A 7-DAY MULTICENTER TRIAL OF IV SILDENAFIL FOR NEONATES WITH PPHN

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Persistent Pulmonary Hypertension of the Newborn (PPHN) is diagnosed in 1.9 per 1,000 live births. The syndrome includes pulmonary vasoconstriction, right-to-left shunting through the ductus arteriosus and/or foramen ovale, and severe hypoxemia without evidence of congenital heart disease. The diverse underlying pathophysiologies of PPHN present early as hypoxic respiratory failure that is not responsive to 100% oxygen. Newborns with hypoxic respiratory failure who are not controlled by mechanical ventilation techniques, surfactant administration, alkalinization, sedation, and neuromuscular blockade are typically treated with inhaled Nitric Oxide (iNO). This treatment increases the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilation areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion ratios toward regions with normal ratios. It is the only selective pulmonary vasodilator that has shown to improve oxygenation in newborns with hypoxic resiratory failure of PPHN. When iNO is not effective, subjects may be maintained with extracorporeal membrane oxygenation (ECMO), which provides pump support for the dysfunctional heart and oxygenation for the failing lungs. ECMO has been described as the most invasive therapeutic modality and the ultimate rescue. Hypoxic respiratory failure is the most common reason for referral for neonatal ECMO. The Neonatal Inhaled Nitric Oxide Study Group (NINOS) and Clinical Inhaled Nitric Oxide Research Group (CINRGI) trials showed that treatment with iNO significantly reduces the need for ECMO in subjects with hypoxic respiratory failure and/or PPHN. Despite this therapeutic benefit, the NINOS and CINRGI trials, 39% and 38% of the subjects who received iNO, respectively, were eventually treated with ECMO because iNO had failed to correct their hypoxic respiratory failure. Recent data (year 2000) shows the survival rate for newborns with PPHN who require ECMO is approximately 80%. Subsequent to NINOS and CINRGI and the widespread availability of iNO, it has become routine in many neonatal centers to treat hypoxic respiratory failure with iNO earlier, ie, in the presence of lesser degrees of hypoxemia, than it was initiated in NINOS and CINRGI (0I>25) and without clinical evidence of PPHN. Background Endothelial nitric oxide dilates pulmonary blood vessels by stimulating intracellular guanylate cyclase, therby elevating intracellular cyclic guanosine monophosphate (CGMP) in pulmonary arterial vascular smooth muscle cells. Elevated CGMP reduces levels of intracellular calcium and thereby causes relaxation of smooth muscle cells, leading to reduction in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). Phosphodiesterase type 5 (PDE5) is an enzyme that metabolizes intracellular CGMP to inactive 5-GMP and is found in human pulmonary arteries. Sildenafil is an inhibitor of PDE5 and hence slows the degradation of CGMP, resulting in lower levels of intracellular calcium and ultimately a reduction in PAP and PVR. It has been shown in isolated perfused lung from rats with pulmonary hypertension that CGMP levels in the perfusate are elevated over 9-fold compared with control lung. In an awake lamb model of acute pulmonary hypertension, cumulative doses of sildenafil (12.5, 25, and 50 mg via nasogastric tube at 15 minute intervals) decreased the PAP 21%, 28%, and 42%, respectively, and the PVR by 19%, 23%, and 45%, respectively. Systemic arterial pressure decreased 12% only after the maximum cumulative sildenafil dose. In a piglet model of pulmonary hypertension induced by endotracheal meconium instillation, IV sildenfil was shown to completely reverse the increase in PVR after just 1 hour of treatment. In comparison, iNO reduced PVR by 40%. PVR remained elevated in control piglets that received no treatment. Sildenafil did not result in systemic vasodilation, demonstrating selective PDE5 inhibition in the pulmonary vasculature.