CLINICAL ANESTHESIA 0195-5616/99 $8.00 + .00

DESFLURANE AND SEVOFLURANE

New Volatile Anesthetic Agents

Kathy W. Clarke, MA, VetMB, DVetMed

Sevoflurane and desflurane are volatile anesthetic agents that have recently received marketing authorization in North America and Europe for use in man. These agents are not new6• 45• 46• 48• 79• 80; investigations into the use of sevoflurane were carried out over 20 years ago. The increase in "day-stay" (outpatient) surgery with its requirement for a rapid and complete recovery together with the realization that no previously available agent was ideal has led to the renewed interest and further development of desflurane and sevoflurane. The amount of published data relating to these agents is enormous, and much of it is repetitive. Fortunately, there are several excellent reviews that draw together the information available.

The ideal volatile anesthetic agent should be nonexplosive and nonflammable, and it should not react with carbon dioxide absorbents. It should have a pleasant smell and be nonirritating; the speed and quality of anesthetic induction and recovery should be rapid and pleas­ant. Potency should be adequate to allow good oxygenation, and muscle relaxation and analgesia during anesthesia should be good. There should be minimal effects on the respiratory and cardiovascular systems, or at the least, these effects should be dose related and predictable. It should not sensitize the heart to epinephrine. It should not be toxic either directly or through metabolic breakdown products, and there should be no unwanted side effects such as convulsive movements or postopera-

From the Royal Veterinary College, University of London, North Mymms, Hatfield, United Kingdom

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE

VOLUME 29 • NUMBER 3 • MAY 1999 793

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tive nausea and vomiting. No existing volatile anesthetic yet fulfills these ideals.47, 79, 91 The three volatile anesthetic agents used most commonly are isoflurane, enflurane, and halothane. All cause cardiovascular depres­sion. Halothane is still widely used in veterinary anesthesia, but in man, its use is limited by the rare complication of immune-mediated hepatitis (see below). Enflurane may induce epileptiform activity, and in humans, it is usually administered with neuromuscular blockade. Isoflurane ap­pears to be the most satisfactory agent to date; although it may induce hypotension, cardiac output is well maintained at end-tidal values close to the minimal alveolar concentration (MAC). Induction and recovery are rapid, but in man, it causes coughing and breath holding if used for anesthetic induction; hence, in medical practice, halothane is still used for this purpose in pediatric cases.

This article examines the properties of sevoflurane and desflurane in relation to both the ideal agent and existing volatile anesthetics and discusses the potential place of these new agents in medical and veteri­nary anesthesia.

PHYSICAL PROPERTIES, POTENCY, AND PHARMACOKINETICS

Desflurane

Desflurane (CHFrO-CHF-CF3), previously known as 1-653, is a methyl-ethyl ether with a molecular weight of 168. In structure, it closely resembles isoflurane (CHF2-0-CHC1-CF3) other than replacement of a chlorine atom by a fluorine atom.20, 21, 45, 46, so, 91 It has a boiling point of 22.8°C (i.e., approximately room temperature), thus necessitating special vaporizers (see below). At sea level, the MAC ranges in man from 9.16 Vol % in neonates to around 6.0% in adults/1 and in animals, it has been reported to be between 5.7% and 10.52% (Table 1). Although the MAC is high compared with currently available inhalation agents (other than nitrous oxide), this is not disadvantageous as it still enables the delivery of adequate oxygen. The degree of variation in measured MAC even in the same species is surprising (Table 2). The MAC depends on a large number of factors,73 including the stimulus used for measurement, age, temperature, and atmospheric pressure, and there is enormous variation among individuals of one species. During experimental studies of the MAC of desflurane in swine23 and ponies12 it was noted that, following marked arousal in response to a stimulus, the anesthetic dose had to be increased greatly before anesthesia could be re-established and that the measured MAC value was considerably elevated. When the experiment was repeated in the same animal on a different day, the MAC had returned to close to mean values. Similar experiences in the clinical situation could be disconcerting.

The solubility partition coefficients of desflurane in blood, oil, and body tissues are low (see Table 2) and are similar to those of nitrous oxide. The low blood:gas (0.42) and brain:blood (1.3) partition coeffi-

~ (.II

Table 1. PHYSICAL PROPERTIES OF VOLATILE ANESTHETIC AGENTS

Property Desflurane Sevoflurane lsoflurane Enflurane Halothane

Boiling point (oq 22.8 58.6 48.5 56.5 50.2 Saturated vapor pressure at 20oC (mm Hg) 664 160 239 172 244 Solubility partition coefficients Blood:gas partition coefficient 0.42 0.68 1.4 1.8 2.5 Brain:blood partition coefficient 1.3 1.7 1.6 1.4 1.9 Fat:blood partition coefficient 27.0 48.0 45.0 36.0 51.0 Oil gas (olive) 19.0 53.0 91.0 96.0 224.0

Data from -Eger EI II: Uptake and distribution. In Miller RD (ed): Anesthesia, ed 4. New York, Churchill Livingstone, 1994, p 102 -Eger EI II: Physicochemical properties and pharmacodynamics of desflurane. Anaesthesia 50(suppl):S3, 1995 -Jones RM: Desflurane and sevoflurane: Inhalation anaesthetics for this decade? Br J Anaesth 65:527, 1990 -Yasuda N, Targ AG, Eger EI II: Solubility of I-653, sevoflurane, isoflurane and halothane in human tissures. Anesth Analg 69:370, 1989

Table 2. MINIMUM ALVEOLAR CONCENTRATIONS* OF DESFLURANE AND SEVOFLURANE IN DOMESTIC ANIMALS

Agent Dogs (Reference) Cats (Reference) Horses (Reference) Goats (Reference) Sheep (Reference)

Desflurane 7.2 (17) 9.79 (63) 10.32 (34)

Sevoflurane 2.36 (50) 2.58 (80) 2.09 (67)

*Expressed as Volume percentages. tH.I.K. Alibhai, Personal communication, 1997.

7.6 (82)

2.31 (2)

10.52t

2.7t

9.5 (57)

3.3 (58)

Nitrous Oxide

-88.0 38,400

0.47 1.1 2.3 1.4

Swine (Reference)

8.28-10.0 (23)

1.97-2.66 (80)

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cients of desflurane result in rapid equilibration of blood and brain levels with alveolar gases20• 21• 24• 48 and, therefore, rapid induction of anesthesia. Speed of recovery, particularly following prolonged anesthe­sia, is dependent not only on the blood gas solubility but also on the solubility of the agent in the tissues with poor blood supply such as fat. The low partition coefficient of desflurane in all tissues93• 94 means that recovery should be rapid, with minimal time between commencement and completion. This has been found to be the case following both short and long periods of anesthesia in all species studied. 20-22• 24, 34• 46• 63

Sevoflurane

Sevoflurane (CH2F-O-CH(CF3)-CF3) is an isopropyl ether with a molecular weight of 200, a boiling point of 58.SOC, and a saturated vapor pressure at 20°C of 160 mm Hg; thus, it can be used in conventional vaporizers.21• 45• 79• 80• 93 The MAC has been reported to range from 1.71% to 2.05% in adult humans45• 79 and from 1.97% to 3.3% in other animals (see Table 2). The blood:gas partition coefficient is 0.68, which is only slightly higher than that of desflurane; thus, with sevoflurane, blood and brain levels rapidly equilibrate with alveolar levels of the anesthetic agent.6• 20• 45• 79• 80 The solubility of sevoflurane in many tissues, particularly in fat (see Table 1), is higher than that of desflurane93• 94; thus, the speed of recovery from sevoflurane theoretically should be slower, particularly following a prolonged anesthetic. This has been shown to be the case/2• 24

but recovery was still more rapid than following similar anesthesia with isoflurane.

CARDIOVASCULAR EFFECTS

Clinical and experimental studies in a large number of species, including man, have compared the cardiovascular effects of both sev­oflurane and desflurane with those of isoflurane, enflurane, and halo­thane. Practically, with the exception of effects on pulse rate (lower with sevoflurane), both agents appear to have cardiovascular effects similar to those of isoflurane. They cause a dose-dependent fall in arterial blood pressure and systemic vascular resistance as well as myocardial depression and a fall in cardiac output at higher doses. In the medical literature, there are contradictory results as to the degree of these changes and as to whether or not they differ from those of isoflurane. Studies differ depending on the species, protocol, levels of hypercarbia, presence and absence of surgical stimulation, and ancillary agents used. Fortunately, the conflicting results have been well reviewed.15• 19• 46• 83• 91

Similar comparative studies from the veterinary literature (see below) appear to give more consistent results.32• 37• 67• 69 Neither desflurane nor sevoflurane sensitizes the heart to epinephrine-induced cardiac arrhyth­mias; in each case, the arrhythmogenic threshold is similar to that of isoflurane and considerably higher than that of halothane.36• 40• 87

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The cardiovascular effects of desflurane are due to two separate mechanisms. First, there is a dose-related cardiovascular depression simi­lar to that caused by isoflurane, and second, under certain circumstances, there is a sympathetically driven stimulation resulting in a rise in heart rate and blood pressure. This "sympathetic storm," as it is known, is of considerable concern in human anesthesia. In clinical trials of desflurane, rises in heart rate and blood pressure were noted at anesthetic induction and when the concentration of desflurane was increased. The situation was mimicked in human volunteers18' 84' 88' 89 and demonstrated that increases of blood pressure and heart rate did not occur with concentra­tions of desflurane at 0.55 MAC but did at 1.66 MAC. The effects were less evident following repetitive increases of the agent. The stimulation was transient but was accompanied by increased blood levels of epi­nephrine and norepinephrine. Similar effects did occur with isoflurane but to a lesser extent. Prior treatment with fentanyl or clonidine blunted the response.84 Sympathetic storms do not occur in similar circumstances in either the dog10 or the pig.49 A higher sympathetic tone during desfl­urane anesthesia may explain the subtle and variable differences noted between the cardiovascular effects of desflurane compared with those of isoflurane (i.e., higher pulse rate, systemic vascular resistance, and better cardiac contractility), as these differences were abolished by autonomic blockade.46' n, 83 Desflurane may cause coronary vasodilation, but there is no evidence of "coronary steal."15' 21' 35' 45' 83 Desflurane has been shown to maintain hepatic, renal, intestinal, and skeletal muscle blood flow in contrast to isoflurane, which decreases regional tissue perfusion to vary­ing degrees in association with systemic hypotension.35 Cardiovascular changes may also be time related, as arterial blood pressure and cardiac output increased after the first 90 minutes in human volunteers undergo­ing 7 hours of anesthesia at 1.6 MAC of desflurane.85

Ebert et aP9 have reviewed the published work concerning the cardiovascular effects of sevoflurane together with information from a number of unpublished studies. The major differences between sev­oflurane and both desflurane and isoflurane are that with sevoflurane, the heart rate is lower and stable and sympathetic storms do not occur in the majority of cases. Sevoflurane produces a dose-dependent de­crease in myocardial perfusion and myocardial oxygen consumption and decreases coronary vascular resistance but does not lead to coronary steal. In clinical trials, high-risk patients were no more likely to undergo myocardial ischemia than those given isoflurane. During deep sevoflur­ane anesthesia, hepatic arterial blood flow is preserved and renal blood flow changes are similar to those induced by isoflurane.

RESPIRATORY EFFECTS

All studies in spontaneously breathing animals demonstrate that both desflurane and sevoflurane cause dose-related respiratory depres-

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sion, with increased concentrations of either agent causing a decreased response to carbon dioxide and increased hypercarbia.30, 45, 46,83 Compara­tive work in the cat and dog37, 40, 67 and in sheep (H. I. K. Alibhai, personal communication, 1997) demonstrated that desflurane, sevoflur­ane, enflurane, isoflurane, and halothane all cause respiratory depres­sion, but the studies had differing results as to the relative order of magnitude. Desflurane causes airway irritation, and induction of anes­thesia in man with this agent results in increased secretions, coughing, and breath holding.46,91 It has been suggested that increasing the concen­tration of desflurane slowly reduces these effects, but in practice, mask induction is not often considered to be acceptable?0, 79 In dogs, however, airway irritation appears to be greatest if induction of anesthesia is achieved slowly,34 and no problems were noted in either dogs or cats with mask induction using high doses to commence.34' 63 In contrast, sevoflurane does not appear to cause any airway irritation, it is pleasant smelling, and in man, mask induction of anesthesia has a high accep­tance.30 Sevoflurane like isoflurane appears to be effective in reversing bronchospasm. 64

CENTRAL NERVOUS SYSTEM EFFECTS

Desflurane and sevoflurane cause the electroencephalographic changes associated with anesthesia and do not cause epileptiform activity?6, 95 In both humans and animals, changes in cerebral blood flow and intracranial pressure are similar to those induced by isoflurane, although there is some inconsistency in the published data.19, 79, 95 High concentrations may increase intracranial pressure, but most studies have shown that this effect is minimal at values around the MAC. The cerebral response to carbon dioxide appears to be maintained; thus, as long as hypocapnia is achieved, either agent can be safely used for neurosurgery, and the resultant rapid recovery is considered to be a particular advan­tage for such cases.46' 79' 81' 91' 95

TOXICITY, METABOLISM, AND STABILITY WITH SODA-LIME

The mode by which volatile anesthetic agents can cause toxicity is complex, but is now well understood.25, 28, 51 Agents in current use are unlikely to be directly toxic, but hypoxia may cause indirect effects; hence, the importance of maintaining hepatic blood flow. All the volatile agents in current use are metabolized to some degree (isoflurane, 1 %; enflurane, 2%-8%; halothane, 20%25) and breakdown products can result in hepatic and renal damage. Hypoxia or enzyme induction by prior drug treatment increases the rate of metabolism; hence, the potential for toxic changes. A further danger may result from interactions between the anesthetic agent and carbon dioxide absorbent.25, 51· 52, 59 Halothane causes two types of hepatic syndromes: a mild one in up to 20% of

DESFLURANE AND SEVOFLURANE 799

exposures and the uncommon but well-known syndrome of "halothane hepatitis," where (usually following a second exposure) massive hepato­cellular necrosis may occur. A degree of hepatic damage occurs as a result of hypoxia; as halothane causes a greater reduction of hepatic blood flow than does isoflurane, this may be the cause of the dose­related damage. There are species-related differences, and guinea pigs are susceptible to hepatic damage via oxidative metabolites.25• 51 The extensive metabolism of halothane is catalyzed by enzymes such as cytochrome P450. Breakdown products include trifluoroacetyl halides, which can link to liver proteins. In some cases, antibodies are formed against the halothane-induced antigen, resulting in immune-mediated liver damage. Isoflurane and enflurane produce similar breakdown products to halothane but to a lesser extent; thus, autoimmune-mediated hepatitis may occasionally occur.28• 51 When given for prolonged periods, methoxyflurane, resulted in renal damage thought to be due to the action of free fluoride ions formed from hepatic metabolism. 51 The threshold for plasma fluoride to cause nephrotoxicity is approximately 50 mmol/L ~ 1 • 16

Serum fluoride levels frequently exceed 20 mmol/L ~ 1 after prolonged enflurane anesthesia, but this appears to have only transient effects, and serious renal damage is rare.51

Desflurane is extremely stable; thus, it may be expected to have minimal hepatic or renal toxicity. Its metabolic pathway is similar to that of isoflurane; compounds such as trifluoroacetic acid are breakdown products28• 54; thus, there is theoretical potential for immune-mediated hepatitis, but the low degree of metabolism (0.2%) coupled with the kinetics, which ensure rapid removal of the agent, mean that the chance is minimal. 85 Similarly, minimal increases in serum or urinary inorganic fluoride are found even after prolonged anesthesia.21• 24• 54

Desflurane is stable in the presence of normally hydrated (13%-15% water) carbon dioxide absorbents; however, when passed through dry soda-lime or Barolyme, it is degraded to carbon monoxide.21• 26 For a given level of dryness, Barolyme produces more carbon monoxide than does soda-lime. The problem is not just limited to desflurane26 and is mainly seen with "fail-safe" anesthetic machines, where, if not specifi­cally "switched off," dry oxygen flows continuously for prolonged peri­ods when the machine is not in use.

In contrast, sevoflurane is metabolized to a moderate extent (ap­proximately 5% }79 and also breaks down in the presence of carbon dioxide absorbents. Liver metabolism does not result in trifluoroacetic acid; thus, immune-mediated hepatitis is unlikely. Metabolic products include hexafluroisopropanol, which is rapidly conjugated and unlikely to cause toxicity, and inorganic fluoride ions,Z8• 51• 52• 79 a situation that has caused concern in relation to the nephrotoxic effects of methoxyflurane. The level of serum inorganic fluoride previously considered to be toxic (50 mmol/L ~ 1) can be reached under certain circumstances with sev­oflurane anesthesia as well as with enflurane anesthesia. Sevoflurane has been administered to more than 1 million people with no reports of renal failure. 24• 59• 79 Suggestions as to why this should be safe are that the

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rapid elimination of sevoflurane from the tissues reduces the toxicity and that methoxyflurane toxicity is due to intrarenal metabolism and intrarenal fluoride levels rather than to serum values. 51- 53, 59

Sevoflurane does not react with carbon dioxide absorbents to pro­duce carbon monoxide to any significant degree but, more seriously, produces a number of breakdown products, including "Compound A" (CF3 = C(CF3)-0-CH2F) which is nephrotoxic in rats. Most work suggests that toxic values (in rats) exceed 1000 ppm, but recent studies have suggested that lower levels (even as low as 50 ppm) may cause medul­lary tubular necrosis? Numerous studies have investigated the concen­trations of Compound A that occur and have shown that it is greatest at higher temperature, with dry absorbents, with low-flow or closed systems and, not surprisingly, with high concentrations of sevoflurane.5'

59, 66, 79 Levels in both man and dog using closed circuits are usually about 20 ppm but may exceed 50 ppm in individual cases?9 Nevertheless, in man, there is no evidence that renal failure results from sevoflurane anesthesia. 59

INTERACTION WITH OTHER AGENTS

Desflurane and sevoflurane may be used in conjunction with other agents (e.g., premedicants, anticholinergics, analgesics, intravenous in­duction agents, nitrous oxide, neuromuscular blocking drugs) that are likely to be administered during the perioperative period. Interactions between such medications and desflurane and sevoflurane are the same as would occur with any other anesthetic agent. For example, nitrous oxide and alpha2-adrenoceptor agonists reduce the MAC values of des­flurane and sevoflurane. 34, 46, 79 Both anesthetic agents augment the action of neuromuscular blocking agents/9' 91 and desflurane has been shown to significantly reduce neuromuscular function when used alone.46

METHODS OF ADMINISTRATION

Vaporizers

Desflurane boils at close to room temperature (see Table 1) and cannot be used in a draw-over or conventional temperature-compen­sated vaporizer. The Tee 6 (Datex-Ohmeda, Hatfield, UK) is a highly sophisticated electronically controlled vaporizer that heats the agent, converting it into a gas that is mixed with the carrier gases.29' 86 The vaporizer can deliver up to 18% desflurane. With oxygen as the carrier gas, the output is quite accurate at flow rates between 200 mL/min and 10 L/min, but when nitrous oxide is included, the output may be lower (up to 2% less desflurane than expected) due to the effect of viscosity on the electromechanical coupling device.43' 86 The unit does not work until the temperature in the sump reaches the required level; this can

DESFLURANE AND SEVOFLURANE 801

take from 30 seconds to several minutes depending on the amount of agent and the ambient temperature. Electronic fail-safe devices prevent any output if the vaporizer is not working correctly. As the recovery from desflurane is so rapid that anesthesia may lighten before the fault is corrected, it is advisable to have intravenous anesthetic to hand. One major advantage of the Tee 6 is its filling system. The bottle of desflurane is inserted directly into the filling port of the vaporizer, the unit cannot be overfilled, and no desflurane is spilt. Refilling can be carried out while the vaporizer is in use, but the agent should be pre-warmed or only small aliquots added, as a fall in temperature may trigger the fail­safe mechanism. Not surprisingly, the Tee 6 is quite expensive, a fact often cited as the major disadvantage of using desflurane, but the lack of wasted agent may rapidly compensate for the initial purchase cost.

In contrast, the physical characteristics of sevoflurane closely resem­ble those of enflurane (see Table 1); hence, agent-specific vaporizers similar to those for other volatile agents are available from commercial sources. Early sevoflurane vaporizers had a maximum output of around 5%, but this proved to be inadequate for rapid mask induction, 55• 68 and the most recent models now have an output of up to 8%.79 The use of sevoflurane in two types of enflurane-specific vaporizers demonstrated that at flow rates of 4 L/minute or below, the delivered sevoflurane concentrations were close to the expected output as shown on the dial but that the output was less reliable at higher flow rates.31 Although the use of unmodified enflurane vaporizers for sevoflurane cannot be recommended, it is probable that redundant vaporizers can be recali­brated at service. Sevoflurane may also be used in noncalibrated dra­wover vaporizers.65

Closed and Low-Flow Circuits

Economic factors are likely to dictate that the new anesthetic agents be administered mainly by low-flow and closed methods. The low solubility of desflurane and sevoflurane means that the inspired and expired concentrations rapidly equilibrate5• 20• 21; thus, even when used with an out-of-circuit vaporizer, the inspired concentration from an in­circle system soon becomes close to that of the vaporizer dial and remains so even when flow rates are reduced to the minimum required to replace oxygen utilization.

The boiling point of desflurane prevents it from being used with an in-circle vaporizer, although, theoretically, it could be administered by injection of the liquid into a closed circuit. Muir and Gadaswski65 investi­gated the efficacy and safety of administering sevoflurane utilizing an in-circle vaporizer from which the wick had been removed; even without the wick, "bench" in vitro tests demonstrated that at the maximal vapor­izer setting, concentrations of up to 8% sevoflurane could accumulate in the circle. The circuit, with suitable vaporizer settings, was then used to administer sevoflurane at approximately 1.5 MAC to dogs with low-

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flow oxygen (approx 15 mL/kg/min) or with the circuit totally closed. Vaporizer settings required were the same for both spontaneous and controlled ventilation in the low-flow situation but were reduced when the circuit was totally closed. Anesthesia was maintained easily and safely, and cardiopulmonary values were similar and acceptable in all three situations. Compound A reached a mean level of 21 ppm (i.e., similar to values recorded in man79) and did not differ between the three modes of use. The authors concluded that sevoflurane could be used safely and economically via closed circuit anesthesia.65

CLINICAL EXPERIENCE IN MAN

A large number of studies on the use of desflurane and sevoflurane in man have been reported in the anesthetic literature. The results of the earlier trials have been well reviewed 14• 46• 55• 70• 77- 79• 91; more recent studies have confirmed the facts noted earlier. The studies have demonstrated that both agents appear to be safe in normal clinical use and have emphasized the ease of stabilizing anesthesia as well as the rapid and complete recovery. Concerns encountered with desflurane are its irritant effects, fears over the possibility of sympathetic storms (although this complication is rarely mentioned in the clinical studies), and cost of the vaporizer. For sevoflurane, interest has centered on the speed and quality of anesthetic induction and recovery as well as on the potential for toxic effects. With both agents, the need for adequate analgesia has been noted as has the major side effect of postoperative nausea and vomiting; this side effect has negated the advantage of rapid recovery and delayed early discharge of the patient. The incidence of postoperative nausea and vomiting has varied greatly between trials, ranging from 0%4 to 32% of patients,74 and may be influenced by ancillary agents such as opioids as well as by the surgery performed. In a study comparing prolonged sevoflurane and desflurane anesthesia in human volunteers, where no other agents were administered, the incidence of postanesthetic vomiting was quite low.24

In man, desflurane has been used mainly for day-case (outpatient) surgery.14• 46• 70• 90• 91 Commonly, anesthesia induced with propofol and maintained with desflurane has been compared with anesthesia induced and maintained with either isoflurane or propofol infusion. In most studies, emergence from anesthesia and time to total wakefulness has been the most rapid with desflurane, and preemptive analgesia has been essential. Time to discharge has been identical, however. The incidence of postoperative nausea and vomiting after desflurane has been similar to that after isoflurane but greater than that following propofol in most studies.41 A recent report4 compared desflurane, isoflurarte, and propofol infusion in spontaneously breathing patients and found no significant differences in recovery times, postoperative analgesic requirements, or incidence of postoperative nausea and vomiting, which was low with all regimes and did not occur following desflurane. Interestingly and

DESFLURANE AND SEVOFLURANE 803

unexpectedly, pulse rates were lowest with desflurane. Stable anesthesia was difficult to achieve with propofol but was easily maintained with either volatile agent.

Sevoflurane has been used to induce anesthesia in pediatric cases, and in such studies, it has usually been compared with halothane.5' 56,

78, 79 Anesthetic induction is fast and usually smooth, but episodes of "agitation" occur more frequently than with halothane. Agitation can be reduced by a more rapid induction such as that achieved by incorporat­ing nitrous oxide or by the single breath technique. Recovery has been rapid, with the incidence of postoperative nausea and vomiting similar to that after halothane. Induction of anesthesia with sevoflurane can also be acceptable in adults,33' 79 but in most such studies, sevoflurane has been used for maintenance following intravenous induction and has been compared with isoflurane and propofol infusion. Although re­covery following sevoflurane was faster, time to discharge did not differ. 8, 74, 78, 79

DESFLURANE AND SEVOFLURANE IN VETERINARY ANESTHESIA

Small Animals

The pharmacological studies of desflurane and sevoflurane in ani­mals reviewed above have provided useful information, but the results are not always directly applicable to the practice of veterinary anesthesia. The pharmaceutical company that markets sevoflurane has supported veterinary experimental and clinical studies in a number of species, the results of which have just become available. In contrast, there appears to be little commercial interest, at least in Europe, for desflurane in veterinary anesthesia, and the limited published reports reflect this apa­thy.

The actions of desflurane in the cat have been investigated by McMurphy and Hodgson.62' 63 Desflurane (18%) induced anesthesia rap­idly (mean of 6.2 minutes to endotracheal intubation) and smoothly with no coughing or excessive salivation such as is reported in man. Recovery to standing occurred within 4 minutes and was calm as long as the endotracheal tube was removed immediately. The MAC was 9.7% ± 0.7%. With spontaneous ventilation, at both 1.3% and 1.7% MAC of desflurane, the cardiac index was higher and peripheral resistance was lower with desflurane than the published values for halothane or isoflurane. Desflurane at 1.7 MAC caused profound hypoventilation; however, in all but one cat (which stopped breathing), the respiratory rate was maintained. Controlled ventilation caused a fall in cardiac out­put.

In the dog, the MAC of desflurane has been reported as 7.2%17 and 10.3%.34 As is the case in the cat, anesthetic induction with 18% desflur­ane was rapid and smooth with minimal salivation.34 Following 9 hours

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of desflurane anesthesia, a good quality of recovery occurred in a mean time of 6 minutes. A study of the cardiovascular changes of 1.1 MAC, 1.25 MAC, and 1.5 MAC of desflurane with spontaneous and controlled ventilation in Beagle dogs10 demonstrated effects similar to those seen in the cat. Increasing desflurane concentration caused a small fall in blood pressure, cardiac output, and pulse rate, although the pulse rate was elevated at 1.1 MAC compared with nonanesthetized values. The changes in arterial pressure were considerably less than those reported in earlier pharmacological studies in which neuromuscular blocking agents had been usedP The highest dose of desflurane caused hypoven­tilation. Recovery was rapid, but one dog vomited 2 hours after anesthe-sia.

The MAC of sevoflurane has been measured as 2.58% in cats80 and as 2.09% to 2.36% in dogs. 5°' 67 In cats, the cardiopulmonary effects of sevoflurane have been compared with those of isoflurane, enflurane, and halothane.37' 40 Sevoflurane produced dose-dependent respiratory depression (associated with reduced respiratory rate) and a fall in arterial blood pressure. At 1 MAC and 1.5 MAC, these changes were of a degree similar to those induced by isoflurane and considerably less than those of enflurane. To simulate clinical circumstances, sevoflurane was com­pared with halothane and isoflurane with and without nitrous oxide in cats that had been premedicated with atropine and ketamine.38 Arterial blood pressure was better maintained in cats receiving sevoflurane, and hypercapnia was similar to that achieved with isoflurane and less than that achieved with halothane. In all cases, anesthetic induction was smooth, and recovery was rapid and uncomplicated.

Comparative studies of the cardiopulmonary effects of sevoflurane, enflurane, isoflurane, and halothane in spontaneously breathing dogs67

demonstrated that sevoflurane caused a dose-dependent decrease in arterial blood pressure and systemic vascular resistance, but that even at 2 MAC, cardiac index was well maintained, partly because of a significant increase in heart rate. Cardiac index was also well maintained with isoflurane and halothane. Enflurane caused the greatest cardiovas­cular depression. With all agents, arterial carbon dioxide tension rose and, with the exception of halothane, respiratory rate fell with increasing concentrations. Mutoh et al69 also investigated the practicality of rapid inhalation induction of anesthesia with the four agents (at 2.5 MAC) and the cardiopulmonary changes that accompanied it. During the induction process with isoflurane, sevoflurane, or enflurane, there was an increase in heart rate and sometimes in arterial blood pressure, but with halo­thane, this stimulation did not occur. Following intubation and mainte­nance for 30 minutes with 1.5 MAC, blood pressure fell (most severely with enflurane), but cardiac output was well maintained.

In Beagle dogs, the speed and quality of anesthetic induction with sevoflurane, with the concentrations of agent being gradually increased, was significantly faster (5.7 ± 1.6 minutes to intubation) than that with isoflurane (8.6 ± 2.6 minutes), but following 30 minutes of anesthesia, there were no differences in speed or quality of recovery.42 Rapid indue-

DESFLURANE AND SEVOFLURANE 805

tion with 2.5 MAC of sevoflurane was also satisfactory in the experimen­tal situation.69 However, in an extensive clinical trial involving 120 dogs, a rapid technique with approximately 2 MAC of sevoflurane (the maxi­mum dose available from the vaporizer used) and 50% nitrous oxide proved unsatisfactory in large dogs.68 Flecknall et aF7 found that induc­tion of anesthesia in the rabbit with sevoflurane (as with isoflurane) caused breath holding and marked struggling; thus, sevoflurane may prove to be less valuable as an anesthetic induction agent in animals than it is in children.

Large Animals

The efficacy and actions of desflurane have been studied in the horse11• 12• 44• 75• 82 and sheep57 and those of sevoflurane have been studied in the horse/· 2• 3• 9• 13• 32• 60• 61• 71• 92 sheep,56 and cattle.39 Full details are not appropriate in this review, but the potential for use in the horse may well influence the future availability of these agents to the veterinary profession. The cardiovascular effects of both desflurane and sevoflurane in the horse appear to be similar to those in other species; there is dose­dependent hypotension and a fall in systemic vascular resistance and cardiac output.1• 75 Following induction of anesthesia with xylazine and intravenous anesthetic agents, at 1.1 MAC of desflurane, there was marked hypotension, but cardiac output was maintained at preanesthetic values.11 Similar studies with sevoflurane13• 32 suggested that cardiac output was depressed to a greater extent, but the numbers in all of these studies were quite small. Comparative studies suggest that the cardiopulmonary changes seen with sevoflurane in the horse are similar to those produced by isoflurane.32 In clinical trials in the horse of both desflurane44 and sevoflurane/1 the authors have been enthusiastic about the ease of maintaining stable anesthesia even with low-flow or closed­circuit anesthesia and the rapid and complete recovery. Following desfl­urane anesthesia, recovery commenced so rapidly (6 minutes) that it was essential to provide sedation. Animals that received this sedation got to their feet more slowly, but once standing, they were fully coordi­nated within minutes. A clinical trial of sevoflurane in 40 horses demon­strated that following the administration of postanesthetic xylazine, horses gained their feet in a mean time of 33 minutes and time to good coordination was 44 minutes. There has been some discussion as to the quality of recovery following sevoflurane anesthesia; in most cases, it is considered to be preferable to that following the use of isoflurane.60• 61

FUTURE ROLE OF DESFLURANE AND SEVOFLURANE IN VETERINARY ANESTHESIA

In summary, desflurane and sevoflurane are volatile anesthetic agents that have kinetics enabling rapid induction, ease of stabilization

806 CLARKE

(even with fully closed circuits), and rapid complete recovery from anesthesia. For all practical purposes, cardiopulmonary effects of both are similar to those of isoflurane. The disadvantages of desflurane are that it requires a sophisticated vaporizer and that in man (and to a lesser extent in domestic animals), it has some irritant effects on the airway and can cause sympathetic stimulation. Sevoflurane is not an irritant and appears to be acceptable for anesthetic induction in humans but not always in animals. The major disadvantage of sevoflurane is potential renal toxicity both from fluoride and from breakdown products with carbon dioxide absorbents, but, to date, such toxicity has not been recorded in clinical practice. With both agents, the rapid recovery means that immediate postoperative analgesia is essential. In man, postopera­tive nausea and vomiting has been reported as a side effect of both agents, but this may relate to ancillary medications used. Neither desfl­urane nor sevoflurane yet fulfills the requirements for the ideal volatile anesthetic agent.

The future veterinary use of desflurane and sevoflurane depends on their future in human anesthesia, on economic factors, and on their advantages in veterinary anesthesia when compared with existing agents. The published clinical trials in human anesthesia do not ade­quately reflect the enthusiasm there appears to be (at least in the United Kingdom) for the use of sevoflurane, although desflurane appears to be less popular for the reasons outlined above. All new pharmaceutical agents are expensive, but ease of use of closed circuits reduces cost. In the horse, rapid kinetics are a particular advantage, and clinical trials have suggested that both desflurane and sevoflurane may prove to be superior to existing volatile anesthetics in this species. In dogs and cats, the need for rapid kinetics is less; indeed, until their effect is appreciated, these agents may increase the risk of overdose. Nevertheless, the ease of maintaining a stable level of anesthesia is appreciated for all species, and the reports of clinical trials in small animals currently being under­taken with sevoflurane are awaited with interest.

The final place of desflurane and sevoflurane in veterinary anesthe­sia is dependent on their success in medical anesthesia and on support for veterinary use from the pharmaceutical companies. It is hoped that veterinary anesthetists may soon have the opportunity to use these new and useful volatile anesthetic agents.

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