Long-duration low-flow sevoflurane and isoflurane effects on postoperative renal and hepatic function.

UNLABELLED: Sevoflurane degradation by carbon dioxide absorbents during low-flow anesthesia forms the haloalkene Compound A, which causes nephrotoxicity in rats. Numerous studies have shown no effects of Compound A formation on postoperative renal function after moderate-duration (3-4 h) low-flow sevoflurane; however, effects of longer exposures remain unresolved. We compared renal function after long-duration low-flow (<1 L/min) sevoflurane and isoflurane anesthesia in consenting surgical patients with normal renal function. To maximize degradant exposure, Baralyme was used, and anesthetic concentrations were maximized (no nitrous oxide and minimal opioids). Inspired and expired Compound A concentrations were quantified. Blood and urine were obtained for laboratory evaluation. Sevoflurane (n = 28) and isoflurane (n = 27) groups were similar with respect to age, sex, weight, ASA status, and anesthetic duration (9.1 +/- 3.0 and 8.2 +/- 3.0 h, mean +/- SD) and exposure (9.2 +/- 3.6 and 9.1 +/- 3.7 minimum alveolar anesthetic concentration hours). Maximum inspired Compound A was 25 +/- 9 ppm (range, 6-49 ppm), and exposure (area under the concentration-time curve) was 165 +/- 95 (35-428) ppm. h. There was no significant difference between anesthetic groups in 24- or 72-h serum creatinine, blood urea nitrogen, creatinine clearance, or 0- to 24-h or 48- to 72-h urinary protein or glucose excretion. Proteinuria and glucosuria were common in both groups. There was no correlation between Compound A exposure and any renal function measure. There was no difference between anesthetic groups in 24- or 72-h aspartate aminotransferase or alanine aminotransferase. These results show that the renal and hepatic effects of long-duration low-flow sevoflurane and isoflurane were similar. No evidence for low-flow sevoflurane nephrotoxicity was observed, even at high Compound A exposures as long as 17 h. Proteinuria and glucosuria were common and nonspecific postoperative findings. Long-duration low-flow sevoflurane seems as safe as long-duration low-flow isoflurane anesthesia. IMPLICATIONS: Postoperative renal function after long-duration low-flow sevoflurane (with Compound A exposures greater than those typically reported) and isoflurane anesthesia were not different, as assessed by serum creatinine, blood urea nitrogen, and urinary excretion of protein and glucose. This suggests that low-flow sevoflurane is as safe as low-flow isoflurane, even at long exposures.

Comparison of renal function following anesthesia with low-flow sevoflurane and isoflurane.

STUDY OBJECTIVE: To evaluate postoperative renal function after patients were administered sevoflurane under conditions designed to generate high concentrations of compound A. STUDY DESIGN AND SETTING: A multicenter (11 sites), multinational, open-label, randomized, comparative study of perioperative renal function in patients who have received low-flow (< or = 1 L/min) sevoflurane or isoflurane. PATIENTS: 254 ASA physical status I, II and III patients requiring endotracheal intubation for elective surgery lasting more than 2 hours. INTERVENTIONS: After induction, low-flow anesthesia was initiated at a flow rate < or = 1 L/min. Blood and urine samples were studied to assess postoperative renal function. MEASUREMENTS AND MAIN RESULTS: Measurements of serum BUN and creatinine, and urine glucose, protein, pH, and specific gravity were used to assess renal function preoperatively and up to 3 days postoperatively. Serum inorganic fluoride ion concentration was measured at preinduction, emergence, and 2, 24 and 72 hours postoperatively. Compound A concentrations were measured at two sites for those patients receiving sevoflurane. Adverse experience data were analyzed. One hundred eighty-eight patients were considered evaluable (98 sevoflurane and 90 isoflurane). Peak serum fluoride concentrations were significantly higher after sevoflurane (40 +/- 16 microM) than after isoflurane (3 +/- 2 microM). Serum creatinine and BUN decreased in both groups postoperatively; glucosuria and proteinuria occurred in 15% to 25% of patients. There were no clinically significant differences in BUN, creatinine, glucosuria, and proteinuria between the low-flow sevoflurane and low-flow isoflurane patients. CONCLUSIONS: There were no statistically significant differences in the renal effects of sevoflurane or isoflurane in surgical patients undergoing low-flow anesthesia for up to 8 hours. Low-flow sevoflurane anesthesia under clinical conditions expected to produce high levels of compound A appears as safe as low-flow isoflurane anesthesia.

Absence of biochemical evidence for renal and hepatic dysfunction after 8 hours of 1.25 minimum alveolar concentration sevoflurane anesthesia in volunteers.

BACKGROUND: Sevoflurane is degraded by carbon dioxide absorbents to a difluorovinyl ether (compound A) that can cause renal and hepatic injury in rats. The present study applied sensitive markers of renal and hepatic function to determine the safety of prolonged (8 h), high concentration (3% end-tidal) sevoflurane anesthesia in human volunteers. METHODS: Thirteen healthy male volunteers provided informed consent to undergo 8 h of 1.25 minimum alveolar concentration sevoflurane anesthesia delivered with a fresh gas flow of 2 l/min. Glucose, protein, albumin, N-acetyl-beta-D-glucosaminidase (NAG), and alpha- and pi-glutathione-S-transferase (GST) levels were analyzed in urine collected at 24 h before and for 3 days after sevoflurane anesthesia. Daily blood samples were analyzed for creatinine, blood urea nitrogen (BUN), alanine aminotransferase, alkaline phosphatase, and bilirubin concentrations. Circuit compound A and plasma fluoride concentrations were measured. RESULTS: During anesthesia, average and maximum inspired compound A concentrations were 27 +/- 7 and 34 +/- 6 (mean +/- SD) and median mean blood pressure, esophageal temperature, and end-tidal carbon dioxide levels were 63 mmHg, 36.8 degrees C, and 32 mmHg, respectively. The average serum inorganic fluoride concentration 2 h after anesthesia was 66.2 +/- 14.7 microM. Results of tests of hepatic function and renal function (BUN, creatinine concentration) were unchanged after anesthesia. Glucose, protein, albumin, and NAG excretion were not significantly increased after anesthesia. Urine concentrations of alpha-GST and pi-GST were increased on day 1 after anesthesia and alpha-GST was increased on day 2 after anesthesia but returned to normal afterward. CONCLUSIONS: Prolonged (8 h), high concentration (3%) sevoflurane anesthesia administered to volunteers in a fresh gas flow of 2 l/min does not result in clinically significant changes in biochemical markers of renal or hepatic dysfunction.

Cysteine conjugate beta-lyase-dependent metabolism of compound A (2-[fluoromethoxy]-1,1,3,3,3-pentafluoro-1-propene) in human subjects anesthetized with sevoflurane and in rats given compound A.

BACKGROUND: Sevoflurane undergoes Baralyme- or soda lime-catalyzed degradation in the anesthesia circuit to yield compound A (2-[fluoromethoxy]-1,1,3,3,3-pentafluroro-1-propene), which is nephrotoxic in rats and undergoes metabolism via the cysteine conjugate beta-lyase pathway in those animals. The objective of these experiments was to test the hypothesis that compound A undergoes beta-lyase-dependent metabolism in humans. METHODS: Human volunteers were anesthetized with sevoflurane (1.25 minimum alveolar concentration, 3%, 2 l/min, 8 h) and thereby exposed to compound A. Urine was collected at 24-h intervals for 72 h after anesthesia. Rats, which served as a positive control, were given compound A intraperitoneally, and urine was collected for 24 h afterward. Human and rat urine samples were analyzed by 19F nuclear magnetic resonance spectroscopy and gas chromatography-mass spectrometry for the presence of compound A metabolites. RESULTS: Analysis of human and rat urine showed the presence of the compound A metabolites S-[2(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-N-acetyl-L- cysteine, (E)- and (Z)-S-[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-N-acetyl- L-cysteine, 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid, 3,3,3-trifluorolactic acid, and inorganic fluoride. The presence of 2-(fluoromethoxy)3,3,3-trifluoropropanoic acid and 3,3,3-trifluorolactic acid in human urine was confirmed by gas chromatography-mass spectrometry. CONCLUSIONS: The formation of compound A-derived mercapturates shows that compound A undergoes glutathione S-conjugate formation. The identification of 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid and 3,3,3-trifluorolactic acid in the urine of humans anesthetized with sevoflurane shows that compound A undergoes beta-lyase-dependent metabolism. Metabolite formation was qualitatively similar in both human volunteers anesthetized with sevoflurane, and thereby exposed to compound A, and in rats given compound A, indicating that compound A is metabolized by the beta-lyase pathway in both species.

[Kidney function in test subjects: published results and clinical relevance]. / Nierenfunktion bei Probanden. Publizierte Ergebnisse und klinische Relevanz.

Sevoflurane degrades in CO2 absorbents to produce compound A, which may have hepatotoxic potential in humans. Several recent studies in human volunteers have been performed to evaluate this potential. Three studies have evaluated sevoflurane administered to volunteers using a 3% concentration for 8 h duration at approximately 2 L/min flow rate. The initial investigation found high excretion of protein, glucose and renal tubular enzymes in the urine of the volunteers receiving sevoflurane. Subsequent investigations using identical protocols found more minor or absent changes in excretion of these markers. One additional investigation in volunteers studied 3% sevoflurane anesthesia for 4 h duration using a low-flow (1 L/min) technique. No significant excretion of protein, glucose or renal enzymes was observed. Application of these results to clinical practice must be interpreted in light of the experimental nature of the anesthetic administration. Although some controversy remains, these data, combined with results of recent studies in surgical patients, suggest that renal function following modest duration low-flow sevoflurane anesthesia is similar to that following isoflurane anesthesia.

High carboxyhemoglobin concentrations occur in swine during desflurane anesthesia in the presence of partially dried carbon dioxide absorbents.

BACKGROUND: Increased carboxyhemoglobin concentrations in patients receiving inhalation anesthetics (desflurane, enflurane, and isoflurane) have been reported. Recent in vitro studies suggest that dry carbon dioxide absorbents may allow the production of carbon monoxide. METHODS: The authors used high fresh oxygen flow (5 or 10 l/min) through a conventional circle breathing system of an anesthesia machine for 24 or 48 h to produce absorbent drying. Initial studies used 10 l/min oxygen flow with the reservoir bag removed or with the reservoir bag left in place during absorbent drying (this increases resistance to gas flow through the canister). A third investigation evaluated a lower flow rate (5 l/min) for absorbent drying. Water content of the absorbent and temperature were measured. Pigs received a 1.0 (human) minimum alveolar concentration desflurane anesthetic (7.5%) for 240 min using a 1 l/min oxygen flow rate with dried absorbent. Carbon monoxide concentrations in the circuit and carboxyhemoglobin concentrations in the pigs were measured. RESULTS: Pigs anesthetized with desflurane using Baralyme exposed to 48 h of 10 l/min oxygen flow (reservoir bag removed) had extremely high carboxyhemoglobin concentrations (more than 80%). Circuit carbon monoxide concentrations during desflurane anesthesia using absorbents exposed to 10 l/min oxygen flow (reservoir bag removed, 24 h) reached peak values of 8,800 to 13,600 ppm, depending on the absorbent used. Carboxyhemoglobin concentrations reached peak values of 73% (Baralyme) and 53% (soda lime). The water content of Baralyme decreased from 12.1 +/- 0.3% (mean +/- SEM) to as low as 1.9 +/- 0.4% at the bottom of the lower canister (oxygen flow direction during drying was from bottom to top). Absorbent temperatures in the bottom canister increased to temperatures as high as 50 degrees C. With the reservoir bag in place during drying (10 l/min oxygen flow), water removal from Baralyme was insufficient to produce carbon monoxide (lowest water content = 5.5%). Use of 5 l/min oxygen flow (reservoir bag removed) for 24 h did not reduce water content sufficiently to produce carbon dioxide with desflurane. CONCLUSIONS: An oxygen flow rate of 10 l/min for 24 h in a conventional anesthesia circuit can dry carbon dioxide absorbents sufficiently to produce extremely high levels of carbon monoxide with high carboxyhemoglobin concentrations in desflurane-anesthetized pigs. When the reservoir bag is in place on the anesthesia machine or when a lower oxygen flow rate (5 l/min) is used, carbon dioxide absorbent drying still occurs, but 24-48-h exposure time is insufficient to allow for carbon monoxide production with desflurane.

Assessment of low-flow sevoflurane and isoflurane effects on renal function using sensitive markers of tubular toxicity.

BACKGROUND: Carbon dioxide absorbents degrade sevoflurane, particularly at low gas flow rates, to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A). Compound A causes renal proximal tubular injury in rats but has had no effect on blood urea nitrogen (BUN) or creatinine concentrations in patients. This investigation compared the effects of low-flow sevoflurane and isoflurane on renal tubular function in surgical patients using conventional (BUN and creatinine) and finer indices of renal injury, specifically those biomarkers sensitive for compound A toxicity in rats (glucosuria, proteinuria, and enzymuria [N-acetyl-beta-D-glucosaminidase (NAG) and alpha-glutathione-S-transferase (alpha GST)]). METHODS: Consenting patients with normal preoperative renal function at two institutions were randomized to receive sevoflurane (n = 36) or isoflurane (n = 37) in oxygen and air. Total gas flow was 1 l/min, opioid doses were minimized, and barium hydroxide lime was used to maximize anesthetic degradation. Inspiratory and expiratory compound A concentrations were quantified every 30-60 min. Blood and urine were obtained before and 24-72 h after anesthesia for laboratory evaluation. RESULTS: Sevoflurane and isoflurane groups were similar with respect to age, weight, sex, American Society of Anesthesiologists status, anesthetic duration (3.7 or 3.9 h), and anesthetic exposure (3.6 or 3 minimum alveolar concentration [MAC]-hour). Maximum inspired compound A concentration (mean +/- standard deviation) was 27 +/- 13 ppm (range, 10-67 ppm). Areas under the inspired and expired compound A concentration versus time curves (AUC) were 79 +/- 54-ppm-h (range, 10-223 ppm-h) and 53 +/- 40 ppm-h (range, 6-159 ppm-h), respectively. There was no significant difference between anesthetic groups in postoperative serum creatinine or BUN, or urinary excretion of protein, glucose, NAG, proximal tubular alpha GST, or distal tubular pi GST. There was no significant correlation between compound A exposure (AUC) and protein, glucose, NAG, alpha GST, or pi GST excretion. Postoperative alanine and aspartate aminotransferase concentrations were not different between the anesthetic groups, and there were no significant correlations between compound A exposure and alanine or aspartate aminotransferase concentrations. CONCLUSIONS: The renal tubular and hepatic effects of low-flow sevoflurane and isoflurane were similar as assessed using both conventional measures of hepatic and renal function and more sensitive biochemical markers of renal tubular cell necrosis. Moderate duration low-flow sevoflurane anesthesia, during which compound A formation occurs, appears to be as safe as low-flow isoflurane anesthesia.

Compound A concentrations during sevoflurane anesthesia in children.

BACKGROUND: Sevoflurane is a new inhalation agent that should be useful for pediatric anesthesia. Sevoflurane undergoes degradation in the presence of carbon dioxide absorbents; however, quantification of the major degradation product (compound A) has not been evaluated during pediatric anesthesia. This study evaluates sevoflurane degradation compound concentrations during sevoflurane anesthesia using a 2-1 fresh gas flow and a circle system with carbon dioxide absorber in children with normal renal and hepatic function. METHODS: The concentrations of compound A were evaluated during sevoflurane anesthesia in children using fresh soda lime as the carbon dioxide absorbent. Nineteen patients aged 3 months-7 yr were anesthetized with sevoflurane (2.8% mean end-tidal concentration) using a total fresh gas flow of 21 in a circle absorption system. Inspiratory and expiratory limb circuit gas samples were obtained at hourly intervals, and the samples were analyzed using a gas chromatography-flame ionization detection technique. Carbon dioxide absorbent temperatures were measured in the soda lime during anesthesia for hepatic and renal function studies. Venous blood samples were obtained before anesthesia, at the end of anesthesia, and 2h after anesthesia for plasma inorganic fluoride ion concentration. RESULTS: The maximum inspiratory concentration of compound A was 5.4 +/- 4.4 ppm (mean +/- SD), and the corresponding expiratory concentration was 3.7 +/- 2.7 ppm (mean +/- SD). The maximum inspiratory compound A concentration in any patient was 15 ppm. Mean concentrations of compound A peaked at intubation and remained stable, declining slightly after 120 min of anesthesia. The duration of anesthesia was 240 +/- 139 min (mean +/-SD). Maximum soda lime temperature ranged between 23.1 degrees C and 40.9 degrees C. There was a positive correlation between maximum absorbent temperature and maximum compound A concentration (r2 = 0.58), as well as between the child's body surface area and maximum compound A concentration (r2 = 0.59). Peak plasma inorganic fluoride ion concentration was 21.5 +/- 6.1 microgmol/1. There were no clinically significant changes in hepatic or renal function studies performed 24 h postanesthesia. CONCLUSIONS: Sevoflurane anesthesia of 4 h in normal children using a 2-1 flow circle system produced concentrations of compound A of 15 ppm or less. There was no evidence of abnormality of renal or hepatic function up to 24 h after anesthesia; however, larger studies will be required to confirm the absence of organ toxicity.

Cardiovascular effects of sevoflurane compared with those of isoflurane in volunteers.

BACKGROUND: Sevoflurane is a new inhalational anesthetic with desirable clinical properties. In some clinical situations, an understanding of the detailed cardiovascular properties of an anesthetic is important, so the authors evaluated the hemodynamic effects of sevoflurane in healthy volunteers not undergoing surgery. METHODS: Twenty-one subjects were randomized to receive sevoflurane, isoflurane, or sevoflurane: 60% N2O. Anesthesia was induced and maintained by inhalation of the designated anesthetic. Hemodynamic measurements were performed before anesthesia, during controlled ventilation, during spontaneous ventilation, and again during controlled ventilation after 5.5 h of anesthesia. RESULTS: A few subjects became excessively hypotensive at high anesthetic concentrations (2.0 minimum alveolar concentration [MAC] sevoflurane, 1.5 and 2.0 MAC isoflurane), preventing data collection. Sevoflurane did not alter heart rate, but decreased mean arterial pressure and mean pulmonary artery pressure. Cardiac index decreased at 1.0 and 1.5 MAC, but in subjects with mean arterial pressure > or = 50 mmHg returned to baseline values at 2.0 MAC when systemic vascular resistance decreased. Sevoflurane did not alter echocardiographic indices of ventricular function, but did decrease an index of afterload. Sevoflurane caused a greater decrease in mean pulmonary artery pressure than did isoflurane, but the cardiovascular effects were otherwise similar. Administration of sevoflurane with 60% N2O, prolonged administration or spontaneous ventilation resulted in diminished cardiovascular depression. CONCLUSIONS: At 1.0 and 1.5 MAC, sevoflurane was well tolerated by healthy volunteers. At 2.0 MAC, in subjects with mean arterial pressure > or = 50 mmHg, no adverse cardiovascular properties were noted. Similar to other contemporary anesthetics, sevoflurane caused evidence of myocardial depression. Hemodynamic instability was noted in some subjects at high anesthetic concentrations in the absence of surgical stimulation. The incidence was similar to that with isoflurane. The cardiovascular effects of sevoflurane were similar to those of isoflurane, an anesthetic commonly used in clinical practice since 1981.

Relationship of inspired anesthetic concentration to plasma concentration and urinary excretion of sevoflurane metabolites in rats.

In patients, plasma concentrations of sevoflurane metabolites may be independent of inspired sevoflurane concentration over a defined dose range. In contrast, studies using rabbits have found that plasma concentrations and urinary excretion of fluoride ion are dose-dependent up to 3% inspired sevoflurane. We measured sevoflurane metabolite concentrations in adult male Sprague-Dawley rats and related them to inspired sevoflurane concentrations. When plasma concentrations and urinary excretion of metabolites were measured in vivo, they were dependent on inspired anesthetic concentration at concentrations less than 1.25%, but became less dose-dependent at higher anesthetic concentrations. Sevoflurane metabolism by precision-cut liver slices in vitro became dose-independent at more than 10-30 microM sevoflurane. No evidence of substrate inhibition was observed. These data provide evidence that sevoflurane metabolite concentrations are almost independent of inspired anesthetic concentration over at least part of the clinically used concentration range.

Sevoflurane degradation product concentrations with soda lime during prolonged anesthesia.

STUDY OBJECTIVES: To evaluate the decomposition of sevoflurane in soda lime during prolonged sevoflurane anesthesia in humans. To evaluate for evidence of renal or hepatotoxicity as a result of exposure to these sevoflurane degradation compounds. DESIGN: Prospective evaluation in healthy volunteers. SETTING: Clinical research unit and postanesthesia care unit of a university hospital. PATIENTS: Six healthy male volunteers. INTERVENTIONS: Subjects were anesthetized with sevoflurane 1 to 1.2 minimum alveolar concentration for greater than 9 hours with a semiclosed circuit anesthetic technique (5-liter total flow) with fresh soda lime as the absorbent. MEASUREMENTS AND MAIN RESULTS: Laboratory tests of renal and hepatic function were performed before anesthesia and 1 and 5 days after anesthesia. During sevoflurane anesthesia, inhalation and exhalation circuit limb gas samples were obtained for degradation compound analysis. Only one degradation product, fluoromethyl-2,2-difluoro-1-(trifluoromethyl) vinyl ether (compound A), was detected. Inhalation concentration was maximal (7.6 +/- 1.0 ppm) at 2 hours and did not increase further after this time point. There were no differences in preanesthesia and postanesthesia tests of hepatic and renal function. CONCLUSIONS: Levels of the degradation compound (compound A) produced in semiclosed circuit sevoflurane anesthesia with soda lime are well below potential toxic levels and thus appear safe. When sevoflurane is administered under these conditions for prolonged anesthesia, concentrations of compound A do not continue to increase throughout anesthesia.

Renal concentrating function with prolonged sevoflurane or enflurane anesthesia in volunteers.

BACKGROUND: Sevoflurane, a new inhalational anesthetic, is biotransformed, producing peak plasma inorganic fluoride concentrations that may exceed 50 microM. We evaluated plasma inorganic fluoride concentrations with prolonged (> 9 MAC-h) sevoflurane or enflurane anesthesia in volunteers and compared renal concentrating function with desmopressin testing 1 and 5 days after anesthesia. METHODS: Fourteen healthy male volunteers received either enflurane or sevoflurane (1-1.2 MAC) for more than 9 MAC-h. Each volunteer was administered three tests of renal concentrating function, with intranasal desmopressin and urine collections performed 1 week before anesthesia and 1 and 5 days after anesthesia. Venous blood samples were obtained for plasma fluoride concentrations during and after anesthesia. Creatinine clearance was determined by 24-h urine collections 7 days before and 4 days after anesthesia. Urine samples were obtained before and 1, 2, and 5 days after anesthesia for determination of n-acetyl-beta-glucosaminidase and creatinine concentrations. RESULTS: Prolonged sevoflurane anesthesia (9.5 MAC-h) did not impair renal concentrating function on day 1 or 5 postanesthesia, as determined by desmopressin testing. Maximal urinary osmolality on day 1 postanesthesia was decreased (< 800 mOsm/kg) in two of seven enflurane-anesthetized volunteers; however, mean results did not differ from the those of the sevoflurane group. Mean peak plasma fluoride ion concentrations were 23 +/- 1 microM 6 h postanesthesia for enflurane and 47 +/- 3 microM at the end of anesthesia for sevoflurane (P < 0.01). There were no changes in creatinine clearance or urinary n-acetyl-beta-glucosaminidase concentration in either anesthetic group. DISCUSSION: Prolonged sevoflurane anesthesia did not impair renal concentrating function, as evaluated with desmopressin testing 1 and 5 days postanesthesia in healthy volunteers. Although with prolonged enflurane anesthesia, mean maximal osmolality values on day 1 postanesthesia did not differ from sevoflurane values, there was evidence in two volunteers at this time point of impairment in renal concentrating function, which normalized 5 days postanesthesia. These results occurred despite a higher peak plasma fluoride ion concentration and greater total inorganic fluoride renal exposure with sevoflurane anesthesia.

A simplified gas chromatographic method for quantifying the sevoflurane metabolite hexafluoroisopropanol.

BACKGROUND: The results of sevoflurane biotransformation (fluoromethyl-1,1,1,3,3,3,-hexafluoro-2-propyl ether) to inorganic fluoride have been examined. However, these investigations have lacked a simplified assay for determining the primary organic metabolite, hexafluoroisopropanol. Previous attempts have involved extensive extraction steps, complicated derivatization techniques, or sophisticated detectors. METHODS: After enzymatic hydrolysis of conjugates, hexafluoroisopropanol is detected readily using a head space gas chromatographic analysis with a flame ionization detector. RESULTS: The gas chromatographic technique was linear from 10 to 800 microM with a correlation coefficient of 0.999. The detection limit was 10 microM in urine and 25 microM in blood. CONCLUSIONS: This simplified approach does not require the extraction, derivatization, or mass spectrometric detectors of previous methods. As sevoflurane utilization and research increases, this assay should allow for a variety of laboratory and clinical disposition studies to be performed.

Renal function after sevoflurane or enflurane anesthesia in the Fischer 344 rat.

Sevoflurane is metabolized to inorganic fluoride, a potential nephrotoxin. To evaluate the nephrotoxic potential of sevoflurane, 1-yr-old male Fischer 344 rats were anesthetized with 10 minimal alveolar anesthetic concentration (MAC) h sevoflurane or enflurane with or without pretreatment with biotransformation-enhancing agents. Peak serum fluoride levels reached 35 microM with sevoflurane anesthesia after pretreatment with phenobarbital and 40 microM after enflurane anesthesia after pretreatment with isoniazid. One day after anesthesia, sevoflurane-anesthetized rats concentrated urine normally in response to subcutaneous administration of 1-deamino-8-D-arginine vasopressin and exhibited no increase in urinary excretion of N-acetyl beta-glucosaminidase. Isoniazid-treated, enflurane anesthetized rats developed a 31% reduction in maximal urinary concentrating ability and a 3.5-fold increase in excretion of N-acetyl-beta-glucosaminidase. Sevoflurane produced no evidence of fluoride-induced nephrotoxicity in noninduced or enzyme-induced rats. Under similar conditions, enflurane produced laboratory evidence of nephrotoxicity.

Plasma inorganic fluoride levels with sevoflurane anesthesia in morbidly obese and nonobese patients.

Administration of several of the inhaled anesthetics result in plasma inorganic fluoride concentrations that are higher in obese compared to nonobese patients. Sevoflurane, a new inhaled anesthetic, is metabolized to inorganic fluoride; however, plasma inorganic fluoride levels with sevoflurane anesthesia in obese subjects have not been evaluated. We studied plasma inorganic fluoride concentrations during and after sevoflurane surgical anesthesia in morbidly obese (n = 13, body mass index > 35) and nonobese (n = 10) patients. Sevoflurane anesthesia in 60% nitrous oxide/40% oxygen was administered with a semiclosed circle absorption system. Mean anesthetic duration was 1.4 minimum alveolar anesthetic concentration (MAC) hours (sevoflurane MAC = 2.05%) for both groups. Pre- and postoperative blood urea nitrogen, creatinine, and liver function tests were evaluated. Venous blood samples were obtained during and after anesthesia for plasma inorganic fluoride analysis. In six morbidly obese and nonobese patients arterial blood samples were obtained during and after sevoflurane anesthesia for determining sevoflurane blood concentration. Plasma fluoride concentrations during and after anesthesia did not differ between morbidly obese and non-obese groups. Peak plasma inorganic fluoride ion concentrations were 30 +/- 2 mumol/L (mean +/- SEM) in obese and 28 +/- 2 mumol/L in nonobese patients 1 h after discontinuing anesthesia. The hourly rate of change of fluoride ion concentration in plasma during anesthesia was similar between the groups. The maximal recorded plasma fluoride concentrations were 49 mumol/L in an obese patient and 42 mumol/L in a nonobese patient. Pre- and postoperative hepatic and renal tests did not differ significantly in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatic elimination of diazepam: interactions with albumin, desflurane and sevoflurane.

We have studied the effect of sevoflurane and desflurane on the hepatic elimination of diazepam, by incubating slices of rat livers in a closed system. Protein free and protein containing (albumin 10 g litre-1) buffers were used to examine the effect of the anaesthetics on enzyme activity and diazepam binding to albumin. Both anaesthetics (in concentrations of 0.5, 1.5 and 3.0 mmol litre-1) reduced the elimination of diazepam slightly in the absence of albumin, while the presence of the protein increased elimination to a maximum of 30% at the greatest concentration of the anaesthetics. These data support previous observations that volatile anaesthetics may interact pharmacokinetically with both liver enzyme activity and drug binding to albumin.

Quantification of the degradation products of sevoflurane in two CO2 absorbants during low-flow anesthesia in surgical patients.

Sevoflurane, a new inhalational anesthetic agent has been shown to produce degradation products upon interaction with CO2 absorbants. Quantification of these sevoflurane degradation products during low-flow or closed circuit anesthesia in patients has not been well evaluated. The production of sevoflurane degradation products was evaluated using a low-flow anesthetic technique in patients receiving sevoflurane anesthesia in excess of 3 h. Sevoflurane anesthesia was administered to 16 patients using a circle absorption system with O2 flow of 500 ml/min and average N2O flow of 273 ml/min. Preoperative and postoperative hepatic and renal function studies were performed. Gas samples were obtained from the inhalation and exhalation limbs of the anesthetic circuit for degradation product analysis and analyzed by gas chromatography/mass spectrometry for four degradation products. The first eight patients received sevoflurane anesthesia using soda lime, and the following eight patients received anesthesia using baralyme as the CO2 absorbant. CO2 absorbant temperatures were measured during anesthesia. Of the degradation products analyzed, only one compound [fluoromethyl-2, 2-difluoro-1-(trifluoromethyl) vinyl ether], designated compound A, was detectable. Concentrations of compound A increased during the first 4 h of anesthesia with soda lime and baralyme and declined between 4 and 5 h when baralyme was used. Mean maximum inhalation concentration of compound A using baralyme was 20.28 +/- 8.6 ppm (mean +/- SEM) compared to 8.16 +/- 2.67 ppm obtained with soda lime, a difference that did not reach statistical significance. A single patient achieved a maximal concentration of 60.78 ppm during low-flow anesthesia with baralyme. Exhalation concentrations of compound A were less than inhalation concentrations, suggesting patient uptake.(ABSTRACT TRUNCATED AT 250 WORDS)