Direct cardiac effects of intracoronary bupivacaine, levobupivacaine and ropivacaine in the sheep

1 The racemic local anaesthetic agent bupivacaine is widely used clinically for its long duration of action. Levobupivacaine and ropivacaine are bupiv acaine enantiopure congeners, developed to improve upon the clinical safety of bupivacaine, especially the risk of fatal arrhythmogenesis. 2 In previous preclinical studies of the safety of these drugs with intrave nous administration in conscious ewes over a wide dose range, we found that central nervous system (CNS) excite-toxicity reversed the cardiac depressa nt effects when doses approached the convulsant threshold and thus preclude d accurate comparison of their cardiovascular system (CVS) effects. 3 To study CVS effects over a wide range of doses with minimal CNS and othe r influences, brief (3 min) infusions of bupivacaine, levobupivacaine or ro pivacaine were administered into the left main coronary arteries of previou sly instrumented conscious ewes (similar to 50 Kg body weight). After dose- ranging studies, the drugs were compared in a randomized, blinded, parallel group design. Equimolar doses were increased from 8 mu mol (approximate to 2.5 mg) in 8 mu mol increments, to either a fatal outcome or a 40 mu mol (a pproximate to 12.5 mg) maximum. 4 All three drugs produced tachycardia, decreased myocardial contractility and stroke volume and widening of electrocardiographic QRS complexes. Thirt een of 19 animals died of ventricular fibrillation: four of six with bupiva caine (mean+/-s.e.mean actual fatal dose: 21.8+/-6.4 mu mol), five of seven with levobupivacaine (22.9+/-3.5 mu mol), four of six with ropivacaine (22 .9+/-5.9 mu mol). No significant differences in survival or in fatal doses between these drugs were found. 5 The findings suggest that ropivacaine, levobupivacaine and bupivacaine ha ve similar intrinsic ability to cause direct fatal cardiac toxicity when ad ministered by left intracoronary arterial infusion in conscious sheep and d o not explain the differences between the drugs found with intravenous dosa ge.