Inhaled Nitric Oxide and Severe Hypoxic Respiratory Failure

By Richard A. Ehrenkranz, MD, FAAP

In december 1992, nitric oxide (no) was featured in Science as the molecule of the year.1 In October 1992, two groups had reported successful clinical treatment with inhaled NO in infants with severe pulmonary hypertension of the newborn (PPHN) who were considered to be candidates for treatment with extracorporeal membrane oxygenation (ECMO).2,3 Neonatologists have subsequently wondered whether inhaled NO was the "silver bullet" with respect to the treatment of PPHN, a long sought specific pulmonary vasodilator. The results of two multicenter, randomized controlled trials have demonstrated that inhaled NO is capable of significantly reducing the need for ECMO in infants with hypoxic respiratory failure.4,5

The NINOS (Neonatal Inhaled Nitric Oxide Study Group) trial was terminated after enrollment of 235 infants, when a planned review of the data revealed that the predetermined boundary of statistical significance had been crossed.4 The 121 control and 114 treated infants were similar for pre-randomization variables including the initial PaO2. Death at younger than 120 days of age or the need for ECMO occurred in 64% of control vs. 46% of inhaled NO-treated infants (P = 0.006). Death occurred in 20 (16%) of the controls and 16 (14%) of the NO-treated infants (NS), but significantly fewer of the NO-treated group received ECMO (55% vs 39%; P = 0.014). The inhaled NO group had significant improvements in PaO2 and in OI when compared to the control group.

The trial reported by Roberts et al was stopped because inhaled NO was found to increase systemic oxygenation significantly when compared to control gas.5 Fifty-eight infants—28 controls and 30 NO-treated infants—were enrolled in this trial. There were no differences in pre-randomization variables. Systemic oxygenation increased in 16 of the 30 NO-treated infants (53%) but in only two of the 28 control patients (7%; P = 0.002) in response to study gas. Forty percent of the NO-treated group required ECMO—significantly less than the 20 of 28 control infants (71%; P = 0.02).

In both studies, decisions about initiating ECMO were made by the perinatal clinical teams on the basis of center-specific criteria. In addition, both studies reported that inhaled NO treatment was safe, well-tolerated, and relatively easy to administer. Potentially toxic elevations of methemoglobin and nitrogen dioxide (NO2) were not observed.

Although the conclusions of these studies are similar, several important differences in their design should be noted. The primary hypothesis tested by the NINOS trial evaluated a clinically important outcome: whether the administration of inhaled NO to infants with hypoxic respiratory failure would reduce the risk of death and/or the initiation of ECMO from 50% in the control infants to 30% in infants treated with inhaled NO.4 Roberts et al, in contrast, evaluated a physiological response to therapy with study gas.5

While both studies reported similar results, only the NINOS trial had the statistical power to conclude that inhaled NO reduced the need for ECMO in infants with hypoxic respiratory failure. However, the results of both of these studies, especially when combined, support the recommendation made by the NINOS investigators that appropriate conventional treatment, including the use of surfactant and high frequency ventilation by experienced clinicians, should precede the administration of inhaled NO. When such management fails to lead to improvement, treatment with inhaled NO should be considered since it will reduce the number of infants who need ECMO.

A New Drug Application (NDA) seeking approval for the use of inhaled NO treatment of term and near-term infants with hypoxic respiratory failure has been submitted to the FDA by Ohmeda, Inc., a Division of BOC Gases. That application is currently under review, and a decision is anticipated before the end of 1997. Until that time, inhaled NO is considered to be an investigational treatment.

Several issues, including inhaled NO’s efficacy in infants with congenital diaphragmatic hernia (CDH) and in preterm infants with severe hypoxic respiratory failure and its effect on long-term neurodevelopmental outcome, remain unresolved. A separate parallel randomized, controlled trial of inhaled NO in infants with CDH was conducted.6 This study demonstrated that although inhaled NO produced a short-term improvement in oxygenation in some infants with CDH, it did not reduce the need for ECMO or death.

Inhaled NO will remain an investigative therapy for preterm infants with hypoxic respiratory failure, even if it is approved for term and near-term infants. It will be essential that all infants exposed to inhaled NO be evaluated in newborn follow-up programs. NICUs without ECMO capability that choose to administer inhaled NO should identify an available ECMO bed for possible transfer of a patient whenever inhaled NO therapy is initiated and fails to produce an improvement. v


1. Culotta E, et al. Molecule of the year: NO news is good news. Science 1992;258:1862-1863.

2. Roberts JD, et al. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992; 340:818-819.

3. Kinsella JP, et al. Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:819-820.

4. Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly-full term infants with hypoxic respiratory failure. N Engl J Med 1997; 336:597-604.

5. Roberts JD Jr, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med 1997;336:605-610.

6. Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 1997;99:838-845.