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 mumol/L, and the blocks were tested sequentially. Stopping rules were defined for systemic hypotension (phenylephrine dose during cardiopulmonary bypass > or = 5.0 mg; phenylephrine dose during cardioplegic induction > or = 800 micrograms) and AV block (permanent pacemaker insertion; temporary pacing dependency for > 90 minutes after cardiopulmonary bypass). Doses of 1, 2.5, 5, 10, and 25 mumol/L were well tolerated. With 50 mumol/L, systemic hypotension occurred during cardioplegic induction in 3 of 4 patients versus 1 of 24 (P < .005) at all lower concentrations (880 +/- 217 versus 297 +/- 286 micrograms 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 mumol/L (n = 4) were tested. Hypotension during cardioplegic induction was more prevalent (P = .05) with the higher doses (15 mumol/L, 394 +/- 189 micrograms, 1 of 12 patients; 20 mumol/L, 360 +/- 355 micrograms, 2 of 8 patients; 25 mumol/L, 600 +/- 478 micrograms, 2 of 4 patients). There were no differences with respect to systemic hypotension during cardiopulmonary bypass or for pacing > 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 mumol/L, depending on the delivery system.

Optimal antithrombotic therapy following aortocoronary bypass: a meta-analysis.

To evaluate the role of antithrombotic therapy, on preserving graft patency, we performed a meta-analysis of randomized clinical trials involving aspirin (ASA), dipyridamole (D), anticoagulants (AC) and placebo or nontreatment controls (P). Manual literature searches were performed supplemented by computerized MEDLINE listings complete to July 1991. Saphenous vein graft occlusion was determined by angiography (patients with > or = 1 distal anastomotic occlusion). The trial data were aggregated with the methods of Mantel and Haenszel. The results are reported as odds ratios (OR) +/- 95% confidence intervals (CI). Seventeen trials were evaluated. Aspirin strongly influenced graft occlusion [ASA +/- D vs P: OR 0.60, 95% CI 0.51, 0.71, P < 0.0001], but dipyridamole provided no additional benefit [ASA+D vs ASA: OR 0.94, 95% CI 0.72, 1.24, P = 0.71]. Anticoagulants reduced graft occlusion [AC vs P: OR 0.56, 95% CI 0.33, 0.93, P = 0.025] and the results were similar to that achieved with aspirin [ASA vs AC: OR 0.95, 95% CI 0.62, 1.44, P = 0.87]. The combination of aspirin and anticoagulants was superior to anticoagulants alone in two limited trials [ASA+AC vs AC: OR 0.55, 95% CI 0.33, 0.88, P = 0.01]. A low (100 mg) to medium (325 mg) daily aspirin dosage was more effective than a high dose (975 mg). Early postoperative treatment (< or = 6 h) strongly influenced graft occlusion while preoperative administration provided no additional benefit. No mortality advantage was identified for any antithrombotic therapy. Aspirin or anticoagulants enhance saphenous vein graft patency following aortocoronary bypass surgery, and a combination thereof deserves further investigation in a trial large enough to detect the effects of these treatments with respect to clinical events.