PROJECT SUMMARY/ABSTRACT Sudden cardiac arrest is a leading cause of death in the United States, with an overall mortality rate of 90%. Brain injury accounts for 67% of deaths for patients who have their heart restarted after out-of-hospital cardiac arrest, and up to 50% of survivors have cognitive dysfunction. Historically, large animal cardiac arrest models (i.e., canines) were instrumental in the successful translation of hypothermic targeted temperature management, which is the only therapy clinically proven to reduce brain injury after cardiac arrest other than early CPR and defibrillations. However, currently available large animal models (i.e., swine) lack face validity because their mild injury severity, largely used to enable behavioral outcome assessment, does not model the neurocognitive deficits of human cardiac arrest victims. Large animal models are also cost prohibitive when their outcomes are quantified with clinical endpoints measured over multiple days during and after receiving ICU-level care. This limits the ability to adequately power studies that use these models. Given these issues, almost every neuroprotective therapy that demonstrated efficacy in these models has failed in human clinical trials. The lack of a validated, feasible large animal model of cardiac arrest is hindering the translation of the neuroprotective therapies that cardiac arrest patients desperately need. We will overcome the translational barrier and limitations of existing long-term models by developing a valid, clinically relevant, and cost-effective short-term cardiac arrest swine model of severe primary brain injury. Supported by emerging clinical data, we expect that quantitative endpoints of brain injury measured at 24 hours after return of spontaneous circulation will reflect the severity of primary brain injury and thereby enable reliable efficacy testing of neuroprotective therapies. In the R61 phase (Years 1 and 2), we will develop and validate a short-term swine model of severe primary brain injury following cardiac arrest. We will demonstrate the internal, face, and construct validities of clinically available blood-based brain injury biomarkers, brain electrophysiology, and neuropathology in our swine cardiac arrest model. Upon successful completion of the quantitative R61 milestones we have defined, we will confirm the predictive validity of these quantitative endpoints by confirming their treatment effects after hypothermic targeted temperature management in the R31 phase. Through this study, we will establish a feasible, lower-cost, and clinically relevant swine cardiac arrest model with quantitative pharmacodynamic biomarkers of post-cardiac arrest primary brain injury that can be used to validate neuroprotective therapies, which will catalyze translation to clinical trials.