Epinephrine (adrenaline) is widely used as a primary adjuvant for improving perfusion pressure and resuscitation rates during cardiopulmonary resuscitation (CPR). Epinephrine is also associated with significant myocardial dysfunction in the post-resuscitation period. We tested the hypothesis that the cardiac effects of epinephrine vary according to the duration of cardiac arrest.Cardiac arrest (CA) was induced in Sprague–Dawley rats with an IV bolus of KCl (40μg/g). Three series of experiments were performed with CPR begun after 2, 4, or 6min of cardiac arrest. Epinephrine (0.01mg/kg) IV or placebo was given immediately in the 2 and 4min CA groups. In the 6min group, CPR was started after 6min CA and epinephrine was given at 15min if no return of spontaneous circulation (ROSC) occurred. Time to ROSC was recorded in all groups. Cardiac function was determined with trans-thoracic echocardiography at baseline, 5, 30 and 60min after ROSC.After 2min CA, 8/8 (100%) placebo animals and 8/8 (100%) epinephrine animals attained ROSC. Cardiac index was significantly increased during the first 60min in the epinephrine group compared with the placebo group (p<0.01). After 4min of cardiac arrest, 14/29 (48%) placebo animals and 14/16 (88%) epinephrine animals attained ROSC (p<0.01). Cardiac index after ROSC returned to baseline in both groups, although tended to be lower in the epinephrine group. After 6min CA, 10/31 (32%) animals attained ROSC without epinephrine and 17/21 (81%) animals with epinephrine (p<0.01). Post-ROSC depression of cardiac index was greatest in the epinephrine group (p<0.05).As the duration of cardiac arrest increases, a paradoxical myocardial epinephrine response develops, in which epinephrine becomes increasingly more important to attain ROSC, but is increasingly associated with post-ROSC myocardial depression.