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REGIONAL ANESTHESIA

Systemic Toxicity and Resuscitation in Bupivacaine-, Levobupivacaine-, or Ropivacaine-Infused Rats

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

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We compared the systemic toxicity of bupivacaine, levobupivacaine, and ropivacaine in anesthetized rats. We also compared the ability to resuscitate rats after lethal doses of these local anesthetics. Bupivacaine, levobupivacaine, or ropivacaine was infused at a rate of 2 mg · kg^-1 · min^-1 while electrocardiogram, electroencephalogram, and arterial pressure were continuously monitored. When asystole was recorded, drug infusion was stopped and a resuscitation sequence was begun. Epinephrine 0.01 mg/kg was administered at 1-min intervals while external cardiac compressions were applied. Resuscitation was considered successful when a systolic arterial pressure 100 mm Hg was achieved within 5 min. The cumulative doses of levobupivacaine and ropivacaine that produced seizures were similar and were larger than those of bupivacaine. The cumulative doses of levobupivacaine that produced dysrhythmias and asystole were smaller than the corresponding doses of ropivacaine, but they were larger than those of bupivacaine. The number of successful resuscitations did not differ among groups. However, a smaller dose of epinephrine was required in the Ropivacaine group than in the other groups. We conclude that the systemic toxicity of levobupivacaine is intermediate between that of ropivacaine and bupivacaine when administered at the same rate and that ropivacaine-induced cardiac arrest appears to be more susceptible to treatment than that induced by bupivacaine or levobupivacaine.

IMPLICATIONS: We compared the systemic toxicity induced by constant infusions of bupivacaine, levobupivacaine, and ropivacaine in anesthetized rats. The systemic toxicity of levobupivacaine was less than that of bupivacaine but more than that of ropivacaine. Ropivacaine-induced cardiac arrest was more susceptible to treatment than that induced by bupivacaine or levobupivacaine.

	Introduction

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The administration of local anesthetics carries the potential hazard of intravascular injection, inducing life-threatening central nervous system (CNS) and cardiovascular (CV) toxicity (1). Since Albright published an alarming editorial about the severity of CV toxicity of bupivacaine in 1979 (2), motivated researchers have worked to develop new long-acting amide local anesthetics with less CV toxicity. As a result, ropivacaine was introduced into clinical practice. Although bupivacaine has been marketed as a 50:50 racemic mixture of two optically active enantiomers in levorotatory S- and dextrorotatory R-configurations, ropivacaine is made and used as a pure levorotatory S-enantiomer (3). In vitro (4,5) and in vivo studies (6–10) have demonstrated that ropivacaine has less potential for CNS and CV toxicity than bupivacaine. Recently, levobupivacaine, the pure levorotatory S-enantiomer of bupivacaine, has been evaluated as a new long-acting amide local anesthetic with less CV toxicity. As a result, it has been demonstrated either in vitro (11,12) or in vivo (13,14) that levobupivacaine has less potential for CNS and CV toxicity when compared with R-bupivacaine or bupivacaine.

An important issue that requires investigation is whether levobupivacaine is superior to ropivacaine. With regard to the relative systemic toxicity of levobupivacaine and ropivacaine, only a few data comparing the CV toxicity of these local anesthetics are available (15–17). In addition, there is a lack of data comparing the difficulty of resuscitation after lethal doses of these local anesthetics, except for one recently published report (18). We designed the present study to compare the CNS and CV toxicity of bupivacaine, levobupivacaine, and ropivacaine in anesthetized rats. We also compared the ability to resuscitate rats after lethal doses of these anesthetics.

	Methods

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All surgical procedures and experimental protocols were approved by the Institutional Animal Care and Use Committee. Thirty-six male Sprague-Dawley rats, weighing 330–380 g, were studied. The animals were randomly assigned to one of the three groups: a Bupivacaine group (n = 12), a Levobupivacaine group (n = 12), and a Ropivacaine group (n = 12). Anesthesia was induced with 4% isoflurane in oxygen in a 1-L container. The trachea was cannulated via 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 at 35 to 45 mm Hg. Needle electrodes were placed for recording lead II of the electrocardiogram (ECG) and frontooccipital electroencephalogram. Body temperature was measured rectally and maintained at 37° to 38°C by using a heating lamp.

During surgical preparation, anesthesia was maintained with 3% isoflurane in oxygen. The inspired concentration of isoflurane was continuously monitored using a calibrated anesthetic gas monitor. A cannula was placed through the right femoral vein into the vena cava for local anesthetic infusion and for administration of epinephrine. The right femoral artery was cannulated for arterial pressure monitoring and for blood sampling. Arterial pressure, ECG, and electroencephalogram were continuously recorded.

After surgical preparation, anesthesia was maintained with 1% isoflurane in oxygen. A constant infusion of vecuronium bromide was started at 0.1 mg · kg^-1 · min^-1 to produce muscle paralysis. Then the animals were left undisturbed for at least 20 min. After stable vital signs and satisfactory blood-gas values were confirmed, drug infusion was begun with bupivacaine 0.5%, levobupi- vacaine 0.5%, or ropivacaine 0.5% at a rate of 2 mg · kg^-1 · min^-1. An electronic syringe pump was used for the infusion. The following toxic end points were recorded, and the cumulative doses of local anesthetics required to produce them were calculated: first seizure activity (SZ), defined as the appearance of multiple sharp waves of >100 µV on the electroencephalogram; first dysrhythmia (DYS), defined as the appearance of ventricular cardiac rhythm disturbance on the ECG accompanied by an abnormal pulsation on the arterial pressure trace; and asystole (ASYS), defined as the lack of recognizable beat on the ECG for 1 min after the appearance of the last systole.

When ASYS was recorded, drug infusion was stopped. Isoflurane was discontinued and the animals were ventilated with 100% oxygen. After 1 min, a resuscitation sequence was begun. Epinephrine 0.01 mg/kg was administered IV at 1-min intervals until a spontaneous ECG rhythm returned. At the same time, external cardiac compressions were applied at a rate of approximately 300 bpm to produce a systolic arterial pressure >40 mm Hg. Cardiac compressions were continued until self-sustained pulsatile flow returned. The animals were considered to have been successfully resuscitated if a self-sustained systolic arterial pressure of 100 mm Hg or more was achieved within 5 min.

Arterial blood was drawn for analysis of plasma concentrations of local anesthetics at the onset of SZ, DYS, and ASYS, and at the time when successful resuscitation was achieved. Plasma was separated and frozen at -80°C until the day of analysis. Plasma concentrations of local anesthetics were determined by high-performance liquid chromatography based on the method reported by Adams et al. (19). A linear standard curve was obtained over a range of 0.5 to 60 µg/mL for each of the local anesthetics. The coefficients of variation for the assay of bupivacaine, levobupivacaine and ropivacaine were 1.8%, 4.1%, and 3.7%, respectively.

Data are presented as mean ± SD unless otherwise indicated. Between-group comparisons were performed by 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 Student’s t-test. Multiple analysis of variance was used to compare heart rate (HR) and mean arterial pressure (MAP) versus time for the three groups. Categorical variables were analyzed using the ² and Kruskal-Wallis tests and are presented as frequency and percentage. A P value < 0.05 was considered to be statistically significant.

	Results

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Body weight, baseline blood gases, HR, and MAP did not differ significantly among the groups (Table 1).

View larger version (27K): [in this window] [in a new window]   Figure 1. Cumulative doses (A) and plasma concentrations (B) of local anesthetics at the onset of first seizure activity, first dysrhythmia, and asystole in the Bupivacaine (open bars; n = 12), Levobupivacaine (hatched bars; n = 12), and Ropivacaine (solid bars; n = 12) groups. Each bar represents mean ± SD. *P < 0.05 compared with the Bupivacaine group. P < 0.05 compared with the Levobupivacaine group.

After the beginning of drug infusion, HR decreased in all animals. The HR change preceding SZ did not differ significantly among the groups (Fig. 2). After the beginning of drug infusion, a significant increase in MAP was noted in the three groups. No statistically significant difference was seen in the maximal increase in MAP from the baseline value in the Bupivacaine (21 ± 7 mm Hg), Levobupivacaine (23 ± 8 mm Hg), and Ropivacaine (24 ± 18 mm Hg) groups. The MAP change preceding SZ did not differ significantly among the groups (Fig. 2). HR and MAP decreased gradually between the onset of SZ and DYS in the Levobupivacaine and Ropivacaine groups (Fig. 2). The rates of decline in HR and MAP during this period were slower in the Ropivacaine group than in the Levobupivacaine group. After the onset of DYS, HR and MAP decreased rapidly in all animals.

View larger version (17K): [in this window] [in a new window]   Figure 2. Heart rate (A) and mean arterial pressure (B) before the infusion of local anesthetics (0 min), and at the onset of first seizure activity, first dysrhythmia, and asystole in the Bupivacaine (filled squares; n = 12), Levobupivacaine (open circles; n = 12), and Ropivacaine (filled circles; n = 12) groups. Each symbol represents mean ± SD; (a), (b), and (c) indicate the onset of first dysrhythmia in the Bupivacaine, Levobupivacaine, and Ropivacaine groups, respectively.

View larger version (20K): [in this window] [in a new window]   Figure 3. Plasma concentrations of bupivacaine (open bar; n = 11), levobupivacaine (hatched bar; n = 10), and ropivacaine (solid bar; n = 11) at the time when successful resuscitation was achieved. Each bar represents mean ± SD. *P < 0.05 compared with the Bupivacaine and Levobupivacaine groups.

	Discussion

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Our results also demonstrate that the CV toxicity of levobupivacaine is intermediate between that of ropivacaine and bupivacaine when administered at the same rate. DYS induced by bupivacaine may be associated with decreased intraventricular conduction velocity and reentry phenomenon (20). Mazoit et al. (15) reported that bupivacaine, levobupivacaine, and ropivacaine induce a maximum increase in QRS duration in the isolated rabbit heart in the respective ratio of 1:0.4:0.3. In the present study, the cumulative doses of bupivacaine, levobupivacaine, and ropivacaine required to produce DYS were in the respective ratio of 1:3.3:6.9, indicating that the dysrhythmogenic potential of levobupivacaine is intermediate between that of ropivacaine and bupivacaine. In addition, the plasma concentration of levobupivacaine at the onset of DYS was also intermediate between those of ropivacaine and bupivacaine. The results of the present study are consistent with the observation that ropivacaine and levobupivacaine have less potential for producing DYS compared with bupivacaine in vivo (7,8,10,13,14). Groban et al. (17) reported that the incidence of extrasystoles induced by programmable electrical stimulation after incremental overdosage with bupivacaine or levobupivacaine was more frequent than that with ropivacaine in anesthetized dogs.

With regard to the mechanism of death from bupivacaine toxicity, some propose that it results from a direct myocardial depression (8,17), and others propose that it results from ventricular dysrhythmias (7,13). Morrison et al. (16) reported that the cardiotoxicity potency ratios for bupivacaine, levobupivacaine, and ropivacaine, when injected directly into the coronary arteries in anesthetized pigs, are 2.1:1.2:1. In the present study, HR and MAP were well maintained until the onset of DYS in the levobupivacaine- or ropivacaine-infused animals. However, HR and MAP decreased abruptly thereafter. Therefore, we suppose that DYS may also play a significant role as a cause of death from CV toxicity induced by levobupivacaine or ropivacaine in our ventilated rat model.

In the present study, the cumulative dose of levobupivacaine required to produce ASYS was also intermediate between those of ropivacaine and bupivacaine. The finding is consistent with previous reports that the fatal doses of ropivacaine and levobupivacaine are larger than that of bupivacaine in awake sheep (7,14) and that the cumulative dose of ropivacaine inducing ASYS is larger than that of bupivacaine in anesthetized rats (10).

Interestingly, no difference was seen between the plasma concentrations of bupivacaine, levobupivacaine, and ropivacaine at the onset of ASYS despite the fact that there was a significant difference between the plasma concentrations of these drugs at the onset of DYS. Consistent with our finding, Dony et al. (10) reported that the plasma concentrations of bupivacaine and ropivacaine at the onset of ASYS were similar when injected at the same rate in anesthetized rats. Our finding is also consistent with the report of Groban et al. (18) that the plasma concentrations of bupivacaine, levobupivacaine, and ropivacaine were similar at the onset of CV collapse after incremental overdosing with these drugs. Bupivacaine, levobupivacaine, and ropivacaine are extensively metabolized by the hepatic cytochrome P450 (CYP) system, primarily CYP3A4 and CYP1A2 isoforms (21,22). Therefore, hepatic dysfunction attributable to CV depression induced by local anesthetic toxicity is likely to have significant effects on the elimination of these drugs. The results of the present study indicate that the metabolism of ropivacaine was maintained better than that of bupivacaine or that of levobupivacaine during the CV depressive state between the onset of DYS and ASYS.

Our results demonstrate that the ability to resuscitate animals after lethal doses of bupivacaine, levobupivacaine, and ropivacaine is similar. Groban et al. (18), comparing cardiac resuscitation after incremental overdosage with bupivacaine, levobupivacaine, and ropivacaine in anesthetized dogs, reported that mortality from these anesthetics was 50%, 30%, and 10%, respectively. In their study, however, resuscitative procedures were started in the majority of animals according to the hypotension criterion defined as a MAP 45 mm Hg. In our study, by contrast, a resuscitation sequence was begun in every animal after the recognition of spontaneous ASYS.

During the resuscitation period, epinephrine was administered because it is effective for local anesthetic toxicity in dogs (23), cats (24), and rats (25). In the present study, ropivacaine-intoxicated animals were resuscitated successfully with a smaller amount of epinephrine than the other animals. In addition, the plasma concentration of ropivacaine at the time when successful resuscitation was achieved was larger than that of bupivacaine or levobupivacaine. These findings indicate that ropivacaine-induced cardiac arrest is more susceptible to treatment than that induced by bupivacaine or levobupivacaine. In the report of Groban et al. (18), epinephrine induced ventricular DYS more frequently in bupivacaine-intoxicated dogs than in dogs given ropivacaine. However, in our study, no significant difference was seen between the local anesthetics in the incidence of DYS during resuscitation.

The experimental design used in this study has its own limitations. First, isoflurane was used for basal anesthesia. Isoflurane attenuates bupivacaine-induced dysrhythmias and seizures in pigs (26) and in rats (27). However, we believe that the comparative findings obtained in the present study are valid because isoflurane was administered to all animals in all three groups. Second, systemic toxicity was induced by a constant infusion of local anesthetics. This technique allows the toxic end points to occur with predictable doses of each anesthetic (28). However, the slower rate of infusion compared with bolus injection allows the administration of larger doses of local anesthetic before the onset of each toxic end point (29). Third, the local anesthetics were administered at equivalent doses. Polley et al. (30) reported that ropivacaine is 40% less potent than bupivacaine based on the comparison of the 50% effective concentrations of these anesthetics for epidural analgesia in labor. Their findings suggest that the apparent advantages of ropivacaine in terms of lower systemic toxicity may be offset by a decreased analgesic potency. However, controversy still exists with regard to the relative clinical potency of ropivacaine and bupivacaine because numerous studies describe equipotent analgesia between them (31). Therefore, the choice between long-acting amide local anesthetics in clinical practice requires further investigation, particularly to compare toxicity at equipotent doses.

In summary, we conclude that the CNS toxicity of levobupivacaine and ropivacaine is similar and less than that of bupivacaine; the CV toxicity of levobupivacaine is intermediate between that of ropivacaine and bupivacaine when administered at the same rate; the ability to resuscitate animals after lethal doses of these drugs is similar; and ropivacaine-induced cardiac arrest appears to be more susceptible to treatment than that induced by bupivacaine or levobupivacaine.

	Acknowledgments

 
The authors thank Chiroscience Ltd., Cambridge, UK, Maruishi Pharmaceutical Co., Ltd., Osaka, Japan, and Astra Pain Control AB, Södertälje, Sweden for supplying the local anesthetics. The authors also thank Ms. Keiko Yachi and Ms. Yuko Yamamoto for their technical support and assistance.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999