Parts of this chapter have been reproduced from Richards-Belle et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text includes minor additions and formatting changes to the original text.
Background and rationale
Over 18,000 critically ill children are admitted to paediatric intensive care units (PICUs) in the UK each year.2 Respiratory support is the most common intervention undertaken in UK PICUs: national audit data from the Paediatric Intensive Care Audit Network (PICANet) show that nearly 75% of admissions between 2017 and 2019 received either invasive (via an endotracheal tube or tracheostomy) and/or non-invasive respiratory support (NRS) during their PICU stay.2 Although invasive ventilation can be life-saving, there are concerns regarding its complications, such as ventilator-induced lung injury, need for prolonged sedation and nosocomial respiratory tract infections.3 This has encouraged the greater adoption of NRS techniques in PICUs worldwide.4–6 In critically ill adults and premature newborns, evidence from randomised controlled trials (RCTs) supports the early use of NRS to reduce invasive ventilation and improve survival in specific patient subgroups.7–10 In critically ill infants and children, there is a dearth of high-quality RCT evidence; yet the use of NRS has increased over the years in UK PICUs as well as internationally.2,11,12
Non-invasive respiratory support is currently used in two distinct clinical scenarios: (1) in acutely ill children, to prevent intubation and ventilation (step-up treatment), and (2) in children who have just come off invasive ventilation, to prevent reintubation (step-down treatment). Traditionally, the first-line mode of NRS used in the PICU setting has been continuous positive airway pressure (CPAP), which involves the delivery of pressurised oxygen/air through a face mask or nasal prongs.13 Despite the absence of large RCTs to confirm the effectiveness of CPAP, it is a mode of NRS that PICU clinicians have been familiar with and has used for over three decades. However, CPAP has two main limitations: (1) the need for a tight-fitting patient interface such as face mask, hood or nasal prongs to avoid leakage of gas from the ventilator circuit (which frequently causes patient discomfort/agitation as well as nasal and facial pressure sores with prolonged use, leading to treatment failure) and (2) the risk of serious complications such as pneumothorax or pneumomediastinum (which usually necessitates close monitoring and a high level of skilled nursing input).
Over the past decade, a novel mode of NRS called high-flow nasal cannula therapy (HFNC), which involves the delivery of heated and humidified air/oxygen through thin-bore nasal cannula, has rapidly gained popularity. This is despite the absence of RCT evidence to support its effectiveness in the PICU setting.14,15 The main reason for its increasing use is related to patient comfort and ease of use.15 Heating and humidification of gases during HFNC therapy prevent rapid drying of airway mucosa and decreases the metabolic work of breathing, and the high gas flow rate used (typically 8–10× minute ventilation) enables the reliable delivery of the set fraction of inspired oxygen (FiO2). HFNC does not require a tight seal, and its patient interface (nasal prongs) is well tolerated by children. Delivery of heated and humidified medical gases to the patient at high gas flow rates (matching or exceeding the patient’s own peak inspiratory flow rate) has been shown to confer a diverse range of beneficial effects such as reduction of airway resistance, reduction of dead space by nasopharyngeal washout with fresh gas, as well as delivery of positive airway pressure (like CPAP).15,16 There is strong evidence from physiological and observational studies to support the use of HFNC in PICU: studies in infants and children confirm that HFNC reduces the work of breathing and improves oxygenation and ventilation.17,18 In single-centre observational studies, the use of HFNC has been shown to be associated with a dramatic reduction in the rate of intubation and invasive ventilation.19–21
Prior to the FIRST-line support for Assistance in Breathing in Children (FIRST-ABC) RCTs, there were two Cochrane reviews (published in 2014) that examined the effectiveness of HFNC in children – both found no RCTs comparing HFNC with CPAP.22,23 The first review focused on bronchiolitis only, and the second covered all other causes of respiratory failure. Subsequently, two RCTs had been completed comparing HFNC with CPAP. The first was a single-centre RCT from Bangladesh and the second was a multicentre non-inferiority trial in bronchiolitis conducted in France.
In premature newborns, several RCTs had compared HFNC with CPAP; however, an evidence synthesis (HTA 14/151/03) concluded that there was a lack of convincing evidence that HFNC is superior or inferior to nasal CPAP and recommended more RCTs.24 In adult critical care, Cochrane and other systematic reviews did not find sufficient evidence from good quality studies to determine if HFNC was effective compared to non-invasive ventilation.25,26
The evidence available from the two paediatric RCTs did not definitively support the effectiveness of either HFNC or CPAP in critically ill children. Relatively small numbers of patients were enrolled in these trials, resulting in wide confidence intervals (CIs); and different definitions of a composite, subjective primary outcome (‘treatment failure’) were used that did not correlate with more objective patient-centred outcomes, such as rate of intubation or duration of respiratory support. The ‘treatment failure’ rates reported also differ from treatment failure rates seen in routine practice. Importantly, the RCTs did not study the effectiveness of HFNC for step-up as well as step-down (post-extubation) care in children with a range of diagnoses, making it impossible to generalise their findings to contemporary practice in UK PICUs.
Widespread dissemination of HFNC in the absence of high-quality evidence would represent premature adoption of a technology without rigorous evaluation of associated risks and benefits. In particular, the benefits of HFNC (improved patient comfort, safety profile and ease of nursing care) need to be balanced against its potential risks (serious complications such as air leak, abdominal distension and nosocomial infection as well as excess mortality from delayed intubation and unnecessary prolongation of PICU/hospital stay).27–29
Our trial hypothesis was that in critically ill children assessed by the treating clinician to require NRS, first-line use of HFNC is non-inferior to CPAP in terms of time to liberation from respiratory support.
Aims and objectives
The aim of the FIRST-ABC RCTs was to evaluate the clinical and cost-effectiveness of the use of HFNC as the first-line mode of NRS in critically ill children: (1) with an acute illness and (2) within 72 hours of being extubated following a period of invasive ventilation (step-down RCT).
The primary objective was to evaluate the non-inferiority of HFNC, as compared with CPAP, when used as the first-line mode of NRS in children, both as a step-up and as a step-down treatment, on the time to liberation from respiratory support, defined as the start of a 48-hour period during which the child was free of all forms of respiratory support [non-invasive (HFNC, CPAP, pressure support and bilevel support) as well as invasive mechanical ventilation (IMV)].