Michio Morio

Reaction of sevoflurane and its degradation products with soda lime : toxicity of the byproducts

Sevoflurane previously has been reported to undergo extensive degradation in the presence of soda lime. To more completely characterize the extent and significnce of this reaction, we studied degradation of sevoflurane with and without soda lime, as well as the toxicity and mutagenicity of the degradation products. Two degradation products detected were CF2 = C(CF3)OCH2F (compound A) and CH3OCF2CH(CF3)OCH2F (compound B). During circulation of 1%, 2%, and 3% sevoflurance in a closed anesthesia circuit for 8 h, peak concentrations of compound A were 13.3 +/- 0.27, 30.2 +/- 0.10, and 42.1 +/- 1.07 ppm at 2 h, respectively. The concentrations of compound B did not exceed 2 ppm. The temperature of the soda lime was 43.3 +/- 2.8 degrees C at 1 h and increased gradually to 47.9 +/- 1.5 degrees C after 8 h. In closed flasks with soda lime, the magnitude of the decrease in sevoflurance concentrations (3%) and of the increase in compound A concentrations was temperature dependent. The peak concentrations of compound A at 23 degrees C, 37 degrees C, and 54 degrees C were 32.8 +/- 6.8 at 2 h, 46.6 +/- 1.0 at 0.5 h, and 78.5 +/- 2.3 ppm at 0.5 h, respectively. The LC50 (50% lethal concentration) of compound A in Wistar rats was 1,090 ppm in males and 1,050 ppm in females exposed for 1 h. The LC50 was 420 ppm in males and 400 ppm in females exposed for 3 h. The chronic toxicity of compound A in Wistar rats was studied by exposing rats 24 times, for 3 h each, to initial concentrations of 30, 60, or 120 ppm in a ventilated chamber. At all concentrations, there were no apparent effects other than a loss of body weight in females (120 ppm) on the final day (P < 0.01). Compound A did not induce mutation on the reverse (Ames) test at less than 2,500 micrograms/dish (culture medium 2.7 ml) with activation by S-9 mixture, and below 1,250 micrograms/dish (culture medium 2.7 ml) without activation, in four strains of S. typhimurium and in 1 strain of E. coli. Exposure of fibroblasts to 7,500 ppm of compound A for 1 h, compound A did not induce structural change. In a study of acute toxicity of compound B, there was no toxicity in Wistar rats after 3 h of exposure at 2,400 ppm. The reverse (Ames) test for compound B was negative at 625-1,250 micrograms/dish.(ABSTRACT TRUNCATED AT 400 WORDS)

Volatile Metabolites of Halothane in the Rabbit

To date, carbon dioxide is the only volatile metabolite that has been identified to result from the biotransformation of halothane. This study was undertaken to determine whether other volatile metabolites might be formed. Expiratory gas from four rabbits given halothane by inhalation and from three rabbits into which the halothane was injected intraperitoneally was analyzed by gas chromatography. Qualitative analysis of the metabolites was made by injecting 50–70 µ1 of the expired halothane condensed in an ultralow-temperature device (−80 C) attached to the mass spectrometer. Gas chromatography revealed two volatile metabolites between the air peak and the halothane peak. They were identified by mass spectra to be CF2:CHCl and CF3CH2Cl. These volatile metabolites appeared immediately after the beginning of anesthesia. The present investigation suggests the possible existence of a previously unknown metabolic pathway of defluorination and debromination occurring in the early stage of halothane biotransformation. These volatile metabolites may be toxic, highly reactive intermediates that undergo further biotransformation.

A possible role of cytochrome P450 in anaerobic dehalogenation of halothane

Abstract NADPH reduced rabbit liver microsomal enzymes catalyzed anaerobic dehalogenation of halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) to produce CF2CHCl and CF3CH2Cl. Anaerobic dehalogenation was optimal at pH7.4 and was blocked by either oxygen or carbon monoxide. The degree of inhibition of anaerobic dehalogenation by carbon monoxide was closely correlated to the proportion of carbon monoxide complex of cytochrome P450. Anaerobic dehalogenation was enhanced by pretreatment of the animals with phenobarbital but not with methylcholanthrene.

Anaerobic dehalogenation of halothane by reconstituted liver microsomal cytochrome P-450 enzyme system☆

Abstract Cytochrome P-450 from liver microsomes of phenobarbital-treated rabbits catalyzed anaerobic dehalogenation of halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) when combined with NADPH and NADPH-cytochrome P-450 reductase. Cytochromes P-450B1 and P-448 from liver microsomes of untreated rabbits were less active. Triton X-100 accelerated the reaction. Unlike anaerobic dehalogenation of halothane in microsomes, the major product was 2-chloro-1,1,1-trifluoroethane and 2-chloro-1,1-difluoroethylene was negligible. These products were not detected under aerobic conditions, and dehalogenation activity was inhibited by carbon monoxide, phenyl isocyanide and metyrapone.

Biotransformation of isoflurane: urinary and serum fluoride ion and organic fluorine

The serum and urinary concentrations of fluorinated metabolites of isoflurane after inhalation of three different concentrations of isoflurane were studied in 18 ASA physical status 1 or 2 patients, scheduled for orthopedic or otolaryngeal surgery. Isoflurane was administered for 60 min during fentanyl-nitrous oxide-oxygen, and its end-tidal concentration was maintained at 0.3, 0.6, or 1.15% (groups I, II, and III). The organic fluorine was determined by combustion and fluoride ions were analyzed by ion chromatography. The amounts were expressed in terms of fluoride ion. The concentrations of serum fluoride ion and organic fluorine increased significantly 15 min after the onset of inhalation of isofluorane. The mean peak values of fluoride ions were 3.8 ± 1.1, 3.9 ± 1.4, and 4.2 ± 0.9 mole/1 (M ± SD) in patients in groups I, II, and III, respectively. The half-lives of fluoride ion and of organic fluorine as metabolites of isoflurane, calculated from the amounts excreted in urine, were 36 h and 41 h, respectively. The cumulative amounts of fluoride ion and organic fluorine excreted up to the 6th postoperative day were 548 ± 230 and 785 ± 452 moles in group I, 594 ± 138 and 1,378 ± 807 moles in group II, and 1,302 ± 496 and 728 ± 265 moles (M ± SD) in group III, respectively. The urinary excreted fluoride ion increased in proportion to the dose of isoflurane and approximately 1.3 mmol was excreted per 1 MAC X hour inhalation of isoflurane. The authors concluded that isoflurane might be biotransformed to a greater extent than reported previously, although the serum fluoride ion level was found to be low.

Biotransformation and toxicity of inhalational anaesthetics

SummaryIn summary, anaesthetics and drugs used perioperatively are all xenobiotics and can be metabolized mainly by microsomal enzyme systems, which have a high activity in the liver. These enzyme systems are induced by repeated pre-administration of drugs, such as barbiturates and others which are used during the preoperative period. However, according to some reports, aerobic and anaerobic metabolism is inhibited by the simultaneous administration of drugs, such as isoflurane and halothane, halothane and enflurane, and cimetidine and halothane.Hypoxia is also an important factor in hepatic disorders and it is well known that anaerobic metabolism of halothane is increased by hypoxia and its intermediate production produces a free radical. Theoretically, this free radical is involved in hepatic disorders.In practice, in order to prevent hepatic dysfunction before, during and after anaesthesia, hypoxia and repeated pre-administration of enzyme-inducing drugs should be avoided. However, the choice and combination of drugs which inhibit drug metabolism and prevent hepato and/or nephro toxicity should be examined by further investigation.RésuméLes agents anesthésiques et autres médicaments utilisés dans la période péri-opératoire sont tous xénobiotiques et peuvent être métabolisés surtout par les systèmes enzymatiques du microsome, qui ont une activité élevée dans le foie. Ces systèmes enzymatiques sont induits par une pré-administration répétée de certaines substances, telles les barbituriques et autres qui sont utilisés pendant la période pré-opératoire. Cependant, selon certains travaux, le métabolisme aérobique et anaérobique est inhibé par l’administration simultanée de substances, telles l’isoflurane et l’halothane, l’halothane et l’enflurane, et la cimetidine et l’halothane.L’hypoxie est aussi un facteur important dans 1’apparition des problèmes hépatiques et il est bien connu que le métabolisme anaérobique de l’halothane est augmenté par l’hypoxie, et à un stage intermédiaire produit des radicaux libres. Sur une base théorique ces radicaux libres sont impliqués dans les dysfonctions hépatiques.En pratique, dans le but de prévenir la dysfonction hépatique avant, pendant et après l’anesthésie, il faut éviter l’hypoxie et l’administration répétée d’inducteurs enzymatiques avant l’anesthésie. Cependant, le choix et la combinaison de substances qui inhibent le métabolisme des médicaments et préviendront l’hépato ou la néphrotoxicité devrait faire 1’objet de travaux dans le futur.

Clinical Classification and Incidence of Malignant Hyperthermia in Japan

Denborough and Lovell [1] first described malignant hyperthermia (MH) as an inherited syndrome in 1960. At present, it is generally accepted that MH is triggered by many anesthetics. Succinylcholine chloride (SCC) and volatile anesthetics have been especially implicated as important triggering drugs [2,3]. With these triggering drugs, induced hypermetabolism produces tachycardia, increased O2 consumption and CO2 production, premature ventricular contraction, hypotension and hypertension, cyanosis, tachypnea, muscle rigidity, and hyperthermia as the signs of MH. Also seen as complications of MH are electrolyte imbalances, myoglobinuria, hyperkalemia, creatine phosphokinase (CPK) elevation, impaired coagulation, renal failure, and severe metabolic and respiratory acidosis.

Knee-chest position improves pulmonary oxygenation in elderly patients undergoing lower spinal surgery with spinal anesthesia

STUDY OBJECTIVE To define the effect of the knee-chest position on pulmonary oxygenation in patients who underwent lower spinal operations under spinal anesthesia. DESIGN Clinical, prospective study. SETTING Inpatient anesthesia and orthopedic surgery clinic at a municipal hospital. PATIENTS Fifty-six patients (30 males and 26 females) who underwent lower spinal surgery under spinal anesthesia. INTERVENTIONS After administering hyperbaric tetracaine solution and fixing the anesthesia level in the supine position for 15 minutes, patients were turned to the knee-chest position. They breathed room air normally. MEASUREMENTS AND MAIN RESULTS Arterial blood gas tensions were measured in the supine position 15 minutes after administration of the tetracaine solution and 15 minutes after turning patients to the knee-chest position. Patients were classified into six groups according to their age: patients in their teens and 20s, 30s, 40s, 50s, 60s, and 70s. In the supine position, the mean values of the alveolar arterial oxygen tension difference (A-aDO2) of patients in their 50s, 60s, and 70s were significantly higher than those of patients in their teens and 20s, 30s, and 40s. In the knee-chest position, these high values of A-aDO2 in the older patient groups decreased significantly, thereby eliminating any significant difference in A-aDO2 among all age groups. To determine the mechanism of the improvement of pulmonary oxygenation in the elderly patients, the effect of the knee-chest position on lung volumes was studied in eight young volunteers. CONCLUSION A significant improvement of pulmonary oxygenation was seen in elderly patients who underwent lower spinal operation with spinal anesthesia when they were turned to the knee-chest position. The knee-chest position has a beneficial effect on pulmonary oxygenation in elderly patients who are given spinal anesthesia.

Dose-related Sevoflurane Metabolism to Inorganic Fluoride in Rabbits

Serum concentrations and urinary excretion of inorganic fluoride (fluoride ion), a metabolite of sevoflurane, were measured by an ion-chromatographic analyzer after inhalation of three different concentrations of sevoflurane in adult, male Japanese white rabbits weighing 2.6-3.6 kg. Sevoflurane was administered at concentrations of 0% (control), 1%, 2% and 3% (Groups I, II, III and IV, respectively) through a sevoflurane vaporizer for 2 hr under controlled ventilation. Blood and urine samples were collected during and after termination of sevoflurane inhalation at scheduled time intervals for 24 hr. The total volume of urine, the urinary pH and the osmolality of serum and urine were not significantly different among any of the groups. Osmolality of the serum and urine was within normal range in all groups of animals. The mean serum peak values of fluoride ion were 0.7 +/- 0.5, 22.8 +/- 8.7, 31.8 +/- 11.0 and 41.5 +/- 13.2 microM (mean +/- SD) in groups I, II, III and IV, respectively. Peak values were recorded within 15 min after the termination of inhalation. The cumulative amounts of fluoride ion excreted in urine in 24 hr were calculated to be 5.0 +/- 1.6, 26.1 +/- 6.7, 41.4 +/- 11.3 and 64.3 +/- 18.0 mumol (mean +/- SD) in groups I, II, III and IV, respectively. Regression analysis revealed significant correlations between the formation and excretion of fluoride ion, and the dose of sevoflurane (r = 0.85, p less than 0.05 and r = 0.89, p less than 0.05, respectively). The authors conclude that the formation and excretion of fluoride ion after sevoflurane anesthesia is dependent on the dose of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Excretion of trifluoroacetic acid as a metabolite of halothane in digestive juices.

The excretion of trifluoroacetic acid (TFAA) in bile, saliva and gastric juice of two groups of guinea pigs with bile fistulae was measured by ion-chromatography during inhalation of halothane (0.25% and 1.0% ) for two hours and after inhalation of halothane. In another two groups without bile fistulae, excretion of TFAA was measured in saliva and gastric juice during and after inhalation of same concentrations of halothane.The excretion of TFAA increased with time and showed the highest concentrations in the saliva. The highest excretion rate and cumulative amounts of excreted TFAA were observed in bile. The cumulative amounts of TFAA excreted into the bile, saliva and gastric juice was 4.85±1.87 μmol, 0.89±0.62 μmol, 0.11 ± 0.06 μmol, respectively, after inhalation of 0.25% halothane and 5.36±2.29 μmol, 1.50±0.59 μmol, 0.25±0.19 μmol, respectively, after inhalation of 1.0% halothane. The excretion of TFAA in bile and saliva was saturated after inhalation of the higher concentration of halothane. The excretion of TFAA into the gastric juice was higher with 1.0% concentration of halothane and in animals without bile fistulae.We concluded that TFAA a metabolite of halothane is excreted not only in bile but also in saliva and gastric juice. Biotransformation of halothane in salivary glands seems very likely. A small amount of TFAA excreted in bile enters the enterohepatic circulation. The excretion of TFAA in digestive juice seems to be controlled by a rate-limiting mechanism.