The NONA-LISA Trial (NONA-LISA)

The NONA-LISA trial will be an investigator-initiated, multicentre, pragmatic, parallel-group, blinded RCT conducted at four university hospitals across Denmark. A total of 324 inborn premature infants will be included within 36 months at four neonatal intensive care units (NICUs) across Denmark (approximately 2 infants per month per unit). The aim is to compare LISA using a non-pharmacological approach alone with routine analgesic treatment combined with a non-pharmacological approach (according to local guidelines) regarding LISA failure defined as the need for positive pressure ventilation for 30 min or more (cumulated) within 24 hours after the procedure in infants born prior to 30 gestational weeks.

Background Less Invasive Surfactant Administration (LISA) is a way of applying surfactant in the trachea by use of a catheter during spontaneous breathing and after applying nasal continuous positive airway pressure (nCPAP). However, use of pre-procedure analgesia with risk of apnoea may prevent LISA to achieve its full potential. Aim This study aims to compare the LISA procedure using a non-pharmacological approach to the LISA procedure using analgesic treatment with 0.5-1 mcg/kg fentanyl in infants born at 24 to 29 completed gestational weeks who fulfil the criteria for surfactant treatment. Trial design The NONA-LISA trial will be an investigator-initiated, multicentre, pragmatic, parallel-group, blinded RCT conducted at four university hospitals across Denmark. A total of 324 inborn premature infants will be included within 36 months at four neonatal intensive care units (NICUs) across Denmark (approximately 2 infants per month per unit). Participants Eligible infants will be born at 24+0 to 29+6 weeks of gestation meeting the criteria for surfactant treatment by LISA and not meeting any of the exclusion criteria: PPROM >3 weeks and suspicion of oligohydramnion or lung hypoplasia Requiring intubation or mechanical ventilation at any time before randomisation Suspicion of pneumothorax or pulmonary haemorrhage or pleural effusion Major congenital malformation (e.g., congenital heart disease, oesophageal atresia, esophago-tracheal fistula, diaphragmatic hernia, abdominal wall defect) or chromosomal abnormality or inherited disorders of metabolism Interventions The randomisation will be stratified according to trial site and gestational age (GA) less than 28 or 28+ gestational weeks. Both groups will receive treatment by experienced teams of neonatal nurses and neonatologists. Both groups will receive the non-pharmacological approach as the basic treatment (part of routine). Additional analgesics will be provided at the discretion of the clinician. Patients will receive the unit's standard pre- and post-procedure care, and both procedures will use video laryngoscopes. Participants in the control group will receive surfactant after receiving intravenous analgesics. Participants in the intervention group (LISA using the non-pharmacological approach) will receive surfactant after receiving a similar volume of intravenous isotonic saline solution. Outcomes The primary outcome will be LISA failure in terms of the need for endotracheal intubation and mechanical ventilation more than 30 minutes (cumulated) within 24 hours after the procedure. Secondary outcomes are outlined in the Outcome section. Sample size We have calculated our sample size based on the primary outcome with an alpha of 5%, a power of 80%, and a ratio of 1:1 between intervention and control groups. Based on previous studies, we anticipate an incidence of "positive pressure ventilation for at least 30 minutes (cumulated) within 24 hours after procedure" in the control group around 45%. Using 30% incidence reduction as anticipated intervention effect, we will need to randomise a total of 324 infants.

The randomisation will be stratified according to trial site and gestational age (GA) less than 28 or 28+ gestational weeks. Both groups will receive treatment by experienced teams of neonatal nurses and neonatologists. Both groups will receive the non-pharmacological approach as the basic treatment (part of routine).

Participant, care provider, investigator and outcomes assessor will initially be blinded to treatment with analgesia or placebo (isotonic saline solution). Need for additional doses of analgesia will be decided according to section "Interventions" and will not be blinded. To reduce risk of interpretation bias, primary analyses will be performed blinded to the group allocation (Group A compared with Group B) and will be presented to all authors, who will agree on two alternative written interpretations before the randomisation code will be unblinded.

The staff will perform Less Invasive Surfactant Administration using standard 0.5-1 mcg/kg fentanyl intravenously for LISA. In both groups, patients will receive the unit's standard pre- and post-procedure care including their non-pharmacological approach, use of atropine, caffeine, and naloxone at the discretion of the clinician based on local protocols and guidelines. All medications will be registered.

The staff will perform Less Invasive Surfactant Administration using the standard pre- and post-procedure care including non-pharmacological treatment. The patients will not receive pharmacological analgesic treatment routinely. In both groups, patients will receive the unit's standard pre- and post-procedure care including their non-pharmacological approach, use of atropine, caffeine, and naloxone at the discretion of the clinician based on local protocols and guidelines. All medications will be registered.

The staff will perform Less Invasive Surfactant Administration using the standard pre- and post-procedure care including non-pharmacological treatment. The patients will not receive pharmacological analgesic treatment routinely.

The primary outcome will be LISA failure in terms of the need for endotracheal intubation and mechanical ventilation for at least 30 minutes (cumulated) within 24 hours after the procedure.

Incidence of additional fentanyl administration including number of injection(s), dosage, cumulated dose, and indications defined as pain/discomfort/sedation/other.

Procedural time consumption from the introduction of the laryngoscope blade into the oral cavity to removal of the catheter.

Incidence of massive pulmonary haemorrhage within 48 hours after LISA (defined as the aspiration of haemorrhagic secretions from the trachea concurrent with the need for escalated respiratory support).

Inclusion Criteria: Infants born at one of the trial sites with a gestational age of 24+0 to 29+6 weeks and meeting the criteria for surfactant treatment by LISA. Exclusion Criteria: prolonged premature rupture of membrane more than three weeks and suspicion of oligohydramnios or lung hypoplasia, endotracheal intubation at any time before LISA, suspicion of pneumothorax, pulmonary haemorrhage or pleural effusion, major congenital anatomical anomalies as described by the European Surveillance of Congenital Anomalies (EUROCAT).

The datasets used and/or analysed during the current study will be available from the principal investigator on reasonable request after publication of results.