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Sevoflurane
ULTANE(TM) (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. Sevoflurane, Physical Constants are:
Vapor pressure in mm Hg: Distribution Partition Coefficients at 37oC:
Mean Component/Gas Partition Coefficients at 25oC for Polymers Used Commonly in Medical Applications
Sevoflurane is nonflammable and nonexplosive as defined by the requirements of International Electrotechnical Commission 601-2-13. Sevoflurane is a clear, colorless, stable liquid containing no additives or chemical stabilizers. Sevoflurane is nonpungent. It is miscible with ethanol, ether, chloroform and petroleum benzene, and it is slightly soluble in water. Sevoflurane is stable when stored under normal room lighting conditions according to instructions. Sevoflurane is chemically stable. No discernible degradation occurs in the presence of strong acids or heat. The only known degradation reaction in the clinical setting is through direct contact with CO2 absorbents (soda lime and Baralyme®) producing 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 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. Baralyme® causes more production of Compound A than does soda lime. Laboratory simulations have shown that the concentration of these degradants is inversely correlated with the fresh gas flow rate Sevoflurane degradation in soda lime has been shown to increase with temperature. Since the reaction of carbon dioxide with absorbents is exothermic, this 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 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). 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 concentrations of Compound A measured in the anesthesia circuit when sevoflurane is used clinically are not known to be deleterious to humans. Sevoflurane is not corrosive
to stainless steel, brass, aluminum,
nickel-plated brass, chrome-plated brass or copper
beryllium.
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 @ 37o 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. 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 (FaO) 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. 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 Special Populations Following Administration of Sevoflurane
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:
2. Recovery of cognitive function and motor coordination was evaluated based on:
3. Other recovery times were:
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
n = number of patients with recording of events. Table 3: Recovery Variables for Evaluable Adult Patients in Two Comparative Studies: Sevoflurane versus Isoflurane
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
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. 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. The types of patients are summarized as follows: Table 5: Patients Receiving Sevoflurane in Clinical Trials
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
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
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 1588 pediatric patients aged 1 day to 18 years, and ASA physical status I or II (927 sevoflurane, 661 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%). 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: Possibly/Probably Causally Related). Table 8: Incidence of Pediatric Induction Events
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 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 M.C. 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-N22O 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 proof 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 I.P. 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.
Sevoflurane is indicated for induction and maintenance of general anesthesia in adult and pediatric patients for inpatient and outpatient surgery.
The concentration of sevoflurane being delivered from a vaporizer during anesthesia should be known. This may be accomplished by using a vaporizer calibrated specifically for sevoflurane. The administration of general anesthesia must be individualized based on the patient's response. Pre-anesthetic Medication: No specific premedication is either indicated or contraindicated with sevoflurane. The decision as to whether or not to premedicate and the choice of premedication is left to the discretion of the anesthesiologist. Induction: Sevoflurane has a nonpungent odor and does not cause respiratory irritability; it is suitable for mask induction in pediatrics and adults. Maintenance: Surgical levels of anesthesia can usually be achieved with concentrations of 0.5 - 3% sevoflurane with or without the concomitant use of nitrous oxide. Sevoflurane can be administered with any type of anesthesia circuit. Table 9: MAC Values for Adults and Pediatric Patients According to Age
@ In 3 - < 5 year old pediatric patients, 60% N2O/40% O2 was used. HOW SUPPLIED ULTANE(TM) (sevoflurane), Volatile Liquid for Inhalation, is packaged in amber colored bottles containing 250 mL sevoflurane, List 4456, NDC # 0074-4456-02. SAFETY AND HANDLING Occupational Caution There is no specific work exposure limit established for sevoflurane. However, the National Institute for Occupational Safety and Health has recommended an 8 hour time-weighted average limit of 2 ppm for halogenated anesthetic agents in general (0.5 ppm when coupled with exposure to N2O). STORAGE Store at controlled room temperature, 15o - 30o C (59o - 86oF). Caution: Federal (USA) law prohibits dispensing without prescription.
Adverse events are derived from controlled clinical trials conducted in the United States, Canada, and Europe. The reference drugs were isoflurane, enflurane, and propofol in adults and halothane in pediatric patients. The studies were conducted using a variety of premedications, other anesthetics, and surgical procedures of varying length. Most adverse events reported were mild and transient, and may reflect the surgical procedures, patient characteristics (including disease) and/or medications administered. Of the 5182 patients enrolled in the clinical trials, 2906 were exposed to sevoflurane, including 118 adults and 507 pediatric patients who underwent mask induction. Each patient was counted once for each type of adverse event. Adverse events reported in patients in clinical trials and considered to be possibly or probably related to sevoflurane are presented within each body system in order of decreasing frequency in the following listings. One case of malignant hyperthermia was reported in pre-registration clinical trials. Adverse Events During the Induction Period (from onset of anesthesia by mask induction to surgical incision) Incidence >1% Adult Patients (N = 118) Cardiovascular: Bradycardia 5%, Hypotension 4%, Tachycardia 2% Nervous System: Agitation 7% Respiratory System: Laryngospasm 8%, Airway obstruction 8%, Breathholding 5%, Cough Increased 5% Pediatric Patients (N = 507) Cardiovascular: Tachycardia 6%, Hypotension 4% Nervous System: Agitation 15% Respiratory System: Breathholding 5%, Cough Increased 5%, Laryngospasm 3%, Apnea 2% Digestive System: Increased salivation 2% Adverse Events During Maintenance and Emergence Periods, Incidence >1% (N = 2906) Body as a whole: Fever 1%, Shivering 6%, Hypothermia 1%, Movement 1%, Headache 1% Cardiovascular: Hypotension 11%, Hypertension 2%, Bradycardia 5%, Tachycardia 2% Nervous System: Somnolence 9%, Agitation 9%, Dizziness 4%, Increased salivation 4% Digestive System: Nausea 25%, Vomiting 18% Respiratory System: Cough increased 11%, Breathholding 2%, Laryngospasm 2% Adverse Events, All Patients in Clinical Trials (N = 2906), All Anesthetic Periods, Incidence <1% (reported in 3 or more patients) Body as a whole: Asthenia, Pain Cardiovascular: Arrhythmia, Ventricular Extrasystoles, Supraventricular Extrasystoles, Complete AV Block, Bigeminy, Hemorrhage, Inverted T Wave, Atrial Fibrillation, Atrial Arrhythmia, Second Degree AV Block, Syncope, S-T Depressed Nervous System: Crying, Nervousness, Confusion, Hypertonia, Dry Mouth, Insomnia Respiratory System: Sputum Increased, Apnea, Hypoxia, Wheezing, Bronchospasm, Hyperventilation, Pharyngitis, Hiccup, Hypoventilation, Dyspnea, Stridor Metabolism and Nutrition: Increases in LDH, AST, ALT, BUN, Alkaline Phosphatase, Creatinine, Bilirubinemia, Glycosuria, Fluorosis, Albuminuria, Hypophosphatemia, Acidosis, Hyperglycemia Hemic and Lymphatic System: Leucocytosis, Thrombocytopenia Skin and Special Senses: Amblyopia, Pruritus, Taste Perversion, Rash, Conjunctivitis Urogenital: Urination Impaired, Urine Abnormality, Urinary Retention, Oliguria See WARNINGS for information regarding malignant hyperthermia. Laboratory Findings: Transient elevations in glucose, liver function tests, and white blood cell count may occur as with use of other anesthetic agents.
In clinical trials, no significant adverse reactions occurred with other drugs commonly used in the perioperative period, including: central nervous system depressants, autonomic drugs, skeletal muscle relaxants, anti-infective agents, hormones and synthetic substitutes, blood derivatives, and cardiovascular drugs. Intravenous Anesthetics: Sevoflurane administration is compatible with barbiturates, propofol, and other commonly used intravenous anesthetics. Benzodiazepines and Opioids: Benzodiazepines and opioids would be expected to decrease the MAC of sevoflurane in the same manner as with other inhalational anesthetics. Sevoflurane administration is compatible with benzodiazepines and opioids as commonly used in surgical practice. Nitrous Oxide: As with other halogenated volatile anesthetics, the anesthetic requirement for sevoflurane is decreased when administered in combination with nitrous oxide. Using 50% N2O, the MAC equivalent dose requirement is reduced approximately 50% in adults, and approximately 25% in pediatric patients (see DOSAGE AND ADMINISTRATION) Neuromuscular Blocking Agents: As is the case with other volatile anesthetics, sevoflurane increases both the intensity and duration of neuromuscular blockade induced by nondepolarizing muscle relaxants. When used to supplement alfentanil-N2O anesthesia, sevoflurane and isoflurane equally potentiate neuromuscular block induced with pancuronium, vecuronium or atracurium. Therefore, during sevoflurane anesthesia, the dosage adjustments for these muscle relaxants are similar to those required with isoflurane. Potentiation of neuromuscular blocking agents requires equilibration of muscle with delivered partial pressure of sevoflurane. Reduced doses of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation. Among available nondepolarizing agents, only vecuronium, pancuronium and atracurium interactions have been studied during sevoflurane anesthesia. In the absence of specific guidelines:
The effect of sevoflurane on the duration of depolarizing neuromuscular blockade induced by succinylcholine has not been studied. Renal or Hepatic Function Results of evaluations of laboratory parameters (e.g., ALT, AST, alkaline phosphatase, and total bilirubin, etc.), as well as investigator-reported incidence of adverse events relating to liver function, demonstrate that sevoflurane can be administered to patients with normal or mild-to-moderately impaired hepatic function. However, patients with severe hepatic dysfunction were not investigated. Occasional cases of transient changes in postoperative hepatic function tests were reported with both sevoflurane and reference agents. Sevoflurane was found to be comparable to isoflurane with regard to these changes in hepatic function. Based on the incidence and magnitude of changes in serum creatinine, in patients with exposure up to 9.6 MAC-hours of anesthesia, no evidence for increased risk of developing renal dysfunction was found. Serum fluoride levels
increased with duration
and concentration
of exposure to sevoflurane. The highest measured serum
fluoride level was
111 µM and a level of 29.5 µM was seen as late as 92
hours post exposure. A
25% reduction in maximum
urine-concentrating ability
has been seen following enflurane anesthesia
with mean peak serum
inorganic fluoride
levels of 33.6 µM and values above 20 µM for 18 hours.
Elevated fluoride levels after sevoflurane were not associated with
impairment of renal
function, presumably because of its rapid elimination
at the end of anesthesia.
Sevoflurane should be administered only by persons trained in the administration of general anesthesia. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. Since levels of anesthesia may be altered rapidly, only vaporizers producing predictable concentrations of sevoflurane should be used. Compound A is produced when sevoflurane interacts with soda
lime and Baralyme®
(See Because clinical experience in administering sevoflurane to patients with renal insufficiency (creatinine >1.5 mg/dL) is limited, its safety in these patients has not been established. Malignant Hyperthermia In susceptible individuals, potent inhalation anesthetic agents, including sevoflurane, may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. In clinical trials, one case of malignant hyperthermia was reported. In genetically susceptible pigs, sevoflurane induced malignant hyperthermia. The clinical syndrome is signaled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anesthesia, acute hypoxia, hypercapnia, and hypovolemia. Treatment of malignant hyperthermia includes discontinuation of triggering agents, administration of intravenous dantrolene sodium, and application of supportive therapy. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be monitored and sustained if possible. Sevoflurane may present an increased risk in patients with known sensitivity to volatile halogenated anesthetic agents.
During the maintenance of anesthesia, increasing the concentration of sevoflurane produces dose-dependent decreases in blood pressure. Due to sevoflurane's insolubility in blood, these hemodynamic changes may occur more rapidly than with other volatile anesthetics. Excessive decreases in blood pressure or respiratory depression may be related to depth of anesthesia and may be corrected by decreasing the inspired concentration of sevoflurane. The recovery from general anesthesia should be assessed carefully before a patient is discharged from the post-anesthesia care unit. Drug Interactions In clinical trials, no significant adverse reactions occurred with other drugs commonly used in the perioperative period, including: central nervous system depressants, autonomic drugs, skeletal muscle relaxants, anti-infective agents, hormones and synthetic substitutes, blood derivatives, and cardiovascular drugs. Intravenous Anesthetics: Sevoflurane administration is compatible with barbiturates, propofol, and other commonly used intravenous anesthetics. Benzodiazepines and Opioids: Benzodiazepines and opioids would be expected to decrease the MAC of sevoflurane in the same manner as with other inhalational anesthetics. Sevoflurane administration is compatible with benzodiazepines and opioids as commonly used in surgical practice. Nitrous Oxide: As with other halogenated volatile anesthetics, the anesthetic requirement for sevoflurane is decreased when administered in combination with nitrous oxide. Using 50% N2O, the MAC equivalent dose requirement is reduced approximately 50% in adults, and approximately 25% in pediatric patients (see DOSAGE AND ADMINISTRATION) Neuromuscular Blocking Agents: As is the case with other volatile anesthetics, sevoflurane increases both the intensity and duration of neuromuscular blockade induced by nondepolarizing muscle relaxants. When used to supplement alfentanil-N2O anesthesia, sevoflurane and isoflurane equally potentiate neuromuscular block induced with pancuronium, vecuronium or atracurium. Therefore, during sevoflurane anesthesia, the dosage adjustments for these muscle relaxants are similar to those required with isoflurane. Potentiation of neuromuscular blocking agents requires equilibration of muscle with delivered partial pressure of sevoflurane. Reduced doses of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation. Among available nondepolarizing agents, only vecuronium, pancuronium and atracurium interactions have been studied during sevoflurane anesthesia. In the absence of specific guidelines:
The effect of sevoflurane on the duration of depolarizing neuromuscular blockade induced by succinylcholine has not been studied. Renal or Hepatic Function Results of evaluations of laboratory parameters (e.g., ALT, AST, alkaline phosphatase, and total bilirubin, etc.), as well as investigator-reported incidence of adverse events relating to liver function, demonstrate that sevoflurane can be administered to patients with normal or mild-to-moderately impaired hepatic function. However, patients with severe hepatic dysfunction were not investigated. Occasional cases of transient changes in postoperative hepatic function tests were reported with both sevoflurane and reference agents. Sevoflurane was found to be comparable to isoflurane with regard to these changes in hepatic function. Based on the incidence and magnitude of changes in serum creatinine, in patients with exposure up to 9.6 MAC-hours of anesthesia, no evidence for increased risk of developing renal dysfunction was found. Serum fluoride levels increased with duration and concentration of exposure to sevoflurane. The highest measured serum fluoride level was 111 µM and a level of 29.5 µM was seen as late as 92 hours post exposure. A 25% reduction in maximum urine-concentrating ability has been seen following enflurane anesthesia with mean peak serum inorganic fluoride levels of 33.6 µM and values above 20 µM for 18 hours. Elevated fluoride levels after sevoflurane were not associated with impairment of renal function, presumably because of its rapid elimination at the end of anesthesia. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies on carcinogenesis have not been performed. No mutagenic effect was noted in the Ames test and no chromosomal aberrations were induced in cultured mammalian cells. Pregnancy Category B Reproduction studies have been performed in rats and rabbits at doses up to 1 MAC (minimum alveolar concentration) without CO2 absorbent and have revealed no evidence of impaired fertility or harm to the fetus due to sevoflurane at 0.3 M.C. the highest nontoxic dose. Developmental and reproductive toxicity studies of sevoflurane in animals in the presence of strong alkalies (i.e., degradation of sevoflurane and production of Compound A) have not been conducted. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, sevoflurane should be used during pregnancy only if clearly needed. Labor and Delivery Sevoflurane has been used as proof of general anesthesia for elective cesarean section in 29 women. There were no untoward effects in mother or neonate. (See CLINICAL PHARMACOLOGY, Clinical Trials.) The safety of sevoflurane in labor and delivery has not been demonstrated. Nursing Mothers The concentrations of sevoflurane in milk are probably of no clinical importance 24 hours after anesthesia. Because of rapid washout, sevoflurane concentrations in milk are predicted to be below those found with many other volatile anesthetics. Geriatric Use MAC decreases with increasing age. The average concentration of
sevoflurane to achieve MAC
in an 80 year old is approximately 50% of that required in a 20
year old.
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