PHASE-1 HUMAN TRIAL OF ADENOSINE-POTASSIUM CARDIOPLEGIA

Background The cardioprotective role of adenosine in various models of ischemia-reperfusion, including adenosine supplementation to cardiopl egic formulations, has been studied extensively. The appropriate dose of adenosine in humans is uncertain and could be limited by systemic h ypotension or AV block. Methods and Results An open-label, nonrandomiz ed phase 1 adenosine dose-ranging study was performed. Patients schedu led 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 adenosi ne added to the initial 1000-mL dose and final 500-mL dose. Patients w ere studied in blocks of 4 per concentration. An escalating adenosine dosage schedule was planned to produce blood cardioplegia concentratio ns from 0 to 250 mu mol/L, and the blocks were tested sequentially. St opping rules were defined for systemic hypotension (phenylephrine dose during cardiopulmonary bypass greater than or equal to 5.0 mg; phenyl ephrine dose during cardioplegic induction greater than or equal to 80 0 mu g) and AV block (permanent pacemaker insertion; temporary pacing dependency for >90 minutes after cardiopulmonary bypass). Doses of 1, 2.5, 5, 10, and 25 mu mol/L were well tolerated. With 50 mu mol/L, sys temic hypotension occurred during cardioplegic induction in 3 of 4 pat ients versus 1 of 24 (P<.005) at all lower concentrations (880 +/- 217 versus 297 +/- 286 mu g phenylephrine per patient). The studies were repeated with an 8:1 blood-to-crystalloid cardioplegia delivery system . Adenosine concentrations of 0 (n=4), 15 (n=12), 20 (n=8), and 25 mu mol/L (n=4) were tested. Hypotension during cadioplegic induction was more prevalent (P=.05) with the higher doses (15 mu mol/L, 394 +/- 189 mu g, 1 of 12 patients; 20 mu mol/L, 360 +/- 355 mu g, 2 of 8 patient s; 25 mu mol/L, 600 +/- 478 mu g, 2 of 4 patients). There were no diff erences with respect to systemic hypotension during cardiopulmonary by pass or for pacing >90 minutes after discontinuation of cardiopulmonar y bypass, and no patient required permanent pacing. There have been no deaths, Q-wave myocardial infarctions, intra-aortic balloon pump inse rtions, or cerebral infarctions in the total sample of 56 patients. Co nclusions Our initial investigations have shown that adenosine can be safely administered during cardiopulmonary bypass. The authors recomme nd that further studies are warranted using adenosine 15 to 25 mu mol/ L, depending on the delivery system.