Early Inhaled Nitric Oxide for Respiratory Failure in Newborns

Respiratory failure occurs in near term and term infants as a complication of perinatal
aspiration syndromes, pneumonia, sepsis, respiratory distress syndrome and primary pulmonary
hypertension. Recently a collaborative trial of the NICHD Neonatal Research Network and the
Canadian Inhaled Nitric Oxide Study Group (the NINOS trial) demonstrated that inhaled nitric
oxide (iNO) reduced the number of deaths and the need for extracorporeal membrane oxygenation
(ECMO) therapy -- a lung bypass mechanism -- from 64 percent to 46 percent. The standard
recommended threshold for initiation of iNO therapy, based on this trial, was an oxygenation
index (OI) >=25.

The purpose of this study is to determine if administration of inhaled nitric oxide earlier
in the course of respiratory failure and to infants with less severe respiratory failure,
decreases the incidence of ECMO or death, as suggested by the sub-group analysis of the
original NINOS trial. This prospective, randomized controlled trial tested whether initiating
iNO therapy earlier would reduce death and reduce the use of ECMO therapy compared with the
standard recommendation threshold.

Infants who were born at >34 weeks' gestation (near- or full-term) were enrolled when they
required assisted ventilation and had an oxygenation index (OI) >15 and <25 on any 2
measurements in a 12-hour interval. Infants were randomized to receive either early iNO or to
simulated initiation of iNO (control). Infants who had an increase in OI to 25 or more were
given iNO as standard therapy. The neurodevelopment of the subjects were evaluated at 18-22
months corrected age.

The study compared the outcome of infants received iNO at OI >15 and <25, with a control
group that received a simulated early procedure with iNO actually given based on the standard
recommendation. iNO was delivered at 20 ppm during the initial dose-response evaluation.
Infants in either group who showed subsequent deterioration with OI >25 on two consecutive
measurements at least one hour apart, or a rapid deterioration with OI >30 on two consecutive
measurements 15 minutes apart, received iNO therapy as part of standard medical management.
Specific guidelines were followed for the use of high frequency ventilation and surfactant
during study gas administration to prevent them from confounding the results of the study.

Study recruitment was discontinued after 3 years due to a persistent decline in enrollment.

Infants were given neurodevelopmental exams at 18-22 months corrected age.

Inclusion Criteria:

- Infants born at >34 weeks gestational age

- Require assisted ventilation for hypoxic respiratory failure

- Have a diagnosis of primary persistent pulmonary hypertension (PPHN), respiratory
distress syndrome, perinatal aspiration syndrome, pneumonia/sepsis, or suspected
pulmonary hypoplasia

- Have an oxygenation index >15 and <25 based on 2 arterial blood gases taken at least
15 minutes apart or an Fi02 >80%

- In-dwelling arterial line

- Parental consent

Exclusion Criteria:

- Known structural congenital heart disease, except patent ductus arteriosus and atrial
level shunts

- Congenital diaphragmatic hernia

- Use of high frequency jet ventilation at the time of randomization

- Prior exposure to inhaled nitric oxide therapy