Ischemic Postconditioning during Cardiopulmonary Resuscitation Improves Acute Outcomes in a Porcine Model of Prolonged Cardiac Arrest

University of Minnesota Ph.D. dissertation. August 2017. Major: Integrative Biology and Physiology. Advisor: Demetri Yannopoulos. 1 computer file (PDF); ix, 133 pages.Cardiac arrest (CA) is the cessation of blood flow due to electrical or mechanical failure of the heart resulting in whole-body ischemia. Out-of-hospital CA (OHCA) is a medical emergency occurring in approximately 350,000 people in the United States each year with a survival rate of 5-15%. Mechanical improvements to cardiopulmonary resuscitation (CPR) as well as organizing a systems-based approach to resuscitation have resulted in only modest improvements in survival. Novel resuscitation strategies are necessary to improve survival following OHCA. Two phases of injury are associated with prolonged ischemia: an initial injury during untreated ischemia, followed by paradoxical damage that occurs upon reperfusion. During CA, ischemic injury occurs prior to resuscitation efforts, whereas reperfusion injury begins when CPR is initiated. The extent and development of reperfusion injury during resuscitation following OHCA is poorly characterized. Postconditioning, a suite of strategies applied after a lethal ischemia to mitigate reperfusion injury, can attenuate infarct size and organ dysfunction in the heart and brain when applied early during reperfusion. Following a CA, reperfusion is initiated with CPR. Thus, postconditioning strategies are predicted to have the greatest efficacy when applied during CPR for the treatment of CA. Ischemic postconditioning (IPC), a technique of non-lethal pauses in blood flow during early reperfusion, has demonstrated protection of vital organs after focal ischemia. The ability to protect multiple organs makes IPC an appealing therapeutic for the whole-body ischemia of CA. Further, IPC is ideal for CA because controlled pauses in reperfusion can be accomplished simply by interrupting continuous chest compressions. The central hypothesis of this work is that IPC implemented at the initiation of CPR can improve cardiac and neurologic recovery after prolonged CA. This work details experiments investigating the feasibility and efficacy of implementing a simple IPC strategy at the onset of CPR to mitigate organ and mitochondrial dysfunction following prolonged ventricular fibrillation (VF) CA. In a porcine model, IPC drastically improved cardiac function and neurologically favorable survival after 15 minutes of VF CA. IPC also improved hemodynamics during CPR and increased cardiac mitochondrial function in the acute phase of resuscitation. A combination of IPC with other postconditioning strategies promoted cardiac and neurologic recovery after 17 minutes of untreated VF CA, a duration not previously compatible with positive outcomes in a porcine model. The mechanisms that mediate cardiac and neurologic protection remain undetermined, though evidence suggests increased coronary perfusion pressure during resuscitation is necessary and sufficient to restore acute cardiac mitochondrial function after prolonged VF CA. These experiments highlight the impact of early CPR interventions on long-term outcomes, and emphasize the importance of continued innovation in resuscitation therapies. Every incremental improvement to resuscitation care has the potential to save thousands of lives