Research

JAMA Pediatrics | Original Investigation | CARING FOR THE CRITICALLY ILL PATIENT

Noninvasive High-Frequency Oscillatory Ventilation vs Nasal Continuous

Positive Airway Pressure vs Nasal Intermittent Positive Pressure
Ventilation as Postextubation Support for Preterm Neonates in China
A Randomized Clinical Trial
Xingwang Zhu, MD; HongBo Qi, MD; Zhichun Feng, MD; Yuan Shi, MD, PhD;
Daniele De Luca, MD, PhD; for the Nasal Oscillation Post-Extubation (NASONE) Study Group

Visual Abstract
IMPORTANCE Several respiratory support techniques are available to minimize the use of Supplemental content
invasive mechanical ventilation (IMV) in preterm neonates. It is unknown whether
noninvasive high-frequency oscillatory ventilation (NHFOV) is more efficacious than nasal
continuous positive airway pressure (NCPAP) or nasal intermittent positive pressure
ventilation (NIPPV) in preterm neonates after their first extubation.

OBJECTIVE To test the hypothesis that NHFOV is more efficacious than NCPAP or NIPPV
in reducing IMV after extubation and until neonatal intensive care unit discharge among
preterm neonates.

DESIGN, SETTING, AND PARTICIPANTS This multicenter, pathophysiology-based,

assessor-blinded, 3-group, randomized clinical trial was conducted in 69 tertiary referral
neonatal intensive care units in China, recruiting participants from December 1, 2017,
to May 31, 2021. Preterm neonates who were between the gestational age of 25 weeks
plus 0 days and 32 weeks plus 6 days and were ready to be extubated were randomized to
receive NCPAP, NIPPV or NHFOV. Data were analyzed on an intention-to-treat basis.

INTERVENTIONS The NCPAP, NIPPV, or NHFOV treatment was initiated after the first
extubation and lasted until discharge.

MAIN OUTCOMES AND MEASURES Primary outcomes were total duration of IMV, need for
reintubation, and ventilator-free days. These outcomes were chosen to describe the effect
of noninvasive ventilation strategy on the general need for IMV.

RESULTS A total of 1440 neonates (mean [SD] age at birth, 29.4 [1.8] weeks; 860 boys
[59.7%]) were included in the trial. Duration of IMV was longer in NIPPV (mean difference,
1.2; 95% CI, 0.01-2.3 days; P = .04) and NCPAP (mean difference, 1.5 days; 95% CI, 0.3-2.7
days; P = .01) compared with NHFOV. Neonates who were treated with NCPAP needed
reintubations more often than those who were treated with NIPPV (risk difference: 8.1%;
95% CI, 2.9%-13.3%; P = .003) and NHFOV (risk difference, 12.5%; 95% CI, 7.5%-17.4%;
P < .001). There were fewer ventilator-free days in neonates treated with NCPAP than in
those treated with NIPPV (median [25th-75th percentile] difference, −3 [−6 to −1] days;
P = .01). There were no differences between secondary efficacy or safety outcomes, except
for the use of postnatal corticosteroids (lower in NHFOV than in NCPAP group; risk difference,
7.3%; 95% CI, 2.6%-12%; P = .002), weekly weight gain (higher in NHFOV than in NCPAP
Author Affiliations: Author
group; mean difference, −0.9 g/d; 95% CI, −1.8 to 0 g/d; P = .04), and duration of study affiliations are listed at the end of this
intervention (shorter in NHFOV than in NIPPV group; median [25th-75th percentile] article.
difference, −1 [−3 to 0] days; P = .01). Group Information: Members of the
NASONE Study Group appear in
CONCLUSIONS AND RELEVANCE Results of this trial indicated that NHFOV, if used after Supplement 3.
extubation and until discharge, slightly reduced the duration of IMV in preterm neonates, Corresponding Author: Yuan Shi,
and both NHFOV and NIPPV resulted in a lower risk of reintubation than NCPAP. MD, PhD, Department of
Neonatology, Children's Hospital of
All 3 respiratory support techniques were equally safe for this patient population.
Chongqing Medical University,
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03181958 Ministry of Education Key Laboratory
of Child Development and Disorders,
Key Laboratory of Pediatrics in
Chongqing, China, No. 136,
Zhongshan 2nd Road, Yuzhong
JAMA Pediatr. 2022;176(6):551-559. doi:10.1001/jamapediatrics.2022.0710 District, Chongqing 401122, China
Published online April 25, 2022. (shiyuan@hospital.cqmu.edu.cn).

(Reprinted) 551
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 Research Original Investigation
M
any preterm neonates eventually need invasive
m e c h a n i c a l ve nt i l at i o n ( I M V ) d u r i ng t h e i r
hospitalization.1,2 Invasive mechanical ventilation is
associated with bronchopulmonary dysplasia (BPD), later neu-
rological impairment, and rehospitalization during the first
year of life. 3-5 To minimize IMV, neonatal intensive care
units (NICUs) use nasal continuous positive airway pressure
(NCPAP) and various noninvasive ventilation modes.
Nasal continuous positive airway pressure is a commonly
established respiratory support used after extubation,
but many patients do not respond to NCPAP and need
reintubation.6 Nasal intermittent positive pressure ventila-
tion (NIPPV) is a noninvasive ventilation mode that delivers
intermittent peak pressure on positive end-expiratory pres-
sure with a given inspiratory time and frequency.7 Use of
NIPPV reduces the need for IMV more effectively compared
with NCPAP, but does not substantially reduce BPD.8 More-
over, NIPPV in neonates is usually unsynchronized given that
synchronization is difficult to achieve because of leaks, high
respiratory rate, low tidal volume, and irregular breathing pat-
tern. Noninvasive high-frequency oscillatory ventilation
(NHFOV) is an unconventional noninvasive ventilation mode
that applies a bias flow to generate a continuous distending
pressure with active oscillations that are superimposed on
spontaneous tidal breathing.9 Noninvasive high-frequency os-
cillatory ventilation may be beneficial because it allows a high
mean airway pressure (Paw) to be reached, theoretically re-
ducing gas trapping with the superimposed oscillations. More-
over, NHFOV is gaining popularity at least in some countries10
because of its advantages, such as no need for synchroniza-
tion, efficiency in carbon dioxide removal, easy alveolar re-
cruitment, and noninvasive interface.11
Nasal continuous positive airway pressure is the current
standard of care for preterm neonates early in life (that is, be-
fore surfactant administration, if any).12,13 Although NCPAP,
NIPPV, and NHFOV are alternative strategies to ventilate pa-
tients later during the NICU stay, it is unclear which ventila-
tion mode should be preferred; thus, a multigroup design is
appropriate. We conducted a multicenter, pathophysiology-
based, assessor-blinded, 3-group, randomized clinical trial
with parallel design to test the hypothesis that NHFOV is
more efficacious than NCPAP or NIPPV in reducing the need
for IMV after extubation and until NICU discharge among
preterm neonates.
Methods
Study Design and Eligibility Criteria
The trial protocol14 (Supplement 1) was approved by the eth-
ics committee of the Third Affiliated Hospital of Chongqing
Military Medical University. Written informed consent was
obtained from parents or guardians antenatally or on NICU ad-
mission, and data were treated according to all relevant local
regulations. We followed the Consolidated Standards of
Reporting Trials (CONSORT) reporting guideline.15
A total of 69 tertiary referral NICUs in China participated
in this randomized clinical trial. Attending neonatologists
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NHFOV vs NCPAP vs NIPPV as Postextubation Support in Preterm Neonates
Key Points
Question What is the best noninvasive ventilation mode to reduce
postextubation invasive respiratory support in preterm neonates?
Findings In this randomized clinical trial of 1440 preterm
neonates, noninvasive high-frequency oscillatory ventilation
(NHFOV) slightly reduced the duration of invasive ventilation.
Both NHFOV and nasal intermittent positive pressure ventilation
had a lower risk of reintubation than nasal continuous positive
airway pressure.
Meaning Findings of this trial indicate that NHFOV and nasal
intermittent positive pressure ventilation in neonates provide a
small advantage of reduced need for invasive respiratory support
when used from extubation and until discharge.
screened the neonates daily for eligibility. Neonates who met
all of the following conditions were enrolled: (1) gestational age
between 25 weeks plus 0 days and 32 weeks plus 6 days, (2)
received assistance from any IMV mode, (3) postconcep-
tional age younger than 36 weeks, and (4) readiness for first-
time extubation (extubation readiness was described in the pro-
tocol [Supplement 1]). Neonates were excluded if they had (1)
major congenital anomalies or chromosomal abnormalities;
(2) neuromuscular diseases; (3) upper respiratory tract abnor-
malities; (4) surgical conditions; (5) grade IV intraventricular
hemorrhage occurring before the first extubation; (6) birth
weight of less than 600 g; or (7) suspected congenital lung
diseases, malformations, or pulmonary hypoplasia.
Race and ethnicity data were not collected. All of the par-
ticipants were Chinese newborns.
Randomization and Blinding
Between December 1, 2017, and May 31, 2021, neonates were
randomized to receive NCPAP, NIPPV, or NHFOV when extu-
bation was deemed imminent (within 1 hour of the planned
extubation); they were randomized to a study group after the
decision to extubate (Figure). Simple centralized randomiza-
tion was done according to a software-generated random num-
ber sequence that was posted on a dedicated and secured
website. The website generated the randomization, but the se-
quence was concealed from investigators at each of the par-
ticipating sites. Neonates who were randomized to 1 group
could not cross over to the others during the study. In case of
reintubation, when the neonate was reextubated, the same
treatment was provided and managed according to the trial
protocol.14
Because of the nature of the intervention, blinding of the
clinicians was impossible and blinding of the neonates made
no sense. However, the outcome assessors were blinded be-
cause the outcome data were recorded by investigators who
were not working in the NICU and who reviewed patient files
while blinded for the allocated treatment. An assessor was
nominated for each participating NICU.
Devices and Interfaces
We used either variable- or continuous-flow devices to pro-
vide NCPAP. Given that neonatal ventilators rarely offer this
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 NHFOV vs NCPAP vs NIPPV as Postextubation Support in Preterm Neonates
Figure. CONSORT Diagram
1974 Assessed for eligibility
481 Excluded
80 Met at least 1 exclusion criterion
315 Parent(s) refused to participate
86 Hospital transfer before randomization
1493 Randomized
501 Allocated to NCPAP and received 495 Allocated to NIPPV and received
the allocated intervention the allocated intervention
21 Discontinued NCPAP 15 Discontinued NIPPV
480 Analyzed 480 Analyzed
option, NIPPV was unsynchronized. Noninvasive high-
frequency oscillatory ventilation was provided only with pis-
ton or membrane oscillators that were able to produce active
expiration. The complete list of devices allowed in the study
is described in the trial protocol (Supplement 1). The NCPAP,
NIPPV, and NHFOV were administered through the same
short binasal prongs because these prongs are more com-
monly used in the participating NICUs and have good me-
chanical characteristics.16-18 Prong size was chosen as the best
fitting according to the diameter of the nares (the largest ones
that fit the nares without blanching the surrounding tissues)
and the manufacturer’s recommendations. Particular care
(eg, pacifiers and positioning) was taken to reduce leaks.
Ventilatory Management
Neonates who were randomized to NCPAP were given an ini-
tial pressure of 5 cm H2O, which can be increased to 8 cm H2O
according to oxygenation. Neonates who were randomized to
NIPPV were initially treated with the following parameters: (1)
positive end-expiratory pressure of 4 cm H2O, which can be
increased to 8 cm H2O according to oxygenation; (2) peak in-
spiratory pressure of 15 cm H2O, which can be increased to 25
cm H2O according to chest expansion and PaCO2 levels; (3) fre-
quency of 30 breaths per minute, which can be increased to
50 breaths per minute according to chest expansion and PaCO2
levels; and (4) inspiratory time set between 0.45 and 0.5 sec-
onds according to pressure waveform and leaks evaluation.
Neonates who were randomized to NHFOV received starting
treatments with the following parameters: (1) Paw of 10 cm H2O
and titrated within the 5- to 16-cm H2O range according to
the open lung strategy, similar to invasive high-frequency os-
cillatory ventilation targeting a fraction of inspired oxygen
(FiO2) of 25% to 30%19; (2) inspiratory time of 50%, which was
kept unchanged18; (3) frequency of 10 Hz and titrated within
the 8- to 15-Hz range; and (4) amplitude of 25 cm H2O and ti-
trated within 25- to 50-cm H2O range. Frequency and ampli-
tude were titrated according to PaCO2 levels, rather than on the
magnitude of chest oscillations, because carbon dioxide clear-
ance also occurs in the upper airway dead space.20
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Original Investigation Research
497 Allocated to NHFOV and received
the allocated intervention
NCPAP indicates nasal continuous
17 Discontinued NHFOV positive airway pressure; NIPPV, nasal
intermittent positive pressure
ventilation; NHFOV, noninvasive
480 Analyzed
high-frequency oscillatory
ventilation.
For all groups, if the maximal parameters were not enough
to maintain preductal saturation between 90% and 95%, the
FiO2 was gradually increased up to 0.40. Parameters were
managed and weaned as described in the trial protocol. A dedi-
cated training program was deployed to disseminate this
management policy to all participating NICUs.14
Cointerventions and Concurrent Monitoring
Routine medical care and nursing were not changed solely for
study purposes apart from the trial intervention. Nonpharma-
cologic sedation with pacifiers and 33% glucose solutions were
provided when needed; no other sedation was allowed. Vital
parameters monitoring and point-of-care ultrasonography
were performed, and blood gases were measured in arterial-
ized capillary samples or using transcutaneous devices.14 All
other typical NICU procedures and treatments were provided
according to shared best clinical practices.
Outcomes
The primary outcomes were (1) total duration of IMV during the
NICU stay, (2) need for reintubation (criteria for reintubation
were fixed), and (3) ventilator-free days, as defined in the pub-
lished protocol.14 These 3 primary outcomes were chosen to
describe the general need for IMV from different points of view.
Secondary outcomes were represented by several effi-
cacy and safety end points, as detailed in the protocol. Nasal
injury was evaluated with a dedicated score.21 We also ana-
lyzed the duration of the study intervention and supplemen-
tal oxygen.
Statistical Analysis
A prospective, cohort, nonrandomized pilot study compar-
ing postextubation NIPPV and NHFOV in preterm neonates
provided data on the duration of IMV.22 This previous study
showed a decrease in IMV duration of approximately 30%
for patients who received NHFOVvs NIPPV, although this
report was included only in an abstract.22 A randomized trial
of NIPPV vs NCPAP showed a similar 30% reduction in IMV
duration.23 Because these previous trials did not have the
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 Research Original Investigation NHFOV vs NCPAP vs NIPPV as Postextubation Support in Preterm Neonates

Table 1. Baseline Characteristics of the Study Population

No. (%)
Characteristic NCPAP group (n = 480) NIPPV group (n = 480) NHFOV group (n = 480)
Gestational age at birth, mean (SD), wk 29.5 (1.7) 29.4 (1.8) 29.4 (1.8)
Neonates between
25 wk + 0 d and 27 wk + 6 d 63 (13.1) 75 (15.6) 80 (16.7)
28 wk + 0 d and 29 wk + 6 d 166 (34.6) 182 (37.9) 152 (31.7)
30 wk + 0 d and 32 wk + 6 d 251 (52.3) 223 (46.5) 248 (51.6)
Birth weight, mean (SD), g 1341 (318.0) 1334 (366.0) 1317 (353.0)
Neonates with birth weight <1000 g 67 (14.0) 82 (17.1) 93 (19.4)
Abbreviations: CRIB II, Clinical Risk
Female sex 208 (43.3) 188 (39.2) 184 (38.3) Index for Babies II; FiO2, fraction of
Male sex 272 (56.7) 292 (60.8) 296 (61.7) inspired oxygen; NCPAP, nasal
SGA neonates 45 (9.4) 42 (8.8) 36 (7.5) continuous positive airway pressure;
NHFOV, noninvasive high-frequency
Twins 132 (27.5) 145 (30.2) 148 (30.8)
oscillatory ventilation; NIPPV, nasal
Cesarean delivery 259 (53.9) 256 (53.3) 260 (54.1) intermittent positive pressure
Prenatal corticosteroid prophylaxisa 207 (43.1) 235 (48.9) 218 (45.4) ventilation; OI, oxygenation index;
CRIB II score, mean (SD)b 5.2 (3.0) 5.2 (3.3) 5.4 (3.2) Paw, mean airway pressure;
5-min Apgar score, median 9 (8-9) 9 (8-9) 9 (8-9) SGA, small for gestational age.
(25th-75th percentile) a
Prenatal corticosteroid was
Surfactant replacementc 408 (85.0) 417 (86.9) 404 (84.1) considered if complete (two 12-mg
Early-onset sepsis 13 (2.7) 13 (2.7) 11 (2.3) doses of betamethasone, 24 hours
apart from each other).
Postnatal age at first extubation, 3 (2-6) 4 (2-7) 3 (2-7)
b
median (25th-75th percentile), d CRIB-II, pH, and OI
Before extubation, mean (SD) (OI = [FiO2 × Paw] × 100/PaO2)
OIb 3.5 (4.1) 3.6 (2.2) 3.8 (2.7) were dimensionless variables.
c
pHb 7.37 (0.10) 7.36 (0.35) 7.35 (0.29) Surfactant replacement was always
performed by intubation-
PaCO2, mm Hg 37.9 (10.6) 37.8 (10.4) 38.7 (10.4)
surfactant-extubation technique.

same design as the present trial, we were cautious and
aimed at a difference of 20% in the reduction of IMV dura-
tion. Considering a mean (SD) IMV duration of 10 (8.5) days,
which was derived from the aforementioned studies, α = .05
(with a Bonferroni correction for multiple comparisons of
0.017), and β = 95%, we enrolled 480 neonates in each
group with a 1:1:1 ratio. Thus, a total of at least 1440 neo-
nates had to be enrolled. An interim analysis was previewed
at greater than 50% enrollment (and was realized after the
trial protocol publication), analyzing safety data and quality
indicators.
Outcomes were analyzed on an intention-to-treat basis.
We calculated a risk difference (with 95% CI) for dichoto-
mous outcomes and mean (with 95% CI) or median (25th-
75th percentile, using Hodges-Lehmann) differences for con-
tinuous outcomes between the study groups. We conducted
χ2 tests to compare dichotomous outcomes and parametric
(using 1-way analysis of variance, followed by Sidak post hoc
test if needed) or nonparametric tests (Mann-Whitney test,
followed by Conover-Iman post hoc test if needed) as appro-
priate to compare continuous outcomes. Reintubations over-
time were also analyzed with Kaplan-Meier curves and con-
trasted with a log-rank test. Two-sided P < .05 was considered
to be statistically significant. Analyses were performed with
SPSS, version 16 (IBM).
Results
A total of 1493 neonates underwent randomization. The allo-
cated treatment was interrupted in 53 neonates because their
parents or guardians withdrew their consent for participa-
tion; these patients received routine clinical care, and their trial
data were destroyed.14 As a result, 1440 neonates were ana-
lyzed (Figure). These neonates had a mean (SD) age at birth of
29.4 (1.8) weeks and included 580 girls (40.3%) and 860 boys
(59.7%). The 3 groups (NCPAP, NIPPV, and NHFOV) were bal-
anced in terms of basic characteristics (Table 1). The interim
analysis did not reveal any safety problem. The trial was com-
pleted without any particular adverse event, need for discon-
tinuation, or protocol modification. eTable 1 in Supplement 2
describes the devices used in the trial.
Primary Outcomes
The total duration of IMV was different between the study
groups. Duration of IMV was longer in the NIPPV (mean dif-
ference, 1.2; 95% CI, 0.01-2.3 days; P = .04) and NCPAP (mean
difference, 1.5 days; 95% CI, 0.3-2.7 days; P = .01) groups than
in the NHFOV group, whereas no significant difference was ob-
served between the NIPPV and NCPAP groups (Table 2). The
frequency rates of reintubation and reintubation within 48
hours from extubation were different between the study groups
and significantly higher in the NCPAP group vs the NHFOV
group (risk difference, 12.5%; 95% CI, 7.5%-17.4%; P < .001) and
vs the NIPPV group (risk difference: 8.1%; 95% CI, 2.9%-
13.3%; P = .003), although no difference was observed be-
tween the NIPPV and NHFOV groups (Table 2). These results
were confirmed by Kaplan-Meier analysis, whose curves were
significantly different (eFigure in Supplement 2).
The reasons for reintubation were similar between the
study groups (eTable 2 in Supplement 2). Ventilator-free days
differed between the study groups and were significantly fewer

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 NHFOV vs NCPAP vs NIPPV as Postextubation Support in Preterm Neonates Original Investigation Research

Table 2. Primary Outcome Results

No. (%) NCPAP vs NIPPV NCPAP vs NHFOV NIPPV vs NHFOV

NCPAP group NIPPV group NHFOV group Post hoc Post hoc Post hoc
Outcome (n = 480) (n = 480) (n = 480) Difference P value Difference P value Difference P value
Total duration 7.8 (7.2) 7.3 (9.2) 6.2 (5.7) Mean .75 Mean (95% CI): .01 Mean .04
of IMV, (95% CI): 0.44 1.5 (0.3 to 2.7) (95% CI): 1.2
mean (SD), d (−0.7 to 1.6) (0.01 to 2.3)
Reintubations, % 123 (25.6) 84 (17.5) 63 (13.1) Risk (95% CI): .003 Risk (95% CI): <.001 Risk (95% CI): .07
8.1 (2.9 to 12.5 (7.5 to 4.4 (0.2 to
13.3) 17.4) 8.9)
Reintubations 97 (20.2) 55 (11.4) 43 (8.9) Risk (95% CI): <.001 Risk (95% CI): <.001 Risk (95% CI): .20
within 48 h, % 8.7 (4.1 to 11.2 (6.8 to 2.5 (−1.3 to
13.3) 15.7) 6.4)
Ventilator-free days, 32 (20 to 45) 35 (21 to 52) 34 (17 to 52) Median .01 Median .62 Median .08
median (25th-75th (25th-75th (25th-75th (25th-75th
percentile) percentile): −3 percentile): −2 percentile): 1
(−6 to −1) (−3 to 2) (0 to 5)

Abbreviations: IMV, invasive mechanical ventilation; NCPAP, nasal continuous positive airway pressure; NHFOV, noninvasive high-frequency oscillatory ventilation;
NIPPV, nasal intermittent positive pressure ventilation.

Table 3. Secondary Efficacy Outcomes

No. (%) NCPAP vs NIPPV NCPAP vs NHFOV NIPPV vs NHFOV

NIPPV
NCPAP group group NHFOV group Post hoc Post hoc Post hoc
Outcome (n = 480) (n = 480) (n = 480) Difference P value Difference P value Difference P value
BPD 184 (38.3) 182 (37.9) 163 (34) Risk (95% CI): .89 Risk (95% CI): .16 Risk (95% CI): .20
0.4 (−5.7 to 6.5) 4.3 (−1.7 to 3.9 (−2.1 to 10)
10.4)
Moderate-to-severe 75 (15.6) 66 (13.8) 52 (10.8) Risk (95% CI): .38 Risk (95% CI): .09 Risk (95% CI): .39
BPDa 4.5 (−5.4 to 8.9 (−1.3 to 4.4 (−5.6 to
14.3) 18.7) 14.2)
Postnatal 98 (20.4) 77 (16.0) 63 (13.1) Risk (95% CI): .08 Risk (95% CI): .002 Risk (95% CI): .20
corticosteroidsb 4.4 (−0.5 to 9.2) 7.3 (2.6 to 12) 2.9 (−1.6 to 7.4)
In-hospital mortality 5 (1.0) 4 (0.8) 8 (1.7) Risk (95% CI): .74 Risk (95% CI): .40 Risk (95% CI): .25
0.2 (−1.2 to 1.7) −0.7 (−1 to 2.3) −0.9 (−0.7 to
2.5)
BPD/mortalityc 189 (39.4) 186 (38.8) 171 (35.6) Risk (95% CI): .84 Risk (95% CI): .23 Risk (95% CI): .32
0.6 (−5.5 to 6.8) 3.8 (−2.4 to 9.8) 3.2 (−3.0 to 9.2)
Duration of allocated 12 (6 to 12 (6 to 10 (5 to 18) Median .29 Median .10 Median .01
intervention, median 20) 22) (25th-75th (25th-75th (25th-75th
(25th-75th percentile): −1 percentile): 1 percentile): −1
percentile), dd (−2 to 1) (0 to 2) (−3 to 0)
Duration of 25 (14 to 24 (12 to 22 (11 to 37) Median .78 Median .10 Median .18
supplemental oxygen, 39) 37) (25th-75th (25th-75th (25th-75th
median (25th-75th percentile): 1 percentile): 3 percentile): 2
percentile), d (−2 to 2) (0 to 4) (−1 to 4)
Abbreviations: BPD, bronchopulmonary dysplasia; NCPAP, nasal continuous administration is known to be harmful. Use of postnatal corticosteroids and
positive airway pressure; NHFOV, noninvasive high-frequency oscillatory the diagnosis of BPD were reported among survivors and until hospital
ventilation; NIPPV, nasal intermittent positive pressure ventilation. discharge.
a c
Severity of BPD was classified according to the 2001 definition from the BPD/mortality was the composite end point represented by BPD development
National Institute of Child Health and Human Development. or in-hospital mortality.
b d
Postnatal corticosteroids were given after the study intervention (ie, after Duration of allocated intervention was the duration of treatment with NCPAP,
extubation) and always after the first week of age, as earlier corticosteroid NIPPV, or NHFOV.

in the NCPAP group than in the NIPPV group (median [25th-
75th percentile] difference, −3 [−6 to −1] days; P = .01) (Table 2).
In addition, NHFOV provided better oxygenation after extu-
bation (eTable 3 in Supplement 2).
Secondary Outcomes
Secondary efficacy outcomes did not differ significantly
between the study groups, except for postnatal corticoste-
roids and the duration of study intervention. Postnatal corti-
costeroids were used less in the NHFOV group than in the
NCPAP group (risk difference, 7.3%; 95% CI, 2.6%-12%;
P = .002), whereas the duration of the study intervention
was shorter in the NHFOV group than in the NIPPV group
(median [25th-75th percentile] difference, −1 [−3 to 0] days;
P = .01) (Table 3).
Similarly, the study groups did not differ significantly in
secondary safety outcomes, except for weekly weight gain,
which was higher in neonates who were treated with NHFOV
than those who received NCPAP (mean difference, −0.9 g/d;
95% CI, −1.8 to 0 g/d; P = .04) (Table 4). Secondary extrapul-
monary outcomes were also similar among the 3 groups
(eTable 4 in Supplement 2).

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 Research Original Investigation NHFOV vs NCPAP vs NIPPV as Postextubation Support in Preterm Neonates

Table 4. Secondary Safety Outcomes

Mean (SD) NCPAP vs NIPPV NCPAP vs NHFOV NIPPV vs NHFOV

NHFOV
NCPAP group NIPPV group group Post hoc Post hoc Post hoc
Outcome (n = 480) (n = 480) (n = 480) Differencea P value Differencea P value Differencea P value
Air leaks, 4 (0.8) 9 (1.9) 3 (0.6) Risk (95% CI): .16 Risk (95% CI): 0.2 .70 Risk (95% CI): .08
No. (%)b −1.1 (−0.5 to 2.8) (−1.1 to 1.6) 1.3 (−0.2 to
2.9)
Weekly weight 12 (4) 12 (6) 13 (5) Mean (95% CI): .81 Mean (95% CI): .04 Mean (95% CI): .25
gain, g/d −0.3 (−1.2 to 0.6) −0.9 (−1.8 to 0) −0.6 (−1.5 to
0.3)
Apnea (No./wk) 5 (4) 4 (4) 4 (4) Mean (95% CI): .29 Mean (95% CI): .13 Mean (95% CI): .97
0.5 (−0.2 to 1.2) 0.6 (−0.1 to 1.3) 0.1 (−0.6 to
0.9)
Nasal injury 0 (0-1) 0 0 (0-1) Median .61 Median .40 Median .17
score, median (25th-75th (25th-75th (25th-75th
(25th-75th percentile): 0 percentile): 0 percentile): 0
percentile), dc
Grade III-IV nasal 17 (3.5) 17 (3.5) 23 (4.8) Risk (95% CI): 0 >.99 Risk (95% CI): .33 Risk (95% CI): .33
injury, No. (%) (−2.4 to 2.4) −1.2 (−1.3 to 3.9) −1.2 (−1.3 to
3.9)
PIPP scored 7.5 (1.9) 7.6 (2.0) 7.4 (2.0) Risk (95% CI): .38 Risk (95% CI): 0.1 .63 Risk (95% CI): .19
−0.1 (−0.4 to 0.2) (−0.2 to 0.4) 0.2 (−0.1 to
0.5)
Abbreviations: NCPAP, nasal continuous positive airway pressure; median score and as number of grade III-IV lesions.
NHFOV, noninvasive high-frequency oscillatory ventilation; NIPPV, nasal d
PIPP score was calculated in the first 48 hours from the study intervention.
intermittent positive pressure ventilation; PIPP, Premature Infant Pain Profile. Both nasal skin injury and PIPP score were dimensionless values.
a
All outcomes were considered among survivors and until hospital discharge. Data were not available for 90 infants in the CPAP (continuous positive airway
b
Air leaks were considered if they occurred after the study intervention. pressure) group, 90 infants in the NIPPV group, and 143 infants in the NHFOV
c
group.
Nasal injury was evaluated with a dedicated score21 and reported both as

did not reach statistical significance. These differences in the

Discussion
To our knowledge, this was the first large trial in preterm neo-
nates that compared NCPAP, NIPPV, and NHFOV as respira-
tory support after extubation until NICU discharge without any
change of ventilatory policy. Neonates who were supported
with NHFOV had a slightly shorter duration of IMV than those
supported with NIPPV and NCPAP. Moreover, NHFOV and
NIPPV resulted in lower risk of reintubation compared with
NCPAP, whereas there were significantly more ventilator-
free days with NIPPV than NCPAP.
These results are novel and may help in choosing the re-
spiratory support strategy for preterm neonates after extuba-
tion until their NICU discharge. This area is complex, and
many strategies are possible; therefore, a multigroup study de-
sign was suitable to allow a quicker and more effective
investigation.24 We believe the findings expand the current
knowledge, particularly on NHFOV, which was previously
investigated only in retrospective studies25,26 and small trials;
these past studies suggested the possible benefits of NHFOV,
as also reported in a recent meta-analysis.9
We found that NHFOV had some advantages over NCPAP
and NIPPV in that it reduced the use of invasive respiratory sup-
port as globally evaluated by the primary outcomes. With
NHFOV, IMV duration decreased by approximately 20% com-
pared with NCPAP and by approximately 15% compared with
NIPPV. Consistently, reintubations in NHFOV-treated neo-
nates were significantly less frequent than in neonates who re-
ceived NCPAP. Reintubations and ventilator-free days also
tended to favor NHFOV over NIPPV, although these results
use of invasive support may seem small (approximately 1-1.5
fewer days of IMV, and approximately −12% of reintubations),
but every additional day of IMV27 and each reintubation28 has
been associated with adverse outcomes, although these data
were produced in younger preterm populations.
The critical level of IMV duration that significantly in-
creases the risk of adverse respiratory outcome remains un-
clear given that this threshold may be longer4 than the ben-
efit provided by NHFOV. The less frequent early reintubations
and the better postextubation gas exchange that were ob-
served with NHFOV suggest that NHFOV might reduce extu-
bation failure primarily because of the respiratory disorder
while the reasons for reintubations are similar across the 3
groups. This finding may be explained by the interaction be-
tween worsening respiratory failure requiring reintubation
and some factors, such as lower gestational age and greater
respiratory severity before extubation, that need to be inves-
tigated in subgroup analyses.
Reducing IMV could be helpful in decreasing BPD preva-
lence. Invasive mechanical ventilation is a proinflammatory
trigger that contributes to BPD development,29 whereas rein-
tubation is associated with the occurrence of ventilator-
associated pneumonia, which also increases BPD risk.30 None-
theless, BPD is a complex multifactorial, pathobiological
process and can be diagnosed in preterm infants who have
never been treated with invasive ventilation.31 Thus, we did
not find any difference in BPD prevalence between the 3
groups, but we did find less need for postnatal corticoste-
roids in the NHFOV group. These observations must be inter-
preted cautiously and warrant future explanatory trials or

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 NHFOV vs NCPAP vs NIPPV as Postextubation Support in Preterm Neonates
subgroup analyses.32 Such studies should examine whether
NHFOV is the best choice for neonates with evolving BPD as-
sociated with lung inflammation that is induced or aggra-
vated by IMV. As for other complex syndromes,33 it is un-
likely that one solution would fit all, and NHFOV could be
useful for a more personalized approach for these patients after
adequate training is provided. Together with the reduced
duration of study intervention in the NHFOV group, this is-
sue requires dedicated studies with pharmacoeconomic
analysis to ascertain whether wide implementation of NHFOV
is suitable.
The trial design was based on pathophysiological prin-
ciples to guide respiratory support, and the results may be ex-
plained in the context of the ventilatory strategy. In the NHFOV
group, Paw was started at the optimal level for the postsur-
factant phase.19 We kept a 2- to 3-cm H2O difference in initial
Paw between the study groups, and Paw was further titrated
to provide better alveolar recruitment with NIPPV and NHFOV
than with NCPAP. Other parameters were managed according
to bench and physiological data to optimize carbon dioxide
clearance, which, during NHFOV, seemed to occur not only in
the alveoli.20,34 It was difficult to distinguish between the prop-
erties of the examined ventilation modes and the different
ventilatory settings given that these settings were purposely
decided based on the mechanical properties of the ventila-
tory mode. It would have been difficult to increase the NCPAP
level without any superimposed ventilation because doing so
might theoretically induce gas trapping.11 Previous trials have
compared ventilatory techniques at equal Paw but, unsurpris-
ingly, have not reported any advantage because similar low-
pressure levels provided similar alveolar recruitment.9 This
situation is a main problem as it prevents the full realization
of the potential of NIPPV and NHFOV.35 Conversely, data have
shown that noninvasive respiratory support with high Paw of-
ten prevents reintubation but have suggested that neonates
treated with high NCPAP rather than with a noninvasive ven-
tilation technique often need an alternate mode of noninva-
sive support.36,37 These data support the findings of the pre-
sent trial, but the small outcome differences and similar
maximum Paw between NIPPV and NHFOV groups suggest that
increasing Paw is the crucial point. It remains unclear whether
applying NIPPV with higher pressure is safer and more suit-
able than using NHFOV and how to address the need for syn-
chronization during NIPPV.
We chose the 3 primary outcomes to describe the global
burden of care associated with IMV. Although the interven-
tions in the trial can directly change the need for reintuba-
tion, they may only indirectly affect the total duration of IMV
because this duration may be influenced by several factors.
However, we reduced this influence because the extubation
and reintubation criteria were dictated, and the same inter-
vention was maintained during the trial.14
We did not find significant differences in other second-
ary efficacy outcomes. However, these outcomes included
complex multifactorial end points, such as BPD and mortal-
ity, which may be influenced by many concurrent factors and
for which the trial was likely underpowered. Secondary safety
outcome analysis showed that the 3 techniques were equally
jamapediatrics.com
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Original Investigation Research
safe, and comfort with these modes was similar across the
study groups. This finding is important for NHFOV because it
was the most recent technique and was based on high Paw, and
amplitude could theoretically have resulted in air leaks, na-
sal trauma, or discomfort. Thus, the findings were consistent
with those of a recent cross-sectional study that reported
NHFOV provided good patient comfort, which was not ad-
versely affected by increasing Paw.38 These results were also
consistent with those of previously published smaller trials in-
vestigating the use of NHFOV for shorter times.9
These findings should be compared with those of trials ex-
amining postextubation NHFOV.39-41 In a smaller trial involv-
ing a more mature population, NHFOV did not reduce reintu-
bations, but a pattern of less feeding intolerance was reported.39
In the present trial, NHFOV was not used according to a patho-
physiologically driven strategy; thus, NIPPV and NHFOV were
set at the same Paw, and NHFOV provided only small
amplitudes.39 Chen et al40 found fewer reintubations in a
patient population whose age was similar to the population in
the trial by Seth et al39 but who had mixed severity because
the population also included infants who were recovering from
acute respiratory distress syndrome.40 The benefit of NHFOV
was more evident in smaller and sicker infants.40 In a small
single-center trial with a design and population that were analo-
gous to those in the present trial, Li et al41 reported results that
were similar to our findings. In addition, a meta-analysis of
trials of NHFOV as the primary respiratory support in neo-
nates with respiratory distress syndrome showed fewer intu-
bations compared with NCPAP.42 These observations suggest
that an NHFOV strategy that is based on higher Paw might
reduce IMV, particularly in neonates with younger gesta-
tional age or who are recovering from more severe respira-
tory failure. These results could be different if NHFOV were
applied with other interfaces and pressures or if devices that
did not provide active oscillations were used. These issues
require further specific studies to clarify the best way to
apply NHFOV.
Strengths and Limitations
This study has some strengths. The trial used a large popula-
tion and rigorous design, including physiologically targeted
ventilatory management that tried to mimic, whenever pos-
sible, the high-quality design of pharmacological trials. More-
over, the trial received national public funding43 and was
conducted with advice from a large network of international
experts who received specific training and shared basic clini-
cal practices.
This study also has some limitations. The blinding pro-
cess was imperfect because of the type of intervention. We ad-
dressed this limitation by using prespecified outcome defini-
tions and blinding the assessors, although this solution did not
completely eliminate the problem. We did not provide higher
NCPAP levels because of the risk of gas trapping. Moreover,
European guidelines do not recommend these higher levels,13
and they are not the standard of care in Chinese NICUs. Syn-
chronized NIPPV might have led to better results, but synchro-
nization during noninvasive ventilation is unavailable in most
neonatal ventilators; thus, synchronization remains to be
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 Research Original Investigation NHFOV vs NCPAP vs NIPPV as Postextubation Support in Preterm Neonates

studied in dedicated trials using specific devices. It is un-
known to what extent these results can be generalized to popu-
lations with different genetic backgrounds. This trial should
be considered a pragmatic trial that recruited neonates who
might have been reintubated for several reasons; explana-
tory trials may be conducted in subgroups identified from the
findings of this trial. For instance, we enrolled a population of
very preterm neonates who received relatively uncommon
prenatal corticosteroids. Very small neonates were excluded
from the study because their resuscitation depended on par-
ents’ wishes and resuscitation was not constantly provided in
Chinese NICUs. It remains to be determined whether the re-
sults would be the same at younger gestational age or among
neonates who received more common corticosteroid prophy-
laxis. The former information can be obtained by planned
subgroup analyses of the data set, and the latter will need dedi-
cated trials in different settings.
Conclusions
This randomized clinical trial found that NHFOV, if used
after extubation and until the NICU discharge, slightly re-
duced the duration of IMV in preterm neonates, whereas both
NHFOV and NIPPV had a lower risk of reintubation than NCPAP.
These 3 respiratory support techniques were equally safe.

ARTICLE INFORMATION
Accepted for Publication: January 12, 2022.
Published Online: April 25, 2022.
doi:10.1001/jamapediatrics.2022.0710
Author Affiliations: Children's Hospital of
Chongqing Medical University, Ministry of
Education Key Laboratory of Child Development
and Disorders, Key Laboratory of Pediatrics,
Chongqing, China (Zhu, Shi); First Affiliated
Hospital of Chongqing Medical University,
Chongqing, China (Qi); Affiliated BaYi Children’s
Hospital, People's Liberation Army General
Hospital, Beijing, China (Feng); Division of
Pediatrics and Neonatal Critical Care, Assistance
Publique–Hôpitaux de Paris, Paris-Saclay University
Hospitals, Medical Centre A. Béclère, Paris, France
(De Luca); Physiopathology and Therapeutic
Innovation, Institut National de la Santé et de la
Recherche Médicale U999 Unit, Paris Saclay
University, Paris, France (De Luca).
Author Contributions: Prof Shi had full access to all
of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis. Drs Zhu, Qi, and Feng contributed
equally as co–first authors. Profs Shi and De Luca
contributed equally as co–last authors.
Concept and design: Zhu, Shi, De Luca.
Acquisition, analysis, or interpretation of data:
Zhu, Qi, Feng, Shi.
Drafting of the manuscript: Zhu, Shi, De Luca.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Zhu, Shi.
Obtained funding: Shi.
Administrative, technical, or material support:
Zhu, Shi.
Supervision: Qi, Feng, Shi, De Luca.
Other - instruction on the used technique: De Luca.
Conflict of Interest Disclosures: Prof De Luca
reported receiving grants, personal fees, and
nonfinancial support from Vyaire Medical Inc;
personal fees from Getinge; and personal fees from
Philips outside the submitted work. No other
disclosures were reported.
Funding/Support: The trial was funded by grant
cstc2016shms-ztzx13001 from the Scientific
Research Projects Unit of Chongqing Medical
University.
Role of the Funder/Sponsor: The funder had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Group Information: NASONE Study Group
members and centers are listed in Supplement 3.
Data Sharing Statement: See Supplement 4.
Additional Contributions: We thank the families of
all infants who participated in the study and the
staff members who cared for them.
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