Non-invasive high-frequency oscillation ventilation versus nasal CPAP as primary respiratory support in preterm neonates ≥ 30 weeks with RDS: a non-inferiority randomized controlled trial.

UNLABELLED: The purpose of this study is to evaluate if non-invasive high-frequency oscillation ventilation (NHFOV) is non-inferior to nasal continuous positive airway pressure (CPAP) as primary non-invasive respiratory support (NRS) in preterm neonates of ≥ 30 weeks' gestation with respiratory distress syndrome (RDS). In this open-label randomized controlled trial (RCT) with a non-inferiority design conducted in a lower middle-income country, 142 preterm neonates were randomized to receive NHFOV (n = 71) or CPAP (n = 71) at equivalent pressures after lung recruitment with nasal mask (NM) interface. A non-inferiority margin of 20% was pre-specified and a two-sided 90% confidence interval (CI) standardly used in non-inferiority trials was chosen. For the outcome treatment failure (requirement of an alternate NRS as rescue), the event rate was 4.2% in both groups, risk difference (RD) with 90% CI being 0.00 (- 0.06 to + 0.06), and that for IMV requirement was - 0.01 (- 0.04 to 0.01). Since upper limits of CIs for both primary outcomes were well below the non-inferiority margin, NHFOV was proven to be non-inferior compared to CPAP. Duration of primary NRS was significantly lesser (median difference (MD) (95% CI), 7 h lesser (- 14 to 0); p = 0.03) and ventilator-free days for primary NRS were significantly higher (MD (95% CI), 0.30 days (0.00 to 0.60); p = 0.02) in the NHFOV group.

CONCLUSION: In preterm neonates of ≥ 30 weeks' gestation with RDS, NHFOV delivered through NM at equivalent pressures is non-inferior to CPAP when used as primary NRS. The finding of shorter NRS duration with NHFOV needs to be proven in adequately powered trials. Use of NM interface with equivalent pressures addresses the lacunae in the current literature on NHFOV and provides a rigorous comparison between the two NRS modes.

TRIAL REGISTRATION: www.ctri.nic.in , id CTRI/2024/10/074939, registered on 8 October 2024.

WHAT IS KNOWN: • CPAP as initial respiratory support for preterm neonates with RDS is the standard of care in LMICs. • NHFOV is more efficacious than CPAP when used as a post-extubation respiratory support modality, evidence for the same being uncertain when used as primary support.

WHAT IS NEW: • NHFOV is non-inferior to CPAP as primary support in preterm neonates ≥ 30 weeks with RDS for the outcomes of treatment failure and IMV requirement with equivalent pressures after lung recruitment and nasal mask interface. • A superiority design RCT comparing these two non-invasive respiratory support modalities in this subgroup of preterm neonates may not be feasible. The low baseline event rate of IMV necessitates an impractically large sample size to achieve adequate power.