Meta-analysis of inhaled nitric oxide in premature infants: an update

The role of inhaled nitric oxide (iNO) in the treatment of severe hypoxemic respiratory failure of term neonates has been firmly established in several randomized trials. In contrast, the use of iNO in premature newborns has remained controversial. We performed a meta-analysis of five published randomized controlled trials involving a total of 808 infants below 34 weeks of gestation.

The rates of major intracranial hemorrhage (ICH) were similar in both groups (42 of 208 infants receiving iNO vs 52 of 185 controls, relative risk (RR) 0.72, 95 % confidence interval (CI) 0.50-1.02) as was the mortality rate (169 of 415 receiving iNO vs 155 of 393 controls, RR 1.03, 95 % CI 0.87-1.22). Of 415 infants receiving iNO, 188 infants were diagnosed as having chronic lung disease (CLD), compared to 215 of 393 control infants. The RR in favor of iNO was 0.83, 95 % CI 0.72-0.95, p = 0.0092. Treatment failure, defined as death or CLD was significantly reduced in the iNO group (iNO: 126 of 208 infants versus control: 139 of 185, RR in favor of iNO 0.81, 95 % CI 0.70-0.93, p = 0.0025).

We conclude that the use of iNO may decrease the CLD and the combined endpoint CLD and mortality in preterm infants with hypoxemic respiratory failure. However, the most recent and by far largest study was terminated due to an increase in severe ICH. Therefore a cautious use of iNO in preterm infants at risk for ICH is mandatory. Further studies with appropriate neurodevelopmental follow-up need to elucidate if the reduction of CLD in very low birth weight infants is potentially associated with modifications in neurodevelopmental outcome.