FIRST-line support for Assistance in Breathing in Children (FIRST-ABC): a master protocol of two randomised trials to evaluate the non-inferiority of high flow nasal cannula therapy versus continuous positive airway pressure for non-invasive respiratory support in paediatric critical care

HYPOTHESIS: In critically ill children assessed by the treating clinician to require non-invasive respiratory support (NRS), first-line use of high flow nasal cannula (HFNC) is non-inferior to continuous positive airway pressure (CPAP) in time to liberation from respiratory support. DESIGN: Master protocol comprising two multi-centre, parallel groups, non-inferiority RCTs with shared infrastructure, and integrated health-economic evaluation. SETTING: 25 paediatric critical and intensive care units (PICUs). TARGET POPULATION: Critically ill children requiring NRS for an acute illness (step-up RCT) or within 72 hours of extubation following a period of invasive ventilation (step-down RCT). INCLUSION CRITERIA: For patients accepted for admission to participating unit - (1) Age >36 weeks corrected gestational age and <16 years AND (2) assessed by the treating clinician to require NRS, EITHER (A) for an acute illness (step-up RCT) OR (B) within 72 hours of extubation following a period of IMV (step-down RCT). EXCLUSION CRITERIA: assessed by the treating clinician to require immediate intubation and invasive ventilation due to severe hypoxia, acidosis and/or respiratory distress, upper airway obstruction or recurrent apnoeas; tracheostomy in place; received HFNC/CPAP for >2 hours in the prior 24 hours; on home non-invasive ventilation prior to PICU/HDU admission; presence of untreated air-leak (pneumothorax/pneumomediastinum); midfacial/craniofacial anomalies (unrepaired cleft palate, choanal atresia) or recent craniofacial surgery; agreed 'not for intubation' or other limitation of critical care treatment plan in place; previously recruited to the FIRST-ABC trial; clinician decision to start other form of non-invasive respiratory support (i.e. not HFNC or CPAP). INTERVENTION: HFNC using any approved device at a starting flow rate of 2 litres/minute/kg body weight (or equivalent). COMPARATOR: CPAP using any approved device and interface using a starting set expiratory pressure of 7-8 cm H2O. CONSENT: Written informed consent will be deferred due to the emergency nature of the treatment. PRIMARY OUTCOME: Time from randomisation to liberation from respiratory support (start of a 48-hour period during which the child was free of all forms of support). OTHER OUTCOMES: Rate of (re-)intubation at 48 hours; mortality at PICU/HDU discharge, d60 and d180; duration of PICU/HDU and hospital stay; patient comfort, during randomised treatment and during non-invasive respiratory support (i.e. HFNC and/or CPAP), measured using the COMFORT-B score; proportion of patients in whom sedation is used during non-invasive respiratory support; parental stress, in hospital at/around time of consent, measured using the Parental Stressor Scale: PICU; health-related Quality of Life at six months using age-appropriate Pediatric Quality of Life Inventory (Peds-QL) and Child Health Utilities 9-Dimensions (CHU-9D). Cost-effectiveness analysis: total costs, QALYs and net monetary benefit at 6 months. SAMPLE SIZE: A sample size of 600 patients in each of the two RCTs provides 90% power with a type I error rate of 2.5% (one-sided) to exclude the prespecified non-inferiority margin of HR=0.75 (corresponding to approximately a 16-hour increase in median time to liberation based on pilot RCT data), allowing for censoring due to death or transfer, withdrawal/refusal of deferred consent and exclusion due to non-adherence in the per-protocol population. CARE PATHWAYS: CURRENT: Both NRS modes are used commonly in UK PICUs. PLANNED: Pragmatic inclusion criteria will allow the treating clinician to decide when to start NRS. Treatments will be randomly allocated. Clinicians can switch/escalate NRS if prespecified criteria are met. Written guidance will be provided on weaning of HFNC and CPAP. All other treatments will be at the discretion of the clinical team. TIMELINES: Total 48 months (HRA approval 1-4; site approvals/training 5-12; patient recruitment 7-36; internal pilot 7-12; follow-up 8-42; analysis/dissemination: step-down RCT 30-36, step-up RCT 43-48). EXPERTISE: Family members, trialists, epidemiologist, statistician, health economists and clinicians.