Invasive mechanical ventilation is one of the most common interventions in PICU. Although continuous positive airway pressure (CPAP) and high-flow nasal cannula (HFNC) have been used for post-extubation non-invasive respiratory support in PICUs worldwide, there are no RCTs looking at how effective they are, rate of adverse events, and their cost-effectiveness. In 2018, Ramnarayan et al’s multicenter pilot RCT confirmed the feasibility of an RCT comparing CPAP with HFNC. A master protocol for two RCTs, Step Up and Step Down was designed to compare HFNC and CPAP. The First-Line Support for Assistance in Breathing in Children (FIRST-ABC) Step Down RCT was a pragmatic, open-label, multicenter, parallel-group, non-inferiority trial.
Ramnarayan P, Richards-Belle A, Drikite L, et al; FIRST-ABC Step-Down RCT Investigators and the Paediatric Critical Care Society Study Group. Effect of high-flow nasal cannula therapy vs continuous positive airway pressure following extubation on liberation from respiratory support in critically ill children: a randomized clinical trial. JAMA. Published online April 7, 2022. doi: 10.1001/jama.2022.3367
Who were the patients?
They recruited 600 children, between 36 weeks corrected gestational age and 16 years, from 22 PICUs in the United Kingdom. Each required non-invasive respiratory support within 72 hours after extubation. After exclusions, 553 children were included in the primary analysis. 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 = 299) or CPAP of 7 to 8 cm H2O (n = 301).
What were the outcomes measured?
Time from randomisation to liberation from respiratory support, as defined as the start of a 48-hour period during which the child was free from all forms of respiratory support (invasive or non-invasive). An adjusted hazard ratio (HR) of 0.75 was chosen to assess for noninferiority – in the pilot trial 0.75 corresponded to a 16-hour increase in time to liberation, the maximum clinically acceptable difference between HFNC and CPAP.
- Mortality at PICU discharge, day 60 and day 180
- Rate of reintubation at 48 hours
- Duration of PICU and acute hospital stay
- Patient comfort, assessed using the COMFORT Behaviour (COMFORT-B) scale 24
- Sedation use during non-invasive 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
- Health economic outcomes
What were the results?
First, let’s focus on the results for the primary outcome.
The median time from randomisation to liberation from respiratory support was longer in children managed on HFNC at 50.5 hours versus 42.9 hours for CPAP. HFNC failed to meet the non-inferiority criteria to CPAP.
The mortality (by day 180) was significantly higher in the HFNC group (5.6%) vs CPAP group (2.4%) (adjusted OR, 3.07 [95% CI, 1.1-8.8]). The authors were unable to explain this finding.
Treatment failure, switching from HFNC to CPAP or escalation to intubation and ventilation, occurred in 37.1% of HFNC group and 33.7% of the CPAP group. In the HFNC group, this was mostly due to clinical deterioration. In the CPAP group, it was mostly due to patient discomfort.
There was no significant difference between HFNC and CPAP groups regarding:
- Mortality at PICU discharge and at day 60
- The rate of reintubation within 48 hours (HFNC, 13.3%; CPAP, 11.5%)
- The length of PICU or acute hospital stay
- The use of sedation. More than half of children in both groups received sedation, without difference in the COMFORT-Behavioural scale
- Rates of adverse events. Adverse events were low in both groups: 8.9% of patients in the HFNC and 10.3% in the CPAP
What were the limitations?
This was a non-blinded trial. The authors tried to minimise bias by ensuring care was protocolised. However, the decision to change respiratory support from HFNC to CPAP did not strictly adhere to the study protocol. This introduced potential practice variation.
There was significant heterogeneity between the two groups. Patients in the HFNC group included more neonates, and fewer patients with bronchiolitis compared to the CPAP group.
There was potential selection bias given that the decision to institute respiratory support was based on clinician determination. No data on feeding was collected as part of 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. Suitable patients were recruited at 22 participating PICUs across England, Wales and Scotland if assessed by the treating clinician to require non-invasive respiratory support within 72 hours post-extubation.
Was the exposure accurately measured to minimise bias?
Participants were randomised to either HFNC or CPAP at a 1:1 ratio. Blinding was not possible due to the nature of the intervention.
Was the outcome accurately measured to minimise bias?
Yes. Outcomes were measured at specific pre-defined time-points (liberation from respiratory support, mortality, rate of reintubation) and via validated scales (COMFORT Behaviour scale and Parental Stressor Scale: PICU).
Have the authors identified all important confounding factors?
Yes. The authors performed subgroup analyses of the primary outcome. The results remained unchanged.
Was the follow-up of the subjects complete and accurate?
Patients were followed up for 180 days. The parents completed a questionnaire to assess health-related quality of life and health service and resource use.
What were the results?
HFNC was inferior to CPAP among paediatric patients requiring post-extubation non-invasive respiratory support. It took longer to wean children from non-invasive respiratory support in children managed with HFNC post-extubation than those managed on CPAP.
Do you believe the results?
Can the results be applied to a local population?
This study included 22 of the 28 PICUs in the UK and provided a representative sample of PICU patients. Additionally, there was good adherence to the study protocol. The generalisability of results to other countries/centres may be limited due to the use of clinician determination of the need for respiratory support. Clinician experience of HFNC and CPAP, as well as their availability, may limit the generalizability of the results.
Do the results fit with the other evidence available?
This is the only RCT comparing HFNC and CPAP as post-extubation non-invasive respiratory support.
What did the authors conclude, and what can we take away from this study?
In paediatric patients requiring non-invasive respiratory support after extubation, weaning respiratory support took longer in children on HFNC compared to those on CPAP. CPAP use may be a better a post-extubation respiratory support technique.
And finally, a comment from the lead author, Padmanabhan Ramnarayan
Every year, thousands of children receive invasive ventilation in paediatric intensive care units. Many of them are extubated onto non-invasive modes of breathing support such as HFNC and CPAP. FIRST-ABC is the first RCT to directly compare these two commonly used modes following the extubation of children. The trial showed that the time to liberation from all forms of respiratory support was longer for HFNC patients (a median difference of around 8 hours). HFNC was not non-inferior to CPAP – the advantages of HFNC (ease of use, patient comfort) were outweighed by the additional time spent on respiratory support. The vast majority of UK PICUs participated in the trial, supporting its generalizability, and adherence to the trial algorithms was good.
Pending further RCT evidence, the trial shows that CPAP may be the preferred first-line mode for post-extubation support, and HFNC should be reserved for patients who do not tolerate CPAP.
One of the other findings from the trial was that nearly 45% of extubated children received some form of non-invasive breathing support following extubation, highlighting potential overuse. Future research should consider how to better risk stratify patients before extubation and use noninvasive support only in high-risk patients.