Abstract 220: Intralipid Fails to Rescue Bupivacaine-Induced Cardiotoxicity in the Presence of the Opioid Antagonist Naloxone

Abstract

Introduction: Exogenous opioids such as morphine protect the heart against I/R injury. This action is mediated through opioid receptors as Naloxone, an opioid receptor antagonist, inhibits the cardioprotective effect of ischemic preconditioning. Here we explored the involvement of opioid receptors in lipid-mediated rescue of Bupivacaine-induced cardiac toxicity. Methods: Young male SD rats (300-350 g) were anesthetized with ketamine (80 mg/kg) and xylazine (8 mg/kg) and ventilated with a ventilator. The M-mode echocardiography and Electrocardiograms were acquired throughout the experiment. Asystole was achieved with a single injection of Bupivacaine (10mg/kg over 20 s, intravenously), and resuscitation with Intralipid (5ml/kg bolus, and 0.5ml/kg/min maintenance) along with cardiac massage was started immediately. Some rats were pre-treated with different doses of Naloxone (1 mg/kg, 10 µg/kg, 5 µg/kg and 1 µg/kg) 2 min prior to inducing asystole with Bupivacaine. Results: Administration of Bupivacaine resulted in asystole and Intralipid therapy improved the heart rate gradually within 10 min: 73.3±3.3 beats/min at 1min (23% recovery), 180±23 beats/min at 5 min (56% recovery), and 243±20 beats/min at 10 min (76% recovery, n=6). The left ventricular systolic function was also fully recovered in all rats within 5 min of lipid treatment as the ejection fraction (EF) and fractional shortening (FS) were similar to their baseline values (EF=70±3%, FS=40±3%, n=6)., Interestingly, Intralipid failed to rescue Bupivacaine overdose in rats pretreated with a high dose of Naloxone (1mg/kg) as there was no recovery of cardiac function within 10 min of lipid therapy (n=5). In rats pretreated with lower doses of Naloxone of 5 µg /kg and 10 µg /kg (n=4/group), the heart rate and cardiac function were partially recovered. Lowering the dose of Naloxone further to 1 µg /kg resulted in 76% recovery of the heart rate at 10 min. Complete recovery of the left ventricular systolic function was observed in this group within 10 min of lipid treatment as EF and FS were similar to their baseline values (EF= 73±3%, FS=43±3, n=4). . Conclusions: The opioid receptor antagonist Naloxone abolishes lipid rescue of Bupivacaine-induced cardiotoxicity in a dose-dependent manner.