The NONA-LISA Trial

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 at one of the trial sites meeting the criteria for first-choice surfactant treatment by LISA as described by Sweet et al.: worsening babies with RDS and FiO2 \> 0.30 on CPAP pressure ≥6 cm H2O. Infants will be excluded if they have any of the exclusion criteria: 1) suspicion of lung hypoplasia, 2) endotracheal intubation at any time before randomisation, 3) suspicion of pneumothorax, pulmonary haemorrhage or pleural effusion before LISA, 4) major congenital anatomical anomalies as described by the European Surveillance of Congenital Anomalies (EUROCAT).

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 the routine). Additional analgesics will be provided at the clinician's discretion. Patients will receive the unit's standard pre-procedure 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 of this trial is the need for invasive ventilation, meaning mechanical or manual ventilation via an endotracheal tube for at least 30 min (cumulated) within 24 h of the procedure. Non-invasive ventilation (NIV) is not included in the primary outcome.

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.

• Incidence of additional fentanyl administration [Срок оценки: During the procedure, an average of 5-10 minutes.]
• Pain or discomfort during the procedure (according to COMFORTneo score >14). [Срок оценки: 24 hours after procedure]
• Bradycardia <100 BPM for a minimum duration of 4 seconds. [Срок оценки: 24 hours after procedure.]
• Need for a second dose of surfactant [Срок оценки: 24 hours after procedure.]
• Escalation from LISA to INSURE in the same attempt [Срок оценки: 24 hours after procedure.]
• Apnoea that require bag and mask ventilation during the procedure [Срок оценки: 24 hours after procedure.]
• Observed surfactant reflux [Срок оценки: 24 hours after procedure.]
• Desaturation with SaO2 (right extremity measure) <85% during the procedure [Срок оценки: 24 hours after procedure.]
• Procedural time consumption from the introduction of the laryngoscope blade into the oral cavity to removal of the catheter. [Срок оценки: 24 hours after procedure.]
• Number of attempts of insertion of the catheter in the trachea. [Срок оценки: 24 hours after procedure.]
• Number of attempts of insertion of the laryngoscope in the oral cavity. [Срок оценки: 24 hours after procedure.]
• Time from meeting the criteria for surfactant treatment until surfactant administration [Срок оценки: 24 hours after procedure.]