NICHD, INO Therapeutics, and MRC University-Industry Program

Nitric oxide (NO) is an endogenous vasodilator released by vascular endothelial cells. Several studies done in fetal lambs have shown that NO release is an important step in the modulation of perinatal pulmonary vasodilation. The use of NO given by inhaled route to treat pulmonary hypertension has also been investigated in sheep. Thus NO in doses of 20-80 parts per million (ppm) was shown to inhibit pulmonary hypertension caused by infusion of a thromboxane analogue or hypoxia. The application of this therapy to treat newborn infants with pulmonary hypertension was first reported in 1992 by Kinsella et al and Roberts et al. These pilot studies have shown that inhaled NO in doses of 5-80 ppm improves oxygenation significantly in neonates with persistent pulmonary hypertension (PPHN).

Toxicity to nitric oxide therapy is dose dependent and results in methemoglobinemia and pulmonary injury due to NO and NO2 (nitrogen dioxide) - NOx. In anesthetized dogs, 2% INO or NO2 resulted in death due to methemoglobinemia, hypoxemia and pulmonary edema. In rats, 1500 ppm of INO for 15 minutes or 1000 ppm for 30 minutes produced no detectable changes in pulmonary histology, but resulted in death due to methemoglobinemia. NO2 is more toxic than NO, and exposure to 25-50 ppm of NO2 for 30 minutes produced increased lung weight and histologic evidence of lung injury, while none was seen at lesser times and concentrations. Therefore, it is important to keep the levels of exposure to NO2 at < 5 ppm, as recommended by occupational safety health guidelines. Similarly, the risk of methemoglobin exceeding 5% is not increased when INO is used at doses of < 40 ppm.

Recently, two randomized, prospective placebo controlled trials reported the impact of INO on neonatal respiratory disease. The collaborative trial of NICHD Neonatal Research Network and Canadian Inhaled Nitric Oxide Study Group (CINOS) demonstrated that INO decreases mortality or the need for extra-corporeal membrane oxygenation (ECMO) from 64% in the control group to 46% in term/near term infants with respiratory failure. Subanalysis of data collected by NICHD-CINOS study group showed that for infants who were enrolled at an initial oxygenation index of 25-29.9, use of INO reduced the need for ECMO/death from 61% to 28%. The NICHD-CINOS trial did not have the sample size to study the impact of INO therapy used at an earlier stage in respiratory failure on morbidity. However, data collected from the 53 infants with initial OI of 25-29.9 in this trial suggested that further reductions in mortality or the need for ECMO are possible with early use of INO in term/near term infants with respiratory failure. In addition, infants in the NICHD-CINOS trial who were randomized to INO therapy were initially treated with 20 ppm of NO. The dose of NO was increased to 80 ppm for those infants that did not respond at 20 ppm. Analysis of data from initial response indicated that infants who failed to respond to 20 ppm did not show a significant response to 80 ppm of NO. Analysis of weaning strategy used in this trial and the dose response study of Finer et al indicate that significant response to NO occurs at doses of 1-5 ppm. These data indicate that optimum therapeutic effect may be seen at doses of < 20 ppm of NO.

The purpose of this study is to determine if administration of INO earlier in the course of respiratory failure or 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. In addition, we will use doses of INO < 20 ppm during the initial dose-response evaluation and during study gas administration. Infants will be enrolled at gestational age > 34 weeks (near term and term). The study will be prospective, randomized and double masked. The study will compare the outcome of infants receiving INO at OI > 15 and < 25, with a control group that does not receive early INO. Infants in either group who show subsequent deterioration with OI > 25 on two consecutive arterial blood gases (ABGs) at least one hour apart or a rapid deterioration with OI >30 on two consecutive ABGs 15 min apart will receive open label INO therapy as part of standard medical management. Specific guidelines will be followed for the use of high frequency ventilation and surfactant during study gas administration to prevent them from confounding the results of the trial.

Primary hypothesis: The proposal tests the hypothesis that use of INO in term/near term infants requiring ventilator support for respiratory failure with an oxygenation index (OI) >15 and < 25 will decrease the probability of initiation of ECMO/death before discharge from 35% in the control group to 20% in the early INO group, a relative reduction of 43%. The hypothesis will be tested in a prospective, randomized, masked trial comparing the use of INO with a control group of infants that do not receive INO at this OI. Infants in either group who have no response to study gas and show subsequent deterioration with OI > 25 on two consecutive ABGs one hour apart or OI > 30 on two consecutive ABGs 15 min apart will receive open label INO therapy as part of their medical management.

Secondary hypotheses: The secondary hypotheses are as follows

(1)Early INO therapy will reduce the probability of OI exceeding 25 on two consecutive blood gases drawn at least one hour apart or OI > 30 on two consecutive ABGs 15 min apart.
(2)Early INO therapy will reduce the probability of OI exceeding 40 on two consecutive arterial blood gases done at least 30 min apart.
(3)There will be no difference in neurodevelopmental or hearing impairments evaluated at 18-24 months of corrected age between INO treated and control groups.

Drug, Phase IV, Multi Center

Inhaled nitric oxide is delivered to the infant directly through the ventilator circuit, which causes no discomfort. This drug has been delivered in multi-center studies without major side effects and its use has been approved by the Food and Drug Administration. However, there may be unknown risks/discomforts involved.

Nitric Oxide has the advantage that it is non-invasive and has fewer potential side effects over more invasive treatments; however, there are no guarantees that this therapy will work for your baby. If there is no response to study gas, the study gas will be stopped and medical support will be continued with the addition of Nitric Oxide. If your baby responds to inhaled study gas, it will be continued until his/her condition improves.