100 Cardioprotective Effects of Cyclosporine in a Newborn Piglet Model of Asphyxia: A Dose-Response Study

Abstract

Introduction: Myocardial depression following asphyxia of the newborn is a significant cause of mortality. Cyclosporine reduces myocardial damage in adult patients undergoing percutaneous coronary intervention for myocardial infarction. However, the potential cardioprotective effects of cyclosporine in neonates have not yet been studied. We hypothesize that cyclosporine in asphyxiated newborn piglets will improve cardiac function, systemic hemodynamics and oxygen metabolism. Methods: Thirty-six piglets (1-4 days-old) were instrumented for continuous monitoring of cardiac output and systemic arterial pressures. After stabilization, normocapnic alveolar hypoxia (10-15% oxygen) was instituted for 2h followed by reoxygenation with 100% oxygen for 0.5h, then 21% for 3.5h. Piglets were block randomized to receive one of three cyclosporine intravenous boluses (2.5, 10 or 25 mg/kg) or placebo (normal saline, control) after 5 minutes of 100% reoxygenation (n=8/group). Blood samples were collected for analysis of blood gases and plasma troponin. Statistical analysis performed using ANOVA. Results: All piglets demonstrated cardiogenic shock (cardiac output 45% of baseline), hypotension (systemic arterial pressure 30mmHg) and acidosis (pH=7.04) at the end of 2h of hypoxia. Cyclosporine treatment at reoxygenation caused dose-related improvements in cardiac output and oxygen delivery compared to controls (both P< 0.05). Cyclosporine at 10 mg/kg significantly improved stroke volume compared to controls, demonstrating preservation of cardiac function. Plasma troponin, a marker of myocardial damage, was significantly higher in controls than that of 2.5 and 10 mg/kg cyclosporine treatment groups. Conclusion: We first demonstrated that the post-resuscitation administration of cyclosporine caused dose-related preservation of cardiac function in newborn piglets following asphyxia-reoxygenation.