Early Use of Inhaled Nitric Oxide in Preterm Infants: Is there a Rationale for Selective Approach?

Abstract

Background Inhaled nitric oxide (iNO) is being increasingly used in preterm infants < 34 weeks with hypoxemic respiratory failure (HRF) and/or pulmonary hypertension (PH). Objective To evaluate the risk factors, survival characteristics, and lung histopathology in preterm infants with PH/HRF. Methods Retrospective chart review was conducted to determine characteristics of 93 preterm infants treated with iNO in the first 28 days and compared with 930 matched controls. Factors associated with survival with preterm HRF and smooth muscle actin from nine autopsies were evaluated. Results Preterm neonates treated with iNO had a higher incidence of preterm prolonged rupture of membrane (pPROM ≥ 18 hours), oligohydramnios and delivered by C-section. In infants treated with iNO, antenatal steroids (odds ratio [OR],3.7; confidence interval [CI], 1.2-11.3; p = 0.02), pPROM (OR, 1.001; CI, 1.0-1.004; p = 0.3), and oxygenation response to iNO (OR, 3.7; CI, 1.08-13.1; p = 0.037) were associated with survival. Thirteen infants with all three characteristics had 100% (13/13) survival without severe intraventricular hemorrhage (IVH)/periventricular leukomalacia (PVL) compared with 48% survival (12/25, p = 0.004) and 16% severe IVH/PVL without any of these factors. Severity of HRF correlated with increased smooth muscle in pulmonary vasculature. Conclusion Preterm infants with HRF exposed to antenatal steroids and pPROM had improved oxygenation with iNO and survival without severe IVH/PVL. Precisely targeting this subset may be beneficial in future trials of iNO.

Fig. 1

Multiple logistic regression of factors associated with survival in preterm infants treated with inhaled nitric oxide (N = 93).

Fig. 2

Flow sheet for preterm infants treated with inhaled nitric oxide (iNO) stratified for major outcome: mortality, bronchopulmonary dysplasia, intraventricular hemorrhage grade 3 and grade 4 and periventricular leukomalacia based on factors such as antenatal steroids, prolonged rupture of membrane, and short-term oxygenation response to iNO. Data represented as number of infants/percentage.

Fig. 3

(A) Hematoxylin and eosin (H&E) stain showing intra-acinar arteries from a 25-week gestation infant with hypoxemic respiratory failure. (B) Smooth muscle actin (SMA) stain showing the smooth muscle area ratio (SMR) measurement (ratio of smooth muscle area shown between the two fluorescent green circles to total area of vessel). The SMR was high (0.80) suggestive of increased muscularization. (C) A 27-week gestation infant who died of gastrointestinal pathology showing normal appearance of intra-acinar arteries (H&E stain) with (D) incomplete or partial muscularization (SMA staining, fig. D).

Fig. 4

Scatter plot depicting the positive correlation between respiratory severity score and smooth muscle area ratio of the intra-acinar arteries.

Fig. 5

Risk factors associated with development of pulmonary hypertension (PH) and/or hypoxemic respiratory failure (HRF) in preterm infants include cesarean section delivery, extreme prematurity, and preterm prolonged rupture of membrane (pPROM). A subset of preterm infants with PH and/or HRF with prenatal steroids (possibly by enhancing the effect of soluble guanylyl cyclase), pPROM and PH physiology may respond to inhaled nitric oxide with improved survival.