The goal of this observational study is to evaluate different methods of surfactant administration in preterm infants with respiratory distress syndrome (RDS). Preterm infants often have immature lungs and a deficiency of surfactant, a substance that helps keep the lungs open and supports oxygen exchange.Surfactant can be delivered to the lungs using different techniques, including INSURE (brief intubation), LISA (via a thin catheter), SALSA (via a laryngeal mask airway), and traditional administration via endotracheal intubation followed by mechanical ventilation. The main question this study aims to answer is:Which method of surfactant administration is associated with better clinical outcomes in preterm infants with RDS?The study will prospectively collect clinical data on infants receiving surfactant as part of standard care, with long-term follow-up using data from the Swedish Neonatal Quality Register. The results are intended to be used to inform the design of a future randomized multicenter study.

Background Complications of preterm birth are the leading cause of child mortality worldwide, with respiratory distress syndrome (RDS) as a major contributor. RDS is primarily caused by surfactant deficiency due to immature lungs. Early surfactant therapy, in combination with antenatal corticosteroids and non-invasive respiratory support such as continuous positive airway pressure (CPAP), is central to treatment. However, mechanical ventilation is associated with an increased risk of lung injury and bronchopulmonary dysplasia (BPD), prompting the development of less invasive surfactant administration techniques.

Surfactant Administration Methods Three main methods are currently used in spontaneously breathing preterm infants. The INSURE method involves transient intubation for surfactant delivery followed by extubation. Less Invasive Surfactant Administration (LISA) uses a thin catheter inserted below the vocal cords under laryngoscopy, allowing continued spontaneous breathing. LISA is recommended as first-line treatment in European guidelines due to improved outcomes compared to INSURE. However, both methods require laryngoscopy and are technically demanding, with potential adverse events.

Surfactant Administration via Laryngeal or Supraglottic Airways (SALSA) is a newer, less invasive technique that delivers surfactant via a supraglottic airway without laryngoscopy or passage through the vocal cords. Preliminary studies suggest comparable effectiveness to INSURE and CPAP, with potential safety advantages. Historically, SALSA has been limited to larger infants due to lack of appropriately sized devices, but newly available CE-marked devices now enable its use in extremely preterm infants.

Rationale Despite widespread use of INSURE, LISA, and SALSA, there are no direct comparisons between LISA and SALSA, and real-world data on their implementation, safety, and outcomes are limited. In Sweden, these methods are used variably across neonatal units, and their relative use and outcomes have not been systematically evaluated. The availability of smaller supraglottic airway devices now allows evaluation of SALSA in the most vulnerable population, including extremely preterm infants.

Aim The primary aim is to prospectively evaluate and compare the feasibility, safety, clinical performance, and procedural characteristics of surfactant administration methods (SALSA, LISA, INSURE) in spontaneously breathing preterm infants in a real-world clinical setting.

Secondary aims include comparison with infants receiving surfactant via intubation followed by mechanical ventilation, evaluation of short- and long-term clinical outcomes, and generation of data to inform the design of a future randomized multicentre trial.

Study Design This is a prospective, multicentre, observational study conducted in neonatal intensive care units (NICUs) in Region Västra Götaland (VGR), Sweden. No interventions are introduced, and all treatment decisions are made according to local clinical guidelines.

Study Population Eligible participants are preterm infants (37 weeks' gestation) receiving their first surfactant treatment within 48 hours of birth due to suspected or confirmed RDS. Infants are included regardless of administration method.

Data Collection and Follow-up Data are collected from routine clinical documentation, structured procedure forms, clinician surveys, and the Swedish Neonatal Quality Register (SNQ). Variables include perinatal factors, procedural details, respiratory outcomes, and morbidity. Infants are followed until discharge and, where applicable, at 2 and 5.5 years of age using SNQ data.

Outcomes The primary outcome is treatment failure, defined as the need for mechanical ventilation or repeat surfactant administration within 72 hours. Secondary outcomes include changes in oxygenation, need for respiratory support, adverse events, procedural characteristics, and short- and long-term morbidity and mortality. Clinician-reported feasibility and ease of use are also assessed.

Statistical Considerations All eligible infants will be included over a three-year period, with an expected sample size of approximately 300 infants. Analyses will include descriptive statistics, unadjusted comparisons, and multivariable regression models, with propensity score matching to address confounding.

Ethics Ethical approval has been granted by the Swedish Ethical Review Authority. Written informed consent is obtained from caregivers for participation and for permission to collect and analyse observational data. Participation is voluntary and does not affect the infant's clinical care.

Significance This study will provide real-world evidence on the use, safety, and outcomes of different surfactant administration methods, including the implementation of SALSA in extremely preterm infants. The results will inform clinical practice and provide essential data for the design of a future large-scale randomized multicentre trial.

Inclusion Criteria:

• Patient has received surfactant by any administration method
• Gestational age below 37 weeks'
• First surfactant treatment given before 48 hours of age
• Confirmed or suspected diagnosis of respiratory distress syndrome (RDS)

Exclusion Criteria:

• Not fulfilling above inclusion criteria

Newborn infants admitted to neonatal units in Västra Götaland Region, Sweden.

Individual participant data may be made available upon reasonable request to the principal investigator. Data will be shared in a de-identified form to the greatest extent possible, following review and approval to ensure compliance with informed consent provisions, ethics committee approval, and applicable legal and data protection requirements.