Delayed Afterdepolarization Inhibitor: A Potential Pharmacologic Intervention to Improve Defibrillation Efficacy

INTRODUCTION: Electrical and optical mapping studies of defibrillation have demonstrated that following shocks of strength near the defibrillation threshold (DFT), the first several postshock cycles always arise focally. No immediate postshock reentry was observed. Delayed afterdepolarizations (DADs) have been suggested as a possible cause of this rapid repetitive postshock activity. The aim of this study was to test the hypothesis that DFT is decreased by application of a DAD inhibitor. METHODS AND RESULTS: Six pigs (30-35 kg) were studied. First, control DFT was determined using a three-reversal up/down protocol. Each shock (RV-SVC, biphasic, 6/4 msec) was delivered after 10 seconds of ventricular fibrillation (VF). Then, flunarizine (a DAD inhibitor) was injected intravenously (2 mg/kg bolus and 4 mg/kg/hour maintenance) and the DFT was again determined. A third DFT was determined 50 minutes after drug infusion was terminated to allow the drug to wash out. DFT after flunarizine application (520 +/- 90 V, 14 +/- 3 J) was significantly lower than control DFT (663 +/- 133 V, 23 +/- 4 J). After the drug washed out, DFT (653 +/- 107 V, 22 +/- 4 J) returned to the control DFT value (P = 0.6). Flunarizine reduced the DFT approximately 22% by leading-edge voltage and approximately 40% by energy. CONCLUSION: Flunarizine, a DAD inhibitor, significantly improved defibrillation efficacy. This finding suggests that DADs could be the source of the rapid repetitive focal activation cycles arising after failed near-DFT shocks before degeneration back into VF. Future studies are needed to investigate the cause of the earliest postshock activation and to determine if the DADs are responsible.