| ||||||||||||||
|
|
|||||||||||||
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 |
|---|
|
|
|---|
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 |
|---|
|
|
|---|
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 (57). 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 |
|---|
|
|
|---|
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 |
|---|
|
|
|---|
|
|
|
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.
|
| Discussion |
|---|
|
|
|---|
-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 |
|---|
| References |
|---|
|
|
|---|
This article has been cited by other articles:
![]() |
S. E. Copeland, L. A. Ladd, X.-Q. Gu, and L. E. Mather The Effects of General Anesthesia on the Central Nervous and Cardiovascular System Toxicity of Local Anesthetics Anesth. Analg., May 1, 2008; 106(5): 1429 - 1439. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Oda, T. Funao, K. Tanaka, and A. Asada Vasodilation Increases the Threshold for Bupivacaine-Induced Convulsions in Rats Anesth. Analg., March 1, 2004; 98(3): 677 - 682. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. M. Klein, T. Pierce, Y. Rubin, K. C. Nielsen, and S. M. Steele Successful Resuscitation After Ropivacaine-Induced Ventricular Fibrillation Anesth. Analg., September 1, 2003; 97(3): 901 - 903. [Abstract] [Full Text] [PDF] |
||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|