Intrapericardial Delivery of Amiodarone Rapidly Achieves Therapeutic Levels in the Atrium

Abstract

Amiodarone is widely used worldwide as an important drug for managing supraventricular arrhythmias, regardless of its association with potentially severe side effects due to systemic toxicity. Amiodarone reduces the incidence of atrial fibrillation after cardiac surgery, but oral therapy requires a presurgery loading period, lasting from 1 to 4 weeks. In this study, we showed that it is possible to rapidly obtain therapeutic cardiac tissue levels of the drug by infusing aqueous amiodarone intrapericardially, without appreciable systemic exposure. We also examined the long-term histologic safety of intrapericardial infusion. In this observational study, 9 adult sheep, randomized into 3 groups of 3 animals each, were given low (2.5 -mg/h), medium (10-mg/h), or high (50-mg/h) dosages of amiodarone by continuous infusion intrapericardially for 72 hours. An intrapericardial drain prevented tamponade from fluid build-up. Levels of amiodarone and its active metabolite, desethylamiodarone (DEA), were assessed both in plasma and in transmural biopsy specimens taken from the left atrial appendage and left and right ventricular myocardium. Cardiac, hepatic, and renal functions were also assessed. Humane euthanization was performed after 3 months, and cardiac and thoracic tissues were assessed for evidence of epicarditis, severe fibrotic changes, or other adverse effects potentially caused by the local amiodarone administration. Pericardial infusion resulted in rapid uptake and high concentrations of amiodarone and DEA in the myocardial tissues, without an appreciable systemic presence of either drug. The highest and lowest levels of these agents were observed in the left atrium and left ventricle, respectively. Drug concentrations in all cardiac biopsy specimens were similar to, or higher than, those reportedly observed in patients taking long-term oral amiodarone. At 90 days, postmortem microscopic, biochemical, and hematologic evaluation of end-organ tissues from the 8 surviving sheep showed no adverse effects. Excessive inflammation or fibrotic changes were not observed in these 8 sheep. The ninth sheep died prematurely, and its death was deemed not to be related to this study. Short-term intrapericardial delivery of amiodarone is a safe method for rapidly obtaining therapeutic atrial-tissue drug levels. When begun perioperatively, this method may prevent postoperative atrial fibrillation similarly to oral or intravenous amiodarone therapy. However, we have shown that pericardial administration avoids systemic drug distribution and thus may greatly decrease the systemic complicationsresulting from this drug.