Chronic Sildenafil for Severe Diaphragmatic Hernia

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DESCRIPTION (provided by applicant): Congenital diaphragmatic hernia (CDH) occurs 1 in 3000 live births. Infants born with severe CDH have poor lung function and persistent pulmonary hypertension of the newborn, secondary to pulmonary hypoplasia. These infants require aggressive, prolonged neonatal support. Postnatal lung growth is critical for long-term survival in severe CDH. However, measures required to support these infants may cause direct lung injury, impairing further growth. Normal alveolar development is dependent on normal microvascular growth. Therefore, in severe CDH, vascular injury may also impact postnatal lung growth and development. Experimental models of pulmonary hypertension (PH) demonstrate attenuation of abnormal pulmonary vascular remodeling with early manipulation of the nitric oxide (NO)-cyclic guanosine monophosphate pathway through administration of inhaled NO or phosphodiesterase-5 inhibitors. The local and systemic factors that result in abnormal postnatal lung and vascular growth, development, and remodeling in the CDH population are unknown. However, chronic PH and chronic lung disease are significant problems in this population, resulting in late mortality, extended neonatal hospital stays and prolonged supplemental oxygen therapy, which is associated with poor neurodevelopmental outcome in children with CDH. The aims of this study are 1) to evaluate pulmonary vascular function and reactivity in severe CDH in the subacute stage of illness; 2) to evaluate the effect of chronic sildenafil on pulmonary vascular function and reactivity in a randomized clinical trial; and 3) to compare 1 & 2 year health and neurodevelopmental outcomes in severe CDH after chronic sildenafil therapy in infancy. This project has the further aim of extending and developing the research expertise of the Principal Investigator, so that she may be positioned for an independent research career. This broad objective will be accomplished through completion of the scientific protocol, didactic training, and careful mentoring by successful senior faculty members at her institution.