Sevoflurane: Approaching the Ideal Inhalational Anesthetic A Pharmacologic, Pharmacoeconomic, and Clinical Review

Transcription

1 CNS Drug Reviews Vol. 7, No. 1, pp Neva Press, Branford, Connecticut Sevoflurane: Approaching the Ideal Inhalational Anesthetic A Pharmacologic, Pharmacoeconomic, and Clinical Review Leticia Delgado-Herrera, Randall D. Ostroff, and Sharon A. Rogers + Abbott Laboratories, Hospital Products Division, Abbott Park, IL, USA; + The Ledell Group, Vernon Hills, IL, USA Key Words: Inhalation anesthesia Minimum alveolar concentration (MAC) Sevoflurane. ABSTRACT Sevoflurane is a safe and versatile inhalational anesthetic compared with currently available agents. Sevoflurane is useful in adults and children for both induction and maintenance of anesthesia in inpatient and outpatient surgery. Of all currently used anesthetics, the physical, pharmacodynamic, and pharmacokinetic properties of sevoflurane come closest to that of the ideal anesthetic (200). These characteristics include inherent stability, low flammability, non-pungent odor, lack of irritation to airway passages, low blood:gas solubility allowing rapid induction of and emergence from anesthesia, minimal cardiovascular and respiratory side effects, minimal end-organ effects, minimal effect on cerebral blood flow, low reactivity with other drugs, and a vapor pressure and boiling point that enables delivery using standard vaporization techniques. As a result, sevoflurane has become one of the most widely used agents in its class. HISTORY OF ANESTHESIOLOGY With the introduction of diethyl ether in 1846, the search for more effective anesthetics was begun. From 1846 through the 1950s, all available agents were either explosive in oxygen andor toxic. The poor pharmacodynamic and pharmacokinetic properties of these early agents and their toxicity led to a continuing search for new, improved anesthetics (314). Desired properties of an ideal agent included inherent stability, lack of flammability Address correspondence and reprint requests to: Leticia Delgado-Herrera, RPh, MS, Abbott Laboratories, Hospital Products Division, 200 Abbott Park Road, Abbott Park, IL 60064, USA. herreld@hpd.abbott.com 48

2 SEVOFLURANE ANESTHESIA 49 Anesthetics used in clinical practice (cumulative) Chloroform Ether NO 2 *Sevoflurane *Desflurane *Enflurane *Isoflurane Halothane *Methoxyflurane *Fluroxene Ethyl vinyl ether Propyl methyl ether Trichloroethylene Isopropenyl vinyl ether Cyclopropane Vinethene Ethylene Ethyl chloride Year introduced Fig. 1. History of inhalation anesthetics. Compounds containing fluorine. Adapted from ref. 196 with permission from McMahon Publishing Group. in combination with oxygen or nitrous oxide, low blood:gas solubility to allow rapid induction of and recovery from anesthesia as well as rapid control of the anesthesia depth, lack of irritation to airway passages, minimal respiratory and cardiovascular effects as well as reversible central nervous system (CNS) effects, wide concentration range between the desired effect and toxicity, absence of toxicity or other unwanted effects with normal doses or repeated exposure, and no interaction or toxicity with other drugs (139,200). In the first 100 years of anesthesia use, no anesthetic contained fluorine; whereas, all anesthetics introduced after 1950 contain fluorine, with the exception of propyl methyl ether and ethyl vinyl ether. As presented in Fig. 1, fluoride was substituted for other halogens in the molecule because it decreased flammability and toxicity of the agent, and increased stability of the carbonhydrogen bond. An added benefit to the use of fluorine over other halogens is its lower reactivity with the ozone layer (139,200). Few inhalant anesthetics have been developed since the advent of the ethers, nitrous oxide, and chloroform (Fig. 1). Presently six inhalational agents, nitrous oxide, sevoflurane, halothane, enflurane, isoflurane, and desflurane are commercially available in the United States and the majority of the world. With the exception of halothane and nitrous oxide, all currently used inhalational anesthetics are ethers, as presented in Fig. 2. Halothane and sevoflurane are suitable for mask induction of anesthesia; whereas, isoflurane, enflurane and desflurane are not. This is due to their pungent odor and tendency to cause airway irritation. Of the currently available anesthetics, halothane was the first to be introduced in Because it was the only available agent used for mask induction of anesthesia, it was the inhalational agent of choice for surgery. However, halothane has several undesirable characteristics including a sensitization of the heart to endogenous or exogenous catecholamines, serious arrhythmias when administered with epinephrine, occasional hepatic necrosis, and lack of control of anesthesia depth due to high blood:gas solubility (6,62,138, 196,200).

3 50 L. DELGADO-HERRERA ET AL. H F F F F C F C O C C F F F C Br C H H H F Sevoflurane F Cl Halothane F H F F F F F H F F C C O C H F C C O C H F C C O C H F F F Cl F F F Cl Desflurane Enflurane Isoflurane Fig. 2. Chemical structures of sevoflurane and other inhalational anesthetic agents. F Enflurane and later its isomer isoflurane were first synthesized in the 1970s. Isoflurane has many features of an ideal inhalational anesthetic and as such is considered to be the gold standard with which all new agents are compared (120,196). These characteristics include minimal respiratory and cardiovascular effects, reversible CNS effects, wide concentration range between the desired effect and toxicity, and absence of toxicity or other unwanted effects with normal doses or repeated exposure. Isoflurane has been and continues to be the most widely administered inhalational anesthetic in the United States (196). Desflurane and sevoflurane were also synthesized in the 1970s. Unique attributes of both these agents include rapid induction of and recovery from general anesthesia. Because of the increased focus on day surgeries and short hospital visits over the last 10 years, these characteristics have resulted in renewed interest in both of these agents. As shown in Table 1, both sevoflurane and desflurane have blood: gas solubility coefficients of less than 1 (64,192). This ratio is similar to nitrous oxide and results in rapid induction of and awakening from anesthesia. Desflurane was introduced into clinical practice in the United States in Sevoflurane was discovered as a new anesthetic agent in 1971 (320). However, because isoflurane and enflurane were approved for use as inhalational anesthetics about the same time, clinical studies on sevoflurane were not performed. During the 1980s, interest in the compound was renewed in Japan. Subsequently, it was approved in Japan in 1990, in several Central and South American countries in 1994, and in the United States and many Latin American and European countries in 1995 (30). Since its approval, sevoflurane has become a very successful inhalational anesthetic sold throughout the world (30). Currently, the most commonly used inhalational anesthetics in the United States are isoflurane, sevoflurane, and desflurane, ranking first, second, and third, respectively (Abbott Laboratories, marketing information). These three anesthetics account for 97% of the market for inhalation agents. Pharmacodynamic properties of sevoflurane are similar to desflurane and isoflurane (196).

4 SEVOFLURANE ANESTHESIA 51 TABLE 1. Physical features of inhalation anesthetic agents Measuremennts Sevoflurane Isoflurane Desflurane Halothane Methoxyflurane Nitrous oxide Pungency Pleasant Unpleasant Very Mildly NA NA unpleasant unpleasant Vapor pressure NA NA at 20 C (mm Hg) Boiling point NA NA at 760 mm Hg ( C) Potency (MAC)* Partition coefficient (solubility) + Oil:gas Blood:gas Tissue:blood NA NA Brain NA 1.06 Heart NA NA Liver NA NA Kidney NA NA Muscle NA NA Fat NA 2.3 *MAC is the minimum alveolar concentration or potency of an agent at steady state expressed as a percentage of one atmosphere that prevents movement in 50% of exposed persons. + Ratio of the concentration of the drug in 2 phases or tissues in steady state. NA, data not available or studied. Adapted from ref. 236 with permission from Adis International. In this article, the clinical and safety profile of sevoflurane is reviewed and compared with other general anesthetics regarding physical properties, pharmacokinetics, clinical evaluation, and pharmacoeconomics. PHYSICAL PROPERTIES Sevoflurane and desflurane (difluoromethyl-1-fluoro-2,2,2,-trifluoroethyl ether) represent a new generation of inhalation anesthetic agents. As shown in Table 1, these agents are characterized by low solubility in lipids or blood compared to isoflurane, enflurane or halothane (192,333). The lower blood: gas solubility coefficients of desflurane and sevoflurane result in faster induction and recovery times as shown in Fig. 3 (see Pharmacokinetics section). Sevoflurane also has a lower tissue: blood partition coefficient making it less soluble in body tissues than halothane but not isoflurane or desflurane. Halothane is the most soluble anesthetic in brain, heart, liver, kidney, muscle, and fat followed by sevoflurane then isoflurane and desflurane (Table 1). The brain: blood coefficient is highest for halothane > sevoflurane > isoflurane > desflurane (with values of 1.94, 1.70, 1.57, and 1.29, respectively). Unlike other inhalation agents, the blood:gas partition coefficient of sevoflurane does not differ significantly from neonates to adults (63,180,192).

5 52 L. DELGADO-HERRERA ET AL. Uptake 1 1 Elimination A I F F / NO 2 Halothane Isoflurane Sevoflurane Desflurane Administration time (min) A AO F F / NO 2 Halothane Isoflurane Sevoflurane Desflurane Elimination time (min) Fig. 3. Rate of sevoflurane uptake and elimination. F A, alveolar sevoflurane concentration; F I, inspired sevoflurane concentration; F AO, alveolar sevoflurane concentration before discontinuation of anesthesia. Adapted from ref. 334 with permission from Lippincott, Williams & Wilkins. The structures of sevoflurane, enflurane, isoflurane, desflurane, and halothane are shown in Fig. 2. Halothane is the only anesthetic that is not an ether molecule; it is a trifluorinated, monochlorinated, monobrominated ethane. Structurally, enflurane, isoflurane, and desflurane contain a difluoro-methyl group and a fluorinated-ethyl group. Enflurane and isoflurane are isomers (same molecular formula). Desflurane is similar to enflurane and isoflurane; however, within the ethyl portion of the molecule, there is a single substitution of a chloride atom (isoflurane) for a fluoride atom. This single substitution makes desflurane considerably less potent than isoflurane. Structurally, sevoflurane is a poly-fluorinated methyl isopropyl ether [fluoromethyl- 2,2,2,-trifluoromethyl) ethyl ether] (86). Sevoflurane is a colorless, nonflammable liquid of mild, nonpungent odor. Following sevoflurane, halothane is the least pungent anesthetic agent (Table 1). Both sevoflurane and halothane are used routinely for mask induction of anesthesia. Isoflurane, enflurane and desflurane have a pungent odor, which renders them undesirable for mask induction of anesthesia (Table 1). The anesthetic potency of an inhalation anesthetic can be defined as the minimum alveolar concentration (MAC) that prevents movement in 50% of individuals exposed to a painful stimulus, such as a skin incision. The MAC for sevoflurane in adults ranges from (145,262). Compared with sevoflurane, the MAC for desflurane and isoflurane in adults is 6.0 and 1.15, respectively (Table 1) (247,286). As shown in Table 2, the MAC of sevoflurane decreases with increasing age (79,132,145,146,163,180,215,262). Unlike other anesthetics, the solubility of sevoflurane in blood decreases with age (63,179). The use of nitrous oxide or other CNS depressants decreases the MAC of inhalational agents (79,80,145,180). For example, sevoflurane anesthesia in the presence of 60% nitrous oxide decreased the MAC of sevoflurane by 24% compared with oxygen alone (180). The vapor pressure of sevoflurane at 20 C is 157 mm Hg compared to isoflurane, halothane, desflurane, with vapor pressures of 238, 243, and 669 mm Hg, respectively (270).

6 SEVOFLURANE ANESTHESIA 53 Sevoflurane, isoflurane, and halothane are administered to patients using a conventional vaporizer calibrated for that particular agent. In contrast, administration of desflurane requires a heated, pressurized vaporizer, due to its high vapor pressure and low-boiling point at 22.8 C (106,293,323). PHARMACOKINETICS Absorption, Distribution, and Elimination Sevoflurane and desflurane have low blood:gas solubility compared with other inhalational anesthetics resulting in rapid induction of and recovery from anesthesia (Table 1). Low solubility of sevoflurane in blood predicts a rapid rate of increase in the alveolar blood concentration of sevoflurane (F A ) as it quickly equilibrates with the concentration of inspired sevoflurane (F I ) and the F A F I ratio approaches 1.0 (153). A direct comparison of the kinetics of uptake of various inhalation anesthetics in humans showed that the uptake of sevoflurane and desflurane was faster than that of isoflurane or halothane (Fig. 3). Healthy volunteers who received sevoflurane 30 min after initiation of anesthesia in nitrous oxide demonstrated that the F A F I ratio (alveolar washin after 30 min) was 0.85, compared with of 0.73 for isoflurane and 0.58 for halothane, respectively (333,334). Only desflurane (F A F I = 0.90) in nitrous oxide (F A F I = 0.99) had a faster washin rate than sevoflurane. Low blood:gas solubility of sevoflurane predicts a rapid rate of decrease in the alveolar blood concentration of sevoflurane. Estimates of the rate of elimination can be made by determination of the F A F AO ratio, where F AO is defined as the alveolar concentration of sevoflurane before discontinuation of anesthesia. As demonstrated in Fig. 3, the rate of elimination of sevoflurane within the first 2 h after administration was greater than that of isoflurane and halothane but somewhat less than desflurane (178,333,334). The distribution of sevoflurane to body compartments is presented in Table 3. A mammillary model was used to estimate the distribution and elimination or washout (the rate of decrease of F A ) of sevoflurane from five compartments: the lungs, the vessel-rich organs, muscle, fat adjacent to the vessel-rich organs, and peripheral fat (333,334). Of all tissues measured, muscle tissue received the greatest volume of sevoflurane, desflurane, TABLE 2. Effect of age on the MAC of sevoflurane in humans Atmospheres (mean percentage) Age Oxygen alone 60% Nitrous oxide <28 Days Months Year(s) Years Years >63 Years Adapted from ref. 236 with permission from Adis International.

7 54 L. DELGADO-HERRERA ET AL. TABLE 3. Tissue distribution and washout of sevoflurane in humans Blood flow (ml100 mltissuemin) Tissue Volume (L) Mammilary time constant (min) Compartment Sevo Iso Des Sevo Iso Des Sevo Iso Des Halo Lungs 0.58* Organs* Muscle Fat* Peripheral fat *Organs are vessel-rich and fat is adjacent to vessel-rich organs. + Statistically significant difference at P < 0.05, n = 17. Sevo, sevoflurane; Iso, isoflurane; Des, desflurane; Halo, halothane. Adapted from ref. 236 with permission from Adis International. and isoflurane, followed by vessel-rich organs. Estimated blood flow to peripheral fat was shown to be statistically significantly greater with sevoflurane compared to isoflurane (334). Furthermore, sevoflurane levels measured in fat tissue adjacent to vessel-rich organs were statistically significantly lower than isoflurane levels within this tissue. Elimination rates (mamillary time constants) were fastest for desflurane followed by sevoflurane, isoflurane, and halothane (Table 3). Metabolism Over the past few decades, there has been great demand for new inhalation anesthetic agents that undergo little or no metabolism or degradation. This demand arose because of concern over the observed toxicity of metabolic or degradative by-products, i.e., nephrotoxicity associated with methoxyflurane or hepatotoxicity induced with halothane (43,195,249). As shown in Fig. 4, sevoflurane undergoes a 3 5% dose-dependent hepatic biotransformation in vivo to the principal organic byproduct hexafluoroisopropanol (HFIP), inorganic fluoride ions, and carbon dioxide (124,136,155,275). HFIP accounts for 82% of the organic fluorinated metabolites (124,313). In vitro and in vivo studies have shown that cytochrome P450 2E1 is the principal isoform involved in the metabolic defluorination of sevoflurane (154,156,157). HFIP is rapidly glucuronidated in vivo, and then the glucuronide conjugate is excreted primarily in urine (Fig. 4) (95,102, 136,155,161). The HFIP glucuronide has an excretion half-life of approximately 25 h, although the majority of glucuronide is excreted within the first 12 h (155). In vitro, cytochrome P450 2E1 defluorinates anesthetics in the corresponding order: methoxyflurane (75%) > halothane (46%)

8 SEVOFLURANE ANESTHESIA 55 H CF 3 C O CH 2 F Cytochrome P450 2E1 H CF 3 C O OH+HC F+F +CO 2 CF 3 CF 3 Hexafluoroisopropanol (HFIP) Uridine diphosphate glucuronyl transferase CF 3 COOH H C CF 3 O O OH Fig. 4. In vivo biotransformation of sevoflurane. Adapted from ref. 236 with permission from Adis International. OH OH HFIP-glucuronide > enflurane (2 8%) > sevoflurane (3 5%) > isoflurane (0.2%) > desflurane (less than the limit of quantitation) (33,36,124,154,275). The degree of sevoflurane metabolism is dose-dependent and related to the duration of anesthesia (86). In rats, serum levels and urinary excretion of fluoride and HFIP increased up to 1.25% inspired sevoflurane but was dose-independent above that concentration (190). In humans, peak plasma inorganic fluoride ion concentration correlated with duration of sevoflurane exposure (82). However, in a study measuring inorganic fluoride production after sevoflurane exposure of less than or greater than 7 h, no significant difference in the rate of decrease in fluoride concentration was observed for up to 20 h post-anesthesia between treatment groups (219). In addition, the half-lives of serum inorganic fluoride were also comparable. Intrarenal defluorination is implicated as the cause of renal toxicity in methoxyflurane but occurs to a much lesser extent in patients receiving sevoflurane (157). Two separate in vitro studies measured the pharmacokinetics of inorganic fluoride production from sevoflurane in human kidney microsomes compared with human liver microsomes, respectively (154,157). As shown in Table 4, kidney and liver microsomes in the presence of sevoflurane produced inorganic fluoride at a rate of 0.05 and 4 nmolmg h, respectively. Methoxyflurane-treated kidney and liver microsomes produced inorganic fluoride at a rate of 0.19 and 10 nmolmgh, respectively. Therefore, liver microsomes metabolize sevoflurane and methoxyflurane at a much greater rate than kidney microsomes, and kidneys treated with methoxyflurane produced 4 times the amount of inorganic fluoride compared to sevoflurane. Moreover, in the clinical setting, no evidence of renal toxicity has ever been reported due to inorganic fluoride production from sevoflurane anesthesia. The total inorganic fluoride concentration and duration of exposure rather than peak fluoride concentrations are thought to be responsible for the nephrotoxicity observed after

9 56 L. DELGADO-HERRERA ET AL. methoxyflurane anesthesia (86). Inorganic fluoride levels would be expected to be higher for longer duration methoxyflurane exposure, since both the rate of inorganic fluoride production is greater and the elimination rate is slower (154,157). Plasma inorganic fluoride levels decrease rapidly within hours after sevoflurane metabolism but inorganic fluoride that is produced after methoxyflurane metabolism persists for 4 6 days (82). Halogenated anesthetics have been associated with drug-induced hepatitis. Shortly after halothane was introduced into clinical practice, postoperative hepatitis was observed ranging in severity from mild jaundice to fatal, fulminant hepatic necrosis. Fulminant hepatic necrosis is characterized by fever, markedly increased liver function enzymes and bilirubin levels, hepatomegaly, hepatic encephalopathy, and jaundice (249). It is often fatal. Although the incidence of halothane-induced hepatic necrosis is low, estimates range between 1:6000 and 1:35,000. The potential severity of hepatic injury with halothane prompted rigorous evaluation of all other inhalation agents for potential hepatotoxicity (249). Furthermore, the risk of halothane-induced hepatitis is amplified with repeated exposure to halothane over a short period of time. Drug-induced hepatitis is much less frequent with other halogenated anesthetics than observed with halothane (249). Twenty-four cases of enflurane-induced hepatotoxicity were reported with similar clinical, biochemical, and histological features previously observed with halothane-induced hepatotoxicity (184). Cases of isoflurane-induced hepatitis have been reported and in one instance resulted in patient death following repeated exposures to isoflurane anesthesia (100,261). In one case, autopsy revealed the cause of death to be fulminant liver necrosis (100). A single case of lethal hepatitis occurred after desflurane anesthesia (149). The surgery proceeded uneventfully and on day 6 post-anesthesia, the patient complained of fever, which increased in subsequent days, chills; urinary frequency; and diarrhea; bacteremia was present in the urine. On day 11, plasma liver function enzymes increased until time of death on day 15. A biopsy of the liver indicated multiple areas of yellow necrosis and microscopic examination of hepatocytes revealed a massive herpes virus infection. A causal connection to desflurane was possible, although the presence of herpes virus may indicate alternative etiologies. A single case of hepatitis was reported after sevoflurane exposure in an 11-month-old boy (227). Liver function enzymes were elevated and viral hepatitis testing was negative, although sevoflurane was positive in the lymphocyte stimulation test. Therefore, sevoflurane was suspected as the causative agent. Cross-reactivity among anesthetics has been observed. For example, 16 patients (67%) with enflurane-induced hepatitis had previously been exposed to either halothane or enflu- TABLE 4. Mean fluoride production in humaan kidney and liver microsomes after exposure to sevoflurane or methoxyflurane Number Mean Fluoride Production S.E.M. of organs Methoxyflurane (nmolmgh) Sevoflurane (nmolmgh) Kidney Liver Adapted from refs. 154,157 with permission from Lippincott, Williams & Wilkins.

10 SEVOFLURANE ANESTHESIA 57 F H F C F C Cl Halothane Br F F C O C OH F Cytochrome P450 OH F O HO 2 F Trifluoroacetic acid F C C Br -HBr F C C Cl F Cl F Acid chloride HCl F O F C C N protein Fig. 5. Biotransformation of halothane. Adapted from ref. 90 with permission from Lippincott, Williams & Wilkins. F Trifluoroethyl protein conjugate rane (184). Another patient exposed to sevoflurane experienced hepatitis after receiving enflurane 46 days earlier (275). In 2 patients with a history of halothane hepatitis, liver dysfunction was reported after isoflurane anesthesia (110,118). An additional patient may have been sensitized to desflurane-induced hepatitis after two previous exposures to halothane (193). Presumably, these patients experienced hepatitis as a result of immunologically induced hepatocellular necrosis from previous exposure to halogenated anesthetics. Halothane, and to a lesser extent, enflurane, isoflurane, and desflurane, is metabolized to trifluoroacetic acid as presented in Fig. 5. Sevoflurane is not metabolized to trifluoroacetic acid. The metabolism of halothane to trifluoroacetic acid is at least 12% and has been detected up to 12 days after 75 min of exposure to anesthetic (250). Trifluoroacetic acid is not a naturally occurring compound and is highly reactive with proteins and nucleic acids. Conjugates between liver proteins and trifluoroacetic acid were observed in rats following anesthesia, as presented in Fig. 6. A statistically significant increase in covalently bound fluoride was observed in hepatic proteins following 1.5 MAC halothane anesthesia compared to control, or 1.5 MAC sevoflurane or desflurane anesthesia (107). The amount of fluoride bound to hepatic proteins was comparable between the control and sevoflurane- and desflurane-treated tissues. Assuming that production of fluoride-bound proteins is responsible for drug-induced hepatitis, the frequency would be lower with desflurane compared to halothane as a result of lower production of these proteins. On the other hand, since sevoflurane is not metabolized to trifluoroacetic acid, it is unlikely that the agent undergoes bioactivation to a reactive species capable of binding to hepatic proteins (151). HFIP, the metabolite of sevoflurane, has a much lower reactivity than trifluoroacetic acid and is excreted at a very high rate.

11 58 L. DELGADO-HERRERA ET AL. 8 nmoles of fluoride released / mg of liver protein Sevoflurane Desflurane Halothane Control Fig. 6. Amount of fluoride bound to hepatic protein following 1.5 MAC of inhalants in rats. Statistically significant difference from control value (P < 0.05, n = 3 per group). Adapted from ref. 107 with permission from Lippincott, Williams & Wilkins. CLINICAL EVALUATION Sevoflurane has been available in Japan since 1990, 5 years longer than in the United States and Europe. Within that 5-year period, numerous case reports were published using sevoflurane anesthesia for a variety of surgical procedures (96,170,176,194,210,290,311). These noncomparative data confirm the safety and efficacy of sevoflurane and generally agree with results of comparative controlled studies conducted later. Following approval in North and South America, and Europe in 1995, sevoflurane has been demonstrated to be a versatile anesthetic agent that is particularly well suited for ambulatory surgeries. As the number of ambulatory surgeries increases (because of the cost-containment issue), a concomitant increase in the use of sevoflurane is expected. A total of 40 clinical trials were conducted prior to submission and approval of sevoflurane globally (271). Some of these trials were blinded, randomized, and controlled. Controlled trials compared sevoflurane with the inhalational agents, isoflurane, halothane, enflurane, or propofol (an intravenous agent). In adults, isoflurane is considered the gold standard with which all other agents are compared. Therefore, the majority of studies compared sevoflurane with isoflurane. In children, sevoflurane is typically compared with halothane, the only other agent that can be used for mask induction of anesthesia. Adults, the elderly, and children were examined in these comparative trials of ambulatory and inpatient surgeries of short and long duration. The effects of sevoflurane on the cardiovascular, respiratory, renal, hepatic, and neurological systems were examined. Specialized uses for sevoflurane in neurosurgery, obstetrics, and in high-risk situations were also assessed. As a result of these controlled trials, sevoflurane is indicated for induction and maintenance of general anesthesia in adult and pediatric patients for inpatient and outpatient surgery (271). Adult Anesthesia Mask induction, maintenance, and recovery The feasibility of mask induction with sevoflurane was recognized early in the development of the drug. In adult anesthesia, overall use of mask induction as a technique has grown primarily due to the approval of sevoflurane as an anesthetic agent. Properties in-

12 SEVOFLURANE ANESTHESIA 59 herent to sevoflurane, including the lack of irritation to airways and low blood:gas solubility coefficient properties, make mask induction the technique of choice in some surgical situations. Mask induction with sevoflurane is particularly effective when the trachea is difficult to intubate or is obstructed, when the anesthesiologist is unable to place an intravenous line in an awake patient, or when the patient is needle phobic (260,322). Furthermore, mask induction with sevoflurane has been shown to be comparable to intravenous anesthesia. For example, sevoflurane induction can occur at a rate as rapid as induction with intravenous drugs with a comparable incidence of complications. In addition, sevoflurane has a high patient approval rating, and its cost is comparable to standard intravenous techniques. These combined factors have led to the use of sevoflurane anesthesia. Induction of anesthesia with sevoflurane using a face mask is a safe technique. Both 100% oxygen and mixtures of oxygennitrous oxide have been used for mask induction with sevoflurane. The bronchodilating action of sevoflurane has been shown to exceed isoflurane and is comparable to halothane (254). Sevoflurane has also been shown to be the least irritating anesthetic agent compared to halothane, enflurane, and isoflurane (52,137,235). Sevoflurane does not increase airway secretions, and this property along with lack of pungency reduces the likelihood of further complications, such as laryngospasm, coughing, and breathholding (212). Excitation, as manifested by spontaneous movement, has been reported during sevoflurane anesthesia; however, this has not been sufficient to interfere with the induction procedure or influence patient satisfaction (137,235). Mask induction of anesthesia with sevoflurane is performed using one of the following methods: incremental increases in concentration, vital capacity induction, or tidal breathing. With all three techniques, fresh gas flow rate ranges between 4 6 Lmin initially and is reduced to 3 Lmin after approximately 3 min. Further reductions in fresh gas flow can be achieved in the ensuing minutes depending on clinical circumstances. Rapid induction without excitation can be achieved using vital capacity rapid inhalation induction and is preferable to standard inhalation induction or intravenous techniques because an extended excitatory phase may be avoided (236). Using rapid induction, a patient exhales to residual volume and inhales high concentrations of anesthetic up to vital capacity (27). Anesthetics currently used for vital capacity rapid inhalation induction include sevoflurane and halothane (256,326,336). When inspired at a concentration of 8%, sevoflurane produces loss of consciousness for time periods comparable to those produced by intravenous anesthetics and for less time than other inhalational anesthetics (104). In terms of induction speed, studies carried out both in Japan and in the United States have indicated that loss of the eyelash reflex could be achieved in less than 60 sec with increasing sevoflurane concentration (97,339). The use of nitrous oxide was shown to decrease the time required to achieve rapid induction (97,341). Loss of ciliary (eyelash) reflex is achieved in the corresponding order: sevoflurane > isoflurane > halothane and is reflective of low blood:gas solubility (70,278). In both pediatric and adult patients, increasing the depth of sevoflurane anesthesia allows laryngeal mask airway or tracheal intubation to be performed without the use of muscle relaxants (132,212). Several minutes after initiating 6 to 7% sevoflurane, laryngoscopy insertion and visual inspection were successfully performed in anesthetized, spontaneously ventilating healthy persons (212). The average times to laryngeal mask airway insertion and tracheal intubation in 20 adults who were not premedicated are shown in

13 60 L. DELGADO-HERRERA ET AL. 8 6 Tracheal intubation Time (min) O 2 Laryngeal mask airway NO 2 /O 2 NO 2 /O 2 Fig. 7. Time to adequate intubation conditions or conditions of laryngeal mask airway insertion with sevoflurane anesthesia, n = 20. Adapted from ref Fig. 7. Laryngeal mask airway insertion occurred in a mean time of 1.7 min; the mean tracheal intubation time was performed after 4.7 and 6.4 min in the presence or absence of nitrous oxide, respectively. In 24 healthy adults, sevoflurane was administered after pretreatment with intravenous midazolam, fentanyl, or midazolam combined with fentanyl (213). Volunteers premedicated with fentanyl had statistically significantly lower times to loss of lid-lash reflex compared to midazolam or both agents together. However, the combined use of midazolam and fentanyl decreased the time to tracheal intubation to 2.5 min compared to 4.3 min with fentanyl alone or 3.1 min with midazolam alone. Observed heart rate increases after intubation were lower with fentanyl followed by fentanyl plus midazolam then midazolam. Fentanyl alone was associated with more airway management complications (e.g., stridor and breathholding) during induction, and several patients treated with this agent had inadequate airway conditions even after 6.5 min of sevoflurane exposure. In another study, fentanyl was shown to attenuate the heart rate and mean arterial pressure to tracheal intubation, even with decreasing concomitant sevoflurane concentration (148). Overall, small doses of intravenous sedatives prior to surgery not only improved the speed and quality of the induction process but also facilitated placement of the endotracheal tube or laryngeal mask airway. Propofol is an intravenous anesthetic especially used for the induction and maintenance of ambulatory surgery (49). Like sevoflurane, its popularity results from its ability to facilitate a rapid, smooth induction and fast recovery, with a low incidence of postoperative adverse effects (54,59,135,241). In many studies, the time course to induction with sevoflurane has been comparable to that of propofol (104,239). Some studies have indicated that induction of anesthesia with sevoflurane took 30 to 60 sec longer than with propofol, depending on the end point measured and the concentration of sevoflurane used (202,307). Specifically, propofol had a significantly faster time to cessation of finger tapping; however, during the final stages of induction, sevoflurane in nitrous oxide had a faster time to the establishment of regular breathing (113). Compared with propofol, sevoflurane is an acceptable alternative for the induction andor maintenance of anesthesia (135,325). Anesthesia with sevoflurane using vital capacity induction was compared with intravenous propofol in 56 adults (241). All measures of induction were significantly shorter with sevoflurane than propofol and overall recovery times and incidences of adverse events were similar. Sevoflurane-treated patients experienced more coughs, hiccups, and

14 SEVOFLURANE ANESTHESIA 61 Incidence (%) Sevoflurane ( n = 25) Isoflurane ( n = 25) 0 Coughing Breathholding Laryngospasm Fig. 8. Mask induction characteristics: sevoflurane versus isoflurane. Statistically significant difference in coughing (P < 0.001). Adapted from ref. 278 with permission from Lippincott, Williams & Wilkins. postoperative nausea while propofol-treated patients experienced greater blood pressure changes. Consequently, more rapid induction times observed in sevoflurane patients were not associated with faster recovery from anesthesia. In a noncomparative study of over 25,000 patients receiving propofol anesthesia, the incidence of hypotension was 15.7%. Hypotension was more common in the elderly, females, Caucasians, those undergoing abdominal and integumentary procedures, and in conjuction with certain opioids (130). Two studies compared vital capacity induction with tidal breathing techniques for induction of anesthesia with sevoflurane (5,340). In the first study, the mean time to induction was statistically significantly faster and fewer adverse events were observed in 35 volunteers anesthetized using the vital capacity technique (340). In contrast, the second study revealed no induction differences using tidal breathing versus vital capacity techniques (5). Induction times for sevoflurane may be dependent on the technique used for induction; however, differences observed in induction times compared to propofol are not likely to be clinically relevant. In any case, the lack of induction complications with sevoflurane facilitates a smoother transition to maintenance (less postinduction coughing), shorter time to spontaneous ventilation, and earlier emergence from anesthesia (56,307). Sevoflurane is well tolerated with few complications during induction. The total number of adverse events from the sevoflurane clinical program were determined and compiled for the package insert. During tidal induction with sevoflurane, the incidence of adverse events in adults and children is as follows: 7 15% agitation, 3 8% laryngospasm, 2% apnea, 5% bradycardia, 6% tachycardia, 4% hypotension, and 2% increased salivation (313). Other adverse events reported after recovery from sevoflurane include 25% nausea, 18% vomiting, 11% hypotension, 11% coughing, 9% agitation, 9% somnolence, 6% shivering, 5% bradycardia, 4% increased salivation, and 4% dizziness (313). Adverse events during mask induction with sevoflurane versus halothane, isoflurane, or propofol were compared (Figs. 8 10). As presented in Fig. 8, a statistically significantly lower incidence of coughing was observed during induction in sevoflurane-treated patients (278). Figure 9 shows that the incidence of complicated induction including coughing was statistically significantly greater in halothane-treated patients (237). In addition, a statistical significant number of sevoflurane-treated patients classified sevoflu-

15 62 L. DELGADO-HERRERA ET AL. Incidence (%) Complicated induction Sevoflurane ( n = 17) Isoflurane ( = 15) n0% for sevoflurane Coughing Pleasant odor Fig. 9. Mask induction characteristics: sevoflurane versus halothane. Statistically significant difference in odor and incidence of complicated induction (P < 0.05). Adapted from ref. 337 with permission from the Canadian Anesthesiologists Society. Complicated incidence (%) Apnea Sevoflurane ( n = 51) Isoflurane ( n = 51) Post-induction coughing Fig. 10. Induction characteristics: sevoflurane versus propofol. Statistically significant difference in incidence of apnea and post-induction coughing at P < 0.01 and P = 0.03, respectively. Adapted from ref. 307 with permission from Oxford University Press. rane as having a pleasant smell. As presented in Fig. 10, and compared to propofol anesthesia, sevoflurane resulted in a statistically significantly lower incidence of apnea and postinduction coughing (307). Regardless of the F I, sevoflurane has been shown to have a low incidence of induction-related problems with fewer induction complications compared to halothane (337). Furthermore, fewer induction-related complications were associated with vital capacity induction compared to tidal breathing techniques or incremental increases in sevoflurane concentration (338,340). A number of studies have shown that rapid induction with sevoflurane does not produce significant changes in heart rate from baseline values (97, ). Although these trials report statistically significant blood pressure decreases of up to 25% from baseline, systolic and diastolic pressures are maintained at relatively safe levels, >90 and >45 mm Hg, respectively. During tracheal intubation, sevoflurane anesthesia was associated with less tachycardia and hypertension than isoflurane (309). Intraoperative cardiovascular stability was achieved with sevoflurane and desflurane, with heart rate and mean arterial pressure within 20% of baseline during the entire maintenance period (216). However, from induction to surgical incision times, heart rate was lower with sevoflurane (216).

16 SEVOFLURANE ANESTHESIA 63 Recovery from anesthesia comparing sevoflurane, isoflurane, and propofol was reviewed in a recent meta-analysis (252). The following recovery parameters were compared: emergence, extubation, response to commands, orientation, first analgesic, and recovery discharge (Tables 5 and 6). Twelve studies comparing sevoflurane to isoflurane were identified but only 9 studies met the requirements for the meta-analysis; whereas 7 studies comparing sevoflurane to propofol were identified but only 5 met the requirements for the meta-analysis. In pooled data, sevoflurane showed statistically significant less time to endotracheal extubation, emergence, response to command, orientation, and first postoperative analgesic compared with isoflurane (31,47,83,228,238,245,263,278). In pooled data, sevoflurane showed statistically significant less time to emergence, endotracheal extubation, response to command, and response to orientation compared with propofol (54,81,248,284,321). Times to recovery room discharge were comparable in both sets of pooled data. Another analysis of anesthesia recovery was completed that examined data from over 2000 patients (8 phase IIIII clinical studies) randomized to receive sevoflurane or isoflurane (59). Compared with isoflurane, sevoflurane anesthesia resulted in significantly shorter times to emergence, response to command, orientation, and first analgesic. In addition, times to recovery end points increased with increasing case duration for patients receiving isoflurane but not sevoflurane. Patients older than 65 years of age had longer times to orientation, but within any age group, orientation was always significantly faster with sevoflurane anesthesia. Recovery from anesthesia was compared using sevoflurane versus desflurane in 60 adult women undergoing laparoscopic tubal ligation (303). Recovery parameters of times to eye opening, command response, orientation, sitting in bed, sitting with legs dangling, standing, walking, discharge, and departure were marginally but not significantly better with sevoflurane. Psychomotor function tests and recovery indices were marginally but not significantly improved with sevoflurane. The recovery of cognitive functions for sevoflurane and propofol were compared in 50 patients undergoing ambulatory surgery (206). Recovery was faster in sevoflurane-treated patients using the digit-symbol substitution test. Aldrete scores, a measure of patient recovery, were significantly better in sevoflurane-treated patients at all assessment times. Rapid washout permits quicker recovery from sevoflurane anesthesia; this may result in an early perception of pain, because subanesthetic blood levels of sevoflurane are not analgesic (308). Overall, total visual analog scale scores for pain, anxiety, coordination, or sleepiness are generally similar in patients recovering from sevoflurane or propofol anesthesia (321). Postoperative nausea and vomiting are among the most common adverse events that delay patients discharge from the hospital or result in unscheduled overnight admissions (77,126,174,233). The reported rates of postoperative nausea and vomiting are highly variable. Causal factors implicated in postoperative emesis include patient predisposition, age, sex, weight, concurrent illness, the anesthetic agent, addition of nitrous oxide, and length of anesthesia (77,233). The incidence of nausea and vomiting were comparable in patients treated with sevoflurane and isoflurane with no significant difference in the number of patients requiring antiemetic therapy after general anesthesia (72). Nausea was reported significantly more often with sevoflurane than with propofol (129,185,321). Several surveys have been conducted postsurgery, to determine patient satisfaction with the anesthesia experience. Using vital capacity inhalation, patient surveys indicated

17 TABLE 5. Studies comparing the effects of sevoflurane with isoflurane: differences in mean data* n Differences in time (min) Reference SevoIso Emergence Response to commands Extubation Orientation First analgesic Recovery room discharge Pooled data Mean Confidence interval *Differences in time are the mean sevoflurane time minus the mean isoflurane time. Differences are reported as mean pooled variance., Data not collected. Sevo, sevoflurane; iso, isoflurane. Adapted from ref. 252 with permission from Munksgaard. TABLE 6. Studies comparing the effects of Sevoflurane with propofol: differences in mean data* n Differences in time (min) Reference SevoPro Emergence Response to commands Extubation Orientation Recovery room discharge Pooled data Mean Confidence interval *Differences in time are the mean sevoflurane time minus the mean propofol time. Differences are reported as mean pooled variance. Data not collected. Sevo, sevoflurane; Pro, propofol. Adapted from ref. 252 with permission from Munksgaard. 64 L. DELGADO-HERRERA ET AL.

18 SEVOFLURANE ANESTHESIA 65 Fig. 11. Effects of sevoflurane on heart rate in healthy volunteers. Statistically significant difference in heart rate (P < 0.05). Adapted from ref. 56 with permission from Lippincott, Williams & Wilkins. Heart rate beats / min Conscious baseline Isoflurane Sevoflurane Desflurane Minimum alveolar concentration an overall preference for sevoflurane, finding anesthesia more pleasant with sevoflurane than with isoflurane or halothane at statistically significant levels (P < 0.05) (278,337). In healthy adults treated with sevoflurane, there was 100% acceptance of mask induction (212). Cardiovascular and hemodynamic effects In general, the cardiovascular effects of sevoflurane are quite similar to isoflurane (58, 191,253). Unlike other inhalational anesthetics, sevoflurane maintains a stable heart rate with increasing concentration, a benefit to patients with cardiovascular disease. Sevoflurane use is accompanied by improved patient outcomes with increasing depth of anesthesia as a result of a more stable heart rate, lack of hypertension, and the absence of sympathoexcitation and endocrine responses. Heart rate. The minimal effects of sevoflurane on heart rate were first observed in healthy volunteers (124). Rapid increases in inspired concentrations of either isoflurane or desflurane have been shown to initiate tachycardia and might predispose at-risk populations to myocardial ischemia (12,56). By contrast, increasing concentrations of sevoflurane have been associated with similar or lower heart rates compared to isoflurane or desflurane in both, volunteers and patients (56,83,191). The effects of sevoflurane, isoflurane, and desflurane on heart rate in response to increasing concentrations of these agents were measured in healthy volunteers (Fig. 11). At concentrations up to 1.0 MAC, neither sevoflurane nor desflurane increased heart rate, whereas isoflurane caused an initial increase in heart rate that was sustained with increasing MAC (56). Above 1.0 MAC, both desflurane and sevoflurane were associated with an increase in heart rate, although the increase was more pronounced with desflurane (12,56). In contrast, introduction of 1.0 MAC sevoflurane for maintenance of anesthesia in healthy volunteers and 1.5 MAC 2 min later did not alter heart rate compared with baseline (12). In the same study, desflurane introduced initially at 1.0 and 1.5 MAC 2 min later caused an increase in heart rate compared with baseline and was significantly greater compared with sevoflurane. Another comparative study reported a significant increase in heart rate in 21 healthy volunteers exposed to 1.5 and 2.0 MAC of isoflurane but not sevoflurane (191). The effects of sevoflurane or isoflurane on heart rate were also measured in 75 patients undergoing elective surgery (Fig. 12).

19 66 L. DELGADO-HERRERA ET AL. Heart rate (beats / min) Isoflurane Sevoflurane 60 Baseline emergence 30 post prior post prior post intubation incision incision to end emergence of anesthesia Time (min) Fig. 12. Effects of sevoflurane or isoflurane on heart rate in elective surgical cases. Statistically significant difference in heart rate from the period immediately prior to surgical incision to 60 min after the initiation of surgery (P < 0.05, n = 50 for sevoflurane and n = 25 for isoflurane). Adapted from ref. 83 with permission from Lippincott, Williams & Wilkins. Sevoflurane use was associated with significantly lower heart rates than isoflurane from the period immediately before surgical incision, 1 to 3 min after incision, and 1 h after incision (83). As the depth of anesthesia increases after induction, sevoflurane and other inhalational anesthetics generally decrease heart rate, mean arterial pressure, and other hemodynamic variables (83,216,259,278,298). After intubation and surgical incision, heart rate is significantly higher in patients receiving isoflurane anesthesia compared with those receiving sevoflurane anesthesia (47,83). Heart rate and blood pressure were measured in response to tracheal intubation after vital capacity induction with four concentrations of sevoflurane between 3 and 6% (209). The hemodynamic profile between treatment groups was similar, with a slight hypertensive and tachycardiac response to intubation. In a comparative study of patients undergoing elective surgery with preexisting coronary artery disease and hypertension, heart rate and arterial blood pressure responses between sevoflurane and isoflurane were similar (253). Neither anesthetic was associated with a greater frequency of intervention for hemodynamic deviation. Blood pressure. Several studies have compared hypotensive effects of several different inhalational anesthetics. The mean arterial blood pressure was measured in adult volunteers who were not premedicated (Fig. 13) (56). Sevoflurane, isoflurane, and desflurane produced dose-dependent decreases in mean arterial blood pressure, and the effects were comparable. Forearm vascular resistance was measured in adult volunteers who were not premedicated, as presented in Fig. 14 (56). A progressive decrease in forearm vascular resistance was observed with increasing concentrations of sevoflurane, isoflurane, and desflurane. This decrease became statistically significantly lower with sevoflurane at 1.5 MAC than with desflurane or isoflurane. When sevoflurane or desflurane was introduced for maintenance of anesthesia in 20 healthy adults, mean arterial pressure was rela-