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ANESTHETIC PHARMACOLOGY

Vasodilation Increases the Threshold for Bupivacaine-Induced Convulsions in Rats

From the Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan

Address correspondence and reprint requests to Yutaka Oda, Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Osaka City University, 1-5-7 Asahimachi, Abeno-ku, Osaka 545-8586, Japan. Address email to odayou{at}msic med.osaka-cu.ac.jp.

Bupivacaine affects the vascular resistance by peripheral and central nervous system (CNS) mechanisms. As vasoconstrictors increase the CNS toxicity of IV bupivacaine, vasodilators may decrease its CNS toxicity. We examined the hypothesis that vasodilators decrease the CNS toxicity of bupivacaine in awake, spontaneously breathing rats. Male Sprague-Dawley rats were randomly divided into control (C), nicardipine (N), and phentolamine (P) groups (n = 12 in each group). Racemic bupivacaine was administered IV at 1 mg/kg/min until tonic/clonic convulsions occurred. Saline, nicardipine (0.4 µg/min), and phentolamine (10 µg/min within 5 min, 50 µg/min thereafter) were simultaneously administered with bupivacaine in groups C, N, and P, respectively. Mean arterial blood pressure was significantly increased by infusion of bupivacaine in group C and was maintained at baseline levels before the onset of convulsions in groups N and P. The convulsive dose of bupivacaine in group C was 5.8 ± 1.5 mg/kg, but was significantly larger in groups N and P (7.6 ± 1.5 and 8.1 ± 1.1 mg/kg, P = 0.02 and 0.001, respectively). However, there were no differences in total or protein-unbound plasma concentration of bupivacaine or in concentration of bupivacaine in the brain at the onset of convulsions among the 3 groups. We conclude that nicardipine and phentolamine increase the cumulative dose but do not affect the threshold plasma or brain concentrations required for bupivacaine-induced convulsions.

IMPLICATIONS: Bupivacaine, a long-acting local anesthetic, induces central nervous system toxicity when its plasma concentration is increased. Nicardipine and phentolamine increased the cumulative dose but did not affect the threshold plasma concentrations, required for bupivacaine-induced convulsions, suggesting that both nicardipine and phentolamine inhibited the increase in the plasma concentration of bupivacaine by inducing peripheral vasodilation.