PROJECT SUMMARY Despite the potential for patients to make a full recovery after experiencing an out-of-hospital cardiac arrest (OHCA) due to ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT), mortality remains near 75%. This higher mortality is partly because upwards of 50% of patients do not respond to initial defibrillation attempts. My career goal is to become an independent, federally funded physician-scientist leading a research program focused on improving outcomes for patients experiencing OHCA. My K23’s overall objectives are to evaluate if earlier antiarrhythmic administration is associated with improved survival after VF/VT OHCA, how the route of administration interacts with this association, and if changing the sequence of antiarrhythmics for VF/VT OHCA can reduce the time to antiarrhythmic therapy in a pilot feasibility trial. My central hypothesis is that early amiodarone administration in VF/VT OHCA can improve survival significantly compared to current guidelines. The rationale is that current cardiac arrest care guidelines for delaying antiarrhythmic therapy until after three shocks may reduce the efficacy of these agents, increase overall arrest duration, and reduce survival compared to an early antiarrhythmic approach. I will complete my overall objectives through three specific aims: (1) to assess the association between the timing and route of amiodarone administration in VF/VT OHCA and patient survival prospectively; (2) to measure the serum amiodarone concentration of VF/VT OHCA patients to compare the bioavailability of intraosseous routes to intravenous while accounting for time since drug administration; and (3) to perform a pilot, stepped-wedge cluster randomized trial evaluating a modified algorithm for VF/VT treatment to reduce the interval from arrest to amiodarone administration. These three aims will be accomplished over five years through seamless continuation of a pilot cohort, using the region’s highest volume cardiac arrest receiving hospital to collect serum drug concentrations, and using existing infrastructure to conduct a pilot cluster trial. Complementing these aims are five career development aims to facilitate training in (1) exception from informed consent randomized controlled trials; (2) population pharmacokinetic analytic techniques; (3) causal inference and multilevel modeling; (4) adaptive clinical trial methodology; and (5) the K-to-R transition. This proposal is significant as it focuses on improving care in the high-mortality condition of cardiac arrest, aligning with the NHLBI strategic objectives of levering data science and optimizing therapeutic strategies for improving health. The research is innovative because it uses a cohort that captures novel data elements, combining this with the use of serum drug concentrations to evaluate the efficacy of the intraosseous route to ultimately inform, in combination with pilot trial results, future studies investigating the optim...