Early iNO for Oxidative Stress, Vascular Tone and Inflammation in Babies With Hypoxic Respiratory Failure

• Responsiveness to study treatment. [ Time Frame: Arterial oxygen concentration will be measured upon enrollment and at specific time points in the first 36 hours of study intervention to compare the change in arterial oxygen concentration from baseline up to hour 36. ] [ Designated as safety issue: No ]
  Earlier administration of iNO to infants with HRF/PPHN will lessen reactive oxygen species formation resulting in improved responsiveness to the drug as measured by the initial changes in arterial oxygen concentration after administration of the drug.
• Expression of endothelin-1. [ Time Frame: Concentration of endothelin-1 will be measured upon enrollment and at specific time points in the first 36 hours of study intervention to compare the change in concentration from baseline up to hour 36. ] [ Designated as safety issue: No ]
  Earlier treatment with iNO may potentiate pulmonary vasodilation by modulating endothelin-1 expression.
• Markers of inflammation. [ Time Frame: Concentrations of pro and anti-inflammatory markers will be measured upon enrollment and at specific time points in the first 36 hours of study intervention to compare the change in concentrations from baseline up to hour 36. ] [ Designated as safety issue: No ]
  Early iNO may up-regulate production of endogenous anti-inflammatory eicosanoids such as PGE2. Additionally, avoidance of hyperoxia in these patients may mitigate pro-inflammatory cytokines known to potentiate lung injury.
• Duration of oxygen treatment. [ Time Frame: Participants will be followed for the duration of their hospital stay, with an expected average stay of 4 weeks. ] [ Designated as safety issue: No ]
  Early administration of iNO to infants with HRF will result in at least a 15% reduction in total days of oxygen therapy.
• Expression of VEGF (vascular endothelial growth factor). [ Time Frame: Concentration of VEGF will be measured upon enrollment and at specific time points in the first 36 hours of study intervention to compare the change in concentration from baseline up to hour 36. ] [ Designated as safety issue: No ]
  Earlier treatment with iNO may potentiate pulmonary vasodilation by preventing hyperoxic down regulation of VEGF.

The investigators in this study are concerned about the harmful effects of oxygen exposure in newborn infants, particularly at high concentrations. Inhaled nitric oxide (iNO) is an FDA approved drug for the treatment of hypoxic respiratory failure (HRF) in term and late-preterm babies greater than 34 weeks gestation. Hypoxic respiratory failure occurs when a patient's lungs cannot get enough oxygen into their bloodstream. This condition is traditionally treated with high concentrations of oxygen and most often requires the patient be placed on a ventilator (breathing machine). The administration of inhaled nitric oxygen directly into the lungs often improves blood oxygen levels and allows caretakers to reduce the amount of oxygen given to the baby. The purpose of this research study is to evaluate if giving the inhaled nitric oxide earlier in the course of disease improves the effectiveness of the drug, reduces the amount of cellular injury from oxygen exposure, and decreases the total amount of time a patient requires supplemental oxygen. This study uses an FDA approved drug in a new manner.

• Persistent Fetal Circulation Syndrome
• Hypertension, Pulmonary, of Newborn, Persistent
• Persistent Pulmonary Hypertension of Newborn

• Experimental: Early inhaled nitric oxide
  Patients randomized to receive iNO at OI 10-15.
  Intervention: Drug: Inhaled nitric oxide
• Placebo Comparator: Bioinert inhaled gas
  Patients randomized to bioinert inhaled gas at OI 10-15.
• Active Comparator: Crossover iNO
  Patients who deteriorate on placebo gas and crossover to iNO at OI >20 on two consecutive blood gases.
  Intervention: Drug: Inhaled nitric oxide

Inclusion Criteria:

• Gestational age ≥ 35 weeks gestation
• Age of life ≤ 48 hours
• Diagnosis of hypoxic respiratory failure (HRF) as defined by a post-ductal SaO2 ≤90% in ≥50% oxygen with a PEEP of ≥ 6cm or an oxygenation index (OI) ≥ 10 but ≤ 15 when mean airway pressure and PaO2 are known.

Exclusion Criteria:

• Gestational age < 35 weeks gestation.
• Post-natal age > 48 hours.
• Previous treatment with 100% oxygen for longer than 4 hours.
• Confirmed congenital diaphragmatic hernia.
• Suspected or confirmed congenital airway or pulmonary anomaly.
• Suspected or confirmed chromosomal anomaly or genetic aberration, with the exception of patients with trisomy 21 who do not have complex congenital heart disease.
• Infants with pneumothorax as the primary cause of their HRF.
• Infants with confirmed complex congenital heart disease.