Optimal Oxygenation in Neonatal Lung Injury

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Project summary: Optimal oxygenation in neonatal lung injury Whole-body hypothermia is currently the standard of care for moderate to severe hypoxic-ischemic encephalopathy (HIE). HIE is commonly associated with meconium aspiration syndrome (MAS) and persistent pulmonary hypertension of the newborn (PPHN). Therapeutic hypothermia can cause pulmonary vasoconstriction and exacerbate PPHN and is currently the leading indication for extracorporeal membrane oxygenation in California. The optimal target SpO2, and pulmonary vasodilator regimen that results in improvement in both pulmonary and neurological outcomes in PPHN and HIE is not known. We hypothesize that targeting 95-98% SpO2 (compared to 91-95% - current standard of care) and intravenous (IV) sildenafil will minimize brain injury and enhance pulmonary vasodilation. The first specific aim focuses on changes in gas exchange and cerebral hemodynamics with two SpO2 target ranges during 72-hours of whole-body hypothermia. The second specific aim focuses on oxidative stress and neuroprotection offered by iNO and sildenafil following birth asphyxia during hypothermia and ventilation at two different SpO2 targets. The final specific aim evaluates the impact of hypothermia on pulmonary hemodynamics and pharmacokinetics of sildenafil. Hypoxemic respiratory failure secondary to MAS and PPHN is common during whole-body hypothermia. Results from this study will inform the design of future clinical trials by defining the optimal SpO2, temperature, and pulmonary vasodilators while managing neonates with PPHN and HIE. The therapeutic potential of a commonly available and less expensive agent such as sildenafil in improving both pulmonary and neurological outcomes following birth asphyxia will be explored in this proposal.