Abstract / Summary
Background: Persistent pulmonary hypertension of the newborn (PPHN) may respond incompletely to inhaled nitric oxide (iNO) when poorly recruited lung limits delivery to ventilated alveoli. We evaluated whether high-frequency oscillatory ventilation (HFOV) combined with iNO improved clinical and physiologic outcomes compared with conventional mechanical ventilation (CMV) + iNO or HFOV alone.
Methods: In this prospective, single-center, 3-arm, open-label randomized clinical trial, 138 neonates born at 34 weeks of gestation or later with echocardiographically confirmed PPHN and an oxygenation index of 25 or greater were randomized 1:1:1 to HFOV + iNO, CMV + iNO, or HFOV alone. The principal complete-case per-protocol analysis included 126 infants (42 per group) with ascertainable 120-day primary outcomes who completed the assigned strategy without a major protocol deviation. The possible influence of the 12 unavailable primary outcomes was evaluated in post hoc randomized-denominator extreme-case sensitivity analyses. The primary outcome was death or extracorporeal membrane oxygenation (ECMO) within 120 days.
Results: In the complete-case per-protocol population, death or ECMO occurred in 3 of 42 infants (7.1%) assigned to HFOV + iNO, 11 of 42 (26.2%) assigned to CMV + iNO, and 14 of 42 (33.3%) assigned to HFOV alone (overall p = 0.012). For HFOV + iNO versus CMV + iNO, the risk ratio was 0.27 (95% CI, 0.08-0.91), and the risk difference was -19.0 percentage points (95% CI, -34.5 to -3.6; Holm-adjusted p = 0.038). For HFOV + iNO versus HFOV alone, the risk ratio was 0.21 (95% CI, 0.07-0.69) and the risk difference was -26.2 percentage points (95% CI, -42.4 to -9.9; Holm-adjusted p = 0.011). The mean oxygenation index at 72 h was 7.1 (SD, 2.8), 11.0 (SD, 3.8), and 15.9 (SD, 4.5), respectively (group-by-time interaction p < 0.001). The overall primary comparison remained significant under symmetric extreme-case assignments for the unavailable outcomes but not under the differential worst-case assumption for HFOV + iNO (p = 0.222).
Conclusions: In the observed per-protocol population, HFOV + iNO was associated with fewer deaths or ECMO events and faster improvement in oxygenation and right-ventricular echocardiographic measures than either comparator. Because 12 randomized infants were excluded and the overall comparison was not robust to the differential worst-case missing-outcome assumption, confidence in the apparent treatment effect is limited. These findings are exploratory and hypothesis-generating, do not establish efficacy, and require confirmation in a prospectively registered multicenter trial with complete outcome ascertainment.