Hypoxic-Ischemic Encephalopathy (HIE) in neonates occurs in 1-6/1000 live births and results in significant morbidity and mortality1. Therapeutic hypothermia is the first treatment to have demonstrated success in reducing the risk of death or severe disability, although it is not completely efficacious with death or adverse neurodevelopmental outcome in 40-55% of neonates in randomized trials 2-7. Following a hypoxic-ischemic insult, there are different phases of cerebral injury during which timely administration of phase-specific therapeutic agents in addition to hypothermia can provide additional neuroprotection and promote repair in experimental models8. An exciting therapeutic emerging in pilot clinical trials is erythropoietin (EPO). EPO enhances neurogenesis and repair and treatment can be effective even when delayed till 24 hours after injury 9. Unfortunately, early markers that identify the phase of injury and repair are not yet well understood in human neonates and the ascertainment of useful developmental outcomes require, at minimum 18 months of follow up. Potential biomarkers in humans include real-time measures of brain function (EEG), metabolism (1H-MRS - lactate, creative, N-acetyl aspartate) and evidence of parenchymal brain injury (MRI) 10. We propose that these biomarkers can assist in interpreting the timing and severity of injury, provide information on the mechanisms of injury, and can delineate those neonates who could benefit from additional neuroprotection. The importance of the identification of these at-risk neonates for enrollment in further trials of neuroprotectants ws supported by an NICHD workshop 11. During this career development award I will study the ability of early and continuous monitoring of brain function and advanced imaging techniques to evaluate brain metabolism and identify neonates that may benefit from neuroprotective agents and strategies. Currently, MRI is done late, from 5-12 days after birth, to provide prognostic information for parents. However, if done earlier, in conjunction with other biological markers, imaging may be able to rationally guide adjunctive therapies that are now being considered for clinical trials. This proposal will add the unique ability to provide continuous bedside monitoring and early advanced imaging to an ongoing NIH funded longitudinal study of specialized MRI techniques in prognosticating outcome in neonates with HIE. Use of continuous EEG and serial MRI will allow us to visualize the phases of injury, the cerebral response to therapy and to understand the appropriate windows for intervention. I will obtain specific training in quantitativ advanced imaging, neurophysiology, analysis of complex longitudinal data and in clinical trial design and implementation. I have assembled a multi-disciplinary mentoring team and comprehensive training plan will guide me in carrying out the research proposed and enable me to become a leader in neonatal neurocritical care and neuroprotective intervention trials, with successful attainment of an R01.

Public Health Relevance

Public Health Relevance Neonates with hypoxic-ischemic brain injury are at risk of dying or developing significant cognitive or motor impairments. These neonates can now be treated with hypothermia, which improves outcomes in some, but 40-55% still dies or develops significant disabilities. Identifying early biomarkers of outcome would facilitate selection of neonates for trials of additional neuroprotective agents and treatment with these agents in conjunction with hypothermia may further reduce their risk of death or life-long disability.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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Neurological Sciences Training Initial Review Group (NST)
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Hirtz, Deborah G
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Lemmon, Monica E; Boss, Renee D; Bonifacio, Sonia L et al. (2017) Characterization of Death in Neonatal Encephalopathy in the Hypothermia Era. J Child Neurol 32:360-365
Wietstock, S O; Bonifacio, S L; Sullivan, J E et al. (2016) Continuous Video Electroencephalographic (EEG) Monitoring for Electrographic Seizure Diagnosis in Neonates: A Single-Center Study. J Child Neurol 31:328-32
Wietstock, Sharon O; Bonifacio, Sonia L; McCulloch, Charles E et al. (2015) Neonatal Neurocritical Care Service Is Associated With Decreased Administration of Seizure Medication. J Child Neurol 30:1135-41
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Bonifacio, S L; deVries, L S; Groenendaal, F (2015) Impact of hypothermia on predictors of poor outcome: how do we decide to redirect care? Semin Fetal Neonatal Med 20:122-7
Mrelashvili, Anna; Bonifacio, Sonia L; Rogers, Elizabeth E et al. (2015) Outcome After Therapeutic Hypothermia in Term Neonates With Encephalopathy and a Syndromic Diagnosis. J Child Neurol 30:1453-8
Glass, Hannah C; Rogers, Elizabeth E; Peloquin, Susan et al. (2014) Interdisciplinary approach to neurocritical care in the intensive care nursery. Semin Pediatr Neurol 21:241-7
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Sampson, Mario R; Frymoyer, Adam; Rattray, Benjamin et al. (2014) Predictive performance of a gentamicin population pharmacokinetic model in neonates receiving full-body hypothermia. Ther Drug Monit 36:584-9