DIASTOLIC CLOSING MARGIN PREDICTS BRAIN INJURY IN PREMATURE INFANTS

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 DESCRIPTION (provided by applicant): This is a revised application for a K23 Award for Dr. Christopher Rhee, an assistant professor and board- certified neonatologist in the Department of Pediatrics at Baylor College of Medicine (BCM) and Texas Children's Hospital (TCH). I am well-qualified and highly motivated to pursue a career in academic medicine with a research focus on neonatal brain injury and cerebral hemodynamics. This K23 award will provide the support necessary for me to: (1) become an expert in premature brain injury; (2) conduct clinical investigations to define optimal brain perfusion parameters; (3) relate changes in brain perfusion to outcomes of interventricular hemorrhage (IVH), white matter injury, and neurodevelopmental outcomes; (4) gather data for the purpose of designing an intervention trial to identify and treat patients based on individualized brain perfusion parameters; and (5) develop an independent research career. I will use research and educational resources at the Texas Medical Center to advance my research career development. The neonatal intensive care unit at TCH is one of the largest in the country and offers the opportunity and resources to learn from an especially large population of premature infants. With more than 100 premature infants with birth weight ≤1000 grams born at TCH annually, we have the diversity and number of patients to perform meaningful clinical research and make an impact on patient care. I have assembled a knowledgeable, diverse, and multidisciplinary mentoring group from neonatology, critical care, anesthesiology, neurology, neuroradiology and developmental pediatrics to guide my career and this proposal. I have been working for the past 5 years in the basic science laboratory of Ken Brady, M.D., (secondary mentor) to learn techniques of brain and kidney perfusion monitoring in animal-models of hemorrhagic-induced shock and have translated these applications to premature infants. I have published the results of both animal and clinical research. Over the past 3 years, I have been working with Jeffrey R. Kaiser, M.D., (primary mentor) to further understand the development of premature cerebral hemodynamics, to explore use of magnetic resonance imaging techniques to evaluate white matter brain injury, and to learn the technique of transcranial Doppler ultrasound to evaluate cerebral blood flow clinically in premature infants. In conjunction with the research plan, I intend develop the skill set to become a leader in premature brain injury. To achieve these goals, I will utilize the resources and expertise of my mentors and Advisory Committee. I will formally take didactic courses, perform selected readings, and attend symposiums on brain physiology and neuroimaging to broaden my knowledge base. In addition, I will have hands-on tutorials learning transcranial Doppler from Dr. Kaiser, advanced physiologic waveform analysis from Dr. Brady, and neuroimaging techniques from Drs. Elisabeth Wilde, Ph.D. and Jill Hunter, Ph.D. Finally, I will meet weekly with my primary and secondary mentor and quarterly with my Advisory Committee to evaluate my progress and discuss changes to my career development plan. I have now developed a brain perfusion parameter, the diastolic closing margin (DCM) that offers a novel way to normalize arterial blood pressure to the critical closing pressure (zero-flow pressure) of the brain vasculature. My preliminary findings demonstrate an association of high brain perfusion pressure (high DCM) with IVH, and I have orally presented this data at the 2014 Pediatric Academic Society meeting and have published two manuscripts from this work. Drs. Kaiser and Brady will provide me with the research tools, research space and scientific guidance to help to ensure my success. The objective of this proposal is to assess the ability of the DCM to predict hemorrhagic and ischemic brain injury in premature infants. My central hypothesis is that a high DCM is associated with IVH, indicating a hyperperfusion injury, and a low DCM is associated with white matter injury, indicating an ischemic injury. If this hypothesis is correct, the mechanism and logical care goals for the most common brain injuries in premature infants will be delineated. My long-term goal is to define clinically relevant brain-specific hemodynamic parameters that can be used at the bedside to prevent hemorrhagic and ischemic brain injury and thereby improve neurodevelopmental outcomes. I will gather necessary preliminary data for the design of a future hemodynamic intervention trial aimed at preventing the most common forms of premature brain injury, in a subsequent R01: Aim 1. Prospectively determine whether a high brain perfusion pressure (high DCM) is predictive of interventricular hemorrhage. Aim 2. Prospectively determine whether a low brain perfusion pressure (low DCM) is predictive of white matter injury. Aim 3. Determine whether physiologic measurements of brain perfusion are predictive of neurodevelopmental outcomes. The K23 will allow me the protected time to conduct this research and continue my career development towards my goal of becoming a successful and independent clinical scientist.