The morphologic spectrum of halothane-induced hepatic injury: analysis of 77 cases.

Hepatic histopathology and clinical-pathologic correlations were studied in 77 patients who met clinical criteria for halothane hepatotoxicity. They were divided into groups based on the type of surgery (minor or major) and outcome (nonfatal, biopsy group or fatal, autopsy group). The two nonfatal groups (minor surgery and major surgery) and the two fatal groups (minor surgery and major surgery) were comparable with regard to age, time of onset from exposure, peak aminotransferase values and peak bilirubin determinations.

Comparison of the requirements for hepatic injury with halothane and enflurane in rats.

A rat model of enflurane-associated hepatotoxicity was compared with the halothane-hypoxia (HH) model (adult male rats, phenobarbital induction, 1% halothane, 14% O2, for 2 hr). The enflurane-hypoxia heating (EHH) model involved exposing phenobarbital-pretreated male adult rats to 1.5-1.

[Drug damage to the liver: role of reactive metabolites and pharmacokinetics].

Metabolism of drugs by the drug-metabolizing enzyme system usually results in the formation of less toxic substances that are readily excreted. A major advance in toxicology, however, has been the observation that the same enzyme system can also activate innocuous drugs into reactive and highly toxic metabolites. Depending on their chemical nature, these metabolites either covalently bind to cellular macromolecules, give rise to toxic oxygen species, or react with membrane lipids to form lipid peroxides.

[Hemorrhagic shock and encephalopathy. Its possible relation with heat stroke].

A comparative study of two patients, one affected by haemorrhagic shock and encephalopathy (HSE) and the other by heatstroke is reported. Both presented shock, disseminated intravascular coagulation, neurological damage and hepatopathy. A lowered alpha 1-antitrypsin concentration as well as a slightly increased circulating immune complexes and complement consumption were observed in the HSE patient but not in the heatstroke one.

Sex differences in halothane metabolism and hepatotoxicity in a rat model.

This study was designed to investigate sex differences in halothane metabolism and hepatotoxicity in the hypoxic rat model. Phenobarbital-induced male and female rats were anesthetized with 1% halothane in 14% oxygen for two hours. Female rats were found to metabolize halothane by the oxidative pathway to a similar extent as males, but the extent of metabolism by the reductive pathway was less in females.

Immunological studies on the mechanism of halothane-induced hepatotoxicity: immunohistochemical evidence of trifluoroacetylated hepatocytes.

The fulminant hepatotoxicity caused by halothane has been thought to have an immunological basis because this toxicity occurs most often after repeated administration of halothane and because sera from patients recovering from severe halothane hepatotoxicity contain antibodies that bind to the surface membranes of hepatocytes of rabbits treated with halothane. In order to determine whether the major reactive metabolite of halothane, trifluoroacetyl halide, covalently binds to hepatocytes, we have developed specific and sensitive peroxidase enzyme-linked immunosorbent assays and an indirect immunofluorescence staining method for identifying trifluoroacetylated (TFA)-hepatocytes. Liver sections prepared from rats at 4 hr after halothane administration were stained preferentially in the centrilobular region with anti-TFA serum whereas livers of control rats showed no staining.

Respective roles of hypoxia and halothane metabolism in halothane-induced liver injury in rats.

To evaluate the respective roles of halothane metabolism and hypoxia in rats with halothane hepatotoxicity, experiments were designed with special reference to blood gas. After pretreatment with phenobarbital (80 mg per kg., i.

Guinea-pig model of halothane-associated hepatotoxicity in the absence of enzyme induction and hypoxia.

Halothane anesthesia (1%) administered in 21% oxygen for 4 hr to an outbred strain of guinea pig in the absence of enzyme induction resulted in liver damage in 40 of the 65 animals studied. Necrosis was either confluent around the central veins or in scattered foci throughout the lobules. Damage was present on the second and third days after anesthesia.

[Hepatic injury and halogenated anesthetics: preliminary clinical experience].

The potential hepatotoxic activity of isoflurane, a volatile anesthetic agent recently introduced in Italy, has been investigated by the Authors in the present study. Hepatic markers blood level (GPT, gamma GT, alkaline phosphatase and albumin) have been checked preoperatively and at day 1 and 4 postoperatively in a group of 35 patients who underwent general anesthesia for plastic surgery operations by means of isoflurane. As control group 32 patients were tested, treated with general anesthesia for the same type of surgery by means of halotane.

Nitrous oxide, too, is hepatotoxic in rats.

Anesthetic hepatotoxicity was tested under various conditions of hypoxia in rats pretreated with phenobarbital. Administration of 0.3 MAC halothane or fentanyl in 9% oxygen (fractional concentration of inspired oxygen = 0.

The involvement of endotoxin in halothane-associated liver injury.

Since endotoxin, lipopolysaccharides (LPS), have been implicated as a causative factor in the development of hepatic necrosis in rats exposed to hepatotoxic levels of several chemical agents, the role of LPS in the halothane-hypoxia (HH) model of hepatic damage in male Sprague-Dawley rats was investigated. When injected intravenously immediately after halothane anesthesia, a subnecrotic dose of LPS (0.5 mg/kg; Escherichia coli 026:B6) was found to markedly potentiate HH-induced hepatic necrosis.

The effect of halothane, isoflurane, and blood loss on hepatotoxicity and hepatic oxygen availability in phenobarbital-pretreated hypoxic rats.

This study evaluated the role of ventilatory and circulatory depression in anesthesia-induced hepatotoxicity in rats. Male Sprague-Dawley rats (181 animals) were pretreated with phenobarbital and exposed to hypoxia (FIO2 = 0.14) for 2 hr.

Effect of nitrous oxide on halothane-induced hepatotoxicity in hypoxic, enzyme-induced rats.

The degree of hepatotoxicity induced by halothane in hypoxic (14% inspired oxygen), enzyme-induced (phenobarbitone treatment for 10 days), male Sprague-Dawley rats was assessed by histological examination and analysis of serum aspartate aminotransferase (Asp. AT) concentrations. There was a significant direct, linear relationship between dose of halothane and histology score (P = 2.

Paradoxical effects of perturbation of intracellular levels of glutathione on halothane-induced hepatotoxicity in hyperthyroid rats.

Exposure of hyperthyroid rats to halothane results in a centrilobular necrosis of the liver and an 11-fold increase in serum glutamate-pyruvate transaminase (SGPT) levels. These effects are not seen in euthyroid animals. Paradoxically, administration of diethylmaleate to hyperthyroid rats significantly decreased the levels of hepatic glutathione and blocked the halothane-induced hepatic necrosis as well as decreased the elevation of SGPT.

The pharmacology of isoflurane.

The physical and pharmacological properties of the structural isomers isoflurane and enflurane differ from each other and from those of other potent inhaled anaesthetics. The minimum alveolar concentration (MAC) for isoflurane (1.15%) is one-and-one-half times that for halothane (0.

Effects of cimetidine and ranitidine on halothane metabolism and hepatotoxicity in an animal model.

This study was undertaken to determine the effects of two H2-receptor antagonists, cimetidine and ranitidine, on halothane metabolism and hepatotoxicity in the hypoxic Fisher 344 rat model for halothane hepatitis. In this model, liver injury is caused by toxic intermediates formed during metabolism of halothane by a reductive pathway. Administration of cimetidine (120 mg/kg ip) 20 min prior to anesthesia led to inhibition of the reductive pathway, as assessed by measurement of the exhaled metabolites, 2-chloro-1,1,1-trifluoroethane and 2-chloro-1,1-difluoroethylene, during anesthesia, and urinary fluoride excretion in the 22-hr postanesthesia period.

Characterization of hyperthyroidism enhancement of halothane-induced hepatotoxicity.

Administration of anesthetic doses of halothane to hyperthyroid male rats results in the development of hepatic necrosis. The severity of the hepatic lesion was dependent on the dose of triiodothyronine (T3) and the length of time it was administered. Pretreatment of rats with iodinated metabolites of thyroxin which do not induce hyperthyroidism did not result in any signs of hepatotoxicity after halothane exposure.

Contrasting effects on halothane hepatotoxicity in the phenobarbital-hypoxia and triiodothyronine model: mechanistic implications.

Factors affecting halothane (H) hepatotoxicity were investigated in two animal models: 1) the phenobarbital-hypoxia model, and 2) the triiodothyronine (T3) model; in the latter we previously have shown that centrilobular necrosis occurs in T3 pretreated rats anesthetized with 1% H, in 21% oxygen for 2 h. Feeding worsens the hepatotoxic effects of H in the T3 model. SGPT levels were higher (P less than 0.

Influence of dithiocarb, (+)-catechin and silybine on halothane hepatotoxicity in the hypoxic rat model.

In phenobarbital (phenemalum NFN)-pretreated male rats exposed to 1% halothane for 2 hrs under hypoxic conditions (10% O2), significant increases in serum enzyme activities of alanine aminotransferase and sorbitol dehydrogenase were observed 24 and 48 hrs later indicating liver damage. In this known model of halothane hepatotoxicity, pretreatment with (+)-catechin (200 mg/kg orally) or silybine (150 mg/kg orally) protected against halothane-induced liver injury, whereas diethyldithiocarbamate (200 mg/kg orally) failed to be effective. Halothane decreased the concentration of reduced glutathione in liver only under hypoxic conditions indicating that glutathione might be involved in the non-oxidative metabolic pathways of halothane.

Halothane hepatotoxicity in hyperthyroid rats as compared to the phenobarbital-hypoxia model.

Halothane hepatotoxicity was observed after exposing hyperthyroid rats to 0.625% halothane for 4 hr under hypoxic conditions (10% O2). In this model, increases in serum enzyme activities of the alanine aminotransferase (GPT) and the sorbitol dehydrogenase (SDH) were evident immediately following exposure and were six-fold higher than in the phenobarbital-hypoxic model.

Enflurane hepatotoxicity. A clinicopathologic study of 24 cases.

Analysis of 24 cases of enflurane anesthesia-associated hepatic injury shows that the clinical, biochemical, and histologic features are similar to those seen with halothane- and methoxyflurane-related hepatitis. Postoperative fever was the presenting symptom in 19 patients. Jaundice occurred in 19 patients after a mean latent period of 8 days.