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

Abstract

Importance: The optimal first-line mode of noninvasive respiratory support for acutely ill children is not known.

Objective: To evaluate the noninferiority of high-flow nasal cannula therapy (HFNC) as the first-line mode of noninvasive respiratory support for acute illness, compared with continuous positive airway pressure (CPAP), for time to liberation from all forms of respiratory support.

Design, setting, and participants: Pragmatic, multicenter, randomized noninferiority clinical trial conducted in 24 pediatric critical care units in the United Kingdom among 600 acutely ill children aged 0 to 15 years who were clinically assessed to require noninvasive respiratory support, recruited between August 2019 and November 2021, with last follow-up completed in March 2022.

Interventions: Patients were randomized 1:1 to commence either HFNC at a flow rate based on patient weight (n = 301) or CPAP of 7 to 8 cm H2O (n = 299).

Main outcomes and measures: The primary outcome was time from randomization to liberation from respiratory support, defined as the start of a 48-hour period during which a participant was free from all forms of respiratory support (invasive or noninvasive), assessed against a noninferiority margin of an adjusted hazard ratio of 0.75. Seven secondary outcomes were assessed, including mortality at critical care unit discharge, intubation within 48 hours, and use of sedation.

Results: Of the 600 randomized children, consent was not obtained for 5 (HFNC: 1; CPAP: 4) and respiratory support was not started in 22 (HFNC: 5; CPAP: 17); 573 children (HFNC: 295; CPAP: 278) were included in the primary analysis (median age, 9 months; 226 girls [39%]). The median time to liberation in the HFNC group was 52.9 hours (95% CI, 46.0-60.9 hours) vs 47.9 hours (95% CI, 40.5-55.7 hours) in the CPAP group (absolute difference, 5.0 hours [95% CI -10.1 to 17.4 hours]; adjusted hazard ratio 1.03 [1-sided 97.5% CI, 0.86-∞]). This met the criterion for noninferiority. Of the 7 prespecified secondary outcomes, 3 were significantly lower in the HFNC group: use of sedation (27.7% vs 37%; adjusted odds ratio, 0.59 [95% CI, 0.39-0.88]); mean duration of critical care stay (5 days vs 7.4 days; adjusted mean difference, -3 days [95% CI, -5.1 to -1 days]); and mean duration of acute hospital stay (13.8 days vs 19.5 days; adjusted mean difference, -7.6 days [95% CI, -13.2 to -1.9 days]). The most common adverse event was nasal trauma (HFNC: 6/295 [2.0%]; CPAP: 18/278 [6.5%]).

Conclusions and relevance: Among acutely ill children clinically assessed to require noninvasive respiratory support in a pediatric critical care unit, HFNC compared with CPAP met the criterion for noninferiority for time to liberation from respiratory support.

Trial registration: ISRCTN.org Identifier: ISRCTN60048867.

Figure 1.. Participant Flow in the FIRST-ABC Step-Up Trial

CPAP indicates continuous positive airway pressure; HFNC, high-flow nasal cannula. ^aNumbers meeting individual exclusion criteria do not add to the total because some patients met more than 1 criterion. ^bAmong exclusions based on clinical decision, 167 were due to preference for HFNC; 54 were due to preference for CPAP; 73 were due to other reasons (main other clinical reasons were unavailability of a pediatric intensive care bed [precluding initiation of CPAP if randomized to CPAP, whereas HFNC could be delivered on the ward; n = 14], concerns regarding availability of suitable masks for CPAP [n = 7], cardiac disease [n = 7], and concerns regarding wheeze and unsuitability of CPAP [n = 4]); and 31 were due to reasons not specified.

Figure 2.. Time to Liberation From Respiratory Support in the Primary Analysis and Per-Protocol Analysis Populations

CPAP indicates continuous positive airway pressure; HFNC, high-flow nasal cannula. Median observation time in the primary analysis set for the HFNC group was 50.0 (IQR, 25.5-96.6) hours and in the CPAP group was 44.8 (IQR, 24.3-92.9) hours; median observation time in the per-protocol analysis set for the HFNC group was 49.9 (IQR, 25.4-95.8) hours and in the CPAP group was 44.7 (IQR, 24.3-90.0) hours.

Figure 3.. Subgroup Analysis of the Primary Outcome of Liberation From Respiratory Support in the Primary Analysis Population

CPAP indicates continuous positive airway pressure; Fio₂, fraction of inspired oxygen; HFNC, high-flow nasal cannula; Spo₂, peripheral oxygen saturation. P values test for an interaction between the subgroup categories and the effect of CPAP vs HFNC in the adjusted Cox regression model. Dashed vertical line indicates margin of noninferiority, 0.75.