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PubMed1999

The anesthetic and physiologic effects of an intravenous administration of a halothane lipid emulsion (5% vol/vol)

UNLABELLED: The i.v. administration of < or = 9 mL of nonvaporized liquid halothane causes significant pulmonary damage, cardiovascular decompensation, and death. To determine whether liquid halothane mixed in a lipid emulsion would alter these toxic effects, six swine were evaluated in a randomized cross-over study. The pulmonary, analgesic, hemodynamic, and histopathologic effects of liquid halothane (25 mL) mixed with a liquid carrier (475 mL, Liposyn III 20%) and administered by constant infusion were compared with halothane administered by a calibrated vaporizer. Three swine received the halothane lipid emulsion (HLE), followed by inhaled halothane. Three additional swine received inhaled halothane, followed by the HLE. There were no changes in pulmonary compliance or arterial blood gases during or after the administration of equivalent volumes of halothane (13.75 mL) either by infusion of HLE or by inhalation of halothane. The end-tidal halothane concentration for the minimum alveolar anesthetic concentration was 0.79% +/- 0.08% during HLE administration and 1.13% +/- 0.12% for inhaled halothane (P < 0.001). Hemodynamic variables and blood halothane levels by gas chromatography were measured at end-tidal concentrations of 0.6%, 1.2%, and 1.8%. Blood halothane levels (mg/mL) were significantly higher (P < 0.05) after the administration of HLE at end-tidal halothane concentrations of 1.2% (0.49 +/- 0.19 vs 0.82 +/- 0.18) and 1.8% (0.79 +/- 0.17 vs 1.29 +/- 0.34). When compared at equivalent blood levels, HLE caused fewer changes in the left ventricular end-diastolic pressure, mean arterial pressure, and dP/dt than inhaled halothane. There was no evidence of pulmonary histopathologic damage 4-8 h after the infusion of 500-700 mL of HLE. This novel method of delivery of a volatile anesthetic seems to lack the toxicity of direct i.v. administration of liquid halothane. It may be a useful alternative to traditional administration via a vaporizer. IMPLICATIONS: Halothane causes pulmonary dysfunction and death when given i.v. in liquid form. Six swine received a halothane lipid emulsion i.v. to evaluate the anesthetic and physiologic effects. No pulmonary toxicity or deaths were associated with the halothane lipid emulsion. The anesthetic profile was similar to delivery of halothane via a vaporizer.

Anesthetics, Inhalation↗
PubMed1991

Halothane inhibits two components of calcium current in clonal (GH3) pituitary cells.

The effect of halothane on isolated calcium (Ca2+) current of clonal (GH3) pituitary cells was investigated using standard whole-cell clamp techniques at room temperature. Halothane (0.1-5.0 mM) reversibly reduced both the low-threshold, transient [low-voltage-activated (LVA)] component and the high-threshold [high-voltage-activated (HVA)] component of Ca2+ current. Halothane had little effect on the voltage dependence of activation or inactivation of either component of Ca2+ current. Inhibition of the peak high-threshold Ca2+ current was half-maximal at about 0.8 mM halothane, with maximal inhibition (100%) occurring with 5 mM halothane. When measured at the end of a 190-msec command step, half-maximal reduction of high-threshold current occurred at less than 0.5 mM halothane. The low-threshold transient current was less sensitive to halothane, with half-maximal inhibition of peak transient current activated at -30 mV occurring at approximately 1.3 mM. The effect of halothane on the HVA current was apparently not mediated by changes in intracellular Ca2+ concentration. The ability of halothane to inhibit Ca2+ current was unaffected by either the inclusion of the rapid Ca2+ buffer 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid (BAPTA) in the recording pipette or exposure of the cell to 10 mM caffeine. To assess the selectivity of the effect of halothane, the actions of halothane on two components of voltage-activated potassium (K+) current observed in the absence of extracellular Ca2+ and on voltage-dependent sodium (Na+) current were also examined. Halothane had no effect on the voltage-dependent, inactivating K+ current of GH3 cells at concentrations up to 1.2 mM. In contrast, the non-inactivating K+ current, though less sensitive to halothane than either Ca2+ current, was reduced by about 40% by 1.2 mM halothane at +20 mV. Peak Na+ current was also blocked by halothane, but 50% block required around 2.6 mM halothane with little effect at 1.6 mM. Reduction of Na+ current was associated with a substantial negative shift in the steady-state inactivation curve. Although the results indicate that a number of voltage-dependent ionic currents are sensitive to halothane, both components of Ca2+ current exhibit a greater sensitivity to halothane than any of three other voltage-dependent currents in GH3 cells. These results show that GH3 cell Ca2+ currents are selectively inhibited by clinically appropriate concentrations of halothane and that the reduction of Ca2+ current can account for the inhibition by halothane of TRH- or KCl-induced prolactin secretion in GH3 cells.

Calcium Channels↗
PubMed1993

[Halothane absorption by dry soda lime].

Humidified soda lime is commonly used to eliminate carbon dioxide from the circulatory system. Little is known about adverse reactions to accidentally dried soda lime. Therefore, a case of unexpected absorption of halothane by dry soda lime is reported. These observations were confirmed by a simulation with relevance to anaesthetic practice. CASE REPORT. A 46-year-old ASA class I patient was scheduled for elective surgery. After induction of general anaesthesia with 500 mg thiopentone, followed by 100 mg suxamethonium, the trachea was intubated. The patient was ventilated with nitrous oxide in oxygen and 1.5 vol% of halothane for several minutes in the induction room. After being connected to a new circulatory system in the operating theatre, the patient was ventilated but, in addition inspiratory and expiratory anaesthetic gas concentrations were measured. Despite a vaporizer position of 1.5 vol% the inspiratory concentration of halothane was below 0.2 vol%. Disconnecting the tube, the typical odour of halothane was missing in the inspiratory line of the circulatory system, but was present in the fresh gas tube. Furthermore, the lower part of the soda lime canister was surprisingly hot. After removing both the absorbers, the inspiratory halothane concentration immediately normalized. The absorbers were replaced by canisters filled with fresh soda lime, and the anaesthesia was terminated without further complications. An absorption of halothane by dried soda lime was suspected. METHODS OF SIMULATION. In the first simulation four circulatory systems with two soda lime canisters each were perfused with 21 of oxygen for 48 h. In the second simulation four soda lime canisters placed in one circulatory system were perfused with 1 l for 120 h. For measurement of halothane absorption each canister was placed in a circulatory system. The canister was perfused with a fresh gas flow of 2 l of oxygen and a vaporizer position up to 1.3 vol% of halothane. By the time an equilibrium was reached, i.e., in- and outflow concentrations of halothane were equal for a 3-min period, further halothane vaporization was stopped. In a 30-s interval the soda lime temperature and the gas concentration entering and leaving the soda lime canister were registered. Subsequently, the humidity of the soda lime was determined. RESULTS. In the first simulation 6 of the 8 canisters showed a humidity of soda lime of 15.5% of 19%, with halothane being absorbed in one case. Normally, the equilibrium between in- and outflow gas concentration was reached after 3.5-4 min. In the remaining two canisters the humidity was 14% and 9%. Only a small amount of halothane vapour was absorbed. The halothane concentrations were in equilibrium after 10 to 13 min. The probes from the second simulation revealed a humidity of soda lime of 2% to 8.7%. Below a humidity of 4% the concentration of halothane leaving the canister was greatly reduced. It took 63 min to reach a steady state in the 2% humidity probe and the temperature rose to 43.1 degrees C. CONCLUSIONS. Accidental perfusion of the circulatory system with dry oxygen can cause a reduction in the humidity of soda lime. Dried soda lime delays the increase of halothane concentration in the inspiratory limb. The absorption of halothane is accompanied by an increase in the temperature of the soda lime. Therefore, in every situation lacking a sufficient anaesthetic level during inhalation anaesthesia, absorption of the vaporized anaesthetic must be excluded. Only dried soda lime can absorb halothane.

Adsorption↗
PubMed1996

Characterization of the NADPH-dependent covalent binding of [14C]halothane to human liver microsomes: a role for cytochrome P4502E1 at low substrate concentrations.

Activation of halothane to trifluoroacetyl halide, followed by covalent binding to proteins (neoantigen formation) has been proposed to be the mechanism by which halothane causes immune hepatitis. The aim of this study was to identify the cytochrome P450 (CYP) enzyme primarily responsible for the NADPH-dependent covalent binding of [14C]halothane to human liver microsomes. Human liver microsomes were incubated in the absence and presence of NADPH with various concentrations of halothane (from 4.6 to 3,300 microM) to examine the effects of substrate concentration on the nonspecific and specific (NADPH-dependent) binding of [14C]halothane to microsomal protein. As a function of substrate concentration, the specific binding of [14C]halothane to human liver microsomes was biphasic, suggesting that the activation of halothane is catalyzed by a high-affinity enzyme(s) at low substrate concentrations (<150 microM) and by a low-affinity enzyme(s) at high substrate concentrations (>150 microM). For the high-affinity enzyme, the apparent KM for the covalent binding of [14C]halothane was approximately 10 microM, and Vmax was approximately 32 pmol equivalents of halothane bound/mg protein/min under conditions where covalent binding was directly proportional to incubation time and protein concentration. Ten individual samples of human liver microsomes were incubated with a low concentration of halothane (35 microM) to determine the sample-to-sample variation in the specific binding of [14C]halothane to microsomal protein. Covalent binding ranged from 10 to 40 pmol equivalents of halothane bound/mg protein/min and was highly correlated (r2 = 0.93) with the sample-to-sample variation in chlorzoxazone 6-hydroxylase activity, which reflects the levels of CYP2E1. These results suggest that CYP2E1 is the high-affinity enzyme in human liver microsomes responsible for activating halothane to a reactive metabolite. This is supported by the observation that 4-methylpyrazole, a CYP2E1 inhibitor, inhibited the NADPH-dependent binding of [14C]halothane to microsomal protein. The sample-to-sample variation in the covalent binding of [14C]halothane at high substrate concentrations did not correlate with any known CYP enzyme activity. This suggests that several enzymes catalyze the oxidation of halothane at higher substrate concentrations. In conclusion, at pharmacologically relevant concentrations, the covalent binding of halothane to human liver microsomes is primarily catalyzed by CYP2E1.

Autoradiography↗
PubMed1994

A model for fatal halothane hepatitis in the guinea pig.

BACKGROUND: In the guinea pig, depleting hepatic glutathione before inhaling subanesthetic 0.1% halothane increases covalent binding of halothane biotransformation intermediates to hepatic protein and potentiates resultant liver injury. Because inhalation of a higher concentration of halothane is known to produce greater levels of covalent binding than with subanesthetic halothane, this study was undertaken with 0.25-1.0% halothane concentrations to further examine glutathione depletion as an etiology for halothane hepatitis. METHODS: Male Hartley guinea pigs were injected intraperitoneally with either vehicle control solution (Veh) or 1.6 g/kg buthionine sulfoximine (BSO), to decrease hepatic glutathione by > 80%, 24 h before a 4-h exposure to 0.25%, 0.5%, or (v/v) halothane with 40% O2. Some BSO-pretreated animals also received 2.0 g/kg glutathione monoethyl ester (GEE), intraperitoneally, 2 h before inhaling halothane to replenish hepatic glutathione. RESULTS: Glutathione-depleted animals developed significantly worse hepatic injury with each halothane concentration. One-third to one-half of BSO+halothane-treated animals developed fatal submassive to massive hepatic necrosis. Covalent binding of halothane intermediates to hepatic protein increased by 45% in BSO + 1.0% halothane-treated guinea pigs. Administration of GEE to BSO-pretreated animals before 1.0% halothane decreased binding to protein and blunted development of liver necrosis. Following Veh + 1.0% halothane, hepatic glutathione was found to be decreased by 60%. CONCLUSIONS: Glutathione would appear to help protect hepatocytes to some degree from covalent binding by reactive halothane biotransformation intermediates. These studies present the first animal model to produce fatal halothane-induced hepatic necrosis.

Animals↗