7. Project Summary/Abstract . Cardiac arrest is a common and devastating emergency of the heart and the brain. More than 380,000 patients suffer out of hospital cardiac arrest (OHCA) each year in the US. Improvements in cardiac resuscitation (the early links in the “chain of survival” for patients with OHCA) are tempered by our limited ability to resuscitate and protect the brain from global cerebral ischemia. Neurological death and disability are common outcomes in survivors of cardiac arrest. Therapeutic cooling of comatose patients resuscitated from shockable rhythms may markedly increase the rate of good neurological outcome, but poor outcomes still occur in as many as 50%, and the benefit of cooling in those resuscitated from asystole and pulseless electrical activity has not been evaluated in a randomized study. Even in patients with shockable rhythms, prior trials showing efficacy have been questioned. Therapeutic cooling is already a guideline-recommended and commonly used treatment in comatose survivors of cardiac arrest, but because of limited data, the optimal duration and patient selection criteria remain unknown and cooling devices are not FDA approved for this indication. Preclinical data and mechanistic studies strongly suggest that durations of hypothermia longer than those typically used may minimize brain injury. This study will determine if identifying an optimal duration of therapeutic hypothermia can improve outcomes, and if development of a duration response curve can substantiate efficacy in a wider patient population of cardiac arrest survivors. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having good outcome. The overarching goal of this project is to identify clinical strategies that will increase the number of patients with good neurological recovery from cardiac arrest. The results of this trial will be immediately significant, impacting both clinical practice and regulatory evaluation. The trial uses innovative adaptive dose finding methods that allow exploration of a wide range of potential durations and efficiently allocate subjects where they will be most informative. The study methods also include innovative approaches to traditional outcome assessment and innovative outcome assessment tools, including the NIH Toolbox. The study will be conducted in the NIH SIREN Emergency Clinical Trials infrastructure. SIREN leverages existing resources to achieve economies of scale, maintain talented rapidly responding teams to screen and enroll subjects in the emergency department setting, and to continue clinical investigations through the ICU stay and beyond with proven performance.