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Anesth Analg 1999;88:155-159
© 1999 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

A Comparison of the Effects of Propofol and Sevoflurane on the Systemic Toxicity of Intravenous Bupivacaine in Rats

Shigeo Ohmura, MD, Toshikazu Ohta, MD, Ken Yamamoto, MD, and Tsutomu Kobayashi, MD

Department of Anesthesiology and Intensive Care Medicine, School of Medicine, Kanazawa University, Kanazawa, Japan

Address correspondence and reprint requests to Shigeo Ohmura, MD, Department of Anesthesiology and Intensive Care Medicine, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan. Address e-mail to ohmura{at}med.kanazawa-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We compared the effects of propofol and sevoflurane on bupivacaine-induced central nervous system and cardiovascular toxicity in rats. Thirty-four male Sprague-Dawley rats were anesthetized with 70% N2O/30% O2 plus the 50% effective dose (ED50) of propofol (propofol group, n = 12); 70% N2O/30% O2 plus ED50 of sevoflurane (sevoflurane group, n = 11); or 70% N2O/30% O2 (control group, n = 11). Bupivacaine was infused at a constant rate of 2 mg · kg-1 · min-1 while electrocardiogram, electroencephalogram, and invasive arterial pressure were continuously monitored. The cumulative doses of bupivacaine that induced dysrhythmias, seizures, and 50% reduction of heart rate were larger in the propofol and sevoflurane groups than in the control group. The cumulative dose of bupivacaine that induced a 50% reduction in the mean arterial blood pressure was larger in the propofol group than in the sevoflurane and control groups. The margin of safety, assessed by the time between the onset of dysrhythmias and 50% reduction of mean arterial blood pressure, was wider in the propofol group than in the sevoflurane group. We conclude that propofol and sevoflurane attenuate bupivacaine-induced dysrhythmias and seizures and that propofol has a wider margin of safety than sevoflurane.

Implications: In anesthetized patients, dysrhythmias may be the only warning sign of intravascular injection of bupivacaine. Because propofol has a wider margin of safety than sevoflurane, life-threatening cardiovascular depression may be prevented by stopping the injection of bupivacaine at the onset of dysrhythmias during propofol anesthesia.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Regional anesthesia is widely used in combination with general anesthesia to reduce intraoperative general anesthetic requirements and for postoperative pain relief. Administration of local anesthetics has a potential hazard of intravascular injection, inducing life-threatening central nervous system (CNS) and cardiovascular toxicity (1). However, local anesthetics are often administered during general anesthesia, when the patient cannot verbalize the early warning symptoms of intravascular injection, such as metallic taste, dizziness, or tinnitus (2). Therefore, for the safe management of patients receiving local anesthetics during general anesthesia, the effects of general anesthetics on the local anesthetic toxicity must be elucidated.

Using regional anesthesia as an adjunct, general anesthesia can be maintained with either volatile or IV anesthetics. Concerning the effects of volatile anesthetics on the local anesthetic toxicity, Badgwell et al. (3) reported that isoflurane plus nitrous oxide prevents or attenuates bupivacaine-induced dysrhythmias and seizures in pigs. Fukuda et al. (4) also demonstrated that sevoflurane is equivalent to isoflurane for attenuating bupivacaine-induced dysrhythmias and seizures in rats. Concerning the effects of IV anesthetics on local anesthetic toxicity, several reports have indicated an anticonvulsant effect of propofol on bupivacaine- and lidocaine-induced seizures in rats (5–7). However, whether propofol is as effective as volatile anesthetics for attenuating the systemic toxicity of bupivacaine has not been investigated. We designed the present study to compare the effects of propofol and sevoflurane on bupivacaine-induced CNS and cardiovascular toxicity in rats.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The experimental protocol was approved by our animal care committee. Thirty-four male Sprague-Dawley rats, 10–11 wk of age, weighing 310–385 g, were studied. The rats were randomly assigned to one of the three groups: a propofol group (n = 12), a sevoflurane group (n = 11), and a control group (n = 11). Anesthesia was induced with 5% sevoflurane in oxygen in a 1-L container. The trachea was cannulated via a tracheostomy. The lungs were mechanically ventilated using a piston ventilator with a tidal volume of 12 mL/kg at a frequency of 40–55 breaths/min to maintain the PaCO2 between 35 and 45 mm Hg. Needle electrodes were placed for recording lead II of the electrocardiogram (ECG) and frontooccipital electroencephalogram (EEG). Body temperature was measured rectally and maintained between 37 and 38°C by using a heating lamp.

During surgical preparation, anesthesia was maintained with 70% N2O/30% O2 and 4% sevoflurane. The inspired concentrations of sevoflurane and nitrous oxide were continuously monitored using a calibrated anesthetic gas monitor. A cannula was placed through the right femoral vein into the vena cava for infusion of bupivacaine. Another cannula was placed into the left femoral vein for administration of other drugs (see below). The right femoral artery was cannulated for arterial pressure monitoring and for blood sampling. ECG, EEG, heart rate (HR), and mean arterial pressure (MAP) were continuously recorded.

After surgical preparation, a constant IV infusion of vecuronium was started at 0.1 mg · kg-1 · min-1 to produce muscle paralysis. After a stabilization period of approximately 20 min, anesthesia was changed according to the group assignment. In the propofol group, sevoflurane was discontinued and anesthesia was maintained with 70% N2O/30% O2 plus the 50% effective dose (ED50) of propofol infusion. The ED50 value used for propofol infusion in rats was 650 µg · kg-1 · min-1 (8), which was determined by using the tail-clamp technique. A 1% propofol solution was continuously infused IV at 3.9 mL · kg-1 · h-1. In the sevoflurane group, anesthesia was maintained with 70% N2O/30% O2 plus ED50 of sevoflurane. The ED50 value used for sevoflurane in rats was 2.8% (9), which corresponds to the minimum alveolar anesthetic concentration determined by using the tail-clamp technique. In the control group, sevoflurane was discontinued and anesthesia was maintained with 70% N2O/30% O2 (N2O alone). Propofol vehicle (10% Intralipid®; Kabi Pharmacia, Uppsala, Sweden) was continuously infused IV at 3.9 mL · kg-1 · h-1 in the sevoflurane and control groups.

Thirty minutes after the change in anesthesia, baseline recordings were obtained, and arterial blood was sampled for blood gas analysis. Bupivacaine was then continuously infused IV at 2 mg · kg-1 · min-1 using an electronic infusion pump.

The following toxic end points were recorded, and the cumulative doses of bupivacaine required to produce them were calculated: first dysrhythmia (DYS), defined as the first appearance of cardiac rhythm disturbance on the ECG accompanied by an abnormal pulsation on the arterial pressure trace; first seizure activity (SZ), defined as the appearance of multiple sharp waves of >100 µV on the EEG; 25% reduction of HR from the baseline value (HR-25%); 50% reduction of HR from the baseline value (HR-50%); 25% reduction of MAP from the baseline value (MAP-25%); 50% reduction of MAP from the baseline value (MAP-50%); final systole (FSYS), defined as the last recognized beat on the ECG, allowing 1 min for additional beats to appear.

The time between DYS and MAP-50% was also measured to evaluate the margin of safety between the onset of dysrhythmias and life-threatening cardiovascular depression.

All data are presented as means ± SD. Between-group comparisons were performed using one-way analysis of variance and were assessed by using Scheffé's F-test. Within-group comparisons were performed by using repeated-measures one-way analysis of variance and were assessed by using the paired t-test. Multiple analysis of variance was used to compare MAP and HR versus time for the three groups. A P value <0.05 was considered to be statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Body weight, baseline blood gases, and baseline HR did not differ significantly among the groups (Table 1). In contrast, baseline MAP differed among groups, and the lowest baseline MAP was observed in the sevoflurane group (Table 1).


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  		Table 1. Baseline Data
 
All animals developed dysrhythmias, seizures, and cardiac arrest. The cumulative dose of bupivacaine required to produce DYS was significantly larger in the propofol (13.4 ± 6.8 mg/kg) and sevoflurane (19.8 ± 7.5 mg/kg) groups than in the control group (6.9 ± 0.8 mg/kg) (Fig. 1). The cumulative dose of bupivacaine required to produce SZ was also larger in the propofol (31.1 ± 3.6 mg/kg) and sevoflurane (19.1 ± 2.2 mg/kg) groups than in the control group (6.9 ± 0.6 mg/kg) (Fig. 1). Compared with the sevoflurane group, the dose that induced DYS in the propofol group was significantly smaller, and the dose that induced SZ in the propofol group was significantly larger (Fig. 1). In the sevoflurane and control groups, no statistically significant differences were seen between the cumulative doses that produced DYS and SZ. In the propofol group, by contrast, the cumulative dose that produced SZ was significantly larger than the dose that produced DYS.



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  		Figure 1. Cumulative doses of bupivacaine required to produce first dysrhythmia and first seizure activity in the propofol ({blacksquare}; n = 12), sevoflurane ({image}; n = 11), and control ({square}; n = 11) groups. Each bar represents mean ± SD. *P < 0.05 compared with the control group. {dagger}P < 0.05 compared with the sevoflurane group. In the propofol group, the cumulative dose that induced first seizure activity was significantly larger than the cumulative dose that induced first dysrhythmia.

 
The cumulative doses of bupivacaine required to produce HR-25% and HR-50% were significantly larger in the propofol group (10.8 ± 2.5 mg/kg and 23.2 ± 8.2 mg/kg) than in the control group (7.9 ± 0.8 mg/kg and 11.8 ± 3.6 mg/kg) (Fig. 2). The cumulative dose that produced HR-50% was also larger in the sevoflurane group (23.9 ± 9.3 mg/kg) than in the control group (Fig. 2). No statistically significant differences were seen between the propofol and sevoflurane groups with regard to the cumulative doses that produced HR-25% and HR-50%. The cumulative doses of bupivacaine required to produce MAP-25% and MAP-50% were significantly larger in the propofol group (31.1 ± 7.4 mg/kg and 35.8 ± 8.2 mg/kg) than in the sevoflurane (18.2 ± 11.5 mg/kg and 26.3 ± 9.7 mg/kg) and control (16.7 ± 5.2 mg/kg and 23.8 ± 8.2 mg/kg) groups (Fig. 2). The cumulative dose that produced FSYS did not differ significantly among the propofol (43.9 ± 8.9 mg/kg), sevoflurane (39.1 ± 6.8 mg/kg), and control (39.1 ± 9.5 mg/kg) groups.



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  		Figure 2. Cumulative doses of bupivacaine required to produce 25% and 50% reduction of basal heart rate (HR-25% and HR-50%), 25% and 50% reduction of basal mean arterial pressure (MAP-25% and MAP-50%), and final systole (FSYS) in the propofol ({blacksquare}; n = 12), sevoflurane ({image}; n = 11), and control ({square}; n = 11) groups. Each bar represents mean ± SD. *P < 0.05 compared with the control group. {dagger}P < 0.05 compared with the sevoflurane group.

 
DYS preceded MAP-50% in all animals. The time between DYS and MAP-50% was significantly longer in the propofol (11.2 ± 5.6 min) and control (8.4 ± 4.1 min) groups than in the sevoflurane group (3.3 ± 3.8 min).

After beginning the bupivacaine infusion, a significant increase in MAP was noted in the control and propofol groups (Fig. 3). The maximal increase in MAP from the baseline value until DYS was larger in the control (41.6 ± 10.0 mm Hg) and propofol (51.7 ± 15.5 mm Hg) groups than in the sevoflurane group (11.0 ± 4.9 mm Hg). After beginning the bupivacaine infusion, HR decreased in all groups (Fig. 3). The HR change preceding DYS did not differ significantly among the groups.



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  		Figure 3. Mean arterial pressure (MAP) and heart rate (HR) versus IV bupivacaine infusion (2 mg · kg-1 · min-1) time until first dysrhythmia occurred in the three groups. In the propofol group (•), n = 12 until 3 min; n = 9 until 4 min; n = 6 until 5 min; n = 5 until 7 min; n = 4 until 8 min; and n = 3 until 9 min. In the sevoflurane group ({circ}), n = 11 until 5 min; n = 10 until 6 min; n = 9 until 8 min; n = 6 until 9 min; n = 5 until 10 min; and n = 3 until 11 min. In the control group ({square}), n = 11 until 2 min; and n = 10 until 3 min. Each symbol represents mean ± SD. MAP increased significantly above baseline (0 min) beyond 2 min in the propofol and control groups. In the sevoflurane group, MAP was higher than baseline at 2 min, but it decreased significantly below baseline after 5 min. HR values decreased significantly below baseline after 2 min in all the groups.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our results demonstrate that propofol and sevoflurane attenuate bupivacaine-induced dysrhythmias and seizures in rats. The results of the present study are consistent with the observation that bupivacaine-induced dysrhythmias are prevented or attenuated by isoflurane and sevoflurane (3,4). Although the mechanism of this antidysrhythmic effect is not clear, a central site of action is suggested. Heavner (10) reported that the intracerebroventricular administration of bupivacaine can produce ventricular dysrhythmias, tachycardia, and hypertension in cats. Thomas et al. (11) reported that the direct application of bupivacaine within the medullary regions of the CNS can result in ventricular dysrhythmias, bradycardia, and hypotension in rats. Bernards and Artru (12) hypothesized that the dysrhythmias and hypertension produced by the intracerebroventricular administration of bupivacaine are caused by an increase in autonomic nervous system outflow by blockade of the inhibitory {gamma}-aminobutyric acid (GABA) neurons. Because propofol enhances GABA-mediated chloride ion conductance in some neuronal systems (13), the antidysrhythmic effect of propofol observed in this study may be caused by GABA potentiation within the CNS. However, the blockade of autonomic nervous system by propofol seems to be less complete than the blockade by sevoflurane because hypertensive reactions preceding DYS could not be prevented by propofol. Although the ED50 of propofol had an antidysrhythmic effect on bupivacaine-induced dysrhythmias in this study, Kamibayashi et al. (14) reported that propofol enhances epinephrine-induced dysrhythmias in a dose-dependent manner in dogs. Further studies are indicated to determine whether larger doses of propofol enhance bupivacaine-induced dysrhythmias and myocardial depression.

In this study, propofol and sevoflurane had an anticonvulsant effect on bupivacaine-induced seizures. The finding is consistent with that of Fukuda et al. (4) with regard to sevoflurane. The finding is also consistent with the several reports on the effects of propofol on local anesthetic-induced seizures. Heavner et al. (5) reported that propofol is effective in stopping bupivacaine-induced seizures in rats. Dose-dependent suppression of lidocaine-induced seizures by propofol was also demonstrated in rats (6,7). Local anesthetic-induced seizures seem to originate from subcortical sites, such as the amygdala and hippocampus (15). Propofol may inhibit these subcortical sites more specifically than sevoflurane because the anticonvulsant effect of propofol is superior to that of sevoflurane at the ED50. Although bupivacaine-induced seizures were not completely inhibited by propofol in the present study, previous reports demonstrated that larger doses of propofol, such as 48 mg · kg-1 · h-1 after a 8-mg/kg bolus (6) or 40 mg · kg-1 · h-1 after a 10-mg/kg bolus (7) completely inhibit lidocaine-induced seizures in rats.

Reduction in HR and MAP was a late manifestation of systemic toxicity of bupivacaine. The results of the present study show that propofol, as well as sevoflurane, has a protective effect against bupivacaine-induced reduction in HR. They also show that propofol, but not sevoflurane, has a protective effect against a bupivacaine-induced reduction in MAP. Although the reason for this difference between propofol and sevoflurane is not clear, two factors may be involved. First, incomplete blockade of autonomic nervous system by propofol, as assessed by the hypertensive reactions observed in the propofol group, may have a beneficial effect against bupivacaine-induced myocardial depression. Second, the direct myocardial depressant effect of sevoflurane, as assessed by the lowest baseline MAP observed in the sevoflurane group, may exacerbate bupivacaine-induced myocardial depression.

Our data further suggest that sevoflurane has a narrow margin of safety between DYS and life-threatening cardiovascular depression. Therefore, during sevoflurane anesthesia, DYS may warn of impending cardiac depression induced by bupivacaine. However, propofol has a wider margin of safety than sevoflurane. Therefore, during propofol anesthesia, life-threatening cardiovascular depression may be prevented by stopping the injection of bupivacaine at DYS. Because dysrhythmias may be the only warning sign observed in the anesthetized patient, propofol would be a better choice than sevoflurane to use in combination with bupivacaine.

In an in vitro experiment using isolated guinea pig ventricle muscle, Clarkson and Hondeghem (16) demonstrated that bupivacaine increases the degree of myocardial sodium channel blockade as HR increases. Therefore, increased HR may influence the cumulative doses of bupivacaine that induce dysrhythmias. De Kock et al. (17) suggested that the increased toxic threshold of bupivacaine in rats pretreated with clonidine may be explained by clonidine-induced bradycardia. Fukuda et al. (4) suggested that the increased threshold for bupivacaine-induced dysrhythmias in rats anesthetized with sevoflurane or isoflurane may be explained by bradycardia induced by volatile anesthetics. However, Bernards and Artru (18) reported that HR does not correlate well with the threshold for bupivacaine-induced dysrhythmias in rabbits anesthetized with halothane and nitrous oxide. In the present study, HR did not correlate well with the cumulative doses of bupivacaine that induced dysrhythmias because neither baseline HR nor the HR change preceding DYS differed significantly among groups.

The propofol solution contains Intralipid® as vehicle. Weinberg et al. (19) reported that an infusion of Intralipid® reduces bupivacaine-induced cardiovascular toxicity in rats. Therefore, to eliminate the effects of the Intralipid® contained in the propofol solution, Intralipid® was administered at the same rate of infusion as propofol in the sevoflurane and control groups. In the present study, systemic toxicity of bupivacaine was induced by a constant IV infusion of bupivacaine. This technique allows the toxic end points to occur with predictable doses of bupivacaine (20). However, the cumulative doses of bupivacaine required to produce the toxic end points are considerably affected by the rate of infusion (21). In this study, nitrous oxide was used for basal anesthesia. De Jong et al. (22) reported that nitrous oxide increases the threshold for lidocaine-induced seizures in cats. However, we believe that the comparative findings obtained in the present study are valid because nitrous oxide was administered to all animals in all three groups. In addition, vecuronium was administered to produce muscle paralysis. However, the use of vecuronium had little influence on the data because none of the muscle relaxants used in clinical anesthesia have been reported to cause either EEG or clinical seizure activity (15).

In summary, we conclude that 1) propofol and sevoflurane attenuate bupivacaine-induced dysrhythmias and seizures in rats; 2) they also have a protective effect against bupivacaine-induced reduction in HR; 3) propofol, but not sevoflurane, has a protective effect against bupivacaine-induced reduction in MAP; and 4) propofol has a wider margin of safety than sevoflurane between DYS and life-threatening cardiovascular depression.


   Acknowledgments
 
The authors thank Ms. Nobuko Ohmoto, Ms. Keiko Yachi, and Ms. Yuko Yamamoto for their technical support and assistance.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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  12. Bernards CM, Artru AA. Hexamethonium and midazolam terminate dysrhythmias and hypertension caused by intracerebroventricular bupivacaine in rabbits. Anesthesiology 1991;74:89–96.[Web of Science][Medline]
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Accepted for publication October 7, 1998.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press