Title: 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
Funder: Department of Health and Social Care

Abstract: Each year, around 20,000 children are admitted to NHS paediatric critical care units. Many of these children need breathing support while in the unit. The most invasive form of breathing support is when a child has a tube inserted into their windpipe and is put on a breathing machine (ventilator). To reduce the number of children needing invasive support, non-invasive methods like Continuous Positive Airway Pressure (CPAP) are used. CPAP provides oxygen or air through a face mask or into the nose. Although CPAP is beneficial, some children find it uncomfortable and some have complications._x000D_ _x000D_ A more recent alternative is called High Flow Nasal Cannula (HFNC). HFNC provides oxygen or air through tiny tubes inserted into the nostrils. Less is known about how beneficial or safe HFNC is, however, many hospitals are starting to use HFNC instead of CPAP as it is easier to use and some children appear more comfortable on it. This means that there is widespread variation across the country in which method is used. Before HFNC is adopted more widely, it is crucial that its role is studied closely. _x000D_ _x000D_ We will study whether HFNC is as effective as CPAP by carrying out two randomised clinical trials (RCTs) under one framework (FIRST-ABC). The RCTs will include 1,200 children (600 in each), from 25 paediatric critical care units over a 30-month period, in two distinct clinical scenarios:_x000D_ 1. in critically ill children requiring non-invasive respiratory support for an acute illness (step-up RCT); and_x000D_ 2. in critically ill children requiring non-invasive respiratory support within 72 hours of extubation following a period of invasive ventilation (step-down RCT)._x000D_ _x000D_ In each RCT, children will be randomly assigned to either CPAP or HFNC as first-line method of non-invasive breathing support. All other treatments will left to the clinical team. We will measure whether children receiving HFNC are free from any form of breathing support as quickly as those receiving CPAP. We will also study a number of other important patient factors, including how often children need to be put on a ventilator and parents’ satisfaction/stress with each form of breathing support. We will also compare the costs. _x000D_ _x000D_ Since breathing support is emergency life-saving treatment, we will defer seeking written informed consent from parents/guardians until there is time to fully discuss the study with them. Two parents have joined our research team to help us develop the study and oversee its conduct and management. Findings will be disseminated widely through medical and lay press and on our website and will inform national policy relating to breathing support in sick children. FIRST-ABC will provide much needed evidence and will have a large and immediate impact on how sick children are cared for in the NHS.

Lay abstract: 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. _x000D_ _x000D_ DESIGN: Master protocol comprising two multi-centre, parallel groups, non-inferiority RCTs with shared infrastructure, and integrated health-economic evaluation. _x000D_ _x000D_ SETTING: 25 paediatric critical and intensive care units (PICUs). _x000D_ _x000D_ 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). _x000D_ _x000D_ 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). _x000D_ _x000D_ 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)._x000D_ _x000D_ INTERVENTION: HFNC using any approved device at a starting flow rate of 2 litres/minute/kg body weight (or equivalent). _x000D_ _x000D_ COMPARATOR: CPAP using any approved device and interface using a starting set expiratory pressure of 7-8 cm H2O. _x000D_ _x000D_ CONSENT: Written informed consent will be deferred due to the emergency nature of the treatment. _x000D_ _x000D_ 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). _x000D_ _x000D_ 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. _x000D_ _x000D_ 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. _x000D_ _x000D_ CARE PATHWAYS: _x000D_ _x000D_ CURRENT: Both NRS modes are used commonly in UK PICUs. _x000D_ _x000D_ 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. _x000D_ _x000D_ 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). _x000D_ _x000D_ EXPERTISE: Family members, trialists, epidemiologist, statistician, health economists and clinicians.

Research activity codes: 6.3 MEDICAL DEVICES
Health categories: RESPIRATORY