The Off-Label Use of Inhaled Nitric Oxide as a Rescue Therapy in Neonates with Refractory Hypoxemic Respiratory Failure: Therapeutic Response and Risk Factors for Mortality

摘要

Objectives: The indication of inhaled nitric oxide (iNO) used in preterm infants has not been well defined. Neonates with refractory hypoxemia may benefit from the pulmonary vasodilatory effects of iNO. The aim of this study was to investigate the off-label use of iNO as a rescue therapy. Methods: Between January 2010 and December 2017, all neonates who received iNO as a rescue therapy from a tertiary-level medical center were enrolled, and those who were not diagnosed with persistent pulmonary hypertension of newborn (PPHN) were defined as having received off-label use of iNO. The controls were 636 neonates with severe respiratory failure requiring high-frequency oscillatory ventilation but no iNO. Results: A total of 206 neonates who received iNO as a rescue therapy were identified, and 84 (40.8%) had off-label use. The median (interquartile) gestational age was 30.5 (26.3–37.0) weeks. Neonates receiving iNO had significantly more severe respiratory failure and a higher oxygenation index than the controls (p < 0.001). Respiratory distress syndrome and secondary pulmonary hypertension after severe bronchopulmonary dysplasia (BPD) were the most common causes of the off-label iNO prescription. Of the 84 neonates with off-label use of iNO, 53 (63.1%) had initial improvement in oxygenation, but 44 (52.4%) eventually died. The overall mortality rate was 41.7% (86/206). After multivariate logistic regression, extremely preterm (odds ratio [OR] 5.51; p < 0.001), presence of pulmonary hemorrhage (OR 2.51; p = 0.036) and severe hypotension (OR 2.78; p = 0.008) were the independent risk factors for final mortality. Conclusions: iNO is applicable to be an off-label rescue therapy for premature neonates with refractory hypoxemia due to severe pulmonary hypertension and bronchopulmonary dysplasia.