Background: Respiratory distress syndrome (RDS) is a leading cause of morbidity and mortality in preterm neonates due to surfactant deficiency and immature lung development. Non-invasive respiratory support, particularly nasal continuous positive airway pressure (nCPAP), is standard for management. This study aimed to compare the efficacy and safety of direct weaning from nCPAP versus transition to HHFNC in preterm neonates <32 weeks gestation with RDS.

Methods: In this prospective randomized controlled trial conducted at the NICU of RNT Medical College, Udaipur, 148 preterm neonates were randomized into two groups: Group A (nCPAP weaning) and Group B (HHFNC weaning). Primary outcome was successful weaning from non-invasive ventilation. Secondary outcomes included weaning failure rates, duration of respiratory support, hospital stay, complications, and mortality. Biochemical parameters were also assessed.

Results: The HHFNC group showed significantly higher weaning success (78.4% vs. 52.7%, p=0.003), lower weaning failure post-discontinuation (18.9% vs. 40.5%, p=0.004), and fewer complications (12.2% vs. 31.1%, p=0.005), especially nasal trauma. Mortality was significantly lower in the HHFNC group (4.1% vs. 13.5%, p=0.042). There were no significant differences in biochemical markers between groups. The restricted mean time to clinical outcome supported the non-inferiority of HHFNC to nCPAP.

Conclusions: HHFNC is a safe, effective, and superior alternative to direct nCPAP weaning in preterm neonates with RDS. It offers higher weaning success, fewer complications, and reduced mortality, supporting its integration into standard neonatal respiratory care protocols.