Research

JAMA | Original Investigation | CARING FOR THE CRITICALLY ILL PATIENT

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
Padmanabhan Ramnarayan, MD; Alvin Richards-Belle, BSc; Laura Drikite, MSc; Michelle Saull, BSc;
Izabella Orzechowska, MSc; Robert Darnell, MA; Zia Sadique, PhD; Julie Lester, BA; Kevin P. Morris, MD;
Lyvonne N. Tume, PhD; Peter J. Davis, MBChB; Mark J. Peters, PhD; Richard G. Feltbower, PhD;
Richard Grieve, PhD; Karen Thomas, MSc; Paul R. Mouncey, MSc; David A. Harrison, PhD; Kathryn M. Rowan, PhD;
for the FIRST-ABC Step-Up RCT Investigators and the Paediatric Critical Care Society Study Group

Visual Abstract
IMPORTANCE The optimal first-line mode of noninvasive respiratory support for acutely ill Supplemental content
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
Author Affiliations: Author
mean difference, −3 days [95% CI, −5.1 to −1 days]); and mean duration of acute hospital stay affiliations are listed at the end of this
(13.8 days vs 19.5 days; adjusted mean difference, −7.6 days [95% CI, −13.2 to −1.9 days]). The article.
most common adverse event was nasal trauma (HFNC: 6/295 [2.0%]; CPAP: 18/278 [6.5%]). Corresponding Author:
Padmanabhan Ramnarayan, MD,
CONCLUSIONS AND RELEVANCE Among acutely ill children clinically assessed to require Section of Anaesthetics, Pain
noninvasive respiratory support in a pediatric critical care unit, HFNC compared with CPAP Medicine, and Intensive Care,
met the criterion for noninferiority for time to liberation from respiratory support. Department of Surgery and Cancer,
Norfolk Place, Faculty of Medicine,
TRIAL REGISTRATION ISRCTN.org Identifier: ISRCTN60048867 Imperial College London, London W2
1PG, England (p.ramnarayan@
imperial.ac.uk).
Section Editor: Christopher
Seymour, MD, Associate Editor, JAMA
JAMA. 2022;328(2):162-172. doi:10.1001/jama.2022.9615 (christopher.seymour@jamanetwork.
Published online June 16, 2022. org).

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 Effect of HFNC vs CPAP Therapy on Liberation From Respiratory Support in Acutely Ill Children
R
espiratory support was the most common interven-
tion provided in pediatric critical care units in the United
Kingdom between 2017 and 2019.1 Recognition of the
risks associated with invasive mechanical ventilation has led
to greater use of noninvasive modes of respiratory support in
acutely ill children, such as high-flow nasal cannula therapy
(HFNC), continuous positive airway pressure (CPAP), and non-
invasive ventilation.2-5
High-flow nasal cannula therapy has become a popular
mode of noninvasive respiratory support in the pediatric criti-
cal care setting due to its ease of use, perceived greater pa-
tient comfort, and the ability to discharge children still receiv-
ing HFNC to general wards.6 A recent international survey of
clinicians indicated that HFNC was frequently used as the first-
line mode for respiratory support in a range of diseases such
as bronchiolitis, asthma, pneumonia, and cardiac failure.7 In
a retrospective cohort study involving 92 hospitals in the
United States, HFNC was used as the first-line respiratory sup-
port mode in 85% of children with bronchiolitis,8 and use of
HFNC has been shown to reduce the need for invasive me-
chanical ventilation.9 However, there is little randomized clini-
cal trial (RCT) evidence to support the clinical effectiveness of
HFNC in acutely ill children.10-12
Following a pilot RCT to confirm feasibility for a defini-
tive trial,13 First-Line Support for Assistance in Breathing in
Children (FIRST-ABC) was designed as a master protocol of 2
pragmatic RCTs (“step-up” and “step-down”), with shared in-
frastructure and integrated health economic evaluation, to
evaluate the clinical effectiveness and cost-effectiveness of
HFNC vs CPAP.14 In the step-down RCT, HFNC did not meet
the criterion for noninferiority.15 This article reports the re-
sults of the step-up RCT, which tested the hypothesis that first-
line use of HFNC was noninferior to CPAP in terms of time to
liberation from respiratory support in acutely ill children ad-
mitted to pediatric critical care units.
Methods
Trial Design and Oversight
The FIRST-ABC step-up RCT was a pragmatic,16 unblinded,
multicenter, parallel-group, noninferiority trial. The master
protocol was approved by the East of England–Cambridge
South Research Ethics Committee and the UK Health Re-
search Authority and was published prior to completion of trial
recruitment.14 The trial protocol and the statistical analysis plan
appear in Supplement 1.
A “research without prior consent” model was approved
because the decision to commence respiratory support in
acutely ill children was often made urgently, and both HFNC
and CPAP were widely used. Written informed consent was
sought from parents or legal guardians as soon as possible and
appropriate following randomization.17,18 Data collected up to
refusal or withdrawal of consent were retained unless par-
ents or legal guardians requested otherwise.
The trial was funded by the UK National Institute for Health
Research, which convened an independently chaired and ma-
jority-independent trial steering committee and an indepen-
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Original Investigation Research
Key Points
Question In acutely ill children clinically assessed to require
noninvasive respiratory support in a pediatric critical care unit,
is first-line use of high-flow nasal cannula therapy (HFNC)
noninferior to continuous positive airway pressure (CPAP) in terms
of time to liberation from all forms of respiratory support?
Findings In this randomized noninferiority trial of 600 acutely ill
children clinically assessed to require noninvasive respiratory
support, median time to liberation was 52.9 hours for HFNC
vs 47.9 hours for CPAP. The 1-sided 97.5% confidence limit
for the hazard ratio was 0.86, falling within the noninferiority
margin of 0.75.
Meaning Among acutely ill children clinically assessed to require
noninvasive respiratory support in a pediatric critical care unit,
HFNC met the criterion for noninferiority compared with CPAP for
time to liberation from respiratory support.
dent data monitoring and ethics committee. The trial was man-
aged by the Clinical Trials Unit at the UK Intensive Care National
Audit & Research Centre (ICNARC).
Sites and Participants
The trial was conducted in 24 National Health Service pedi-
atric critical care units (intensive care and high-dependency
care units) in England, Wales, and Scotland. Children aged from
birth (>36 weeks corrected gestational age) up to 15 years who
were admitted or being admitted to participating critical care
units were eligible if assessed by the treating clinician to re-
quire noninvasive respiratory support for an acute illness. Main
exclusion criteria were clinical decision to start a mode other
than CPAP or HFNC (eg, noninvasive ventilation), receipt of
either CPAP or HFNC for more than 2 hours prior to random-
ization, and preadmission receipt of domiciliary respiratory
support (eAppendix in Supplement 2).
Randomization
Randomization was conducted using a concealed central-
ized telephone-/web-based system based on a computer-
generated random sequence stratified by site and age (<12
months vs ≥12 months) using permuted block sizes of 2 and
4. Children were randomized in a 1:1 ratio to HFNC or CPAP.
Allocated noninvasive respiratory support was commenced as
soon as possible after randomization.
Trial Interventions
Trial algorithms, developed following consultation with sites
and finalized at a collaborators’ meeting, specified clinical pro-
cedures for the initiation, maintenance, and weaning from
HFNC and CPAP (eFigures 1 and 2 in Supplement 2). Children
randomized to HFNC were started at a flow rate based on body
weight (for <12 kg, 2 L/kg per minute; for ≥12 kg, see eFigure 1
in Supplement 2). When a child was deemed ready for wean-
ing, the flow rate was reduced by 50%. Children randomized
to CPAP were started at a pressure of 7 to 8 cm H2O. When a
child was deemed ready for weaning, the pressure was re-
duced to 5 cm H2O. Both HFNC and CPAP were delivered
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 Research Original Investigation Effect of HFNC vs CPAP Therapy on Liberation From Respiratory Support in Acutely Ill Children
through devices and interfaces already used as part of rou-
tine care at sites. For both groups, the fraction of inspired oxy-
gen (FIO2) was titrated to maintain peripheral oxygen satura-
tion (SpO2) of 92% or higher.
In line with previous RCTs,19-21 and to reflect clinical prac-
tice, clinicians were permitted to switch from HFNC to CPAP
(or vice versa) or escalate to other modes of noninvasive
respiratory support or invasive mechanical ventilation if pre-
specified treatment failure criteria were met (FIO2 ≥0.60, severe
respiratory distress, patient discomfort). Because it was not
possible to blind caregivers to trial interventions, bias was mini-
mized by specifying the same weaning criteria for HFNC and
CPAP, the same number of weaning steps, minimum twice-
daily clinical evaluations to assess progression through the trial
algorithm, and use of an online training package to strengthen
protocol adherence.
Study Outcomes
The primary outcome was time from randomization to libera-
tion from respiratory support, defined as the start of the 48-
hour period during which a participant was free from all re-
spiratory support (invasive or noninvasive), excluding
supplemental oxygen.
Secondary outcomes included mortality at critical care unit
discharge; rate of intubation at 48 hours; durations of critical
care unit and acute hospital stay; patient comfort, assessed
using the COMFORT Behavior Scale22; sedation use during non-
invasive respiratory support; and parental stress at or around
the time of consent, measured using the Parental Stressor Scale:
Pediatric Intensive Care Unit.23 Mortality at 60 and 180 days
and quality-of-life and cost-effectiveness outcomes are not re-
ported in this article. Adverse events were monitored and re-
corded up to 48 hours after liberation from respiratory sup-
port. The data collection schedule is shown in eTable 1 in
Supplement 2.
Sample Size Calculation
It was estimated that 508 observed events would achieve 90%
power with a 1-sided type I error rate of 2.5% to exclude the
prespecified noninferiority margin of a hazard ratio of 0.75. In
the pilot RCT, a hazard ratio of 0.75 corresponded to approxi-
mately a median 16-hour increase in time to liberation for
HFNC.13 Clinical members and the parent representative on the
trial team agreed that this was the maximum clinically accept-
able difference between HFNC and CPAP. To account for cen-
soring from death or transfer and refusal or withdrawal of con-
sent and to retain sufficient power for a per-protocol analysis,
the target sample size was set at 600 patients. A single planned
interim analysis for safety using unadjusted log-rank tests for
superiority of the primary end point (using a Peto-Haybittle
stopping rule of P < .001, 2-sided) and for all-cause mortality
to day 60 (P < .05, 2-sided) was carried out after recruitment
and follow-up to day 60 of 300 patients.
Statistical Analysis
Analyses of the primary and secondary outcomes were per-
formed according to randomization group in all consented pa-
tients who commenced any respiratory support, invasive or
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noninvasive, following randomization (primary analysis set)
and in all consented patients who met the eligibility criteria
and commenced the randomized treatment (per-protocol
analysis set). Agreement of results from both analyses was
required to conclude noninferiority.24 Analyses followed a pre-
specified statistical analysis plan published before trial re-
cruitment was completed (Supplement 1).
The primary analysis was performed using Cox regres-
sion to calculate hazard ratios with 1-sided 97.5% CIs, ad-
justed for the prespecified baseline covariates of age (<12
months vs ≥12 months); SpO2:FIO2 ratio; severity of respira-
tory distress (severe vs mild or moderate); comorbidities (none
vs neurological/neuromuscular vs other); reason for admis-
sion (bronchiolitis vs other respiratory [airway problem,
asthma/wheeze, or any other respiratory reason] vs cardiac vs
other [neurological, sepsis/infection, any other reason]); re-
ceipt of noninvasive respiratory support at randomization
(yes/no); and site (treated as a random factor using shared
frailty). Patients were censored either at time of last known
respiratory support (for those who withdrew consent or
were discharged while still receiving respiratory support)
or at time of death (if death occurred prior to liberation from
respiratory support). The level of missingness of baseline
covariates was assessed, and where necessary missing values
were replaced using multivariable imputation using chained
equations. The assumption of proportional hazards was
assessed visually and by evaluating a Cox model with a time-
dependent covariate. As the Kaplan-Meier curves of time to
liberation appeared to cross between days 5 and 6, an addi-
tional post hoc test of proportionality (using Schoenfeld
residuals) was performed, which did not indicate any signifi-
cant violation of the assumption of proportional hazards
(P = .46). Comparison of Kaplan-Meier curves with Cox pre-
dictions showed good agreement between actual and
predicted time to liberation for both treatment groups. High-
flow nasal cannula therapy was considered noninferior to
CPAP if the bound of the 1-sided 97.5% CI for the adjusted
hazard ratio was greater than 0.75 in both the primary analy-
sis set and the per-protocol analysis set.
All secondary outcomes were evaluated for statistical
superiority using a 2-sided significance threshold of P = .05.
Binary outcomes were reported as unadjusted absolute risk
reductions and odds ratios and as adjusted odds ratios calcu-
lated using multilevel logistic regression. Continuous out-
comes were reported as unadjusted mean differences (with
95% bootstrapped CIs) and as adjusted differences calculated
using linear regression. All adjusted effect estimates were
adjusted for the same baseline covariates as defined for the
primary analysis. Because of the potential for type I error due
to multiple comparisons, findings for analyses of secondary
end points should be interpreted as exploratory.
Prespecified subgroup analyses of the primary outcome
were conducted testing interactions for age, SpO2:FIO2 ratio,
severity of respiratory distress, comorbidities, reason for ad-
mission, and receiving vs not receiving noninvasive respira-
tory support at randomization.
Planned sensitivity analyses included a repeat of the
primary analysis using alternative durations: from start of
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 Effect of HFNC vs CPAP Therapy on Liberation From Respiratory Support in Acutely Ill Children Original Investigation Research

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

18 976 Patients admitted to pediatric intensive

care/high-dependency units assessed

15 151 Excluded (did not meet inclusion criteria)

14 537 Did not require noninvasive respiratory support for an acute illness
125 Younger than 36 weeks’ corrected gestational age or older than 16 years
489 Both (did not meet age criteria and did not require support)

3825 Met inclusion criteria

3225 Excluded
2376 Met ≥1 exclusion criteriaa
1085 Received HFNC or CPAP for >2 hours in prior 24 hours
509 Receiving home noninvasive ventilation prior to admission
393 Clinician decision to start form of noninvasive respiratory
support other than HFNC or CPAP
275 Had tracheostomy in place
101 Required immediate intubation and invasive ventilation
84 Previously recruited to FIRST-ABC master protocol
38 Had “not for intubation” order or other limitation
of critical care in place
37 Had mid or craniofacial anomalies (unrepaired cleft palate,
choanal atresia) or recent craniofacial surgery
16 Had untreated air leak (pneumothorax/pneumomediastinum)
849 Were eligible but did not undergo randomization
438 Missed or identified too late
325 Clinical decisionb
50 Research site lacked sufficient HFNC/CPAP devices
17 Parental decision
3 COVID-19 restrictions
1 Language barrier
15 No reason provided

600 Randomized

301 Randomized to receive HFNC 299 Randomized to receive CPAP

300 Included in baseline characteristic reports 295 Included in baseline characteristic reports
1 Request for all trial data to be removed 4 Request for all trial data to be removed

295 Started respiratory support (primary analysis set)
290 Started allocated treatment
(per-protocol analysis set)
3 Started CPAP
1 Started other noninvasive support
1 Started invasive mechanical ventilation
5 Did not start respiratory support
278 Started respiratory support (primary analysis set)
246 Started allocated treatment
(per-protocol analysis set)
25 Started HFNC
4 Started other noninvasive support
3 Started invasive mechanical ventilation
17 Did not start respiratory support

281 Had evaluable time to liberation from
respiratory support
14 Time to liberation censored
7 Refusal of consent retrospectively
4 Died prior to liberation from respiratory support
2 Discharged home with respiratory support
1 Transferred to other critical care unit with
respiratory support
264 Had evaluable time to liberation from
respiratory support
14 Time to liberation censored
5 Refusal of consent retrospectively
4 Died prior to liberation from respiratory support
4 Discharged home with respiratory support
1 Transferred to other critical care unit with
respiratory support

CPAP indicates continuous positive airway pressure; HFNC, high-flow nasal
cannula.
a
Numbers meeting individual exclusion criteria do not add to the total because
some patients met more than 1 criterion.
b
Among 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.

respiratory support to liberation from respiratory support; from respiratory support by including them in a sensitivity analy-
randomization to start of weaning; and from randomization sis of the primary end point that assigned them to a nominal
to meeting weaning criteria. A post hoc analysis was per- 2 hours of respiratory support.
formed to assess the effect of patients who did not start any Stata/MP version 16.1 (StataCorp) was used for all analyses.

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 Research Original Investigation Effect of HFNC vs CPAP Therapy on Liberation From Respiratory Support in Acutely Ill Children

Table 1. Baseline Characteristics of the Primary Analysis Population

High-flow nasal cannula Continuous positive airway
Characteristics (n = 295) pressure (n = 278)
Age, median (IQR), mo 10 (2-31) 9 (1-27)
Age, No. (%)
≤28 d 31 (10.5) 37 (13.3)
29-180 d 87 (29.5) 80 (28.8)
181-364 d 49 (16.6) 43 (15.5)
1y 41 (13.9) 44 (15.8)
2-4 y 40 (13.5) 27 (9.7)
5-10 y 29 (9.8) 26 (9.4)
11-15 y 18 (6.1) 21 (7.6)
Sex, No. (%)
Female 116 (39.3) 110 (39.6)
a
Male 179 (60.7) 168 (60.4) Data were recorded at or within 1
No. (%) with ≥1 comorbidity 143 (48.5) 128 (46.2) hour prior to randomization, except
for COMFORT Behavior Scale score,
Main reason for admission, No. (%) n = 295 n = 277 which was the last recorded value
Bronchiolitis 143 (48.5) 138 (49.6) prior to randomization.
b
Other respiratory condition 55 (18.6) 57 (20.5) Respiratory distress was defined as
Asthma/wheeze 31 (10.5) 20 (7.2) mild (1 accessory muscle used, mild
indrawing of subcostal and
Sepsis/infection 24 (8.1) 23 (8.3) intercostal muscles, mild tachypnea,
Cardiac 17 (5.8) 12 (4.3) no grunting); moderate (2 accessory
Upper airway problem 15 (5.1) 12 (4.3) muscles used, moderate indrawing
of subcostal and intercostal muscles,
Neurological 4 (1.4) 2 (0.7) moderate tachypnea, occasional
Other 6 (2.0) 13 (4.7) grunting); or severe (use of all
Receiving noninvasive respiratory support 66 (22.4) 65 (23.4) accessory muscles, severe indrawing
at randomization, No. (%) of subcostal and intercostal muscles,
severe tachypnea, regular grunting).
Clinical characteristics at randomizationa n = 244 n = 227
Data on severity of respiratory
Respiratory distress, No. (%)b distress were missing for 102
None 14 (4.7) 12 (4.3) children, 60% of whom were from 3
of the 24 sites.
Mild 47 (15.9) 39 (14.0)
c
COMFORT Behavior Scale scores
Moderate 140 (47.5) 136 (48.9)
range from 5 (most sedated) to 30
Severe 43 (14.6) 40 (14.4) (least sedated). A mean value of 15
Respiratory rate, median (IQR), /min 48 (38-60) [n = 286] 49 (39-60) [n = 272] indicates a comfortable patient who
is easily arousable and is not
Peripheral oxygen saturation, median (IQR), % 97 (94-99) [n = 285] 97 (94-99) [n = 275]
agitated. Data on COMFORT
Fraction of inspired oxygen, median (IQR) 0.30 (0.21-0.48) [n = 288] 0.30 (0.21-0.44) [n = 271] Behavior Scale scores were missing
Ratio of peripheral oxygen saturation to 313 (198-424) [n = 287] 330 (218-438) [n = 271] for 434 children, mainly because
fraction of inspired oxygen, median (IQR) some sites did not collect COMFORT
Heart rate, median (IQR), /min 155 (140-171) [n = 291] 154 (140-173) [n = 272] Behavior Scale scores when children
were randomized prior to critical
COMFORT Behavior Scale score, mean (SD)c 16.2 (4.7) [n = 79] 15.3 (5.5) [n = 60]
care unit admission.

lar baseline characteristics (Table 1). In baseline variables that

Results
Trial Sites and Patients
From August 10, 2019, to November 7, 2021, 18 976 patients
admitted were screened in the 24 participating critical care
units, of whom 1449 were deemed eligible for the trial. Six
hundred children (41%) were randomized; consent was in
place for 595 children. Median time from randomization to
consent was 2 calendar days. Characteristics of the partici-
pating critical care units are shown in eTable 2 in Supple-
ment 2. Recruitment was paused twice at most sites due to
the COVID-19 pandemic (eFigure 3 in Supplement 2). The pri-
mary analysis set consisted of 573 children in whom respira-
tory support was commenced (HFNC group, n = 295; CPAP
group, n = 278) (Figure 1). The randomized groups had simi-
were used for the adjusted analysis, numbers of patients with
missing data were low (range, 0-15) for all variables except for
level of respiratory distress, for which data were missing for
102 patients. Baseline characteristics of children who were
and were not receiving respiratory support at randomization
are shown in eTable 3 in Supplement 2. The per-protocol
analysis included 533 children (HFNC group, n = 288; CPAP
group, n = 245) (eFigure 4 in Supplement 2); baseline charac-
teristics were similar to those in the primary analysis
(eTable 4 in Supplement 2).
Clinical Management
In both groups, the allocated treatment was started in the ma-
jority of children who started respiratory support (HFNC group:
290/295 [98.3%]; CPAP group: 246/278 [88.5%]). High-flow

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 Effect of HFNC vs CPAP Therapy on Liberation From Respiratory Support in Acutely Ill Children Original Investigation Research

Table 2. Primary and Secondary Outcomes in the HFNC vs CPAP Groups

Effect estimate (95% CI)

Outcomes HFNC CPAP Difference (95% CI) Unadjusteda Adjustedb
Primary analysis
Total No. analyzed 295 278
Primary outcome
Time from randomization 52.9 (46.0-60.9) 47.9 (40.5-55.7) AD, −5.0 (−10.1 to 17.4) HR, 1.03 (0.87-1.22) HR, 1.03 (0.86 to 1.22)
to liberation from respiratory
support, median (95% CI), h
Secondary outcomes
Mortality at critical care unit 5/292 (1.7) 4/274 (1.5) AD, 0.3 (−1.8 to 2.3) OR, 1.18 (0.31-4.43) OR, 1.22 (0.32 to 4.62)
discharge, No./total (%)
Intubation at 48 h, No./total (%) 45/292 (15.4) 44/276 (15.9) AD, −0.5 (−6.5 to 5.5) OR, 0.96 (0.61-1.51) OR, 0.99 (0.61 to 1.62)
Duration of critical care unit stay, 5.0 (8.2) 7.4 (18.9) MD, −2.4 (−4.8 to 0.0) MD, −3.0 (−5.1 to −1.0)
mean (SD), d [n = 288] [n = 270]
Duration of acute hospital stay, 13.8 (26.8) 19.5 (47.7) MD, −5.7 (−12.2 to 0.8) MD, −7.6 (−13.2 to −1.9)
mean (SD), d [n = 279] [n = 260]
COMFORT Behavior Scale score,
mean (SD)c
While receiving randomized 14.1 (3.6) 14.4 (4.8) MD, −0.4 (−1.3 to 0.5) MD, −0.6 (−1.4 to 0.2)
treatment [n = 194] [n = 142]
While receiving HFNC or CPAP 13.9 (3.5) 13.7 (3.7) MD, 0.2 (−0.6 to 0.9) MD, 0.2 (−0.5 to 0.8)
[n = 201] [n = 169]
Use of sedation during 81/292 (27.7) 97/262 (37.0) AD, −9.3 (−17.1 to −1.5) OR, 0.65 (0.46-0.93) OR, 0.59 (0.39 to 0.88)
noninvasive respiratory support,
No./total (%)
Parental stress score at time 1.5 (0.8) 1.6 (0.7) MD, 0.0 (−0.2 to 0.1) MD, −0.1 (−0.2 to 0.1)
of consent, mean (SD)d [n = 180] [n = 185]
Per-protocol analysis
Total No. analyzed 288 245
Primary outcome
Time from randomization 52.7 (45.0-60.1) 45.4 (40.2-53.7) AD, 7.3 (−7.3 to 22.2) 1.05 (0.88-1.25) 1.03 (0.86 to 1.23)
to liberation from respiratory
support, median (95% CI), h
Secondary outcomes
Mortality at critical care unit 5/285 (1.8) 3/243 (1.2) AD, 0.5 (−1.5 to 2.6) OR, 1.43 (0.34-6.04) OR, 1.46 (0.35 to 6.22)
discharge, No./total (%)
Intubation at 48 h, No./total (%) 43/285 (15.1) 36/243 (14.8) AD, 0.3 (−5.8 to 6.4) OR, 1.02 (0.63-1.65) OR, 1.07 (0.64 to 1.81)
Duration of critical care unit stay, 4.7 (7.3) 7.7 (19.9) MD, −3.0 (−5.7 to −0.3) MD, −3.5 (−5.6 to −1.4)
mean (SD), d [n = 281] [n = 242]
Duration of acute hospital stay, 13.7 (26.9) 20.8 (50.3) MD, −7.1 (−14.5 to 0.3) MD, −8.8 (−14.8 to −2.8)
mean (SD), d [n = 272] [n = 231]
COMFORT Behavior Scale score,
mean (SD)c
While receiving randomized 14.1 (3.6) 14.5 (4.7) MD, −0.4 (−1.3 to 0.5) MD, −0.6 (−1.4 to 0.2)
treatment [n = 193] [n = 139]
While receiving HFNC or CPAP 13.9 (3.5) 13.6 (3.6) MD, 0.3 (−0.5 to 1.0) MD, 0.2 (−0.4 to 0.9)
[n = 197] [n = 157]
Use of sedation during 80/286 (28.0) 93/237 (39.2) AD, −11.3 (−19.4 to −3.2) OR, 0.60 (0.42-0.87) OR, 0.54 (0.35 to 0.81)
noninvasive respiratory support,
No./total (%)
Parental stress score at time 1.5 (0.8) 1.6 (0.7) MD, 0.0 (−0.2 to 0.1) MD, 0.0 (−0.2 to 0.1)
of consent, mean (SD)d [n = 174] [n = 167]
Abbreviations: AD, absolute difference; CPAP, continuous positive airway respiratory support at randomization (yes vs no), severity of respiratory
pressure; HFNC, high-flow nasal cannula; HR, hazard ratio; MD, mean distress (severe vs mild or moderate), and site (using shared frailty).
difference; OR, odds ratio. c
COMFORT Behavior Scale scores were recorded every 6 hours until liberation
a
Unadjusted effect estimate is not separately reported for some rows because from respiratory support and were aggregated to patient level using the
it is the mean difference as reported in the “Difference” column. median of all recorded scores.
b
Adjusted for prebaseline factors of age (<12 months vs ⱖ12 months), SpO2:FIO2 d
Parental Stressor Scale: Pediatric Intensive Care Unit scores range from 1 (not
ratio, comorbidities (none vs neurological/neuromuscular vs other), reason for stressful) to 5 (extremely stressful). A mean value of 1.6 indicates a low level of
admission (bronchiolitis vs other respiratory vs cardiac vs other reason), parental stress at the time of completing the questionnaire.

nasal cannula flow rate and CPAP pressure delivered during were used to deliver HFNC and CPAP (eTable 6 in Supple-
treatment were as per the trial algorithms (eFigures 5 and 6 in ment 2). Treatment failure requiring either a switch or esca-
Supplement 2), as were switch, escalation, and weaning events lation occurred in 96 of 290 children (33.1%) in the HFNC
(eTable 5 in Supplement 2). A range of devices and interfaces group and in 131 of 246 children (53.3%) in the CPAP group

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 Research Original Investigation Effect of HFNC vs CPAP Therapy on Liberation From Respiratory Support in Acutely Ill Children

Figure 2. Time to Liberation From Respiratory Support in the Primary Analysis

and Per-Protocol Analysis Populations

A Primary analysis set

100
HFNC

CPAP
Patients liberated from support, %

80

60

40

20

0
0 1 2 3 4 5 6 7 8 9 10
Days after randomization
No. at risk
CPAP 278 210 135 92 67 55 48 39 35 31 29
HFNC 295 229 155 105 75 57 46 31 29 22 20

B Per-protocol analysis set

100
HFNC

CPAP
Patients liberated from support, %

80

60

40
CPAP indicates continuous positive
airway pressure; HFNC, high-flow
20
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
0 CPAP group was 44.8 (IQR, 24.3-92.9)
0 1 2 3 4 5 6 7 8 9 10
Days after randomization hours; median observation time in the
No. at risk per-protocol analysis set for the HFNC
CPAP 246 186 119 82 60 49 43 36 32 28 27 group was 49.9 (IQR, 25.4-95.8) hours
HFNC 290 225 152 102 72 54 43 29 27 20 18 and in the CPAP group was 44.7
(IQR, 24.3-90.0) hours.

(eFigure 7 in Supplement 2) after a median of 6.1 hours and 4.5
hours following randomization, respectively. More patients
switched from CPAP to HFNC (76/246 [30.9%]) than from
HFNC to CPAP (58/290 [20.0%]). Reasons for switching were
mainly related to clinical deterioration in the HFNC group and
to patient discomfort in the CPAP group (eTable 7 in Supple-
ment 2). Children who switched from CPAP to HFNC for dis-
comfort reasons were older compared with children who did
not switch (median age, 12 months vs 3 months).
Primary Outcome
The median time from randomization to liberation from
respiratory support was 52.9 hours (95% CI, 46.0-60.9 hours)
for HFNC and 47.9 hours (95% CI, 40.5-55.7 hours) for CPAP
(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-⬁). The
bound of the 1-sided 97.5% CI of 0.86 fell within the pre-
specified noninferiority margin. Time to liberation for HFNC
and CPAP based on whether treatment failure occurred or not
is shown in eFigure 8 in Supplement 2. A summary of the
treatments provided over time is shown in eFigure 9 in
Supplement 2.
Similar results were seen in the per-protocol analysis
(Table 2 and Figure 2). In prespecified subgroup analyses,
there was a significant difference in effect between patients
who were receiving respiratory support at randomization, in
whom CPAP was more effective, and those who were not,
in whom CPAP was less effective (Figure 3). Planned sensitiv-
ity analyses did not alter the interpretation of the primary
analyses (eTable 8 in Supplement 2).

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 Effect of HFNC vs CPAP Therapy on Liberation From Respiratory Support in Acutely Ill Children Original Investigation Research

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

Events/ Hazard ratio Favors Favors

Subgroup person-days (95% CI) CPAP HFNC P value
Age, mo .59
<12 317/1560 1.07 (0.85-1.34)
≥12 228/1357 0.97 (0.74-1.27)
Respiratory distress .63
Not severe 372/1700 1.05 (0.86-1.28)
Severe 81/379 0.92 (0.58-1.48)
SpO2:FIO2 ratio by quintile .50
≤184 104/666 0.89 (0.60-1.33)
>184 to ≤250 122/396 0.90 (0.62-1.31)
>250 to ≤366 100/764 1.24 (0.82-1.87)
>366 to ≤452 106/431 1.13 (0.75-1.68)
>452 102/570 1.06 (0.71-1.58)
Comorbidities .55
None 297/712 0.99 (0.78-1.26)
Neurological/neuromuscular 77/411 0.88 (0.55-1.39)
Other 170/1794 1.17 (0.86-1.61)
Reason for admission .41
Bronchiolitis 275/793 0.96 (0.76-1.23)
Other respiratory 180/1245 1.08 (0.79-1.46)
Cardiac 26/569 1.91 (0.87-4.21) CPAP indicates continuous positive
Other reason 63/311 0.91 (0.55-1.51) airway pressure; FIO2, fraction of
Receiving support at randomization .03 inspired oxygen; HFNC, high-flow
No 417/2535 1.14 (0.94-1.40) nasal cannula; SpO2, peripheral
Yes 128/382 0.73 (0.51-1.04) oxygen saturation. P values test for
Overall 545/2918 1.03 (0.86-1.22) an interaction between the subgroup
categories and the effect of CPAP vs
0.5 1 5 HFNC in the adjusted Cox regression
Hazard ratio (95% CI) model. Dashed vertical line indicates
margin of noninferiority, 0.75.

Secondary Outcomes
Secondary outcomes are shown in Table 2 and in eTable 9 in
Supplement 2. The rate of intubation within 48 hours was not
significantly different between the groups (HFNC group: 15.4%;
CPAP group: 15.9%; adjusted odds ratio, 0.99; 95% CI, 0.61-
1.62). Sedation use while receiving HFNC or CPAP was lower
in the HFNC group (27.7% vs 37.0% for CPAP; adjusted odds
ratio, 0.59; 95% CI, 0.39-0.88). Duration of critical care unit
stay was significantly shorter in the HFNC group (mean, 5 days
vs 7.4 days for CPAP; adjusted mean difference, −3.1 days [95%
CI, −5.1 to −1.0 days]). The mean parental stress score was low
in both groups (HFNC group: 1.5; CPAP group: 1.6).
Post Hoc Analysis
The post hoc analysis including patients who did not start any
respiratory support also confirmed the noninferiority of HFNC
(eTable 9 and eFigure 10 in Supplement 2).
Adverse Events
The number of children with 1 or more adverse events was low
in both groups, occurring in 24 of 295 children (8.1%) in the
HFNC group and in 39 of 278 (14.0%) in the CPAP group
(P = .03; see eTable 10 in Supplement 2). Nasal trauma was
more common in the CPAP group (6.5% vs 2.0% for HFNC).
Four serious adverse events, all cardiac arrests (HFNC group:
n = 1; CPAP group: n = 3), were reported, none judged to be re-
lated to the randomized intervention.
Discussion
In this multicenter pragmatic randomized clinical trial, first-
line use of HFNC in acutely ill children admitted to a critical care
unit and assessed to require noninvasive respiratory support met
the criterion for noninferiority compared with CPAP for time
from randomization to liberation from respiratory support.
Five RCTs have previously compared HFNC with CPAP in
acutely ill children, 4 in infants with bronchiolitis (n = 285)
and 1 in a resource-limited setting in children with pneumo-
nia (n = 158).21,25-28 The current study was a pragmatic trial
conducted in a heterogeneous group of acutely ill children.
While bronchiolitis represented nearly half of the trial popu-
lation, other respiratory diseases, asthma/wheeze, cardiac
conditions, and sepsis were also included. Nearly 63% of chil-
dren had moderate or severe respiratory distress at baseline
and 42% had an SpO2:FIO2 ratio of less than 265, consistent
with an oxygenation deficit usually seen in cases of pediatric
acute respiratory distress syndrome. 20,29 About 23% of
enrolled children had already received noninvasive respira-
tory support prior to randomization, most commonly HFNC,
reflecting its frequent use in acute care prior to critical care
admission. Previous RCTs in bronchiolitis used “treatment
failure” as the primary outcome; however, there has been
criticism that it does not reflect patient outcomes.30-32 In this
trial, time to liberation from respiratory support was chosen

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 Research Original Investigation Effect of HFNC vs CPAP Therapy on Liberation From Respiratory Support in Acutely Ill Children

as a sensitive measure of both intubation and prolonged use
of noninvasive respiratory support. This approach was sup-
ported by previous qualitative work,33,34 as well as pretrial
consultation, which indicated that being free of any “breath-
ing machine” was a key priority for parents and guardians.
The main trial finding of noninferiority of first-line use of
HFNC in acutely ill children was consistent across the pri-
mary and per-protocol analyses. It is, however, different from
the findings of the FIRST-ABC Step-Down RCT, in which
HFNC was not found to be noninferior to CPAP in children
extubated after invasive mechanical ventilation.15 One expla-
nation may be the higher rate of treatment failure during use
of CPAP in this step-up trial (53.3% vs 33.7% in the step-down
RCT); more children were switched from CPAP to HFNC,
mainly because of patient discomfort (30.9% vs 12.3% in the
step-down RCT), which may have minimized any differences
between the groups. In contrast, the proportion of children
switching from HFNC to CPAP was similar in both trials
(20.0% vs 23.5%). Only about 25% of the CPAP group were
still receiving CPAP 24 hours after commencing treatment,
whereas nearly 50% of the HFNC group were still receiving
HFNC. The wide range of devices and interfaces used to pro-
vide CPAP may have resulted in ineffective delivery and
greater patient asynchrony, particularly in older children, in
whom a switch from CPAP to HFNC because of discomfort
was more common.
The main trial finding of noninferiority needs to be inter-
preted in conjunction with the findings of the secondary out-
comes. There was a statistically significant difference in
sedation use between the groups (27.7% for HFNC vs 37.0%
for CPAP). However, COMFORT Behavior Scale scores were
similar in the HFNC and CPAP groups. There was no differ-
ence in mortality or rate of intubation between the 2 groups.
Reasons for the statistically significant differences in mean
durations of critical care unit and hospital stay (longer for
the CPAP group) are unclear. Nasal trauma was more com-
mon in the CPAP group. Subgroup analysis showed that the
effect of HFNC differed between children who were and were
not receiving respiratory support at randomization, with a
point estimate consistent with inferiority of HFNC for those
already receiving support.
This trial has several strengths. First, to our knowledge, it
is the largest RCT comparing 2 commonly used modes of non-
invasive respiratory support, with the potential to inform clini-
cal practice. Second, the age of recruited children was repre-
sentative of contemporary UK practice: in 2018, 50.5% of
patients admitted to UK pediatric intensive care units receiv-
ing respiratory support were infants younger than 1 year (56%
in this trial).1 Third, there was good adherence to trial algo-
rithms. Fourth, several sensitivity analyses and a post hoc
analysis were conducted to test the robustness of the pri-
mary analysis.
Limitations
This trial has several limitations. First, it was not possible to
blind clinicians to the allocated treatment, which may have in-
fluenced decisions to switch or escalate treatment or to start
respiratory support at all. This was highlighted in the high rate
of switching from CPAP to HFNC for perceived patient dis-
comfort, and a larger than anticipated number of patients in
the CPAP group who did not start any respiratory support af-
ter randomization. Second, the pragmatic inclusion criteria re-
sulted in a heterogeneous population of acutely ill children,
mostly younger than 2 years, and although prespecified sub-
group analyses based on age, diagnosis, and receipt of prior
noninvasive respiratory support are reported, there may be
other unidentified subgroups (for example, children aged ≥10
years) for whom one treatment is more effective over an-
other. Third, nearly 1000 children who had received more than
2 hours of prior noninvasive respiratory support were ex-
cluded from the trial because HFNC is increasingly started out-
side the critical care setting. Fourth, several eligible patients
were not recruited owing to clinical preference, and some chil-
dren (especially older children randomized to CPAP) did not
undergo any respiratory support after randomization, which
created an imbalance between the groups.35 Fifth, because data
related to feeding were not collected as part of the trial, it was
not possible to assess the effect of feeding on patient comfort.
Conclusions
Among acutely ill children assessed to require noninvasive
respiratory support and admitted to a pediatric critical care
unit, HFNC compared with CPAP met the criterion for nonin-
feriority for time to liberation from respiratory support.

ARTICLE INFORMATION
Accepted for Publication: May 23, 2022.
Published Online: June 16, 2022.
doi:10.1001/jama.2022.9615
Author Affiliations: Section of Anaesthetics,
Pain Medicine, and Intensive Care, Department of
Surgery and Cancer, Faculty of Medicine, Imperial
College London, London, England (Ramnarayan);
Children’s Acute Transport Service, Great Ormond
Street Hospital for Children NHS Foundation Trust,
London, England (Ramnarayan); Clinical Trials Unit,
Intensive Care National Audit and Research Centre,
London, England (Richards-Belle, Drikite, Saull,
Orzechowska, Darnell, Thomas, Mouncey, Harrison,
Rowan); Department of Health Services Research
and Policy, London School of Hygiene and Tropical
Medicine, London, England (Sadique, Grieve);
parent representative, Sussex, England (Lester);
Birmingham Children’s Hospital, Birmingham
Women’s and Children’s NHS Foundation Trust,
Birmingham, England (Morris); Institute of Applied
Health Research, University of Birmingham,
Birmingham, England (Morris); School of Health
and Society, University of Salford, Salford, England
(Tume); Paediatric Intensive Care Unit,
Bristol Royal Hospital for Children, University
Hospitals Bristol and Weston NHS Foundation
Trust, Bristol, England (Davis); Paediatric Intensive
Care Unit, Great Ormond Street Hospital for
Children NHS Foundation Trust and NIHR
Biomedical Research Centre, London, England
(Peters); University College London Great Ormond
Street Institute of Child Health, London, England
(Peters); Leeds Institute for Data Analytics, School
of Medicine, University of Leeds, Leeds, England
(Feltbower).
Author Contributions: Ms Thomas and Dr Harrison
had full access to all of the data in the study and
take responsibility for the integrity of the data and
the accuracy of the data analysis.
Concept and design: Ramnarayan, Sadique, Lester,
Morris, Tume, Davis, Peters, Grieve, Mouncey,
Harrison, Rowan.
Acquisition, analysis, or interpretation of data:
Ramnarayan, Richards-Belle, Drikite, Saull,
Orzechowska, Darnell, Sadique, Tume, Davis,
Peters, Feltbower, Grieve, Thomas, Mouncey,
Harrison, Rowan.

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 Effect of HFNC vs CPAP Therapy on Liberation From Respiratory Support in Acutely Ill Children
Drafting of the manuscript: Ramnarayan,
Richards-Belle, Saull, Orzechowska, Lester, Tume,
Davis, Peters, Thomas.
Critical revision of the manuscript for important
intellectual content: Richards-Belle, Drikite, Darnell,
Sadique, Morris, Tume, Davis, Peters, Feltbower,
Grieve, Mouncey, Harrison, Rowan.
Statistical analysis: Orzechowska, Sadique,
Feltbower, Grieve, Thomas.
Obtained funding: Ramnarayan, Sadique, Peters,
Grieve, Mouncey, Harrison, Rowan.
Administrative, technical, or material support:
Richards-Belle, Drikite, Saull, Darnell, Morris, Davis,
Peters, Feltbower, Mouncey, Rowan.
Supervision: Ramnarayan, Richards-Belle, Davis,
Peters, Mouncey, Harrison, Rowan.
Conflict of Interest Disclosures: Dr Ramnarayan
reported receipt of personal fees from Fisher &
Paykel Healthcare and Sanofi. No other disclosures
were reported.
Funding/Support: This trial was funded by the
National Institute for Health and Care Research
(NIHR) Health Technology Assessment Programme
(project number 17/94/28). Great Ormond Street
Hospital for Children NHS Foundation Trust was the
trial sponsor.
Role of the Funder/Sponsor: The NIHR approved
the design of the study and monitored the conduct
of the study. Neither the NIHR nor the Great
Ormond Street Hospital for Children NHS
Foundation Trust had any role in the collection,
management, analysis, and interpretation of the
data; preparation, review, or approval of the
manuscript; or decision to submit the manuscript
for publication, and neither had the right to veto
publication or control the decision regarding to
which journal the manuscript was submitted.
Group Information: The FIRST-ABC Step-Up RCT
Investigators are listed in Supplement 3. Trial
steering committee members included Carrol
Gamble, PhD (chair, independent); Bronagh
Blackwood, PhD (independent); Cormac
Breatnach, MD, PhD (independent); Richard
Jenkin (lay representative, independent); Duncan
Young, DM (independent); Madeleine Wang
(lay representative, independent); Jennifer Whitty,
PhD (independent); Padmanabhan Ramnarayan,
MD (nonindependent); and Paul Mouncey, MSc
(nonindependent). Independent data monitoring
and ethics committee members included Neal J.
Thomas, MD, MSc (chair); Robinder Khemani, MD;
and Clíona McDowell, MSc.
Meeting Presentation: Presented at the Critical
Care Reviews Meeting; June 16, 2022; Belfast,
Northern Ireland.
Data Sharing Statement: See Supplement 4.
Additional Contributions: We thank all of the trial
participants and their families for giving their time
to participate in the trial.
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