Sevoflurane Dailymed

Abuse Section

Description

Sevoflurane USP, 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. The second 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).

Figure 1. Fresh Gas Flow Rate versus Compound A Levels in a Circle Absorber System



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.

Figure 2. Carbon Dioxide Flow versus Compound A and Maximum Temperature

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.

Figure 2a. ppm·hr versus MAC·hr at Flow Rate of 1 L/min

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 toxicity occurs 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 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.

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 (F_A) toward the inspired concentration (F_I) 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 F_A/F_I 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.

F_A/F_I data from this study were compared with F_A/F_I 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 (F_A), relative to the last alveolar concentration (Fa_O) 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.

Figure 3. Ratio of Concentration of Anesthetic in Alveolar Gas to Inspired Gas

Figure 4. Concentration of Anesthetic in Alveolar Gas Following Termination of Anesthesia

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.

Figure 5. Serum Inorganic Fluoride Concentrations for Sevoflurane and Other Volatile Anesthetics

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 12μM and 90μM. As shown in Figure 6, peak concentrations occur within 2 hours of the end of anesthesia and are less than 25μM (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 > 50μM were correlated with the development of vasopressin-resistant, polyuric, renal failure. In clinical studies with sevoflurane, there were no reports of toxicity associated with elevated fluoride ion levels.

Figure 6. Fluoride Ion Concentrations Following Administration of Sevoflurane (mean MAC = 1.27, mean duration = 2.06 hr) Mean Fluoride Ion Concentrations (n = 48)

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 (C_max) determined in individual studies of special populations are displayed below.

Table 1. Fluoride Ion Estimates in Special Populations 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.   Â

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], Trieger 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 ≥ 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. Â

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. Â

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. Â

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:

Figure 7. Heart Rate



Figure 8. Mean Arterial Pressure



Figure 9. Systemic Vascular Resistance



Figure 10. Cardiac Index



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.

Pharmacogenomics

RYR1 and CACNA1S are polymorphic genes, and multiple pathogenic variants have been associated with malignant hyperthermia susceptibility (MHS) in patients receiving volatile anesthetic agents, including sevoflurane. Case reports as well as ex-vivo studies have identified multiple variants in RYR1 and CACNA1S associated with MHS. Variant pathogenicity should be assessed based on prior clinical experience, functional studies, prevalence information, or other evidence (see CONTRAINDICATIONS , WARNINGS - Malignant Hyperthermia ).

CLINICAL STUDIES

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

 Table 5. Patients Receiving Sevoflurane in Clinical Studies

 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 MaintenanceÂ	 0.64 ± 0.03	 0.66 ± 0.03	 0.8 ± 0.5	 7.3 ± 2.3
 Anesthesia	 MAC·hr.	 MAC·hr.	 MAC·hr.	 mg/kg/hr.
 Exposure ± SD	 (n = 245)	 (n = 249)	 (n = 166)	 (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.   Â

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	 1.27 MAC·hr.	 1.58 MAC·hr.	 1.43 MAC·hr.	 7.0 mg/kg/hr
 Anesthesia	 ± 0.05	 ± 0.06	 ± 0.94	 ± 2.9
 Exposure ± SD	 (n = 271)	 (n = 282)	 (n = 93)	 (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.   Â

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. Â

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 patients, age 40-87 years who were at mild-to-moderate risk for myocardial ischemia and were undergoing elective non-cardiac surgery. Forty-six percent (46%) of the operations were cardiovascular, with the remainder evenly divided between gastrointestinal and musculoskeletal and small numbers of other surgical procedures. The average duration of surgery was less than 2 hours. Anesthesia induction usually was performed with thiopental (2-5 mg/kg) and fentanyl (1-5 mcg/kg). Vecuronium (0.1-0.2 mg/kg) was also administered to facilitate intubation, muscle relaxation or immobility during surgery. The average MAC dose was 0.49 for both anesthetics. There was no significant difference between the anesthetic regimens for intraoperative hemodynamics, cardioactive drug use, or ischemic incidents, although only 83 patients in the sevoflurane group and 85 patients in the isoflurane group were successfully monitored for ischemia. The outcome was also equivalent in terms of adverse events, death, and postoperative myocardial infarction. Within the limits of this small multicenter study in patients at mild-to-moderate risk for myocardial ischemia, sevoflurane was a satisfactory equivalent to isoflurane in providing supplemental inhalation anesthesia to intravenous drugs.

Cesarean Section

Sevoflurane (n = 29) was compared to isoflurane (n = 27) in ASA Class I or II patients for the maintenance of anesthesia during cesarean section. Newborn evaluations and recovery events were recorded. With both anesthetics, Apgar scores averaged 8 and 9 at 1 and 5 minutes, respectively.

Use of sevoflurane as part of general anesthesia for elective cesarean section produced no untoward effects in mother or neonate. Sevoflurane and isoflurane demonstrated equivalent recovery characteristics. There was no difference between sevoflurane and isoflurane with regard to the effect on the newborn, as assessed by Apgar Score and Neurological and Adaptive Capacity Score (average = 29.5). The safety of sevoflurane in labor and vaginal delivery has not been evaluated.

Neurosurgery

Three studies compared sevoflurane to isoflurane for maintenance of anesthesia during neurosurgical procedures. In a study of 20 patients, there was no difference between sevoflurane and isoflurane with regard to recovery from anesthesia. In 2 studies, a total of 22 patients with intracranial pressure (ICP) monitors received either sevoflurane or isoflurane. There was no difference between sevoflurane and isoflurane with regard to ICP response to inhalation of 0.5, 1.0, and 1.5 MAC inspired concentrations of volatile agent during N2O-O2-fentanyl anesthesia. During progressive hyperventilation from PaCO₂ = 40 to PaCO2 = 30, ICP response to hypocarbia was preserved with sevoflurane at both 0.5 and 1.0 MAC concentrations. In patients at risk for elevations of ICP, sevoflurane should be administered cautiously in conjunction with ICP-reducing maneuvers such as hyperventilation.

Hepatic Impairment

A multicenter study (2 sites) compared the safety of sevoflurane and isoflurane in 16 patients with mild-to-moderate hepatic impairment utilizing the lidocaine MEGX assay for assessment of hepatocellular function. All patients received intravenous propofol (1-3 mg/kg) or thiopental (2-7 mg/kg) for induction and succinylcholine, vecuronium, or atracurium for intubation. Sevoflurane or isoflurane was administered in either 100% O2 or up to 70% N2O/O2. Neither drug adversely affected hepatic function. No serum inorganic fluoride level exceeded 45 μM/L, but sevoflurane patients had prolonged terminal disposition of fluoride, as evidenced by longer inorganic fluoride half-life than patients with normal hepatic function (23 hours vs. 10-48 hours).

Renal Impairment

Sevoflurane was evaluated in renally impaired patients with baseline serum creatinine > 1.5 mg/dL. Fourteen patients who received sevoflurane were compared with 12 patients who received isoflurane. In another study, 21 patients who received sevoflurane were compared with 20 patients who received enflurane. Creatinine levels increased in 7% of patients who received sevoflurane, 8% of patients who received isoflurane, and 10% of patients who received enflurane. Because of the small number of patients with renal insufficiency (baseline serum creatinine greater than 1.5 mg/dL) studied, the safety of sevoflurane administration in this group has not yet been fully established. Therefore, sevoflurane should be used with caution in patients with renal insufficiency (see WARNINGS).