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

Abstract

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.

Therapeutic Effects and Outcomes of Rescue High-Frequency Oscillatory Ventilation for Premature Infants With Severe Refractory Respiratory Failure

“…Limited data about rescue use of HFOV in premature infants with severe respiratory failure can be found in the literature because it is di cult to de ne the "rescue" use of HFOV and conduct a randomized control trial [9,20,23,24]. Therefore, most studies have focused on comparisons between elective HFOV versus conventional ventilation [14][15][16]18].…”

“…Little data exist to guide early adjuvant therapy use in neonates with severe respiratory failure who receive HFOV. In out institute, iNO has been used as the off-label rescue regimen for preterm neonates with refractory respiratory failure with/without documented PPHN [24]. Because a proportion of preterm neonates presenting with severe hypoxemia during the immediate postnatal period is associated with acute pulmonary hypertension [35], iNO has been proven effective as rescue therapy for these patients [24,35,38,39].…”

“…In out institute, iNO has been used as the off-label rescue regimen for preterm neonates with refractory respiratory failure with/without documented PPHN [24]. Because a proportion of preterm neonates presenting with severe hypoxemia during the immediate postnatal period is associated with acute pulmonary hypertension [35], iNO has been proven effective as rescue therapy for these patients [24,35,38,39]. However, some patients received iNO due to BPD with secondary pulmonary hypertension and iNO was not effective in this subjects, which was compatible with previous studies that found later use of iNO is only effective to prevent BPD [40,41].…”

“…In cases with systemic hypotension, cardiovascular inotropic agents, including dopamine and dobutamine, milrinone and/or epinephrine would be used. Inhaled nitric oxide (iNO) (Solmix 1000; Dutch Technical Gas Company, Tilburg, The Netherlands) was used from 20 ppm to a maximum of 80 ppm, based on the clinical practices [24]. Surfactant (beractant, Sruventa; Ross Laboratories, Columbus, PH; one dose = 100 mg/kg) was administered to newborns with meconium aspiration syndrome (MAS) and respiratory distress syndrome (RDS).…”

Therapeutic effects and outcomes of rescue high-frequency oscillatory ventilation for premature infants with severe refractory respiratory failure

“…In cases with systemic hypotension, cardiovascular inotropic agents, including dopamine and dobutamine, milrinone and/or epinephrine would be used. Inhaled nitric oxide (iNO) (Solmix 1000; Dutch Technical Gas Company, Tilburg, The Netherlands) was used from 20 ppm to a maximum of 80 ppm, based on the clinical practices 25 . Surfactant (beractant, Sruventa; Ross Laboratories, Columbus, PH; one dose = 100 mg/kg) was administered to newborns with meconium aspiration syndrome (MAS) and respiratory distress syndrome (RDS).…”