ENHANCEMENT OF BUPIVACAINE TOXICITY BY DILTIAZEM IN ANAESTHETIZED DOGS

Abstract

We have studied the cardiovascular effects of graded doses of bupivacaine in the absence or presence of clinical concentrations (approximately 250 micrograms litre-1) of diltiazem in fentanyl-pentobarbitone anaesthetized dogs. Bupivacaine was given, increasing in a stepwise manner, as a loading dose (200, 400 or 600 micrograms kg-1) followed by a 30-min i.v. infusion (25, 100 or 200 micrograms kg-1 min-1, respectively). Thereafter, bupivacaine was infused at 400 micrograms kg-1 min-1 until each animal died. Group A (n = 7) received bupivacaine, group B (n = 5) diltiazem (400 micrograms kg-1 followed by 12 micrograms kg-1 min-1) and group C (n = 7) received diltiazem followed by bupivacaine given as in group A. Lethal plasma concentrations of bupivacaine were significantly smaller (P < 0.01) in group C (7.1 (SEM 0.7) vs 12.6 (1.5) mg litre-1). Bupivacaine produced similar decreases in cardiac index, left ventricular (LV) segmental work and the first derivative of LV pressure (LV dP/dt) in the absence and presence of diltiazem. In group A, bupivacaine increased systemic vascular resistance index (SVRI) and thus mean arterial pressure (MAP) was maintained. In group C, SVRI, reduced by diltiazem per se, did not increase in response to bupivacaine, so MAP was not maintained. Death resulted from a progressive decrease in cardiac contractility and MAP. Plasma concentrations of bupivacaine attained at the three doses were similar in the absence and presence of diltiazem. This study has shown that the toxicity of bupivacaine was increased approximately two-fold by diltiazem.