Authors' objectives: Despite the increasing use of non-invasive respiratory support in paediatric intensive care units, there are no large randomised controlled trials comparing two commonly used non-invasive respiratory support modes, continuous positive airway pressure and high-flow nasal cannula therapy. To evaluate the non-inferiority of high-flow nasal cannula, compared with continuous positive airway pressure, when used as the first-line mode of non-invasive respiratory support in acutely ill children and following extubation, on time to liberation from respiratory support, defined as the start of a 48-hour period during which the child was free of respiratory support (non-invasive and invasive). Nearly 75% of the 18,000 critically ill children admitted annually to UK paediatric intensive care units (PICUs) receive invasive or non-invasive respiratory support (NRA). NRS is used commonly in PICUs, usually to support acutely ill children with respiratory failure or to provide post-extubation support. Although there are no randomised controlled trials (RCTs), continuous positive airway pressure (CPAP) has been widely used for NRS; however, it can be uncomfortable and associated with complications such as air leak and nasal trauma. An alternate mode of NRS, high-flow nasal cannula (HFNC), which is easy to use and is well tolerated by children, has gained popularity. The potential benefits of HFNC (patient comfort, safety profile and ease of nursing care) must be balanced against its potential risks (air leak, abdominal distension and nosocomial infection). To date, there have been no large RCTs comparing HFNC with CPAP in the PICU setting. Following a successful pilot RCT, which supported the feasibility of performing a large pragmatic clinical trial comparing CPAP and HFNC in critically ill children, and informed its design and conduct, the FIRST-line support for Assistance in Breathing in Children (FIRST-ABC) was set up as a master protocol to answer the research question: in a child requiring NRS, either for acute illness or post-extubation support, which first-line mode of NRS is the most clinically and cost-effective treatment?

Authors' results and conclusions: In the step-up randomised controlled trial, out of 600 children randomised, 573 were included in the primary analysis (median age 9 months). Median time to liberation was 52.9 hours for high-flow nasal cannula (95% confidence interval 46.0 to 60.9 hours) and 47.9 hours (95% confidence interval 40.5 to 55.7 hours) for continuous positive airway pressure (adjusted hazard ratio 1.03, one-sided 97.5% confidence interval 0.86 to ∞). The high-flow nasal cannula group had lower use of sedation (27.7% vs. 37%) and mean duration of acute hospital stay (13.8 days vs. 19.5 days). In the step-down randomised controlled trial, of the 600 children randomised, 553 were included in the primary analysis (median age 3 months). Median time to liberation for high-flow nasal cannula was 50.5 hours (95% confidence interval, 43.0 to 67.9) versus 42.9 hours (95% confidence interval 30.5 to 48.2) for continuous positive airway pressure (adjusted hazard ratio 0.83, one-sided 97.5% confidence interval 0.70 to ∞). Mortality at day 180 was significantly higher for high-flow nasal cannula [5.6% vs. 2.4% for continuous positive airway pressure, adjusted odds ratio, 3.07 (95% confidence interval, 1.1 to 8.8)]. Among acutely ill children requiring non-invasive respiratory support, high-flow nasal cannula met the criterion for non-inferiority compared with continuous positive airway pressure for time to liberation from respiratory support whereas in critically ill children requiring non-invasive respiratory support following extubation, the non-inferiority of high-flow nasal cannula could not be demonstrated. Step-up randomised controlled trial Sites and patients Of the 18,976 admitted children screened across 24 sites, 1449 were deemed eligible for the trial, of whom 600 (41%) were randomised between 10 August 2019 and 7 November 2021. Consent was in place for 595 children. The primary analysis set consisted of 573 children in whom respiratory support was commenced (HFNC: 295; CPAP: 278). The randomised groups had similar baseline characteristics. The median age of participants was around 9 months, 60% were male, and nearly 50% had bronchiolitis. The per-protocol analysis included 533 children (HFNC: 288; CPAP: 245); baseline characteristics were similar to the primary analysis. Among acutely ill children requiring NRS, HFNC met the criterion for non-inferiority compared with CPAP for time to liberation from respiratory support, whereas in critically ill children requiring NRS following extubation, the non-inferiority of HFNC could not be demonstrated. Implications for health care High-flow nasal cannula is a reasonable first-line option for NRS in an acutely ill child requiring NRS. Around one in three children will fail HFNC, mainly due to clinical deterioration, and will require a switch to CPAP or escalation. On the other hand, in the post-extubation setting, CPAP is a reasonable first-line option for NRS. Around one in three children will fail CPAP, mainly due to patient discomfort.

Authors' recommendations: Recommendation 1 Secondary analyses exploring patient characteristics and patterns of physiological parameters that predict treatment failure, including intubation. Compare protocolised approaches to initiation of post-extubation respiratory support with standard care in future clinical trials. Explore alternative approaches for evaluating heterogeneity of treatment effect both from a clinical and cost-effectiveness point of view. Explore reasons for increased mortality in HFNC group within step-down RCT.

Authors' methods: A master protocol comprising two pragmatic, multicentre, parallel-group, non-inferiority randomised controlled trials (step-up and step-down) with shared infrastructure, including internal pilot and integrated health economic evaluation. Twenty-five National Health Service paediatric critical care units (paediatric intensive care units and/or high-dependency units) across England, Wales and Scotland. Critically ill children assessed by the treating clinician to require non-invasive respiratory support for (1) acute illness (step-up randomised controlled trial) or (2) within 72 hours of extubation (step-down randomised controlled trial). High-flow nasal cannula delivered at a flow rate based on patient weight (Intervention) compared to continuous positive airway pressure of 7–8 cm H2O pressure (Control). The primary clinical outcome was time to liberation from respiratory support. The primary cost-effectiveness outcome was 180-day incremental net monetary benefit. Secondary outcomes included mortality at paediatric intensive care unit/high-dependency unit discharge, day 60 and day 180; (re)intubation rate at 48 hours; duration of paediatric intensive care unit/high-dependency unit and hospital stay; patient comfort; sedation use; parental stress; and health-related quality of life at 180 days. The interventions were unblinded. A heterogeneous cohort of children with a range of diagnoses and severity of illness were included. Trial design and governance FIRST-line support for Assistance in Breathing in Children was a master protocol comprising two pragmatic, multicentre, parallel groups, non-inferiority RCTs (step-up RCT and step-down RCT) with shared infrastructure, including an internal pilot stage and integrated health economic evaluation. The trial was approved by East of England – Cambridge South Research Ethics Committee and the UK Health Research Authority. The National Institute for Health Research convened a majority independent Trial Steering Committee and an independent Data Monitoring and Ethics Committee. The trial was sponsored by Great Ormond Street Hospital NHS Foundation Trust and co-ordinated by the Intensive Care National Audit & Research Centre Clinical Trials Unit. To achieve 90% power with a type I error rate of 2.5% (one-sided) to exclude the prespecified non-inferiority margin of hazard ratio (HR) = 0.75, 508 events were required to be observed. Anticipating 5% censoring for death or transfer, allowing for withdrawal/refusal of consent, and for exclusion due to non-adherence in the per-protocol population, we planned to recruit a total sample size of 600 patients in each RCT. Children were screened and randomised if they were: admitted/accepted for admission to a participating PICU/high-dependency unit (HDU) aged > 36 weeks corrected gestational age and

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/17/94/28

Year Published: 2025

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/PDBG1495

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/PDBG1495

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk