British Journal of Anaesthesia 1996; 76: 435–445
REVIEW ARTICLE
Sevoflurane—a long-awaited volatile anaesthetic
I. SMITH, M. NATHANSON AND P. F. WHITE
In evaluating any newly introduced anaesthetic, it is
worth comparing its properties with those of a
theoretical “ideal” volatile agent which would have
a low solubility in blood to allow for rapid equilibration between delivered concentration and the
effect site in the central nervous system (CNS). This
would facilitate rapid induction of anaesthesia, allow
easier titration of anaesthetic dose to the desired
effect during the maintenance period and permit
rapid emergence and recovery at the end of anaesthesia. An ideal anaesthetic should also be easy to
deliver and devoid of perioperative side effects and
toxicity.
Desflurane (Suprane) was the last new volatile
anaesthetic introduced into clinical practice in 1992.
Although relatively insoluble and easy to titrate
during the maintenance period, desflurane is not a
practical induction agent because of its irritant effects
on the airway. The theoretically improved control
over depth of anaesthesia during the maintenance
period afforded by desflurane is complicated by its
tendency to induce cardiovascular stimulation when
the delivered concentration is increased rapidly [16,
85). In addition, desflurane requires unusually
complex vaporizer technology for its administration.
Sevoflurane has been in clinical use in Japan since
1990 and has recently gained approval for use in
Great Britain, the United States and much of the rest
of the world. This review considers the clinical
properties of sevoflurane in relation to existing
volatile anaesthetics (table 1) and the “ideal” volatile
agent.
Sevoflurane (fig. 1) was first synthesized in 1968 by
Regan at Travenol Laboratories, Illinois, while he
was investigating a series of halomethyl polyfluoroisopropyl ethers. The compound was initially
reported by his co-workers in 1971 [83]. The group
at Travenol went on to describe the results of animal
experiments which characterized the important clinical properties of the new anaesthetic [84]. Development was later to be impeded by apparent toxic
effects, eventually shown to be a consequence of
flawed experimental design [36]. The first volunteer
trials, reported by Holaday and Smith in 1981, were
encouraging [37]. However, further work was slow
because of the problems of biotransformation and
stability with soda lime. The volatile anaesthetic
isoflurane was felt at the time to be a more suitable
drug for commercial development [8]. Baxter
Travenol sold the rights to sevoflurane to Anaquest
(Ohmeda/BOC), who in turn sold these to Maruishi
Company. Maruishi continued research and development, eventually releasing sevoflurane for
clinical use in Japan in May 1990. By the end of
1993, an estimated 1 million patients had received
sevoflurane [18]. The continuing search for an
inhaled agent with rapid induction, emergence and
recovery characteristics has stimulated the recent reexamination of sevoflurane. The considerable resources necessary to introduce another volatile
anaesthetic into the western marketplace have resulted in the purchase and subsequent development
of sevoflurane by a multinational company, namely
Abbott Laboratories.
History of sevoflurane
Physical properties of sevoflurane
Research to develop a safe, non-inflammable inhaled
anaesthetic agent began in the 1930s when chemists
discovered that the substitution of fluorine for other
halogens “lowers the boiling point, increases stability, and generally decreases toxicity” [5]. This
work was continued by McBee, who used his
knowledge of fluorine chemistry gained from working on the “Manhattan” atomic bomb project, to
investigate a number of fluorine-containing compounds, none of which was eventually suitable for
clinical use. In 1951, Suckling synthesized halothane, and soon the search for other clinically useful
fluorine-containing anaesthetics began in earnest.
Sevoflurane is related structurally to isoflurane and
enflurane (fig. 1), and not surprisingly shares many
of the physical properties of these dugs; (interestingly, desflurane is even more closely related
structurally to isoflurane, yet desflurane has quite
unique physical properties). Sevoflurane has a boiling point of 58.6 ⬚C and a saturated vapour pressure
(SVP) of 160 mm Hg at 20 ⬚C. These values are
similar to those of halothane, enflurane and isoflurane. The blood:gas partition coefficient of
sevoflurane is 0.69 [78]. This is approximately half
(Br. J. Anaesth. 1996; 76: 435–445)
Key words
Anaesthetics volatile, sevoflurane.
IAN SMITH, BSC, MB, BS, FRCA, Keele University, North
Staffordshire Hospitals, Newcastle Road, Stoke-on-Trent,
Staffordshire ST4 6QJ. MICHAEL NATHANSON, MB, BS, MRCP, FRCA,
Queen’s Medical Centre, University of Nottingham, Nottingham.
PAUL F. WHITE, PHD, MD, FANZCA, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Correspondence to I.S.
436
British Journal of Anaesthesia
Table 1 Comparison of sevoflurane with existing volatile anaesthetics (scale: 0 worst, best)
Property
Halothane
Enflurane
Isoflurane
Desflurane
Sevoflurane
Induction characteristics
Haemodynamic stability
Respiratory irritation
Ease of titration
Emergence characteristics
Postoperative side effects
Potential toxicity/metabolism
Cost (at low flow)
0
0
0
0
Figure 1 Chemical structure of sevoflurane compared with the
other available volatile anaesthetic agents.
that of isoflurane (1.43) and compares favourably
with the blood:gas solubility of both desflurane
(0.42) and nitrous oxide (0.44). The low blood:gas
solubility of sevoflurane should provide for rapid
induction of, and recovery from, anaesthesia.
The minimum alveolar concentration (MAC) of
sevoflurane is reported to be between 1.71 % [43]
and 2.05% [73]. This value was reduced to 0.66 % in
an adult population by addition of approximately
60 % nitrous oxide [43]. The MAC value of
sevoflurane, and therefore the typical maintenance
concentration, is almost identical to that of enflurane.
The MAC for sevoflurane, in common with other
anaesthetics, is somewhat higher in children. Typical
values are 2.6 % (reduced to 2.0 % by nitrous oxide)
in children and 3.3 % in neonates [51].
Clinical properties of sevoflurane
INDUCTION OF ANAESTHESIA
While it is unlikely that inhalation induction of
anaesthesia will replace the use of rapid-acting i.v.
induction agents, insertion of an i.v. needle (or
cannula), and even injection of i.v. anaesthetics (e.g.
methohexitone, etomidate, propofol), may cause
considerable discomfort, especially in children.
While the use of local anaesthetics can reduce this
discomfort, poor veins and a lack of co-operation can
make i.v. induction of anaesthesia impractical for
many patients. Induction of anaesthesia by mask
may be preferable in some of these patients, assuming
that this could be accomplished rapidly and
smoothly. Finally, inhalation induction may be
desirable on those occasions when there is a danger
of airway obstruction following rapid loss of consciousness.
Anaesthetic vapours with a low blood:gas solubility coefficient should permit rapid induction of
anaesthesia as the alveolar concentration equilibrates
rapidly with the inspired (delivered) concentration.
Based on solubility characteristics, inhalation induction should take longest with halothane, and
become increasingly more rapid with enflurane,
isoflurane, sevoflurane and desflurane, respectively.
However, the ability to deliver an inspired concentration sufficiently high to induce anaesthesia is
limited by the effects of the anaesthetic vapour on the
patient’s airway. In practice, agents such as enflurane, isoflurane and desflurane are irritating to the
airway, resulting in coughing, breath-holding, excessive salivation and even laryngospasm. As a result,
the rate of equilibration is reduced and induction is
slower than would be predicted from the blood : gas
solubility value alone. For example, inhalation
induction with desflurane resulted in airway complications in 30–40 % of healthy, day-case patients,
with occasional prolonged or failed inductions [82],
while desflurane appears to be even more irritant in
children, with up to 58 % of cases coughing [92].
In contrast, sevoflurane is pleasant-smelling
and relatively non-irritating to the airways, permitting a high inspired concentration to be
inhaled without side effects or discomfort. When a
group of unpremedicated patients undergoing major
gynaecological surgery were allowed to breathe 5 %
sevoflurane in an oxygen–nitrous oxide mixture,
anaesthesia was induced within 10925 s [76]. Anaesthesia was induced successfully in all 25 patients,
none of whom coughed, experienced apnoea, laryngospasm or other airway-related side effects. Yurino
and Kimura studied a group of unpremedicated
volunteers in whom anaesthesia was induced by
breathing oxygen–nitrous oxide to which sevoflurane
was added, beginning at 0.5 % and increasing to a
maximum of 4.5 % in increments of 0.5 % every 3–4
breaths [90]. Using this traditional (stepwise) technique, anaesthesia was induced in 10819 s. Laryngospasm and breath-holding were not observed, and
while coughing occurred in 12.5 % of subjects, this
was described as “mild” and did not adversely affect
haemoglobin oxygen saturation [90]. When 4.5 %
Sevoflurane
sevoflurane was administered to a similar group of
volunteers as a single, vital capacity breath, loss of
consciousness was achieved in only 5410 s, while
the incidence of coughing was reduced to 6.3 % [90].
Compared with isoflurane, vital capacity single
breath induction with 1.7 MAC of sevoflurane was
more rapid (12024 vs 14539 s) and associated
with significantly fewer respiratory complications
[89]. For example, coughing occurred in 43 % of
patients breathing isoflurane compared with none
with sevoflurane. In addition, one patient (4.8 %) in
the isoflurane group developed laryngospasm, and
the technique was abandoned in another patient
because of excessive involuntary movements [89].
The majority of patients (60 %) found sevoflurane to
be “pleasant smelling”, while 75 % found isoflurane
“unpleasant” [89]. The use of even higher concentrations of sevoflurane (up to 8 % on the newest
vaporizers) permits even more rapid induction of
anaesthesia. Using 7.5 % sevoflurane as a single vital
capacity breath allowed loss of consciousness in
4116 s [91]. However, coughing was more common
(25 %) when 7.5 % sevoflurane was used in a tidal
breathing induction technique, resulting in slower
induction of anaesthesia (5213 s) [91].
Inhalation induction is practised more commonly
in children than in adults, and halothane has been
considered the drug of choice. Early clinical experience from Japan suggested that inhalation induction with sevoflurane was “smoother” compared
with halothane in children [61]. Most early investigations have reported inhalation induction times in
children to be similar, irrespective of whether
sevoflurane or halothane were administered [63, 67].
However, in at least one investigation, the average
concentration of halothane administered was considerably higher (in terms of MAC-multiples) compared with sevoflurane, which may have distorted
the results obtained [63]. Lerman and colleagues
achieved an average time to loss of the eyelash reflex
of 54 s in infants (: 1 yr) and 73–80 s in children
aged 3–12 yr when a traditional induction sequence
was used in a non-comparative evaluation [51].
Sevoflurane was administered in oxygen, commencing at 1.5 %, and increased by 1.5 % every 3 breaths.
Premedication was not administered, and the incidence of airway-related complications was very low
in all age groups [51]. Continuing the induction
sequence, tracheal intubation was possible with deep
sevoflurane anaesthesia after 4–5 min [51]. Smooth
and uneventful tracheal intubation requires a sevoflurane concentration approximately 33 % above the
MAC value [39]. However, insertion of the less
stimulating laryngeal mask airway is possible at 1
MAC of sevoflurane [80].
Recent investigations in the paediatric population
have demonstrated more rapid induction of anaesthesia with sevoflurane compared with halothane
[1, 20, 32, 81]. For example, children receiving a
stepwise induction technique lost their eyelash reflex
in 1.7 min with sevoflurane compared with 2.2 min
with halothane (P : 0.001) [1]. Similarly, Epstein
and colleagues completed induction of anaesthesia in
children in 9731 s using sevoflurane compared
with 12036 s with halothane (P : 0.05) [20]. Even
437
more rapid induction was reported in children aged
1–12 yr by Greenspun and co-workers [32]. Loss of
the eyelash reflex occurred in 1.00.2 min with
sevoflurane compared with 1.40.4 min with halothane (P 0.0002), using a similar induction technique to the two previous studies [32]. Taivainen
and colleagues also achieved induction times of
1 min with sevoflurane, administering concentrations up to 7 % [81]. Significantly more children
rated their induction with sevoflurane as “pleasant”
compared with halothane (56 % vs 20 %) and
expressed a preference for a similar technique in the
future (76 % vs 44 %) [81]. Although Sarner and
colleagues did not detect any difference in induction
times when comparing sevoflurane in oxygen with
sevoflurane–nitrous oxide and halothane–nitrous
oxide, omission of nitrous oxide increased the
incidence of excitatory activity on induction with
5–35 % sevoflurane [72].
Therefore, sevoflurane appears to be a practical
and well-tolerated inhalation induction agent in all
age groups investigated to date. In children, it will
challenge halothane as the inhalation induction agent
of choice. Although the use of sevoflurane for
inhalation induction in adults is likely to be more
limited, it provides a viable alternative to i.v.
induction techniques. Before sevoflurane can be
recommended for use in association with the “difficult airway”, its safety in partial airway obstruction
and in patients with irritable airways needs to be
investigated.
MAINTENANCE OF ANAESTHESIA
Anaesthetists are familiar with the titration of volatile
agents to maintain an appropriate “depth” of
anaesthesia. The rapidity with which alteration in
the anaesthetic vaporizer dial setting results in a
change in the level of anaesthesia is determined by
the difference between the anaesthetic concentration
delivered by the vaporizer and the concentration in
the CNS [18]. The ratio of these two concentrations
is influenced by the extent of rebreathing, which in
turn depends on the type of anaesthetic circuit and
the total fresh gas flow, in addition to anaesthetic
uptake from the alveoli. For a given degree of
rebreathing, the less soluble volatile agents allow for
more rapid and precise control of anaesthetic depth,
as their uptake from the alveoli is less than for agents
with a higher blood:gas solubility. Although large
alterations in the administered anaesthetic concentration may induce airway irritation in lightly
anaesthetized, spontaneously breathing patients, this
is rarely a problem after i.v. induction of anaesthesia
or when neuromuscular blockers and controlled
ventilation are used.
As the ratio between the delivered and alveolar
concentration of sevoflurane is four times less than
that achieved with isoflurane at a given fresh gas
flow, greater precision in the control of anaesthetic
depth should be achieved with this new agent [18].
Because it is even less soluble than sevoflurane,
desflurane results in a delivered : alveolar concentration difference that is five times smaller than
isoflurane. However, rapid increases in the delivered
438
concentration of desflurne can induce transient
increases in heart rate, arterial pressure, or both [16,
85]. While these changes do not appear to pose a
significant hazard to most patients, the phenomenon
may deter anaesthetists from adjusting the depth of
anaesthesia as rapidly as the physical properties of
desflurane would allow in patients with pre-existing
cardiovascular disease. In contrast, these excitatory
phenomena are not observed when the level of
sevoflurane anaesthesia is adjusted rapidly [16].
The pharmacodynamic effects of sevoflurane on
the various organ systems appear to be similar to
those of other commonly used halogenated ethers.
Sevoflurane produces dose-dependent ventilatory
depression [14] and also reduces respiratory drive in
response to hypoxia and increases in carbon dioxide
partial pressure, comparable with levels achieved
with other ether anaesthetics. It relaxes bronchial
smooth muscle, although perhaps not as effectively
as halothane. Sevoflurane decreases mean arterial
pressure predominantly through decreased peripheral resistance, with cardiac output being well
maintained over the normal anaesthetic maintenance
range. A degree of myocardial depression occurs at
higher concentrations, as a result of an effect on
calcium channels [33]. Sevoflurane does not sensitize
the myocardium to the arrhythmogenic effects of
catecholamines [65]. Sevoflurane has little effect on
normal myocardial blood flow, is a less potent
coronary arteriolar dilator than isoflurane [35], and
does not appear to cause “coronary steal” [44]. In
contrast with other halogenated ethers, sevoflurane
appears to be associated with a lower heart rate [16,
26], which helps to reduce myocardial oxygen
consumption and assists myocardial perfusion. In
addition, the lack of an anaesthetic-specific increase
in heart rate may facilitate the determination of
“depth of anaesthesia”.
Sevoflurane has CNS effects similar to those of
isoflurane and desflurane. Intracranial pressure increases at high inspired concentrations of sevoflurane
(analogous to isoflurane); however, this effect is
minimal over the 0.5–1-MAC range [74]. Sevoflurane is not associated with convulsive or epileptic
activity [74]. Renal and hepatic blood flow are well
preserved with sevoflurane, and organ toxicity has
not been observed to date. There are limited data on
sevoflurane in the obstetric population [30]. However, sevoflurane appears to have similar uterine
effects to isoflurane, and no differences in maternal
or fetal outcome were observed when equianaesthetic
concentrations (0.5 MAC) of these two agents were
compared during elective Caesarean section [30].
Sevoflurane produces clinically useful neuromuscular block and potentiates neuromuscular blockers to
a similar degree to other anaesthetics. It can trigger
malignant hyperpyrexia in susceptible individuals,
and at least four cases have been reported to date
[15].
EMERGENCE AND RECOVERY CHARACTERISTICS
The low blood:gas solubility of sevoflurane should
permit rapid elimination from the CNS. When
sevoflurane and isoflurane were compared as an-
British Journal of Anaesthesia
aesthetic maintenance agents after induction of
anaesthesia with midazolam and thiopentone in
healthy patients undergoing elective operations, the
average times from end of anaesthesia to eye opening
on command were 18.62.0 min for isoflurane and
7.50.5 min for sevoflurane (P : 0.001) [26]. When
propofol was used as the induction agent before
operations lasting approximately 2.5 h, emergence
from
sevoflurane–nitrous
oxide
anaesthesia
(4.12.2 min) was still significantly more rapid
compared
with
isoflurane–nitrous
oxide
(6.72.2 min) [76].
Recovery from the newer volatile anaesthetic
agents appears relatively unaffected by the duration
of anaesthetic exposure, whereas recovery from more
soluble agents increases in direct proportion to the
length of anaesthetic administration [19]. While
emergence times from sevoflurane remained reasonably constant over a range of anaesthetic durations
from 1–7 MAC-h in healthy patients undergoing
elective surgery, emergence times from isoflurane
demonstrated a five-fold difference over a similar
range of exposure times [26]. Nevertheless, Quinn
and colleagues failed to detect any difference in
emergence times between sevoflurane and isoflurane
after operations lasting 3 h [68]. However, sevoflurane was associated with faster emergence compared with isoflurane using a similar technique for
gynaecological operations of shorter duration, suggesting that the use of intraoperative opioid analgesics may have masked differences between the two
groups in the former study, which also involved very
small numbers of patients [68].
Rapidly eliminated anaesthetic agents are used
most commonly for day-case anaesthesia, where
rapid, clear-headed recovery may allow for earlier
discharge of patients. In a randomized (non-blinded)
investigation, Fredman and colleagues [23] compared a variable rate continuous infusion of propofol
with sevoflurane for maintenance of anaesthesia in
combination with nitrous oxide after induction of
anaesthesia with propofol in a group of patients
undergoing day-case gynaecological or ENT operations. The investigation also included a third group
of patients who received sevoflurane–nitrous oxide
for both induction and maintenance of anaesthesia.
There were no significant differences in early or
intermediate recovery times between the three
treatment groups (table 2). Pencil and paper tests
also failed to detect any significant differences
between the three treatment groups in terms of
postoperative sedation or psychomotor impairment
[23]. In a similar investigation during day-case
surgery procedures lasting approximately 90 min,
emergence from sevoflurane anaesthesia required
10.46.5 min compared with 11.011.0 min after
propofol anaesthesia [38]. In common with the study
of Fredman and colleagues [23], both groups of
patients received propofol for induction and nitrous
oxide for maintenance of anaesthesia [38].
When sevoflurane was compared with desflurane
for maintenance of anaesthesia in a group of women
undergoing day-case laparoscopic sterilization, mean
time to eye opening after desflurane (4.8 (SD 2.4) min)
occurred significantly earlier compared with sevo-
Sevoflurane
439
Table 2 Recovery times (mean (SD)) for the three different anaesthetic techniques after day-case anaesthesia
(propofol–propofol/nitrous oxide (N2O), propofol–sevoflurane/nitrous oxide and sevoflurane/nitrous oxide).
Adapted from Fredman and colleagues [23], with permission
Number (n)
Anaesthesia time (min)
Eye opening (min)
Extubation (min)
Verbal commands (min)
Orientation (min)
Ambulation (min)
Fit for discharge (min)
Future preference (%)
Propofol:
propofol–N2O
Propofol:
sevoflurane–N2O
Sevoflurane–N2O:
sevoflurane–N2O
50
74 (29)
9 (4)
10 (5)
11 (5)
13 (7)
146 (71)
183 (82)
98
48
78 (28)
9 (5)
11 (6)
12 (7)
13 (7)
156 (73)
184 (82)
96
48
82 (26)
10 (5)
11 (6)
12 (6)
15 (10)
165 (67)
207 (65)
97
Table 3 Comparison of emergence and recovery times (mean
(SD)) in day-case patients undergoing gynaecological
laparoscopies with a propofol–sevoflurane/nitrous oxide (N2O)
or a propofol–desflurane/nitrous oxide technique. * P < 0.05
compared with sevoflurane group. Adapted from Nathanson
and colleagues [64], with permission
Propofol:
Propofol:
sevoflurane–N2O desflurane–N2O
Number (n)
Anaesthesia time (min)
Eye opening (min)
Extubation (min)
Obey commands (min)
Orientation (min)
Transfer to phase II
recovery (min)
Ambulation (min)
Discharge (min)
21
79 (17)
7.8 (3.8)
8.2 (3.2)
10.2 (5.3)
11.2 (5.1)
41 (11)
124 (37)
193 (54)
21
92 (31)
4.8 (2.4)*
5.1 (3.2)*
6.4 (4.7)
9.3 (5.1)
51 (20)
126 (36)
201 (90)
Figure 2 Heart rate (HR) values (mean, SEM) before
anaesthesia (Pre) and after induction of anaesthesia and skin
incision (Inc), in patients anaesthetized with propofol–
desflurane–nitrous oxide ( ) or propofol–sevoflurane–
nitrous oxide ( ). * P : 0.05 compared with desflurane group.
Modified from Nathanson and colleagues [64], with permission.
flurane (7.8 (3.8) min) (table 3) [64]. In this preliminary investigation, anaesthesia was induced with
propofol and fentanyl, and the volatile anaesthetic
agents were titrated to maintain haemodynamic
stability in an attempt to ensure comparable levels of
anaesthesia (fig. 2) [64]. Despite more rapid emergence from desflurane anaesthesia, subsequent recovery end-points (e.g. orientation, ambulation and
hospital discharge) did not differ between the two
anaesthetic groups. There were also no differences in
subjective feelings or psychomotor function during
the recovery period, suggesting that any differences
between these two anaesthetic agents are of minimal
clinical significance when used for day-case anaesthesia [64].
Sevoflurane and desflurane have also been compared as anaesthetic maintenance agents in children
[86]. In this study, anaesthesia was induced in both
groups with halothane, which was then discontinued
and the maintenance anaesthetic introduced. In
common with the findings of Nathanson and colleagues, [64] in adults, emergence was delayed in
children anaesthetized with sevoflurane compared
with desflurane. However, the more rapid emergence
after desflurane (52 min vs 114 min) was associated with a significantly higher incidence (55 %) of
agitation and excitement in these children [86].
Although early recovery was also delayed after
sevoflurane (197 min vs 114 min for desflurane),
later recovery events were similar after both maintenance anaesthetics [86].
When halothane is used for induction of anaesthesia in children, it is often used subsequently as
the anaesthetic maintenance agent. In comparison
with halothane, the use of sevoflurane for induction
and maintenance of anaesthesia permitted significantly more rapid eye opening (4.31.1 vs
9.52.7 min) after the end of anaesthesia [63]. The
difference in recovery times persisted throughout the
postoperative period, and allowed the children who
had received sevoflurane to be discharged home
almost 50 min earlier than those exposed to halothane (8823 vs 13721 min, respectively) [63].
The postoperative effects of halothane may be
prolonged. In one group of paediatric inpatients,
psychomotor performance on the Trieger dot test
was significantly better for at least 6 h after sevoflurane anaesthesia compared with halothane [81].
Epstein and colleagues reported significantly faster
emergence from sevoflurane anaesthesia compared
with halothane (9.92.9 min vs 12.54.7 min),
despite a higher MAC-multiple of sevoflurane
concentration at the end of anaesthesia [20]. Similar
findings were observed in another group of children
undergoing minor surgical procedures with halothane or sevoflurane anaesthesia [67]. Tracheal
extubation was possible 5 min earlier in children
anaesthetized with sevoflurane compared with halothane (P : 0.01), while response to commands
occurred 15 min earlier after sevoflurane [67]. However, a rigid hospital procedure prevented differences
in discharge times from being detected in this
440
investigation [67]. After ENT operations, discharge
times did not differ following sevoflurane or halothane anaesthesia, despite more rapid awakening and
early recovery with sevoflurane [32]. However, the
requirements for postoperative opioid analgesia may
have masked differences between the groups, while
hospital discharge may also have been delayed by a
relatively high incidence of postoperative vomiting
in both groups of children [32]. In contrast, another
clinical investigation demonstrated earlier hospital
discharge after anaesthesia with sevoflurane compared with halothane, despite similar emergence
times with both agents [72].
Metabolism and toxicity
In contrast with other recently introduced volatile
anaesthetics, sevoflurane is a comparatively unstable
molecule. It undergoes a moderate degree of metabolism (approximately 5 %) [6] and also breaks down
in the presence of soda lime and Baralyme at elevated
temperatures [79]. Both processes result in potentially toxic products. However, unlike other
anaesthetic ethers, sevoflurane does not possess a
CF2H group, and so (similar to halothane) does not
result in the production of carbon monoxide in
association with excessively dry carbon dioxide
absorbants [22].
Sevoflurane is metabolized by the liver to produce
hexafluoroisopropanol and inorganic fluoride ions
[24, 37, 50]. In humans, up to 5 % of the administered dose of sevoflurane undergoes metabolism
[48, 75], catalysed by the 2E1 isoform of cytochrome
P450 [45, 49]. Studies in animals have demonstrated
that this enzyme can be induced by phenobarbitone
[11, 54], isoniazid [69] and ethanol [55], leading to
increased serum inorganic fluoride concentration
and urinary excretion of fluoride ions.
British Journal of Anaesthesia
Figure 3 Concentrations of serum fluoride ions (mean, SEM)
detected before induction of anaesthesia (Preop.), 30 min after
induction (Begin surgery), immediately after the end of
anaesthesia (End surgery), and 1 h and 24 h after operation in
the propofol-isoflurane ( ), propofol-sevoflurane ( ) and
sevoflurane-sevoflurane ( ) groups. * P : 0.05 compared with
propofol-isoflurane group. Modified from Smith, Ding and
White [76], with permission.
Figure 4 Correlation between serum fluoride ions measured
immediately after discontinuation of anaesthesia and anaesthetic
exposure in MAC-h for patients receiving sevoflurane for
maintenance of anaesthesia (r 2 0.45). Modified from Smith,
Ding and White [76], with permission.
RENAL EFFECTS
Clinical experience with methoxyflurane suggested
that renal impairment could occur if a “threshold”
serum fluoride concentration of 50 ␮mol litre1 was
exceeded [13], although clinically evident renal
dysfunction was rarely observed at concentrations
less than 80 ␮mol litre1 [58]. After administration of
sevoflurane anaesthesia for 1 h, Holaday and Smith
found a mean serum fluoride concentration of
22 ␮mol litre1 in six volunteers [37]. Smith, Ding
and White measured serum fluoride concentrations
in 50 patients receiving sevoflurane anaesthesia for
gynaecological surgery of 135 min mean duration
[76]. Fluoride concentrations increased rapidly after
exposure to sevoflurane (fig 3), and reached a mean
concentration of 25 ␮mol litre1 at the end of operation. Frink and colleagues reported a mean peak
plasma fluoride concentration of 29.3 ␮mol litre1 2 h
after the end of surgical anaesthesia with 1–7
MAC-h of sevoflurane [24]. Similarly, Newman and
colleagues found a mean peak fluoride ion concentration of less than 25 ␮mol litre1 after
50–350 min of sevoflurane anaesthesia (mean exposure 0.8 MAC-h) in 25 patients [66]. The highest
individual fluoride concentration recorded in this
investigation was 40.4 ␮mol litre1 [66]. Unlike other
fluoride-producing
volatile
anaesthetics
(e.g.
methoxyflurane, halothane, enflurane), fluoride
concentrations in morbidly obese patients exposed to
sevoflurane were no higher than those detected in
patients of normal weight [27].
A positive correlation has been demonstrated
between peak concentrations of fluoride ions and
duration of exposure to sevoflurane (fig. 4). After 1.1
MAC-h of sevoflurane, Shiraishi and Ikeda found
that the mean peak serum inorganic fluoride concentration was only 19.3 ␮mol litre1 [75]. In another
study, plasma concentrations of inorganic fluoride
were less than 50 ␮mol litre1 in all patients receiving
less than 2 MAC-h of sevoflurane, whereas peak
plasma concentrations exceeded 50 ␮mol litre1 in
five patients receiving an average of 4.7 MAC-h [24].
Smith, Ding and White reported a plasma fluoride
concentration of 51.4 ␮mol litre1 after 7.9 MAC-h
of sevoflurane [76]. The peak concentration of
inorganic fluoride after sevoflurane is similar to that
after enflurane anaesthesia [57]. In a volunteer study
comparing the effects of prolonged anaesthesia with
sevoflurane or enflurane on renal concentration
Sevoflurane
441
Figure 5 Degradation products of sevoflurane in soda lime under experimental conditions (艌65 ⬚C).
function, the mean peak plasma inorganic fluoride
concentration was 47 ␮mol litre1 after more than 9
MAC-h of sevoflurane anaesthesia [28]. Although
three of the seven volunteers had a peak plasma
fluoride concentration in excess of 50 ␮mol litre1,
there was no demonstrable impairment of renal
concentrating ability in the sevoflurane group [28].
In contrast, two of the seven volunteers in the
enflurane group had reduced maximal urinary osmolality in response to desmopressin (compared with
their pre-anaesthesia values) despite a mean peak
plasma inorganic fluoride concentration of only
23 ␮mol litre1 [28]. In another volunteer study
involving prolonged anaesthesia, higher peak serum
fluoride ions were achieved after 3, 6 and 9 MAC-h
of sevoflurane than after similar durations of exposure to enflurane [62]. However, the area under
the fluoride concentration–time curves was similar
for comparable exposures to either anaesthetic
(because of the lower solubility of sevoflurane), and
no volunteer demonstrated any impairment of urine
concentrating ability [62].
No alterations in urinary enzymes or postoperative
renal function were detected after sevoflurane anaesthesia (0.8–2 %) lasting 9–10 h, despite a mean
peak serum fluoride concentration in excess of
50 ␮mol litre1 [56]. In a small (n 8) group of
patients exposed to prolonged sevoflurane anaesthesia and in whom peak serum fluoride concentration exceeded 50 ␮mol litre1, a slight reduction in
urine concentrating ability in response to vasopressin
was observed compared with a similar group of
patients anaesthetized with isoflurane [34]. However,
this difference was not statistically significant and, in
addition, patients anaesthetized with sevoflurane had
also received more perioperative fluid, which may
have affected urine concentrating ability [34]. The
nephrotoxic effects of sevoflurane and enflurane have
recently been compared in patients with chronically impaired renal function, defined as a serum
creatinine concentration of 艌1.5 mg dl1 (130 ␮mol
litre1) [10]. Sevoflurane and enflurane resulted
in peak serum fluoride concentrations of 25
and 13 ␮mol litre1, respectively, but neither agent
resulted in alterations in postoperative laboratory
tests of renal function or in deterioration in renal
function [10]. Similar findings were obtained in
another preliminary investigation in patients with
renal insufficiency (serum creatinine 130–260 ␮mol
litre1), in whom 0.8–6.5 MAC-h of sevoflurane
anaesthesia did not alter serum creatinine or creatinine clearance [53].
It would appear that renal toxicity is not an
inevitable consequence of exceeding a “threshold”
serum concentration of fluoride ions. Indeed, we
must be careful to avoid “applying a fluoride
hypothesis developed to explain methoxyflurane
nephrotoxicity non-selectively to all anesthetics
without supporting data” [47]. The apparent lack of
renal toxicity with sevoflurane in humans may be
related to its relative insolubility and site of metabolism. Although the rate of in vitro hepatic microsomal metabolism of sevoflurane may be similar to
that of methoxyflurane, the rapid elimination of
sevoflurane reduces the total amount of drug available for in vivo metabolism [12], resulting in a rapid
decrease in organic fluoride concentration after
sevoflurane administration, and probably preventing
exposure to fluoride ions for a long enough duration
to lead to clinically detectable toxicity [24]. Recent
evidence from Kharasch, Hankins and Thummel
[46] suggested that intrarenal production of fluoride
ions may be more important in the aetiology of
methoxyflurane-induced toxicity than peak serum
fluoride concentrations [7].
HEPATIC EFFECTS
The other major breakdown product of sevoflurane
metabolism is hexafluoroisopropanol, an organic
fluoride molecule which is excreted in the urine as a
glucuronide conjugate [37, 41, 54]. Although this
molecule is potentially hepatotoxic, conjugation of
hexafluoroisopropanol occurs so rapidly [48] that
clinically significant liver damage seems theoretically
impossible [8]. Although the production of both
inorganic fluoride ions and hexafluoroisopropanol
can be reduced substantially by the selective cytochrome P450 2E1 inhibitor, disulfiram [45], this is
unlikely to be a necessary clinical strategy.
442
INTERACTION WITH CARBON DIOXIDE ABSORBANTS
Another concern with sevoflurane is its interaction
with carbon dioxide absorbants. Sevoflurane is
absorbed and degraded by both soda lime and
Baralyme [2, 29, 52, 79, 84, 87]. When sevoflurane is
mixed with soda lime, sealed in a flask and heated, a
total of five breakdown products are produced (fig.
5). These have been designated as compounds A, B,
C, D and E [8]. However, only compound A (and to
a lesser extent compound B) is produced under
conditions likely to be encountered clinically. Concern has been raised because these products are toxic
in rats. Morio and colleagues determined that the
concentration of compound A required to kill 50 %
of rats (LC50) after 1 h exposure was 1090 ppm and
1050 ppm for males and females, respectively [59].
The LC50 for compound A was reduced to approximately 400 ppm after 3 h exposure [31, 59]. The
toxicity produced by compound A in rats primarily
involves renal, hepatic and cerebral damage.
If it is assumed that compound A produces
similarly toxicity in humans, are patients likely to be
at significant risk if sevoflurane is delivered from a
circle absorber breathing circuit? The evidence
suggests that the concentration of compound A
achieved in clinical practice is well below the
concentration which is toxic to animals. Bito and
Ikeda exposed patients to similar concentrations of
sevoflurane at various fresh gas flows [3]. Compound
A was the only sevoflurane degradation product
detected at any of the three fresh gas flow rates
examined. The mean maximal concentrations of
compound A detected were 19.74.3, 8.12.7 and
2.11.0 ppm at 1, 3 and 6 litre min1, respectively
[3]. The concentration of compound A remained
relatively constant between 1 and 3 h of exposure to
sevoflurane at all three flow rates [3]. Frink and
colleagues examined sevoflurane degradation products during low-flow (770 ml min1) anaesthesia
using either soda lime or Baralyme as the absorbent
[29]. All patients received an anaesthetic concentration of sevoflurane for at least 3 h. As in the
previous study, compound A was the only breakdown product detected within the circle system. The
mean maximal concentration of compound A was
8.22.7 ppm when soda lime was used as the
absorbant and 20.38.7 ppm with Baralyme [29].
The highest concentration of compound A detected
in any individual patient was 15.2 ppm with soda
lime and 60.8 ppm with Baralyme [29]. Concentrations of compound A increased progressively over
the first 4 h of anaesthesia and then declined with
continuing exposure to sevoflurane [29]. Similar
findings were obtained in another study using even
lower gas flows (350 ml min1) in association with
soda lime, in which 17 patients received an average
of 2.3 MAC-h of sevoflurane [88]. The mean
concentration of compound A was found to be
6 ppm, and the highest recorded value was 22 ppm
[88]. After more prolonged exposure, the mean
maximum concentration of compound A was
7.61.0 ppm, with the highest individual value of
14.1 ppm occurring after 5 h exposure to sevoflurane
at a flow of 5 litre min1 [40]. Even after 9 h exposure
British Journal of Anaesthesia
to 1–1.2 MAC of sevoflurane anaesthesia at 5
litre min1 in volunteers, peak compound A concentrations averaged only 7.61.0 ppm, with the
maximal concentration occurring after 2 h and
remaining constant or declining thereafter [25].
During prolonged exposure (up to 18 h) at low fresh
gas flows (1 litre min1), the mean peak concentrations of compound A achieved were 23.6 ppm
and 32.0 ppm using soda lime and Baralyme,
respectively [4]. The highest concentration of compound A detected in any patient was 37.4 ppm when
soda lime was used as the absorbant, and 41.2 ppm
with Baralyme. Compound A concentrations peaked
in the first 2–4 h, remained relatively constant from
4–10 h and then declined with continuing anaesthesia
[4]. Compound B was detected in small quantities
(艋 0.2 ppm) in two of the patients in the Baralyme
group, but was not found when soda lime was used
as the absorbant for prolonged anaesthesia [4].
In a totally closed system, a mean concentration
of 19.55.4 ppm of compound A was detected
after 1 h [2]. The concentration of compound A remained relatively constant over the next 4 h and
subsequently decreased slightly with continuing
sevoflurane anaesthesia. The highest concentration
detected in any patient was 30 ppm [2]. Compound
B was also detected in 70 % of patients during
closed circuit anaesthesia, although the concentration
did not exceed 1.5 ppm in any patient [2].
Degradation of sevoflurane appears to be
temperature-dependent [59, 79, 87]. The higher concentration of compound A which is produced by
interaction with Baralyme probably occurs as a
consequence of the higher temperature attained in
this absorbant compared with soda lime [29].
Similarly, increased minute ventilation and greater
carbon dioxide production both increase absorbant
temperature, and hence production of compound A
[21]. Chilling soda lime by immersing the carbon
dioxide absorbant canister into an ice bath prevented
formation of compounds B, C and D and significantly
reduced the formation of compound A in a model
lung [70]. The production of compound A by
interaction with Baralyme is reduced by the presence
of water, and also decreases as Baralyme becomes
exhausted [87]. These factors may also limit sevoflurane breakdown in clinical practice. Finally, the
concentration of compound A is highest during lowflow anaesthesia, and decreased by increasing fresh
gas flow [3]. The use of higher flow rates probably
increases the washout of breakdown products, while
reducing rebreathing and producing lower absorbant
temperatures [18].
The amount of compound A produced under a
variety of clinically relevant circumstances has
always been substantially lower than that which
produces acute toxicity in animals. Compound B is
somewhat less toxic than compound A [59], and is
formed only in a totally closed anaesthetic breathing
system or after prolonged anaesthesia at very low
flows. However, the concentration recorded is orders
of magnitude below the toxic concentration. A
further concern has been raised recently because of
the finding that exposure of rats to compound A at
concentrations of 950 ppm results in renal cortico-
Sevoflurane
medullary tubular necrosis [31]. Clearly, this concentration is much closer to that which has been
achieved clinically. However, the natural history and
clinical relevance of these histological findings are
unknown, as all rats in this study were killed within
4 days of exposure to compound A. Indeed, the renal
damage appeared to be less extensive 4 days after
exposure to compound A than on the first day,
suggesting that the lesions were at least partially
reversible [31]. Furthermore, it should also be
mentioned that the objectivity of this investigation
has been questioned by the editor of the journal in
which the article was published [71]. A follow-up
study by the same investigative group showed that
renal injury in rats required at least 200 ppm when
exposure to compound A was limited to 1 h [42]. It
is not known whether compound A has a similar
pattern of toxicity in humans [17].
Sevoflurane has now been administered to about 1
million patients in Japan without reports of serious
adverse reactions or significant hepatic or nephrotoxicity [9, 60]. In addition, no evidence of renal
injury or impairment has been detected in any of the
published studies of sevoflurane anaesthesia in
humans [10, 24, 28, 50, 53, 75, 76]. The effects of
multiple exposures to sevoflurane anaesthesia have
been evaluated recently in primates [77]. Although
subtle increases in hepatic enzymes were detected,
these were less marked than the increase caused by
multiple exposures to other volatile anaesthetics. No
evidence of histopathological toxicity was detected
after 24 exposures to 3–5 MAC-h of sevoflurane in
cynomolgus monkeys [77]. Thus the toxicity of
sevoflurane would appear to be more of a theoretical
than a clinical problem. However, with worldwide
clinical exposure to this volatile anaesthetic, any
significant toxic effects should become apparent in
the near future.
Conclusion
Sevoflurane is not the “ideal” volatile anaesthetic.
However, its low blood : gas solubility in combination
with minimal airway irritation allows for smooth and
rapid induction of anaesthesia. Although these
properties may be of benefit to adult patients,
sevoflurane is likely to become an even more popular
choice for paediatric anaesthesia. Rapid recovery
compared with halothane, and smooth and calm
emergence are also advantageous in children. For
adults, the relative insolubility of sevoflurane should
facilitate control of anaesthetic depth during the
maintenance period, even at low gas flows. Combined
with conventional vaporizer technology and a familiar concentration range, anaesthetists should have
little difficulty in using sevoflurane as a maintenance
anaesthetic. Rapid emergence from anaesthesia with
sevoflurane facilitates more efficient patient turnover
and may confer additional benefits after more
prolonged anaesthesia.
While sevoflurane diverges from the mythical
ideal anaesthetic in its degree of metabolism and
potentially toxic byproducts, the body of experimental and clinical evidence to date suggests that
sevoflurane is safe when administered under the
443
usual clinical conditions. Further investigations may
be required before sevoflurane can be declared safe
under all circumstances (e.g. low-flow or closed
circuit anaesthesia, in the presence of chronic renal
insufficiency). For the present, it is wise to caution
against the use of sevoflurane in patients with
significantly impaired renal function [58] and for
prolonged anaesthesia at very low total fresh gas
flows (:2 litre min1). Indeed, the USA product
licence for sevoflurane contains just such restrictions,
although similar limitations have not been applied in
the UK.
The relative cost of sevoflurane is unknown at
present. Sevoflurane can be administered safely at
low gas flows (2–3 litre min1), and its low solubility
will assist in adjusting its delivery. Further investigations are required to determine the most beneficial
and cost effective use of sevoflurane. Nevertheless,
the long-awaited arrival of this volatile agent should
prove to be a most useful addition to clinical
anaesthesia.
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