Search

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.

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)

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

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.

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.

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

Hepatic necrosis was induced in rats by a single exposure to 1 per cent halothane in oxygen following pretreatment with a single dose of Aroclor 1254, a polychlorinated biphenyl. The hepatic lesion was centrilobular and multifocal, and morphologically similar to that reported to occur in man. In-vitro incubation with 14C-halothane indicated an enhanced covalent binding of halothane metabolites to hepatic microsomal macromolecules, particularly lipids, following Aroclor 1254 pretreatment. Lipoperoxidation of microsomal unsaturated fatty acids was not observed with these animals.

Hepatic microsomal lipoperoxidation in vivo is stimulated by anesthetic concentrations of halothane (Fluothane) and chloroform in phenobarbital-pretreated rats. Diethyl ether and fluroxene (Fluoromar) do not share this property in the rat. Studies in vitro show no enhancement of lipoperoxidation, but in this circumstance metabolism of the anesthetics is minimal. It is speculated that enhancement of metabolism of halothane and chloroform by phenobarbital induction is capable of fostering a peroxidative breakdown of hepatic microsomal polyenoic lipid esters.

Halothane depresses the metabolism of amobarbital, hexobarbital, pentobarbital, and aminopyrine (type I substrates) by rat hepatic microsomal enzymes. This inhibition is dose-dependent, reversible, noncompetilive, and independent of the lipid solubilities of the substrates. In contrast, the metaboli

The halogenated inhalation anesthetics continue to be an important group of drugs in current anesthesia practice. The purpose of this article is to discuss current concepts of the mechanisms of halothane-induced hepatotoxicity and to attempt to answer the question: Do all halogenated inhalation anesthetics share halothane's propensity to hepatotoxicity?

In this manuscript we report our attempts to determine if 14C-halothane or its metabolites interact with DNA. Three bioactivation systems were used: in vitro microsomal incubations, isolated hepatocytes, and in vivo administration. Even though we used optimal conditions for bioactivation, no significant covalent binding of 14C to DNA was observed. Slight 14C activity above background (6 dpm/0.1 mg DNA) was observed in the microsomal incubations but is considered insignificant because it was not reduced when NADPH was omitted from the incubations. We are able to demonstrate covalent binding to nuclear lipids and proteins when rats were pretreated with phenobarbital and maintained in a hypoxic environment (14% O2). Similarly, these conditions markedly increased covalent binding of 14C from 14C-halothane to microsomal proteins and lipids. Isolated rat hepatocytes proved to be a viable system for studying the bioactivation of halothane. In this system it was also possible to demonstrate increased binding under N2 and/or phenobarbital pretreatment.

Absolute documentation of the entity labeled halothane hepatitis remains impossible at best, and delineation of its pathogenesis is as will-o'-the-wispish as ever. A variety of causative mechanisms...

A rat model of cnflurane-associated hepatotoxicity was compared with the halothane-hypoxia (HH) model (adult male rats, phenobarbital induction, 1% halothane, 14% O2, for 2 hr). The enflurane-hypoxia heating (EHH) model involved exposing phenobarbital-pretreated male adult rats to 1.5–1.8% enflurane at 10% O2 for 2 hr with external heating to help maintain body temperature. Exposure to either anesthetic without temperature support led to a decrease in body temperature of 7–9°C, while heating the animals during anesthesia resulted in only a 0.5–2°C decrease. Reducing the oxygen tension to 10% O2 combined with heating the animals during exposure produced significant decreases in the oxidative metabolism of both halothane and enflurane as compared to exposures of 14% O2. The same conditions also caused a significant increase in the reductive metabolism of halothane, indicating that a severe hepatic hypoxia or anoxia occurs during anesthesia at 10% O2 with external heating. The time course of lesion development in the HH model paralleled results obtained with an oral dose of CCl4: gradual progression of necrosis up to 24 hr. EHH resulted in a classic hypoxic/anoxic injury with elevated serum glutamate pyruvate transaminase values and a watery vacuolization of centrilobular hepatocytes immediately after exposure. The HH model required phenobarbital pretreatment of the rats for expression of hepatic injury; EHH did not. Heating of the animals during anesthesia exposure was necessary for enflurane-induced hepatotoxicity but had little effect on the HH model. Exposure to 5% O2 without anesthetic mimicked EHH in both requirements for and type of hepatic injury. Thus the HH model appears to act via a bioactiva- tion/chemotoxic mechanism, whereas models of anesthetic- induced hepatotoxicity that require very low oxygen tensions and heating of the animals during exposure result from a severe hypoxia/anoxia of the liver.

The free oxygen concentrations required for reductive defluorination of halothane by rat hepatic microsomes from control and phenobarbital- (PB) and polychlorinated biphenyl-(PCB) treated animals were determined. Halothane-exposed microsomes from treated rats generated measurable levels of fluoride ion after 30 min incubations with oxygen concentrations of 5% or less. Microsomes from control animals produced fluoride only if the free oxygen concentration was 2% or less. During anoxic (0% oxygen) incubations, defluorination rates of 2.10 +/- 0.17, 5.55 +/- 0.38, and 5.46 +/- 0.30 nmol fluoride X mg protein-1 X 30 min-1 were observed for microsomes from control, PB, and PCB rats, respectively. Normalizing the maximal rates of defluorination to the microsomal cytochrome P-450 content yielded values of 5.14 +/- 1.40, 3.70 +/- 0.15, and 2.38 +/- 0.26 nmol fluoride X nmol cytochrome P-450-1 X 30 min-1 for control, PB, and PCB microsomes, respectively. Oxygen concentrations required for reductive metabolism of halothane by isolated rat hepatic microsomes are close to normal physiologic free oxygen concentrations of 4-5% reported for centrilobular areas of the rat liver. Thus even slight reductions in hepatic oxygenation during anesthetic exposure could lead to enhanced reductive biotransformation, an observation found in rat models of halothane-associated hepatic injury. The large differences among the treatment groups in the rates of fluoride ion generated per nanomole cytochrome P-450 indicate that enzyme induction regimens disproportionately increase those isozymes of hepatic cytochrome P-450 that are not involved with the reductive defluorination of halothane.

The rates of biotransformation of halothane and enflurane by rabbit kidney and lung microsomal preparations were compared t the hepatic microsomal biotransformation of these agents. All three microsomal preparations (pulmonary, renal, and hepatic) were found capable of performing oxidative demethylation reactions as well as epoxidation. This was evidenced by the ability of these three microsomal preparations to metabolize benzphetamine, methoxyflurane, and trichloroehylene. Only the liver microsomal preparations were capable of defluorinating enflurane at any appreciable rate (6 +/- 3 pmoles/min/mg of microsomal protein). The three microsomal preparations performed reductive biotransformation of halothane, and the liver microsomes produced more than 3 times as much product as the other tissues. Pulmonary and renal microsomal preparations metabolized halothane reductively about equally. Differences in the solubility of halothane and enflurane in the rabbit pulmonary and hepatic microsomes were not found to be a cause of the differences in biotransformation in these two organs. Extrahepatic biotransformation may be an important factor in the disposition of volatile anesthetics.

A recently reported animal model of halothane-associated hepatotoxicity in males of a colored strain of guinea pig was further characterized as to possible sex and strain specificity in outbred albino Amana, inbred albino Hartley, inbred colored strain 2, and inbred colored strain 13 guinea pigs. Exposure to 1 % halothane for 4 hr in 21 % O2 proved to be hepatotoxic in both sexes. Forty-eight hours after halothane exposure fatty vacuolization of hepatocytes was present in all animals. Histologically identifiable hepatic necrosis occurred in 60% of the guinea pigs exposed, along with concomitant increases in SGPT. Approximately one half of these responding animals had extensive centrilobular necrosis, which was still present 96 hr after halothane exposure. Females of the inbred strain 2 and males and females of strain 13 were the most susceptible to halothane-induced hepatic necrosis whereas the inbred Hartley strain was almost totally refractory to necrosis. Outbred Amana and male inbred strain 2 animals exhibited an intermediate hepatotoxic response. Comparison of the halothane-associated hepatic lesion with that induced by anoxidischemic mechanisms, (exposure to low (8%) oxygen during 1.7% enflurane anesthesia) showed obvious differences in the morphology of the hepatic necrosis and the apparent time course of lesion development. This guinea pig model of halothane-associated hepatotoxicity appears to be superior to previous animal models in that no pretreatment of the guinea pigs is required, both sexes are affected, and the resulting hepatic lesion is more persistent.

Recent studies on rats pretreated with phenobarbital indicate that anesthetic agents may produce hepatic injury even when metabolism of the anesthetic is almost negligible. This implies that anesthesia per se may cause hepatic injury. To evaluate this possibility, we determined the amount of hepatic injury produced by halothane, enflurane, isoflurane, thiopental, and fentanyl in rats pretreated with phenobarbital. Anesthetics were administered in doses ranging from 0.04-1.1 MAC (or their equivalent for thiopental or fentanyl) and were given with 10% oxygen for 2 h. Liver specimens taken 24 h later were examined microscopically for hepatic injury. At concentrations of 5-40% of MAC, all anesthetics produced more hepatic injury than did control conditions (i.e., exposure to only 10% oxygen for 2 h). There were no systematic differences among agents, nor did starvation before anesthetic exposure produce a difference among agents. Therefore, mechanisms other than anesthetic metabolism are needed to explain hepatic injury produced by anesthetic agents.