Toxicity and Biotransformation of Volatile Halogenated Anesthetics in Rat Hepatocyte Suspensions

ABSTRACT

This study, examines the toxicity (as measured by reduced intracellular K⁺ and metabolism (defluorination) of halothane and enflurane in rat hepatocytes in suspension (RHS) with regards to O₂ tension, time, and concentration. In 95% O₂ halothane is more toxic than enflurane when RHS are exposed to 5-20 μ1 of these anesthetics. At these levels halothane is not metabolized while enflurane is metabolized. At 21% O₂ a similar pattern was seen with regards to toxicity. However, metabolism of halothane rapidly reached an elevated level while that of enflurane is reduced when compared to 95% O₂. Thus toxicity of halothane and enflurane at these dose levels appears to be unrelated to metabolism and due solely to a solvent effect.     

Comparative metabolic effects of halothane and enflurane in rat heart cell culture

The effects of halothane and enflurane on the oxygen consumption rates and substrate utilization by beating and nonbeating rat heart myocytes in cell culture were compared. Halothane, on an equal dose and equal MAC (minimum alveolar concentration producing immobilization of 50% of subjects) basis, was significantly more effective than enflurane in reducing total myocyte oxygen consumption and contractile rate. The greater effect of halothane on oxygen consumption was not due entirely to its effect on myocyte contractile rate, since quiescent (nonbeating) cells and cells rendered nonbeating by large doses of halothane also showed greater reductions in oxygen consumption than with large doses of enflurane. Both halothane and enflurane reduced glucose and palmitic acid metabolism by myocytes when compared with controls. However, there were no significant differences between halothane or enflurane with regard to glucose metabolism. Halothane was significantly more effective than enflurane in reducing cellular palmitic acid metabolism. Although palmitic acid uptake by myocytes was reduced to the same extent by both anesthetics when compared with control uptake values, halothane reduced myocyte uptake of glucose to a greater degree than enflurane. The results of this study indicate that halothane is a more potent myocardial metabolic depressant than enflurane.     

Acute interaction of halothane and enflurane with the metabolism of ethanol in isolated hepatocytes and liver cytosol preparations from the rat

The effects of halothane and enflurane on ethanol (40 mM) oxidation were studied in isolated rat hepatocytes. Anaesthetic (halothane, enflurane and diethyl ether) effect on the activity of alcohol dehydrogenase (ADH) was studied in incubations of cytosol preparations from rat liver. Mean rates of ethanol metabolism ranged from 0.44 to 0.49 mumol ethanol metabolized/mg cell protein/hour in control hepatocytes from fasted and fed animals. These rates were enhanced by 2- and 3-fold in hepatocytes from fed and fasted animals, respectively, when pyruvate (5 mM) was added. Halothane and enflurane both caused dose dependent inhibition of ethanol metabolism (15-40%) in all hepatocytes without exogenous addition of pyruvate. The inhibitory effect was present also after pyruvate stimulation in hepatocytes from fasted animals, but disappeared in hepatocytes from fed animals when pyruvate was added. The rate of ethanol oxidation by cells from fed rats was enhanced by approximately 40% when the concentration of ethanol was increased from 20 mM to 80 mM. The anaesthetic inhibition of ethanol metabolism was about 20% more pronounced at the higher ethanol concentration compared to the lower concentration when no pyruvate was added. In the presence of pyruvate the effect of anaesthetics was again reversed regardless of ethanol concentration. Halothane (2 mM) and enflurane (2 mM) both caused about 25% inhibition of the ADH-activity in cytosol preparations while ether (30 mM) caused more than 50% inhibition. No inhibition of hepatocyte uptake of ethanol was caused by any of the three anaesthetics.(ABSTRACT TRUNCATED AT 250 WORDS)     

The release of inorganic fluoride from halothane and halothane metabolites by cytochrome P-450, hemin, and hemoglobin

Halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) releases inorganic fluoride when incubated anaerobically with rat hepatic microsomes reduced with either NADPH or sodium dithionite. Boiled microsomes (cytochrome P-420), hemoglobin, and hemin, each reduced with sodium dithionite, also catalyze the release of inorganic fluoride from halothane, suggesting that the protein portion of cytochrome P-450 is not required for reductive halothane defluorination. 2-Chloro-1,1-difluoroethylene and its bromo analog 2-bromo-1,1-difluoroethylene undergo metabolism in NADPH-reduced microsomes with optimal release of fluoride occurring under air compared to an atmosphere of nitrogen. Neither 2-chloro-1,1,1-trifluoroethane nor 2-bromo-1,1,1-trifluoroethane liberate fluoride in microsomes under air or nitrogen. 2-Chloro-1,1-difluoroethylene and 2-bromo-1,1-difluoroethylene are metabolized predominantly by oxidative cytochrome P-450 metabolism, while reductive pathways utilizing reduced cytochrome P-450, hemoglobin, or hemin liberate fluoride from halothane.     

Glutathione and glutathione S-transferases in rat liver after inhalation of halothane and enflurane

Male Sprague-Dawley rats were exposed in inhalation chambers to halothane and enflurane in concentrations from 50 ppm-1000 ppm (0.0025-0.05 minimum alveolar concentration; MAC) 6 h a day for 3-9 days. Repeated subanaesthetic concentrations were used to avoid effects of general anaesthesia and to increase the metabolized fraction of the inhaled anaesthetics. Exposure to 0.05 MAC of halothane (500 ppm) and enflurane (1000 ppm) for 9 days reduced the activity of glutathione S-transferases. A decrease in liver concentration of reduced glutathione (GSH) was observed after inhalation of enflurane, probably caused by metabolic release of inorganic fluoride. The results indicate a decreased detoxifying capacity of rat liver under the given conditions. Inhalation of occupational related concentrations of the anaesthetics (50 ppm) did neither affect the activity of the transferases nor the concentration of GSH in rat liver.     

Clinical pharmacokinetics of the inhalational anaesthetics

At present, the most widely used inhalational anaesthetics are the halogenated, inflammable vapours halothane, enflurane, isoflurane and the gas nitrous oxide. The anaesthetic effect of these agents is related to their tension or partial pressure in the brain, represented at equilibrium by the alveolar concentration. The minimum alveolar concentration for a specific agent is remarkably constant between individuals. The uptake and distribution of inhalational anaesthetics depends on inhaled concentration, pulmonary ventilation, solubility in blood, cardiac output and tissue uptake. Inhalational anaesthetics are mainly eliminated by pulmonary exhalation, but significant amounts of halothane are removed by hepatic metabolism. Inhalational agents currently in use have acceptable pharmacokinetic characteristics, and clinical acceptance depends on their potential for adverse effects. Induction of anaesthesia with halothane is rapid and relatively pleasant and it is the agent of choice for paediatric anaesthesia. Between 20 and 50% is metabolised, and the parent drug is a potent inhibitor of drug metabolism. Post-operatively enzyme induction may follow. The major disadvantages of halothane are myocardial depression, propensity to evoke cardiac arrhythmias and the rare but serious halothane hepatitis. Induction and recovery from enflurane anaesthesia is rapid. Metabolism accounts for 5 to 9% of the elimination. The metabolic product inorganic fluoride may in rare cases cause renal toxicity. Enflurane is a weak inhibitor of drug metabolism at anaesthetic concentrations. Enflurane depresses circulation more than halothane by reducing both myocardial contractility and systemic vascular resistance, but cardiac rhythm is stable. Enflurane anaesthesia may, unlike the other agents, induce epileptic activity. Enflurane is widely used as replacement for halothane in adults. Despite its low blood-gas solubility, the airway irritability of isoflurane precludes a faster induction of anaesthesia than with halothane. Isoflurane is almost resistant to biodegradation. Myocardial contractility is maintained during isoflurane anaesthesia and cardiac rhythm is stable except for the occurrence of tachycardia in some patients. Isoflurane is the inhalational agent of choice for neurosurgical operations. Sevoflurane is an experimental ether vapour: induction and recovery is fast and pleasant. It is metabolised to the same extent as enflurane and subnephrotoxic concentrations of inorganic fluoride may result. Sevoflurane has fewer respiratory and cardiovascular depressant effects than halothane and may be a future alternative for paediatric anaesthesia.(ABSTRACT TRUNCATED AT 400 WORDS)     

Potential metabolic basis for enflurane hepatitis and the apparent cross-sensitization between enflurane and halothane

Clinical case reports of unexplained hepatic dysfunction following enflurane and isoflurane anesthesia led to the hypothesis that oxidative metabolism of these drugs by cytochromes P-450 produces immunoreactive, covalently bound acylated protein adducts similar to those implicated in the genesis of halothane-induced hepatic necrosis. Microsomal adducts were detected by enzyme-linked immunosorbent assay and immunoblotting techniques utilizing specific anti-trifluoroacetyl (TFA) IgG hapten antibodies in rat liver following enflurane, isoflurane, or halothane administration. Preincubation of the antibodies with microsomes from halothane-pretreated rats or with 500 microM TFA-lysine, markedly inhibited adduct recognition, while preincubation with 500 microM acetyllysine had no effect. The relative amounts of immunoreactive protein adducts formed were halothane much greater than enflurane much greater than isoflurane and correlates directly with the relative extents of metabolism of these agents. These results support the view that acyl metabolites of the volatile anesthetics may become covalently bound to hepatic proteins, thus serving as antigens, and thereby account for the apparent cross-sensitization and idiosyncratic hepatotoxicity reported for these drugs.     

Effects of inhalation anesthetics on airway dynamics determined by phasor analysis of respiratory impedance using the forced oscillation method

By expressing the respiratory system as a two-compartment model and assigning a phasor in the complex plane to each impedance element in the model, the phasor of the respiratory impedance could be constructed graphically, the frequency characteristics determined from the locus of the latter and the effects of variations in the model elements on the frequency characteristics could also be expressed as the locus of the latter. Conversely, it is possible to detect small changes in mechanical properties on the respiratory system by plotting its frequency characteristics on the complex plane. We studied the effects of typical inhalation anesthetics, halothane, enflurane and isoflurane, on the airway dynamics by this method. The inhalation concentration of 1 MAC of halothane and/or enflurane was found to produce bronchodilation associated with a significant reduction in airway resistance, but isoflurane had no such effects. As the magnitude of changes in the real part at 1 Hz, the estimated airway resistance was -2.1 cmH2O/1/s (-25% of the mean value) for halothane, and -0.8 cmH2O/1/s (-11%) for enflurane.     

Porcine brain and myocardial perfusion during enflurane anesthesia without and with nitrous oxide

Brain and myocardial blood flow (MBF) were examined in 10 previously instrumented swine during isocapnic conditions using 15 micron in diameter radionuclide-labeled microspheres that were injected into the left atrium. Minimum alveolar concentration (MAC) of enflurane required to prevent 50% of the pigs from responding by gross purposeful movement to a noxious stimulus was 1.66%. In pigs, 50% nitrous oxide decreased enflurane requirement for 1.0 MAC anesthesia by 0.82%. Each animal was studied during the following conditions: (a) unanesthetized (control); (b) 1.0 MAC enflurane anesthesia (1.66% end-tidal concentration); (c) 1.5 MAC (2.49%) enflurane anesthesia; (d) the equivalent of 1.0 and 1.5 MAC anesthesia produced by enflurane (0.84 and 1.67%) plus 50% nitrous oxide. Cerebral and total brain blood flow values were the same as control values during both levels of enflurane anesthesia. However, blood flow in the brainstem and cerebellum exhibited a dose-related increase; the increment of 28% for each of these regions at 1.5 MAC achieved statistical significance. Vascular resistance in all regions of the brain decreased with enflurane anesthesia. Substitution of 50% nitrous oxide for enflurane to maintain the same level of anesthesia markedly increased cerebral blood flow. At 1.0 and 1.5 MAC anesthesia produced using enflurane plus 50% nitrous oxide, cerebral blood flow was 151 and 183% of the control value, respectively. During enflurane plus nitrous oxide anesthesia equivalent to 1.5 MAC, cerebellar and brain stem blood flow were 135 and 180% of respective control values. MBF in all regions decreased in a dose-related manner with enflurane anesthesia. At 1.5 MAC enflurane, perfusion values in the walls of the left and the right ventricles were 52 and 59% of respective control values. During both levels of enflurane plus 50% nitrous oxide anesthesia, transmural MBF in all regions remained close to awake values. Subendocardial/subepicardial perfusion ration in both ventricles exceeded 1.00 during all steps of the protocol, thereby suggesting that subendocardial O2 delivery kept pace with O2 demand. These experiments have demonstrated that usage of 50% N2O with enflurane to produce equipotent anesthesia resulted in a dramatic increase in cerebral blood flow while MBF remained near awake value.     

Influence of (+)-Catechin and Dithiocarb on the Pharmacokinetics of Phenprocoumon, Tolbutamide and Three Inhalation Anesthetics in rats

Pretreatment with (+)-catechin ((+)-cyanidanol-3, Catergen) (200 mg/kg p.o.) did not alter the elimination of intravenously injected phenprocoumon (0.6 mg/kg) or tolbutamide (100 mg/kg) in rats, while dithiocarb (Sodium diethyl-dithiocarbamate) (200 mg/kg p.o.) prolonged only the elimination half-life of phenprocoumon to a small extent. The metabolism of halothane (100 ppm), enflurane (100 ppm) or methoxyflurane (300 ppm) was studied by measuring the disappearance of the compounds from the atmosphere of a closed exposure system. Pretreatment with (+)-catechin did not impair the metabolic removal of all three anesthetics; in the case of enflurane (+)-catechin caused a small, but significant shortening of the elimination half-life, for enflurane and methoxyflurane the uptake of the compounds into the rats seemed to be impaired under the influence of (+)-catechin. Dithiocarb strongly impaired the in vivo metabolism of halothane and methoxyflurane, whereas that of enflurane remained unaffected.     

Liver function following hypovolemic hypotension in rats anaesthetized with halothane or enflurane

Rats which had approximately 25-30% of their calculated blood volume removed were exposed to halothane (1%) or enflurane (2%) in 33% oxygen for 30 min. Hepatic function was evaluated by determining, at various time intervals, serum activities of glutamic-oxalacetic and glutamic-pyruvic transaminase, acid phosphatase and gamma-glutamyl-transpeptidase. In this model serum enzyme activities and animal mortality were significantly increased when hypovolemic hypotension was induced during halothane anaesthesia. The same events did not occur in bleeding animals anaesthetized with enflurane. The marked disparity in hepatic dysfunction and mortality between halothane and enflurane-anaesthetized rats during hypovolemic hypotension may be explained by the more pronounced decrease of oxygen available for the liver and production of reductive toxic intermediates in animals exposed to halothane.     

Acute effects of halothane and enflurane on drug metabolism and protein synthesis in isolated rat hepatocytes

The metabolism of sulphanilamide, antipyrine and paracetamol was studied in the absence and presence of the anaesthetics halothane and enflurane at three different concentrations (0.5, 1.0 and 2.0 mM) in isolated hepatocytes from the rat. Cell viability and protein synthesis were monitored to evaluate toxic effects. A strong concentration related inhibition of antipyrine oxidation (40-70%) and paracetamol conjugation (20-40%) was caused by both halothane and enflurane. Acetylation of sulphanilamide was not inhibited, however, as a slight augmentation was noticed. A significant dose related decrease of cell viability (3-13%) was caused by both anaesthetics. Dose dependent inhibition of the synthesis of stationary cell proteins (15-60%) and the synthesis/secretion of medium proteins (35-85%) was caused by halothane. Similar but slightly less pronounced effects were caused by enflurane. The present findings show that volatile anaesthetics may have general effects as well as different degrees of specific effects on both membrane bound enzyme and soluble enzyme activities.     

Effect of inhalation anesthetics on antipyrine pharmacokinetics of mice

The effects of the volatile anesthetics, enflurane, isoflurane and halothane, on the pharmacokinetics of antipyrine were examined in mice. The administration of 0.75% isoflurane or 1.0% enflurane in air resulted in a 173 and a 206% increase, respectively, in antipyrine plasma half-life and a 29.1 and a 41.2% decrease in antipyrine total body clearance. There was also an almost 2-fold increase in the volume of distribution of antipyrine. Halothane, at 0.5% in air, had no significant effect upon antipyrine plasma half-life or its volume of distribution. There was no significant change in antipyrine total body clearance and volume of distribution 4 hr after exposure to the volatile agents, but there was a small increase in half-life. The exposures to the volatile anesthetics were also carried out in an atmosphere of 8% oxygen. Antipyrine plasma half-life was increased significantly by 48% in mice breathing 8% oxygen, compared to mice breathing air. Isoflurane in 8% oxygen increased the plasma half-life of antipyrine by 296% compared to mice breathing 8% oxygen. This increase was greater than the effect of isoflurane seen in mice breathing air. Mice breathing halothane in 8% oxygen exhibited a 21% increase in antipyrine plasma half-life and mice breathing enflurane in 8% oxygen, a 117% increase in antipyrine plasma half-life, although the changes were not markedly different from those seen in mice breathing air. Enflurane and isoflurane produced a significant increase in the volume of distribution for antipyrine in the mice breathing 8% oxygen. Total body clearance of antipyrine was decreased markedly in mice breathing isoflurane and enflurane but showed a lesser decrease in mice breathing halothane in 8% oxygen. In vitro in mouse microsomes, halothane, enflurane and isoflurane were all inhibitors of aminopyrine metabolism. Possible mechanisms for these results are discussed.     

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.). It was found that the hyperthyroid state, which is associated with a substantial increase in sensitivity to the hepatotoxic effects of halothane, decreases both oxidative and reductive routes of halothane metabolism in the rat. The production of trifluoroacetic acid (TFA), an oxidative metabolite, as well as that of chlorodifluoroethylene (CDF) and chlorotrifluoroethane (CTF), 2 reductive metabolites, was significantly reduced in hyperthyroid animals. Consistent with these findings serum and urinary bromide levels resulting from the formation of TFA, CDF or CTF were significantly reduced. The only route of halothane metabolism significantly increased by the hyperthyroid condition was the defluorination of halothane. Piperonyl butoxide administration did not render euthyroid animals sensitive to the halothane-induced hepatotoxicity and had no effect on the defluorination of halothane in euthyroid animals. However, piperonyl butoxide markedly increased the hepatotoxicity of halothane in hyperthyroid rats and, except for a modest increase in debromination reactions, decreased all measured indices of halothane metabolism including the defluorination of halothane. Thus, none of the observed changes in halothane metabolism produced by triiodothyronine or piperonyl butoxide treatment could be consistently correlated to the increases in hepatotoxicity linked to these 2 treatments. Based on these studies we suggest that the halothane hepatotoxicity induced in the hyperthyroid rat results from effects produced by either the parent compound or an as yet unidentified metabolite. In addition, these studies further demonstrate that considerable mechanistic differences exist for halothane-induced hepatotoxicity when comparing euthyroid and hyperthyroid animal models.     

Biotransformation of halothane in guinea pig liver slices

The biotransformation of halothane was studied using liver slices. Precision-cut Hartley male guinea pig liver slices (1 cm diameter; 250-300 microns thick) were incubated in sealed roller vials containing supplemented Krebs-Henseleit buffer at 37 degrees C under different O2 tensions (2.5, 21, and 95%). After a 1-hr preincubation, halothane was vaporized in the vial producing a 1.9 mM medium concentration. Halothane metabolites (Br-, trifluoroacetic acid, F-) were measured at 2, 4, and 6 hr. Viability of the incubated slices was verified by determining intracellular K+ content and levels of cytochrome P-450, which were maintained under 95% O2 atmosphere but decreased with lower O2 tensions (2.5%). The highest fluoride production was 300 +/- 22 pmol/mg slice weight/6 hr at low O2 tension (2.5%). Defluorination decreased with increasing O2 tension to undetectable levels under 95% O2. Production of the oxidative metabolite, trifluoroacetic acid, was highest at 95% O2 (2.35 +/- 0.17 nmol/mg slice weight/6 hr). Trifluoroacetic acid production decreased with decreasing O2 tension. Br- production was the highest at 21% O2 (1.8 +/- 0.13 nmol/mg slice weight/6 hr). Production of Br- was not dependent on the O2 tension. The guinea pig slices are capable of biotransforming halothane (oxidative/reductive); therefore, this in vitro system appears suitable for studying the biotransformation of halothane.     

Population toxicokinetics of tetrachloroethylene

 In assessing the distribution and metabolism of toxic compounds in the body, measurements are not always feasible for ethical or technical reasons. Computer modeling offers a reasonable alternative, but the variability and complexity of biological systems pose unique challenges in model building and adjustment. Recent tools from population pharmacokinetics, Bayesian statistical inference, and physiological modeling can be brought together to solve these problems. As an example, we modeled the distribution and metabolism of tetrachloroethylene (PERC) in humans. We derive statistical distributions for the parameters of a physiological model of PERC, on the basis of data from Monster et al. (1979). The model adequately fits both prior physiological information and experimental data. An estimate of the relationship between PERC exposure and fraction metabolized is obtained. Our median population estimate for the fraction of inhaled tetrachloroethylene that is metabolized, at exposure levels exceeding current occupational standards, is 1.5% [95% confidence interval (0.52%, 4.1%)]. At levels approaching ambient inhalation exposure (0.001 ppm), the median estimate of the fraction metabolized is much higher, at 36% [95% confidence interval (15%, 58%)]. This disproportionality should be taken into account when deriving safe exposure limits for tetrachloroethylene and deserves to be verified by further experiments. Received: 20 April 1995/Accepted: 24 August 1995     

Inhalation of enflurane and halothane at subanesthetic concentrations and effects on circulating serum testosterone, luteinizing hormone and follicle-stimulating hormone in the male rat

The present study was carried out in order to investigate the effects of inhaled volatile anesthetic gases in subanesthetic concentrations on circulating hormones essential for normal male reproduction. Male mature rats were exposed daily, up to 11 days, to halothane or enflurane in concentrations up to 500 and 1000 ppm, respectively, and thereafter examined for changes in the serum concentration of circulating testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). No significant changes were found for any of the investigated hormones. Based on our results and other reports it is suggested that short-term repeated exposure to halothane and enflurane at subanesthetic concentrations is not associated with any appreciable acute toxicity on male reproductive functions.     

Use of heart cell cultures as a tool for the evaluation of halothane arrhythmia

The effects of various combinations of epinephrine-halothane and epinephrine-enflurane were tested on beating myocardial muscle cells cultured from 2- to 3-day-old rats. A series of culture plates containing myocytes were exposed to 0.5, 1.0, 1.5, and 2% halothane. At each halothane concentration, 9 ng of epinephrine was added, and the rate of contraction and rhythm of myocytes were observed. With increasing halothane concentrations, a significant and progressive increase in the percentage of plates demonstrating arrhythmia was observed. In a separate series of experiments, doses of epinephrine were added following exposure to 1.5% halothane. As the dose of epinephrine was increased progressively more plates displayed arrhythmia. In addition, culture plates were exposed to enflurane (3 and 6%), and epinephrine was added to each plate. No arrhythmia was observed in any of the 3% enflurane exposed plates. However at 6%, 100% of the plates displayed arrhythmia. In another series of experiments the efficaciousness of quinidine, procaine amide, lidocaine, propranolol, and verapamil in converting cell culture arrhythmia to normal rhythm following epinephrine and halothane was tested. Quinidine converted 96% of all arrhythmic plates to normal rhythm, procaine amide 80%, lidocaine 50%, and propranolol 10%. Verapamil failed to convert any arrhythmic plates to normal rhythm. It was concluded from this study that halothane directly “sensitizes” heart cells in tissue culture, and that the “sensitization” process is a linear, dose-dependent phenomenon.     

Practical treatment recommendations for the safe use of anaesthetics.

General anaesthesia is the reversible depression of central nervous system function. There is still no agreement over what constitutes depth of anaesthesia, and the clinical anaesthetist must thus titrate drug input according to clinical signs (heart rate, blood pressure, somatic movement, autonomic responses). The potency of inhalational agents may be expressed in terms of the MAC (minimum alveolar concentration); comparable end-points (including blood concentrations) have been proposed for the intravenous agents. Kinetic infusion regimens can be constructed for the intravenous agents to achieve the ED95 concentrations required to provide clinically adequate anaesthesia. However, because of individual differences in drug kinetics and dynamics, as well as the influences of disease states and intercurrent therapy, the clinician will titrate the dose according to response. Administration of volatile or intravenous anaesthetics by fixed regimens may result in either overdosage or the risk of patient awareness. The choice of anaesthetic drug is usually based on the nonhypnotic side effects of the different agents--including their central and regional cardiovascular effects, the speed and completeness of recovery, and the need to provide intraoperative analgesia. In addition, special techniques and drugs are often needed for neurosurgical, cardiothoracic and obstetric anaesthesia. All anaesthetic agents (inhalation and intravenous) have other side effects (such as cardiorespiratory depression and organ toxicity related to the liver or kidney). Both halothane and enflurane may be responsible for postoperative hepatic dysfunction, while the metabolism of enflurane can also result in nephrotoxicity in patients with pre-existing renal dysfunction. Isoflurane has been reported to cause 'coronary steal' in patients with ischaemic heart disease through its coronary vasodilator properties.(ABSTRACT TRUNCATED AT 250 WORDS)     

Respiratory and cardiovascular effects of halothane, isoflurane and enflurane delivered via a Jackson-Rees breathing system in temperature controlled and uncontrolled rats

We studied the respiratory and cardiovascular effects of 1.25 MAC halothane, isoflurane and enflurane in oxygen delivered via the Jackson-Rees breathing system in 10 rats. Mean arterial pressure, heart rate and respiratory rate were depressed significantly (P less than 0.05) in rats (n = 5) whose body temperature was not controlled after 2 hr of anesthesia regardless of the inhalational agent. Respiratory and metabolic acidosis developed. The respiratory and cardiovascular depression was most marked under enflurane anesthesia. In normothermic rats (n = 5) the initial cardiovascular depression stabilized after 30 min of halothane and isoflurane anesthesia. Moderate respiratory depression developed (PCO2 48.42 +/- 2.48 torr with halothane vs. 41.02 +/- 1.68 torr with isoflurane). Because the cardiovascular and respiratory changes caused by halothane and isoflurane were far less than changes produced by enflurane, halothane or isoflurane is preferable to enflurane for maintaining anesthesia in rats. Maintenance of constant temperature minimizes the cardiovascular and respiratory disturbances.