Inhaled Prostaglandin E1 (IPGE1) for Hypoxemic Respiratory Failure (NHRF)

Hypoxemic respiratory failure in the newborn (NHRF) is usually associated with widespread
vasoconstriction of the pulmonary microvasculature giving rise to intra- and extra-pulmonary
shunts and profound hypoxemia. The goal of therapy is to decrease the regional pulmonary
vascular resistance of ventilated lung areas thus decreasing intrapulmonary shunting and
selectively reducing the pulmonary-artery pressure without causing systemic vasodilation.
Intravenously administered vasodilators lack pulmonary selectivity leading to systemic side
effects. Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized
the treatment of respiratory failure in the newborn. However, there is lack of sustained
improvement in 30-46% of infants; moreover, INO requires specialized systems for
administration, making the treatment expensive. Aerosolized prostaglandins I2 and E1 have
been reported to be effective selective pulmonary vasodilators in animals and human adults.
In addition, inhaled prostaglandin I2 (IPGI2) has also been reported to be effective in
preterm and term newborns, and children with pulmonary hypertension. Although intravenous
PGE1 is widely used in neonates, the use of the inhaled form has not been reported in
newborns with pulmonary hypertension. Compared to PGI2, PGE1 has a shorter half-life, lower
acidity constant (pKa) (6.3 versus 10.5), bronchodilator action, anti-proliferative and
anti-inflammatory effects on the alveolar, interstitial and vascular spaces of the lung.
Prostaglandin nebulization can be used without the sophisticated technical equipment needed
for controlled NO inhalation and hence is less expensive. It has no known toxic metabolites
or toxic effects. Prostaglandins and nitric oxide (NO) relax the vascular smooth muscles
through two different second-messenger systems; therefore, in combination, INO and IPGE1 may
have synergistic effect. The existing literature suggests that inhaled PGE1 is a potential
effective vasodilator in the treatment of NHRF . We have reported the safety and feasibility
of short-term administration of inhaled PGE1 in an un-blinded Phase I/II dose-escalation
study. Four doses ranging from 25 to 300 ng/kg/min were tested for a maximum duration of 3
hours. We have also reported the stability of IPGE1, its emitted dose and aerosol particle
size distribution (APSD) in a neonatal ventilator circuit. In addition we have demonstrated
the safety of high dose IPGE1 (1200 ng/kg/min) over 24 hours in ventilated piglets. In the
current protocol, we propose a pilot to evaluate the feasibility and safety of prolonged
IPGE1 in NHRF. Two doses of IPGE1 (300 and 150 ng/kg/min) will be tested followed by weaning
for a maximum duration of 72 hours to determine feasibility, safety, optimal dose and
duration of therapy in 50 patients in ten NICHD NRN sites. An IND status has been approved by
the FDA for this trial.

Inclusion Criteria:

- Gestational age less than or equal to 34 weeks

- Postnatal age less than or equal to 7 days (168 hours).

- Assisted ventilation for hypoxemic respiratory failure.

- Diagnosis of NHRF including perinatal aspiration syndrome (meconium, blood, or
amniotic fluid), suspected/proven pneumonia/sepsis, respiratory distress syndrome,
idiopathic persistent pulmonary hypertension of the newborn (PPHN) or suspected
pulmonary hypoplasia.

- Receiving INO for at least 1 hour and not >72 hours.

- Oxygenation Index (OI ) ≥ 15 on any 2 arterial blood gases 15 minutes to 12 hours
apart while on INO.

- An indwelling arterial line is present

Exclusion Criteria:

- Any infant in whom a decision has been made not to provide full treatment (e.g.
chromosomal anomalies, severe birth asphyxia).

- Known structural congenital heart disease except patent ductus arteriosus and
atrial/ventricular level shunts.

- Congenital diaphragmatic hernia.

- Thrombocytopenia unresponsive to platelet transfusion.

- Enrollment in a conflicting and/or Investigational New Drug (IND) clinical trial.