Fluroxene toxicity induced by phenobarbital.

Because of reports of fluroxene toxicity in man, the effect of phenobarbital treatment on the toxicity and metabolism of fluroxene was studied in 9 rhesus monkeys. Six monkeys that were exposed to a mean calculated alveolar fluroxene concentration of 5.8% for 4-hr periods up to a total of 16 hr showed no evidence of toxicity. Two animals were sacrificed after a single 4-hr exposure to obtain control measures of fluroxene metabolites in tissues. Four monkeys that had previously survived received exposures to fluroxene and 3 monkeys that had no exposure to fluroxene died during fluroxene anesthesia after treatment with phenobarbital (mean time, 3 hr). Toxicity was manifested by arterial hypotension, pulmonary edema, and arterial hypoxemia. Phenobarbital treatment enhanced production of fluroxene metabolites, including the highly toxic trifluoroethanol. Concentrations of trifluoroethanol in mixed-expired gas, blood, and urine, and of total nonvolatile fluorine in blood, urine, and tissues of animals treated with phenobarbital were 2 to 10 times as in control animals. The results suggest that the rhesus monkey is a valuable model for the study of fluroxene pharmacology and that inclusion of an enzyme-inducing challenge in the evaluation of potential toxicity of other anesthetics seems warranted.

Absorption, biotransformation, and storage of halothane.

Current knowledge of the quantitative aspects of biotransformation of halothane and the fate of its metabolites are reviewed. Absorbed quantities of the inhalation anesthetic average 12.7 and 18 g during 1 and 2 hr, respectively, of anesthesia. Reported fractions of halothane recovered as urinary metabolites range from 10 to 25%. An analysis of reports of bromide ion accumulation in plasma during and following anesthesia suggests that metabolism of halothane continues for 20-40 hr after exposure and that 22-24% of absorbed halothane is metabolized following 8 hr of anesthesia. Half-times for excretion of trifluoroacetic acid (TFA), a principal urinary metabolite of halothane, tend to confirm that biotransformation proceeds for 2 to 3 days following exposure. Other urinary metabolites which occur in small amounts include a dehydrofluorinated metabolite of halothane conjugated with L-cysteine and N-trifluoroacetyl-n-ethanolamine, both of which are evidence of the occurrence of reactive intermediates during the metabolism of halothane. Support for free radical formation has come from in vivo and in vitro demonstrations of stimulation of lipoperoxidation of polyenoic fatty acids by halothane. Irreversible binding of halothane metabolites to microsomal proteins and phospholipids has been shown to depend on the microsomal P-450 cytochrome system. Irreversible binding is increased by microsomal enzyme induction and by anaerobic conditions. Hypoxia increases irreversible binding to phospholipids, augments the release of inorganic fluoride and is followed by centrilobular hepatic necrosis. It is concluded that one-fourth to one-half of halothane undergoes biotransformation in man. One fraction is excreted as trifluoroacetic acid, chloride and bromide. A second fraction is irreversibly bound to hepatic proteins and lipids. Under anaerobic conditions fluoride is released, binding to phospholipids is increased, and hepatic necrosis may occur.

Opening and closing mechanisms of the larynx.

Opening and closing of the larynx are determined by the intrinsic and extrinsic muscles acting on the elastic forces in the tongue, pharynx, larynx, and trachea. The pharynx is opened or closed by two mechanisms: (1) Contractions of the cricothyroid and of the intrinsic muscles of the larynx open and close the vocal cords. (2) The false cords, ventricle, and true cords accordion open or close in a bellows mechanism. We conclude that the posterior cricoarytenoid opens the laryngeal airway. The cricothyroid together with the posterior cricoarytenoid accentuates this opening. The larynx is also opened by the geniohyoid, mylohyoid, sternothyroid, and middle constrictor. The thyrohyoid, cricothyroid, sternohyoid, and inferior constrictor close the laryngeal airway. Abnormalities in the soft tissues of the neck or of the innervation of the larynx, pharynx, and neck muscles may severely interfere with patency of the laryngeal airway. This occurs in such conditions as vocal cord paralysis, sleep apnea, multiple sclerosis, amyotrophic lateral sclerosis, spastic dysphonia, mandibular fractures or hypodevelopment, and cerebrovascular disease.

Biotransformation in man and clinical toxicity of volatile anesthetics.

Delayed toxic reactions following general anesthesia are dependent on biotransformation of ansethetic drugs. Up to ten grams of metabolites of the more extensively metabolized volatile anesthetics may undergo irreversible intracellular binding. This could contribute importantly to the incidence of hepatic necrosis. A second important cause of toxic reactions is production of toxic metabolites. Nephrotoxicity with impairment of urine concentrating ability following methhoxyflurane anesthesia correlates best with blood fluoride levels and total urinary oxalate. A possible role of enzyme induction in hepatic and hepatorenal failure following, fluroxene anesthesia is suggested by recent studies in the monkey, which demonstrate that pretreatment with phenobarbital results in increased production of a toxic metabolite and conversion of a well tolerated anesthesia to a rapidly lethal one. Improvement in the safety to general anesthesia can be expected from either of two developments: production of anesthetics which are resistant to biotransformation, or development of drugs which will inhibit biotrasnformation during and immediately following anesthesia when maximum rates of biotransformation tend to occur. An important additional safeguard will have been achieved when a successful method is found to identify before exposure patients who may susceptible to delayed toxic reactions.

Sevoflurane: an experimental anesthetic.

Sevoflurane is nonexplosive and, in clinically useful concentrations, nonflammable. It is relatively chemically inert in that it can be stored without preservative, and undergoes limited dehydrofluorination in moist alkali. It does not sensitize the heart to epinephrine or cause alterations of hematologic or serum clinical chemistry values after repeated exposures in animals or in man after a single exposure. It depresses respiration and cardiovascular functions in experimental animals and man, but less than halothane. It is metabolized to a limited extent, releasing subnephrotoxic amounts of fluoride ion. Sevoflurane warrants further testing in man.

Effect of nitrous oxide on the oxyhemoglobin dissociation curve and PO2 measurements.

Blood from 20 ASA physical status I patients collected before and after induction of anesthesia was used in vitro to reexamine the effects of nitrous oxide on the oxyhemoglobin dissociation curve and the response of the oxygen electrode. The preinduction P50 values with and without 70% N2O were 28.4 +/- 0.1 mmHg and 26.8 +/- 0.1 mmHg, respectively. The postinduction P50 values with and without N2O were unchanged, namely 28.4 +/- 0.1 mmHg and 26.8 +/- 0.1 mmHg, respectively. Our data confirm the observation that N2O causes a small elevation of P50 (P less than 0.001) and that this effect is both rapidly inducible and reversible. Our results also indicate that N2O has no effect on polarographic PO2 measurements.

Uptake and clearance of inhalation anesthetics in man.

The uptake, distribution, and clearance of inhaled vapors is governed by rules of partial pressure equilibration in a multicompartmental system. Since halogenated anesthetic agents are not soluble in water, biotransformation is their only clearance pathway during anesthesia. When apparent steady state is reached, the rate of overall metabolism can be determined from the pulmonary uptake rate. As a result of metabolism, pulmonary uptake increases but the concentration of inhaled vapor in blood and tissues decreases, and only a fraction of uptake is exhaled following anesthesia. Uptake and pulmonary clearance of five halogenated anesthetic agents were studied in 45 surgical patients. The susceptibility to biotransformation increases in the following order: isoflurane, enflurane, halothane, fluroxene, methoxyflurane.

Uptake and excretion of 1-bromo-1,2,2-Trifluorocyclobutane (42M-9) in man: comparative study on pharmacokinetics and metabolism of inhalation anesthetics.

1-bromo-1,2,2-trifluorocyclobutane (42M-9) has physical properties similar to those of methoxyflurane and has been suggested for use as an anesthetic agent. Its MAC value, predicted from its lipid solubility, is 0.26 percent. No clinically significant changes were observed in cardiovascular or respiratory function or in clinical laboratory tests. Ventricular dysrhythmias were not seen in this study at analgesic concentrations in contrast to those reported at anesthetic concentrations by others. Pulmonary uptake was high and wash-out was slow. The total amount exhaled comprised 60 percent of the dose. Fluorine, equivalent to 11 percent of total uptake, was rapidly excreted in urine as nonvolatile fluorinated metabolites. An additional 9 percent of 42M-9 was degraded to fluroide and excreted in urine. Since an amount of fluoride equivalent to that excreted in the urine tends to be deposited in the skeleton, approximately 29 percent of uptake may possibly be accounted for as metabolites. Based on fluorine recovery, the fate of 11 percent of 42M-9 uptake remains unknown. The kinetics of uptake, metabolism and excretion of 42M-9 did not differ significantly over a five-fold change of inspired concentration. A comparison of the pulmonary clearance of unaltered 42M-9 and the fraction of uptake converted to urinary metabolites or unrecovered with those of other volatile halogenated anesthetics and their physical properties supports the conclusion that 42M-9 is relatively resistant to biotransformation.

The pharmacokinetics of metabolism of inhalation anaesthetics. A simulation study.

The non-steady state metabolism of inhalation anaesthetics during anaesthesia and recovery was simulated with a linear and non-linear whole body compartmental model. These two models were studied for nine anaesthetics during 1-MAC anaesthesias lasting 1, 4 and 8 h and recovery from 5 to 10 days. Both models demonstrated significant metabolism for several days following anaesthesia. For the linear model, both the percentage and the molar quantity of anaesthetic metabolized increased with increased duration of anaesthesia, increased anaesthetic fat solubility and increased assumed rate of hepatic metabolism. For the non-linear model, the duration of anaesthesia had little effect on the percentage metabolized but demonstrated increased molar quantities of anaesthetic metabolized with increased duration of anaesthesia and increased fat solubility. The agreement between the results obtained from the non-linear model and experimental data in the literature suggests that many inhalation anaesthetics belong to a class of xenobiotics whose biotransformation is limited by the same or similar non-linear rate-limiting step(s). A difference in the quantities of anaesthetic metabolized would be a direct consequence of the tissue solubilities of the anaesthetic.

Clinical characteristics and biotransformation of sevoflurane in healthy human volunteers.

Sevoflurane was submitted to phase-1 studies in man following extensive testing in animal species during maintenance, was administered with oxygen to produce one hour of anesthesia in six healthy adult male volunteers. Respiratory and cardiovascular functions, the electroencephalogram, arterial blood gases, blood sevoflurane, inorganic fluoride and total, nonvolatile fluorine concentrations, and inspired and mixed expired sevoflurane concentrations were measured during exposure. Concentrations of expired sevoflurane, blood and urinary fluoride, and total nonvolatile fluorine metabolites were also measured after anesthesia. During exposure spontaneous respiratory frequency increased 28 per cent, respiratory minute volume changed insignificantly, and PaCO2s averaged 50 torr. PaCO2s remained near 400 torr. Arterial systolic blood pressure declined an average of 17 per cent. Pulse rate changed insignificantly. After an hour of exposure arterial blood serum inorganic fluoride concentrations averaged 22 microM and plasma nonvolatile organic fluorine concentrations averaged 9.1 mg/l, or 61.3 microM. Uptake of sevoflurane averaged 94 (+/- 63 SD) mmol. Following exposure 37 (/+- 12) mmol of unaltered sevoflurane were estimated to be excreted in exhaled air and 0.90 mmol of inorganic fluoride were excreted in the urine. Recoveries in exhaled air and urine averaged 51.5 (+/- 22.4) per cent of uptake. There was no significant drug-exposure-related change in the chest radiogram, electrocardiogram, electroencephalogram, urinalysis results, complete blood count, prothrombin time, serum electrolytes, transaminases, or hepatic and renal functions during four weeks following exposure compared wth preexposure values. Sevoflurane produced anesthesia of excellent quality; it appears to undergo limited biotransformation and to have little or no systemic toxicity.

A latex bag tonometer for determining the anaesthetic blood/gas partition coefficient.

Many techniques for measurement of the tissue/gas partition coefficient are valid. Each has specific advantages and shortcomings. All the methods require suitable analytic equipment and means for controlling temperature. The disadvantages of a particular technique, the ability to cope with them and the availability of the necessary apparatus are the determining factors in choosing the best method. The latex bag tonometer has a precision and ease which compares favourably with previously described techniques for measuring anaesthetic blood/gas partition coefficients. The technique was successfully used to show the effect of in vivo haemodilution on the halothane blood/gas partition coefficient.

Effect on isoflurane anaesthesia and surgery on thyroid function in man.

The effect of isoflurane (Forane) anaesthesia and surgery on thyroid function was investigated in nine male patients. Isoflurane anaesthesia alone for 30 minutes prior to the start of surgery increased plasma triiodothyronine uptake (T3U) and thyroxine (T4) level by 18 and 20 per cent, respectively. Free thyroxine index (FTI) values in blood increased by 62 per cent during the same period. One hour of surgical procedure further elevated these parameters. Our data indicate that isoflurane anaesthesia and surgery increase circulating thyroxine in man.

Effect of isoflurane anaesthesia and surgery on carbohydrate metabolism and plasma cortisol levels in man.

The present study was undertaken to investigate in nine male surgical patients the effects of isoflurane anaesthesia alone on the carbohydrate metabolism by determining plasma growth hormone (GH), insulin, blood glucose, and cortisol, and to compare them with the effects of anaesthesia associated with surgical operations. Determination of plasma GH, insulin, cortisol, and blood glucose were made simultaneously before induction of isoflurane anaesthesia, after maintenance of anaesthesia for 15 minutes and 30 minutes and during and after conclusion of the operation. Plasma GH concentrations showed a significant elevation during isoflurane anaesthesia, and maintained a similar high level one hour after the start of the operation. An insignificant elevation in plasma insulin level and significant increases in blood glucose were noted during anaesthesia and operation. Plasma cortisol levels increased insignificantly during anaesthesia, but increased markedly during operation. Our observations would suggest that the increased blood level of GH and elevated blood cortisol play a part in the increase of blood glucose during isoflurane anaesthesia and surgical operations in man.

Metabolism of methoxyflurane in man.

Excretion of methoxyflurane was studied in 12 patients receiving anesthesia in a closed rebreathing circuit at a constant alveolar concentration of approximately 0.24 per cent. The mean methoxyflurane uptake was 18 g (range 7.6-31 g) during a mean time of anesthesia administration of 2 hours, 18 minutes (range 55-309 minutes). An average of 19 per cent of the uptake was recovered unchanged in the exhaled air after anesthesia. Urinary excretion of organic fluorine, fluoride, and oxalic acid was equivalent to 29, 7.7 and 7.1 per cent of methoxyflurane uptake, respectively. Approximately a third of the uptake remained unrecovered. It is postulated that a portion of the unrecovered drug became permanently bound to tissues and hence its excretion was delayed beyond the period of the study.

Isoflurane and enflurane-induced hepatic necrosis in triiodothyronine-pretreated rats.

Exposure of triiodothyronine (T3)-pretreated rats to 1.3% isoflurane, 1.8% enflurane, or 1% halothane in 21% oxygen (air) for two hours resulted in hepatic centrilobular necrosis. The incidence of the liver lesion was 28, 24, and 92% after exposure to isoflurane, enflurane, and halothane, respectively. Histopathologic grading indicated that the necrosis was more severe after halothane than after isoflurane or enflurane anesthesia. No lesion was observed in livers prepared from non-anesthetized T3-pretreated rats or in livers prepared from rats which were pretreated with the vehicle for T3 and then anesthetized with either isoflurane, enflurane, or halothane. Hepatic necrosis was not observed in vehicle-treated rats exposed to isoflurane in 12% oxygen or in vehicle-treated rats that were deprived of food for 12 hours prior to exposure to isoflurane under hypoxic conditions. Food restriction to maintain the body weight gain of vehicle-treated rats similar to that of T3-treated rats did not result in hepatotoxicity after exposure to halothane in 21% oxygen. Liver necrosis did not occur in pentobarbital anesthetized (40 mg/kg, intraperitoneally) T3-pretreated rats. These results indicate that isoflurane and enflurane, like halothane, can induce hepatic centrilobular necrosis in T3-pretreated rats. The mechanism for liver toxicity of these volatile anesthetic agents in this model remains to be determined.

Resistance of isoflurane to biotransformation in man.

Pulmonary and renal excretion of isoflurane and its metabolites was studied in nine surgical patients following administration of known quantitities of isoflurane. Uptake and pulmonary washout were predictable by a mathematical model for inert vapors. The agreement between predicted and experimental data supports the view that isoflurane is subject to little or no biotransformation. The average recovery in exhaled air was 95 per cent, SE 7 per cent. The postoperative increase of urinary excretion of fluoride and organic fluorine accounted for less than 0.2 per cent of fluorine administered as isoflurane. This small extent of biotransformation is probably biologically insignificant, but only after extensive clinical experience can the hazard of delayed toxic response be conclusively evaluated.