Inhaled nitric oxide for respiratory failure in preterm infants

Review question: Does giving inhaled nitric oxide gas to preterm infants with pulmonary disease improve survival without long-term brain or lung injury?

Background: Breathing failure in preterm newborn babies may be complicated by raised pressure within the vessels that carry blood to the lungs (pulmonary hypertension). Mechanically assisted ventilation is used to support such infants, and sedative medications may be given. Inhaled nitric oxide gas (iNO) helps regulate muscle tone in the arteries of the lungs and decreases pulmonary hypertension; therefore, it may reduce the need for assisted ventilation, leading to less lung injury. However, iNO has effects on platelet function and is believed to potentially increase bleeding (haemorrhage), in particular bleeding into the brain.

Study characteristics: Review authors found 17 randomised controlled trials of iNO in the preterm newborn through searches updated until January 2016. These trials studied preterm babies with very different baseline characteristics; therefore, we decided to divide them into three groups: (1) trials of babies treated in the first few days of life with severe lung disease, (2) studies providing treatment after the first few days of life to babies who were at increased risk of chronic lung disease and (3) trials providing routine early treatment for babies who experienced respiratory distress.

Key results: In none of the three groups of trials did iNO improve survival, and no consistent evidence suggests that iNO decreases lung injury. Studies in group 1 (early rescue treatment) reported a 20% increase in severe bleeding into the brain. This finding was close to statistically significant. The quality of the evidence was moderate to high.

This review of studies found that inhaled nitric oxide therapy does not appear to improve the chances of improved outcomes for preterm infants with pulmonary disease. When given to babies who were very ill, iNO did not seem to help and may have contributed to increased risk of intracranial haemorrhage.

Authors' conclusions: 

iNO does not appear to be effective as rescue therapy for the very ill preterm infant. Early routine use of iNO in preterm infants with respiratory disease does not prevent serious brain injury or improve survival without BPD. Later use of iNO to prevent BPD could be effective, but current 95% confidence intervals include no effect; the effect size is likely small (RR 0.92) and requires further study.

Read the full abstract...

Inhaled nitric oxide (iNO) is effective in term infants with hypoxic respiratory failure. The pathophysiology of respiratory failure and the potential risks of iNO differ substantially in preterm infants, necessitating specific study in this population.


To determine effects of treatment with inhaled nitric oxide (iNO) on death, bronchopulmonary dysplasia (BPD), intraventricular haemorrhage (IVH) or other serious brain injury and on adverse long-term neurodevelopmental outcomes in preterm newborn infants with hypoxic respiratory failure.

Owing to substantial variation in study eligibility criteria, which decreases the utility of an overall analysis, we divided participants post hoc into three groups: (1) infants treated over the first three days of life because of defects in oxygenation, (2) preterm infants with evidence of pulmonary disease treated routinely with iNO and (3) infants treated later (after three days of age) because of elevated risk of BPD.

Search strategy: 

We used standard methods of the Cochrane Neonatal Review Group. We searched MEDLINE, Embase, Healthstar and the Cochrane Central Register of Controlled Trials in the Cochrane Library through January 2016. We also searched the abstracts of the Pediatric Academic Societies.

Selection criteria: 

Eligible for inclusion were randomised and quasi-randomised studies in preterm infants with respiratory disease that compared effects of iNO gas versus control, with or without placebo.

Data collection and analysis: 

We used standard methods of the Cochrane Neonatal Review Group and applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence.

Main results: 

We found 17 randomised controlled trials of iNO therapy in preterm infants. We grouped these trials post hoc into three categories on the basis of entry criteria: treatment during the first three days of life for impaired oxygenation, routine use in preterm babies along with respiratory support and later treatment for infants at increased risk for bronchopulmonary dysplasia (BPD). We performed no overall analyses.

Eight trials providing early rescue treatment for infants on the basis of oxygenation criteria demonstrated no significant effect of iNO on mortality or BPD (typical risk ratio (RR) 0.94, 95% confidence interval (CI) 0.87 to 1.01; 958 infants). Four studies examining routine use of iNO in infants with pulmonary disease reported no significant reduction in death or BPD (typical RR 0.94, 95% CI 0.87 to 1.02; 1924 infants), although this small effect approached significance. Later treatment with iNO based on risk of BPD (three trials) revealed no significant benefit for this outcome in analyses of summary data (typical RR 0.92, 95% CI 0.85 to 1.01; 1075 infants).

Investigators found no clear effect of iNO on the frequency of all grades of IVH nor severe IVH. Early rescue treatment was associated with a non-significant 20% increase in severe IVH.

We found no effect on the incidence of neurodevelopmental impairment.