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Summary A major question often asked about sevoflurane is why, if it meets all the needs of the practitioner, was it not introduced earlier? After all, the drug has been around since 1975. Most of the reasons sevoflurane has been somewhat of a ‘late bloomer’ have been due to hesitations on the part of the drug manufacturers. This has been discussed in a recent editorial ( Brown and Frink, 1992 ). The authors feel that sevoflurane is a useful drug which may have certain advantages over currently available halogenated anaesthetics. Some of the advantages of sevoflurane are listed. 1. Cardiovascular. There is reason to believe that in clinical practice sevoflurane may cause less cardiovascular depression than other drugs. These clinical impressions are subtle, but seem inevitable after clinical familiarity with the drug is obtained. It does not appear to produce tachycardia in humans. Certainly, sevoflurane is less arrhythmogenic than other inhalation anaesthetics in use. The anaesthetic is very ‘user friendly’. 2. Induction and awakening time are remarkably short and smooth. 3. Paediatric inhalation induction is unparalleled with other anaesthetics, including halothane. Certainly sevoflurane may be a ‘niche’ drug for such use, to answer a question poised in the introduction of this chapter. 4. The potential toxicity for interaction of sevoflurane and CO 2 absorbents is probably more theoretical than real. This is an area, however, where more investigation, both clinical and laboratory, is needed. In summary, sevoflurane at the present time seems to offer many advantages over currently available drugs. Its place in practice will be determined by experience in clinical practice.

BACKGROUND Sevoflurane, a new inhalational anesthetic, is biotransformed, producing peak plasma inorganic fluoride concentrations that may exceed 50 microM. We evaluated plasma inorganic fluoride concentrations with prolonged (> 9 MAC-h) sevoflurane or enflurane anesthesia in volunteers and compared renal concentrating function with desmopressin testing 1 and 5 days after anesthesia. METHODS Fourteen healthy male volunteers received either enflurane or sevoflurane (1-1.2 MAC) for more than 9 MAC-h. Each volunteer was administered three tests of renal concentrating function, with intranasal desmopressin and urine collections performed 1 week before anesthesia and 1 and 5 days after anesthesia. Venous blood samples were obtained for plasma fluoride concentrations during and after anesthesia. Creatinine clearance was determined by 24-h urine collections 7 days before and 4 days after anesthesia. Urine samples were obtained before and 1, 2, and 5 days after anesthesia for determination of n-acetyl-beta-glucosaminidase and creatinine concentrations. RESULTS Prolonged sevoflurane anesthesia (9.5 MAC-h) did not impair renal concentrating function on day 1 or 5 postanesthesia, as determined by desmopressin testing. Maximal urinary osmolality on day 1 postanesthesia was decreased (< 800 mOsm/kg) in two of seven enflurane-anesthetized volunteers; however, mean results did not differ from the those of the sevoflurane group. Mean peak plasma fluoride ion concentrations were 23 +/- 1 microM 6 h postanesthesia for enflurane and 47 +/- 3 microM at the end of anesthesia for sevoflurane (P < 0.01). There were no changes in creatinine clearance or urinary n-acetyl-beta-glucosaminidase concentration in either anesthetic group. DISCUSSION Prolonged sevoflurane anesthesia did not impair renal concentrating function, as evaluated with desmopressin testing 1 and 5 days postanesthesia in healthy volunteers. Although with prolonged enflurane anesthesia, mean maximal osmolality values on day 1 postanesthesia did not differ from sevoflurane values, there was evidence in two volunteers at this time point of impairment in renal concentrating function, which normalized 5 days postanesthesia. These results occurred despite a higher peak plasma fluoride ion concentration and greater total inorganic fluoride renal exposure with sevoflurane anesthesia.

Study Objectives: To evaluate the decomposition of sevoflurane in soda lime during prolonged sevof lurane anesthesia in humans. To evaluate for evidence of renal or hepatotoxicity as a result of exposure to these sevoflurane degradation compounds. Design: Prospective evaluation in healthy volunteers. Setting: Clinical research unit and postanesthesia care unit of a university hospital. Patients: Six healthy male volunteers. Interventions: Subjects were anesthetized with sevoflurane 1 to 1.2 minimum alveolar concentration for greater than 9 hours with a semiclosed circuit anesthetic technique (5-liter total flow) with fresh soda lime as the absorbent. Measurements and Main Results: Laboratory tests of renal and hepatic function were performed before anesthesia and 1 and 5 days after anesthesia. During sevoflurane anesthesia, inhalation and exhalation circuit limb gas samples were obtained for degradation compound analysis. Only one degradation product, fluoromethyl-2,2-difluoro-l-(trifluoromethyl) vinyl ether (compound A), was detected. Inhalation concentration was maximal (7.6 ± 1.0 ppm) at 2 hours and did not increase further after this time point. There were no differences in preanesthesia and postanesthesia tests of hepatic and renal function. Conclusions: Levels of the degradation compound (compound A) produced in semiclosed circuit sevoflurane anesthesia with soda lime are well below potential toxic levels and thus appear safe. When sevoflurane is administered under these conditions for prolonged anesthesia, concentrations of compound A do not continue to increase throughout anesthesia.

Administration of several of the inhaled anesthetics result in plasma inorganic fluoride concentrations that are higher in obese compared to nonobese patients. Sevoflurane, a new inhaled anesthetic, is metabolized to inorganic fluoride; however, plasma inorganic fluoride levels with sevoflurane anesthesia in obese subjects have not been evaluated. We studied plasma inorganic fluoride concentrations during and after sevoflurane surgical anesthesia in morbidly obese (n = 13, body mass index > 35) and nonobese (n = 10) patients. Sevoflurane anesthesia in 60% nitrous oxide/40% oxygen was administered with a semiclosed circle absorption system. Mean anesthetic duration was 1.4 minimum alveolar anesthetic concentration (MAC) hours (sevoflurane MAC = 2.05%) for both groups. Pre- and postoperative blood urea nitrogen, creatinine, and liver function tests were evaluated. Venous blood samples were obtained during and after anesthesia for plasma inorganic fluoride analysis. In six morbidly obese and nonobese patients arterial blood samples were obtained during and after sevoflurane anesthesia for determining sevoflurane blood concentration. Plasma fluoride concentrations during and after anesthesia did not differ between morbidly obese and non-obese groups. Peak plasma inorganic fluoride ion concentrations were 30 +/- 2 mumol/L (mean +/- SEM) in obese and 28 +/- 2 mumol/L in nonobese patients 1 h after discontinuing anesthesia. The hourly rate of change of fluoride ion concentration in plasma during anesthesia was similar between the groups. The maximal recorded plasma fluoride concentrations were 49 mumol/L in an obese patient and 42 mumol/L in a nonobese patient. Pre- and postoperative hepatic and renal tests did not differ significantly in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

We compared blood pressure and heart rate changes in healthy patients during anesthesia with sevoflurane (n = 50) versus isoflurane (n = 25) and the rate of recovery after such anesthesia. After premedication with intravenous administration of midazolam, induction of anesthesia with thiopental, and intubation of the trachea facilitated with succinylcholine or vecuronium, anesthesia was maintained with approximately 1 MAC (sevoflurane, 2.05%; isoflurane, 1.15%) of the volatile anesthetic in oxygen for the duration of the operation. Anesthetic concentration was varied as indicated to maintain arterial blood pressure at +/- 20% of baseline values. Sevoflurane and isoflurane produced similar systolic and diastolic arterial blood pressures, but heart rate after incision was faster in patients given isoflurane. Recovery of response to command was shorter in patients given sevoflurane than that in patients given isoflurane (7.5 +/- 0.5 min versus 18.6 +/- 2.0 min). Consistent with this finding, venous blood drawn after anesthesia showed a more rapid initial decay with sevoflurane. Nausea and vomiting were comparable in both groups. We conclude that sevoflurane anesthesia, as compared with isoflurane, is associated with possible advantageous effects on heart rate and recovery.

Inhalational anesthetics produce differential effects on hepatic blood flow and oxygenation that may impact hepatocellular function and drug clearance. In this investigation, the effects of sevoflurane on hepatic blood flow and oxygenation were compared with those of enflurane, halothane, and isoflurane in ten chronically instrumented greyhound dogs. Each dog randomly received enflurane, halothane, isoflurane, and sevoflurane, each at 1.0, 1.5, and 2.0 MAC concentrations. Mean arterial blood pressure and cardiac output decreased in a dose-dependent fashion during all four anesthetics studied. Heart rate increased compared to control during enflurane, isoflurane, and sevoflurane anesthesia and did not change during halothane anesthesia. Hepatic arterial blood flow and portal venous blood flow were measured by chronically implanted electromagnetic flow probes. Hepatic O2 delivery and consumption were calculated after hepatic arterial, portal venous, and hepatic venous blood gas analysis. Hepatic arterial blood flow was maintained with sevoflurane and isoflurane. Halothane and enflurane reduced hepatic arterial blood flow during all anesthetic levels compared to control (P less than 0.05), with marked reductions occurring with 1.5 and 2.0 MAC halothane concomitant with an increase in hepatic arterial vascular resistance. Portal venous blood flow was reduced with isoflurane and sevoflurane at 1.5 and 2.0 MAC. A somewhat greater reduction in portal venous blood flow occurred during 2.0 MAC sevoflurane (P less than 0.05 compared to control and 1.0 MAC values for sevoflurane). Enflurane reduced portal venous blood flow at 1.0, 1.5, and 2.0 MAC compared to control. Halothane produced the greatest reduction in portal venous blood flow (P less than 0.05 compared to sevoflurane).(ABSTRACT TRUNCATED AT 250 WORDS)

Background Sevoflurane is a new inhalation agent that should be useful for pediatric anesthesia. Sevoflurane undergoes degradation in the presence of carbon dioxide absorbents; however, quantification of the major degradation product (compound A) has not been evaluated during pediatric anesthesia. This study evaluates sevoflurane degradation compound concentrations during sevoflurane anesthesia using a 2-1 fresh gas flow and a circle system with carbon dioxide absorber in children with normal renal and hepatic function. Methods The concentrations of compound A were evaluated during sevoflurane anesthesia in children using fresh soda lime as the carbon dioxide absorbent. Nineteen patients aged 3 months-7 yr were anesthetized with sevoflurane (2.8% mean end-tidal concentration) using a total fresh gas flow of 21 in a circle absorption system. Inspiratory and expiratory limb circuit gas samples were obtained at hourly intervals, and the samples were analyzed using a gas chromatography-flame ionization detection technique. Carbon dioxide absorbent temperatures were measured in the soda lime during anesthesia for hepatic and renal function studies. Venous blood samples were obtained before anesthesia, at the end of anesthesia, and 2h after anesthesia for plasma inorganic fluoride ion concentration. Results The maximum inspiratory concentration of compound A was 5.4 +/- 4.4 ppm (mean +/- SD), and the corresponding expiratory concentration was 3.7 +/- 2.7 ppm (mean +/- SD). The maximum inspiratory compound A concentration in any patient was 15 ppm. Mean concentrations of compound A peaked at intubation and remained stable, declining slightly after 120 min of anesthesia. The duration of anesthesia was 240 +/- 139 min (mean +/-SD). Maximum soda lime temperature ranged between 23.1 degrees C and 40.9 degrees C. There was a positive correlation between maximum absorbent temperature and maximum compound A concentration (r2 = 0.58), as well as between the child's body surface area and maximum compound A concentration (r2 = 0.59). Peak plasma inorganic fluoride ion concentration was 21.5 +/- 6.1 microgmol/1. There were no clinically significant changes in hepatic or renal function studies performed 24 h postanesthesia. Conclusions Sevoflurane anesthesia of 4 h in normal children using a 2-1 flow circle system produced concentrations of compound A of 15 ppm or less. There was no evidence of abnormality of renal or hepatic function up to 24 h after anesthesia; however, larger studies will be required to confirm the absence of organ toxicity.

Sevoflurane is metabolized to inorganic fluoride, a potential nephrotoxin. To evaluate the nephrotoxic potential of sevoflurane, 1-yr-old male Fischer 344 rats were anesthetized with 10 minimal alveolar anesthetic concentration (MAC) h sevoflurane or enflurane with or without pretreatment with biotransformation-enhancing agents. Peak serum fluoride levels reached 35 microM with sevoflurane anesthesia after pretreatment with phenobarbital and 40 microM after enflurane anesthesia after pretreatment with isoniazid. One day after anesthesia, sevoflurane-anesthetized rats concentrated urine normally in response to subcutaneous administration of 1-deamino-8-D-arginine vasopressin and exhibited no increase in urinary excretion of N-acetyl beta-glucosaminidase. Isoniazid-treated, enflurane anesthetized rats developed a 31% reduction in maximal urinary concentrating ability and a 3.5-fold increase in excretion of N-acetyl-beta-glucosaminidase. Sevoflurane produced no evidence of fluoride-induced nephrotoxicity in noninduced or enzyme-induced rats. Under similar conditions, enflurane produced laboratory evidence of nephrotoxicity.

This issue of the Canadian Journal of Anaesthesia contains the article by Crawford et al. entitled "Haemodynamic and organ blood flow responses to sevoflurane during spontaneous ventilation in the rat: a dose response study." The salient point of the paper is the conclusion that in this model, sevoflurane maintains both cardiovascular stability and organ blood flow to a remarkably salubrious degree. Other investigations have produced similar results in animals attesting that this inhalational anaesthetic appears to produce less cardiovascular sequelae than other inhalation anaesthetics at equipotent concentrations. The readers may well query "if this inhalation anaesthetic is so good, where has it been all these years?" Sevoflurane has been knocking around for over 15 yr since first synthesized and described by Wallin etal. l from Baxter-Travenol laboratories. The first volunteer trials (Phase I trials) were conducted by Holaday and Smith 2 over ten years ago. These trials proceded very well and the investigators gave sevoflurane high marks at this early stage. Analysis of the reasons why the halogenated inhalation anaesthetic is not now available for clinical use is complex. Sevoflurane received early investigative interest about the same time that isoflurane was in its last stages of development. On the surface, isoflurane had many salient features to recommend it over sevoflurane, a potential commercial as well as clinical rival. First, isoflurane is biotransformed to a far lesser extent than sevoflurane. Approximately 1% of absorbed isoflurane is metabolized contrasted to approximately 3% sevoflurane. Since isoflurane was marketed to replace enflurane (also metabolized to a degree similar to sevoflurane), the lack of biotransformation of isoflurane was a cardinal virtue promoting acceptance by anaesthetists. This, after all, was the decade in which biotransformation of halogenated anaesthetics was determined to be a b~te noire. Methoxyflurane renal toxicity and halothane hepatic toxicity had been coupled to breakdown of the anaesthetic molecules by the liver to undesirable products. Another di s

The biotransformation and plasma inorganic fluoride ion production of sevoflurane (the new volatile anesthetic) during and after surgical anesthesia was studied in 50 ASA I or II surgical patients. Twenty-five additional patients served as controls by receiving isoflurane. Sevoflurane or isoflurane was administered with a semiclosed (total gas flow, 2 L/min O2) circle absorption system for durations of 1.0 to greater than 7.0 minimal alveolar concentration (MAC) hours for surgical anesthesia (sevoflurane MAC, 2.05%; isoflurane MAC, 1.15%). Preoperative and postoperative blood urea nitrogen and creatinine concentrations were determined. Blood samples were obtained during and after anesthesia in both groups for determining anesthetic blood concentration analysis and plasma fluoride level. Plasma fluoride concentrations did not significantly increase during isoflurane anesthesia. Sevoflurane biotransformation produced a mean peak plasma inorganic fluoride concentration of 29.3 +/- 1.8 mumol/L, 2 h after anesthesia, which decreased to 18 mumol/L concentration by 8 h after anesthesia. The peak plasma inorganic fluoride ion concentration correlated with duration of sevoflurane anesthetic exposure. Five patients given sevoflurane had peak levels transiently exceeding 50 mumol/L, and one of these had a history of ingesting drugs potentially producing hepatic enzyme induction. No increases in postoperative levels of creatinine, blood urea nitrogen, direct bilirubin, or hepatic transaminase and no changes in serum electrolyte level occurred in either anesthetic group. Indirect bilirubin concentration increased significantly after sevoflurane anesthesia, but the increase was not of clinical significance (from 0.30 +/- 0.03 to 0.38 +/- 0.06 mg/dL). Indirect bilirubin concentrations did not increase after isoflurane anesthesia; the concentrations reached 0.31 +/- 0.04 mg/dL and did not differ significantly from those found with sevoflurane.(ABSTRACT TRUNCATED AT 250 WORDS)

Sevoflurane, a new inhalational anesthetic agent has been shown to produce degradation products upon interaction with CO2 absorbants. Quantification of these sevoflurane degradation products during low-flow or closed circuit anesthesia in patients has not been well evaluated. The production of sevoflurane degradation products was evaluated using a low-flow anesthetic technique in patients receiving sevoflurane anesthesia in excess of 3 h. Sevoflurane anesthesia was administered to 16 patients using a circle absorption system with O2 flow of 500 ml/min and average N2O flow of 273 ml/min. Preoperative and postoperative hepatic and renal function studies were performed. Gas samples were obtained from the inhalation and exhalation limbs of the anesthetic circuit for degradation product analysis and analyzed by gas chromatography/mass spectrometry for four degradation products. The first eight patients received sevoflurane anesthesia using soda lime, and the following eight patients received anesthesia using baralyme as the CO2 absorbant. CO2 absorbant temperatures were measured during anesthesia. Of the degradation products analyzed, only one compound [fluoromethyl-2, 2-difluoro-1-(trifluoromethyl) vinyl ether], designated compound A, was detectable. Concentrations of compound A increased during the first 4 h of anesthesia with soda lime and baralyme and declined between 4 and 5 h when baralyme was used. Mean maximum inhalation concentration of compound A using baralyme was 20.28 +/- 8.6 ppm (mean +/- SEM) compared to 8.16 +/- 2.67 ppm obtained with soda lime, a difference that did not reach statistical significance. A single patient achieved a maximal concentration of 60.78 ppm during low-flow anesthesia with baralyme. Exhalation concentrations of compound A were less than inhalation concentrations, suggesting patient uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Verapamil clearance is reduced during halothane administration. This study evaluated relative contributions of reduced hepatic flow rate and hepatic metabolizing enzyme inhibition by halothane as a cause of reduced verapamil clearance. An isolated perfused rat liver model was utilized in which flow rate could be fixed during halothane administration. Perfusions were performed on five to six livers under each of the following conditions: (a) control--40 mL/min flow rate with no anesthetic exposure; (b) 1.5% halothane--40 mL/min; (c) 2.25% halothane--40 mL/min; (d) reduced flow--20 mL/min with no anesthetic exposure; and (e) reduced flow with 1.5% halothane--20 mL/min. Halothane caused dose-dependent decreases in both total hepatic and intrinsic clearance rates (P less than 0.05). With no anesthetic exposure, a flow reduction of 50% (20 mL/min) also gave a large reduction (P less than 0.05) in hepatic clearance of verapamil compared with the control condition (40 mL/min). The addition of 1.5% halothane to the reduced flow condition was not associated with further reduction in hepatic clearance rate. Results of this study suggest that although both reduced hepatic perfusion and hepatic enzymatic inhibition by halothane administration are associated with decreased verapamil clearance, a greater proportion of this decrease appears to be due to reductions in hepatic flow. The present results may apply to other drugs used in anesthesia that have high hepatic extraction ratios; thus, clearance of these drugs may be more dependent on hepatic blood flow than on hepatic enzyme activity.

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)

Halothane (1,1,1-trifluoro-2-bromo-2-chloroethane) is a safe, clinically useful inhalation anesthetic. Rare, unpredictable cases of liver necrosis have been reported following its use. Although the mechanism of this reaction in man is unknown the most plausible is biotransformation to reactive intermediates compounds. The oxidative metabolism of halothane appears to be benign. There is early evidence that reductive (nonoxygen dependent) may be harmful. Since the bromine atom of halothane appears to possess weak bond energy, the reduced, debrominated derivative of halothane, 1,1,1-trifluoro-2-chloroethane, was synthesized and tested for hepatotoxicity in the rat. The derivative is unstable and thus was prepared anaerobically and trapped in propylene glycol solvent. Injection of small amounts of this compound into the portal vein of rats produces extensive liver necrosis. It is postulated that biotransformation of halothane via a reductive pathway could produce this reactive intermediate metabolite. Images FIGURE 1.

A simple and sensitive gas chromatographic method for the determination of 2-chloro-1, 1-difluoroethylene (CDE) and 2-chloro-1,1,1-trifluoroethane (CTE), two highly volatile metabolites of halothane, in blood, liver and isolated hepatic microsomes is described. The entire head-space in equilibrium with a known volume or weight of the sample is injected into the gas chromatograph equipped with a flame ionization detector. Quantification is accomplished with standards prepared by fortifying blank samples with known concentrations of CDE and CTE which are treated under the same conditions as the samples. Detection limits for CDE and CTE were 2 pmole/ml in blood and 10 pmole/g in liver and the mean relative standard deviations are no greater than +/- 6% except for CTE in hepatic microsomes (+/- 9%). A preliminary study of blood CDE and CTE levels in humans anesthetized with halothane is reported.

Chronic pain may occur in the ilioinguinal nerve distribution spontaneously or following herniorrhaphy or other surgery. Primary ilioinguinal neuropathy may also cause abdominal muscle motor weakness resulting in direct hernia. We describe 12 patients with ilioinguinal nerve disorders and discuss therapeutic alternatives and results of treatment.

Three cases of postoperative malignant hyperthermia (MH) episodes, after what was considered to be a "safe" anaesthetic, are described. In each case the temperature rose in a delayed fashion after an uneventful anaesthetic. Treatment included intravenous dantrolene, surface cooling and ventilation with 100 per cent oxygen. Stress in the postoperative period may have been the triggering factor responsible for these reactions. Patients should be monitored well into the postoperative period as MH episodes may occur long after surgery is completed. If stress represents a significant triggering mechanism then no anaesthetic technique can be considered entirely safe.

Since CF3CH2Cl and CF2CHCl are probably the products of reactive intermediates formed during the reductive metabolism of halothane (CF3CHClBr), factors affecting their in vitro and in vivo formation were investigated. In vitro studies with rat hepatic microsomes showed that CF3CH2Cl and CF2CHCl are produced by cytochrome P-450 mediated reductive pathways which were inhibited by the presence of CO. Under conditions of exposure known to promote halothane hepatotoxicity in phenobarbital treated rats (1 per cent halothane, 14 per cent oxygen), the hepatic and blood concentrations of the volatile metabolites were enhanced. Central venous levels of the volatile metabolites were much higher than he concentration in peripheral vessels. The CF3CH2Cl/CF2CHCl ratio in blood was approximately three, whereas the ratio in vitro was almost unity. Liver levels of the two volatile metabolites greatly exceeded the blood levels, but interestingly they were present in equivalent concentrations. The differences in the ratio of CF3CH2Cl to CF2CHCl may be explained by the fact that CF2CHCl is further degraded under oxidative conditions, whereas CF3CH2Cl appears relatively stable. Measurement of these metabolic products in patients undergoing halothane anesthesia may permit rapid detection of an unusually high level of halothane biotransformation along its hepatotoxic pathway.

Since endotoxin, lipopolysaccharides (LPS), have been implicated as a causative factor in the development of hepatic necrosis in rats exposed to hepatotoxic levels of several chemical agents, the role of LPS in the halothane-hypoxia (HH) model of hepatic damage in male Sprague-Dawley rats was investigated. When injected intravenously immediately after halothane anesthesia, a subnecrotic dose of LPS (0.5 mg/kg; Escherichia coli 026:B6) was found to markedly potentiate HH-induced hepatic necrosis. Pretreatment of the animals with the antiendotoxin agent, lactulose, prior to exposure to halothane reduced the hepatic damage normally seen from HH. A possible mechanism of LPS-induced potentiation was indicated by changes in hepatic calcium levels at 24 h after treatment. Endogenous LPS may play a role in HH-induced hepatic necrosis, and the mechanism of LPS-induced potentiation may be due to an LPS-related membrane dysfunction.

Exposure of phenobarbital-pretreated male Sprague-Dawley rats to halothane, 1 per cent, for two hours under conditions of hypoxia (Fl02 0.14) resulted in extensive centrilobular necrosis within 24 hours. Accompanying the morphologic damage were an increase in serum glutamic pyruvic transminase (SGPT) and a decrease in hepatic microsomal cytochrome P-450. Glutathione levels in the liver were unchanged. Phenobarbital-pretreated rats anesthetized with halothane, 1 per cent, at FI02 0.21 had only minor morphologic changes at 24 hours. Hepatic injury was not appearent in any non-phenobarbital-induced rat or in any induced animal exposed to ether at Fl02 0.10 or to halothane at Fl02 0.99. There was a 2.6-fold increase in the 24-hour urinary excretion of fluoride in those rats in which extensive centrilobular necrosis developed. The in-vivo covalent binding to lipids of 14C from 14C-halothane also was increased markedly when 14C-halothane was administered intraperitoneally to phenobarbital-induced rats maintained hypoxic (FI02 0.14) for two hours. These results support the authors' hypothesis that halothane is metabolized to hepatotoxic intermediates by a reductive or non-oxygen-dependent cytochrome P-450-dependent pathway. This animal model of halothane-induced hepatotoxicity may be clinically relevant. A decrease in hepatic blood flow during halothane anesthesia may decrease the P02 available to hepatocytes and thus direct the metabolism of halothane along its reductive, hepatotoxic pathway.

The kinetics of biotransformation of methoxyflurane by rat hepatic microsomes in vitro was studied. The rate of biotransformation as measured by analysis of metabolites continued to increase even at near-saturation concentrations of the anesthetic. Methoxyflurane biotransformation followed either an unbounded curve with empirical formula y = a ln(bx + 1) or an asymptotic curve with formula (see article) No substrate inhibition was observed. Total fluoride Vmax of 135.1 mmumol F-/mg protein/30' was increased to 931.9 by phenobarbital induction; free fluoride Vmax from 39.2 to 403.2. Thus, enzyme induction shifted biotransformation to the production of greater amounts of inorganic free fluoride metabolites than organic fluoride-containing metabolites. Phenobarbital induction caused qualitative as well as quantitative alteration in the biotransformation of methoxyflurane.