Concentration-Dependence of Halothane Metabolism in Rabbits

Effect of end-expiratory halothane concentration on its aerobic and anaerobic metabolism was studied in 20 male rabbits. Biliary excretion of trifluoroacetic acid (TF AA), an aerobic metabolite of halothane, and the pulmonary excretion of CF2CHCl (CDFF) and CF3CH2Cl (CTFE), anaerobic metabolites of halothane, were measured simultaneously during 5 hr of inhalation at various concentrations of halothane (0.02-1.5%). The total amount of biliary TF AA excreted for 5 hr remained unchanged (38.4μmol- 44.lμmol) at each concentration except 0.02%. However, the total amount of CDFE and CTFE excreted for 5 hr increased in a concentration-dependent manner up to 0.5% end-expiratory halothane, and remained unchanged (47.2μmol-64.7μmol) at more than 0.5%. Total biliary excretion of TF AA reached its maximum at a 0.05%. These results suggest that the primary route of halothane metabolism at a subanesthetic concentration is the aerobic pathway which produces TF AA. However, at anesthetic concentration exceeding 0.5%, the anaerobic route which produces volatile CDFE and CTFE plays a role also as an aerobic route.This study was supported in part by Science Research Grants from the Ministry of Education, Science and Culture of Japa

Decomposition of Sevoflurane by Sodalime

Stability of sevoflurane (fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether), a new inhalational anesthetic, in sodalime was examined, and the products of their reaction were identified and quantitated. Five reaction products were identified: fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether, a dehydrofluorination product of sevoflurane which is contained as an impurity in sevoflurane preparations, fluoromethyl 2-methoxy-2,2-difluoro-1-(trifluoromethyl)ethyl ether, a methylation product of fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether and/or sevoflurane, fluoromethyl 2-methoxy-2,2-difluoro-1-(difluoromethylene)ethyl ether and two isomers of fluoromethyl 2-methoxy-2-fluoro-1-(trifluoromethyl)vinyl ether, dehydrofluorination products of fluoromethyl 2-methoxy-2,2-difluoro-1-(trifluoromethyl)ethyl ether. In a closed anesthetic circuit with sodalime connected to a model lung, fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether increased and reached a plateau. Fluoromethyl 2-methoxy-2,2-difluoro-1-(trifluoromethyl)ethyl ether increased linearly and other substances were detected only in a trace amount. In the semi-closed anesthetic circuit with sodalime supplied with 6 liters/min fresh gas flow, no reaction products were detected except fluoromethyl 2,2-difluoro-1- (trifluoromethyl)vinyl ether, which showed a maximum concentration of 2 and 4 ppm when the feeding concentration of sevoflurane was 1.7 and 2.7%, respectively. It is known that fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether is a weak anesthetic with AC_50 =3.58%, LC_50 =10.17% and AI=2.84. These results indicate that sevoflurane can be used with sodalime in a semi-closed anesthetic circuit.This study was supported in part by a Grant-in-aid for Science Research from the Ministry of Education, Science and Culture of Japan and a Grant-in-aid from the Association for the Advancement of Medicine of the Tsuchiya Foundation

Effect of General Anesthesia on Plasma Ascorbic Acid Level

Ascorbic acid (AsA) and dehydroascorbic acid (DHA) in plasma, and the total vitamin C (AsA + DHA) in urine after oral surgery were measured to investigate whether general anesthesia has effects on the level of plasma AsA. Plasma AsA decreased significantly on the 1st and 3rd post-operative day in the general anesthesia group, but not in the local anesthesia group. A decrease in the AsA level was seen in both the halothane group and the neuroleptanesthesia group. Plasma DHA was not detected pre-operatively, but increased post-operatively and the total vitamin C in the urine decreased on the 1st post-operative day in the general anesthesia group. It was concluded that general anesthesia caused a decrease in the plasma AsA level. This can be only partially explained by the oxidation of AsA. We are going to investigate other causes as the degree of decrease of AsA was larger than the degree of increase of DHA

Pharmacokinetic Study on Excretion of Inorganic Fluoride Ion, a Metabolite of Sevoflurane

Blood and urinary inorganic fluoride ion concentration was determined in six healthy volunteers after inhalation of 2% sevoflurane for one hour. The serum inorganic fluoride ion concentration increased 30 min after discontinuation of inhalation to 14.8 ± 3.0 μmol/liter, which was about 10 times higher than the level before inhalation. The serum elimination constant of inorganic fluoride was calculated to be 0.000467 and the half-life was 1,487 min. The urinary excretion rate of inorganic fluoride ion was the highest ( 452 nmol/min) after 12-24 hr. The urinary excretion rate constant of inorganic fluoride was calculated to be 0.000268 and the half-life was 2,583 min. The distribution volume of inorganic fluoride excreted in the urine was calculated to be 127 liters. This value showed that fluoride ion produced in the cell cannot readily pass through the cell membrane due to its polarity, resulting in a delay of the maximum excretion rate of inorganic fluoride until the first or second day after inhalation of the anesthetic.This study was supported in part by a Grant-in-aid for Science Research from the Ministry of Education, Science and Culture of Japan and a Grant-in-aid from the Association for the Advancement of Medicine of the Tsuchiya Foundation

Urinary Excretion of Inorganic and Organic Fluoride after Inhalation of Sevoflurane

This study was designed to investigate the defluorination of sevoflurane in patients. Five patients, scheduled for orthopedic surgery, were administered sevoflurane for 60 min during NLA-nitrous oxide-oxygen. The end-tidal concentration of sevoflurane was adjusted at 0.6% throughout the entire inhalation period. The serum concentration of inorganic F- increased significantly 15 min after the onset of inhalation and reached a plateau at 45 min with a mean value about 15 μM. The serum organic fluoride level increased significantly 45 min after the onset of inhalation and did not change significantly 4 hr later with a mean value of about 140 μM. The elimination half-lives and rate constants were calculated from urinary data to be 2040 min and 0.00034 for inorganic fluoride and 1800 min and 0.00038 for organic fluoride respectively. The ratio organic/inorganic fluoride was calculated to be 2.3.This study was supported in part by a Grant-in-aid for Science Research from the Ministry of Education, Science and Culture of Japan

Clinical Effects of Halothane Concentration on Trifluoroacetic Acid Excretion in Urine

Excreted amount of urinary trifluoroacetic acid (TFA) during and after halothane anesthesia in twelve surgical patients was determined isotachophoretically. The levels of urinary TFA which amount was zero or a trace during the anesthesia increased after discontinuation of halothane inhalation. The values of daily excreted TFA were the highest on the 2.1±0.3 postoperative day (M±SEM). The urinary TFA values of patients inhaling a low concentration (0.8%) of halothane reverted to zero or a trace level on the 11.2±1.0 postoperative day (M±SEM) and the total amount of averaged 21.53 ± 3.23 mmol (M ± SEM). In patients to levels seen on the 7 .0 ± 0.6 postoperative day (M±SEM) and the total amount of TFA excreted was 20.20±4.77 mmol (M±SEM). These clinical findings indicate that the aerobic biotransformation of halothane after anesthesia is enhanced by high concentration of halothane.Supported in part by Research Grants No.57480297 and 57570564 from the Ministry of Education, Science and Culture, Japan. Presented in part at the 7th World Congress of Anesthesiologists, Hamburg, September 1980

Clinical Evaluation and Metabolism of Sevoflurane in Patients

Sevoflurane was submitted to Phase II studies in patients following Phase I studies. Sevoflurane, 2% inspired during maintenance, was administered with 50% N2O in oxygen to produce surgical anesthesia in 9 orthopedic patients of ASA Physical Status I. Under controlled ventilation, endotracheal concentration of sevoflurane was recorded. The blood concentration of sevoflurane was measured during and after the inhalation. Serum, urinary inorganic fluoride, and glucuronide of hexafluoroisopropanol were analysed with ion chromatographic analyzer. The patient inhaled sevoflurane for 3.5 ± 1.6 hr. All the patients were anesthetized and operated uneventfully. Postoperative laboratory findings showed no unexplainable abnormality. The end expiratory concentration of sevoflurane reached a plateau in 4.0 ± 0.8 min and fell rapidly after discontinuation of sevoflurane. Blood concentration of sevoflurane was about 500 μM during inhalation. It decreased promptly after termination of sevoflurane and was not correlated with anesthetic time. The time for verbal response after discontinuation was 11.8 ± 4.2 min. The serum concentration of inorganic fluoride increased after inhalation and reached a plateau (13.7 ± 8.2 μM) in 120 min. The level lasted for 120 min after anesthesia and fell by half at 12 hr after anesthesia. Urinary fluoride concentration varied from 20 to 3,000 μM during the first 12 hr urine, and showed its maximum in the first postoperative 12 or 24 hr urine. The findings that sevoflurane with nitrous oxide and oxygen produced surgical anesthesia without any sequelae and that the serum fluoride level did not exceed the nephrotoxic level warrent the further clinical evaluation in a wider range of subjects.A part of this work was supported by a Research Grant from the Japanese Ministry of Education, Science and Culture and presented at the 8th European Congress of Anaesthesiology, Vienna, Austria, in September, 1986

Influence of polypharmacy on heart rate variability in older adults at the Hiroshima Atomic Bomb Survivors Recuperation Research Center, Japan.

BackgroundMany studies have identified the risk of polypharmacy, but physiological evidence and methods of evaluation in these studies were poor. The relationship between polypharmacy and heart rate variability in older adults remains unclear. We investigated the relationship between polypharmacy in older adults, including atomic bomb survivors, and heart rate variability.MethodsWe surveyed 56 older adults who did not need nursing care assistance in the Hiroshima Atomic Bomb Survivors Recuperation Center. Chronic diseases, types of medication, and lifestyle were assessed, and heart rate variability at rest was measured. We calculated heart rate variability indices including standard deviation of normal-to-normal RR intervals (SDNN), total power (TP), and very low frequency (VLF) and analyzed the relationship between the number of daily medication types and heart rate variability indices in older adults. The differences in heart rate variability indices were analyzed using six medications as a cut-off point.ResultsParticipants included 36 atomic bomb survivors and 20 non-atomic bomb survivors. The mean number of medication types was 3.6±3.4 (mean±standard deviation). SDNN, TP, and VLF decreased with an increased number of medications in all participants (PConclusionsWe found that a lower heart rate variability in older adults, including atomic bomb survivors, is associated with polypharmacy. We showed physiological evidence of the influence of polypharmacy, which may be important for the healthy life expectancy and prognosis in older adults