Phase 1 human trial of adenosine-potassium cardioplegia

Background The cardioprotective role of adenosine in various models of ischemia-reperfusion, including adenosine supplementation to cardioplegic formulations, has been studied extensively. The appropriate dose of adenosine in humans is uncertain and could be limited by systemic hypotension or AV block. Methods and Results An open-label, nonrandomized phase 1 adenosine dose-ranging study was performed. Patients scheduled for primary isolated coronary bypass surgery were eligible for the study. Antegrade warm blood potassium cardioplegia (ratio, 4 :1, blood to crystalloid) was administered in the routine fashion, with adenosine added to the initial 1000-mL dose and final 500-mL dose. Patients were studied in blocks of 4 per concentration. An escalating adenosine dosage schedule was planned to produce blood cardioplegia concentrations from 0 to 250 μmol/L, and the blocks were tested sequentially. Stopping rules were defined for systemic hypotension (phenylephrine dose during cardiopulmonary bypass ≥5.0 mg ; phenylephrine dose during cardioplegic induction ≥800 μg) and AV block (permanent pacemaker insertion ; temporary pacing dependency for >90 minutes after cardiopulmonary bypass). Doses of 1, 2.5, 5, 10, and 25 μmol/L were well tolerated. With 50 μmol/L, systemic hypotension occurred during cardioplegic induction in 3 of 4 patients versus 1 of 24 (P 90 minutes after discontinuation of cardiopulmonary bypass, and no patient required permanent pacing. There have been no deaths, Q-wave myocardial infarctions, intra-aortic balloon pump insertions, or cerebral infarctions in the total sample of 56 patients. Conclusions Our initial investigations have shown that adenosine can be safely administered during cardiopulmonary bypass. The authors recommend that further studies are warranted using adenosine 15 to 25 μmol/L, depending on the delivery system.