High-Frequency Oscillatory Ventilation Combined With Inhaled Nitric Oxide for Persistent Pulmonary Hypertension of the Newborn: A Single-Center Randomized Clinical Trial.

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.