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PubMed1975

In vivo toxic effects of halothane on canine cerebral metabolic pathways.

The effects of high concentrations of halothane on cerebral metabolism were examined in dogs with the aid of an extracorporeal circuit to support the systemic circulation. At blood levels exceeding those representing equilibration with 2.3% halothane, a dose-related decrease in cerebral oxygen consumption (CMR02) occurred that was unrelated to the presence or absence of an active electroencephalogram. In this circumstance, despite adequate oxygen delivery, a dose-related alteration in oxidative phosphorylation also occurred as evidenced by progressive decreases in cerebral concentrations of ATP and phosphocreatine and concomitant increases in cerebral lactate and lactate/pyruvate ratio. These effects were totally reversible, except for persistence of increased of increased CMR02, after return to low halothane concentrations. It is concluded that the mechanisms of the cerebral metabolic effects of halothane differ from those of thiopental and, at high concentrations, are at least in part related to interference with oxidative phosphorylation. These in vivo studies confirm the potentially detrimental effects of high halothane concentrations on cerebral metabolic pathways as demonstrated by others in vitro.

Adenosine Triphosphate↗
PubMed1993

Halothane alters cytosolic calcium transient in tracheal smooth muscle.

Halothane is a potent bronchodilator that attenuates vagally mediated constriction of canine airways, in part by a direct action on the smooth muscle cell. In tracheal smooth muscle, acetylcholine (ACh) produces a transient peak increase in cytosolic ionized calcium concentration ([Ca2+]i), which declines to a sustained plateau concentration that is higher than that of the unstimulated muscle, and a sustained increase in force. The transient peak [Ca2+]i is caused primarily by Ca2+ release from the sarcoplasmic reticulum (SR), whereas the plateau [Ca2+]i is caused primarily by influx of extracellular Ca2+ across the plasma membrane. This study was conducted to investigate the effects of halothane on the 1) transient peak [Ca2+]i during force development (i.e., developed force) and 2) plateau [Ca2+]i during force maintenance (i.e., sustained force) induced by ACh in isolated strips of canine tracheal smooth muscle. Changes in [Ca2+]i were measured with the photoprotein, aequorin. In muscle strips contracted after incubation with 1.1 (n = 5) or 1.5 (n = 5) minimum alveolar concentration (MAC) halothane, halothane significantly attenuated the transient peak aequorin luminescence (AL) and developed force and significantly prolonged the time necessary to reach peak AL and developed force; these effects were not dose dependent. In muscle strips (n = 3) contracted with ACh, addition of halothane caused a reduction in sustained force but no decrease in plateau AL.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1981

Respiratory timing and depth of breathing in dogs anesthetized with halothane or enflurane.

Tidal volume (VT) and inspiratory (TI) and expiratory (TE) times were measured during enflurane and halothane anesthesia in 12 prone dogs before and after bilateral vagotomy. "Elastic" loading or airway occlusion was used to obtain a VT-to-TI relationship in each state and to examine the rate of change in airway pressure. VT, TI, and TE were significantly (P less than 0.05) larger during enflurane than during halothane anesthesia, both before and after bilateral vagotomy. Before vagotomy, the rate of change in airway pressure during airway occlusion was similar for the two agents, as was an index of impedance of the respiratory system (Z'rs). Thus the difference in maximal pressure generated and in VT was most likely due to the difference in TI. Before vagotomy, TI increased as VT decreased with loading during enflurane but not halothane anesthesia, demonstrating a different effect of the two agents on the phasic vagal inspiratory inhibitory mechanism. After bilateral vagotomy, TI was unaltered during elastic loading with both agents but was still significantly longer during enflurane than halothane anesthesia. Thus it was concluded that TI was longer in the enfluraneanesthetized dogs than in the halothane-anesthetized dogs because of a different effect of these two agents on the bulbopontine "pacemaker" mechanism and not because of different effects on the phasic vagal inspiratory inhibitory mechanism.

Anesthesia↗
PubMed1987

Dependence of hepatic gluconeogenesis on PO2: inhibitory effects of halothane.

The dependence of gluconeogenesis and O2 uptake on PO2 in isolated rat hepatocytes is presented. Maintenance of steady-state PO2 was achieved with an oxystat system (Biochem. J. 236: 765-769, 1986). O2 uptake showed a half-maximal (K0.5) value of 0.5 Torr PO2, whereas the glucose synthesis rate was half-maximal at 1.2 Torr PO2. Halothane at concentrations greater than 1 mM exerted a parallel inhibition of O2 uptake and glucose synthesis at all PO2 levels studied. In contrast, at halothane concentrations less than 1 mM, inhibition of glucose synthesis occurred only at less than 20 Torr PO2. At these low concentrations, halothane was without significant effects on cellular O2 uptake. In isolated mitochondria, inhibition of O2 uptake was already half-maximal at a halothane concentration of 0.5 mM. In this subcellular system the inhibitory effect of halothane was independent of PO2. These results demonstrate that the critical PO2 at which cellular O2 utilization begins to decrease and the PO2 at which glucose synthesis begins to decrease are comparable; both PO2 levels are approximately 5 Torr. The metabolic zonation of the liver lobule is discussed in view of the results presented.

Animals↗
PubMed1993

Metabolic response to halothane in piglets susceptible to malignant hyperthermia: an in vivo 31P-NMR study.

Using in vivo 31P-nuclear magnetic resonance spectroscopy, we studied the skeletal muscle metabolism of 17 anesthetized malignant hyperthermia-susceptible piglets and 25 control piglets during and after a halothane stress test. At rest, the phosphocreatine- (PCr) to-ATP ratio was 12% higher in the anesthetized piglets than in the control piglets, which may reflect a higher proportion of fast glycolytic fibers in the former. About 15 min of halothane administration sufficed to provoke onset of a reaction, which was characterized by a reciprocal drop in PCr and an increase in Pi with commencing intracellular acidosis. Halothane was withdrawn after a 20% drop in PCr. Within the next few minutes, intracellular pH dropped sharply and phosphomonoesters (PME) accumulated excessively. ATP was observed to decrease in 8 of the 17 animals. Halothane inhalation provoked a switch of metabolism toward glycolysis. Accumulation of PME suggests a mismatch between glycogenolysis and glycolysis. Despite severe acidification, glycolysis was not completely halted. Recovery of PCr and Pi started approximately 5 min after halothane withdrawal, with a longer time constant for recovery of the former. PME and intracellular pH aberrations lingered and started to recover later. Lost ATP was never restored within the observed recovery period of approximately 20 min.

Adenosine Triphosphate↗
PubMed1990

Alterations in influenza A virus specific immune injury in mice anesthetized with halothane or ketamine.

CD-1 mice infected with a sublethal dose of influenza A virus were anesthetized for 2 h with halothane. These mice were compared to a control group which was similarly infected using ketamine sedation. Mice anesthetized with halothane showed less physical signs of illness and demonstrated less lung histopathology than the control group of mice. Virus titers were reduced in the group of animals exposed to halothane 12 h after infection, but were the same as the infected controls at all other times measured (1-12 days after infection). Morphometric analysis of lung tissue demonstrated a delayed appearance of both neutrophils and monocytes in the halothane-exposed mice. These results suggest that the halogenated volatile anesthetic halothane decreases the pulmonary pathogenesis of influenza A virus by altering the recruitment of immunological effector cells during the course of the infection.

Animals↗
PubMed1997

Interaction of lymphocytes with Kupffer cells from halothane-exposed guinea pigs.

BACKGROUND: The purpose of this study was to investigate lymphocyte adhesion to Kupffer cells as a component of an immune-mediated mechanism for halothane hepatitis. METHODS: Kupffer cells were isolated from guinea pigs exposed to 1.0% halothane/40% oxygen and cultured with various synthetic antigens (trifluoroacetyl-protein adducts or hepatocyte homogenate from halothane-exposed animals). Latex beads were also added to Kupffer cell cultures to determine if activation of these macrophages would result in an increased cellular adhesion. Lymphocytes which had been surfaced-labeled with biotin were added to treated Kupffer cells, and lymphocyte adhesion was determined using a streptavidin-peroxidase reagent for colorimetric detection. RESULTS: Trifluoroacetyl-lysine, trifluoroacetyl-rabbit albumin or guinea pig albumin did not induce lymphocyte adhesion. Latex beads also had no effect on cellular adhesion. A noticeable increase in lymphocyte adhesion to Kupffer cells previously treated with either trifluoroacetyl-guinea pig albumin or hepatocyte homogenate was observed. Stimulation of lymphocytes with phorbol myristate acetate did not have an effect on adhesion. Addition ofantimajor histocompatibility complex II antibody had a significant inhibitory effect on lymphocyte adhesion to Kupffer cells treated with trifluoroacetyl-guinea pig albumin or homogenate. CONCLUSION: These results demonstrate that the halothane trifluoroacetyl-guinea pig albumin antigen and hepatocyte homogenate enhances the adhesion of lymphocytes to cultured Kupffer cells and that this interaction involves major histocompatibility complex II expression on stimulated Kupffer cells. The interaction between Kupffer cells which present specific trifluoroacetyl-antigens and lymphocytes from halothane-exposed animals may play an important role in the pathogenesis of halothane hepatitis.

Anesthetics, Inhalation↗
PubMed2002

Mice display sex differences in halothane-induced polymorphic ventricular tachycardia.

BACKGROUND: Molecularly engineered mice are extensively used as models of cardiovascular diseases, yet little is known about sex differences in the electrophysiology of mouse hearts. METHODS AND RESULTS: This study investigated the influence of sex on drug-induced polymorphic ventricular tachycardia (PVT) in Langendorff-perfused male and female mice hearts (n=54) by injecting a bolus of halothane (1.75 mmol/L) in the perfusate while recording ECGs or optical action potentials (APs). There were no statistically significant differences between male and female hearts (n=54) with respect to mean RR (193+/-5 ms), PR (47+/-1 ms), QT intervals (101+/-3 ms), optical AP durations (APD(75)=23.11+/-4.2 ms), dispersion of refractory periods, and conduction velocities (n=5 male and 5 female). Halothane induced PVTs lasting a mean duration of 90 seconds; in female hearts, 55% of PVTs lasted longer than the median, whereas in male hearts 17% exceeded the mean (P<0.05). The total duration of PVTs exposed a marked sex difference, 378+/-144 seconds in female versus 27+/-10 seconds in male hearts (P<0.05). In optically mapped male hearts, halothane reduced APD(75) (17.61+/-1.6 ms) and then elicited VTs (n=6 of 6), but in female hearts, halothane elicited PVTs (n=1 of 6) or arrested the hearts (n=5 of 6). Except for KCNE1, Northern blots (KCNQ1, MERG, Kv1.5, connexins 40 and 43, TREK1, and TASK1) did not detect sex differences. CONCLUSIONS: This mouse model reveals sex difference in response to a pharmacological challenge yet does not display sex differences in standard electrophysiological parameters. Differences in KCNE1 may contribute to sex differences uncovered by halothane.

Action Potentials↗
PubMed1981

Effects of halothane on protein synthesis and degradation in rabbit pulmonary macrophages.

The effects of exposure to the volatile anesthetic halothane on the synthesis and degradation of rabbit pulmonary macrophage proteins were investigated. Protein synthesis was inhibited rapidly and reversibly when macrophages were exposed to halothane. The magnitude of the inhibition was dependent upon the dose of anesthetic and upon the composition of the medium. The effect of halothane was not associated with increased cell death or with depletion of cellular ATP. Halothane exposure did not affect the ability of the cells to degrade either endogenous proteins or exogenous bovine serum albumin. These results suggested that halothane exposure favored protein catabolism in pulmonary alveolar macrophages though an inhibition of protein synthesis with no change in protein degradation.

Adenosine Triphosphate↗
PubMed2001

The cerebral and systemic kinetics of thiopentone and propofol in halothane anaesthetized sheep.

The cerebral and systemic kinetics of intravenous thiopentone (250 mg over 2 minutes, n=5) and propofol (100 mg over 2 minutes, n=6) were determined in sheep anaesthetized with halothane (2.0%) and mechanically ventilated to an end-expired carbon dioxide tension of 40 mmHg. The sheep were previously instrumented with arterial and sagittal sinus (effluent from the brain) blood sampling catheters. Systemic kinetics were inferred from the time-course of the arterial blood concentrations, and cerebral kinetics from the time-course of the arterio-sagittal sinus concentration difference across the brain. Under halothane anaesthesia, the peak arterial concentrations of each drug occurred at the end of the two-minute infusion, and was 42.3 mg/l and 12.3 mg/l for thiopentone and propofol, respectively. Propofol had a significantly larger systemic clearance (3.19 l/min) than thiopentone (0.99 l/min). The brain concentrations of propofol equilibrated more slowly with the arterial concentrations than those of thiopentone. The extraction ratio across the brain near the end of the infusions (1.5 min) were 0.85 and 0.46 respectively. These data were also compared to analogous previously published data for initially conscious sheep. The systemic kinetics of thiopentone were little affected by halothane anaesthesia. For propofol, halothane anaesthesia was associated with a statistically significant reduction in clearance (50% of awake), a slower initial half-life (247% of awake), and the emergence of a second slower half-life in some sheep. The cerebral kinetics of both drugs were subtly altered by halothane anaesthesia.

Anesthesia, Inhalation↗
PubMed1979

Hepatotoxicity and halothane metabolism in an animal model with application for human toxicity.

Centrilobular necrosis and a ten-fold elevation in serum alanine amino-transferase (ALT) consistently followed 2 hours of 1% halothane anaesthesia in an animal model. Conditional factors were the presence of enzyme induction and moderate hypoxia (14% oxygen), indicating an association between reductive metabolism and hepatotoxicity. Under these conditions there was at least a four-fold increase in reductive metabolites detected in the exhaled air. In clinical studies, reductive metabolites were also detected in the exhaled air of all patients examined, even after halothane anaesthesia with 100% oxygen. The amounts of reductive metabolites were comparable in man and the model, following equivalent halothane doses. It appears that a model with a similar route and rate of halothane biotransformation to man has been identified. The lesion of halothane hepatotoxicity in this model appears to be similar to that reported in man - centrilobular hepatic necrosis.

Alanine Transaminase↗
PubMed1991

N-Trifluoroacetyl-ethanolamine: a proposed urinary metabolite of halothane: validation and measurement in children.

It has been postulated that trifluoroacetyl chloride, a halothane metabolite, can bind covalently with the phosphatidylethanolamine component of the hepatic cell membrane and cause cell necrosis. Breakdown of the necrotic hepatocyte would release N-trifluoroacetyl-ethanolamine (TFAE) into the serum with subsequent urinary excretion. An original High Performance Liquid Chromatography (HPLC) method for the measurement of TFAE is described. In six children 1% halothane was administered for one hour and the halothane uptake measured. Urinary excretion of TFAE was measured for up to eight days and found to be 0.09 +/- 0.07% or less of the absorbed halothane. In children TFAE is not a major urinary metabolite of halothane.

Anesthesia, Inhalation↗
PubMed1994

Sodium nitroprusside induced hypotension: haemodynamic response and dose requirements during propofol or halothane anaesthesia.

This study was designed to investigate the influence of anaesthesia induced and maintained with propofol on the haemodynamic effects and the dose requirements of SNP during the course of induced hypotension. Twenty-four adult ASA physical status I patients undergoing middle ear surgery were randomly assigned to receive anaesthesia with either morphine, thiopentone, d-tubocurarine, halothane 0.6% end-tidal and N2O 70% in oxygen (group I n = 12), or morphine, propofol, d-tubocurarine, propofol infusion 108 micrograms.kg-1.min-1 and N2O in oxygen (group 2 n = 12). Mean arterial blood pressure (MAP) was reduced to 60-65 mmHg in all patients using a continuous infusion of sodium nitroprusside (SNP) 0.01%. Propofol produced a significant (17%) reduction in the MAP before institution of SNP infusion. This was related to a 24% reduction in the systemic vascular resistance index (SVRI). In the halothane group SVRI was significantly reduced during SNP infusion. Halothane anaesthesia was associated with significant reflex tachycardia in response to SNP induced hypotension. Eight patients in the halothane group (66%) required propranolol 0.5-3 mg to control tachycardia. Propofol anaesthesia attenuated significantly the reflex tachycardia in response to SNP induced hypotension. Two patients in the propofol group (16%) required 0.5 mg propranolol to control reflex tachycardia. The mean SNP dose requirements were 7.25 +/- 1.6 and 2.1 +/- 1.4 micrograms. kg-1.min-1 in the halothane and propofol groups, respectively (P < 0.0001). None of the patients in the two groups developed rebound hypertension following SNP withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2002

Relaxation of proximal and distal isolated human bronchi by halothane, isoflurane and desflurane.

Volatile anaesthetics relax airway smooth muscle in vitro. The amount of relaxation might depend on the type and concentration of volatile anaesthetics, the calibre and precontraction level of the bronchi, and also on the species considered. These effects were investigated on isolated human bronchi. Isometric relaxations produced by halothane, isoflurane and desflurane bubbled on human bronchial rings precontracted with carbachol were recorded and compared with time controls. Volatile anaesthetics induced a concentration-dependent relaxation at 0.66, 1.33 and 2 minimum alveolar concentration (MAC). The relaxation was greater in mildly (carbachol 3x10(-7) M) than in highly (carbachol 2x10(-6) M) precontracted bronchi. Halothane was more potent in relaxing distal as compared to proximal bronchi; this differential effect was less pronounced with isoflurane and not observed with desflurane. While the three volatile anaesthetics induced similar relaxation on proximal bronchi, halothane was significantly more potent than desflurane on distal bronchi, with isoflurane being intermediate. The relaxation induced by 1.33 MAC of halothane, isoflurane and desflurane on moderately precontracted distal bronchi (carbachol 1x10(-6) M) was attenuated by pretreatment with glibenclamide 1x10(-5) M. In conclusion, halothane, isoflurane and desflurane exert direct but differential relaxant effects on human isolated bronchial smooth muscle. This may provide supplemental bronchodilation during anaesthesia. Although adenosine triphosphate-sensitive K+ channels are involved in these relaxant effects, they are unlikely to explain the observed differences between the three volatile anaesthetics.

Anesthetics, Inhalation↗
PubMedDate not supplied

Circulatory responses and halothane concentrations during gastric or gallbladder traction with and without neuromuscular blockade.

Systolic and diastolic blood pressures and heart rates did not change significantly and ventricular dysrhythmias did not occur during gastric or gallbladder traction in patients anesthetized with N2O-halothane, with or without d-tubocurarine or pancuronium neuromuscular blockade. Systolic and diastolic blood pressures and heart rates just before abdominal viscera traction were less (p is less than 0.05) in patients paralyzed with d-tubocurarine than with pancuronium despite similar arterial halothane concentrations. In contrast, these measurements in patients without neuromuscular blockade were similar to those during pancuronium paralysis despite significantly greater arterial halothane concentrations in the unparalyzed patients. The authors conclude that circulatory responses during gastric or gallbladder traction are clinically insignificant during N2O-halothane administration, with or without d-tubocurarine or pancuronium neuromuscular blockade. Intraoperative blood pressures and heart rates were influenced by the neuromuscular blocker chosen. Neuromuscular blockade permitted anesthetic maintenance with lower arterial halothane concentrations than when paralysis was not present.

Abdomen↗
PubMedDate not supplied

Arrhythmic doses of epinephrine and dopamine during halothane, enflurane, methoxyflurane, and fluroxene anesthesia in goats.

The cardiac arrhythmicity of epinephrine and dopamine was compared in awake goats and during approximate equivalent levels of halothane, enflurane, methoxyflurane, and fluroxene anesthesia. The arrhythmic threshold dose for epinephrine and dopamine was significantly (p less than 0.05) reduced during halothane anesthesia when compared to values determined in awake animals. Enflurane anesthesia had no significant affect on the arrhythmic threshold dose for either catecholamine. However, methoxyflurane and fluroxene anesthesia significantly (p less than 0.05) elevated the arrhythmic threshold dose for dopamine. Epinephrine produced greater elevations in mean arterial pressure than dopamine with all anesthetics except enflurane, and dopamine produced significantly (p less than 0.05) higher heart rates in the awake animals and those anesthetized with halothane and enflurane. The authors conclude that, in terms of arrhythmic potential, there is no advantage in the use of dopamine rather than epinephrine for the reversal of halothane-induced myocardial depression during halothane or enflurane anesthesia.

Anesthesia, Inhalation↗
PubMedDate not supplied

Halothane effects on conductivity of the AV node and His-Purkinje system in the dog.

His-bundle electrocardiography was used to evaluate the effect of halothane on AV nodal and His-Purkinje system conduction times in the spontaneously beating dog heart. During artrial pacing at basic heart rates of 120 or 200 beats per minute (bpm), an extrastimulus (cycle length longer or shorter than that of the basic rate) was delivered to test the effect of halothane on several parameters of AV nodal conductivity. Included were the functional refractory period, basal conduction time, and fatigue effect (prolongation of basal conduction time as heart rate was increased from 120 to 200 bpm). Increasing MAC level of halothane (1.25 to 2.75 MAC) prolonged both AV node and His-Purkinje conduction times, yet had little effect on the parameters of nodal conductivity tested for. These effects of halothane could be potentially dangerous in the clinical setting for patients with defective AV conduction. In addition, changes in conduction may be in part responsible for arrhythmias seen during halothane anesthesia.

Anesthesia↗
PubMedDate not supplied

Physostigmine and anesthetic requirement for halothane in dogs.

To investigate the effect of physostigmine on central nervous system (CNS) depression produced by halothane, control halothan minimum alveolar concentration (MAC) measured over 1 hour in 7 dogs was compared to MAC 30 minutes after each sequential IV dose of 0.04, 0.4, and 4 mg/kg physostigmine. MAC decreased 6.8, 11.1 (p less than 0.05), and 35.9 (p less than 0.01) percent, respectively. Six dogs were observed for an acute increase in halothane requirement in the first 30 minutes after administration of physostigmine. All 6 showed such a response at 1 or more dose levels, beginning within 1 to 5 minutes after administration and lasting 2 to 30 minutes (p less than 0.05). Five other dogs were tested with neostigmine in the same doses and showed respective decreases in MAC of 7.9, 16.6 (p less than 0.01), and 17.5 ( less than 0.01) percent. No dog showed an acute increase in anesthetic requirement. Intravenous atropine 0.5 mg/kg failed to further alter MAC after 4 mg/kg neostigmine. Physostigmine transiently antagonizes halothane anesthesia, presumably by facilitating cholinergic transmission in the CNS; neostigmine does not. After this initial response, both drugs decrease anesthetic requirement. If these data may be extrapolated to patients, they suggest that physostigmine is not an effective antagonist to postoperative somnolence due to halothane.

Animals↗