Emeritus Faculty, Acad Council, Anesthesiology, Perioperative and Pain Medicine
Methoxyflurane metabolism and renal dysfunction: clinical correlation in man. By Richard I. Mazze, James R. Trudell, and Michael J. Cousins. Anesthesiology 1971; 35:247-52. Reprinted with permission. Serum inorganic fluoride concentration and urinary inorganic fluoride excretion were found to be markedly elevated in ten patients previously shown to have methoxyflurane induced renal dysfunction. Five patients with clinically evident renal dysfunction had a mean peak serum inorganic fluoride level (190 +/- 21 microm) significantly higher (P < 0.02) than that of those with abnormalities in laboratory tests only (106 +/- 17 microm). Similarly, patients with clinically evident renal dysfunction had a mean peak oxalic acid excretion (286 +/- 39 mg/24 h) significantly greater (P < 0.05) than that of those with laboratory abnormalities only (130 +/- 51 mg/24 h). That patients anesthetized with halothane had insignificant changes in serum inorganic fluoride concentration and oxalic acid excretion indicates that these substances are products of methoxyflurane metabolism. A proposed metabolic pathway to support this hypothesis is presented, as well as evidence to suggest that inorganic fluoride is the substance responsible for methoxyflurane renal dysfunction.
View details for Web of Science ID 000240932400030
View details for PubMedID 17006084
Despite mounting clinical evidence that supports its safety, the question of the potential adverse effects of sevoflurane on renal function continues to generate some controversy. This study retrospectively evaluated pooled renal laboratory data from 22 different clinical trials that compared sevoflurane with three widely used anesthetics. The trials examined postoperative changes in serum creatinine and blood urea nitrogen levels from a total of 3, 436 ASA physical status I-IV adult surgical patients administered either sevoflurane (n = 1941) or a control drug (isoflurane, enflurane, or propofol; n = 1495) as the maintenance anesthetic. The incidences of increased serum creatinine and blood urea nitrogen concentrations were similar among patients administered sevoflurane and those administered control drugs. Additionally, no trends specific to sevoflurane were observed with respect to postoperative serum creatinine concentration and fresh gas flow rate, concurrent treatment with nephrotoxic antibiotics, or type of carbon dioxide absorbent.Our data for changes in serum creatinine and blood urea nitrogen indicate that, for exposures of less than 4 minimum alveolar anesthetic concentration/h, sevoflurane is not associated with an increased risk of renal toxicity compared with other commonly used anesthetics. For clinical purposes, the pre- to postoperative changes in serum creatinine and blood urea nitrogen are appropriate measures of renal function in surgical patients.
View details for Web of Science ID 000085562800032
View details for PubMedID 10702457
The effect of trace levels of waste anesthetic gases on the health of postanesthesia care unit (PACU) nurses who work in an unscavenged environment has been questioned, although it seems likely that levels of trace gases in the PACU would be much lower than those in the operating room. In this study, we documented nitrous oxide levels in the ambient air of two large PACUs. Nitrous oxide levels were measured using a time-weighted average monitor worn by 33 PACU workers at two different hospitals for the duration of their shifts. On the same day, patient data were collected at the time of admission to the PACU. Data included age and weight of the patient, type of surgery, anesthetic technique, and end-tidal level of nitrous oxide immediately before the patient left the operating room. The mean time-weighted average nitrous oxide level in PACU A was 2.0 ppm (range 0-6.4); in PACU B, it was undetectable, i.e., < 2.0 ppm. Levels of nitrous oxide to which PACU patient care personnel are exposed are well below the National Institute of Occupational Safety and Health and Occupational Health and Safety Administration recommended exposure level of 25 ppm measured for the duration of anesthetic administration. Implications: Our results indicate that the levels of nitrous oxide in postanesthesia care units with well maintained, modern ventilation systems are very low. Previous research suggests that the health of workers exposed to these levels should not be adversely affected.
View details for Web of Science ID 000081767400042
View details for PubMedID 10439769
Evidence of developmental toxicity of clinically used nondepolarizing muscle relaxants was sought in rat embryos grown in culture. Embryos were explanted at 8 AM on day 9 of gestation (presomite stage, plug day = day 0), and were cultured in rotating bottles with medium containing various concentrations of d-tubocurarine, pancuronium, atracurium, and vecuronium. At 10 AM on day 11 of gestation (forelimb bud stage), culture was terminated and embryos were examined for general morphology. Treatment with tested agents resulted in dose-dependent developmental toxicity; namely, growth retardation seen as decreased crown-rump length, decreased number of somite pairs, and morphologic abnormalities. However, the concentrations that caused toxicity were at least 30-fold greater than serum concentrations clinically achieved in the mother. We conclude that these muscle relaxants have a low potential for causing developmental toxicity during organogenesis.
View details for Web of Science ID A1992HY13700021
View details for PubMedID 1350890
Regional anesthesia with bupivacaine in pediatric patients is often accompanied by light levels of halothane general anesthesia. To determine the potential cardiotoxicity of these two drugs when used together, we defined the interaction between moderate plasma bupivacaine concentrations (1270-1760 ng/mL) and halothane (end-tidal concentrations, 0.5%-1.0%) on ventricular contractility and conduction in 22 closed-chest dogs anesthetized with chloralose. Bupivacaine alone (1-mg/kg intravenous bolus plus a 0.1-mg.kg-1.min-1 constant rate infusion) resulted in significant increases in ventricular conduction time (VCT) and effective refractory period (VERP) and nonsignificant decreases in dP/dtmax and blood pressure. The addition of halothane resulted in hypotension and in progressively increasing plasma bupivacaine levels secondary to reduced hepatic clearance, which led to further dose-related significant increases in VCT and VERP and to significant decreases in dP/dtmax and blood pressure. In other dogs given halothane but in which bupivacaine levels were held constant (1400 ng/mL), VCT remained constant and VERP lengthened slightly, whereas dP/dtmax decreased. We conclude that the combination of bupivacaine and halothane can cause adverse effects on ventricular contractility and intraventricular conduction.
View details for Web of Science ID A1991GG68500012
View details for PubMedID 1897769
Data from three Swedish health care registries--the Medical Birth Registry, the Registry of Congenital Malformations, and the Hospital Discharge Registry--were linked for the 9-year period 1973-1981 to identify women who had appendectomy during pregnancy and their offspring, and to determine several pregnancy outcomes (gestational duration, birth weight, perinatal mortality, and congenital anomalies). Among the 720,000 deliveries during this period, 778 were complicated by appendectomy (one in 936), and the diagnosis of appendicitis was confirmed in 64% of the cases (one in 1440). Significant findings included: 1) an increase in the risk of delivery the week after appendectomy when the operation was performed after 23 weeks' gestation, with no further increase if the pregnancy continued beyond 1 week; 2) a decrease in mean birth weight of 78 +/- 24 g with more infants than expected weighing less than 3000 g; 3) an increase in the number of live-born infants dying within 7 days of birth; 4) no increase in the number of stillborn infants; and 5) no increase in the number of congenitally malformed infants.
View details for Web of Science ID A1991FN40100007
View details for PubMedID 2030853
In previous studies, we have shown that the reproductive toxicity of N2O in rats is prevented by the co-administration of either halothane or isoflurane, whereas treatment with folinic acid, which should reverse the effects of N2O on DNA production, does not prevent toxicity. These results cast doubt on the commonly held theory that inactivation of methionine synthase is the sole cause of N2O-induced reproductive toxicity, and suggest the need for other hypotheses. One such possibility is that N2O causes adverse reproductive toxicity secondary to its sympathomimetic effects. As a first step to test this theory, we studied the effects of phenoxybenzamine (PX), an alpha-1 adrenergic antagonist, on N2O-induced reproductive toxicity using a well-established in vivo rat model. On day 8 of gestation (plug day = day 0), 130 timed-pregnant Sprague-Dawley rats were injected s.c. with either 0.5 ml of either 0.9% saline (control and N2O alone groups) or PX (0.5, 5, or 50 micrograms/kg) in 0.9% saline, the latter the maximum tolerated PX dose. They were then exposed to either air (control) or 60% N2O for 24 hours (all other groups). On day 20 of gestation, cesarean sections were performed and the fetuses were removed and examined for either visceral of skeletal abnormalities. Compared with control, treatment with N2O alone resulted in increased incidences of fetal resorptions, major and minor visceral abnormalities, and minor skeletal abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1991EV80500006
View details for PubMedID 2014480
Swedish health care registries were used to identify women who had surgery during pregnancy and their offspring. Among the 2,252 infants born to women who had first trimester operations during 1973-1981, six had definite diagnoses of neural tube defects (expected number, 2.5). Scrutiny of the records showed that 572 operations occurred during gestational weeks 4-5, the period of neural tube formation, and that the mothers of five of the six infants with neural tube defects had an operation during that period (expected number of neural tube defects, 0.6) although one of the offspring probably had Meckel's syndrome. The relationship between neural tube defects and operation during pregnancy is discussed including the possibility that the association may be random.
View details for Web of Science ID A1990DJ59100007
View details for PubMedID 2353318
Intraventricular conduction disorders and reentrant arrhythmias in dogs can be produced by high plasma bupivacaine concentrations. The authors' aim was to determine if these conduction disturbances also occurred at moderate plasma bupivacaine concentrations (2.2-3.7 micrograms/ml) when in association with other factors which affect intracardiac conduction, such as hyponatremia and hyperkalemia. Thus, duration of the QRS complex, ventricular conduction time, and effective refractory period (ERP) was measured during ventricular pacing at 180 beats per min in 46 anesthetized, closed-chest dogs separated into five treatment groups as follows: group I, an iv bolus of 4 mg/kg of bupivacaine plus an infusion of 0.1 mg.kg-1.min-1 of bupivacaine followed in 50-60 min by 10 ml.kg-1.min-1 of 1.5% glycine iv to produce dilutional hyponatremia; group II, 1.5% glycine alone, as above; group III, bupivacaine, as above, followed in 50-60 min by 0.05 mmol.kg-1.min-1 of KCl iv to produce hyperkalemia; group IV, KCl alone, as above; and group V, bupivacaine, as above, except that the duration of infusion was 90 min. QRS duration and ventricular conduction time, which were prolonged approximately 33% and 61%, respectively, by bupivacaine alone were additionally prolonged 29% and 44%, respectively, when serum sodium concentration was lowered to 114 mmol/l and potassium concentration was raised to 7.7 mmol/l. The combinations of bupivacaine and hyponatremia, and bupivacaine and hyperkalemia tended to increase ERP more than did bupivacaine alone, although these changes were not statistically significant. Wave burst arrhythmias and episodes of ventricular tachycardia occurred spontaneously or were triggered by pacing in those dogs in which conduction time was most prolonged.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1990DH68800016
View details for PubMedID 2350020
Seventy timed-pregnant Sprague-Dawley rats were exposed to either air (control) or 75% nitrous oxide (N2O) for 24 hours on day 8 of gestation. Four rats from each group were killed on days 11-16, 18, and 20, and laparotomy was performed. The viability of the embryos/fetuses was determined, as was the side of tail flexion on days 11 and 12, the direction from which the umbilical artery emerged from the body on days 13 and 14, the side of the body facing the placenta on days 15 and 16, and the side to which the aortic arch curved on days 18 and 20. Mean mortality rate in the control group was 8.9 +/- 6.1% (+/- S.D.), and there were no control embryos/fetuses with altered laterality except the 9% that faced left on day 16. In contrast, N2O treatment on day 8 of gestation resulted in significantly increased mortality (40.8 +/- 3.3%) beginning on day 14 of gestation and increased incidence of altered laterality overall (31.3%) and at all stages of development. The mechanisms underlying these events remain to be defined, as do the implications of our findings for pregnant surgical patients and occupationally exposed workers.
View details for Web of Science ID A1990CM38300001
View details for PubMedID 2321158
The susceptible period of nitrous oxide (N2O) teratogenicity was studied in 170 Sprague-Dawley rats. Seven groups of 20 timed-pregnant rats were exposed to 60% N2O for 24 hours on each of days 6-12 of gestation; a control group of 30 timed-pregnant rats was exposed to air on day 9. On day 20 of gestation, dams were killed and reproductive indices were determined; their fetuses were subsequently examined for external, skeletal, and visceral abnormalities. There were no differences among the groups in the number of implantations and live fetuses, mean fetal weight, and sex ratio. The incidence of fetal wastage was higher than control in N2O-treated groups exposed on days 8 and 11 of gestation. Skeletal malformations of the ribs and vertebrae were increased following exposure on day 9 of gestation. However, the specific minor anomaly, cervical rib, was increased only following exposure on day 8 of gestation. The incidences of right-sided aortic arch and left-sided umbilical artery, abnormalities indicative of altered laterality, were increased following exposure on day 8 of gestation. Nitrous oxide administration during organogenesis causes several reproductive defects by mechanisms which remain to be determined.
View details for Web of Science ID A1989CB97200004
View details for PubMedID 2623632
To define the risk of adverse reproductive outcomes after nonobstetric operations during pregnancy, we linked data from three Swedish health care registries, the Medical Birth Registry, the Registry of Congenital Malformations, and the Hospital Discharge Registry, for the years 1973 to 1981. Adverse outcomes examined were the incidences of (1) congenital anomalies, (2) stillborn infants, (3) infants dead at 168 hours, and (4) infants with very low and low birth weights. There were 5405 operations in the population of 720,000 pregnant women (operation rate, 0.75%). The incidences of congenital malformations and stillbirths were not increased in the offspring of women having an operation. However, the incidences of very-low- and low-birth-weight-infants were increased; these were the result of both prematurity and intrauterine growth retardation. The incidence of infants born alive but dying within 168 hours also was increased. No specific types of anesthesia or operation were associated with increased incidences of adverse reproductive outcomes. The cause of these outcomes was not determined.
View details for Web of Science ID A1989CA61800020
View details for PubMedID 2589435
A carcinogen bioassay of isoflurane was performed in groups of Swiss/Webster mice exposed to either air (n = 181), 0.1% isoflurane (n = 167), or 0.4% isoflurane (n = 165), for 4 h per day, 5 days per week. After 78 weeks of exposure, mice were left untreated for 3 weeks and were then killed. Mice killed at this time when they were 86 weeks of age, and those killed or dying at other times during the study were subjected to complete gross and microscopic examination. Throughout most of the study, mean body weights of mice exposed to 0.1% isoflurane and 0.4% isoflurane were less by 1-5% and 5-8%, respectively, than that of mice exposed to air alone. Otherwise, no gross toxic treatment effects were noted. The first neoplastic lesion was detected 23 weeks after starting treatment and, by the end of the study, 190 tumors had been detected in 179 mice. However, there were no statistical differences among the groups in the number of mice with a particular tumor at a specific site, the ratio of benign to malignant tumors, or the time to tumor appearance. It was concluded that isoflurane is unlikely to have carcinogenic potential and is a remarkably non-toxic anesthetic in mice.
View details for Web of Science ID A1988Q772100018
View details for PubMedID 3189921
The teratogenic and postnatal developmental effects of morphine exposure during pregnancy were studied in Sprague-Dawley rats in three separate experiments using chronically implanted osmotic minipumps in order to avoid respiratory depression. In the first experiment, the teratogenic effects of three different morphine dosages were studied: a low dose (10 mg/kg/day), an intermediate dose (35 mg/kg/day), and a high dose (70 mg/kg/day). On day 5 of gestation, osmotic minipumps that deliver their contents at a constant rate for 15 days were implanted subcutaneously on the back of the rats. On day 20 of gestation, cesarean sections were performed, reproductive indices were determined, and fetuses were examined externally and then preserved for subsequent visceral and skeletal examinations. The pregnancy rate was significantly reduced at the intermediate and high doses to 57% and 6%, respectively (control, 83%). No teratogenic effects were observed at any dosage, but growth retardation was present in the intermediate-dose group. In the second experiment, postnatal survival of the offspring of dams treated with either normal saline, morphine (35 mg/kg/day), or the synthetic opioid, fentanyl (500 micrograms/kg/day) were studied. Offspring of morphine-treated dams had a significantly higher mortality rate, which peaked at 56% within 2 days. No effect was seen after fentanyl treatment. In the third experiment, pups of morphine-treated dams were cross-fostered by saline-treated dams; the postnatal mortality in offspring of morphine-treated dams remained high (62%). Our results indicate that doses of morphine up to 35 mg/kg/day delivered by osmotic minipumps are not teratogenic in rats but cause other adverse fetal effects that result in increased postnatal mortality.
View details for Web of Science ID A1988Q752300001
View details for PubMedID 3238597
The teratogenic effects of nitrous oxide (N2O) on postimplantation rat embryos were studied using a whole embryo culture system to separate the direct effects of N2O from those that are maternally mediated. A total of 100, 10-day-old rat embryos were cultured in either a control atmosphere (75% N2, 20% O2, and 5% CO2), or a N2O atmosphere (75% N2O, 20% O2, and 5% CO2). After 22 h of culture embryos were examined microscopically, and protein and DNA contents were determined. DNA content was significantly lower in the embryos exposed to N2O compared with the controls. Additionally, three malformed embryos and four embryos with left-sided tails were observed in the N2O group, whereas no abnormalities were observed in the control group. There were no differences in crown-rump length, somite numbers, limb bud index, and protein content between the two groups of embryos. The positive findings in this study indicate that whole embryo culture is useful for studying the mechanisms of N2O teratogenicity.
View details for Web of Science ID A1988P966800019
View details for PubMedID 3415019
The teratogenic effects of nitrous oxide (N2O) administered with halothane or folinic acid (FA) were studied in two separate experiments using a total of 206 timed-pregnant Sprague-Dawley rats. In each experiment, rats were exposed to either 1) air (n = 30-40); 2) N2O (50-75% for 24 h on day 8 of pregnancy, n = 20-30); 3) test agent (i.e., 0.27% halothane for 24 h on day 8 of pregnancy; or 5 mg/kg/day of FA on day 5-13 of pregnancy, subcutaneously by osmotic pump, n = 20-30); or 4) N2O + test agent (n = 20-30). Cesarean sections were performed on day 20, and fetuses were examined for visceral and skeletal abnormalities. There were no differences in pregnancy rate, number of implantations and live fetuses per rat, and fetal weight among any of the groups. Treatment with N2O resulted in significantly higher incidences of resorptions and of major visceral and minor skeletal abnormalities. Halothane administered with N2O protected against these effects; folinic acid did not. Using an additional 65 nonpregnant rats, hepatic methionine synthase activity was measured after treatment with 50% N2O, 50% N2O plus 0.27% halothane, or 50% N2O plus 5 mg/kg/day of folinic acid. Methionine synthase activity was equally depressed in all groups. These findings do not support the commonly held theory that inactivation of methionine synthase is the sole cause of N2O teratogenicity; rather, they suggest a multifactorial etiology, which may include changes in uterine blood flow.
View details for Web of Science ID A1988P542800003
View details for PubMedID 3262935
The reproductive and teratogenic effects of sufentanil and alfentanil were studied in a total of 168 Sprague-Dawley rats in two separate experiments. Either sufentanil (10, 50, or 100 micrograms.kg-1.day-1) or alfentanil (8 mg.kg-1.day-1) were administered continuously from day 5 through day 20 of pregnancy using subcutaneously implanted osmotic minipumps. Cesarean sections were performed on day 20 of pregnancy, reproductive indexes were determined, and the 1484 fetuses were examined for external, visceral, and skeletal abnormalities. No significant adverse reproductive or teratogenic effects were observed with either narcotic.
View details for Web of Science ID A1988L894400010
View details for PubMedID 2963565
The reproductive and teratogenic effects of nitrous oxide (N2O), isoflurane, and their combination were studied in 130 timed-pregnant rats. Rats were exposed to either air, 0.35% isoflurane (1/4 MAC), 50% N2O (a known teratogenic concentration), or 50% N2O plus 0.35% isoflurane for 24 h on day 8 of pregnancy. On day 20 of pregnancy, cesarean sections were performed; a total of 1268 offspring were delivered and immediately examined for external abnormalities. They were subsequently examined microscopically either for visceral or skeletal abnormalities. N2O caused significantly higher incidences of early and late resorptions, and major visceral malformations. The addition of isoflurane to N2O prevented the majority of these adverse effects. These results cast doubt on the methionine synthase inhibition theory of N2O teratogenicity.
View details for Web of Science ID A1987K989500014
View details for PubMedID 3688539
A rat model was used to determine whether the metabolism of halothane is changed in the presence of cirrhosis and whether exacerbation of liver dysfunction is correlated with such a change. Cirrhosis was produced by gavaging enzyme-induced male Wistar rats with carbon tetrachloride in corn oil once weekly for 12 weeks. Control rats received corn oil only. After a 3-week period without treatment, blood and urine were collected from each rat for determination of background levels of inorganic fluoride, bromide, and trifluoroacetic acid (halothane metabolites) and for assessment of liver function. Rats were then anesthetized with 1.05% halothane in 50% oxygen for 3 h. Following anesthesia, serial blood and urine samples were taken to monitor halothane metabolism and liver function. No differences were observed between cirrhotic and non-cirrhotic rats in serum levels and urinary excretion of halothane metabolites. However, serum levels of SGOT and SGPT were significantly increased about 1.5-fold in the noncirrhotic group and about 2.5-fold in the cirrhotic group after anesthesia. The increased levels observed in the cirrhotic group were significantly greater than in the noncirrhotic group. The results imply that the exacerbation of liver dysfunction after halothane anesthesia is most likely related to an indirect effect, such as change in liver blood flow, rather than to toxic metabolites.
View details for Web of Science ID A1987K611600008
View details for PubMedID 3674465
The reproductive and teratogenic effects of 35% and 50% nitrous oxide, fentanyl 500 micrograms kg-1/day and their combinations were studied using a total of 419 timed-pregnant Sprague-Dawley rats. On day 7 of pregnancy, osmotic minipumps which delivered either fentanyl 500 micrograms kg-1/day or normal saline for 2 weeks were implanted subcutaneously in the back of the rats. Animals then were exposed to air, 35% nitrous oxide or 50% nitrous oxide for 24 h on day 9 of pregnancy. On day 21 of pregnancy, Caesarean sections were performed and all 2693 offspring were preserved and subsequently examined microscopically for external, visceral and skeletal abnormalities. There were no reproductive or teratogenic effects observed with 35% nitrous oxide, but adverse effects were observed with 50% nitrous oxide. The addition of fentanyl to the nitrous oxide increased the mortality rate among the rats, but did not significantly add to the adverse reproductive or teratogenic effects of nitrous oxide.
View details for Web of Science ID A1987K270400018
View details for PubMedID 3676057
The effect of in vitro exposure to nitrous oxide on rat fetal and maternal methionine synthase activity was investigated. Enzyme solutions were prepared from livers of fetuses and mothers on day 19 of gestation and exposed to air, 50% oxygen or 50% nitrous oxide in oxygen for periods up to 24 h. Normal activity of methionine synthase in the fetus was about 65% of that in the mother. Activity decreased by about 25% over 24 h when the enzyme was incubated at 37 degrees C in the presence of either air or 50% oxygen. Nitrous oxide produced a time-dependent decrease in activity which generally was similar for both fetal and maternal enzyme. After 24 h exposure to nitrous oxide, activity has decreased to 14 and 17% of fetal and maternal control values, respectively.
View details for Web of Science ID A1987J438100016
View details for PubMedID 3651273
Male Fischer 344 rats were used to investigate the hepatic effects of exposure to halothane under normoxic conditions (FIO2 = 0.21) in isoniazid-treated rats. Animals were treated with saline or isoniazid (50 mg/kg) for 7 days and then were exposed to either 1% halothane or air for 2 hr. One-half of the rats from each treatment and exposure group were killed 24 hr postexposure; the remaining were killed 4 days postexposure. Twenty-four hours following halothane exposure, serum transaminase levels were significantly elevated in isoniazid- compared with saline-treated rats (i.e., aspartate aminotransferase = twofold; alanine aminotransferase = seven-fold). Cholesterol levels were significantly depressed by halothane exposure in both saline- and isoniazid-treated rats. Other serum parameters indicative of hepatic and renal function were not different: alkaline phosphatase, total protein, total bilirubin, hematocrit, uric acid, creatinine, urea nitrogen, Na+, K+, Ca2+, and inorganic phosphate. Neither saline-treated nor isoniazid-treated rats exposed to air exhibited histologic evidence of hepatic damage. Halothane-exposed rats, however, showed a circumscribed disruption of cellular morphology. The most severe lesions were observed with isoniazid-treated animals with extensive pericentral hepatocellular necrosis and infiltration by leucocytes and Kupffer cells. Serum concentrations of two products of the oxidative metabolism of halothane, trifluoroacetic acid and bromide, were significantly elevated in isoniazid- compared with saline-treated rats. Serum levels of fluoride, a product of reductive metabolism, were not different. These results strongly suggest that hepatic injury following halothane administration can be produced by intermediates of oxidative metabolism.
View details for Web of Science ID A1987G590000005
View details for PubMedID 3564016
The reproductive and teratogenic effects of lidocaine were studied in 155 Sprague-Dawley rats chronically implanted with osmotic minipumps. Three different lidocaine doses were used as follows: a low dose (100 mg X kg-1 X day-1); an intermediate dose (250 mg X kg-1 X day-1); and a high dose (500 mg X kg-1 X day-1). In the low and intermediate dose groups, lidocaine was administered for two weeks before mating and throughout pregnancy to evaluate reproductive and teratogenic effects. In the high-dose group, lidocaine was administered from days 3 to 17 of pregnancy to evaluate teratogenic effects. On day 21, cesarean section was performed and all of the 1,040 offspring, including those from control and positive control (retinoic acid) groups, were preserved and subsequently examined microscopically to detect external, visceral, and skeletal abnormalities. None was found in lidocaine-treated groups; reproductive indices also were normal. The only treatment effect was a reduction in mean fetal weight in the high-dose group. In a subsequent experiment this was found to be secondary to slightly delayed fetal development. It is concluded that lidocaine is devoid of significant adverse reproductive and teratogenic effects in Sprague-Dawley rats.
View details for Web of Science ID A1986F163200010
View details for PubMedID 3789434
Female Sprague-Dawley rats were administered fentanyl continuously using chronically implanted osmotic minipumps for 2 weeks before breeding and during the entire period of pregnancy. Three different fentanyl dosage regimens were employed, i.e., 10, 100, and 500 micrograms/kg/day. Reproductive indices were determined and the 1,046 offspring delivered at cesarean section were examined for external, visceral, and skeletal abnormalities. There were no major or minor reproductive abnormalities or teratogenic findings in any of the fentanyl-treated groups. We conclude that fentanyl is devoid of adverse reproductive effects in this strain of rats up to dosages of 500 micrograms/kg/day administered by osmotic minipumps. From a methodologic point of view, osmotic minipumps facilitate study of the reproductive effects of narcotics as they allow delivery of dosages that ordinarily would not be tolerated without producing severe respiratory depression.
View details for Web of Science ID A1986D941100006
View details for PubMedID 3764777
A carcinogen bioassay of nitrous oxide (N2O) was performed in groups of male and female Swiss-Webster mice exposed to either air (n = 179), 10% N2O (n = 152), or 40% N2O (n = 151) for 4 h per day, 5 days per week. After 78 weeks of exposure, there was a 5-week period without treatment following which surviving mice were killed. Mice killed at this time or dying in extremis at other times were subjected to complete autopsy unless advanced autolysis or cannibalism precluded examination. Mean body weights for male and female mice in the 10% N2O group were the same as those in the air control group throughout the study, whereas they were 5% less in the 40% N2O group. Mean organ weights for N2O-treated mice were not statistically different from those of control mice. Gross and microscopic examination of tissues revealed a variety of neoplastic and nonneoplastic lesions; however, their presence was unrelated to treatment.
View details for Web of Science ID A1986C527700012
View details for PubMedID 3717637
A total of 305 timed-pregnant Sprague-Dawley rats were exposed for 6 h a day on each of three consecutive days in one of three periods, i.e., pregnancy days 14-16, 11-13, or 8-10, either to 0.55 times the minimum alveolar concentration (MAC) of nitrous oxide (75%) or to 0.75 MAC of halothane (0.8%), isoflurane (1.05%) or enflurane (1.65%); an additional 232 positive-control (retinoic acid) and air control rats were studied. Reproductive indices were determined, and the 5178 offspring delivered at cesarean section were examined for external, internal, and skeletal abnormalities. There were no major or minor teratologic effects in anesthetic treated groups, although several developmental variants were observed in halothane- and enflurane-treated groups. Nitrous oxide exposure on days 14-16 resulted in a three-fold increase in fetal resorptions. The results suggest that the volatile anesthetics are not teratogenic and confirm that nitrous oxide may be associated with increased reproductive loss.
View details for Web of Science ID A1986A233400007
View details for PubMedID 3954129
The effects on fertility and reproductive wastage of 110 female Swiss/Webster mice and postnatal survival of their offspring were examined after exposure to either air, 0.4% isoflurane, or 0.1% isoflurane. Treatments were for 4 h daily for 2 weeks before and during pregnancy. In a second experiment, the effects on fertility of 54 male Swiss/Webster mice and on reproductive wastage of their unexposed mates were examined after 4-h daily exposures to either air, 0.4% isoflurane, or 0.1% isoflurane throughout spermatogenesis and during mating. There were no adverse reproductive effects in either experiment. The lack of toxicity of isoflurane is consistent with the results of other reproductive studies in animals that have examined chronic intermittent exposure to subanesthetic concentrations of halothane, enflurane, methoxyflurane, and nitrous oxide. They suggest that these and lower (trace) levels of anesthetic gases may not be the cause of the harmful reproductive effects said to occur in operating room personnel.
View details for Web of Science ID A1985AVJ9200017
View details for PubMedID 4061920
View details for Web of Science ID A1984AED7100004
Patients and rats with chronic renal insufficiency (CRI) anesthetized with enflurane do not have significantly greater increases in postoperative serum inorganic fluoride levels when compared with subjects with normal renal function. The authors chose to investigate whether this observation is due to decreased anesthetic metabolism, secondary to the renal disease. Thus, male Fischer 344 rats with surgically induced CRI were studied to determine the effect of severe renal impairment: first, on in vivo hepatic function as measured by a serum liver enzyme profile, and second, on in vitro hepatic metabolism as indicated by microsomal anesthetic defluorination rates and cytochrome P-450 levels. Rats were operated on in two stages, 1 week apart, and assigned to one of three groups. Group 1 rats had a capsule stripping of each kidney. Group 2 rats had a capsule stripping of one kidney and then a nephrectomy of the other. Group 3 rats had the upper and lower poles of one kidney excised and then a nephrectomy of the other. There was no change in renal function in rats from Group 1 and 2. Chronic renal insufficiency in Group 3 rats was manifested by threefold elevations in serum creatinine and urea nitrogen levels and reciprocal decreases in clearances. After 89-98 days, blood was obtained for a serum liver enzyme profile and rats were killed for determination of in vitro hepatic metabolism. There were no changes suggestive of hepatic damage.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1984SP80300005
View details for PubMedID 6711854
The potential for fluorinated anaesthetic agents to cause nephrotoxicity can be summarized in two figures: Figure 2 illustrates the time course of anaesthetic defluorination following administration of methoxyflurane, enflurane and isoflurane; Figure 5 depicts changes in urinary osmolality in response to ADH administration versus peak serum fluoride levels after anaesthesia. Figure 2 clearly demonstrates that the shapes of the serum inorganic fluoride curves are different after methoxyflurane, enflurane and isoflurane anaesthesia. Despite the fact that inorganic fluoride has a half life in blood of only 90 minutes, peak levels were maintained for three days after administration of methoxyflurane. By contrast, peak fluoride levels after administration of the other two agents were reached shortly after the end of anaesthesia and they declined rapidly in the postanaesthetic period. To account for the prolonged postanaesthetic elevation of fluoride levels, one only must realize that methoxyflurane is approximately ten times more lipid soluble than either enflurane or isoflurane. Thus, methoxyflurane is present in the body for days after its administration has ended and is available for postoperative metabolism to inorganic fluoride. Peak fluoride levels also are considerably higher after methoxyflurane anaesthesia than after administration of the other two agents. That is because, on a molar basis, methoxyflurane is biochemically more unstable than either enflurane or isoflurane and is metabolized more per unit of time. Consequently, the area under the fluoride curve is much greater after methoxyflurane anaesthesia than after either enflurane or isoflurane. It is the area under the curve which probably best correlates with nephrotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1984SU10800005
View details for PubMedID 6722629
View details for Web of Science ID A1984SU44200001
The possibility that the metabolism of volatile inhalational anesthetics is altered following chronic ethanol consumption was investigated in male Fischer 344 rats. The hepatic microsomal defluorination rates of methoxyflurane, enflurane, and sevoflurane were determined for pair-fed rats receiving ethanol with normal caloric or with 50% of normal caloric intake. For comparison, the effects of phenobarbital treatment on anesthetic defluorination rates also were examined. Fourteen days of ad libitum consumption of 16% ethanol resulted in maximal defluorination rates of the above anesthetics. No overt signs of ethanol toxicity were observed. Ethanol-treated rats with a normal caloric intake had significantly increased microsomal defluorination rates per mg protein compared with pair-fed control rats as follows: methoxyflurane, 190% of control; enflurane, 298% of control; and sevoflurane, 301% of control. Ethanol-treated animals with 50% of normal caloric intake showed similar elevations in microsomal defluorination rates when compared with pair-fed controls. Phenobarbital treatment significantly increased the rate of methoxyflurane defluorination (673% of control), whereas the rates of sevoflurane defluorination (127% of control) and enflurane defluorination (86% of control) were not altered significantly. Phenobarbital treatment increased the microsomal content of cytochrome P-450, while ethanol treatment did not. This study demonstrated that regardless of total caloric intake, chronic ethanol consumption increases defluorination of inhalation anesthetics in Fischer 344 rats. It also illustrated that the two enzyme-inducing agents are unique with respect to the degree to which they enhance anesthetic defluorination.
View details for Web of Science ID A1983QG59000006
View details for PubMedID 6829959
Serum inorganic fluoride (F-) levels were measured in 20 surgical patients treated with 300 mg isoniazid per day for periods of up to one year, prior to anesthesia with enflurane. Thirty-six control patients anesthetized with enflurane, but taking no drugs, also were studied. Regression lines for peak serum fluoride were plotted against enflurane exposure in MAC-hours. Nine isoniazid-treated patients had fluoride levels significantly (P less than 0.001) higher (y = 22.2x + 12.0) than either the 11 other isoniazid-treated patients (y = 5.0x + 8.2) or the 36 control patients (y = 5.4x + 6.3). Peak serum fluoride values in three patients exceeded 100 microM but in no patient did values exceed 10 microM by 48 h after anesthesia. It was concluded that isoniazid treatment resulted in enzyme induction in the nine patients with high peak fluoride levels. This pattern, i.e., induction occurring in approximately one-half the patients, probably is related to the genetically determined bimodal distribution of rapid and slow acetylation of isoniazid.
View details for Web of Science ID A1982NW14800002
View details for PubMedID 7091722
The action of droperidol on left ventricular (LV) performance was examined before angiography in nine unpremedicated patients undergoing cardiac catheterization for stable uncomplicated coronary artery disease. Using local anesthesia, catheters were placed in the left ventricle, thoracic aorta, and pulmonary artery. Cardiac output (CO) and LV pressure derivatives were measured before and 2, 5, 10, 15, and 20 min after intravenous administration of 0.15 mg/kg droperidol. Droperidol administration induced a time-dependent decrease of mean arterial pressure (MAP) (significant at 2, 10, 15, and 20 min) and of cardiac index (CI) (significant at 15 and 20 min) with maximal changes observed at 20 min (-14 per cent for MAP and -15 per cent for CI). in addition, the following changes occurred in variables related to LV performance: 1) a transient increase in both heart rate (HR) (2, 5, and 10 min) and maximum rate of rise of left ventricular pressure/instantaneous left ventricular pressure (dP . dt-1 max . IP-1) (+ 15 per cent for HR and + 14 per cent for dP .dt-1 max . IP-1); 2) an early (2 min) and sustained (5, 10, 15, and 20 min) decrease of left ventricular end-diastolic pressure (LVEDP), maximum at 5 min (-30 per cent); 3) no change in systemic vascular resistance (SVR). This study shows that the fall in MAP which occurs after intravenous administration of clinical doses of droperidol is primarily due to decreased CO, secondary to decreased LVEDP and not to changes in cardiac contractility and in SVR.
View details for Web of Science ID A1982NW14800006
View details for PubMedID 7091716
Reproductive indices and developmental toxicity were evaluated in Swiss/ICR mice chronically exposed to a subanesthetic (0.01 or 0.1 per cent) or an anesthetic (0.5/1.0 per cent) concentration of enflurane. Pregnant mice (443) and fetuses (4743) were examined. In one experiment, groups of females were exposed to 0.01, 0.1, or 0.5/1.0 per cent enflurane for 4 hours per day, 7 days per week for 3 weeks; they were then mated with unexposed males. Exposure of females was continued daily throughout pregnancy. No adverse effects on fertility were observed at any dosage. At the highest dosage, 1.0 per cent, minor developmental variations occurred (i.e., lumbar ribs and increased renal pelvic cavitation). In a second experiment, groups of mice were exposed to 0.01, 0.1 or 1.0 per cent enflurance only on days 6 through 15 of pregnancy for 4 hours per day, after having been mated with untreated males. Abnormalities (i.e., increased incidence of cleft palate, minor skeletal and visceral anomalies, and developmental variants) were again seen only at the highest dosage. In a third experiment, male mice were exposed to 0.01, 0.1 or 0.5/1.0 per cent enflurane for 11 weeks for 4 hours per day, 5 days per week, prior to mating with unexposed females; results of this experiment were negative. In general, enflurane treatments did not adversely affect reproductive indices. Effects on fetal development were minimal, being somewhat greater than those reported in previous experiments with methoxyflurane but less than those seen with halothane. The smallest exposure at which effects were seen was approximately 100 times greater than the level of human occupational exposure in unscavenged operating rooms.
View details for Web of Science ID A1981LT77300010
View details for PubMedID 7235278
To determine whether exposure to trace concentrations of halothane resulted in enzyme induction, antipyrine pharmacokinetics were measured in six anesthetists before and after ten days of exposure to waste halothane. Antipyrine clearance increased by 29 per cent, a clinically small but statistically significant (P < 0.025) change, whereas the apparent volume of antipyrine distribution remained unchanged, indicating that halothane induces antipyrine metabolism. The implications of this finding for anesthetists cannot be simply defined. Enzyme induction may be beneficial or harmful, depending on the relative toxicities of the unbiotransformed parent compounds and their metabolites.
View details for Web of Science ID A1981KY60900011
View details for PubMedID 7457983
Salivary antipyrine clearance was determined before and 4 or 8 days after surgery as a measure of enzyme induction in 25 patients given halothane anesthesia and in 29 patients given neurolept anesthesia for uncomplicated otic surgical procedures. Statistically significant but clinically small increases in antipyrine clearance of 20% and 16% were measured in the halothane and neurolept groups, respectively. Similar decreases in antipyrine half-life were observed; apparent volume of distribution was unchanged. These changes are interpreted as representing a clinically insignificant degree of enzyme induction in most patients. The cause of these changes is not readily apparent. They may be due to the administration of anesthetic and adjuvant drugs, to the stress associated with the entire surgical experience, or to a combination of these factors.
View details for Web of Science ID A1981LN48200009
View details for PubMedID 7194599
To assess the potential for producing nephrotoxicity in rats with abnormal renal function, the renal effects of enflurane or halothane anesthesia, 1 MAC for two hours, were examined in six groups of six Fischer 344 rats each with surgically induced chronic renal impairment. As an additional predisposing factor, gentamicin, 5 mg/kg/day, was administered for one week before and for one week after anesthesia to three of the groups, one anesthetized with enflurane, one anesthetized with halothane, and one unanesthetized. No significant change in renal function could be attributed to either anesthetic agent. Serum inorganic fluoride levels four hours and 24 hours after enflurane anesthesia were similar in the gentamicin-treated and the non-gentamicin-treated groups. Clinically small but statistically significant increases in serum creatinine concentration and urinary flow occurred in all three gentamicin-treated groups during the period of treatment. Anesthesia with either enflurane or halothane in rats with chronic renal impairment treated with gentamicin did not result in additional renal damage.
View details for Web of Science ID A1980KW91600008
View details for PubMedID 7457964
The developmental toxicity of trace, subanesthetic, and anesthetic exposure to methoxyflurane was examined in Swiss/ICR mice. No adverse effects on reproduction or fetal development were demonstrated following exposure to trace (2 ppm) and subanesthetic (60 ppm) concentrations of methoxyflurane for 4 hours daily on days 6 through 15 of pregnancy. Exposure to an anesthetic concentration (2000 ppm; 0.2%) for the same period resulted in decreased fetal weight, decreased ossification, and delayed renal maturation. Additionally, the incidence of minor skeletal anomalies was increased. It is concluded that gestational exposure of mice to trace of subanesthetic concentrations of methoxyflurane does not result in reproductive loss or morphologic abnormalities in their offspring.
View details for Web of Science ID A1980JV06500006
View details for PubMedID 7189979
The possibility that enflurane defluorination is increased following treatment with isoniazid was investigated in male Fischer 344 rats. The effects of various isoniazid dosage regimens on the hepatic microsomal defluorination rates of enflurane were compared with those of several other ether anesthetics, and the conditions for production of maximal enflurane defluorination rates were determined. Seven to ten days of treatment with 50 mg/kg/day isoniazid (Nydrazid) resulted in maximal rates of defluorination of methoxyflurane, enflurane, isoflurane, and sevoflurane with no overt sign of toxicity. Compared with saline treatment of control rats, isoniazid increased defluorination of enflurane 370 per cent, methoxyflurane 259 per cent, sevoflurane 283 per cent, and isoflurane 168 per cent. Previous studies have shown that while the enzyme inducer phenobarbital increased in vitro rates of methoxyflurane defluorination approximately 1000 per cent, the rate of enflurane defluorination remained unchanged or increased by 100 per cent at most. In this study, enhanced hepatic microsomal defluorination was not associated with an increase in cytochrome P-450 per mg protein. Anesthetic defluorination rates were not altered by treatment with chlorobutanol, the preservative contained in Nydrazid.
View details for Web of Science ID A1980KW91600009
View details for PubMedID 7457965
The toxicity and metabolism of the fluorinated anesthetic methoxyflurane were compared in Fischer 344 rats pretreated with phenytoin or phenobarbital. Treatment with either drug potentiated the polyuric effects of methoxyflurane by more than 100%. Also, serum inorganic fluoride (F-) levels and urinary F- excretions after methoxyflurane exposure were comparable in phenytoin- and phenobarbital-treated rats, a 26 to 49% increase as compared to rats treated with methoxyflurane alone. In vitro, 10-fold increases in the rate of hepatic microsomal methoxyflurane defluorination were observed after treatment of rats with either phenytoin or phenobarbital. Kinetic studies with microsomes demonstrated inhibition of methoxyflurane defluorination in the presence of phenytoin. Defluorination of three additional fluorinated ether anesthetics, enflurane, isoflurane and sevoflurane, also was examined in vitro. Phenytoin and phenobarbital treatment resulted in similar enhancement of defluorination of the latter two anesthetics, but not enflurane. Phenytoin and phenobarbital treatment increase defluorination of fluorinated ether anesthetics to approximately the same extent in vitro and in vivo in Fischer 344 rats.
View details for Web of Science ID A1979HH24000005
View details for PubMedID 458627
Aerobic defluorination of the inhalation anaesthetic agent, synthane, was compared with that of methoxyflurane, enflurane and halothane and with two other anaesthetics, isoflurane and sevoflurane. In vitro, in microsomes prepared from phenobarbitone-induced and control livers, synthane and halothane were not defluorinated. The relative order of defluorination of the other anaesthetics was methoxyflurane greater than enflurane greater than isoflurane. In vivo, following 4 h of 1.2% (MAC) synthane anaesthesia, urinary inorganic fluoride excretion was increased by only a trivial amount and only in phenobarbitone-treated rats; polyuria was not observed. Synthane is the least metabolized of the fluorinated ether anaesthetics; its administration will not result in inorganic fluoride nephropathy. An index of nephrotoxic potential for fluorinated anaesthetic agents was formulated utilizing in vitro fluoride production data and oil: gas partition coefficients.
View details for Web of Science ID A1979HL79400005
View details for PubMedID 508489
In an attempt to predict the extent of halothane debromination, antipyrine metabolic clearance rate was measured preoperatively in 22 surgical patients, then correlated with percent hours of subsequent halothane exposure and postoperative serum bromide levels. There was a significant correlation (r = 0.78, p less than 0.001) between peak bromide level and anesthetic exposure but no correlation between peak bromide levels and antipyrine metabolic clearance rate. Thus, antipyrine is of no value for predicting the extent of halothane debromination. Mean peak bromide level 0.97 +/- 0.09 mM occurred on day 3 after anesthesia. This value is well below the psychoactive range. The data, therefore, also suggest that there is not a causal relationship between halothane biotransformation and the clinical syndrome of bromism.
View details for Web of Science ID A1979HW07900006
View details for PubMedID 574731
In an attempt to determine the importance of concentration of an anesthetic agent as a determinant of the extent of its biotransformation, we measured fluoride excretion in groups of Fischer 344 rats treated with one of several subanesthetic or an anesthetic concentration (1 MAC) of either enflurane or methoxyflurane. Anesthetic administrations (2.0% enflurane or 0.26% methoxyflurane) ranged from 0.15 hours (9 minutes) to 4.8 hours. Subanesthetic exposures, all of 48 hours duration, ranged in concentration from 0.2% enflurane to 0.0016% methoxyflurane. Greatest metabolism occurred at the lowest concentration time (MAC-hours) of subanesthetic administrations and at the shortest duration of anesthetic exposure. Increasing time in the case of anesthetizing exposures, or concentration in subanesthetic exposures, increased the amount of metabolite produced. However, the increased production of metabolite was not proportional to the increase of concentration or duration of exposure. Enzyme induction was ruled out as an important factor in the larger amount of metabolism seen during the subanesthetic exposures. Therefore, the exposure of a patient to the metabolites of an anesthetic is actually low although the anesthetic is administered at a high concentration.
View details for Web of Science ID A1979GX94700011
View details for PubMedID 572159
Serum bromide levels were measured in 115 anesthetists by use of x-ray fluorescence spectrometry. Bromide levels peaked at 184 +/- 21 micron in anesthetists regularly exposed to halothane (n = 20), at 58 +/- 4 micron in anesthetists sporadically exposed to halothane (n = 71), and at 46 +/- 3 micron in nonexposed anesthetists (n = 24). Kinetic studies were carried out in five other anesthetists after ten days of exposure to halothane. Average daily halothane concentration was 19.2 +/- 3.2 ppm; duration of exposure was 3.8 +/- 0.2 hours/day. Mean serum bromide level increased from 40 +/- 4 micron before exposure to 220 +/- 36 micron on the last day of exposure. Serum bromide half-life was 14 +/- 1.7 days. The study demonstrates that anesthetists debrominate halothane in a dose-related fashion. Serum bromide levels achieved, however, were far below those reported to result in clinical bromism.
View details for Web of Science ID A1979HB75200009
View details for PubMedID 453592
Chronic renal insufficiency was produced surgically in Fischer 344 rats in order to evaluate the effects of enflurane anesthesia in animals with impaired renal function. Three groups of rats were anesthetized with enflurane: a control group without impairment of renal function (n = 7); a group with minimal impairment of renal function (n = 6); and a group with moderately severe renal impairment (n = 9). Another group of rats with moderately severe renal impairment (n = 8) was anesthetized with halothane. Two hours of anesthesia resulted only in mild transient depression of urea clearance in all groups. Six hours of anesthesia resulted in a 5 to 10 ml/day increase of urinary output in all groups and small increases in urea nitrogen levels in both groups with moderately severe renal impairment. Deterioration of the model was noted late in the experiment; at sacrifice, animals that had been anesthetized with enflurance and four with halothane had terminal renal failure. The morphological lesion in both groups was similar, resembling glomerulonephritis. Thus, there was no difference in the renal response to enflurane or halothane anesthesia among rats with chronic renal insufficiency.
View details for Web of Science ID A1979HS21300007
View details for PubMedID 490324
In 7 subjects, serial EEGs, serum bromide determinations, and psychological tests were done prior to and following 13.83 +/- 0.74 (SEM) MAC-hours of halothane anesthesia. Significant psychological impairment demonstrated 2 days following anesthesia in these subjects was absent 2 weeks following exposure to halothane. Nonspecific postanesthetic slowing of the EEG was found, qualitatively similar to but more marked than that following exposure to enflurane. Generalized EEG slowing, with a tendency toward posterior delta activity and significant reduction of frequency and amplitude of the alpha rhythm, persisted for 6 to 8 days following anesthesia. Rare sharp-wave activity developed in 3 subjects in the 1st week after halothane. A potentially psychoactive postanesthetic serum bromide level of 2.97 +/- 0.17 mEq/L (SEM) was found 5 days following anesthesia. Electroencephalographic changes characteristic of mild bromide intoxication were absent, suggesting that the psychological impairment noted after halothane anesthesia is probably not due to this metabolite; these psychological changes are probably due instead to persistence in the circulation of unchanged halothane.
View details for Web of Science ID A1978EU86000016
View details for PubMedID 565163
Male rats of the Fischer 344, Sprague-Dawley, Brattleboro, and Wistar strains, balb/C mice, and Hartley guinea pigs were divided into 2 treatment groups. One group drank tap water while the other group drank water containing 1 mg/ml of phenobarbital. Animals were exposed to sevoflurane, enflurane, methoxyflurane, isoflurane, or halothane in a closed chamber. In some of the experiments, soda lime was included and in other the chamber was heated to 39 degrees C with a water blanket. Eighty-six percent (43/50) of Fischer 344 rats treated with phenobarbital and esposed to either sevoflurane or enflurane, in the presence of either soda lime or exogenous heat, died within a few hours after exposure. Fischer 344 rats and rats of other strains drinking phenobarbital water and exposed to methoxyflurane were affected, but to a lesser degree. Rats drinking ordinary tap water and phenobarbital-treated rats not exposed to either soda lime or exogenous heat were unaffected. Guinea pigs and mice also were unaffected. We postulate that the toxic response represents a species-specific thermoregulatory defect, precipitated by heat and occurring in rats treated with phenobarbital in combination with sevoflurane, endlurane, or methoxyflurane.
View details for Web of Science ID A1977CV00600003
View details for PubMedID 556915
The effects of prolonged enflurane and halothane administration on urine-concentrating ability were determined in volunteers by examining their responses to vasopressin before anesthesia and on days 1 and 5 after anesthesia. A significant decrease in maximum urinary osmolality of 264 +/- 34 mOsm/kg (26 per cent of the preanesthetic value) was present on day 1 after enflurane anesthesia, whereas subjects anesthetized with halothane had a significant increase in maximum urinary osmolality of 120 +/- 44 mOsm/kg. Serum inorganic fluoride level peaked at 33.6 muM and remained above 20 muM for approximately 18 hours. Thus, the threshold level for inorganic fluoride nephrotoxicity is lower than previously suspected.
View details for Web of Science ID A1977DA54400007
View details for PubMedID 842883
Nephrotoxicity following administration of methoxyflurane has been shown to be directly related to anesthetic metabolism to inorganic fluoride. Enzyme induction should increase metabolic rate and the amount of inorganic fluoride that is released. In vivo studies in Fischer 344 rats show that enzyme induction with phenobarbital or phenytoin increases defluorination following methoxyflurane anesthesia but not after enflurane or isoflurane. In vitro, methoxyflurane defluorinase activity was increased far more than that of any of the other anesthetics. These data suggest that treatment with enzyme inducing drugs increases the risk of nephrotoxocity only if methoxyflurane is the anesthetic agent.
View details for Web of Science ID A1977EU61500027
View details for PubMedID 612443
Investigations of methoxyflurane-induced nephrotoxicity in man have been extensively aided by the use of an animal model. To be of value the animal model must share similar metabolic pathways with man and have the same clinical manifestations of the diseases process. The Fischer 344 rat appears to meet these criteria. The predominant factors in the production of methoxyflurane nephrotoxicity appear to be high methoxyflurane dosage and serum inorganic fluoride concentration. It is likely that secondary factors include: (1) a high rate of methoxyflurane metabolism and sepsitivity of the kidney to inorganic fluoride toxicity: (2) concurrent treatment with other nephrotoxic drugs; (3) preexisting renal disease; (4) surgery of the urogenital tract, aorta, or renal vasculative; (5) repeat administration of methoxyflurane due to accumulation of inorganic fluoride and, perhaps, methoxyflurane induction of its own metabolism: and (6) concurrent treatment with enzyme-inducing drugs such as phenobarbital.
View details for Web of Science ID A1976CP35700011
View details for PubMedID 1001288
The metabolism and renal effects of enflurane were studied during and after anesthesia in ten surgical patients without renal disease; ten control patients received halothane. Enflurane was metabolized to inorganic fluoride with a mean peak serum level of 22.2 +/- 2.8 muM four hours after anesthesia. Urinary inorganic and organic fluoride excretions were increased but oxalic acid excretion was not, suggesting that the latter is not an enflurane metabolite. Postanesthetic renal function, including the response to vasopressin, was normal in both groups. During enflurane anesthesia renal blood flow, glomerular filtration rate, and urinary flow rate were 77, 79, and 67 per cent of control values, respectively. In this study of patients without renal disease, metabolism of enflurane to inorganic fluoride was insufficient to cause clinically significant renal dysfunction.
View details for Web of Science ID A1976BB14800007
View details for PubMedID 1244774
Twenty-five 5-month-old male Fischer-344 rats were randomly divided into 5 groups: Group I, no anesthesia; Group II, 1.4 precent sevoflurane for 2 hours; Group III, 0.1 percent phenobarbital, ad lib, in drinking water for 7 days; followed by 1.4 percent sevoflurane for 2 hours; Group IV, 0.25 percent methoxyflurane, 1 hour; Group V, phenobarbital in water as in Group III, followed by methoxyflurane as in group IV. Pre- and postanesthetic serum and urinary osmolality, Na+, K+, urea nitrogen (BUN), inorganic fluoride (F-) levels, and 24-hour urine volume were measured. Kidney tissue was obtained for examination by light and electron microscopy. Sevoflurane was metabolized to F- to a lesser extent than was methoxyflurane; treatment with phenobarbital-sevoflurane doubled urinary F- excretion, resulting in a value similar to that seen after methoxyflurane alone. There was no functional or morphologic evidence of renal abnormalities in either group of rats anesthetized with sevoflurane. Methoxyflurane dosage was sufficiently low that renal abnormalities did not occur except in rats treated also with phenobarbital; these animals developed polyuria and the morphologic lesion typically associated with F--induced nephrotoxicity.
View details for Web of Science ID A1975AY30100025
View details for PubMedID 1239223
Age as a factor in methoxyflurane nephrotoxicity was evaluated in Fischer 344 rats of various ages by determination of: 1) serum inorganic fluoride and methoxyflurane concentrations, and urinary inorganic fluoride excretion in methoxyflurane-exposed rats; 2) liver microsomal methoxyflurane defluorinase activity; and 3) distribution of injected sodium fluoride. Only rats in the youngest age group (6 weeks) did not develop nephrotoxicity after anesthesia. Older rats had a biphasic rather than a monophasic decay in serum methoxyflurane concentration and also had increased serum inorganic fluoride concentration and urinary inorganic fluoride excretion. Older rats also excreted a greater proportion of an injected dose of sodium fluoride compared to young rats. Microsomal methoxyflurane defluorinase specific activity was similar among rats of all ages. It is likely that increased availability of methoxyflurane due to its greater storage in fat led to more inorganic fluoride production in older compared to younger rats. Bone sequestration of inorganic fluoride in younger rats probably accounts for decreased serum inorganic fluoride levels in that group. Both factors cause significant differences in renal exposure to inorganic fluoride; thus the risk of nephrotoxicity is less in younger animals.
View details for Web of Science ID A1975AU49200005
View details for PubMedID 241841
Specific activities of enflurane, isoflurane, and methoxyflurane defluorinases were measured in microsomes prepared from the livers of Fischer 344 rats; the ratio of these activities was 23:3:1. Pretreatment with phenobarbital significantly increased the defluorinase activities of all three agents. Factors that influence anesthetic drug metabolism are discussed; tissue solubility is considered to be the most important.
View details for Web of Science ID A1975W057500006
View details for PubMedID 1119709
Species, sex and individual differences in serum inorganic fluoride concentrations were demonstrated in mice, guineapigs and rats exposed to either 0.07% or 0.2% enflurane for 35 days, suggesting differences in enflurane biotransformation. Exposure of Fischer 344 rats and Sprague-Dawley rats to 0.2% enflurane for 8 days resulted in enzyme induction as demonstrated by increasing serum inorganic fluoride and cytochrome P-450 concentrations. However, there was no difference in cytochrome P-450 concentrations between the strains despite differences in inorganic fluoride concentration. These results emphasize the multiplicity of factors and the lack of predictability in patterns of enflurane metabolism among species, strains and individuals.
View details for Web of Science ID A1975AZ57600007
View details for PubMedID 1218143
Sevoflurane, 1.4 per cent (MAC), was administered to groups of Fischer 344 rats for 10 hours, 4 hours, or 1 hour; additional rats received 0.5 per cent methoxyflurane for 3 hours or 1 hour. Urinary inorganic fluoride excretion of sevoflurane in vivo was a third to a fourth that of methoxyflurane. However, using hepatic microsomes, sevoflurane and methoxyflurane were defluorinated in vitro at essentially the same rate. The discrepancy between defluorination of sevoflurane and methoxyflurane in vivo and in vitro was probably due to differences in tissue solubility between the drugs. There were no renal functional or morphologic defects following sevoflurane administration. An unexplained adverse effect was significant weight loss, which occurred following all exposures to sevoflurane.
View details for Web of Science ID A1975AG89200008
View details for PubMedID 1147310
View details for Web of Science ID A1974T676200007