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Background: To evaluate the efficacy of warm versus cold and antegrade versus retrograde cardioplegia, 163 patients were randomized in sequence in three groups and underwent isolated coronary artery bypasses (mean, 4 grafts/patients) alternating in sequence., Methods and Results: The demographic profiles were identical. Cold crystalloid cardioplegia (group 1) was delivered through the aortic root intermittently. The warm retrograde (group 2) was started antegrade with high potassium solution until the heart stopped. It was continued with retrograde coronary sinus perfusion, 100 mL/min of warm blood. Cold retrograde blood cardioplegia (4:1) (group 3) was started antegrade and continued retrograde through the coronary sinus. The heart temperature was kept at 10 degrees to 15 degrees C. Patients were evaluated intraoperatively and postoperatively for (1) supraventricular tachycardia, (2) ECG changes, (3) lactate dehydrogenase and total CPK and isoenzyme (MB) studies, and (4) hemodynamic studies in the intensive care unit. Warm retrograde and cold retrograde patients had sampling of the ascending aorta (antegrade) and the coronary sinus (retrograde) measuring pH, A-VO2 differences, and CK enzyme leak., Results: The incidence of supraventricular tachycardia was 29% in group 2, 22% in group 1, 18% in group 3; not significant (NS). CPK isoenzyme MB fraction showed identical levels (NS). The warm heart consumed 1.3 to 1.6 mL O2/100 mL flow, while the cold group 3 showed 0.5 to 0.6 mL O2/100 mL flow (P < .001). Cold crystalloid cardioplegia (group 1) was similar to group 3 (0.3 mL O2/100 mL). All three groups were similar hemodynamically (cardiac output, cardiac index, left ventricular stroke work index). Two of 163 patients died in group 2. Four sustained stroke, three in group 2, one with a fatal outcome., Conclusions: Continuous warm cardioplegia (group 2) did not provide better myocardial protection despite that no CK-MB isoenzyme leak was demonstrated intraoperatively. Intermittent cold crystalloid cardioplegia and cold retrograde provided a clearer operative field and motionless heart. As long as O2 was adequately supplied, under 90 minutes' cross-clamp time, cold crystalloid cardioplegia and cold retrograde blood cardioplegia is safe under hypothermic conditions, whereas warm cardioplegia requires continuous uninterrupted technique with oxygen delivery.