Research paper by Sanjay S. Patel, Karen L. Goa

Indexed on: 31 Oct '12Published on: 31 Oct '12Published in: Drugs


Sevoflurane is an ether inhalation general anaesthetic agent with lower solubility in blood than isoflurane or halothane but not desflurane. The low solubility and the absence of pungency facilitate rapid mask induction; the low blood solubility also expedites ‘wash-out’ and therefore recovery from anaesthesia. Sevoflurane produces dose-dependent CNS, cardiovascular and respiratory depressant effects that generally parallel those of isoflurane.Sevoflurane is degraded by carbon dioxide absorbents to nephrotoxic (in rats) haloalkenes, although renal toxicity has not been observed in humans. Compared with other inhalation anaesthetics, negligible quantities of carbon monoxide are generated from degradation of sevoflurane by carbon dioxide absorbents.Sevoflurane has negligible airway irritant effects, which facilitate s a ‘smooth’ induction, even in comparison with halothane in paediatric patients, and makes sevoflurane especially amenable to rapid induction of anaesthesia in adults and children. Emergence, orientation and postoperative cognitive and psychomotor function recovery of paediatric outpatients is significantly more rapid from sevoflurane than from halothane anaesthesia. In adult inpatients and outpatients, emergence and orientation are significantly faster after sevoflurane than after isoflurane but not desflurane anaesthesia. Other recovery parameters (e.g. times to sitting, ambulation) occur at similar times after either sevoflurane or desflurane anaesthesia. Recovery of psychomotor function occurs at generally similar times after sevoflurane, isoflurane or desflurane.Compared with propofol, sevoflurane facilitates more predictable extubation times and significantly better postoperative modified Aldrete scores in outpatients, although cognitive and psychomotor recovery occurs at similar times for both agents.As a supplement to opioid anaesthesia during coronary bypass graft surgery or in those at risk for myocardial ischaemia, sevoflurane is comparable to isoflurane. Limited data suggest that it is also as useful as isoflurane for the maintenance of anaesthesia during neurosurgical or obstetric procedures.Sevoflurane is well tolerated by adult and paediatric patients during induction of anaesthesia, with a low incidence of mild airway complications (breath-holding, coughing, excitement and laryngospasm). During rapid induction, it is particularly better tolerated than isoflurane or halothane. Sevoflurane has a lower potential for hepatic injury than halothane. Unlike methoxyflurane, sevoflurane undergoes minimal intrarenal defluorination, which may account for the lack of fluoride ion-induced nephrotoxicity in humans, despite elevated plasma fluoride levels after its use.In summary, sevoflurane provides for a rapid and smooth induction of, and recovery from, anaesthesia. These features combined with its favourable cardiovascular profile should make sevoflurane the agent of choice for inhalation induction in adult and paediatric anaesthesia. Although further clinical evaluation will define the role of this agent relative to that of propofol and desflurane, sevoflurane should also prove to be a valuable alternative anaesthetic agent for adults in both outpatient and inpatient surgery.Sevoflurane is a polyfluorinated methyl isopropyl ether inhalation general anaesthetic with lower solubility in blood and body tissues than halothane but not desflurane. Its anaesthetic potency is ≈50% less than that of isoflurane but ≈ 30% more than that of desflurane. Sevoflurane is readily degraded by carbon dioxide absorbents to haloalkene byproducts that are nephrotoxic in rats, but there is no evidence of such toxicity in humans. In contrast to some other inhalation anaesthetic agents, which are degraded by carbon dioxide absorbents with generation of carbon monoxide, sevoflurane degradation generates negligible quantities of carbon monoxide.The dose-dependent EEG and cerebrovascular depressant effects of sevoflurane generally parallel those of isoflurane. Sevoflurane produces cerebrovasodilation, suppresses somatosensory-evoked potentials and facilitates preservation of cerebral blood flow responsiveness to changes in arterial carbon dioxide tension. Cerebral blood flow autoregulation is maintained during sevoflurane anaesthesia, unlike the dose-dependent impairment seen with desflurane or other inhalation agents. As with other inhalation anaesthetics, cerebral metabolism is maintained at a reduced rate during sevoflurane anaesthesia.Sevoflurane is a dose-dependent cardiovascular depressant generally similar to isoflurane and desflurane, with some exceptions. Sevoflurane, unlike isoflurane and desflurane, is not associated with sympathoexcitatory activity upon introduction or with rapid increases in inspired concentrations; in this regard sevoflurane provides a more stable heart rate profile than either isoflurane or desflurane. However, it is similar to these agents in that it does not potentiate cardiac arrhythmias induced by epinephrine (adrenaline). Sevoflurane, like other inhalation anaesthetics, produces a dose-dependent decrease in blood pressure, and, compared with isoflurane, it facilitates rapid alteration of the depth of anaesthesia.In adults, the depression of cardiovascular function and myocardial contractility produced by sevoflurane is similar to that seen with isoflurane but less than that of halothane or enflurane. The cardiovascular depressant effect is attenuated during spontaneous ventilation, in the presence of nitrous oxide 60% or with prolonged exposure to sevoflurane. Sevoflurane has a negligible effect on coronary blood flow, and canine models indicate that, like desflurane, it does not induce a ‘coronary steal’ phenomenon. Sevoflurane is similar to isoflurane in its effects on regional blood flow, including to visceral organs, and systemic vascular resistance. Baroreflex function is reduced by sevoflurane in a manner similar to that of isoflurane and desflurane.Sevoflurane produces a more profound dose-dependent ventilatory depression than is seen with enflurane or halothane at />-1 minimum alveolar concentrations (MAC). The depressant effect leads to a decreased minute respiratory volume. Sevoflurane inhibits hypoxic pulmonary vasoconstriction and tracheal smooth muscle contraction. Compared with other inhalation anaesthetics, sevoflurane causes negligible airway irritation and does not induce the cough reflex.Sevoflurane resembles other inhalation anaesthetics in its effect on neuromuscular relaxation and potentiation of skeletal muscle relaxation induced by neuromuscular blocking agents. It permits tracheal intubation without adjunctive neuromuscular blocking agents; laryngeal mask insertion can also be accomplished with sevoflurane alone at concentrations slightly lower than those required for tracheal intubation.The alveolar equilibration of sevoflurane is rapid (85% complete within 30 minutes) compared with that of isoflurane (73%) or halothane (58%) but not desflurane (90%). The estimated tissue distribution of sevoflurane is similar to that of isoflurane.Sevoflurane is eliminated faster than isoflurane despite its greater blood: tissue partition coefficient. Thus, ‘wash-out’ of sevoflurane in the first 2 hours after discontinuation of anaesthesia is ≈1.6-fold more rapid than with isoflurane but slower than desflurane. Mean pulmonary elimination clearance of sevoflurane (3.58 L/min) is not significantly different from that of isoflurane (3.62 L/min), and total body clearance of both agents is identical (3.6 L/min).Sevoflurane undergoes dose-independent hepatic biotransformation, principally by cytochrome P450 (CYP) 2E1, with 1 to 5% of the absorbed dose of sevoflurane undergoing metabolism to liberate inorganic fluoride ions (F-) and hexafluoroisopropanol (HFIP) as the principal byproducts. The latter compound accounts for 82% of the organic fluorinated metabolites. HFIP is rapidly glucuronidated and then undergoes rapid urinary excretion. Sevoflurane, unlike methoxvflurane, undergoes minimal renal defluorination.Rapid induction of anaesthesia with sevoflurane is as effective as that with isoflurane or halothane and considerably more pleasant. Several clinical studies in outpatient anaesthesia which compared sevoflurane with halothane found that induction of anaesthesia was ‘smoother’ and faster, and tracheal intubation more rapid with sevoflurane. Emergence, extubation, orientation and postoperative recovery of cognitive and psychomotor function after sevoflurane anaesthesia was more rapid than after halothane anaesthesia, although patient readiness for discharge was not consistently earlier.Emergence and orientation from outpatient anaesthesia were more rapid after sevoflurane than after isoflurane anaesthesia in adults but not after desflurane anaesthesia in adults or children, whereas times to ambulation or readiness for discharge were comparable among the 3 agents. Data from inpatient comparative studies of sevoflurane and isoflurane in adults reflected similar trends, with the exception that postoperative orientation in these patients did not occur consistently earlier with sevoflurane. Recovery rates of postoperative psychomotor function after sevoflurane or isoflurane anaesthesia were similar.Extubation times were similar after propofol or sevoflurane, but more predictable with the latter agent in ambulatory patients. Recovery of cognitive and psychomotor functions occurred at similar times for both agents, although postoperative modified Aldrete scores were significantly better with sevoflurane than with propofol. In contrast, data from inpatients show that sevoflurane provided significantly shorter times to extubation, emergence and orientation than did propofol.Present data indicate that, as a supplement to opioid anaesthesia during coronary artery bypass graft surgery or in patients at risk for myocardial ischaemia, sevoflurane is comparable to isoflurane. In obstetric surgery, limited data show that sevoflurane, at 1% end-tidal concentrations, is as useful as isoflurane (0.5%) for the maintenance of anaesthesia, without any adverse maternal or neonatal outcomes. In neurosurgical procedures, sevoflurane anaesthesia produced changes in cerebrovascular haemodynamics comparable to those seen with isoflurane anaesthesia.Sevoflurane, like isoflurane or halothane, is well tolerated by patients predisposed to asthma. In adults and children, it is less pungent than halothane or isoflurane, and airway complications (breath-holding, coughing, excitement and laryngospasm) during induction of anaesthesia are generally mild, transient and lower in incidence. During rapid induction of anaesthesia, sevoflurane is particularly better tolerated than isoflurane or halothane. Changes in haemodynamic variables tend to be minimal during induction and maintenance of anaesthesia with sevoflurane.Occasional agitation upon awakening from sevoflurane anaesthesia has been reported in children, with postoperative restlessness and agitation evident during recovery. Postoperative nausea has occurred in 2 to 74% of patients recovering from sevoflurane anaesthesia, whereas emesis has been reported in 2 to 50% of patients.Sevoflurane has a lower potential for hepatotoxicity than halothane, despite rare reports of transient elevation of hepatic enzymes. However, HFIP-induced toxicity has not been observed in humans. Increases in plasma F- levels after sevoflurane anaesthesia, including multiple exposure to this agent, have not been associated with nephrotoxicity, impairment of renal concentrating function or worsening of renal impairment in humans. Nephrotoxicity induced by pentafluoroisopropenyl fluoromethyl ether (also known as ‘Compound A’ — the principal byproduct from degradation of sevoflurane by carbon dioxide absorbents) has not been observed in humans, although only a limited number of patients exposed to sevoflurane have received the agent via anaesthetic circuits incorporating carbon dioxide absorbents in low-flow systems.Sevoflurane, like other inhalation anaesthetic agents, can trigger malignant hyperthermia and, to date, this syndrome has occurred in 3 Japanese patients.Nitrous oxide and opioids reduce the MAC of sevoflurane. In children, the decrease in MAC is not proportional to the concentration of nitrous oxide.The pharmacological activity of neuromuscular blocking agents is potentiated by sevoflurane, which is also synergistic with lidocaine (lignocaine) and procainamide.Sevoflurane is recommended for induction and/or maintenance of general anaesthesia in adult and paediatric patients undergoing inpatient or outpatient surgical procedures.Inspired concentrations of sevoflurane 1 to 8% can be used for induction of anaesthesia, with or without pre-anaesthetic medication. Anaesthesia can also be induced by rapid inhalation of sevoflurane 6 to 8%. Concentrations of sevoflurane 1.5 to 3% without nitrous oxide (or 0.5 to 3% with nitrous oxide) can be used for maintenance of surgical anaesthesia. At present, because of limited clinical experience with sevoflurane in low-flow systems, fresh gas flow rates <2 L/min are not recommended in a circle absorber system.Sevoflurane should not be administered to patients with known or suspected genetic susceptibility to malignant hyperthermia.