Does Targeted Temperature Management Modify the Association Between Increasing Epinephrine Dose and Survival Outcomes Following Out-of-Hospital Cardiac Arrest?

Introduction: Epinephrine (EPI) improves return of circulation after out of hospital cardiac arrest (OHCA). These beneficial cardiac effects are not accompanied by improved neurological survival possibly due to EPI induced microvascular effects and critical brain ischemia. We hypothesized that these dose-dependent adverse EPI effects may be mitigated by targeted temperature management (TTM) such that the relative benefit of TTM is greater at higher EPI doses. Methods: This was a retrospective cohort study of adult non-traumatic OHCA patients in Seattle and King County, Washington from 2008-2018, who were unconscious at hospital admission. We used logistic regression to assess the relationship among EPI dose, TTM, and survival to hospital discharge, and survival with favorable neurological status (Cerebral Performance Category (CPC) 1 or 2). The model evaluated whether TTM modified the association of increasing EPI dose using an interaction term between TTM and EPI dose. Results were stratified by initial shockable vs non-shockable rhythm. Results: Of 5254 eligible patients, the median EPI dose was 2.0 mg (IQR 1.0 - 3.0); 3052 (58%) received TTM. In all, 2177 (41%) survived to discharge, and 1889 (36%) survived with CPC 1-2. Increasing dose of EPI was associated with a decreasing likelihood of survival (OR 0.58, [95% CI 0.55-0.61] for each additional mg of EPI) and CPC 1-2 (OR 0.56, [0.53-0.59]). The dose-dependent EPI association was modified by TTM. After adjustment for Utstein covariates, for each additional mg of EPI, TTM was associated with a relative stepwise improvement in odds of survival (interaction OR 1.35, [1.23, 1.49]) and CPC 1-2 (OR 1.34, [1.21, 1.50]) (Figure). This interaction was consistent among shockable and non-shockable OHCA (Figure). Conclusions: We observed an interaction between TTM and EPI dose such that the beneficial association of TTM increased with increasing EPI dose, suggesting TTM may attenuate the adverse effects of higher dose EPI.