OBJECTIVES: Epinephrine administered during cardiopulmonary resuscitation (CPR) is known to increase aortic diastolic and myocardial perfusion pressures, while enhancing myocardial blood flow. Optimal dosing of epinephrine during CPR is less certain. Interest in high-dose epinephrine use under such circumstances is increasing. The effect of different doses of epinephrine on simultaneously measured perfusion pressures, myocardial blood flow, cardiac output, and end-tidal CO2 (PCO2) (used as an indirect measure of cardiac output during CPR) is unknown. DESIGN: Prospective, sequential evaluation of no epinephrine, standard dose epinephrine, and high-dose epinephrine. SETTING: An experimental resuscitation laboratory. SUBJECTS: Twelve domestic swine. INTERVENTIONS: Myocardial perfusion pressure, myocardial blood flow, cardiac output, and end-tidal PCO2 were studied after various doses of epinephrine were administered during prolonged CPR. After 3 mins of untreated ventricular fibrillation, each animal received 5 mins of CPR without epinephrine, 5 mins of CPR after standard dose epinephrine (0.02 mg/kg), and 5 mins of CPR after high-dose epinephrine (0.2 mg/kg). Cardiac output and regional myocardial blood flow values were measured with nonradioactive, colored microspheres. MEASUREMENTS AND MAIN RESULTS: Myocardial perfusion pressure (aortic diastolic minus right atrial diastolic) was significantly (p < .05) increased over baseline with high-dose epinephrine (35 +/- 8 vs. 14 +/- 4 mm Hg), but not with standard dose epinephrine (20 +/- 5 vs. 14 +/- 4 mm Hg). Epinephrine's effect on myocardial blood flow was similar, increasing after the high dose (71 +/- 21 vs. 20 +/- 5 mL/min/100 g; p > .05), but not with the standard dose (23 +/- 6 vs. 20 +/- 5 mL/min/100 g). Cardiac output decreased significantly (p < .05) after high-dose epinephrine (7 +/- 1 vs. 13 +/- 1 mL/min/kg). Mean end-tidal PCO2 levels were lower after high-dose epinephrine (15 +/- 2 vs. 20 +/- 2 mm Hg; p < .05) but not after standard dose epinephrine (19 +/- 2 vs. 20 +/- 2 mm Hg). CONCLUSIONS: Standard dose epinephrine had minimal effect on myocardial perfusion pressure, myocardial blood flow, cardiac output, or end-tidal PCO2. High-dose epinephrine enhanced myocardial perfusion pressure and myocardial blood flow despite significantly decreasing cardiac output.