Objective To evaluate the hemodynamic actions of epinephrine combined with different alkaline buffers during experimental, open-chest, cardiopulmonary resuscitation (CPR). Design Prospective, randomized, controlled trial. Setting Experimental animal laboratory in a university hospital. Subjects A total of 28 anesthetized piglets. Interventions After catheterization and application of a pulmonary artery flow probe (transit-time ultrasound flowmetry), the animals were stabilized. Induction of ventricular fibrillation was followed by a 15-min period of CPR, including manual heart compressions and mechanical ventilation with pure oxygen. On commencement of CPR, a 4-min alkaline buffer infusion began, with 50 mmol of sodium bicarbonate (n = 7), tris buffer mixture (n = 7), or tris buffer (n = 7), or, as a control (n = 7), the same volume of normal saline. After 8 mins of CPR, 0.5 mg of epinephrine was given intravenously; after 15 mins, direct current shocks were used to revert the heart to sinus rhythm. Measurements and Main Results Blood flow measured in the pulmonary artery during open-chest CPR was −20% of normal cardiac output. Administration of epinephrine reduced pulmonary artery flow irrespective of buffer. Sodium bicarbonate alone resulted in higher systemic blood pressure than pure tris: tris buffer mixture and normal saline were intermediate. Sodium bicarbonate combined with epinephrine tended to produce lower systemic blood pressure than other combinations. Conclusions Experimental open-chest CPR generates pulmonary artery blood flows (20% of normal cardiac output) that are at best at the lower level of those blood flow rates previously reported (25% to 40% of normal cardiac output) from studies of closed-chest CPR Different alkaline buffers influence circulatory and acid-base parameters differently before and after administration of epinephrine.