Less Invasive Surfactant Administration Compared With Intubation-Surfactant-Extubation (INSURE), Nebulised Surfactant, and Continuous Positive Airway Pressure (CPAP) Alone in Preterm Infants With Respiratory Distress Syndrome: A Systematic Review

The optimal route of surfactant delivery in preterm infants, supported non-invasively, remains contested. Less invasive surfactant administration (LISA), or minimally invasive surfactant therapy (MIST), has been compared with intubation-surfactant-extubation (INSURE), with nebulised surfactant, and with continuous positive airway pressure (CPAP) alone, with inconsistent results. Five databases and registers were searched from January 2021 to July 2026 for randomised controlled trials (RCTs) in preterm infants (<37 weeks) with respiratory distress syndrome. The review was not prospectively registered. Two reviewers independently screened records, extracted data, and applied the revised Cochrane risk-of-bias tool (RoB 2). Reporting followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 and, because no meta-analysis was performed, the Synthesis Without Meta-analysis guideline; certainty was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Eleven RCTs (1,455 infants) were included: eight compared LISA or MIST with INSURE (n = 792), one compared MIST with sham treatment and CPAP alone (n = 485), one compared nebulised poractant alfa with CPAP alone (n = 129), and one compared nebulised surfactant with LISA (n = 49). Compared with INSURE, three trials reported reduced invasive ventilation, but two of these were at high risk of bias, while all five trials showing no difference were at low risk or raised only some concerns; risk of bias and background ventilation mode are therefore confounded, and certainty was very low. Compared with CPAP alone, MIST halved intubation within 72 hours (36.5% compared with 72.1%; risk ratio: 0.50, 95% CI: 0.40-0.64; high certainty) and reduced pneumothorax. In that trial, bronchopulmonary dysplasia among survivors was reduced (0.83, 0.70-0.98), whereas the separate composite of death or BPD was not (0.87, 0.74-1.03). Nebulised surfactant did not reduce respiratory failure compared with CPAP alone. LISA reduces early invasive ventilation compared with CPAP alone. Evidence against INSURE is heterogeneous and of very low certainty, and any attenuation with nasal intermittent positive pressure ventilation is confounded by trial quality and requires prospective testing. Nebulised surfactant remains insufficiently supported, and long-term outcomes are uncertain.