Nasal Continuous Positive Airway Pressure vs Nasal Intermittent Positive Pressure Ventilation in Preterm Infants With Respiratory Distress Syndrome: A Randomized Clinical Trial.

Importance: Respiratory distress syndrome (RDS) remains a leading cause of morbidity and mortality in preterm infants. Evidence regarding the optimal initial noninvasive ventilation (NIV) mode for extremely preterm infants (<30 weeks' gestation) with RDS is inconsistent. Objective: To determine whether nasal continuous positive airway pressure (NCPAP) is noninferior to nasal intermittent positive pressure ventilation (NIPPV) as primary respiratory support before minimally invasive surfactant administration (MISA) for reducing intubation within 72 hours in preterm infants with RDS. Design, Setting, and Participants: This multicenter, noninferiority randomized clinical trial was conducted across 11 tertiary neonatal intensive care units in China from December 2021 to October 2024. The trial was designed to enroll 960 infants but was stopped early after enrolling 312 (32.5% of the target) based on prespecified stopping criteria. The enrolled participants were spontaneously breathing preterm infants at 24 to 29+6 weeks' gestation with a diagnosis of RDS requiring noninvasive respiratory support after birth. Data were analyzed from January 7 to May 9, 2025. Intervention: Infants were randomized 1:1 to receive NCPAP or NIPPV as initial respiratory support. All received MISA within 120 minutes after birth via a 1.67-mm catheter. Main Outcomes and Measures: The primary outcome was NIV failure, defined as requiring intubation and invasive mechanical ventilation within 72 hours after birth. The noninferiority margin was set at a 10% risk difference. Secondary outcomes included NIV failure within 7 days, surfactant redosing, and major complications (eg, pneumothorax, bronchopulmonary dysplasia). Results: A total of 312 preterm infants (median [IQR] gestational age, 28.0 [28.6-29.4] weeks; 174 boys [55.8%]) were randomized to the NCPAP group (153 infants) or the NIPPV group (159 infants). NIV failure within 72 hours occurred in 40 infants (26.1%) in the NCPAP group vs 21 infants (13.2%) in the NIPPV group (adjusted risk difference, 12.8%; 95% CI, 4.2%-21.6%; P = .004; O'Brien-Fleming adjusted α = .005), exceeding the noninferiority margin and conclusively demonstrating inferiority of NCPAP. NIV failure within 7 days was also higher in the NCPAP group (42 infants [27.5%] vs 24 infants [15.1%]; risk difference, 12.4%; 95% CI, 3.4%-21.4%; P = .008). No significant differences were observed between groups for most complications. Conclusions and Relevance: In this randomized clinical trial of preterm infants with RDS, NIPPV with MISA as initial respiratory support significantly reduced NIV failure within 72 hours compared with NCPAP. These findings suggest that NIPPV may be the preferred primary respiratory strategy for this high-risk population, although further evaluation of long-term outcomes is warranted due to early trial termination. Trial Registration: ClinicalTrials.gov Identifier: NCT05137340.