Abstract 22: Systemic Nitrite (NO2-) Levels are Depleted in a Mouse Model of Asystolic Cardiac Arrest and Therapeutic Repletion Improves Survival and Functional Neurological Recovery
Nitrite (NO2) represents a circulating reservoir of nitric oxide (NO) that is reduced to NO during ischemia. In pre-clinical studies, NO2 therapy was cytoprotective following focal heart, brain and liver ischemia-reperfusion. We hypothesized that systemic NO2 is depleted during global ischemia (cardiac arrest) and its early repletion could protect the heart and brain from reperfusion injury. C57BL/6 mice were rendered asystolic using a KCl bolus. After 12 min of warm ischemia (36.5C), paired mice were randomized to IV nitrite (blinded) or saline placebo given just prior to epinephrine, mechanical ventilation and chest compressions. All mice received identical pre- and post-CPR care until euthanasia and had similar physiologic parameters. NO2-treated mice had improved survival 22 hours post-CPR compared to saline-treated controls (HR 2.75 [95% CI:1.1– 6.8]; Table 1⇓). Deaths occurred 1– 6 h post-CPR and were associated with worsened cardiac ejection fraction 1.5h post-CPR. Neurologic function and thermoregulation were significantly improved in NO2-treated 22h survivors vs. paired controls. Cardiac arrest depleted whole blood and plasma NO2 (Table 2⇓). NO2 therapy restored levels near pre-arrest baseline with associated improvements in post-CPR oxygenation, ventilation and pH, without altering metabolic acidosis. Intravenous NO2 as adjunctive therapy to epinephrine early in CPR shows promise in improving cardiac and neurologic outcomes in a mouse model of cardiac arrest. The ease of NO2 delivery (vs. hypothermia), its approval and known safety profile in humans and its efficacy against reperfusion injury after prolonged asystole make NO2 an excellent drug candidate.