Sevoflurane

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Sevoflurane

Dosage Form: Volatile liquid for inhalation

Sevoflurane Description

Sevoflurane, volatile liquid for inhalation, a nonflammable and nonexplosive liquid administered by vaporization, is a halogenated general inhalation anesthetic drug. Sevoflurane is fluoromethyl 2,2,2,-trifluoro-1-(trifluoromethyl) ethyl ether and its structural formula is:

Sevoflurane, Physical Constants are:
Molecular weight 200.05
Boiling point at 760 mm Hg 58.6°C
Specific gravity at 20°C 1.520 - 1.525
Vapor pressure in mm Hg 157 mm Hg at 20°C
197 mm Hg at 25°C
317 mm Hg at 36°C
Distribution Partition Coefficients at 37°C:
Blood/Gas 0.63 - 0.69
Water/Gas 0.36
Olive Oil/Gas 47 - 54
Brain/Gas 1.15
Mean Component/Gas Partition Coefficients at 25°C for Polymers Used Commonly in Medical Applications:
Conductive rubber 14.0
Butyl rubber 7.7
Polyvinylchloride 17.4
Polyethylene 1.3

Sevoflurane is nonflammable and nonexplosive as defined by the requirements of International Electrotechnical Commission 601-2-13.

Sevoflurane is a clear, colorless, liquid containing no additives. Sevoflurane is not corrosive to stainless steel, brass, aluminum, nickel-plated brass, chrome-plated brass or copper beryllium. Sevoflurane is nonpungent. It is miscible with ethanol, ether, chloroform, and benzene, and it is slightly soluble in water. Sevoflurane is stable when stored under normal room lighting conditions according to instructions. No discernible degradation of Sevoflurane occurs in the presence of strong acids or heat. When in contact with alkaline CO2 absorbents (e.g. Baralyme® and to a lesser extent soda lime) within the anesthesia machine, Sevoflurane can undergo degradation under certain conditions. Degradation of Sevoflurane is minimal, and degradants are either undetectable or present in non-toxic amounts when used as directed with fresh absorbents. Sevoflurane degradation and subsequent degradant formation are enhanced by increasing absorbent temperature increased Sevoflurane concentration, decreased fresh gas flow and desiccated CO2 absorbents (especially with potassium hydroxide containing absorbents e.g. Baralyme).

Sevoflurane alkaline degradation occurs by two pathways. The first results from the loss of hydrogen fluoride with the formation of pentafluoroisopropenyl fluoromethyl ether, (PIFE, C4H2F6O), also known as Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl ether, (PMFE, C5H6F6O), also known as Compound B. Thesecond pathway for degradation of Sevoflurane, which occurs primarily in the presence of desiccated CO2 absorbents, is discussed later.

In the first pathway, the defluorination pathway, the production of degradants in the anesthesia circuit results from the extraction of the acidic proton in the presence of a strong base (KOH and/or NaOH) forming an alkene (Compound A) from Sevoflurane similar to formation of 2-bromo-2-chloro-1,1-difluoro ethylene (BCDFE) from halothane. Laboratory simulations have shown that the concentration of these degradants is inversely correlated with the fresh gas flow rate (See Figure 1).

Since the reaction of carbon dioxide with absorbents is exothermic, the temperature increase will be determined by quantities of CO2 absorbed, which in turn will depend on fresh gas flow in the anesthesia circle system, metabolic status of the patient, and ventilation. The relationship of temperature produced by varying levels of CO2 and Compound A production is illustrated in the following in vitro simulation where CO2 was added to a circle absorber system.

Compound A concentration in a circle absorber system increases as a function of increasing CO2 absorbent temperature and composition (Baralyme producing higher levels than soda lime), increased body temperature, and increased minute ventilation, and decreasing fresh gas flow rates. It has been reported that the concentration of Compound A increases significantly with prolonged dehydration of Baralyme. Compound A exposure in patients also has been shown to rise with increased Sevoflurane concentrations and duration of anesthesia. In a clinical study in which Sevoflurane was administered to patients under low flow conditions for ≥2 hours at flow rates of 1 Liter/minute, Compound A levels were measured in an effort to determine the relationship between MAC hours and Compound A levels produced. The relationship between Compound A levels and Sevoflurane exposure are shown in Figure 2a.

Compound A has been shown to be nephrotoxic in rats after exposures that have varied in duration from one to three hours. No histopathologic change was seen at a concentration of up to 270 ppm for one hour. Sporadic single cell necrosis of proximal tubule cells has been reported at a concentration of 114 ppm after a 3-hour exposure to Compound A in rats. The LC50 reported at 1 hour is 1050-1090 ppm (male-female) and, at 3 hours, 350-490 ppm (male-female).

An experiment was performed comparing Sevoflurane plus 75 or 100 ppm Compound A with an active control to evaluate the potential nephrotoxicity of Compound A in non-human primates. A single 8-hour exposure of Sevoflurane in the presence of Compound A produced single-cell renal tubular degeneration and single-cell necrosis in cynomolgus monkeys. These changes are consistent with the increased urinary protein, glucose level and enzymic activity noted on days one and three on the clinical pathology evaluation. This nephrotoxicity produced by Compound A is dose and duration of exposure dependent.

At a fresh gas flow rate of 1 L/min, mean maximum concentrations of Compound A in the anesthesia circuit in clinical settings are approximately 20 ppm (0.002%) with soda lime and 30 ppm (0.003%) with Baralyme in adult patients; mean maximum concentrations in pediatric patients with soda lime are about half those found in adults. The highest concentration observed in a single patient with Baralyme was 61 ppm (0.0061%) and 32 ppm (0.0032%) with soda lime. The levels of Compound A at which toxicityoccurs in humans is not known.

The second pathway for degradation of Sevoflurane occurs primarily in the presence of desiccated CO2 absorbents and leads to the dissociation of Sevoflurane into hexafluoroisopropanol (HFIP) and formaldehyde. HFIP is inactive, non-genotoxic, rapidly glucuronidated and cleared by the liver. Formaldehyde is present during normal metabolic processes. Upon exposure to a highly desiccated absorbent, formaldehyde can further degrade into methanol and formate. Formate can contribute to the formation of carbon monoxide in the presence of high temperature that can be associated with desiccated Baralyme®. Methanol can react with Compound A to form the methoxy addition product Compound B. Compound B can undergo further HF elimination to form Compounds C, D, and E.

Sevoflurane degradants were observed in the respiratory circuit of an experimental anesthesia machine using desiccated CO2 absorbents and maximum Sevoflurane concentrations (8%) for extended periods of time (>2 hours). Concentrations of formaldehyde observed with desiccated soda lime in this experimental anesthesia respiratory circuit were consistent with levels that could potentially result in mild respiratory irritation. Although KOH containing CO2 absorbents are no longer commercially available, in the laboratory experiments, exposure of Sevoflurane to the desiccated KOH containing CO2 absorbent, Baralyme, resulted in the detection of substantially greater degradant levels.

Sevoflurane - Clinical Pharmacology

Sevoflurane is an inhalational anesthetic agent for use in induction and maintenance of general anesthesia. Minimum alveolar concentration (MAC) of Sevoflurane in oxygen for a 40-year-old adult is 2.1%. The MAC of Sevoflurane decreases with age (see DOSAGE AND ADMINISTRATION for details).

Pharmacokinetics

UPTAKE AND DISTRIBUTION

Solubility

Because of the low solubility of Sevoflurane in blood (blood/gas partition coefficient @ 37°C = 0.63-0.69), a minimal amount of Sevoflurane is required to be dissolved in the blood before the alveolar partial pressure is in equilibrium with the arterial partial pressure. Therefore there is a rapid rate of increase in the alveolar (end-tidal) concentration (FA) toward the inspired concentration (FI) during induction.

Induction of Anesthesia

In a study in which seven healthy male volunteers were administered 70% N2O/30% O2 for 30 minutes followed by 1.0% Sevoflurane and 0.6% isoflurane for another 30 minutes the FA/FI ratio was greater for Sevoflurane than isoflurane at all time points. The time for the concentration in the alveoli to reach 50% of the inspired concentration was 4-8 minutes for isoflurane and approximately 1 minute for Sevoflurane.

FA/FI data from this study were compared with FA/FI data of other halogenated anesthetic agents from another study. When all data were normalized to isoflurane, the uptake and distribution of Sevoflurane was shown to be faster than isoflurane and halothane, but slower than desflurane. The results are depicted in Figure 3.

Recovery from Anesthesia

The low solubility of Sevoflurane facilitates rapid elimination via the lungs. The rate of elimination is quantified as the rate of change of the alveolar (end-tidal) concentration following termination of anesthesia (FA), relative to the last alveolar concentration (Fa0) measured immediately before discontinuance of the anesthetic. In the healthy volunteer study described above, rate of elimination of Sevoflurane was similar compared with desflurane, but faster compared with either halothane or isoflurane. These results are depicted in Figure 4.

Yasuda N, Lockhart S, Eger EI II, et al: Comparison of kinetics of Sevoflurane and isoflurane in humans. Anesth Analg 72:316, 1991.

Protein Binding

The effects of Sevoflurane on the displacement of drugs from serum and tissue proteins have not been investigated. Other fluorinated volatile anesthetics have been shown to displace drugs from serum and tissue proteins in vitro. The clinical significance of this is unknown. Clinical studies have shown no untoward effects when Sevoflurane is administered to patients taking drugs that are highly bound and have a small volume of distribution (e.g., phenytoin).

Metabolism

Sevoflurane is metabolized by cytochrome P450 2E1, to hexafluoroisopropanol (HFIP) with release of inorganic fluoride and CO2. Once formed HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolic pathways for Sevoflurane have been identified.In vivo metabolism studies suggest that approximately 5% of the Sevoflurane dose may be metabolized.

Cytochrome P450 2E1 is the principal isoform identified for Sevoflurane metabolism and this may be induced by chronic exposure to isoniazid and ethanol. This is similar to the metabolism of isoflurane and enflurane and is distinct from that of methoxyflurane which is metabolized via a variety of cytochrome P450 isoforms. The metabolism of Sevoflurane is not inducible by barbiturates. As shown in Figure 5, inorganic fluoride concentrations peak within 2 hours of the end of Sevoflurane anesthesia and return to baseline concentrations within 48 hours post-anesthesia in the majority of cases (67%). The rapid and extensive pulmonary elimination of Sevoflurane minimizes the amount of anesthetic available for metabolism.

Cousins M.J., Greenstein L.R., Hitt B.A., et al: Metabolism and renal effects of enflurane in man. Anesthesiology 44:44; 1976* and Sevo-93-044+.

Legend:

Pre-Anesth. = Pre-anesthesia

Elimination

Up to 3.5% of the Sevoflurane dose appears in the urine as inorganic fluoride. Studies on fluoride indicate that up to 50% of fluoride clearance is nonrenal (via fluoride being taken up into bone).

PHARMACOKINETICS OF FLUORIDE ION

Fluoride ion concentrations are influenced by the duration of anesthesia, the concentration of Sevoflurane administered, and the composition of the anesthetic gas mixture. In studies where anesthesia was maintained purely with Sevoflurane for periods ranging from 1 to 6 hours, peak fluoride concentrations ranged between 12 µM and 90 µM. As shown in Figure 6, peak concentrations occur within 2 hours of the end of anesthesia and are less than 25 µM (475 ng/mL) for the majority of the population after 10 hours. The half-life is in the range of 15-23 hours.

It has been reported that following administration of methoxyflurane, serum inorganic fluoride concentrations>50 µM were correlated with the development of vasopressin-resistant, polyuric, renal failure. In clinical trials with Sevoflurane, there were no reports of toxicity associated with elevated fluoride ion levels.

Fluoride Concentrations After Repeat Exposure and in Special Populations

Fluoride concentrations have been measured after single, extended, and repeat exposure to Sevoflurane in normal surgical and special patient populations, and pharmacokinetic parameters were determined.

Compared with healthy individuals, the fluoride ion half-life was prolonged in patients with renal impairment, but not in the elderly. A study in 8 patients with hepatic impairment suggests a slight prolongation of the half-life. The mean half-life in patients with renal impairment averaged approximately 33 hours (range 21-61 hours) as compared to a mean of approximately 21 hours (range 10-48 hours) in normal healthy individuals. The mean half-life in the elderly (greater than 65 years) approximated 24 hours (range 18-72 hours). The mean half-life in individuals with hepatic impairment was 23 hours (range 16-47 hours). Mean maximal fluoride values (Cmax) determined in individual studies of special populations are displayed below.

Table 1: Fluoride Ion Estimates in SpecialPopulations Following Administration of Sevoflurane
n Age (yr) Duration (hr) Dose (MAC•hr) Cmax (µM)
PEDIATRIC PATIENTS
Anesthetic
Sevoflurane-O2 76 0 - 11 0.8 1.1 12.6
Sevoflurane-O2 40 1 - 11 2.2 3.0 16.0
Sevoflurane/N2O 25 5 - 13 1.9 2.4 21.3
Sevoflurane/N2O 42 0 - 18 2.4 2.2 18.4
Sevoflurane/N2O 40 1 - 11 2.0 2.6 15.5
ELDERLY 33 65 - 93 2.6 1.4 25.6
RENAL 21 29 - 83 2.5 1.0 26.1
HEPATIC 8 42 - 79 3.6 2.2 30.6
OBESE 35 24 - 73 3.0 1.7 38.0

n = number of patients studied.

Pharmacodynamics

Changes in the depth of Sevoflurane anesthesia rapidly follow changes in the inspired concentration.

In the Sevoflurane clinical program, the following recovery variables were evaluated:

  1. Time to events measured from the end of study drug:
    • Time to removal of the endotracheal tube (extubation time)
    • Time required for the patient to open his/her eyes on verbal command (emergence time)
    • Time to respond to simple command (e.g., squeeze my hand) or demonstrates purposeful movement (response to command time, orientation time)
  2. Recovery of cognitive function and motor coordination was evaluated based on:
    • psychomotor performance tests (Digit Symbol Substitution Test [DSST], Treiger Dot Test)
    • the results of subjective (Visual Analog Scale [VAS]) and objective (objective pain-discomfort scale [OPDS]) measurements
    • time to administration of the first post-anesthesia analgesic medication
    • assessments of post-anesthesia patient status
  3. Other recovery times were:
    • time to achieve an Aldrete Score of greater than or equal to 8
    • time required for the patient to be eligible for discharge from the recovery area, per standard criteria at site
    • time when the patient was eligible for discharge from the hospital
    • time when the patient was able to sit up or stand without dizziness

Some of these variables are summarized as follows:

Table 2: Induction and Recovery Variables for Evaluable Pediatric Patients in Two Comparative Studies: Sevoflurane versus Halothane
Time to End-Point (min) Sevoflurane Mean ± SEM Halothane Mean ± SEM
Induction 2.0 ± 0.2 (n=294) 2.7 ± 0.2 (n=252)
Emergence 11.3 ± 0.7 (n=293) 15.8 ± 0.8 (n=252)
Response to command 13.7 ± 1.0 (n=271) 19.3 ± 1.1 (n=230)
First analgesia 52.2 ± 8.5 (n=216) 67.6 ± 10.6 (n=150)
Eligible for recovery discharge 76.5 ± 2.0 (n=292) 81.1 ± 1.9 (n=246)

n = number of patients with recording of events.

Table 3: Recovery Variables for Evaluable Adult Patients in Two Comparative Studies: Sevoflurane versus Isoflurane
Time to Parameter: (min) Sevoflurane Mean ± SEM Isoflurane Mean ± SEM
Emergence 7.7 ± 0.3 (n=395) 9.1 ± 0.3 (n=348)
Response to command 8.1 ± 0.3 (n=395) 9.7 ± 0.3 (n=345)
First analgesia 42.7 ± 3.0 (n=269) 52.9 ± 4.2 (n=228)
Eligible for recovery discharge 87.6 ± 5.3 (n=244) 79.1 ± 5.2 (n=252)

n = number of patients with recording of recovery events.

Table 4: Meta-Analyses for Induction and Emergence Variables for Evaluable Adult Patients in Comparative Studies: Sevoflurane versus Propofol
Parameter No. of Studies Sevoflurane Mean ± SEM Propofol Mean ± SEM
Mean maintenance anesthesia exposure 3 1.0 MAC•hr ± 0.8 (n=259) 7.2 mg/kg/hr ± 2.6 (n=258)
Time to induction: (min) 1 3.1 ± 0.18* (n=93) 2.2 ± 0.18** (n=93)
Time to emergence: (min) 3 8.6 ± 0.57 (n=255) 11.0 ± 0.57 (n=260)
Time to respond to command: (min) 3 9.9 ± 0.60 (n=257) 12.1 ± 0.60 (n=260)
Time to first analgesia: (min) 3 43.8 ± 3.79 (n=177) 57.9 ± 3.68 (n=179)
Time to eligibility for recovery discharge: (min) 3 116.0 ± 4.15 (n=257) 115.6 ± 3.98 (n=261)

*Propofol induction of one Sevoflurane group = mean of 178.8 mg ± 72.5 SD (n=165)

**Propofol induction of all propofol groups = mean of 170.2 mg ± 60.6 SD (n=245)

n = number of patients with recording of events.

CARDIOVASCULAR EFFECTS

Sevoflurane was studied in 14 healthy volunteers (18-35 years old) comparing Sevoflurane-O2 (Sevo/O2) to Sevoflurane-N2O/O2 (Sevo/N2O/O2) during 7 hours of anesthesia. During controlled ventilation, hemodynamic parameters measured are shown in Figures 7-10:

Sevoflurane is a dose-related cardiac depressant. Sevoflurane does not produce increases in heart rate at doses less than 2 MAC.

A study investigating the epinephrine induced arrhythmogenic effect of Sevoflurane versus isoflurane in adult patients undergoing transsphenoidal hypophysectomy demonstrated that the threshold dose of epinephrine (i.e., the dose at which the first sign of arrhythmia was observed) producing multiple ventricular arrhythmias was 5 mcg/kg with both Sevoflurane and isoflurane. Consequently, the interaction of Sevoflurane with epinephrine appears to be equal to that seen with isoflurane.

Clinical Trials

Sevoflurane was administered to a total of 3185 patients prior to Sevoflurane NDA submission. The types of patients are summarized as follows:

Table 5: Patients Receiving Sevoflurane in Clinical Trials
Type of Patients Number Studied
ADULT 2223
Cesarean Delivery 29
Cardiovascular and patients at risk of myocardial ischemia 246
Neurosurgical 22
Hepatic impairment 8
Renal impairment 35
PEDIATRIC 962

Clinical experience with these patients is described below.

ADULT ANESTHESIA

The efficacy of Sevoflurane in comparison to isoflurane, enflurane, and propofol was investigated in 3 outpatient and 25 inpatient studies involving 3591 adult patients. Sevoflurane was found to be comparable to isoflurane, enflurane, and propofol for the maintenance of anesthesia in adult patients. Patients administered Sevoflurane showed shorter times (statistically significant) to some recovery events (extubation, response to command, and orientation) than patients who received isoflurane or propofol.

Mask Induction

Sevoflurane has a nonpungent odor and does not cause respiratory irritability. Sevoflurane is suitable for mask induction in adults. In 196 patients, mask induction was smooth and rapid, with complications occurring with the following frequencies: cough, 6%; breathholding, 6%; agitation, 6%; laryngospasm, 5%.

Ambulatory Surgery

Sevoflurane was compared to isoflurane and propofol for maintenance of anesthesia supplemented with N2O in two studies involving 786 adult (18-84 years of age) ASA Class I, II, or III patients. Shorter times to emergence and response to commands (statistically significant) were observed with Sevoflurane compared to isoflurane and propofol.

Table 6: Recovery Parameters in Two Outpatient Surgery Studies: Least Squares Mean ± SEM
Sevoflurane/N2O Isoflurane/N2O Sevoflurane/N2O Propofol/N2O
Mean Maintenance Anesthesia Exposure ± SD 0.64 ± 0.03 MAC•hr (n=245) 0.66 ± 0.03 MAC•hr (n=249) 0.8 ± 0.5 MAC•hr (n=166) 7.3 ± 2.3 mg/kg/hr (n=166)
Time to Emergence (min) 8.2 ± 0.4 (n=246) 9.3 ± 0.3 (n=251) 8.3 ± 0.7 (n=137) 10.4 ± 0.7 (n=142)
Time to Respond to Commands (min) 8.5 ± 0.4 (n=246) 9.8 ± 0.4 (n=248) 9.1 ± 0.7 (n=139) 11.5 ± 0.7 (n=143)
Time to First Analgesia (min) 45.9 ± 4.7 (n=160) 59.1 ± 6.0 (n=252) 46.1 ± 5.4 (n=83) 60.0 ± 4.7 (n=88)
Time to Eligibility for Discharge from Recovery Area (min) 87.6 ± 5.3 (n=244) 79.1 ± 5.2 (n=252) 103.1 ± 3.8 (n=139) 105.1 ± 3.7 (n=143)

n = number of patients with recording of recovery events.

Inpatient Surgery

Sevoflurane was compared to isoflurane and propofol for maintenance of anesthesia supplemented with N2O in two multicenter studies involving 741 adult ASA Class I, II or III (18-92 years of age) patients. Shorter times to emergence, command response, and first post-anesthesia analgesia (statistically significant) were observed with Sevoflurane compared to isoflurane and propofol.

Table 7: Recovery Parameters in Two Inpatient Surgery Studies: Least Squares Mean ± SEM
Sevoflurane/N2O Isoflurane/N2O Sevoflurane/N2O Propofol/N2O
Mean Maintenance Anesthesia Exposure ± SD 1.27 MAC•hr ± 0.05 (n=271) 1.58 MAC•hr ± 0.06 (n=282) 1.43 MAC•hr ± 0.94 (n=93) 7.0 mg/kg/hr ± 2.9 (n=92)
Time to Emergence (min) 11.0 ± 0.6 (n=270) 16.4 ± 0.6 (n=281) 8.8 ± 1.2 (n=92) 13.2 ± 1.2 (n=92)
Time to Respond to Commands (min) 12.8 ± 0.7 (n=270)   18.4 ± 0.7 (n=281) 11.0 ± 1.20 (n=92) 14.4 ± 1.21 (n=91)
Time to First Analgesia (min) 46.1 ± 3.0 (n=233) 55.4 ± 3.2 (n=242) 37.8 ± 3.3 (n=82) 49.2 ± 3.3 (n=79)
Time to Eligibility for Discharge from Recovery Area (min) 139.2 ± 15.6 (n=268) 165.9 ± 16.3 (n=282) 148.4 ± 8.9 (n=92) 141.4 ± 8.9 (n=92)

n = number of patients with recording of recovery events.

PEDIATRIC ANESTHESIA

The concentration of Sevoflurane required for maintenance of general anesthesia is age-dependent (see DOSAGE AND ADMINISTRATION). Sevoflurane or halothane was used to anesthetize 1620 pediatric patients aged 1 day to 18 years, and ASA physical status I or II (948 Sevoflurane, 672 halothane). In one study involving 90 infants and children, there were no clinically significant decreases in heart rate compared to awake values at 1 MAC. Systolic blood pressure decreased 15-20% in comparison to awake values following administration of 1 MAC Sevoflurane; however, clinically significant hypotension requiring immediate intervention did not occur. Overall incidences of bradycardia [more than 20 beats/min lower than normal (80 beats/min)] in comparative studies was 3% for Sevoflurane and 7% for halothane. Patients who received Sevoflurane had slightly faster emergence times (12 vs. 19 minutes), and a higher incidence of post-anesthesia agitation (14% vs. 10%).

Sevoflurane (n=91) was compared to halothane (n=89) in a single-center study for elective repair or palliation of congenital heart disease. The patients ranged in age from 9 days to 11.8 years with an ASA physical status of II, III, and IV (18%, 68%, and 13% respectively). No significant differences were demonstrated between treatment groups with respect to the primary outcome measures: cardiovascular decompensation and severe arterial desaturation. Adverse event data was limited to the study outcome variables collected during surgery and before institution of cardiopulmonary bypass.

Mask Induction

Sevoflurane has a nonpungent odor and is suitable for mask induction in pediatric patients. In controlled pediatric studies in which mask induction was performed, the incidence of induction events is shown below (see ADVERSE REACTIONS).

Table 8: Incidence of Pediatric Induction Events
Sevoflurane (n=836) Halothane (n=660)
Agitation 14% 11%
Cough 6% 10%
Breathholding 5% 6%
Secretions 3% 3%
Laryngospasm 2% 2%
Bronchospasm <1% 0%

n = number of patients.

Ambulatory Surgery

Sevoflurane (n=518) was compared to halothane (n=382) for the maintenance of anesthesia in pediatric outpatients. All patients received N2O and many received fentanyl, midazolam, bupivacaine, or lidocaine. The time to eligibility for discharge from post-anesthesia care units was similar between agents (see CLINICAL PHARMACOLOGY and ADVERSE REACTIONS).

CARDIOVASCULAR SURGERY

Coronary Artery Bypass Graft (CABG) Surgery

Sevoflurane was compared to isoflurane as an adjunct with opioids in a multicenter study of 273 patients undergoing CABG surgery. Anesthesia was induced with midazolam (0.1-0.3 mg/kg); vecuronium (0.1-0.2 mg/kg), and fentanyl (5-15 mcg/kg). Both isoflurane and Sevoflurane were administered at loss of consciousness in doses of 1.0 MAC and titrated until the beginning of cardiopulmonary bypass to a maximum of 2.0 MAC. The total dose of fentanyl did not exceed 25 mcg/kg. The average MAC dose was 0.49 for Sevoflurane and 0.53 for isoflurane. There were no significant differences in hemodynamics, cardioactive drug use, or ischemia incidence between the two groups. Outcome was also equivalent. In this small multicenter study, Sevoflurane appears to be as effective and as safe as isoflurane for supplementation of opioid anesthesia for coronary bypass grafting.

Non-Cardiac Surgery Patients at Risk for Myocardial Ischemia

Sevoflurane-N2O was compared to isoflurane-N2O for maintenance of anesthesia in a multicenter study in 214



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