Description

BACKGROUND

Respiratory distress syndrome (RDS) remains a leading cause of morbidity and mortality among preterm infants worldwide. Surfactant replacement therapy has significantly improved outcomes; however, standard techniques such as INSURE (Intubation-Surfactant-Extubation), while effective in avoiding mechanical ventilation, require endotracheal intubation-a procedure associated with potential complications and demanding considerable clinical expertise. Less invasive methods, such as surfactant administration via a laryngeal mask airway (SALSA), have shown promising results in reducing the need for mechanical ventilation in moderately preterm infants in smaller studies. This approach may be particularly beneficial in low- and middle-income countries (LMICs), where high birth volumes and limited availability of skilled personnel and advanced respiratory support highlight the need for simpler, safer interventions.

Evidence for SALSA in more immature preterm populations and from large randomized controlled trials remains limited. One key barrier to broader adoption has been the lack of appropriately sized supraglottic airway devices for very small infants. A recent feasibility study by this research team, using newly available preterm-sized devices, demonstrated that SALSA is feasible for surfactant delivery in infants weighing between 750 and 1500 grams (NCT06606444). A randomized controlled trial is now warranted to assess the effectiveness and safety of SALSA, particularly in lower-middle-income settings and among extremely low birth weight infants.

AIM AND HYPOTHESIS

This trial primarily aims to evaluate whether surfactant administration via the SALSA method is non-inferior to the current standard INSURE method in preventing IMV in preterm neonates with RDS admitted to a tertiary-level neonatal unit in South-Easia. It also seeks to compare the two methods in terms of safety, ease of use, infant comfort during the procedure, and morbidity during hospital admission.

We hypothesize that in preterm neonates with RDS, born before gestational week 34 and with a birth weight of at least 750 grams (P), surfactant administration via SALSA (I) will be non-inferior to INSURE (C) in preventing invasive mechanical ventilation (IMV) (O) within 72 hours after the procedure (T).

TRIAL DESIGN

This is an investigator-initiated, single-centre, two-arm parallel-group, open-label, non-inferiority RCT with a 1:1 allocation ratio per neonate. The trial entails an internal pilot-phase of the first 100 patients.

PARTICIPANTS

See Eligibility section.

STUDY SITE

Phu San Hanoi Hospital (PSH) is the largest obstetric hospital in Hanoi, Vietnam, with about 40 000 deliveries every year and about 10% preterm births. The neonatal department is divided into three units: a level III NICU (35 beds), a high dependency unit (60 beds), and a Kangaroo mother care (KMC) unit (45 beds) which are staffed by 73 nurses and 21 doctors. Head ultrasound is made within 7 days of life and before discharge for all preterm infants <32 weeks of gestation as routine care, with additional assessments in between as needed. Echocardiography to screen for persistent ductus arteriosus is performed in neonates with clinical signs and treated medically (ibuprofen or paracetamol) if found haemodynamically significant. All infants <32 weeks of gestation are routinely examined for retinopathy of prematurity by ophthalmologist.

STUDY PROCEDURE

All infants requiring surfactant therapy will be screened for eligibility by the NICU team on a continuous basis. Caregivers will be approached for informed consent prior to inclusion. Eligible infants with consent will be randomized immediately before surfactant administration using a computer-generated, block-randomized sequence to receive either SALSA (intervention) or INSURE (control). The interventions are described in detail under "Arms and Interventions." For SALSA, a CE-marked, supraglottic airway device, Neo i-gel®, available in three sizes 0.85, 0.75, and 0.65 (Intersurgical Ltd), will be used. Procedural data will be collected through direct observation by the clinical team, while background characteristics and follow-up variables will be extracted from medical records by the study team. All data will be entered into an electronic case report form (eCRF) in REDCap. A subset of 50 patients per treatment arm will be video-recorded and reviewed for detailed analysis of procedure duration, physiologic stability and pain.

OUTCOMES

The primary outcome is: Failure of surfactant therapy to prevent invasive mechanical ventilation within 72 hours after first surfactant administration.

Decision to initiate mechanical ventilation via intubation will be made at the discretion of the treating physician, guided by the local NICU criteria for mechanical ventilation.

Secondary outcomes are listed under Outcome Measures.

SAMPLE SIZE

According to a baseline study conducted in 2023 (unpublished data), we assume that 21,5% of neonates in the control group (INSURE) would meet failure criteria. If there is no difference between SALSA and INSURE in terms of use of IMV (21,5% in both arms), 418 neonates need to be enrolled to be 80% sure that the upper limit of a one-sided 95% confidence interval will exclude an absolute difference larger than 10% in favour of INSURE. The sample is increased to 440 neonates to take into account a dropout of 5%.

PILOT PHASE

The trial will begin with an internal pilot phase designed to assess the feasibility of recruitment, adherence to trial procedures, data completeness, and intervention fidelity. Efficacy will not be evaluated. The internal pilot phase will enrol 100 neonates (approximately 23% of the total sample size), with recruitment anticipated over 12 months. This design will allow feedback on recruitment capacity and process quality and enabling adaptations.

The pilot phase will assess outcomes related to recruitment feasibility, adherence to intervention, adherence to mechanical ventilation criteria, retention, data completeness, data integrity and acceptability. Pilot outcomes are listed under Outcome Measures.

An interim assessment will be performed after the enrolment of 50 participants or after 12 months, whichever comes first. Only pilot outcomes will be assessed. The final analysis of the pilot phase will take place upon completion of enrolment of 100 participants. Following this evaluation, the Trial Steering Committee will determine whether to continue the study without modifications, implement protocol amendments-such as the inclusion of additional trial sites or adjustments to trial procedures-or temporarily suspend the trial to allow for a redesign. These decisions will be guided by a balanced assessment across all pilot domains.