Thousands of hospitalized children in the United States die from cardiac arrests each year. Brain injury is common among survivors. Therefore, new approaches are needed to not only improve survival, but to preserve brain function of children who suffer a cardiac arrest. Hemodynamic-directed cardiopulmonary resuscitation (HD-CPR) ? where resuscitation is titrated to invasive blood pressure (BP) ? has shown promise in animal models, but its use is not common in clinical practice. Critical limitations for translation may be that optimal BP targets are unknown. In a recently published, large (n=164), multi-center prospective observational trial, the investigative team demonstrated that a mean DBP during CPR ?30 mmHg in children ?1 year-old was associated with greater likelihood of survival to hospital discharge compared to lower DBPs (54% vs. 35%, respectively). In response, the primary objective of this proposal is to evaluate the effect of two different blood pressure targets (HD-CPRSD vs. HD-CPRHP) on survival, utilizing these thresholds. In addition, because most children who survive have a neurologic injury following cardiac arrest, the investigators will determine if different blood pressure strategies have an effect on cerebral blood flow. Concurrently, because not all patients have invasive monitoring in place at the time of arrest, the investigators will further develop a new indication for a novel device that can noninvasively quantify blood flow and oxygenation in the brain, laying the foundation for a paradigm shift in the monitoring and treatment of children before, during, and after a CPR event, where invasive neuromonitoring is rarely used due to perceived/actual risk. Finally, because improving cerebral blood flow during CPR cannot completing reverse/mediate neurologic injury initiated by cardiac arrest, this application will also investigate the role that mitochondria ? the cellular engines of our bodies and key regulators of cellular life/death ? play in the development of brain injury post-cardiac arrest to elucidate potential therapeutic targets; and, based on exciting preliminary data, test a promising, innovative therapeutic that provides an alternative fuel source to mitochondria to preserve cellular energy production mitigating brain injury following cardiac arrest. To achieve these objectives, a large animal randomized trial in a porcine model of pediatric in-hospital cardiac arrest is proposed with the following aims: ? Compare survival and intra-arrest systemic and cerebral hemodynamics between strategy of targeting threshold blood pressure targets HD-CPRSD to one targeting higher goals HD-CPRHP. ? Among animals surviving 24 hours post-IHCA, compare cerebral mitochondrial dysfunction and reactive oxygen species, cerebral metabolism, brain imaging, and neuropathology, and neurofunctional outcomes at 24 hours and at 7 days between those treated with HD-CPRSD and HD-CPRHP. ? Evaluate the effectiveness of a cell permeable succinate prodrug ? a novel mitochondria-targeted therapeutic ? to improve oxidative phosphorylation and attenuate bioenergetic crisis.
Pediatric cardiac arrest affects thousands of hospitalized children each year and is associated with poor survival. Even among survivors, new neurological morbidity is common. The objectives of this grant proposal are as follows: 1) to evaluate the survival effect of two different blood pressure strategies (HD-CPRSD vs. HD- CPRHP) during hemodynamic-directed cardiopulmonary resuscitation (HD-CPR); 2) to obtain data on cerebral blood flow and oxygenation, and to validate the use of a noninvasive measures of these cerebral metrics during pediatric cardiac arrest; 3) to elucidate molecular mechanisms that may contribute to long-term cognitive deficits after pediatric cardiac arrest; and 4) to test a promising mitochondria-directed therapy to preserve cellular energy production.