Systemic Toxicity of Levobupivacaine, Bupivacaine, and Ropivacaine during Continuous Intravenous Infusion to Nonpregnant and Pregnant Ewes

Abstract

Background Levobupivacaine, the single levorotatory isomer of bupivacaine, is now available for clinical use. This study was undertaken to determine whether pregnancy affects the systemic toxicity of levobupivacaine and to compare the systemic toxicity of levobupivacaine with that of bupivacaine and ropivacaine. Methods Chronically prepared nonpregnant and pregnant sheep were randomized to receive an intravenous infusion of 0.52% levobupivacaine, 0.52% bupivacaine, or 0.50% ropivacaine at a constant rate of 0.1 ml x kg(-1) x min(-1) until circulatory collapse. The investigators were blinded to the identity of the local anesthetic. Physiologic parameters, including cardiac rhythm, were monitored throughout the study. Arterial blood samples were obtained before infusion and at the onset of toxic manifestations. These were analyzed for total and free serum drug concentrations as well as arterial blood pH and gas tensions. Results The doses of all three drugs required to produce convulsions were lower in pregnant than nonpregnant animals. However, as the infusion continued, there were no significant differences between pregnant and nonpregnant ewes in the dose of drug required to produce more advanced manifestations of toxicity: hypotension, apnea, and circulatory collapse. The mean cumulative dose and serum concentration at each toxic manifestation was lowest for bupivacaine, intermediate for levobupivacaine, and highest for ropivacaine in both pregnant and nonpregnant animals. For all three local anesthetics, there were no significant differences between pregnant and nonpregnant ewes in total and free serum drug concentrations, except that at circulatory collapse, these were higher in pregnant animals. Conclusions Pregnancy increases the risk of convulsions but not of more advanced manifestations of local anesthetic toxicity. The risk of toxicity is greatest with bupivacaine and least with ropivacaine. However, in actual clinical practice, the risk of systemic toxicity may also be affected by the relative potency and effectiveness of these drugs.