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 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
324
Isotonic saline will be administered intravenously instead of pre-procedure analgesia.
All infants will be treated with the Less Invasive Surfactant Administration (LISA) procedure
Fentanyl 0.5-1.0 mcg/kg will be administered intravenously as pre-procedure analgesia
All infants will receive the same non-pharmacological standard operating procedure.
Neonatalafsnittet, Børn- og Ungeafdelingen, Reberbansgade 15
Aalborg, Denmark
WITHDRAWNDepartment of Paediatrics (Intensive Care Neonatology) and Perinatal Research Unit
Aarhus, Denmark
RECRUITINGDepartment of Neonatal and Pediatric Intensive Care, Blegdamsvej 9
Copenhagen, Denmark
RECRUITINGH.C. Andersen Børne- og Ungehospital, Kløvervænget 23C, Indgang 60
Odense, Denmark
NOT_YET_RECRUITINGLISA failure within 24 hours.
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.
Time frame: 24 hours after procedure.
Incidence of additional fentanyl administration
This will include the number of injection(s), dosage, cumulated dose, and indications defined as pain/discomfort/sedation/other.
Time frame: During the procedure, an average of 5-10 minutes.
Pain or discomfort during the procedure (according to COMFORTneo score >14).
This will include a numerical and a categorical variable (COMFORTneo score \>/\< 14).
Time frame: 24 hours after procedure
Bradycardia <100 BPM for a minimum duration of 4 seconds.
This is a categorical variable (yes/no).
Time frame: 24 hours after procedure.
Need for a second dose of surfactant
This is a categorical variable (yes/no).
Time frame: 24 hours after procedure.
Escalation from LISA to INSURE in the same attempt
This is a categorical variable (yes/no).
Time frame: 24 hours after procedure.
Apnoea that require bag and mask ventilation during the procedure
This is a categorical variable (yes/no).
Time frame: 24 hours after procedure.
Observed surfactant reflux
This is a categorical variable (yes/no).
Time frame: 24 hours after procedure.
Desaturation with SaO2 (right extremity measure) <85% during the procedure
This is a categorical variable (yes/no).
Time frame: 24 hours after procedure.
Procedural time consumption from the introduction of the laryngoscope blade into the oral cavity to removal of the catheter.
This is a categorical variable (yes/no).
Time frame: 24 hours after procedure.
Number of attempts of insertion of the catheter in the trachea.
This is a numerical variable.
Time frame: 24 hours after procedure.
Number of attempts of insertion of the laryngoscope in the oral cavity.
This is a numerical variable.
Time frame: 24 hours after procedure.
Time from meeting the criteria for surfactant treatment until surfactant administration
This is a numerical variable in minutes.
Time frame: 24 hours after procedure.
Incidence of endotracheal intubation.
This is a categorical variable.
Time frame: 48 hours after procedure
Incidence of pneumothorax within 48 hours after LISA.
This is a categorical variable.
Time frame: 48 hours after procedure.
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).
This is a categorical variable.
Time frame: 48 hours after procedure.
Incidence of in-hospital mortality before discharge.
This is a categorical variable.
Time frame: Through study completion, an average of 6 months.
Cumulated duration of mechanical ventilation during hospitalisation.
This is a numerical variable.
Time frame: Before discharge (through study completion, an average of 6 months).
Cumulated duration of positive pressure ventilation during hospitalisation.
This is a numerical variable.
Time frame: Before discharge (through study completion, an average of 6 months).
Incidence of escalation of respiratory support from CPAP to other NIV modes during hospitalisation.
This is a categorical variable.
Time frame: Before discharge (through study completion, an average of 6 months).
Cumulated duration of all types of non-invasive respiratory support during hospitalisation.
This is a numerical variable.
Time frame: Before discharge (through study completion, an average of 6 months).
Cumulated duration of oxygen treatment with fraction of inspired oxygen (FiO2) >0.21.
This is a numerical variable.
Time frame: Before discharge (through study completion, an average of 6 months).
Cumulated duration of any repisratory support during hospitalisation.
This is a numerical variable.
Time frame: Before discharge (through study completion, an average of 6 months).
Duration of hospitalisation.
This is a numerical variable.
Time frame: Before discharge (through study completion, an average of 6 months).
Incidence of necrotising enterocolitis (according to Bell's Staging Criteria).
This is a categorical variable.
Time frame: Before discharge (through study completion, an average of 6 months).
Incidence of treatment-demanding retinopathy of prematurity.
This is a categorical variable.
Time frame: Before discharge (through study completion, an average of 6 months).
Incidence of intraventricular haemorrhage grade 3-4 and periventricular leukomalacia.
This is a categorical variable.
Time frame: Before discharge (through study completion, an average of 6 months).
Composite outcome of death or moderate/severe BPD at 36 weeks of corrected gestational age.
This is a categorical variable.
Time frame: 36 weeks of corrected gestational age.
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