High-Flow Nasal Cannula Versus Continuous Positive Airway Pressure for Initial Respiratory Support in Very Preterm Infants: Study Protocol for a Multicenter Randomized Controlled Trial (SIMPLSAFE3)

Background Non-invasive continuous positive airway pressure (CPAP) is the standard initial respiratory support for preterm infants. However, requirements such as optimal pressure delivery and facemask repositioning, which trigger unwanted reflexes and bradycardia, often necessitate the use of positive pressure ventilation (PPV). Findings from a pilot study suggested that high-flow nasal cannula (HFNC) may be a promising alternative to CPAP, with lower PPV requirements. We hypothesize that HFNC is a safe, effective, and user-friendly alternative to CPAP for stabilizing very preterm infants (28 + 0–31 + 6 weeks of gestation), potentially reducing the need for PPV. We aim to compare HFNC and CPAP as initial respiratory support strategies at birth. Methods This is a multicenter, randomized, stepped-wedge cluster trial. Infants will receive either HFNC (8 L/min) or CPAP (6 cmH₂O) immediately after birth with tactile stimulation. The fraction of inspired oxygen (FiO₂) will start at 0.30. PPV will be initiated if bradycardia or persistently low oxygen saturation (SpO₂) occurs. The primary outcome is stabilization with the assigned support without PPV administration. Secondary outcomes include: (A) achievement of SpO₂ ≥80% at 5 min (with ≤ 2 brief PPV episodes) as a surrogate of safety; (B) achievement of SpO₂ >90% with FiO₂ ≤0.40 at 10 min as a surrogate of efficacy. Overall, 446 infants will be recruited in both arms, with an estimated study duration of 2 years. Discussion The findings may inform future respiratory support guidelines for very preterm infants at birth. Trial registration : ClinicalTrials.gov NCT06543589, registered August 9, 2024.