P35: Nitrite as a novel resuscitation adjunct after ventricular fibrillation cardiac arrest in rats: A preliminary report

Abstract

Background Beside therapeutic hypothermia no novel therapies have been developed to improve outcomes of patients suffering cardiac arrest (CA). In rat models, nitrite NO 2 - has the theoretical advantage of being converted locally to nitric oxide (NO) in ischemic regions improving microcirculation. Nitrite reduced neurological damage after asphyxial CA in rats. Whether nitrite is protective in CA due to ventricular fibrillation (VF) is unclear. Therefore, we developed a novel VF rat CA model to test this hypothesis and characterize nitrite’s pharmacokinetics in this disease model. Methods In this pilot randomized blinded trial, adult male Sprague–Dawley rats were anesthetized, intubated and catheterized (arterial and venous). VF was induced using a bipolar pacing catheter and left untreated for 5 min. Manual cardiopulmonary resuscitation (CPR) with drugs (epinephrine/sodium bicarbonate) and defibrillation was initiated using a predefined protocol simulating current practice. After return of spontaneous circulation (ROSC), rats were randomized to 500 μL placebo (Plasmalyte), low-dose (2 μM) or high-dose (8 μM) intravenous nitrite given as a 5 min infusion at 5 min and 50 min after CPR-start. Nitrite whole blood levels were measured at baseline, before and after each of 2 drug infusions. Hemodynamics and temperature were measured over 60 min after CPR-start; temperature was controlled (37 °C) for 12 h post-arrest. Neurologic Deficit Score (NDS) was assessed on post-arrest days 1–2 and fear-conditioning (a hippocampal-mediated behavior) on days 7–8. On day 8, rats were perfused with formalin and surviving hippocampal CA1 neurons were quantified using HE Fig. 1 ) There were no significant differences between the treatment groups and placebo in regards to baseline nitrite levels, hemodynamics, temperature, NDS, fear conditioning, or CA1 neuronal survival, which was approximately 99 (51–133) cells/mm. Conclusion In this feasibility study, nitrite can be safely administered early after ROSC in a novel though mild model of VF CA. The clearance of the first nitrite dose was faster than the second dose suggesting either alteration in the volume of distribution, perhaps due to tissue saturation with higher doses, or in the half-life. These results are guiding present studies of nitrite in more lethal VF. Disclosure Supported by research grants from the Max Kade Foundation Inc. and the Laerdal Foundation for Acute Medicine.