PROJECT SUMMARY Drug overdose out-of-hospital cardiac arrest (OD-OHCA) is a serious and growing public health threat that is wholly understudied. Currently, we lack a broadly-representative, contemporary clinical profile of OD-OHCA across America and we do not know the relative societal disease burden of OD-OHCA. In addition, we do not have a direct comparison of OD-OHCA and presumed cardiac etiology (C-OHCA) controls statistically matched by age and other key clinical factors. Further, the optimal post-resuscitation treatment for OD-OHCA event survivors is unknown. Our research will address these knowledge gaps. Our central hypothesis is that there will be a substantial public health impact from OD-OHCA relative to other high-burden diseases, statistically significant and clinically important differences between OD-OHCA and propensity-matched C- OHCA outcomes, and potential therapeutic benefit to provision of targeted temperature mangement (TTM) during post-resuscitation critical care. The scientific premise for this work is that we currently do not adequately understand the full scope of OD-OHCA in America, and the Cardiac Arrest Registry to Enhance Survival (CARES) dataset is the largest collection of homogeneous, contemporary data on this cohort for analysis to fill these important knowledge gaps and accelerate the pace of drug abuse research in this area. From CARES, we will create a broadly-representative, contemporary clinical profile of OD-OHCA across America, estimate the public health impact of OD-OHCA as measured by disability-adjusted life years lost (DALY [inclusive of mortality and morbidity]), compare OD-OHCA patient outcomes to propensity-match controls with C-OHCA, and determine the effect of post-resuscitation TTM on patient outcomes as measured by hospital discharge Cerebral Performance Category (CPC) scale scores. This research is significant because currently little is known about substance use disorder from the perspective of OD-OHCA in this rapidly growing segment of society, and our findings can be translated directly into clinical care protocols and will potentially modify care guidelines to save lives. Our work is innovative in that we will be accessing an enormous, broadly-representative repository of prospectively collected and validated data from throughout the country. Further, the highly capable research team has members with priority access to the actively expanding CARES dataset for this analysis, collaborators with considerable expertise in OHCA as well as vast experience in predictive modeling using large datasets. This work will help enable high-quality research to advance scientific knowledge on this potential consequence of addiction and drug use to directly improve patient care for this stigmatized, vulnerable population.

PROJECT NARRATIVE Substance use disorder in the United States is an enormous public health problem but this epidemic, from the perspective of drug overdose out-of-hospital cardiac arrest, is wholly understudied. Our long-term goal is to improve prevention, recognition, treatment, and outcomes in drug overdose out-of-hospital cardiac arrest. The purpose of this research is to provide a better understanding of the scope of the substance use disorder crisis in America from the perspective of this life-threatening consequence of addiction and abuse and to more clearly define the appropriate use of therapeutic hypothermia/targeted temperature management in overdose out-of-hospital cardiac arrest survivors, thereby helping to advance the NHLBI mission to enhance the health of individuals so that they can live longer and more fulfilling lives.