The Role of Cyclosporine Treatment in Cardioprotection during Resuscitation of Asphyxiated Newborn Piglets

  • Author / Creator
    Gill, Richdeep S
  • Asphyxiated neonates often have myocardial depression which is a significant cause of morbidity and mortality. Cardioprotective effects of cyclosporine have been observed in adult animal models and human trials with myocardial infarction. However, the cardioprotective effect of cyclosporine in neonates has not yet been studied. We hypothesize that cyclosporine will improve cardiac function, reduce myocardial injury and preserve cardiac mitochondria during resuscitation of asphyxiated newborn piglets. In addition, we hypothesize that early cyclosporine treatment will lead to superior cardiac recovery compared to delayed treatment. In the first experiment, thirty-six piglets (1-4 days-old) were acutely instrumented for continuous monitoring of cardiac output and systemic hemodynamics. After stabilization, normocapnic alveolar hypoxia (10-15% oxygen) was instituted for 2h followed by reoxygenation (100% FiO2, 0.5h; 21% FiO2, 3.5h). Piglets were block-randomized to receive intravenous boluses of cyclosporine A (2.5, 10 or 25 mg/kg) or in saline (control) at 5 minutes of reoxygenation (n=8/group). Plasma troponin, left ventricle injury markers were determined. HPLC determined pharmacokinetic parameters. In the second experiment, thirty piglets were similarly instrumented with hypoxia and 6h reoxygenation. Piglets were block-randomized to receive cyclosporine (10 mg/kg) early (at 5min) or delayed (at 120min) during reoxygenation, or placebo at both 5min and 125 min reoxygenation (n=8/group). Statistical analyses were performed using ANOVA. In the first experiment, hypoxic piglets had cardiogenic shock and acidosis. Cyclosporine treatment caused bell-shaped improvements in cardiac function and systemic oxygen delivery (p<0.05 vs. controls). Lower troponin levels were associated with cyclosporine exposure (AUC) below 10umol*h/L. Myocardial lactate and cytochrome-c were higher in controls than cyclosporine-treated (10 mg/kg) piglets. Severe damage was observed in mitochondria of control piglets but attenuated with cyclosporine treatment. In the second experiment, early and delayed cyclosporine treatment significantly improved cardiac output and attenuated lactate levels vs. controls. Cardiac function was superior in piglets treated earlier compared to delayed treatment. Firstly, our results demonstrate that the post-resuscitation administration of cyclosporine improves cardiac function, attenuates myocardial injury and preserves cardiac mitochondrial integrity in asphyxiated newborn piglets following resuscitation. Secondly, our results suggest that both early and delayed cyclosporine treatment improves cardiac recovery following asphyxia-reoxygenation, with modest additional benefit of early treatment.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Surgery
  • Supervisor / co-supervisor and their department(s)
    • Cheung, Po-YIn (Pediatrics)/ Bigam, David L (Surgery)
  • Examining committee members and their departments
    • Churchill, Thomas (Surgery)
    • Joynt, Chloe (Pediatrics)