Developing and characterizing a translational neonatal rat cardiac arrest and cardiopulmonary resuscitation model

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Project Summary Cardiac arrest is a major underlying cause of morbidity and mortality and risk factors for pediatric cardiac arrest include early age (<1 year), male sex, requirement for surgical intervention or ventilation and cardiac defects. Improvements in resuscitation have increased survival outcomes after resuscitation however therapies to improve long-term neurological outcomes are lacking. Global ischemia resulting from cardiac arrest causes systemic anoxia/hypoxia, hypercapnia and acidosis, causing injury to the brain and other organ systems. The neurological sequelae following global cerebral ischemia (GCI) include cerebral lesions, seizures and long-term motor, cognitive and emotional abnormalities. Therapeutic hypothermia for neonates suffering a perinatal hypoxic-ischemic event and are less than 6 hours old remains the only intervention to improve outcomes but has limited application for older neonates and long-term neurological impairments remain even in those receiving TH. The goal of this proposal is to advance therapies for neonatal global cerebral ischemia by developing an animal model that more closely resembles the clinical scenario. Importantly, a neonatal CA/CPR model will more recapitulate the systemic reduction in blood flow that occurs during severe hypoperfusion or cardiac arrest. Therefore, we can examine the response of posterior brain regions to ischemic injury and organ-brain interactions that was not previously possible in term-equivalent rodents. In aim 1, we will optimize our cardiac arrest duration to generate pathophysiology that resembles that found in neonatal GCI and will characterize brain injury with histology and magnetic resonance imagine. In aim 2, we will characterize the behavioral deficits that result from neonatal GCI. By completing these aims we will provide a new tool to study neonatal global ischemia that will serve as a foundation for future mechanistic studies and collaborations.