Although continuous positive airway pressure (CPAP) and high-flow nasal cannula (HFNC) are used as noninvasive respiratory support in PICUs worldwide, until Ramnarayan’s 2018 feasibility RCT, no large RCTs had been published directly comparing their clinical effectiveness, adverse event rate, or cost effectiveness. The FIRST-ABC Step Down RCT demonstrated that after extubation, weaning of respiratory support took longer in children on HFNC compared to CPAP. This week in JAMA, the team have published the FIRST-ABC Step Up RCT, a pragmatic, open-label, multicenter, parallel-group, non-inferiority trial comparing HFNC to CPAP in acutely ill pediatric patients admitted to PICU or HDU.
Ramnarayan P, Richards-Belle A, Drikite L et al. Effect of High-Flow Nasal Cannula Therapy vs Continuous Positive Airway Pressure Therapy on Liberation From Respiratory Support in Acutely Ill Children Admitted to Pediatric Critical Care Units A Randomized Clinical Trial. JAMA. doi:10.1001/jama.2022.9615
Who were the patients?
600 children between 36 weeks corrected gestational age and less than 16 years were recruited from 24 PICUs and HDUs in the UK. They each required non-invasive respiratory support for an acute illness between August 2019 and November 2021. Due to COVID-19, recruitment was halted a couple of times at most sites. 573 children were included in the primary analysis (HFNC, n=295, CPAP, n=278). Deferred consent was sought after randomisation.
What was the intervention?
Children were randomised in a 1:1 ratio by computer to either HFNC at a flow rate 2L/kg/min (n = 301) or CPAP of 7 to 8 cm H2O (n = 299) based on site and age (<12 months vs ≥12 months). Clinicians targeted a peripheral oxygen saturation (SpO2) target of ≥92%.
What were the outcomes measured?
This was the time from randomisation to liberation from respiratory support. This was defined as the start of the 48-hour period during which the child was free from invasive or noninvasive respiratory support, excluding supplemental oxygen. An adjusted hazard ratio (HR) of 0.75 was chosen to assess for noninferiority – which in the pilot study corresponded to a 16-hour increase in time to liberation, the maximum clinically acceptable difference between HFNC and CPAP.
- Mortality at critical care discharge
- Rate of intubation at 48 hours
- Duration of critical care and acute hospital stay
- Patient comfort, assessed using the COMFORT Behavior scale
- Sedation during noninvasive respiratory support
- Parental stress measured using the Parental Stressor Scale: PICU at or around time of consent
- Adverse events up to 48 hours after liberation from respiratory support
What were the results?
First, the primary outcome
The median time from randomisation to freedom from respiratory support was 52.9 hours for HFNC and 47.9 hours for CPAP. The adjusted hazard ratio was 1.03. This means that HFNC met the criterion of non-inferiority compared with CPAP. The results were similar even if the analysis was based on the actual treatment received (per-protocol analysis) and based on pre-specified potential confounding factors such as age, SpO2:FiO2 ratio and comorbidities (sensitivity analyses). In children already receiving respiratory support at time of randomisation, CPAP was more effective than HFNC, although this was not statistically significant.
Post-randomisation, the treatment failure rate was higher (defined as a switch or escalation of care) in the CPAP group (b) than the HFNC group (33.1%). The main reason for switching from CPAP was patient discomfort. Clinical deterioration appeared to be the leading reason for swapping over in the HFNC group.
- There was no difference in mortality at critical care discharge, at 1.7% in HFNC group vs 1.5% in CPAP group
- Rate of intubation at 48 hours was similar between groups: HFNC group: 15.4% in the HFNC group vs 15.9% in the CPAP group
- Duration of critical care stay was significantly shorter in the HFNC group at 5 days vs 7.4 days for CPAP. The adjusted mean difference was 3.1 days
- The length of hospital stay was significantly shorter in the HFNC group – 13.8 days vs 19.5 days for CPAP with an adjusted mean difference of -7.6 days
- Patients on HFNC required less sedation (27.7% vs 37.0% for CPAP)
- There was no difference when it came to ratings of patient comfort and parental stress
- There were fewer adverse events in the HFNC group. 8.1% of children had more than one adverse event compared to 14% in the CPAP group. Nasal trauma was more common in the CPAP group (6.5% vs 2.0%)
- There were 4 cardiac arrests (1 in the HFNC group and 3 in the CPAP group). None were judged to be related to the intervention.
What were the limitations?
Because of the nature of the intervention, this was a non-blinded trial. This may have influenced clinicians’ decisions. The authors tried to minimise bias by ensuring care was protocolised, with adhered to.
Since the decision to switch from HFNC to CPAP and vice versa did not strictly adhere to study protocol, there was potential practice variation. A high number of patients were switched from CPAP to HFNC due to discomfort.
The study population was heterogeneous, mostly <2 years old. The authors performed prespecified subgroups analyses to take potential confounding factors into consideration.
The decision to start a child on noninvasive respiratory support was based on clinician judgement, leading to potential selection bias.
Approximately 1000 eligible children were excluded since they had already received HFNC support.
Different HFNC and CPAP devices were used, potentially affecting clinical efficacy and/or patient comfort.
A commonly reported advantage of HFNC compared to CPAP is the ease of feeding. This was not considered in this trial.
CASP checklist – How good was the paper?
Does the study address a clearly focused issue?
Was the cohort recruited in an acceptable way?
Yes. Eligible patients were recruited at 24 participating PICUs and HDUs across England, Wales and Scotland if assessed by the treating clinician to require non-invasive respiratory support in the setting of an acute illness.
Was the exposure accurately measured to minimise bias?
Participants were randomised to either HFNC or CPAP in a 1:1 ratio. Due to the nature of the intervention, blinding was not possible.
Was the outcome accurately measured to minimise bias?
Yes. Primary and secondary outcomes were measured at pre-defined time-points (liberation from respiratory support, mortality at critical care discharge, 48-hour rate of intubation). Secondary outcomes were measured using validated scales for parental stress and patient comfort.
Have the authors identified all important confounding factors?
Yes. Authors performed subgroup, sensitivity and post-hoc analyses of the data to assess for potential confounding factors. Results remained unchanged.
Was the follow up of the subjects complete and accurate?
Yes. Children were followed-up until the end of their hospital stay and for six months longer.
What were the results?
HFNC was non-inferior to CPAP in paediatric patients requiring non-invasive respiratory support for acute illness regarding time to liberation from noninvasive respiratory support. Children treated with HFNC had a shorter critical care and acute hospital stay and received less sedation.
Do you believe the results?
Can the results be applied to a local population?
Yes. This study included a representative sample of children requiring non-invasive respiratory support in critical care units. There was good adherence to the study protocol. The generalisability of the results to other countries or centers may be limited due to resource availability.
Do the results fit with the other evidence available?
This was the largest RCT comparing HFNC and CPAP in paediatric patients presenting with acute illness. Five previous RCTs comparing HFNC and CPAP use in children with bronchiolitis or pneumonia focused on treatment failure as the primary outcome. Some studies showed CPAP to be superior and others found no significant difference. This study focused on the time to liberation from non-invasive respiratory support. It was deemed to be a more sensitive outcome during the pilot RCT and a key priority for parents.
What did the authors conclude, and what can we take away from this study?
In acutely ill paediatric patients requiring noninvasive respiratory support, HFNC was non-inferior for time to liberation from respiratory support compared to CPAP. This, in combination with shorter critical care and acute hospital stay coupled with reduced sedation use, suggests that HFNC may be the preferred non-invasive respiratory support method in acutely ill infants and children.
A comment from the lead author, Padmanabhan Ramnarayan
High-flow nasal cannula is used commonly as the first-line mode of non-invasive respiratory support in acutely ill children, but there is little RCT evidence to support its use. Small RCTs in bronchiolitis have compared HFNC and CPAP with treatment failure as the primary outcome and shown inconsistent results. As such, the imperative for a well-designed large RCT in this area is clear.
The FIRST-ABC Step-Up RCT is the first (and largest) clinical trial comparing HFNC with CPAP in a heterogenous group of acutely ill children needing admission to critical care units in the UK. It was designed as a pragmatic trial, with a clinical decision to start non-invasive support as the main inclusion criterion. The trial found that HFNC was non-inferior to CPAP according to the pre-defined margin (an adjusted hazard ratio of 0.75 for the time to liberation from all forms of respiratory support). COMFORT-B scores were similar across the groups, although the use of sedation was greater in CPAP patients. In addition, the duration of critical care unit stay, and hospital stay were longer in CPAP patients. The rate of nasal trauma was higher in the CPAP group.
At first glance, it seems that the finding of non-inferiority of high-flow is strong. However, there are some caveats. First, the proportion of patients switching from HFNC to CPAP was 20% (mainly for clinical deterioration) whilst the proportion switching from CPAP to HFNC was 31% (mainly for patient discomfort). This means that, 24 hours after starting support, only 25% of children were still receiving CPAP in the CPAP group, while nearly 50% of HFNC group were still receiving HFNC. This has the effect of making the two groups more similar than expected and may have attenuated any potential difference between CPAP and HFNC. Second, a range of interfaces and devices were used for CPAP. This may have compromised its clinical efficacy and may well have affected patient tolerance of CPAP.
Nevertheless, the FIRST ABC step-up RCT is the first trial to demonstrate the non-inferiority of HFNC compared to CPAP in an acutely ill population of children and may be practice-changing.