The ideal anesthetic for ambulatory surgery would provide for a rapid, smooth, and pleasant induction of anesthesia, facilitate maintenance of an adequate depth of anesthesia by permitting rapid changes in the effect site concentration, and result in a prompt emergence and short recovery without postoperative side effects. Although no anesthetic has yet been discovered that possesses all these properties Table 1, recently introduced anesthetics more closely approach these goals.Table 1: Properties of an Ideal General Anesthetic for Ambulatory SurgeryPropofol provides for a rapid, smooth induction of anesthesia and is associated with a fast recovery and low incidence of postoperative side effects [1]. However, it can produce pain on injection and cardiovascular depression, and regulating the depth of anesthesia during the maintenance period may be more difficult than with a volatile anesthetic [2]. Desflurane has an extremely low blood:gas solubility, allowing for precise control of anesthetic depth [3], and it provides for an even more rapid emergence after ambulatory anesthesia than propofol [4]. However, desflurane produces airway irritation during induction of anesthesia [5], requires highly specialized vaporizer technology for its administration, may be associated with significant autonomic stimulation after rapid adjustments in its inspired concentration [6,7], and results in a higher incidence of postoperative nausea and vomiting compared with propofol anesthesia [4]. Although desflurane has the lowest blood:gas solubility of all the available inhaled anesthetics, its use for induction of anesthesia results in airway complications in 30%-40% of patients [3-5]. Based on the limited data available from clinical trials in the outpatient setting, sevoflurane would appear to be an acceptable alternative to propofol and desflurane for use during induction and/or maintenance of ambulatory anesthesia. This article reviews aspects of the pharmacology of sevoflurane that are relevant to its use in the ambulatory setting. Clinical Properties of Sevoflurane Induction of Anesthesia In the ambulatory setting, induction of anesthesia usually involves the administration of a rapid, short-acting intravenous anesthetic (e.g., thiopental, methohexital, propofol). Although this practice is widely accepted, the use of thiopental is often associated with postoperative sedation and drowsiness (so-called "hangover" feeling), methohexital causes excitatory side effects, and the shorter-acting anesthetic propofol often causes pain on injection and varying degrees of cardiovascular depression. In order to provide for a rapid and smooth induction of anesthesia, an inhaled anesthetic with a low blood:gas solubility coefficient and lacking airway irritation is required so that high inspired concentrations can be administered without inducing coughing, breathholding, excessive salivation, or laryngospasm. In a group of female patients pretreated with fentanyl, 1.5 micro gram/kg intravenous and subsequently exposed to a maximum vaporizer concentration of 5% sevoflurane with nitrous oxide (N2 O) 67% in oxygen, anesthesia was induced in 109 +/- 25 s (mean value +/- SD) [8]. No patient experienced breathholding, coughing, or other adverse events related to the airway. In unpremedicated volunteers, induction of anesthesia was even more rapid when a sevoflurane concentration of 4.5% was administered using a single, vital capacity breath induction technique [9]. In comparison with a traditional (stepwise) induction, the single-breath technique permitted earlier loss of consciousness (54 +/- 10 vs 108 +/- 19 s) but was associated with a higher incidence of coughing [9]. Sevoflurane is an effective drug for induction of anesthesia in children undergoing ambulatory procedures [5,10-12]. When sevoflurane was administered to unpremedicated children, the average time to loss of the eyelash reflex ranged from 54 s in infants (<1 yr) to 76 s in children aged 3 to 12 yr, with a low incidence of respiratory complications in both age groups [10]. The quality of an inhaled induction with sevoflurane is similar to or even better than that of halothane [11,12]. Although intravenous induction of anesthesia is likely to remain the standard practice for adult outpatients, sevoflurane will be a useful alternative to intravenous induction techniques in patients with difficult airways because it allows for maintenance of spontaneous ventilation throughout the induction period. In children, intravenous access is more difficult to establish and sevoflurane would appear to be a highly acceptable alternative to halothane or propofol for induction of anesthesia. Use of sevoflurane for induction of anesthesia in adults was associated with slower heart rates than propofol Figure 1[13].Figure 1: Heart rate (HR) (upper panel) and mean arterial pressure (MAP) (lower panel) before induction of anesthesia (Pre), at induction (Ind), at the indicated times after induction, at skin incision (Inc), and at the indicated times after incision in the three treatmemt groups. Symbols represent propofol-propofol-N2 O (filled squares), propofol-sevoflurane-N2 O (open squares), and sevoflurane-N2 O (open circles). Values are mean +/- SEM; *P < 0.05, from propofol-N2 O, paragraph sign P < 0.05 from propofol-N2 O and propofol-sevoflurane-N2 O. Reproduced from Fredman et al. [13] with permission.Maintenance of Anesthesia Although the use of intravenous anesthetic techniques has increased in popularity over the past few years [1,2], most anesthesiologists are still more familiar with the titration of volatile anesthetics during the maintenance period [2]. The degree of control over the "depth of anesthesia" has been defined as the difference between the anesthetic concentration delivered by the vaporizer and the resultant alveolar concentration [3]. The ratio of these two concentrations is determined by the degree of rebreathing (i.e., the fresh gas flow) and the anesthetic uptake by the tissues. At any given fresh gas flow rate, a volatile anesthetic with a low blood:gas partition coefficient will have a lower uptake than a more soluble anesthetic and therefore should provide more precise control of the anesthetic effects. Since desflurane is the least soluble of the volatile anesthetics, it should be the most controllable, with smaller differences between the delivered and alveolar concentrations compared with isoflurane [3]. For sevoflurane, the inspired-to-alveolar difference is also less than that for isoflurane [3], resulting in a degree of control approaching that with desflurane. Since the minimum alveolar anesthetic concentration of sevoflurane (1.9%) is closer to those of isoflurane (1.15%) and enflurane (2.0%), the maintenance concentration of sevoflurane when administered in combination with N2 O will generally be in the familiar 0.5%-2% end-tidal concentration range. Finally, the response to rapid changes in the delivered concentration of desflurane is associated with transient increases in heart rate [6,7]. In contrast, sevoflurane was associated with a slower heart rate in patients undergoing ambulatory surgery Figure 2[1,14], thereby reducing myocardial oxygen consumption and improving myocardial perfusion.Figure 2: Mean heart rate (HR) values (+/- SEM) before induction of anesthesia (Preop) and at the indicated times during the maintenance period with desflurane-N2 O (circles) and sevoflurane-N2 O (squares). P <0.05, significantly different from desflurane-N2 O group. From Nathanson et al. [14], with permission.Emergence and Recovery Characteristics The low solubility of sevoflurane should contribute to a rapid elimination after discontinuation of anesthesia. For operations lasting 1-4 h (with a mean of 135 min), sevoflurane permitted emergence within 4.1 +/- 2.2 min after the end of anesthesia compared with 6.7 +/- 2.2 min with isoflurane [8]. A multicenter trial comparing sevoflurane and isoflurane for ambulatory surgery also found that sevoflurane was associated with a more rapidly emergence from anesthesia [15]. However, recovery of cognitive and psychomotor function, as well as times to being judged "home ready," did not differ between the two groups. Fredman et al. [13] studied outpatients undergoing a variety of gynecologic and otolaryngolic procedures. One group of patients received propofol (1.5-2.0 micro gram/kg) for induction and propofol infusion, 75-160 micro gram centered dot kg-1 centered dot mg-1, and N2 O 60% in oxygen for maintenance; a second group of patients received the same dose of propofol for induction of anesthesia but received sevoflurane-N2 O for maintenance; and a third group received sevoflurane-N2 O for both induction and maintenance of general anesthesia. The emergence and recovery times were similar with all three anesthetic techniques Table 2. Visual analog scales and the digit-symbol substitution test also failed to detect any differences between the groups in terms of the patients' subjective feelings or psychomotor performance during the early postoperative period. The only significant difference between the three techniques was a higher incidence of emetic sequelae in the group in which anesthesia was induced and maintained with sevoflurane-N2 O (33% vs 12% and 18% in the groups in which anesthesia was induced with propofol and maintained with propofol-N2 O or sevoflurane-N2 O, respectively). Similar findings have been obtained by other investigators, who reported emergence times of 11.0 +/- 11.0 min after propofol-N2 O and 10.4 +/- 6.5 min after propofol-sevoflurane-N (2) O in outpatients undergoing surgical procedures lasting 1.5 h [16].Table 2: Comparison of Emergence and Recovery Times in Outpatients Receiving Three Anesthetic Induction and Maintenance TechniquesRecently, Nathanson et al. [14] compared sevoflurane-N2 O and desflurane-N2 O for maintenance of anesthesia in women undergoing outpatient laparoscopic sterilization procedures. After a standardized induction sequence, sevoflurane-N (2) O or desflurane-N2 O was administered for maintenance of anesthesia. The inspired sevoflurane or desflurane concentrations were adjusted to maintain mean arterial pressure values within +/-20% of the preincisional baseline values. At comparable mean arterial pressure values, the heart rate was significantly lower in the sevoflurane group after induction of anesthesia (62 +/- 8 vs 75 +/- 12 bpm). At the end of anesthesia, the mean end-tidal concentration of the inhaled anesthetics was 1.5% for sevoflurane and 4.3% for desflurane. Although desflurane was associated with earlier eye opening and decreased time to tracheal extubation compared with sevoflurane Table 3, these differences did not persist into the later recovery period. No significant differences were detected between the two groups with respect to the time to ambulation or hospital discharge. Furthermore, visual analog scale scores for sedation, lethargy, confusion, coordination, nausea, and pain, as well as psychomotor function testing, revealed similar late recovery profiles after sevoflurane and desflurane.Table 3: Comparison of Emergence and Recovery Times in Outpatients Undergoing Laparoscopic Procedure Under Propofol-Sevoflurane/N2 O or Propofol-Desflurane/N2 O AnesthesiaFrazier and colleagues* compared sevoflurane and desflurane as maintenance drugs in pediatric outpatients after an inhalation induction with halothane. Although desflurane resulted in more rapid emergence (4.7 +/- 1.5 vs 8.0 +/- 3.0 min) and shorter early recovery times (9.3 +/- 1.7 min vs 17.1 +/- 8.0 min), later recovery events did not differ between the two maintenance anesthetic groups. Furthermore, in the desflurane group, significantly more children were agitated (or excessively excited) during the early recovery period. Of interest, desflurane-treated patients had an increased requirement for postoperative analgesics compared with sevoflurane-treated patients. Even though significant differences are apparent in the emergence times, the early advantages of the less-soluble inhaled anesthetics do not persist into the late recovery period. While it may appear that changes in the solubility of inhaled anesthetics do not significantly improve the late recovery profile after outpatient anesthesia, it is possible that the current criteria for determining "fitness for discharge" from the postanesthesia care unit, and subsequently from the ambulatory center, lack the sensitivity necessary to detect clinically significant improvements in the late recovery period. The influence of postoperative pain, as well as the side effects associated with analgesic medications (e.g., postoperative nausea and vomiting), may also obscure differences in recovery between the various anesthetics. *Frazier LJ, Welborn LG, Hannallah RS, Norden. Emergence and recovery characteristics of sevoflurane, halothane, and desflurane in pediatric ambulatory patients. Abstract presented at the 9th annual meeting of the Society for Ambulatory Anesthesia (SAMBA) in Chicago, 1994. Economic Considerations Given the apparent similar outcomes associated with the available general anesthetic techniques for ambulatory surgery, the drug of choice for maintenance of anesthesia will depend on both the relative costs and the ease of administration. Since sevoflurane is still an investigational drug in the United States, its cost is unknown. Although the acquisition price is likely to change from time to time (and even from location to location), the cost of a volatile anesthetic is also dependent on its physical properties (e.g., solubility and potency), as well as the administration technique [3]. For a given volume of liquid anesthetic, desflurane will produce 7% more vapor than isoflurane, while sevoflurane yields 7% less vapor. However, this apparent advantage of desflurane is offset by its lower potency, which requires a significantly larger volume of vapor to achieve a minimum alveolar anesthetic concentration equal to that of both isoflurane and sevoflurane. Sevoflurane is also less potent than isoflurane and therefore requires a larger volume of vapor than does isoflurane to produce the same clinical effect. Consequently, the volume of liquid anesthetic required to achieve a given clinical effect would appear to be greatest with desflurane and least with isoflurane. However, the concentration required for a given effect relates to the alveolar concentration of anesthetic and not to the delivered (inspired) concentration. Because of desflurane's very low solubility, equilibration between inspired and alveolar concentrations occurs more rapidly than with sevoflurane or isoflurane, possibly resulting in more precise control of the depth of anesthesia. As equilibrium is approached with a volatile anesthetic, the delivered anesthetic concentration can be reduced toward the desired alveolar concentration. This suggests that lower volumes of desflurane and sevoflurane (versus isoflurane) may be required for short outpatient procedures [3]. At low total gas flow rates (<2 L/min), the lower uptake of these less-soluble anesthetics may result in significant cost savings once equilibrium has been achieved. The beneficial effects of using low-flow conditions should be greater with the less-soluble inhaled anesthetics like desflurane and sevoflurane. Since there will be less uptake of these anesthetics, the exhaled gases will contain a higher proportion of the inspired anesthetic concentration, and less additional vapor will have to be added to the system [3]. Furthermore, the more rapid response to changes in the anesthetic concentration should reduce the need to increase the fresh gas flow in order to rapidly effect a change in the depth of anesthesia with desflurane or sevoflurane (versus isoflurane or halothane). However, concerns regarding the potential nephrotoxicity of sevoflurane breakdown products (e.g., Compound A) will limit its use with low-flow or closed systems. (The Food and Drug Administration has recommended that sevoflurane not be used at total gas flow rates less than 2 L/min.) In contrast to inhaled anesthetics, the cost of an intravenous anesthetic technique is primarily determined by the dose, which is based in part on the body weight of the patient. There is no equivalent of "low-flow" anesthesia with intravenous anesthetics. Thus, while an intravenous technique may be less expensive than a volatile anesthetic in smaller patients, the economic considerations will be reversed in large (and obese) patients. When the costs of intravenous (propofol) and volatile (isoflurane) anesthetic techniques have been compared for maintenance of ambulatory anesthesia, the inhaled anesthetic is typically found to be less costly [17,18]. However, the decreased incidence of postoperative nausea and vomiting with propofol (versus volatile drugs) may reduce the indirect costs associated with its use (e.g., emesis basins, suction sets, requirements for antiemetic drugs, post-anesthesia care unit nursing time) and thereby facilitate the recovery process. In addition to the costs of the anesthetic drug, the expense associate with the drug's delivery system (e.g., infusion pumps, specialized vaporizers) and drug waste must be taken into consideration in calculating a new drug's overall cost-effectiveness. Although sevoflurane does not require the sophisticated, electrically heated, pressurized vaporizer needed for desflurane, its use does require a dedicated, temperature-compensated, calibrated vaporizer. Higher anesthetic drug costs may be acceptable if they are offset by lower overall costs to the patient and/or the third-party payer. Hospital admissions after day surgery are very expensive, so a reduction in unanticipated admissions and/or the duration of the stay in the outpatient surgery facility may result in significant cost savings. Objective evidence supporting the suggestion that the use of newer anesthetic, analgesic, and muscle relaxant drugs produces significant cost savings (as a result of their more favorable recovery profiles after ambulatory surgery) [19-21] is currently lacking [22]. The comparative pharmacoeconomics of sevoflurane (versus enflurane, isoflurane, desflurane, and propofol) in the outpatient setting will be primarily dependent on the price of the new drug and the total gas flow rates, as well as its impact on patient outcome in routine clinical practice. Meaningful cost-benefit analyses can only be performed once a drug is in widespread clinical use [23]. Summary Sevoflurane appears to have several properties that make it an attractive alternative to the currently available anesthetics for outpatient anesthesia. The relative low solubility of sevoflurane, as well as an impressive lack of airway irritation, makes it a very useful anesthetic for inhalation induction of anesthesia. This feature is likely to make sevoflurane a popular choice for pediatric outpatient anesthesia. For adult outpatients, the relatively low solubility of sevoflurane permits rapid alterations in alveolar concentration during the maintenance period (even when administered at relatively low flow rates of 2-3 L/min), thereby improving control of the depth of anesthesia. Low solubility should also allow for a more predicable emergence from anesthesia (versus isoflurane), thereby facilitating patient turnover in a busy ambulatory surgery center. The commercial development of sevoflurane has been slow because of concerns regarding the potential toxicity of its metabolites and breakdown products [24]. However, the large body of clinical experience from Japan and the worldwide Phase II and III clinical development programs suggests that these concerns may be unfounded. The short duration of exposure in the outpatient setting should further decrease the risk of nephrotoxicity. The relatively low solubility of sevoflurane will facilitate its use with total gas flow rates of 2-3 L/min. In the final analysis, clinicians will have to balance the cost of sevoflurane (versus halothane, enflurane, isoflurane, and desflurane) against its potential advantages in the ambulatory surgery population. Although the search for anesthetics that are more ideally suited for use in the outpatient setting will continue, sevoflurane clearly represents a step in the right direction [3].
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