In the subset of premature infants enrolled in the randomized, placebo-controlled PiNO trial with the diagnosis of PPROM, oligohydramnios, and suspected pulmonary hypoplasia, administration of iNO may be associated with lower mortality and BPD. However, no definitive conclusions can be made about the use of iNO in this specific diagnostic group without larger randomized studies. Data suggest that infants receiving iNO had an acute improvement in oxygenation as well as shorter duration on supplemental oxygen and mechanical ventilation without an increase in severe IVH or PVL in survivors. To our knowledge, this is the first report to characterize iNO treatment-based outcomes among this high-risk patient group within a randomized, controlled trial. All other studies of this population are case series of iNO treatment. Despite the small sample size, this study may still provide useful information to the intensivist considering use of iNO in specific clinical scenarios.
We chose to analyze the outcomes of the subset of patients with suspected pulmonary hypoplasia because of earlier studies suggesting improved oxygenation and survival after iNO in this patient population.4–6,9,10
There are several potential mechanisms by which iNO may benefit this group of infants. iNO acts as a selective pulmonary vasodilator to reduce the pulmonary hypertension associated with lung hypoplasia. iNO has also been shown to improve ventilation-perfusion matching in both adults and term infants with persistent pulmonary hypertension.11–13
Furthermore, iNO may improve airway structure, decrease pulmonary vasculature remodeling, and decrease lung inflammation, especially in the preterm infant vulnerable to developmental disruptions and inflammation after PPROM. Increased radial alveolar counts and decreased smooth muscle are reported in terminal bronchioles of preterm lambs ventilated with iNO.14
Animal studies have also shown reduced vascular remodeling after iNO exposure.15
In a lamb model of severe respiratory distress syndrome, Kinsella and colleagues found that iNO decreased lung neutrophil accumulation. 16
iNO may also replete endogenous NO stores because proinflammatory cytokines and elevated C-reactive protein levels attenuate endogenous NO production.17,18
The PiNO trial of all preterm infants with respiratory failure from which our data set was extracted found that iNO administration did not reduce the incidence of death or BPD. However, post hoc analyses found that infants treated with iNO with birth weight >1000 g had decreased mortality and BPD, whereas those <1000 g had increased rates of death and severe IVH or PVL.7
Subgroup analysis of another randomized trial also suggested a reduction in BPD for those premature infants 1000 to 1250 g receiving iNO.19
Similarly, a retrospective analysis of preterm infants with pulmonary hypertension found that infants >1000 g were more likely to respond to iNO.4
In our subpopulation, the average size of infants was slightly over 1000 g in both study groups. The suggestion of decreased death and BPD without any increase in the rate of severe IVH from our analysis may thus apply to iNO use in larger premature infants.
Three small case series describe preterm infants with oligohydramnios and PPROM who demonstrated improved oxygenation, decreased ventilatory support, and improved survival after treatment with iNO.5,6,9
A retrospective study also found that eight very low-birth-weight infants with oligohydramnios and presumed pulmonary hypoplasia had improved arterial oxygenation and increased survival compared with matched controls and no increase in IVH.10
All studies included infants similar to those reported here with rupture of membranes at <25 weeks’ gestation and most for >14 days. The case series found that two out of three iNO-exposed infants developed subsequent chronic lung disease,5,9
but no comparison group was available. Three of eight infants in one series developed severe IVH after iNO.6
The main difference in results between this sub-group analysis and the previous literature is the additional suggestion of decreased BPD and severe IVH after iNO exposure in this population of infants. The study by Uga et al10
showed no difference in BPD rate between iNO and control groups. However, that study utilized iNO at a starting dose of 30 to 40 ppm compared with the 5 to 10 ppm used in the PiNO trial, with a higher BPD rate in their iNO group (six out of eight infants). The higher dose could have resulted in increased peroxynitrite production and subsequent oxidative injury associated with the pathogenesis of BPD. The concern for increased risk of IVH after iNO exposure was not substantiated by our study. Theoretically, there is an increased risk of hemorrhage due to inhibition of platelet aggregation by iNO. Only one iNO-exposed infant in our study developed severe IVH. No infants from the iNO or control group of Uga et al’s retrospective study developed severe IVH.10
The major limitation of this study is the small sample size of the subgroup. As a retrospective analysis of prospectively collected data, this study was not powered for the analysis. The potential significance of decreased mortality and BPD after iNO exposure must be tempered with this knowledge. However, unlike other published case series, the 12 subjects from this study were within a randomized, controlled trial. A potential limitation is that an intention-to-treat analysis was not used, and infants were classified according to actual iNO exposure. However, this decision only affected classification of one infant. Another study limitation may be the existence of concealed differences between the two study groups. The apparent trend toward worse outcome among control patients may be due in part to group differences in severity of illness, especially given the increased use of inotropes and higher OI in the control group. In addition, the PiNO trial strategy adjusted the iNO dose from 5 to 10 ppm based upon clinical response. Although the majority of iNO-exposed subjects (4/6) had a complete response to only 5 ppm iNO, the different doses of iNO in study subjects may potentially further confound interpretation. Unmeasured variability in the degree of pulmonary hypoplasia among subjects could also influence the effectiveness of therapy as well as outcomes. Unfortunately, echocardiograms were not required of every subject to document pulmonary hypertension. It is very important to emphasize that the suggested potential benefit of iNO is speculative, and based on small numbers of infants.