Background: Nitric oxide is a major endogenous regulator of vascular tone. Inhaled nitric oxide gas has been investigated as a treatment for persistent pulmonary hypertension of the newborn.
Objectives: To determine whether treatment of hypoxaemic term and near-term newborn infants with inhaled nitric oxide (iNO) improves oxygenation and reduces the rates of death, the requirement for extracorporeal membrane oxygenation (ECMO), or affects long term neurodevelopmental outcomes.
Search strategy: Electronic and hand searching of pediatric/neonatal literature and personal data files. In addition we contacted the principal investigators of articles which have been published as abstracts to ascertain the necessary information.
Selection criteria: Randomized and quasi-randomized studies of inhaled nitric oxide in term and near term infants with hypoxic respiratory failure. Clinically relevant outcomes, including death, requirement for ECMO, and oxygenation.
Data collection and analysis: Trial reports were analysed for methodologic quality using the criteria of the Cochrane Neonatal Review Group. Results of mortality, oxygenation, short term clinical outcomes (particularly need for ECMO), and long term developmental outcomes were tabulated.
Statistics: For categorical outcomes, typical estimates for relative risk and risk difference were calculated. For continuous variables, typical estimates for weighted mean difference were calculated. 95% confidence intervals were used. A fixed effect model was assumed for meta-analysis.
Main results: Fourteen eligible randomized controlled studies were found in term and near term infants with hypoxia. Seven of the trials compared iNO to control (placebo or standard care without iNO) in infants with moderate or severe severity of illness scores. Four of the trials compared iNO to control, but allowed back up treatment with iNO if the infants continued to satisfy the same criteria for severity of illness after a defined period of time. Two trials enrolled infants with moderate severity of illness score (OI or AaDO2) and randomized to immediate iNO treatment or iNO treatment only if they deteriorated to more severe criteria. One trial studied only infants with congenital diaphragmatic hernia (Ninos 1997), and one trial enrolled both preterm and term infants (Mercier 1998), but reported the majority of the results separately for the two groups. Inhaled nitric oxide appears to improve outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO. The reduction seems to be entirely a reduction in need for ECMO; mortality is not reduced. Oxygenation improves in approximately 50% of infants receiving nitric oxide. The Oxygenation Index decreases by a (weighted) mean of 15.1 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg. Whether infants have clear echocardiographic evidence of persistent pulmonary hypertension of the newborn (PPHN) or not does not appear to affect outcome. The outcome of infants with diaphragmatic hernia was not improved; indeed there is a suggestion that outcome was slightly worsened. The incidence of disability, incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not.
Authors' conclusions: On the evidence presently available, it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia.