Directory UMM :Data Elmu:jurnal:S:Small Ruminant Research:Vol36.Issue3.2000:
Small Ruminant Research 36 (2000) 241±249
Clinical, cardiopulmonary, hematological and serum biochemical
effects of sevo¯urane and iso¯urane anesthesia in oxygen
under spontaneous breathing in sheep
Y. Hikasaa,*, K. Saitob, K. Takaseb, S. Ogasawarab
a
Department of Veterinary Internal Medicine, Faculty of Agriculture, Tottori University,
4-101 Koyama-Minami, Tottori-shi, Tottori 680-8553, Japan
b
Department of Veterinary Surgery, School of Veterinary Medicine and Animal Sciences,
Kitasato University, Towada-shi, Aomori 034-0021, Japan
Accepted 14 September 1999
Abstract
Effects of sevo¯urane and iso¯urane anesthesia in oxygen on clinical, cardiopulmonary, hematological, and serum
biochemical ®ndings were compared in sheep breathing spontaneously undergoing minor surgical operations during shortterm (60±80 min) or long-term (3±4 h) anesthesia. All sheep were premedicated with atropine sulfate (0.1 mg/kg)
intramuscularly, and 10 min later, induced to anesthesia by intravenous infusion of sodium thiopental (mean 14.1 3.4 S.D.
mg/kg). After intubation, they were anesthetized with either iso¯urane or sevo¯urane in oxygen at a total gas ¯ow rate of 1.5 l/
min. The results revealed that recovery time with sevo¯urane was more rapid than with iso¯urane. Respiration rates, tidal
volume, minute ventilation and heart rates during sevo¯urane anesthesia were similar to those during iso¯urane anesthesia.
The degree of respiratory acidosis during sevo¯urane anesthesia was also similar to that during iso¯urane anesthesia. There
were no signi®cant differences between sevo¯urane and iso¯urane anesthesia in hematological and serum biochemical values.
# 2000 Elsevier Science B.V. All rights reserved.
Keywords: Sevo¯urane; Iso¯urane; Sheep; Inhalation anesthesia; Cardiopulmonary
1. Introduction
A new halogenated inhalant, sevo¯urane, has a low
blood/gas partition coef®cient similar to nitrous oxide
(Strum and Eger, 1987), and produces rapid induction
*
Corresponding author. Tel.: 81-857-31-5432;
fax: 81-857-31-5432.
E-mail address: hikasa@muses.tottori-u.ac.jp (Y. Hikasa)
of and recovery from anesthesia and rapid alteration of
anesthetic depth (Kazama and Ikeda, 1985; Eger and
Johnson, 1987; Hikasa et al., 1996a, 1997b). The
arrhythmogenic dose of adrenaline for sevo¯urane
is higher than that for halothane and en¯urane, and
similar to that for iso¯urane in dogs (Hayashi et al.,
1988) and cats (Hikasa et al., 1996b) Sevo¯urane
appears to be a new anesthetic showing promise.
The anesthetic potency and cardiopulmonary
effects of iso¯urane have been well described in lambs
0921-4488/00/$ ± see front matter # 2000 Elsevier Science B.V. All rights reserved.
PII: S 0 9 2 1 - 4 4 8 8 ( 9 9 ) 0 0 1 2 1 - 2
242
Y. Hikasa et al. / Small Ruminant Research 36 (2000) 241±249
(Brett et al., 1987), goats (Antognini and Eisele, 1993)
and cattle (Greene et al., 1988). Sevo¯urane has been
used as an effective anesthetic producing a rapid
recovery in adult cattle (Hikasa et al., 1994a) and
horses (Hikasa et al., 1994b). The effects of sevo¯urane anesthesia on right ventricular function and
oxygenation for one-lung ventilation with positive
end-expiratory pressure to the dependent lung have
been studied using open-chest sheep (Fujita et al.,
1993). However, there is no information available on
clinical anesthesia with sevo¯urane in small ruminants. The purpose of this study was to compare
the clinical, cardiopulmonary, hematological, and
serum biochemical effects of sevo¯urane-oxygen with
those of iso¯urane-oxygen anesthesia, at a surgical
depth of anesthesia in spontaneously ventilating sheep
undergoing some surgical operations.
2. Materials and methods
2.1. Animals
Twenty-nine healthy sheep (Suffolk or Corriedale)
of either sex (6 months to 5 years of age), weighing
from 33±62 kg bodyweight (mean 46.4 9.9 S.D.
kg), were used in this investigation. Health status
was evaluated on the base of history, physical examinations, complete blood counts, serum biochemical
pro®les, and electrocardiograms using standard
methods. They were given a commercial ruminant
concentrate, hay and water ad libitum. All sheep were
fasted for 24 h before anesthesia. Anesthesia and
selected operations were carried out in a room at
21±248C. Intra- or post-operative analgesics were
not given in any sheep. A broad-spectrum antibiotic,
ampicillin (10 mg/kg) was administered intramuscularly twice a day for 3 days post-operatively in all
sheep.
2.2. Anesthetic procedures
The sheep were randomly assigned into four groups
of 6±9 animals. Two groups of sheep were anesthetized with sevo¯urane or iso¯urane for short-term of
60±80 min, and underwent a surgery for subcutaneous
relocation of the left carotid artery for collection of
arterial blood samples in the future. Another two
groups were anesthetized with sevo¯urane or iso¯urane for long-term of 3±4 h, and underwent operations
for attachments of ruminal ®stula, duodenal cannula
and several electrodes into the duodenal muscles
through the paracostal approach of laparotomy during
anesthesia. All of the surgical procedures just mentioned were done on each of the animals. All sheep
were premedicated intramuscularly with atropine sulfate (0.1 mg/kg; Tanabe, Japan). After 10 min,
anesthesia was induced by intravenous infusion of
sodium thiopental (mean 14.1 3.4 S.D. mg/kg;
Rabonal, Tanabe, Japan). The end-point of the infusion was until the animals lay down and could be
intubated. The animals were placed in lateral recumbency on a surgical table, intubated with a cuffed
endotracheal tube, and anesthetized with either iso¯urane (Forane, Dinabott, Tokyo, Japan) in oxygen
(OI) or sevo¯urane (Sevofrane, Maruishi Pharma,
Osaka, Japan) in oxygen (OS) at a total gas ¯ow rate
of 1.5 l/min delivered to an anesthetic system (Beaver
20, Kimura Medicals, Tokyo, Japan). They were
maintained at a surgical plane of anesthesia while
breathing spontaneously. The depth of anesthesia
was judged by the lack of painful response to surgeries. In addition, the lack of painful response to
clamping the interdigital web of pads with Kocher's
forceps and palpebral response were monitored at 15±
30 min intervals during anesthesia. A positive
response to painful stimuli was de®ned as gross
purposeful muscular movement of the head or extremities. If an animal showed a positive response to the
stimuli, the end-tidal concentration was increased by
10±20% and, after approximately 5 min, the stimuli
were repeated. The palpebral response showed a slight
or no re¯ex during anesthesia.
Agent-speci®c precision vaporizer was used for
sevo¯urane (Mark II, Acoma Medicals, Tokyo,
Japan). Iso¯urane was vaporized from a halothane
vaporizer (Honey Matic M-3, Kimura Medicals,
Tokyo, Japan). The inspired and end-tidal concentrations of the anesthetic gases in specimens drawn from
a sampling catheter positioned in the connection at the
oral end of the endotracheal tube were measured
continuously using an infrared gas analyzer (Capnomac Ultima, Datex, Helsinki, Finland). Airway gas
was continuously sampled at the rate of 200 ml/min
and the gas was not returned to the circuit. Immediately after the surgical operations were completed, the
Y. Hikasa et al. / Small Ruminant Research 36 (2000) 241±249
anesthetic circuit was disconnected from the animal.
The endotracheal tube was removed immediately after
return of swallowing movements. The elapsed times
from discontinuing anesthesia to ®rst lift of the head,
standing and walking were recorded. Although this
study was not double blinded in the recovery time
evaluation, recovery evaluation by the observer was
consistent among all of the sheep and between anesthetics.
2.3. Cardiopulmonary measurements
A lead Apex-Base electrocardiogram (ECG) was
recorded continuously to monitor heart rate (HR) and
heart rhythm throughout the anesthetic period.
Respiration rate (RR), respiratory tidal volume (TV)
and minute ventilation (MV) were measured according to the methods described previously (Hikasa et al.,
1994a, b). Arterial blood samples were collected from
a polyethylene 22-gauge catheter inserted into the
auricular artery prepared previously. Arterial oxygen
and carbon dioxide partial pressures (PaO2 and
PaCO2), arterial pH (pHa), arterial bicarbonate
([HCO3±]a), and base excess (BEa) were measured
according to the procedures reported previously
(Hikasa et al., 1996a, 1997b). The TV and MV were
measured at 15±30-min intervals during anesthesia.
The HR, RR and arterial blood gases were measured
before atropine was injected (baseline), at 15- or 30min intervals during anesthesia, and at 30 and 60 min
postanesthesia.
2.4. Hematological and serum biochemical
measurements
Jugular blood samples were collected before atropine was injected (base-line), at 30±60 min intervals
throughout the anaesthetic period, and at 1 h, 1 or 3
days after discontinuing anesthesia. Packed cell
volume (PCV), red blood cell (RBC) counts, plasma
protein (PP) concentrations, serum aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) activities, blood urea nitrogen
(BUN), creatinine, glucose, sodium, potassium, and
chloride concentrations were determined according to
the procedures described previously (Hikasa et al.,
1997b, 1998).
243
2.5. Statistical analyses
Data were analyzed by one-way analysis of variance for repeated measures to compare time-related
variables within each anaesthetic group and Tukey's
multiple comparison test was used to identify differences between means. For unpaired comparisons
between sevo¯urane and iso¯urane groups the data
underwent an analysis of variance. When the F-value
was not signi®cant, a Student's t-test was used to
determine the signi®cance of differences. When a
signi®cant F-value was found, a Wilcoxon±MannWhitney test was used for the statistical evaluation.
The signi®cance level of all tests was set at P < 0.05.
3. Results
3.1. Maintenance anesthesia and recovery from
anesthesia
The duration (mean S.D.) of anesthesia with
iso¯urane and sevo¯urane was 69 7 and 67
4 min for short-term anesthesia, and 190 17 and
201 20 min for long-term anesthesia, respectively.
Mean end-tidal concentrations of iso¯urane and sevo¯urane during maintenance anesthesia were 0.8±1.0%
and 1.2±1.4% for short-term, and 1.1±1.3% and 1.5±
2.1% for long-term, respectively (Table 1).
Mild salivation was observed during maintenance
anesthesia in all groups. The amount (mean S.D.) of
salivation ¯uids during OI and OS anesthesia were
29 10 and 26 14 ml/h in short-term anesthesia,
and 33 24 and 26 9 ml/h in long-term anesthesia,
respectively. There was no signi®cant difference in the
amount of ¯uids between OI and OS groups.
As shown in Table 2, mean elapsed times to ®rst lift
of the head and standing±walking following OS
anesthesia were signi®cantly shorter than those following OI anesthesia in both short and long-term.
3.2. Cardiopulmonary ®ndings
In all groups, RR during maintenance anesthesia
decreased signi®cantly when compared with base-line
value (value before atropine injection). The HR in all
groups increased signi®cantly from base-line during
maintenance anesthesia. There were no signi®cant
244
Y. Hikasa et al. / Small Ruminant Research 36 (2000) 241±249
Table 1
End-tidal concentrations of iso¯urane and sevo¯urane during short-term or long-term surgical depth of anesthesia in spontaneously breathing
sheep
Period of
anesthesia
Short
Long
Anesthetic
of sheep
Isoflurane
Sevoflurane
Isoflurane
Sevoflurane
Number
8
9
6
6
Time (min) during maintenance anesthesia
15
30
45
60
90
120
150
180±240
x
S.D.
x
S.D.
x
S.D.
x
S.D.
x
S.D.
x
S.D.
x
S.D.
x
S.D.
0.8
1.2
1.0
1.5
0.2
0.3
0.3
0.4
0.7
1.3
1.1
1.6
0.3
0.4
0.2
0.4
0.9
1.3
1.2
1.6
0.3
0.6
0.2
0.4
1.0
1.4
1.2
1.7
0.3
0.8
0.3
0.2
1.2
1.8
0.2
0.5
1.2
1.9
0.3
0.3
1.3
2.0
0.3
0.6
1.3
2.1
0.3
0.4
Table 2
Recovery times from short-term or long-term iso¯urane and sevo¯urane anesthesia in spontaneously breathing sheep
Period of anesthesia
Anesthetic
No. of sheep
Recovery time (min)
To first lift of the head
x
To stand and walk
S.D.
x
S.D.
Short
Isoflurane
Sevoflurane
8
9
8.4
5.1
5.7
2.3
23.0
10.2a
10.5
5.2
Long
Isoflurane
Sevoflurane
6
6
12.6
5.8a
5.7
2.9
37.7
10.8a
21.1
4.5
a
Signi®cantly different from iso¯urane (P < 0.05).
differences between OI and OS groups in both HR and
RR (Fig. 1). However, HR in OI group during longterm anesthesia tended to be higher than that during
OS group. Both TV and MV in OS groups did not
signi®cantly differ from those in OI groups (Fig. 2). In
both OI and OS groups, TV in long-term anesthesia
tended to be higher than that in short-term anesthesia,
but not signi®cantly (Fig. 2). In all groups, no abnormal ECG alterations were observed throughout
anesthesia.
As shown in Fig. 3, the pHa in all groups decreased
signi®cantly during maintenance anesthesia when
compared with base-line value. The PaCO2 and
PaO2 in all groups increased signi®cantly during
maintenance anesthesia. The [HCO3±]a in all groups
increased slightly during anesthesia and at 30±60 min
postanesthesia when compared with base-line value.
The BEa increased slightly at 30±60 min postanesthesia. The degrees of acidosis and hypercapnia in OS
group did not signi®cantly differ from those in OI
group during either short or long-term of anesthesia,
although both acidosis and hypercapnia tended to be
greater in OI group than OS group during long-term
anesthesia. There were no signi®cant differences in
blood gases and acid±base values between OI and OS
groups at any time.
3.3. Hematological and serum biochemical ®ndings
The PCV, PP and RBC values decreased signi®cantly from base-line values during anesthesia in all
groups (Table 3). There were no signi®cant differences
between OI and OS groups in PCV, PP and RBC at any
time (Table 3).
Serum AST, ALT, ALP, glucose, BUN, creatinine,
sodium, potassium and chloride did not signi®cantly
change from base-line values at any time after anesthesia in any group, except that potassium in both OI and
OS groups decreased slightly from base-line values at
60 min of anesthesia. There were no signi®cant differences between OI and OS groups in serum biochemical values at any time.
4. Discussion
The concentration of sevo¯urane during maintenance anesthesia in this study was approximately
Y. Hikasa et al. / Small Ruminant Research 36 (2000) 241±249
245
Fig. 1. Heart and respiration rates during short-term or long-term
iso¯urane and sevo¯urane anesthesia in spontaneously breathing
sheep. Each point and a vertical bar represent the mean S.D.
(n 6±9). (*) Signi®cantly different from base-line values
(P < 0.05).
1.6 times higher than that of iso¯urane. The minimal
alveolar concentration (MAC) of iso¯urane in sheep
has been reported to be 1.41±1.53% (Brett et al., 1987;
Fig. 2. Respiratory tidal volume during short-term or long-term
iso¯urane and sevo¯urane anesthesia in spontaneously breathing
sheep. Each column represents the mean with a vertical bar
indicating S.D. (n 6±9).
Fig. 3. Arterial carbon dioxide partial pressure (PaCO2), pH (pHa),
and bicarbonate ([HCO3±]a) values during short-term or long-term
iso¯urane and sevo¯urane anesthesia in spontaneously breathing
sheep. Each column represent the mean with a vertical bar
indicating S.D. (n 6±9). (*) Signi®cantly different from base-line
values (P < 0.05).
LeDez and Lerman, 1987; Bernards et al., 1996).
Although MAC value of sevo¯urane in sheep is
unknown, it has been reported that the ratio of potencies for any pairing of inhalant anesthetic agents is
constant from species to species (Doi et al., 1988) and
provides a means for assessing the validity of preexisting or newly determined MAC values (Drummond,
1985). The end-tidal sevo¯urane/iso¯urane concentration ratio (equal to approximately 1.6) during maintenance anesthesia in our study is very similar to the
246
Variable
Period of
anesthesia
Anesthetic
No. of
sheep
Base-line
30
S.D.
x
Packed cell
volume (%)
Short
Long
Plasma protein
(g/dl)
Short
Long
a
b
Isoflurane
Sevoflurane
Isoflurane
Sevoflurane
8
9
6
6
Isoflurane
Sevoflurane
Isoflurane
Sevoflurane
8
9
6
6
Time during maintenance anesthesia (min)
33
34
34
35
6.3
6.2
6.9
6.8
Signi®cantly different from base-line value at P < 0.05.
Signi®cantly different from base-line value at P < 0.01.
3
2
3
4
0.3
0.4
0.5
0.4
60
S.D.
x
b
26
28
30a
29b
5.8b
5.8
6.2a
6.1b
3
3
5
3
0.4
0.3
0.6
0.3
90
S.D.
x
b
25
27b
180±240
S.D.
x
60 min
S.D.
x
x
a
2
2
29b
29b
5.6b
5.7b
Time after anesthesia
4
3
29b
29b
3
3
0.3
0.3
6.4b
6.0b
0.5
0.4
6.2b
6.0b
0.6
0.4
29
28b
32
33
5.8b
5.8b
6.2a
6.0b
1 day
S.D.
x
S.D.
2
2
3
4
35
34
37
37
2
2
3
3
0.3
0.3
0.6
0.4
6.5
6.5
6.6
6.6
0.5
0.4
0.6
0.3
Y. Hikasa et al. / Small Ruminant Research 36 (2000) 241±249
Table 3
Hematological values during surgical depth of anesthesia with iso¯urane and sevo¯urane in spontaneously breathing sheep
Y. Hikasa et al. / Small Ruminant Research 36 (2000) 241±249
sevo¯urane/iso¯urane MAC ratio (equal to 1.7) in
humans (Scheller et al., 1988).
The blood/gas partition coef®cient for sevo¯urane
in human blood is much lower than that for halothane
and iso¯urane, and similar to that for nitrous oxide
(Strum and Eger, 1987; Steffey, 1994), indicating that
recovery from anesthesia with sevo¯urane would be
more rapid than that with the other two inhalant
anesthetics. The current results demonstrated clearly
that recovery times following OS anesthesia were
signi®cantly shorter than those following OI anesthesia in both short and long-term of anesthesia in sheep.
These results are in agreement with those obtained
previously in cats (Hikasa et al., 1998).
Sevo¯urane induces dose-dependent respiratory
depression in cats (Hikasa et al., 1997a), dogs (Doi
et al., 1987) and humans (Doi and Ikeda, 1987). The
RR in cats at surgical depth of anesthesia with sevo¯urane-oxygen is reportedly higher than that with
iso¯urane-oxygen (Hikasa et al., 1996a). The present
®ndings in sheep revealed that RR, TV and MV during
sevo¯urane-oxygen anesthesia do not differ from that
during iso¯urane-oxygen anesthesia. The TV during
long-term anesthesia in both OI and OS groups tended
to be higher than that during short-term anesthesia,
suggesting that this may be due to the difference in the
degree of surgical stimulation in the long surgery
versus the short surgery. This study also revealed that
both anesthetics produced respiratory acidosis
(increase in PaCO2 and decrease in pHa), and that
the degree of respiratory acidosis during sevo¯urane
anesthesia did not signi®cantly differ from that during
iso¯urane anesthesia, although respiration acidosis
tended to be greater in iso¯urane than sevo¯urane
during long-term anesthesia. Therefore, the present
®ndings indicate that sevo¯urane, similar to iso¯urane, induces respiratory depression at a light-surgical
depth of anesthesia in sheep. These ®ndings in sheep
are in agreement with those reported in cats (Hikasa
et al., 1996a, 1997b, 1998). In the present study,
however, the PaCO2 during maintenance anesthesia
with either sevo¯urane or iso¯urane is higher than that
reported previously in dogs (Steffey and Howland,
1977; Doi et al., 1987), cats (Hikasa et al., 1996a,
1997b, 1998), and humans (Doi and Ikeda, 1987). In
ruminants, distension of the rumen due to increasing
ruminal gases impairs the ventilation (Ungerer et al.,
1976), and positioning in lateral recumbency is asso-
247
ciated with respiratory depression (Fujimoto and
Lenehan, 1985). These factors may contribute to the
fact that hypercapnia during anesthesia in sheep was
greater than that in small animals reported previously.
It may be desirable that sheep being anesthetized with
either iso¯urane or sevo¯urane are mechanically ventilated in order to avoid hypercapnia.
The HR is unchanged or decreased slightly as
sevo¯urane concentration increased in dogs (Kazama
and Ikeda, 1988) and cats (Hikasa et al., 1997a),
however, it is also reported to increase in dogs (Bernard et al., 1990; Frink et al., 1992b). Iso¯urane has
been reported to induce a slight increase HR in dogs
(Bernard et al., 1990; Frink et al., 1992b), but induce a
decrease in HR in lambs (Brett et al., 1987, 1989) and
in cats (Hikasa et al., 1997b). In the current study, HR
during anesthesia in each group increased from baseline, which is presumably due to the in¯uence of
atropine premedication. There were no signi®cant
differences in HR between the groups, indicating that
HR during OS anesthesia does not differ from that
during OI anesthesia in sheep. However, HR during OI
anesthesia in long-term surgery tended to be higher
than that during OS anesthesia, which may result from
sympathetic activation due to the high PaCO2 in the
long-term OI group. In addition, arrhythmia was not
observed in sheep anesthetized with OS or OI. Therefore, sevo¯urane-oxygen anesthesia produces a stable
HR similar to iso¯urane-oxygen anesthesia in sheep
premedicated with atropine.
The current study revealed that hemodilution occurs
during sevo¯urane anesthesia similar to iso¯urane
anesthesia in sheep. These ®ndings are in agreement
with previous results that a surgical depth of anesthesia with OS or OI induces hemodilution in cats
(Hikasa et al., 1996a, 1998), which may be caused
by sequestration of RBCs in the spleen or by shifts in
body ¯uids associated with the decrease in arterial
pressure due to vasodilation and decreased cardiac
output during anesthesia.
Renal effects of sevo¯urane have been associated
with inorganic ¯uoride production during metabolism,
with resulting nephrotoxicity reported in rats, dogs
and humans (Martis et al., 1981; Frink et al., 1992a).
No such effect was observed in sheep. On the other
hand, the extent of hepatic injury with sevo¯urane
does not differ from that with iso¯urane; both anesthetics being less toxic than halothane in rats (Strum
248
Y. Hikasa et al. / Small Ruminant Research 36 (2000) 241±249
et al., 1987). In the current study, no signi®cant changes
in serum AST, ALT, ALP, glucose, BUN and creatinine values were observed for 3 days post-anesthesia
in all groups. These results indicate that hepatic and
renal injuries are not produced after 3±4 h anesthesia
with sevo¯urane as well as iso¯urane in healthy sheep.
In addition, no marked changes in serum sodium,
potassium and chloride ion concentrations were
observed in both anesthetic groups, indicating that
electrolyte balance during and after anesthesia with
sevo¯urane is similar to iso¯urane in sheep.
In conclusion, this study demonstrated that recovery
time from anesthesia with sevo¯urane-oxygen was
more rapid than with iso¯urane-oxygen in healthy
sheep that underwent minor surgical procedures.
Respiration rates, tidal volume, minute ventilation,
heart rates, arterial blood gases and acid±base values
during sevo¯urane-oxygen anesthesia were similar to
that during iso¯urane-oxygen anesthesia. There were
no signi®cant differences between sevo¯urane-oxygen and iso¯urane-oxygen anesthesia in hematological and serum biochemical values.
Acknowledgements
The authors thank Maruishi Pharmaceutical Co.,
Ltd., for the gift of sevo¯urane, and Miss K. Kondo
and Mrs. T. Kakuta for their technical assistance.
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Clinical, cardiopulmonary, hematological and serum biochemical
effects of sevo¯urane and iso¯urane anesthesia in oxygen
under spontaneous breathing in sheep
Y. Hikasaa,*, K. Saitob, K. Takaseb, S. Ogasawarab
a
Department of Veterinary Internal Medicine, Faculty of Agriculture, Tottori University,
4-101 Koyama-Minami, Tottori-shi, Tottori 680-8553, Japan
b
Department of Veterinary Surgery, School of Veterinary Medicine and Animal Sciences,
Kitasato University, Towada-shi, Aomori 034-0021, Japan
Accepted 14 September 1999
Abstract
Effects of sevo¯urane and iso¯urane anesthesia in oxygen on clinical, cardiopulmonary, hematological, and serum
biochemical ®ndings were compared in sheep breathing spontaneously undergoing minor surgical operations during shortterm (60±80 min) or long-term (3±4 h) anesthesia. All sheep were premedicated with atropine sulfate (0.1 mg/kg)
intramuscularly, and 10 min later, induced to anesthesia by intravenous infusion of sodium thiopental (mean 14.1 3.4 S.D.
mg/kg). After intubation, they were anesthetized with either iso¯urane or sevo¯urane in oxygen at a total gas ¯ow rate of 1.5 l/
min. The results revealed that recovery time with sevo¯urane was more rapid than with iso¯urane. Respiration rates, tidal
volume, minute ventilation and heart rates during sevo¯urane anesthesia were similar to those during iso¯urane anesthesia.
The degree of respiratory acidosis during sevo¯urane anesthesia was also similar to that during iso¯urane anesthesia. There
were no signi®cant differences between sevo¯urane and iso¯urane anesthesia in hematological and serum biochemical values.
# 2000 Elsevier Science B.V. All rights reserved.
Keywords: Sevo¯urane; Iso¯urane; Sheep; Inhalation anesthesia; Cardiopulmonary
1. Introduction
A new halogenated inhalant, sevo¯urane, has a low
blood/gas partition coef®cient similar to nitrous oxide
(Strum and Eger, 1987), and produces rapid induction
*
Corresponding author. Tel.: 81-857-31-5432;
fax: 81-857-31-5432.
E-mail address: hikasa@muses.tottori-u.ac.jp (Y. Hikasa)
of and recovery from anesthesia and rapid alteration of
anesthetic depth (Kazama and Ikeda, 1985; Eger and
Johnson, 1987; Hikasa et al., 1996a, 1997b). The
arrhythmogenic dose of adrenaline for sevo¯urane
is higher than that for halothane and en¯urane, and
similar to that for iso¯urane in dogs (Hayashi et al.,
1988) and cats (Hikasa et al., 1996b) Sevo¯urane
appears to be a new anesthetic showing promise.
The anesthetic potency and cardiopulmonary
effects of iso¯urane have been well described in lambs
0921-4488/00/$ ± see front matter # 2000 Elsevier Science B.V. All rights reserved.
PII: S 0 9 2 1 - 4 4 8 8 ( 9 9 ) 0 0 1 2 1 - 2
242
Y. Hikasa et al. / Small Ruminant Research 36 (2000) 241±249
(Brett et al., 1987), goats (Antognini and Eisele, 1993)
and cattle (Greene et al., 1988). Sevo¯urane has been
used as an effective anesthetic producing a rapid
recovery in adult cattle (Hikasa et al., 1994a) and
horses (Hikasa et al., 1994b). The effects of sevo¯urane anesthesia on right ventricular function and
oxygenation for one-lung ventilation with positive
end-expiratory pressure to the dependent lung have
been studied using open-chest sheep (Fujita et al.,
1993). However, there is no information available on
clinical anesthesia with sevo¯urane in small ruminants. The purpose of this study was to compare
the clinical, cardiopulmonary, hematological, and
serum biochemical effects of sevo¯urane-oxygen with
those of iso¯urane-oxygen anesthesia, at a surgical
depth of anesthesia in spontaneously ventilating sheep
undergoing some surgical operations.
2. Materials and methods
2.1. Animals
Twenty-nine healthy sheep (Suffolk or Corriedale)
of either sex (6 months to 5 years of age), weighing
from 33±62 kg bodyweight (mean 46.4 9.9 S.D.
kg), were used in this investigation. Health status
was evaluated on the base of history, physical examinations, complete blood counts, serum biochemical
pro®les, and electrocardiograms using standard
methods. They were given a commercial ruminant
concentrate, hay and water ad libitum. All sheep were
fasted for 24 h before anesthesia. Anesthesia and
selected operations were carried out in a room at
21±248C. Intra- or post-operative analgesics were
not given in any sheep. A broad-spectrum antibiotic,
ampicillin (10 mg/kg) was administered intramuscularly twice a day for 3 days post-operatively in all
sheep.
2.2. Anesthetic procedures
The sheep were randomly assigned into four groups
of 6±9 animals. Two groups of sheep were anesthetized with sevo¯urane or iso¯urane for short-term of
60±80 min, and underwent a surgery for subcutaneous
relocation of the left carotid artery for collection of
arterial blood samples in the future. Another two
groups were anesthetized with sevo¯urane or iso¯urane for long-term of 3±4 h, and underwent operations
for attachments of ruminal ®stula, duodenal cannula
and several electrodes into the duodenal muscles
through the paracostal approach of laparotomy during
anesthesia. All of the surgical procedures just mentioned were done on each of the animals. All sheep
were premedicated intramuscularly with atropine sulfate (0.1 mg/kg; Tanabe, Japan). After 10 min,
anesthesia was induced by intravenous infusion of
sodium thiopental (mean 14.1 3.4 S.D. mg/kg;
Rabonal, Tanabe, Japan). The end-point of the infusion was until the animals lay down and could be
intubated. The animals were placed in lateral recumbency on a surgical table, intubated with a cuffed
endotracheal tube, and anesthetized with either iso¯urane (Forane, Dinabott, Tokyo, Japan) in oxygen
(OI) or sevo¯urane (Sevofrane, Maruishi Pharma,
Osaka, Japan) in oxygen (OS) at a total gas ¯ow rate
of 1.5 l/min delivered to an anesthetic system (Beaver
20, Kimura Medicals, Tokyo, Japan). They were
maintained at a surgical plane of anesthesia while
breathing spontaneously. The depth of anesthesia
was judged by the lack of painful response to surgeries. In addition, the lack of painful response to
clamping the interdigital web of pads with Kocher's
forceps and palpebral response were monitored at 15±
30 min intervals during anesthesia. A positive
response to painful stimuli was de®ned as gross
purposeful muscular movement of the head or extremities. If an animal showed a positive response to the
stimuli, the end-tidal concentration was increased by
10±20% and, after approximately 5 min, the stimuli
were repeated. The palpebral response showed a slight
or no re¯ex during anesthesia.
Agent-speci®c precision vaporizer was used for
sevo¯urane (Mark II, Acoma Medicals, Tokyo,
Japan). Iso¯urane was vaporized from a halothane
vaporizer (Honey Matic M-3, Kimura Medicals,
Tokyo, Japan). The inspired and end-tidal concentrations of the anesthetic gases in specimens drawn from
a sampling catheter positioned in the connection at the
oral end of the endotracheal tube were measured
continuously using an infrared gas analyzer (Capnomac Ultima, Datex, Helsinki, Finland). Airway gas
was continuously sampled at the rate of 200 ml/min
and the gas was not returned to the circuit. Immediately after the surgical operations were completed, the
Y. Hikasa et al. / Small Ruminant Research 36 (2000) 241±249
anesthetic circuit was disconnected from the animal.
The endotracheal tube was removed immediately after
return of swallowing movements. The elapsed times
from discontinuing anesthesia to ®rst lift of the head,
standing and walking were recorded. Although this
study was not double blinded in the recovery time
evaluation, recovery evaluation by the observer was
consistent among all of the sheep and between anesthetics.
2.3. Cardiopulmonary measurements
A lead Apex-Base electrocardiogram (ECG) was
recorded continuously to monitor heart rate (HR) and
heart rhythm throughout the anesthetic period.
Respiration rate (RR), respiratory tidal volume (TV)
and minute ventilation (MV) were measured according to the methods described previously (Hikasa et al.,
1994a, b). Arterial blood samples were collected from
a polyethylene 22-gauge catheter inserted into the
auricular artery prepared previously. Arterial oxygen
and carbon dioxide partial pressures (PaO2 and
PaCO2), arterial pH (pHa), arterial bicarbonate
([HCO3±]a), and base excess (BEa) were measured
according to the procedures reported previously
(Hikasa et al., 1996a, 1997b). The TV and MV were
measured at 15±30-min intervals during anesthesia.
The HR, RR and arterial blood gases were measured
before atropine was injected (baseline), at 15- or 30min intervals during anesthesia, and at 30 and 60 min
postanesthesia.
2.4. Hematological and serum biochemical
measurements
Jugular blood samples were collected before atropine was injected (base-line), at 30±60 min intervals
throughout the anaesthetic period, and at 1 h, 1 or 3
days after discontinuing anesthesia. Packed cell
volume (PCV), red blood cell (RBC) counts, plasma
protein (PP) concentrations, serum aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) activities, blood urea nitrogen
(BUN), creatinine, glucose, sodium, potassium, and
chloride concentrations were determined according to
the procedures described previously (Hikasa et al.,
1997b, 1998).
243
2.5. Statistical analyses
Data were analyzed by one-way analysis of variance for repeated measures to compare time-related
variables within each anaesthetic group and Tukey's
multiple comparison test was used to identify differences between means. For unpaired comparisons
between sevo¯urane and iso¯urane groups the data
underwent an analysis of variance. When the F-value
was not signi®cant, a Student's t-test was used to
determine the signi®cance of differences. When a
signi®cant F-value was found, a Wilcoxon±MannWhitney test was used for the statistical evaluation.
The signi®cance level of all tests was set at P < 0.05.
3. Results
3.1. Maintenance anesthesia and recovery from
anesthesia
The duration (mean S.D.) of anesthesia with
iso¯urane and sevo¯urane was 69 7 and 67
4 min for short-term anesthesia, and 190 17 and
201 20 min for long-term anesthesia, respectively.
Mean end-tidal concentrations of iso¯urane and sevo¯urane during maintenance anesthesia were 0.8±1.0%
and 1.2±1.4% for short-term, and 1.1±1.3% and 1.5±
2.1% for long-term, respectively (Table 1).
Mild salivation was observed during maintenance
anesthesia in all groups. The amount (mean S.D.) of
salivation ¯uids during OI and OS anesthesia were
29 10 and 26 14 ml/h in short-term anesthesia,
and 33 24 and 26 9 ml/h in long-term anesthesia,
respectively. There was no signi®cant difference in the
amount of ¯uids between OI and OS groups.
As shown in Table 2, mean elapsed times to ®rst lift
of the head and standing±walking following OS
anesthesia were signi®cantly shorter than those following OI anesthesia in both short and long-term.
3.2. Cardiopulmonary ®ndings
In all groups, RR during maintenance anesthesia
decreased signi®cantly when compared with base-line
value (value before atropine injection). The HR in all
groups increased signi®cantly from base-line during
maintenance anesthesia. There were no signi®cant
244
Y. Hikasa et al. / Small Ruminant Research 36 (2000) 241±249
Table 1
End-tidal concentrations of iso¯urane and sevo¯urane during short-term or long-term surgical depth of anesthesia in spontaneously breathing
sheep
Period of
anesthesia
Short
Long
Anesthetic
of sheep
Isoflurane
Sevoflurane
Isoflurane
Sevoflurane
Number
8
9
6
6
Time (min) during maintenance anesthesia
15
30
45
60
90
120
150
180±240
x
S.D.
x
S.D.
x
S.D.
x
S.D.
x
S.D.
x
S.D.
x
S.D.
x
S.D.
0.8
1.2
1.0
1.5
0.2
0.3
0.3
0.4
0.7
1.3
1.1
1.6
0.3
0.4
0.2
0.4
0.9
1.3
1.2
1.6
0.3
0.6
0.2
0.4
1.0
1.4
1.2
1.7
0.3
0.8
0.3
0.2
1.2
1.8
0.2
0.5
1.2
1.9
0.3
0.3
1.3
2.0
0.3
0.6
1.3
2.1
0.3
0.4
Table 2
Recovery times from short-term or long-term iso¯urane and sevo¯urane anesthesia in spontaneously breathing sheep
Period of anesthesia
Anesthetic
No. of sheep
Recovery time (min)
To first lift of the head
x
To stand and walk
S.D.
x
S.D.
Short
Isoflurane
Sevoflurane
8
9
8.4
5.1
5.7
2.3
23.0
10.2a
10.5
5.2
Long
Isoflurane
Sevoflurane
6
6
12.6
5.8a
5.7
2.9
37.7
10.8a
21.1
4.5
a
Signi®cantly different from iso¯urane (P < 0.05).
differences between OI and OS groups in both HR and
RR (Fig. 1). However, HR in OI group during longterm anesthesia tended to be higher than that during
OS group. Both TV and MV in OS groups did not
signi®cantly differ from those in OI groups (Fig. 2). In
both OI and OS groups, TV in long-term anesthesia
tended to be higher than that in short-term anesthesia,
but not signi®cantly (Fig. 2). In all groups, no abnormal ECG alterations were observed throughout
anesthesia.
As shown in Fig. 3, the pHa in all groups decreased
signi®cantly during maintenance anesthesia when
compared with base-line value. The PaCO2 and
PaO2 in all groups increased signi®cantly during
maintenance anesthesia. The [HCO3±]a in all groups
increased slightly during anesthesia and at 30±60 min
postanesthesia when compared with base-line value.
The BEa increased slightly at 30±60 min postanesthesia. The degrees of acidosis and hypercapnia in OS
group did not signi®cantly differ from those in OI
group during either short or long-term of anesthesia,
although both acidosis and hypercapnia tended to be
greater in OI group than OS group during long-term
anesthesia. There were no signi®cant differences in
blood gases and acid±base values between OI and OS
groups at any time.
3.3. Hematological and serum biochemical ®ndings
The PCV, PP and RBC values decreased signi®cantly from base-line values during anesthesia in all
groups (Table 3). There were no signi®cant differences
between OI and OS groups in PCV, PP and RBC at any
time (Table 3).
Serum AST, ALT, ALP, glucose, BUN, creatinine,
sodium, potassium and chloride did not signi®cantly
change from base-line values at any time after anesthesia in any group, except that potassium in both OI and
OS groups decreased slightly from base-line values at
60 min of anesthesia. There were no signi®cant differences between OI and OS groups in serum biochemical values at any time.
4. Discussion
The concentration of sevo¯urane during maintenance anesthesia in this study was approximately
Y. Hikasa et al. / Small Ruminant Research 36 (2000) 241±249
245
Fig. 1. Heart and respiration rates during short-term or long-term
iso¯urane and sevo¯urane anesthesia in spontaneously breathing
sheep. Each point and a vertical bar represent the mean S.D.
(n 6±9). (*) Signi®cantly different from base-line values
(P < 0.05).
1.6 times higher than that of iso¯urane. The minimal
alveolar concentration (MAC) of iso¯urane in sheep
has been reported to be 1.41±1.53% (Brett et al., 1987;
Fig. 2. Respiratory tidal volume during short-term or long-term
iso¯urane and sevo¯urane anesthesia in spontaneously breathing
sheep. Each column represents the mean with a vertical bar
indicating S.D. (n 6±9).
Fig. 3. Arterial carbon dioxide partial pressure (PaCO2), pH (pHa),
and bicarbonate ([HCO3±]a) values during short-term or long-term
iso¯urane and sevo¯urane anesthesia in spontaneously breathing
sheep. Each column represent the mean with a vertical bar
indicating S.D. (n 6±9). (*) Signi®cantly different from base-line
values (P < 0.05).
LeDez and Lerman, 1987; Bernards et al., 1996).
Although MAC value of sevo¯urane in sheep is
unknown, it has been reported that the ratio of potencies for any pairing of inhalant anesthetic agents is
constant from species to species (Doi et al., 1988) and
provides a means for assessing the validity of preexisting or newly determined MAC values (Drummond,
1985). The end-tidal sevo¯urane/iso¯urane concentration ratio (equal to approximately 1.6) during maintenance anesthesia in our study is very similar to the
246
Variable
Period of
anesthesia
Anesthetic
No. of
sheep
Base-line
30
S.D.
x
Packed cell
volume (%)
Short
Long
Plasma protein
(g/dl)
Short
Long
a
b
Isoflurane
Sevoflurane
Isoflurane
Sevoflurane
8
9
6
6
Isoflurane
Sevoflurane
Isoflurane
Sevoflurane
8
9
6
6
Time during maintenance anesthesia (min)
33
34
34
35
6.3
6.2
6.9
6.8
Signi®cantly different from base-line value at P < 0.05.
Signi®cantly different from base-line value at P < 0.01.
3
2
3
4
0.3
0.4
0.5
0.4
60
S.D.
x
b
26
28
30a
29b
5.8b
5.8
6.2a
6.1b
3
3
5
3
0.4
0.3
0.6
0.3
90
S.D.
x
b
25
27b
180±240
S.D.
x
60 min
S.D.
x
x
a
2
2
29b
29b
5.6b
5.7b
Time after anesthesia
4
3
29b
29b
3
3
0.3
0.3
6.4b
6.0b
0.5
0.4
6.2b
6.0b
0.6
0.4
29
28b
32
33
5.8b
5.8b
6.2a
6.0b
1 day
S.D.
x
S.D.
2
2
3
4
35
34
37
37
2
2
3
3
0.3
0.3
0.6
0.4
6.5
6.5
6.6
6.6
0.5
0.4
0.6
0.3
Y. Hikasa et al. / Small Ruminant Research 36 (2000) 241±249
Table 3
Hematological values during surgical depth of anesthesia with iso¯urane and sevo¯urane in spontaneously breathing sheep
Y. Hikasa et al. / Small Ruminant Research 36 (2000) 241±249
sevo¯urane/iso¯urane MAC ratio (equal to 1.7) in
humans (Scheller et al., 1988).
The blood/gas partition coef®cient for sevo¯urane
in human blood is much lower than that for halothane
and iso¯urane, and similar to that for nitrous oxide
(Strum and Eger, 1987; Steffey, 1994), indicating that
recovery from anesthesia with sevo¯urane would be
more rapid than that with the other two inhalant
anesthetics. The current results demonstrated clearly
that recovery times following OS anesthesia were
signi®cantly shorter than those following OI anesthesia in both short and long-term of anesthesia in sheep.
These results are in agreement with those obtained
previously in cats (Hikasa et al., 1998).
Sevo¯urane induces dose-dependent respiratory
depression in cats (Hikasa et al., 1997a), dogs (Doi
et al., 1987) and humans (Doi and Ikeda, 1987). The
RR in cats at surgical depth of anesthesia with sevo¯urane-oxygen is reportedly higher than that with
iso¯urane-oxygen (Hikasa et al., 1996a). The present
®ndings in sheep revealed that RR, TV and MV during
sevo¯urane-oxygen anesthesia do not differ from that
during iso¯urane-oxygen anesthesia. The TV during
long-term anesthesia in both OI and OS groups tended
to be higher than that during short-term anesthesia,
suggesting that this may be due to the difference in the
degree of surgical stimulation in the long surgery
versus the short surgery. This study also revealed that
both anesthetics produced respiratory acidosis
(increase in PaCO2 and decrease in pHa), and that
the degree of respiratory acidosis during sevo¯urane
anesthesia did not signi®cantly differ from that during
iso¯urane anesthesia, although respiration acidosis
tended to be greater in iso¯urane than sevo¯urane
during long-term anesthesia. Therefore, the present
®ndings indicate that sevo¯urane, similar to iso¯urane, induces respiratory depression at a light-surgical
depth of anesthesia in sheep. These ®ndings in sheep
are in agreement with those reported in cats (Hikasa
et al., 1996a, 1997b, 1998). In the present study,
however, the PaCO2 during maintenance anesthesia
with either sevo¯urane or iso¯urane is higher than that
reported previously in dogs (Steffey and Howland,
1977; Doi et al., 1987), cats (Hikasa et al., 1996a,
1997b, 1998), and humans (Doi and Ikeda, 1987). In
ruminants, distension of the rumen due to increasing
ruminal gases impairs the ventilation (Ungerer et al.,
1976), and positioning in lateral recumbency is asso-
247
ciated with respiratory depression (Fujimoto and
Lenehan, 1985). These factors may contribute to the
fact that hypercapnia during anesthesia in sheep was
greater than that in small animals reported previously.
It may be desirable that sheep being anesthetized with
either iso¯urane or sevo¯urane are mechanically ventilated in order to avoid hypercapnia.
The HR is unchanged or decreased slightly as
sevo¯urane concentration increased in dogs (Kazama
and Ikeda, 1988) and cats (Hikasa et al., 1997a),
however, it is also reported to increase in dogs (Bernard et al., 1990; Frink et al., 1992b). Iso¯urane has
been reported to induce a slight increase HR in dogs
(Bernard et al., 1990; Frink et al., 1992b), but induce a
decrease in HR in lambs (Brett et al., 1987, 1989) and
in cats (Hikasa et al., 1997b). In the current study, HR
during anesthesia in each group increased from baseline, which is presumably due to the in¯uence of
atropine premedication. There were no signi®cant
differences in HR between the groups, indicating that
HR during OS anesthesia does not differ from that
during OI anesthesia in sheep. However, HR during OI
anesthesia in long-term surgery tended to be higher
than that during OS anesthesia, which may result from
sympathetic activation due to the high PaCO2 in the
long-term OI group. In addition, arrhythmia was not
observed in sheep anesthetized with OS or OI. Therefore, sevo¯urane-oxygen anesthesia produces a stable
HR similar to iso¯urane-oxygen anesthesia in sheep
premedicated with atropine.
The current study revealed that hemodilution occurs
during sevo¯urane anesthesia similar to iso¯urane
anesthesia in sheep. These ®ndings are in agreement
with previous results that a surgical depth of anesthesia with OS or OI induces hemodilution in cats
(Hikasa et al., 1996a, 1998), which may be caused
by sequestration of RBCs in the spleen or by shifts in
body ¯uids associated with the decrease in arterial
pressure due to vasodilation and decreased cardiac
output during anesthesia.
Renal effects of sevo¯urane have been associated
with inorganic ¯uoride production during metabolism,
with resulting nephrotoxicity reported in rats, dogs
and humans (Martis et al., 1981; Frink et al., 1992a).
No such effect was observed in sheep. On the other
hand, the extent of hepatic injury with sevo¯urane
does not differ from that with iso¯urane; both anesthetics being less toxic than halothane in rats (Strum
248
Y. Hikasa et al. / Small Ruminant Research 36 (2000) 241±249
et al., 1987). In the current study, no signi®cant changes
in serum AST, ALT, ALP, glucose, BUN and creatinine values were observed for 3 days post-anesthesia
in all groups. These results indicate that hepatic and
renal injuries are not produced after 3±4 h anesthesia
with sevo¯urane as well as iso¯urane in healthy sheep.
In addition, no marked changes in serum sodium,
potassium and chloride ion concentrations were
observed in both anesthetic groups, indicating that
electrolyte balance during and after anesthesia with
sevo¯urane is similar to iso¯urane in sheep.
In conclusion, this study demonstrated that recovery
time from anesthesia with sevo¯urane-oxygen was
more rapid than with iso¯urane-oxygen in healthy
sheep that underwent minor surgical procedures.
Respiration rates, tidal volume, minute ventilation,
heart rates, arterial blood gases and acid±base values
during sevo¯urane-oxygen anesthesia were similar to
that during iso¯urane-oxygen anesthesia. There were
no signi®cant differences between sevo¯urane-oxygen and iso¯urane-oxygen anesthesia in hematological and serum biochemical values.
Acknowledgements
The authors thank Maruishi Pharmaceutical Co.,
Ltd., for the gift of sevo¯urane, and Miss K. Kondo
and Mrs. T. Kakuta for their technical assistance.
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