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At least 19 recordsLinked to original sources
PubMed1996

Identification of the enzyme responsible for oxidative halothane metabolism: implications for prevention of halothane hepatitis.

BACKGROUND: Fulminant hepatic necrosis ("halothane hepatitis") is an unusual and often fatal complication of halothane anaesthesia. It is mediated by immune sensitisation in susceptible individuals to trifluoroacetylated liver protein neoantigens, formed by oxidative halothane metabolism. The seminal event in halothane hepatitis is hepatic metabolism, yet the enzyme responsible for oxidative halothane metabolism and trifluoroacetylated neoantigen formation remains unidentified. This investigation tested the hypothesis that cytochrome P450 2E1 (CYP2E1) is responsible for human halothane metabolism in vivo. METHODS: 20 elective surgical patients received either disulfiram (500 mg orally, n = 10) or nothing (controls, n = 10) the night before surgery. Disulfiram, converted in vivo to an effective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1. All patients received standard halothane anaesthesia (1.0% end-tidal, 3 h). Blood halothane and plasma and urine trifluoroacetic acid, bromide, and fluoride concentrations were measured for up to 96 h postoperatively. FINDINGS: Total halothane dose, measured by cumulative end-tidal (3.8 SE 0.1 minimum alveolar concentration hours) and blood halothane concentrations, was similar in the two groups. Plasma concentrations and urinary excretion of trifluoroacetic acid and bromide, indicative of oxidative and total (oxidative and reductive) halothane metabolism, respectively, were significantly diminished in disulfiram-treated patients. In control and disulfiram-treated patients cumulative 96 h postoperative trifluoroacetic acid excretion was 12,900 (SE 1700) and 2010 (440) mumol, respectively (p < 0.001) while that of bromide was 1720 (290) and 160 (70) mumol (p < 0.001). INTERPRETATION: The substantial attenuation of trifluoroacetic acid production by disulfiram after halothane anaesthesia suggests that P450 2E1 is a predominant enzyme responsible for human oxidative halothane metabolism. Inhibition of P450 2E1 by a single preoperative oral disulfiram dose greatly diminished production of the halothane metabolite responsible for the neoantigen formation that initiates halothane hepatitis. Single-dose disulfiram may provide effective prophylaxis against halothane hepatitis.

Adult↗
PubMed1977

Anaesthesia for Caesarean section. Analysis of blood concentrations of halothane using 0.2% or 0.65% halothane with 50% nitrous oxide in oxygen.

In 15 patients anaesthesia for elective Caesarean section was maintained with 50% nitrous oxide in oxygen and a 0.65% halothane supplement. In a further 15 mothers a 0.2% halothane supplement was used. In those mothers receiving 0.65% halothane intermittent measurements were made of maternal arterial halothane concentrations during the uptake and the excretion of the agent. At delivery the foetal umbilical venous concentrations were measured also. The mean time between administering halothane and delivery was 10.5 min (SD 3.5). The mean maternal arterial halothane concentration at delivery was 6.03 mg/100 ml (SD 0.75) and the mean umbilical vein concentration was 2.13 mg/100 ml (SD 0.69). The regression of Apgar scores at 1 min after delivery on umbilical vein halothane concentration at delivery was not significant. In the mothers receiving 0.2% halothane measurements of halothane concentration were made in five patients only. The mean maternal arterial halothane concentration at delivery was 1.56 mg/100 ml (SD 0.52) and the mean umbilical vein and artery concentrations were 0.8 and 0.38 mg/100 ml respectively. The use of 0.2% and 0.65% halothane supplements prevented awareness in all the mothers. However, dreaming occurred in two patients given a 0.2% halothane supplement. Studies are required to establish the minimum halothane supplement required to prevent awareness in a larger series of patients.

Adolescent↗
PubMedDate not supplied

Evidence for expression in human liver of halothane-induced neoantigens recognized by antibodies in sera from patients with halothane hepatitis.

Previous investigations have shown that antibodies in sera from patients with halothane hepatitis recognize neoantigens, expressed in livers of halothane-exposed rabbits and rats, which consist of a halothane metabolite bound covalently to specific microsomal proteins. These studies have suggested that the patients' antibodies may play a role in the pathogenesis of the hepatitis. In the present investigation, human liver biopsy samples were analyzed using an immunoblotting method to seek evidence for expression of halothane-induced neoantigens in humans. Sera from four patients with halothane hepatitis, which recognized halothane-induced rabbit liver neoantigens of 100, 76 and 57 kD, reacted strongly with antigens of very similar molecular weights that were expressed in livers from two patients who had died of cardiac failure following recent anesthesia with halothane. The antigens were not expressed in normal human liver or in livers from three patients who died of cardiac failure following anesthesia with agents other than halothane. The human antigens were not recognized by antibodies present in various control sera. Recognition of the 100- and 76-kD human antigens by the patients' antibodies was greatly reduced by absorption of sera with liver microsomes from halothane-exposed rabbits, but not by absorption of sera with control rabbit microsomes. These results indicate that humans exposed to halothane express liver neoantigens which are analogous to the halothane metabolite-protein neoantigens characterized previously in halothane-exposed animals.

Adult↗
PubMed1999

Halothane presynaptically depresses synaptic transmission in wild-type Drosophila larvae but not in halothane-resistant (har) mutants.

BACKGROUND: General anesthetics produce important changes in neural function, but the relation between the many individual changes produced by anesthetics in neural components and the responsiveness of the whole organism is uncertain. An analysis of genetically altered animals that have modified responses to volatile anesthetics may help to allay this uncertainty. METHODS: The authors evaluated the effect of halothane on synaptic transmission at the larval neuromuscular junction in wild-type (Ore-R) and halothane-resistant (har) mutants of Drosophila melanogaster. The body wall muscles, which are innervated by glutamatergic nerves, were voltage clamped at -60 mV using the patch-clamp technique in the whole cell configuration. Nerve-evoked excitatory junctional currents and miniature excitatory junctional currents were recorded. The effects of halothane on the amplitude of these currents were compared in Ore-R and two bar mutants derived from the Ore-R strain. The time course and frequency of miniature excitatory junctional currents also were analyzed in the presence of halothane. RESULTS: In Ore-R, halothane (1.8%; 1.01 mM) significantly reduced the amplitude of nerve-evoked excitatory junctional currents (61.9+/-17% of control, mean +/- SD; n = 7), but not that of miniature excitatory junctional currents. Conversely, in two har mutants, halothane had no effect on the amplitude of either nerve-evoked excitatory junctional currents or miniature excitatory junctional currents. In Ore-R, the frequency of miniature excitatory junctional currents was decreased significantly in the presence of halothane (0.9-2.7%; 0.52-1.46 mM), whereas halothane did not change the frequency in two har mutants. The miniature excitatory junctional current decay time constant, thought to reflect the kinetic properties of junctional glutamate receptor channels, was not changed by halothane in either the Ore-R strain or the har mutants. CONCLUSIONS: Halothane depresses synaptic transmission at the wild-type Drosophila neuromuscular junction, most likely by affecting presynaptic properties. The absence of an effect by halothane in the har mutants provides evidence that the depression of presynaptic function at the glutamate-mediated synapses is an important contributor to the way halothane alters the responsiveness of the whole animal.

Anesthetics, Inhalation↗
PubMed1991

Comparative hemodynamic effects of halothane and halothane-acepromazine at equipotent doses in dogs.

The purpose of this study was to compare the cardiovascular effects of halothane when used alone at increasing doses (1.2, 1.45 and 1.7 minimum alveolar concentration, MAC) to those produced with equipotent doses of halothane after potentiation of the anesthetic effect with acepromazine (ACP) sedation (45% reduction of halothane MAC). Six healthy mature dogs were used on three occasions. The treatments were halothane and intramuscular (IM) saline (1.0 mL), halothane and ACP (0.04 mg/kg IM), or halothane and ACP (0.2 mg/kg IM). Anesthesia was induced and maintained with halothane in oxygen and the dogs were prepared for the collection of arterial and mixed venous blood and for the determination of heart rate, systolic, diastolic and mean arterial pressure, mean pulmonary arterial pressure (PAP), central venous pressure and cardiac output. Following animal preparation the saline or ACP was administered and positive pressure ventilation instituted. Twenty-five minutes later the dogs were exposed to the first of three anesthetic levels, with random assignment of the sequence of administration. At each anesthetic level, measurements were obtained at 20 and 35 min. Calculated values included cardiac index, stroke index, left ventricular work, systemic vascular resistance, arterial oxygen content, mixed venous oxygen content, oxygen delivery and oxygen consumption. Heart rate was significantly higher with halothane alone than with both halothane-ACP combinations and was significantly higher with high dose ACP compared to low dose ACP. Systolic and mean blood pressures were lowest with halothane alone and highest with 0.2 mg/kg ACP, the differences being significant for each treatment. Oxygen uptake and PAP were significantly lower in dogs treated with ACP. It was concluded that ACP does not potentiate the cardiovascular depression that accompanies halothane anesthesia when the resultant lower dose requirements of halothane are taken into consideration.

Acepromazine↗
PubMed1990

The association of halothane-induced lipid peroxidation with the anaerobic metabolism of halothane: an in vitro study in guinea pig liver microsomes.

The formation of pentane and anaerobic metabolites of halothane (2-chloro-1,1,1-trifluoroethane and 2-chloro-1,1-difluoroethylene) in a mixture of guinea pig liver microsomes and halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) in the presence of NADPH was studied by gas chromatography. Under anaerobic conditions, pentane was formed without halothane and was inhibited by oxygen tension. This anaerobic pentane formation was potentiated 2.5 times by addition of halothane. Halothane-induced pentane formation increased dose-dependently with a halothane concentration of up to 2.1 mmol/liter and then decreased in the presence of increasing concentrations of halothane. Inhibition by a higher substrate was also observed in the formation of anaerobic metabolites of halothane. Antioxidant agents, vitamin E and glutathione, reduced the pentane formation, but did not reduce the anaerobic metabolites of halothane. Metyrapone, an inhibitor of cytochrome P-450, reduced both the pentane and anaerobic metabolites of halothane. These results show halothane-induced lipid peroxidation in association with the anaerobic metabolism of halothane in guinea pig liver microsomes.

Anaerobiosis↗
PubMed1989

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. Significant reductions in both oxidative and overall halothane biotransformation were observed with the use of d-halothane as indicated by decreased plasma levels of trifluoroacetic acid and bromide ion, respectively, immediately following exposure. Plasma fluoride ion, indicative of the reductive metabolism of halothane, was significantly increased with the use of d-halothane. These changes in metabolism were accompanied by a reduced hepatotoxic response as indicated by significantly decreased plasma ALT levels 24-96 h following exposure and a significantly lesser incidence of centrilobular necrosis. Thus, the oxidative biotransformation of halothane is implicated as a mechanism of injury in guinea pigs.

Animals↗
PubMedDate not supplied

Detection of covalently bound halothane metabolites in the hypoxic rat model for halothane hepatotoxicity.

Using a non-radiometric technique, halothane metabolites have been shown to covalently bind to rat hepatic tissue with the production of a lesion. The conditions required for optimizing the lesion (hypoxia and biotransformation enzyme induction) also optimizes the binding of fluorinated halothane residues to hepatic tissue. The maximal binding of fluorinated halothane residues to the liver of rats precedes the development of the hepatic lesion. Female rats, which are resistant to the halothane initiated lesion, have one-third as much covalently bound halothane residue. Biotransformation inhibitors (SKF-525A, metyrapone), which inhibited lesion formation, also inhibit the covalent binding of halothane to hepatic tissue. Cystamine and cysteine, sulfhydryl agents which can inhibit hepatic lesion development when administered four hr after halothane exposure, also suppressed the amount of halothane metabolites covalently bound to hepatic tissue. Using this non-radioactive method for measuring the covalent binding of halothane to hepatic tissue, it appears that the bioactivation of halothane was a necessary event for the appearance of a halothane initiated hepatic lesion.

Animals↗
PubMed1980

Bioactivation and covalent binding of halothane in vitro: studies with [3H]- and [14C]halothane.

To determine if the hydrogen atom of halothane (CF3CHBrCl) is retained on the reactive intermediates that covalently bind to microsomal lipids and protein, [3H]halothane and [14C]halothane were incubated with rat hepatic microsomes and a NADPH generating system. Both [3H]- and [14C]halothane were bioactivated and bound to a greater degree when incubations were performed in a N2 atmosphere rather than an O2 atmosphere. Binding of [3H]- and [14C]halothane equivalents was significanty enhanced when heaptic microsomes from phenobarbital- or Aroclor 1254-treated rats were used in the incubations. Omission of NADPH or incubation with CO was inhibitory to the binding of both [3H]- and [14C]halothane. The apparent kinetic constants for binding or halothane equivalents, Km and Vmax, indicate a significantly higher Km but lower Vmax for the formation and/or binding of 3H-binding equivalents. The results indicate tht halothane is primarily bioactivated under conditions that promote its reductive metabolism and that this reactive metabolism does not involve cleavage of the carbon-hydrogen bond of halothane. Differences in binding under N2 and O2 as well as between [3H]- and [14C]halothane suggest that multiple reactive intermediates may form during the biotransformation of halothane.

Animals↗
PubMed1994

Sera from patients with halothane hepatitis contain antibodies to halothane-induced liver antigens which are not detectable by immunoblotting.

In previous studies, immune responses to novel, halothane-induced hepatic antigens have been implicated in the mechanism of halothane hepatitis. Experiments performed using the technique of immunoblotting have indicated that the halothane-induced antigens comprise a group of halothane metabolite-modified microsomal proteins (trifluoroacetylated proteins). In the present report, we describe detection of an additional and quite distinct group of halothane-induced antigens. The novel halothane-induced antigens were expressed in microsomal fractions from livers of halothane-treated rats and could be detected by enzyme-linked immunosorbent assay (ELISA), but not by immunoblotting. In contrast to the major trifluoroacetyl-protein antigens detectable by immunoblotting, which were soluble in buffer containing 0.1% sodium deoxycholate, the novel antigens detectable by ELISA were not soluble in 0.1% sodium deoxycholate but were soluble in 2% sodium deoxycholate. Expression of the novel antigens was reduced markedly when rats were treated with deuterated halothane, in place of halothane. This suggests that their expression requires metabolism of halothane via the same oxidative, cytochrome P450-mediated pathway known to be responsible for generation of the antigens detectable by immunoblotting. Both the antigens detectable by ELISA and the antigens detected by immunoblotting were expressed slowly in livers of halothane-treated rats and were long-lived. Overall, these results indicate that the technique of immunoblotting is of limited value for detection and characterization of antigens involved in immune-mediated adverse drug reactions.

Animals↗
PubMedDate not supplied

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.p.) for four consecutive days, rats were exposed to 1.0% halothane under a mildly hypoxic condition (FiO2 = 14%) for 2 hr. Since halothane anesthesia caused significant decrease in PaO2 levels, rats exposed to a highly hypoxic atmosphere (FiO2 = 10%) in which PaO2 levels were comparable to those in the halothane group, served as the control. In the halothane group, marked centrilobular necrosis and elevation of SGPT activity were observed; neither significant histological lesions nor elevation of transaminase activity occurred in the highly hypoxic group. Although phenobarbital treatment did not decrease PaO2 levels during halothane anesthesia, the serum fluoride level, which appears to reflect quantitatively the reductive pathway of halothane metabolism, increased. These results strongly indicate that halothane metabolism rather than hypoxia, per se, plays a major role in development of halothane-induced liver injury in rats.

Alanine Transaminase↗
PubMed1982

Systemic and regional blood flow distribution in unanesthetized swine and swine anesthetized with halothane + nitrous oxide, halothane, or enflurane.

In order to study the distribution of cardiac output during various anesthetic regimens, we measured regional organ blood flow using 15 micrometers diameter radionuclide-labeled microspheres injected into the left atrium. Studies were carried out in nine pigs during resting unanesthetized state (control), during halothane (inspired concentration = 1.25 per cent) + nitrous oxide (50 per cent) anesthesia, during halothane (inspired concentration = 2.25 per cent) anesthesia, and during enflurane (inspired concentration = 4.0 per cent) anesthesia. The order of the last two treatments [halothane (2.25 per cent) and enflurane (4.0 per cent)] was randomized among the nine pigs. All anesthetic steps employed intermittent positive-pressure ventilation to maintain PaCO2 close to control values. Animals were allowed to recover towards the control state before changing to the next anesthetic regimen. Forty-five minutes were allowed for equilibration with each anesthetic regimen before hemodynamic measurements were made. In unanesthetized resting swine blood flow received by brain, cardiac ventricles, kidneys, liver (via hepatic artery), gastrointestinal tract, and skeletal muscle was 63.70 +/- 5.56, 128.56 +/- 14.92, 280.89 +/- 19.72, 21.95 +/- 3.25, 148.55 +/- 15.29 and 13.76 +/- 4.12 ml . min-1 . 100 g-1, respectively (mean +/- SEM). Corresponding values for the percentage of cardiac output received by the brain, cardiac ventricles, kidneys, liver (via hepatic artery), and gastrointestinal tract were 1.13 +/- .08, 3.04 +/- 0.13, 12.95 +/- 1.54, 4.27 +/- 0.76, and 18.71 +/- 0.91 per cent, respectively. Cardiac output and mean arterial blood pressure decreased significantly from control values with each of the three anesthetized steps. The decrease in cardiac output was greatest with the halothane anesthesia and least with halothane + N2O. Blood flow per unit weight of the cardiac, renal, and splanchnic tissues decreased significantly with each anesthetic regimen whereas brain blood flow and hepatic arterial blood flow were unaltered from control values. Thus, the per cent cardiac output received by the brain had increased with halothane (119 per cent) and enflurane (102 per cent) anesthesia while it was unaltered from the heart, renal, and splanchnic organs. Percentage of total cardiac output received by liver via the hepatic artery increased by 162 per cent during halothane anesthesia and 133 per cent during enflurane anesthesia, when compared to control values. During halothane + nitrous oxide anesthesia, the per cent of cardiac output going to the brain was not increased significantly. It is concluded that cardiac output as well as individual organ/tissue blood flow was better maintained during halothane + nitrous oxide anesthesia in comparison to halothane or enflurane anesthesia.

Animals↗
PubMed1977

Halothane macrophage migration inhibtiion factor test in halothane-associated hepatitis.

As an index of delayed hypersensitivity in vitro halothane macrophage migration inhibition factor tests (halothane-MIF tests) were performed on peripheral blood lymphocytes from five patients with halothane hepatitis. Twenty-two subjects exposed to halothane, but with no evidence of jaundice, five 'healthy' hospital anaesthetists, nine jaundiced subjects without halothane exposure, and 10 healthy subjects with no history of exposure to halothane were also tested. The halothane-MIF test was positive in four of the five patients with halothane-induced hepatitis; the negative result was in a patient on steroid treatment. The test was negative in all other subjects. Our findings suggest that the halothane-MIF test may be of value in the diagnosis of halothane-induced hepatitis and as a screeening procedure for the identification of susceptible subjects.

Adult↗
PubMed1989

Localization of halothane-induced antigen in situ by specific anti-halothane metabolite antibodies.

Multiple or single halothane exposure of rabbits or guinea pigs induces an antibody reactive with trifluoroacetylated (TFA) proteins. The antigen that initiates this immune response was investigated in halothane-exposed rabbits and guinea pigs for its anatomical location in the liver, the chronology of its expression in situ and exposure conditions which would modulate its expression. Using an immuno-staining technique, binding by an anti-TFA antibody to the antigen was detected in liver tissue from all halothane-exposed rabbits and guinea pigs. Antigen could be detected only in the centrilobular area around the central vein where staining intensity was concentrated in an area seven to nine cells deep. In halothane-exposed rabbits, the appearance of TFA antigen was most predominant on the first and second days following a single exposure. Multiple exposures induced TFA antigen in a larger area around the central vein than did a single exposure. Though maximal expression of TFA antigen occurred following two or three exposures, subsequent exposures did not potentiate antigen expression. In halothane-exposed guinea pigs, exposure to deuterated halothane, which reduces the extent and metabolites of oxidative halothane metabolism, elicited the appearance of TFA antigen around the central veins, although to a lesser extent than during halothane exposure. Halothane-induced antigen was evident in guinea pigs as early as 6 h post-exposure and was still apparent 90 h later. Thus, halothane exposure by inhalation elicits the appearance of TFA protein conjugates which may, in turn, evoke the anti-TFA immune response.

Animals↗
PubMed1984

Porcine regional brain and myocardial blood flows during halothane-O2 and halothane-nitrous oxide anesthesia: comparisons with equipotent isoflurane anesthesia.

Regional distribution of brain and myocardial blood flow were examined in 9 instrumented isocapnic normothermic swine, using 15-microns diameter radionuclide-labeled microspheres injected into the left atrium. Minimal alveolar concentration (MAC) of halothane required to prevent gross purposeful movement in response to a noxious stimulus in 50% of the pigs was found to be 0.70%. Measurements were made on each animal during nonanesthetized state (control), 1.0 and 1.5 MAC halothane anesthesia, and the equivalent of 1.0 and 1.5 MAC halothane anesthesia, using 50% N2O. The order of anesthetized steps was randomized for each pig. Recovery periods of 60 minutes were interposed between the anesthetic treatments. During halothane + 50% N2O anesthesia, heart rate, cardiac output, mean aortic pressure, and rate-pressure product were higher than comparable levels of halothane-O2 anesthesia. Halothane caused dose-dependent vasodilatation in all regions of the brain. Cerebral, cerebellar, and brain-stem blood flows at 1.5 MAC halothane were 135%, 135%, and 115% of respective control values. Substitution of 50% N2O to maintain same MAC dose markedly exaggerated the increment in porcine cerebral and brainstem blood flows, especially at 1.0 MAC when perfusions in these regions were 204% and 128% of respective control values. At 1.5 MAC anesthesia produced by halothane + 50% N2O, the cerebral, cerebellar, and brain stem perfusions were 153%, 146%, and 129% of control values. Transmural myocardial blood flow decreased from control value with both levels of halothane anesthesia, but with equivalent MAC anesthesia produced by halothane + 50% N2O, myocardial perfusion remained near awake values.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Intrauterine exposure to halothane increases murine postnatal autotolerance to halothane and reduces brain weight.

The effect of halothane on prenatal development was assessed using the appearance of postnatal tolerance to the anesthetic and its effect on brain weight. Eighteen 3-month-old mice were repeatedly tested in a rotating cage for loss of righting reflex during exposure to increasing concentrations of halothane on 15 occasions to determine whether or not tolerance to halothane developed. Of these, nine mice were born to dams exposed for 30 min to 2% halothane on days 14 and 17 of gestation. The other nine mice (controls) were born to dams exposed to 100% oxygen for 30 min at the same stage of pregnancy. There was no significant difference in tolerance to halothane between the groups during the first nine days of repeated exposure to halothane. By the 13th and 15th days, however, mice exposed to halothane in utero became more tolerant to 1% halothane than did controls (P less than 0.025). In addition, the mean total brain weight of six 7-week-old mice exposed to 2% halothane in utero for 30 min on days 14 and 17 of gestation was found to be significantly less than the mean total brain weight of six control mice not exposed to halothane in utero (20.83 +/- 0.27 g and 23.07 +/- 0.51 g, respectively, P less than 0.0025). This difference occurred mainly in the brain stem rather than in the forebrain and cerebellum.

Animals↗
PubMed1980

Comparison of the biotransformation and hepatotoxicity of halothane and deuterated halothane.

To investigate the effect of deuterium substitution on the biotransformation and hepatotoxicity of halothane, male, phenobarbital-pretreated rats were exposed for 2 hr to 1% halothane or deuterated halothane (d-halothane) delivered in 14% O2-85% N2. The exposures were performed at mildly hypoxic conditions (14% O2) since it was previously established that the decreased oxygen tension promotes both the reductive metabolism of halothane and halothane-induced liver injury. At the end of anesthesia or at 24 hr, the rats were sarificed so that blood, liver and urine samples could be obtained for measurement of metabolites and assessment of liver damage. Deuterium substitution did not affect the levels of reductive metabolites of halothane (fluoride, CF3CH2Cl and CF2CHCl) nor did it alter the degree of hepatotoxicity as assessed by serum glutamic-pyruvic transaminase levels and morphological examination. The levels of oxidative metabolites (CF3COOH and bromide) were significantly reduced at the end of anesthesia and at 24 hr. It is concluded that halothane-induced hepatotoxicity is initiated by reactive intermediates formed during its reductive metabolism and that cleavage of the C-H bond is not involved in this pathway. The oxidative biotransformation of halothane proceeds by an oxygen insertion reaction at the C-H bond. Thus, the increased stability of the C-D bond explains the reduction in oxidative metabolities observed after exposure to d-halothane.

Animals↗
PubMedDate not supplied

Halothane hepatitis without halothane: role of inapparent circuit contamination and its prevention.

Halothane and other halogenated anesthetic agents are liquids which are highly soluble in rubber and plastic materials widely used as components of anesthesia machines. These agents must be administered using machines equipped with vaporizers. We report a patient with a past history of halothane hepatitis in whom recurrence was suspected despite the fact that halothane had been avoided purposely during the subsequent operation. Circumstances led us to believe that inapparent circuit contamination of vaporizer-equipped anesthesia machine with halothane may be responsible for the inadvertant rechallenge and recurrence of halothane hepatitis. Vaporizer-equipped machines were tested for inapparent contamination with halothane and enflurane using Perkin-Elmer mass spectrometer. Oxygen alone was passed through the anesthesia circuits, and gas in the efferent limbs of the machines was tested for halothane (in eight machines) and enflurane (in two machines) which were found in various concentrations in all machines so tested. Our findings suggest that inapparent contamination may be widely prevalent in vaporizer-equipped anesthesia machines. The validity of this conclusion was confirmed in five patients with previous diagnosis of halothane hepatitis who subsequently underwent operations under general anesthesia during which machines never equipped with vaporizers were successful in preventing recurrence of hepatitis. We conclude that patients with a prior history of halothane hepatitis are at risk of inapparent circuit contamination-induced recurrent hepatitis. Unless such contamination can be confidently excluded, vaporizer-equipped machines should not be used to administer general anesthesia in these susceptible patients.

Anesthesia, General↗