Clinical, cardiopulmonary, hematological and serum biochemical
effects of sevo¯urane and iso¯urane anesthesia in oxygen
under spontaneous breathing in sheep
Y. Hikasa
a,*, K. Saito
b, K. Takase
b, S. Ogasawara
b aDepartment of Veterinary Internal Medicine, Faculty of Agriculture, Tottori University,4-101 Koyama-Minami, Tottori-shi, Tottori 680-8553, Japan
bDepartment 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 short-term (60±80 min) or long-short-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 14.13.4 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
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 *Corresponding author. Tel.:81-857-31-5432;
fax:81-857-31-5432.
E-mail address: hikasa@muses.tottori-u.ac.jp (Y. Hikasa)
(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¯ur-ane sevo¯ur-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 rumi-nants. 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 46.49.9 S.D. kg), were used in this investigation. Health status was evaluated on the base of history, physical exam-inations, 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 intramuscu-larly 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 anesthe-tized 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¯ur-ane 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 men-tioned were done on each of the animals. All sheep were premedicated intramuscularly with atropine sul-fate (0.1 mg/kg; Tanabe, Japan). After 10 min, anesthesia was induced by intravenous infusion of sodium thiopental (mean 14.13.4 S.D. mg/kg; Rabonal, Tanabe, Japan). The end-point of the infu-sion was until the animals lay down and could be intubated. The animals were placed in lateral recum-bency 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 sur-geries. 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 extre-mities. 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.
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 anes-thetics.
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 accord-ing 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 30-min intervals during anesthesia, and at 30 and 60 30-min postanesthesia.
2.4. Hematological and serum biochemical measurements
Jugular blood samples were collected before atro-pine 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 transa-minase (AST), alanine transatransa-minase (ALT) and alka-line 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).
2.5. Statistical analyses
Data were analyzed by one-way analysis of var-iance for repeated measures to compare time-related variables within each anaesthetic group and Tukey's multiple comparison test was used to identify differ-ences between means. For unpaired comparisons between sevo¯urane and iso¯urane groups the data underwent an analysis of variance. When theF-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±Mann-Whitney test was used for the statistical evaluation. The signi®cance level of all tests was set atP< 0.05.
3. Results
3.1. Maintenance anesthesia and recovery from anesthesia
The duration (meanS.D.) of anesthesia with iso¯urane and sevo¯urane was 697 and 67 4 min for short-term anesthesia, and 19017 and 20120 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 (meanS.D.) of salivation ¯uids during OI and OS anesthesia were 2910 and 2614 ml/h in short-term anesthesia, and 3324 and 269 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 fol-lowing OI anesthesia in both short and long-term.
3.2. Cardiopulmonary ®ndings
differences between OI and OS groups in both HR and RR (Fig. 1). However, HR in OI group during long-term 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 abnor-mal ECG alterations were observed throughout anesthesia.
As shown in Fig. 3, the pHain 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±]ain 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 postanesthe-sia. 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 anesthe-sia 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 dif-ferences between OI and OS groups in serum bio-chemical values at any time.
4. Discussion
The concentration of sevo¯urane during mainte-nance anesthesia in this study was approximately
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 Anesthetic Number Time (min) during maintenance anesthesia
anesthesia of sheep 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. Short Isoflurane 8 0.8 0.2 0.7 0.3 0.9 0.3 1.0 0.3
Sevoflurane 9 1.2 0.3 1.3 0.4 1.3 0.6 1.4 0.8
Long Isoflurane 6 1.0 0.3 1.1 0.2 1.2 0.2 1.2 0.3 1.2 0.2 1.2 0.3 1.3 0.3 1.3 0.3 Sevoflurane 6 1.5 0.4 1.6 0.4 1.6 0.4 1.7 0.2 1.8 0.5 1.9 0.3 2.0 0.6 2.1 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 To stand and walk
x S.D. x S.D.
Short Isoflurane 8 8.4 5.7 23.0 10.5
Sevoflurane 9 5.1 2.3 10.2a 5.2
Long Isoflurane 6 12.6 5.7 37.7 21.1
Sevoflurane 6 5.8a 2.9 10.8a 4.5
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;
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 poten-cies 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 preex-isting or newly determined MAC values (Drummond, 1985). The end-tidal sevo¯urane/iso¯urane concen-tration ratio (equal to approximately 1.6) during main-tenance anesthesia in our study is very similar to the
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 meanS.D. (n6±9). (*) Signi®cantly different from base-line values (P< 0.05).
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. (n6±9). (*) Signi®cantly different from base-line values (P< 0.05).
Table 3
Hematological values during surgical depth of anesthesia with iso¯urane and sevo¯urane in spontaneously breathing sheep
Variable Period of Anesthetic No. of Base-line Time during maintenance anesthesia (min) Time after anesthesia anesthesia sheep
30 60 90 180±240 60 min 1 day
x S.D. x S.D. x S.D. x S.D. x S.D. x S.D. x S.D.
Packed cell Short Isoflurane 8 33 3 26b 3 25b 2 29a 2 35 2
volume (%) Sevoflurane 9 34 2 28 3 27b 2 28b 2 34 2
Long Isoflurane 6 34 3 30a 5 29b 4 29b 3 32 3 37 3
Sevoflurane 6 35 4 29b 3 29b 3 29b 3 33 4 37 3
Plasma protein Short Isoflurane 8 6.3 0.3 5.8b 0.4 5.6b 0.3 5.8b 0.3 6.5 0.5 (g/dl) Sevoflurane 9 6.2 0.4 5.8 0.3 5.7b 0.3 5.8b 0.3 6.5 0.4 Long Isoflurane 6 6.9 0.5 6.2a 0.6 6.4b 0.5 6.2b 0.6 6.2a 0.6 6.6 0.6 Sevoflurane 6 6.8 0.4 6.1b 0.3 6.0b 0.4 6.0b 0.4 6.0b 0.4 6.6 0.3 aSigni®cantly different from base-line value atP< 0.05.
bSigni®cantly different from base-line value atP< 0.01.
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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 anesthe-sia in both short and long-term of anestheanesthe-sia 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¯ur-ane, 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-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 ven-tilated 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 (Ber-nard 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 base-line, 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 PaCO2in the long-term OI group. In addition, arrhythmia was not observed in sheep anesthetized with OS or OI. There-fore, 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 anesthe-sia 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.
et al., 1987). In the current study, no signi®cant changes in serum AST, ALT, ALP, glucose, BUN and creati-nine 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-oxy-gen and iso¯urane-oxysevo¯urane-oxy-gen anesthesia in hematologi-cal and serum biochemihematologi-cal 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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