PROJECT SUMMARY/ABSTRACT Over 356,000 cases of out-of-hospital cardiac arrest (OHCA) occur in the US each year, nearly 90% of which are fatal.2 While 99.7% of OHCA in patients over age 60 are cardiac in etiology, a meaningful proportion of OHCA for patients between 20 and 59 years of age are drug-related.3 We previously used data from the NHLBI-funded Postmortem Systematic Investigation of Sudden Cardiac Death (POST SCD)4 to investigate the prevalence of occult drug-related cardiac arrest. We found that 10.3% of OHCA in San Francisco between 2011-2016 were due to occult opioid overdose5 – cases without a history or evidence of drug use that would otherwise have been attributed to a non-overdose cause, such as sudden cardiac death. While it is currently unknown whether naloxone – an opioid receptor competitive antagonist – is beneficial to patients experiencing opioid-associated (OA)-OHCA, a recent American Heart Association scientific statement identified the rigorous evaluation of naloxone’s efficacy in OA-OHCA as an important knowledge gap.1 However, no evidenced-based method to identify OA-OHCA in real-time currently exists, making the targeted-evaluation of naloxone’s efficacy in this group difficult. Our study team leveraged data from the POST SCD study to develop the NAloxone Cardiac ARrest Decision Instrument (NACARDI) – two exam-based criteria that improve the pre-test probability of occult OA-OHCA from 10.3% to 20.6%.6 These criteria were derived from patients in San Francisco County who died of OHCA in the field. The objective of this K38 grant is to answer two outstanding questions: 1) Are the NACARDI criteria valid in OHCA patients who survive to the emergency department (ED), and 2) Are the NACARDI criteria externally generalizable outside of San Francisco? My central hypothesis is that the NACARDI criteria are externally valid and generalizable for identifying patients at risk for occult OA-OHCA. My long-term goal is to use the results of this K38 to develop validated inclusion criteria for a future multi-center NACARDI-enriched clinical trial of naloxone in suspected OA-OHCA. Aim 1 of this proposal will validate the NACARDI criteria in OHCA patients who survived to the ED by calculating screening characteristics for NACARDI in a retrospective cohort of all OHCA patients who were transported to two major hospitals in San Francisco between 2011-2021, using blood and urine toxicology screens to identify OA-OHCA. Aim 2 will refine and externally validate the NACARDI criteria using data from the Canadian Sudden Cardiac Arrest Network (C-SCAN), an EMS- and coroner-based dataset of OHCA patients who died in the field in Toronto, Canada between 2018-2022. Occult opioid overdose will be identified in the C-SCAN dataset through medical examiner adjudication. The NACARDI criteria are innovative because they allow for evidence-based real-time identification of patients at risk for occult OA-OHCA, instead of relying on the current practices of ...