BACKGROUND: Blood cardioplegia and terminal warm blood cardioplegic reperfusion ("hot shot") reduce myocardial injury and improve metabolic recovery in hypoxic but not normoxic experimental models. However, there is little evidence of a benefit of either technique in pediatric clinical practice compared with crystalloid cardioplegia. METHODS: Pediatric patients undergoing cardiac surgery were randomized to receive intermittent antegrade cold crystalloid cardioplegia, cold blood cardioplegia, or cold blood cardioplegia with a hot shot. Right ventricular biopsy specimens were collected before ischemia, at the end of ischemia, and 20 minutes after reperfusion. Cellular metabolites were analyzed. In acyanotic patients postoperative serum troponin I levels were also measured at 1, 4, 12, 24, and 48 hours. RESULTS: Of 103 patients recruited, 32 (22 acyanotic and 10 cyanotic), 36 (24 acyanotic and 12 cyanotic), and 35 (25 acyanotic and 10 cyanotic), respectively, were allocated to the groups receiving cold crystalloid cardioplegia, cold blood cardioplegia, and cold blood cardioplegia with a hot shot. Cyanotic patients were younger, with longer crossclamp times. There were no significant differences in clinical outcomes between cardioplegic methods. The cardioplegic method had no overall effect in terms of adenosine triphosphate, ln(adenosine triphosphate/adenosine diphosphate), or ln(glutamate) in acyanotic patients (P =.11, P =.66, and P =.30, respectively). Also, there was no significant difference between groups in troponin I release. However, in cyanotic patients cold blood cardioplegia with a hot shot significantly reduced the decrease in adenosine triphosphate, ln(adenosine triphosphate/adenosine diphosphate), and glutamate observed at the end of ischemia and after reperfusion compared with the decrease seen in those receiving cold crystalloid cardioplegia (P =.002, P =.003, and P =.008, respectively), with cold blood cardioplegia representing an intermediate. CONCLUSIONS: For cyanotic patients (younger, with longer crossclamp times), cold blood cardioplegia with a hot shot is the best method of myocardial protection. For acyanotic patients (older, with shorter crossclamp times), cardioplegic technique is not critical.