicity in guinea pigs. Animals were exposed to halothane, isoflurane or enflurane. Enhancement of microsomal lipid peroxidation was specific to halothane.

Enhanced in vivo-lipid peroxidation associated with halothane hepatotoxicity in rats.

To study the role of lipid peroxidation in halothane-induced hepatic damage, ethane exhalation by rats exposed to 1% halothane for 1 hour was determined under normoxic (21% O2) and hypoxic (6% O2) conditions. The effects of microsomal enzyme induction by phenobarbital and/or glutathione depletion on this parameter of in vivo lipid peroxidation were studied. To assess the degree of liver damage, serum activities of liver specific enzymes (glutamate-pyruvate-transaminase, GPT, and sorbitol dehydrogenase, SDH) were measured 3 hrs after the end of exposure.

Effects of piperonyl butoxide on halothane hepatotoxicity and metabolism in the hyperthyroid rat.

A series of experiments were conducted to examine the potential role of phase I metabolism in halothane-induced liver injury in the hyperthyroid rat. The metabolism of halothane was determined in both hyperthyroid (triiodothyronine, 3 mg/kg per day, for 6 days) and euthyroid rats and in animals pre-treated with the cytochrome P-450 inhibitor piperonyl butoxide (75-100 mg/kg, i.p.

Halothane hepatotoxicity and reductive metabolism of halothane in acute experimental liver injury in rats.

Reductive metabolism of halothane was measured after acute liver injury induced by galactosamine (1.0 g/kg, IP) in rats. On the seventh day of liver injury, when previously elevated serum alanine aminotransferase levels had returned to near normal range, anaerobic release of fluoride from halothane by hepatic microsomes, which appears to reflect the reductive pathway of halothane metabolism, was still remarkably decreased (1.