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Repeated administration of epinephrine is associated with unfavorable cerebral outcome after out-of-hospital cardiac arrests (OHCA), but the timing of epinephrine administration has not been considered.The aim of the study was to analyze the effects of repeated epinephrine administration after OHCA on favorable cerebral function coded by cerebral performance categories (CPC 1–2).A nationwide, retrospective, population-based observational study was conducted by using Utstein-style data between 2010 and 2012 in Japan. The total of 11,876 cardiogenic and witnessed OHCA were stratified into 3 categories by the number of times epinephrine was administered (single, double, and three or more). In addition, the time elapsed between the emergency call and the initial epinephrine administration was divided into 3 time intervals (5 to 20 min for the early administration group [EAG], 21 to 26 min for the intermediate administration group [IAG], and 27 to 60 min for the late administration group [LAG]). The primary endpoint was CPC 1–2 at 1 month after cardiac arrest. A multivariable logistic regression was used for analysis.Achievement of CPC 1–2 at 1 month was 4.8% for single, 2.4% for double, and 1.7% for three or more administered doses. For single and three or more administrations, CPC 1–2 was significantly higher in the IAG than in the LAG (adjusted odds ratio [AOR], 3.54, 3.02; 95% confidence interval [CI], 2.04–6.39, 1.16–9.43, for single and three or more administrations, respectively). The EAG showed significantly higher achievement of CPC 1–2 in all the epinephrine administration groups (AOR, 9.26, 7.57, 4.07; 95% CI, 5.44–16.59, 3.39–19.60, 1.59–12.69, for single, double, and three or more administrations, respectively).Repeated epinephrine administration improved CPC 1–2 outcome when epinephrine was administrated within 20 min after an emergency call for witnessed cardiogenic OHCA.