Santos et al. BMC Pediatrics(2024) 24:595
https://doi.org/10.1186/s12887-024-05058-6

BMC Pediatrics

RESEARCH

Open Access“Comparison between high-flow
nasal cannula (HFNC) therapy
and noninvasive ventilation (NIV) in children
with acute respiratory failure by bronchiolitis:a randomized controlled trial”
Ana Carolina Etrusco Zaroni Santos1*, Carolina Marques Caiado1, Alessandra Geisler Daud Lopes1, Gabriela
Cunha de França1, Ana Karolina Antunes Eisen2, Danielle Bruna Leal Oliveira2,3, Orlei Ribeiro de Araujo4 and Werther
Brunow de Carvalho5
Abstract
Background The objective of this study was to compare HFNC therapy to noninvasive ventilation (NIV/BiPAP) in
children with bronchiolitis who developed respiratory failure. We hypothesized that HFNC therapy would not be
inferior to NIV.
Methods This was a noninferiority open-label randomized single-center clinical trial conducted at a tertiary Brazilian
hospital. Children under 2 years of age with no chronic conditions admitted for bronchiolitis that progressed to mild
to moderate respiratory distress (Wood-Downes-Férres score < 8) were randomized to either the HFNC group or NIV(BiPAP) group through sealed envelopes. Vital signs, FiO2, Wood-Downes-Férres score and HFNC/NIV parameters
were recorded up to 96 h after therapy initiation. Children who developed respiratory failure despite receiving
initial therapy were intubated. Crossover was not allowed. The primary outcome analyzed was invasive mechanicalventilation requirement. The secondary outcomes were sedation usage, invasive mechanical ventilation duration, the
PICU LOS, the hospital LOS, and mortality rate.
Results A total of 126 patients were allocated to the NIV group (132 randomized and 6 excluded), and 126 wereallocated to the HFNC group (136 randomized and 10 excluded). The median age was 2.5 (1–6) months in the NIVgroup and 3 (2–7) months in the HFNC group (p = 0,07). RSV was the most common virus isolated in both groups(72% vs. 71.4%, NIV and HFNC, respectively). Thirty-seven patients were intubated in the NIV group and 29 wereintubated in the HFNC group (29% vs. 23%, p = 0.25). According to the Farrington-Manning test, with a noninferiority
margin of 15%, the difference was 6.3% in favor of HFNC therapy (95% confidence interval: -4.5 to 17.1%, p < 0.0001).

*Correspondence:
Ana Carolina Etrusco Zaroni Santos
anazaroni@gmail.com
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Santos et al. BMC Pediatrics(2024) 24:595

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There was no significant difference in the PICU LOS or sedation duration. Sedation requirement, hospital LOS andinvasive mechanical ventilation duration were lower in the HFNC group.
Conclusion HFNC therapy is noninferior to NIV in infants admitted with mild to moderate respiratory distress causedby bronchiolitis that progresses to respiratory failure.
Trial registration numbers U1111-1262-1740; RBR-104z966s. Registered 03/01/2023 (retrospectively registered).
ReBEC: https://ensaiosclinicos.gov.br/rg/RBR-104z966s.
Keywords Respiratory failure, Bronchiolitis, High-flow nasal cannula, Noninvasive ventilation

Introduction
High-flow nasal cannula (HFNC) therapy is an easyto-apply supplemental oxygen therapy that provides aheated and humidified gas mixture through a nonocclusive interface. In addition to enabling the delivery ofa high fraction of inspired oxygen (FiO2), this therapy
provides a flow of oxygen that is greater than the patient’s
peak inspiratory flow, potentially leading to low levels of
positive alveolar opening pressure, decreasing inspiratory
resistance, and reducing respiratory work by flushing thenasopharyngeal dead space [1–5].
HFNC therapy has been increasingly applied in thelast two decades in both pediatric and adult populations, and it is currently a well-established therapy in theliterature for patients who develop respiratory failure.
However, there are still questions about the correct timeto initiate HFNC therapy and how to escalate treatment
in cases of therapy failure. In children, HFNC therapy
was first introduced to treat preterm infants as an alternative to continuous positive airway pressure (CPAP)
therapy. Over the years, the application of HFNC therapy
has been widespread mainly in patients hospitalized forbronchiolitis [6–9].
Acute viral bronchiolitis is the most common lower
respiratory disease and the primary reason for hospitalization among infants. According to a survey carriedout in the United States (US) between 2010 and 2019,
approximately 20% of hospitalized patients required
intensive care, 4.9% required noninvasive mechanicalventilation (NIV), and 3.3% required invasive mechanical ventilation [10]. In a cross-sectional analysis of children admitted for bronchiolitis also performed in the US
from 2000 to 2016, an increase in the hospitalization cost
was observed—from $449 million to $734 million—after
adjustment for inflation [11].
Among the few options for evidence-based supportive care available for patients with bronchiolitis, HFNC
therapy has gained relevance mainly due to its easy application outside the pediatric intensive care unit (PICU),
comfort, low sedation requirements, and tolerability.
Recent studies have demonstrated that HFNC therapy issuperior to low-flow oxygen therapy. However, to date,
few randomized clinical trials evaluating the effectivenessof HFNC therapy versus NIV (CPAP and BiPAP – bilevel

positive airway pressure), especially related to treatment
failure and the need for invasive mechanical ventilation,
have been published. Furthermore, most of these studies
have some methodological limitations, such as the failure
criteria not being well described, the lack of an established HFNC weaning protocol, the use of a small sample, the lack of clinical reassessment scores, the restricted
populations analyzed, the inclusion of a small numberof intubated patients, and the use of a short assessment
period. All these biases could interfere with external validation of the use of HFNC therapy in the pediatric population [12–18].
Therefore, new studies are necessary to compare
HFNC therapy to NIV (CPAP/BiPAP) for bronchiolitis,
especially regarding treatment failure and the need formechanical ventilation [6, 18].
The objective of this study was to compare HFNC
therapy to NIV (BiPAP) in children with bronchiolitis
who experienced mild to moderate respiratory distressand who required noninvasive respiratory support. We
hypothesized that HFNC therapy would not be inferior
to NIV (BiPAP).

Materials and methods
This noninferiority randomized single-center clinical trial
was carried out between February 9, 2021, and May 3,2023, in the emergency department and PICU of Hospital Municipal Infantil Menino Jesus (HMIMJ), São Paulo,
Brazil. This 92-bed tertiary pediatric hospital comprises
a 20-bed PICU with a monthly average admission rate of
approximately 70 patients.
This study was approved by the Institutional Review
Board (IRB) of the hospital (Hospital Municipal Infantil Menino Jesus Research Ethics Committee; approval
number 39509820.0.0000.5639, 11/24/2020; trial registration number: U1111-1262-1740; RBR-104z966s,
03/01/2023). Although the clinical trial was submitted before patient randomization, its registration wasapproved later because some formatting and data adjustments were required. All methods were performed inaccordance with the ethical standards as laid down in
the Declaration of Helsinki and its later amendments orcomparable ethical standards. Written informed consent
was obtained from a parent and/or legal guardian before

Santos et al. BMC Pediatrics(2024) 24:595

the data were collected by the physician responsible forstarting the protocol.
Patients admitted with a diagnosis of mild to moderate acute respiratory distress (Wood-Downes-Férres
score < 8 points) caused by bronchiolitis were randomized
into two groups using sealed envelopes (the HFNC or
NIV groups) [19, 20]. Clinical physician and physiotherapist teams were responsible for identifying potentiallyeligible study participants. Patients who were admitted
to the pediatric ward without respiratory distress but
who later met these inclusion criteria were included in
the study. Randomization could occur at admission or at
any time during the hospital stay after respiratory failure
was diagnosed. Each randomized patient received a kitof printed documents to be filled out: a form with vital
signs, a form with ventilation scores and parameters,
scales for bedside assessment and a consent form. Afterthe protocol was completed, all records were gathered,and the data were transferred to a digital dataset. Eachpatient receiving NIV or HFNC therapy was transferredto the PICU depending on bed availability.
Local training for device usage and protocol application was carried out with physicians and physiotherapists
before and during the research. Training efficacy evaluation was not performed.
The HFNC system used was an Airvo 2 (Fisher &Paykel), and the initial flow was 2 L/kg/min. The NIV
system used was DX 3010/3020 (Dixtal). The initialinspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP) values were definedaccording to the institutional protocol (BiPAP – bilevel
positive air pressure: EPAP 4 to 6 cmH2O, IPAP 8 to 12
cmH2O) and adjustment through clinical evaluation. Frequency of rescue breathing, and asynchronies was notregistered. In both groups, a binasal prong was used. FiO2
was titrated to maintain a peripheral oxygen saturation
between 94 and 99%. All eligible patients who developed
mild to moderate respiratory distress were connected
to a nonrebreathing mask until randomization was performed and the device was properly installed.
The inclusion criteria were children under 2 years ofage admitted for bronchiolitis that progressed to mild
to moderate respiratory distress (WDF score < 8 points)
during hospitalization. Bronchiolitis was clinicallydefined by upper respiratory tract (runny nose, sneezing)
and lower respiratory tract (tachypnea, wheezing, coughing, crackling and use of accessory muscles) symptoms[21]. Blood laboratory investigations were not mandatory
for this trial.
The exclusion criteria were severe respiratory distress(WDF score ≥ 8 points), gestational age less than 35
weeks, bronchopulmonary dysplasia, cyanotic congenital
heart disease or hemodynamic repercussion, liver disease, neuromuscular disease, or tracheostomy. Infants

Page 3 of 12with a positive viral panel result for SARS-CoV-2, those
whose parents refused to participate in this study andthose with missing fulfilled forms were also excluded.
Vital signs, WDF score, peripheral oxygen saturation(SpO2), and FiO2 were recorded at 0 h, 2 h, 6 h, 12 h, 24 h,
48 h, 72 h and 96 h after HFNC therapy or NIV therapy
initiation. The variables assessed included age, weight,
sex, comorbidities, previous respiratory hospitalization, the Pediatric Index of Mortality – version 2 (PIM 2)
score, viral panel results, the need for antibiotics, nasal
septum injury status, sedative usage, HFNC/NIV duration, invasive mechanical ventilation duration, PICU
length of stay (LOS), the hospital LOS, and the mortality
rate [22–24].
The Comfort behavior scale (Comfort-B) and Richmond Agitation-Sedation Scale (RASS) were standardized scales for sedative adjustments. The drugs
administered for this purpose were dexmedetomidine,
ketamine, lorazepam, methadone, and clonidine [25, 26].
The Fischer scale was applied daily to evaluate nasal septum injuries [27].
Early enteral feeding initiation was recommended anddepended on the clinician’s judgment. Oral food (liquid or solid) intake was permitted in the HFNC group,particularly during treatment weaning, and its initiation
was allowed depending on respiratory distress status. For
patients on NIV, an enteral diet was mandatorily provided through nasogastric or orogastric tubes.
Viral panel analysis was carried out through quantitative reverse transcription polymerase chain reaction(RT‒qPCR) in partnership with the Institute of Biomedical Sciences II at the University of São Paulo. The samples
were collected during emergency department or PICU
admission, and the following viruses were detected:
respiratory syncytial virus, human metapneumovirus,
influenza virus (IA and IB), parainfluenza virus 1, 2, 3 and4, seasonal coronaviruses (types OC43, HKU1, NL63 and229E), human adenovirus, human enterovirus, humanrhinovirus, SARS-CoV-2 and human bocavirus.
The criteria for indicating HFNC/NIV therapy failure and the need for mechanical ventilation were signsof severe respiratory distress (WDF score of 8 to 14
points), a respiratory rate > 60 bpm (in children up to 1
year old) or > 40 bpm (in children aged 1 to 2 years), ora heart rate > 160 bpm. For this study, crossover was notallowed, and patients who experienced therapy failure
were intubated. Although the intervention could not bemasked, all the investigators remained unaware of thepartial results. For patients who experienced respiratory
improvement, an HFNC weaning protocol was administered according to the institutional protocol. NIV weaning was carried out according to daily reassessments andclinical judgment.

Santos et al. BMC Pediatrics(2024) 24:595

The primary outcome was the need for invasive
mechanical ventilation. The secondary outcomes analyzed were sedation usage, invasive mechanical ventilation duration, the PICU LOS, the hospital LOS, and themortality rate.
The hospital’s epidemiological data and the reasonsfor hospitalization classified by the International Classification of Diseases (ICD-10 J21 – acute bronchiolitis)
recorded at admission were retrospectively collectedfrom the patients’ electronic medical records. The purpose was to determine the fraction of study participants,
the primary reason for intensive care and the need forinvasive mechanical ventilation. Data on the enteralfeeding duration and antibiotic administration were also
obtained retrospectively.
Statistical analysis

This was an open-label and randomized study. Randomization was carried out using sealed envelopes. The
sample size was calculated based on a pilot study carriedout in Brazil. Considering the success rate, 252 patients(126 in each group) were needed to exclude a differenceof more than 15% with a certainty of 80% in favor of the
CPAP group [28]. To determine noninferiority, the Farrington-Manning test was applied to calculate the difference in success rates with a 95% confidence interval forthe primary outcome. The Farrington-Manning method
for rate differences tests the null hypothesis of H0​: p1​−p2​=δ. The rejection of the null hypothesis allows the conclusion that the rate of success in group one is at least therate of success in group two plus the delta value [29]. We
established a delta value of 15%, which is arbitrary but
has been used in the literature [12]. To compare distributions between groups, the Wilcoxon/Mann‒Whitney
test was used, and the chi‒square test was used to compare frequencies between groups. The cumulative probabilities of “surviving” without the need for intubation
over the time of observation were compared using the log
rank test. To compare repeated measurements, we used
the Friedman test, with post hoc analysis by the Wilcoxon paired test (signed rank), with Bonferroni correction. The magnitude of the effect of HFNC therapy andNIV on vital parameters was assessed using Cohen’s “d”
test (Cohen’s d). The interpretation of Cohen’s d is as follows: small effect (d: 0.2 - <0.5), moderate effect (d = 0.5 <0.8) and large effect (d ≥ 0.8) [30]. The statistical analyses
were performed using R: A language and environment
for statistical computing (R Foundation for StatisticalComputing, Vienna, Austria) [31].
The interrater reliability of the WDF score was notevaluated. The standard method was applied for missing data, which is the analysis of complete cases notusing any replacement or imputation technique [32].
The percentages of missing data for each period were as

Page 4 of 12

follows: 0 h (0), 2 h (0.5%), 6 h (0.4%), 12 h (1.2%), 24 h
(0.9%), 48 h (0.4%), 72 h (0.8%) and 96 h (0). Missing data
occurred as a result of incomplete forms. The CONSORT
guidelines for reporting randomized trials in journals andabstracts were applied for text structuring [33, 34].

Results
A total of 132 patients were randomized to the NIVgroup, and 136 patients were randomized to the HFNC
group. Of these, six patients were excluded from the NIVgroup, and 10 were excluded from the HFNC group,
totaling 126 patients in the NIV group and 126 patientsin the HFNC group. The reasons for exclusion were failure to fully comply with the protocol, a diagnosis of heartdisease with hemodynamic repercussions during hospitalization, external transfer, a lack of written informed
consent, and a positive viral panel result for SARSCoV-2. Figure 1 shows the study flowchart for the period
between February 2021 and May 2023.
During this period, 1007 patients were admitted tothe hospital for bronchiolitis. Of these patients, 649(64%) were transferred to the PICU, and 146 (22%)
required invasive mechanical ventilation. For the analyzed patients, nine (7%) patients in the HFNC group andthree (2%) patients in the NIV group were weaned from
respiratory support in the emergency room and were
not transferred to the PICU. One patient from the NIVgroup and three patients from the HFNC group weretransferred to another hospital after protocol finalization(respiratory failure and invasive mechanical ventilation
requirement). Their collected data were used only for the
primary outcome analysis.
The demographic data and other relevant characteristics are described in Table 1.
Thirty-seven patients in the NIV group were intubated (29%), and 29 patients in the HFNC group wereintubated (23%, p = 0.25). According to the FarringtonManning test, within the noninferiority margin of 15%,the difference was 6.3% in favor of HFNC therapy (95%
confidence interval: -4.5 to 17.1%, p < 0.0001). Most of the
intubations occurred within the first 24 h after starting
NIV or HFNC therapy: 62% in the NIV group and 72%
in the HFNC group. According to the log rank test, thecumulative probabilities of intubation were similar during the observation period (p = 0.33). The device settings
along the time points are shown in Fig. 2.
Both NIV and HFNC therapy promoted a reductionin heart and respiratory rates and, consequently, in the
WDF score. For the consecutive heart rate measurementsin the NIV group, the Friedman p value was < 0.0001. The
most pronounced effect on the reduction in the heart
rate was observed when comparing the 12-h measurement with the measurement at the beginning of therapy:
Cohen’s d was estimated to be -1,1 (95% CI -1.38 to -0.82;

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Fig. 1 Study flowchartlarge effect). The p value obtained by the Wilcoxon paired
test was < 0.0001. In the HFNC group, a greater effect
was also observed when comparing the heart rate at 12-hwith the initial heart rate: Cohen’s d was − 0.86 (95% CI-1.14 to -0.58 - large effect; p < 0.0001).
The reduction in the respiratory rate in the NIV group
was also significant (p < 0.0001). A larger effect was estimated when comparing the 24-h measurement and theinitial measurement. Cohen’s d was − 1.04 (95% CI -1.36
to -0.73 - large effect; p < 0.0001). In the HFNC group,
the most pronounced effect was observed when comparing the 72-h measurement with the initial measurement:
Cohen’s d was − 1.1 (95% CI -1.44 to -0.75 - large effect;p < 0.0001).
The WDF score decreased markedly in the NIV groupduring the first two hours of therapy: Cohen’s d was− 0.84 (95% CI -1.1 to -0.57 – large effect; p < 0.0001).
Comparing the 48-h measurements with the initial measurements, Cohen’s d was − 2.27 (95% CI -2.7 to -1.8 –large effect, p < 0.0001). In the HFNC group, Cohen’s d
was estimated to be -0.72 for the first two hours (-0.99
to – 0.47 – medium effect; p < 0.0001). A larger effect wasobserved when comparing the 72-h and initial measurements (Cohen’s d -2.15, 95% CI -2.6 to -1.74, p < 0.0001).

The pulse oximetry saturation/fraction of inspired oxygen ratio (SpO2/FiO2) increased slowly in both groups.
The Friedman p value was < 0.0001 for all measurements. The effect in the first two hours was negligible for
the NIV and HFNC groups. In the NIV group, a greater
effect was observed when comparing the 72-h measurement and the initial measurement (Cohen’s d 1.7; 95%
CI 1.15–2.2 – large effect, p < 0.0001). In the HFNC
group, the most pronounced effect was also observed
when comparing the initial and 72-hour measurements;
Cohen’s d was estimated to be 1.54 (95% CI 1.17–1.91,
large effect, p < 0.0001). These measurements and effects
are illustrated in Fig. 3.
There were no patients with nasal pressure injuries
in the HFNC group. In the NIV group, 11 patients presented with nasal trauma (Fischer stage 1 or 2).

Discussion
In our study, we analyzed young and eutrophic infants
who were admitted for bronchiolitis, the vast majorityof whom were admitted during their first wheezing episode and had respiratory syncytial virus isolated from aviral panel. This population portrays classic bronchiolitis

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Table 1 Demographic and clinical characteristics
Age (months, IQR)
Weight z score for age (mean, SD)
Female (N, %)Previous wheezing (N, %)Previous respiratory hospitalization (N, %)NIV/HFNC duration (hours, median, IQR)
Initial FiO2 (mean, SD)
Initial WDF (mean, SD)
Initial SpO2 (mean, SD)
Sedation (N, %)Sedation (days, median, IQR)
Nasogastric tube (days, median, IQR)
PICU LOS (days, median, IQR)
Hospital LOS (days, median, IQR)
Invasive mechanical ventilation duration (days, median, IQR)
Antibiotic use (n, %)Ventilator-associated pneumonia
PIM 2 score (mean, SD)
Virus isolated (RT‒qPCR)
Respiratory syncytial virus
Bocavirus
Adenovirus
Seasonal coronavirus
Parainfluenza 3/4
Human metapneumovirus
Rhinovirus/enterovirus

NIV
2.5 (1–6)-0.18 (1.18)
52 (41%)39 (31%)30 (23.8%)
48 (24–78)
40.8 (10.8)
5.9 (0.9)
97.6 (1.9)
121 (96%)
3 (2–4)3 (2–4)5 (3–10)9 (6–14)5 (3.7–7)
62 (49%)1 (2%)
1.8 (1.7)

HFNC
3 (2–7)-0.18 (1.11)
41 (32.5%)
32 (25.3%)
22 (17.4%)
77.5 (46.5–108)
36.2 (10.6)
5.9 (1.1)
97.4 (1.9)
54 (42.8%)
2 (1–4)4 (2–5)5 (4–7)8 (6–10)4 (2.5–4.5)
49 (38%)
1 (3,4%)
1.5 (1.4)

p
0.07
0.95
0.15
0.3
0.2
0.00030.00020.9
0.25< 0.001
0.08
0.012
0.3
0.006
0.02
< 0.001
0.49

91 (72.2%)
4 (3.2%)6 (4.8%)4 (3.2%)7 (5.6%)
5 (4%)
2 (1.6%)

90 (71.4%)
11 (8.7%)9 (7.1%)8 (6.3%)
5 (4%)
4 (3.2%)2 (1.6%)-

SD: standard deviation
IQR: interquartile range 0.25–0.75
RT‒qPCR: quantitative reverse transcription polymerase chain reaction
p values were calculated by chi-square or Wilcoxon tests, as appropriate

without risk factors, such as prematurity and cardiopathies [10, 11, 35].
Although the therapy duration was significantly longer
in the HFNC group [77.5 (46.5–108) versus 48 (24–78)
hours, p = 0,0003], this finding does not seem to haveinfluenced the PICU LOS or hospital LOS. We could notassess if the establishment of a HFNC weaning protocol
directly impacted the longer duration of therapy.
In our study, although the sedation duration was similar between the groups, the percentage of patients who
required pharmacological measures was significantly
greater in the NIV group [121 (96%) versus 54 (42,8%)
patients, p < 0.001]. Moreover, children receiving NIV
had a greater incidence of nasal injury. There are few
studies comparing HFNC therapy and NIV that haveused the need for sedation as an outcome. In a review
published in 2015 by Hutchings et al., despite not finding
an objective difference in patient comfort, nasal injury
was significantly greater in the NIV group. Furthermore,
for parents, HFNC therapy seems to increase the possibility of parent contact and interactions with children
during treatment. In a study evaluating clinical practices

related to HFNC therapy, only 6.5% of Brazilian pediatric intensivists affirmed that they frequently use sedatives
for patients receiving HFNC therapy. Comfort and synchrony play a role in the NIV success rate, especially inthe pediatric population, considering the particularities
in children’s airway anatomy. At our institution, neurally
adjusted ventilatory assistance (NAVA) was not available for this purpose. Furthermore, bronchiolitis, a lower
respiratory tract disease characterized by a mixed patternof restriction and obstruction, adequate air entry, may
be further impaired in nonsedated and asynchronous
patients [9, 36–38].
The enteral feeding duration was longer in the HFNC
group than in the NIV group [3 (2–4) versus 4 (2–5) days,
p = 0,012]. Although both groups demonstrated clinicalimprovement over time (considering vital signs and WDF
score), this assessment was only carried out in the first
96 h of protocol initiation. After this period, we cannot
assume whether the longer time in HFNC therapy may
have impacted the longer time of enteral tube use. In
addition, there were no well-defined protocol for startingor discontinuing enteral feeding.

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Fig. 2 The mean values of the devices used for NIV and HFNC therapy. The p values refer to observed differences between FiO2 utilized in the NIV andHFNC groups at the time points (hours). IPAP: Inspiratory positive airway pressure; EPAP: Expiratory positive airway pressure. FiO2: Fraction of inspired
oxygen

The need for antibiotics was greater in the NIV groupthan in the HFNC group [62 (49%) versus 49 (38%)
patients, p < 0.001]. Although these data alone are notobjective, previous studies have demonstrated that bacterial coinfection and antibiotic therapy use are related
to PICU admission and the need for mechanical ventilation in children with severe bronchiolitis. There are few
publications evaluating the use of antibiotics and clinical outcomes in patients admitted for bronchiolitis who
receive HFNC therapy. In these patients, antibiotic therapy does not seem to increase the need for mechanicalventilation. However, the analyses were heterogeneousand had many limitations. New studies with high-quality
evidence are needed to evaluate this association. Patientson mechanical ventilation are prone to ventilator-associated pneumonia (VAP), one of the most common healthcare-associated infections in the PICU. Nevertheless, in
our results ventilator-associated pneumonia (VAP) does
not appear to be an influencing factor in this higher ATB
requirement since the VAP incidence in both groups was
similar [7, 39–42].
Another interesting finding was the persistently higher
FiO2 demand in the NIV group to maintain an SpO2
between 94 and 99%. In our hospital, the use of nasal
prongs in infants is the standard interface applied. One
possibility for this occurrence is air leak pressure due tothe use of prongs instead of masks, which can lead toalveolar opening impairment. Furthermore, agitation and
NIV asynchrony could contribute to higher FiO2 values.

We cannot assume that lower target SpO2 levels could
influence this difference. Currently, lower SpO2 thresholds are considered safe for some specific populations.
However, for critical bronchiolitis patients who progress
to respiratory failure, a well-established SpO2 thresholdhas not yet been defined [6, 21, 43, 44].
All four clinical markers evaluated (heart rate, respiratory rate, WDF score and SpO2/FiO2) demonstrated significant variations in both groups throughout the period
analyzed. Among these markers, the WDF score showed
the earliest variation (2 h after protocol initiation), followed by the heart rate and respiratory rate. The SpO2/
FiO2 ratio exhibited the slowest variation. The WDF score
was developed in the 1970s to evaluate asthma status andbegan to be applied in cases of bronchiolitis. According to our analysis, WDF score improvement seemed tooccur earlier than did the other variables analyzed. Thismay have been because the isolated analyses of the heartrate, the respiratory rate and SpO2/FiO2 are nonspecificand can suffer some interference from a series of factors,
such as fever, the use of sedatives (such as dexmedetomidine), crying and sepsis [19, 20]. Respiratory failure isclassically classified into hypoxemic (tipe 1) or hypercapnic failure (tipe 2). For this definition, arterial blood gas
sample may be required and could be a challenge, considering children’s anatomy and the risk of respiratory
deterioration in case of agitation during the procedure.
Thence, in pediatric clinical practice, the standardization of non-invasive scores with high predictive value

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Fig. 3 Boxplots showing variations in the heart rate, respiratory rate, WDF score and SpO2/FiO2. The means are represented by dots. The brackets markthe time intervals where the largest effect sizes were observed

Santos et al. BMC Pediatrics(2024) 24:595

for respiratory failure has been encouraged by current
guidelines to make continuous patient assessment moreobjective. There are several scores published in the literature that are applied to this aim. However, few of thesemethods have been widely validated. In a systematic
review that evaluated 32 scales for assessing bronchiolitis
severity, WDF score was among the 6 considered the best
available instrument. For this classification the following criteria were accounted: instrument’s items origin,assessment by the instrument’s items of endorsement frequency, reliability, validity, usability, and responsiveness.
In a recent prospective observational study comparing 9
severity scales for bronchiolitis, WDF was one of themapplied. The authors did not find a significant accuracy
difference between them for access bronchiolitis severity
respiratory status. Furthermore, in our research, we also
pondered the fact that this scale was familiar to some
professionals prior to protocol initiation [7, 45–47].
The PICU LOS was similar between the groups. However, the hospital LOS and duration of mechanical ventilation were shorter in the HFNC group. Some factors
may have contributed to a longer hospital stay in the NIVgroup: absence of a specific weaning protocol, greateruse of sedation and consequently increased risk of withdrawal and delirium syndrome and, although not significant, the mean duration of mechanical ventilation inpatients who failed NIV was slightly higher, which may
have contributed to a longer hospital stay. The degreeof respiratory distress at the beginning of the protocol
was similar between groups and does not appear to haveinfluenced the outcome.
According to our protocol, all patients who received
HFNC therapy or NIV were transferred to the PICU.
Only a small percentage of patients completed the protocol in the emergency room while a PICU bed was
not available. In some centers, HFNC therapy has been
administered in emergency and pediatric wards. Nonetheless, in our study, PICU requirements could not becompared.
Another important question concerns the cost of hospitalization. Since our internal electronic system did notallow the individualization of all expenses per patient,
it was not possible to carry out this analysis between
groups. However, because we observed a shorter hospital LOS, less sedative administration, a lower rate of nasal
injury, and a shorter duration of mechanical ventilationin the HFNC group, we may infer that these findings
could contribute to reducing patient-related costs.
Finally, in our analysis, we were able to conclude that
HFNC therapy is no less effective than NIV in mild or
moderate bronchiolitis. To our knowledge, most of the
published observational studies, clinical trials and metaanalyses of HFNC therapy and NIV (CPAP/BiPAP) havecompared the superiority of one therapy over the other;

Page 9 of 12

the results are divergent or inconclusive, and the studies have several limitations [14–16, 18, 48, 49]. However,
it is worth noting that the nonsignificance in traditional
testing does not support the nondifference conclusion. For this purpose, noninferiority studies and, more
specifically, equivalence trials should be performed.
Nonetheless, to carry out equivalence studies, the necessary sample size is generally large, which can limit andextend the research. In this way, noninferiority trials havegained relevance by contributing to the understandingof comparative analysis. Furthermore, it is important tohighlight that once noninferiority is significantly demonstrated, the secondary outcomes and benefits of HFNC
therapy, such as better tolerability, less sedative usage,and easier handling and application outside the PICU
ward, gain more relevance [50].
In a recent review published about HFNC therapy forbronchiolitis, the authors concluded that more studies comparing HFNC therapy and NIV are necessary.
The Pediatric Acute Lung Injury Consensus Conference(PALICC-2) also recommends further studies to elucidate
the importance of HFNC therapy in the management of
respiratory distress syndrome in children. It is notableto reinforce that our results were found in patients withmild to moderate respiratory distress. Those patients
who presented with severe bronchiolitis and evidence ofacute respiratory distress syndrome (ARDS) could initially benefit from end-expiratory pressure (EPAP) andwere excluded from randomization. Despite that consideration, we assume that our results can contribute to theunderstanding of therapy adjustment in cases of bronchiolitis that progress to respiratory failure [6, 18].
This study has several limitations: it was carried out
in a single center and had a small sample size. It was notpossible to blind patients or researchers. The hospital is
primarily a teaching institution with 24-h resident coverage led by staff in the emergency department and PICU.
The initiation of HFNC/NIV therapy was determined byclinicians, and children who were admitted for severe
respiratory distress were not randomized. Only failure
criteria were established. There was no specific protocol
for NIV weaning, only for HFNC weaning. NIV asynchrony was not evaluated and might have influenced
sedation requirement as well as the respiratory failure
rate. Furthermore, crossover was not allowed, and noother ventilatory therapy support was provided (e.g., NIV
in the case of HFNC therapy failure) before intubation.
Extubation failure was not evaluated. Several risk factors
for intubation and ICU admission (blood gas analysis,
radiological changes, vasoactive drugs, bacterial coinfection, and fluid overload) were not evaluated. In addition,
this research was initiated during the coronavirus disease2019 pandemic, a period in which viral circulation andclinical presentation changed. Therefore, it is not possible

Santos et al. BMC Pediatrics(2024) 24:595

to say thus far whether these findings will be only isolated
points or trends. We cannot assess the cost-effectivenessof both modalities of respiratory support. Usually, HFNC
therapy itself is more expensive than NIV, which may
impair its application, especially in low-income countries[38, 51, 52].
Nevertheless, the population analyzed reflects the
majority of patients treated in clinical practice—infants
under 2 years old admitted to emergency and PICU
departments with no comorbidities and a positive panel
result for respiratory syncytial virus—which makes its
external validation possible. In addition, the rate of therapy failure and need for invasive mechanical ventilation
were similar to those in previous publications. Considering state-of-the-art HFNC therapy for bronchiolitis, ourstudy can clarify its clinical applicability in the pediatricpopulation [48].

Conclusion
HFNC therapy is noninferior to NIV in infants admitted
for bronchiolitis in mild to moderate respiratory distress.
This therapy could also contribute to a shorter durationof mechanical ventilation, a shorter hospital LOS, and areduced need for sedatives.
Abbreviations
BiPAP	Bilevel positive airway pressure
CI	Confidence interval
Comfort-B	Comfort behavior scale
CPAP	Continuous positive airway pressure
EPAP	Expiratory positive airway pressure
FiO2	Fraction of inspired oxygen
HFNC	High-flow nasal cannula
HMIMJ	Hospital Municipal Infantil Menino Jesus
ICD	International classification of diseases
IPAP	Inspiratory positive airway pressure
IRB	Institutional review board
LOS	Length of stayMV	Mechanical ventilation
NAVA	Neurally adjusted ventilatory assistance
NIV	Noninvasive mechanical ventilation
PALICC	Pediatric Acute Lung Injury Consensus Conference
PICU	Pediatric intensive care unit
PIM	Pediatric index of mortality
RASS	Richmond agitation-sedation scale
ROX	Respiratory oxygenation
RT-qPCR	Quantitative reverse transcription polymerase chain reaction
SARS-CoV-2	Severe acute respiratory syndrome coronavirus 2
SpO2	Peripheral oxygen saturation
US	United States
VAP	Ventilator-associated pneumonia
WDF	Wood-Downes-Férres score
Author contributions
ACEZS was the principal and corresponding author and contributed to thedesign, analysis, interpretation of data and drafted the submitted version.
CMC, AGDL, GCF, AKAE, and DBLO contributed to the acquisition data. ORA
contributed to the analysis and interpretation of data. WBC contributed to thedesign, analysis, and interpretation of data. All authors reviewed and approved
the final manuscript.

Page 10 of 12

Funding
Fisher & Paykel provided the materials and equipment. The funders had norole in the study design, data collection and analysis, decision to publish, or
preparation of the manuscript.
Data availability
Santos, ACEZ (Forthcoming 2024). “Comparison between high-flow nasal
cannula (HFNC) therapy and noninvasive ventilation (NIV) in children
with acute respiratory failure by bronchiolitis: Dataset from a randomized
controlled trial” [Dataset]. Dryad. https://doi.org/10.5061/dryad.4xgxd25jh [53]Declarations
Ethics approval and consent to participate
All methods were performed in accordance with the ethical standards as laid
down in the Declaration of Helsinki and its later amendments or comparable
ethical standards. Written informed consent was obtained from a parent and/or legal guardian. This study was approved by the Institutional Review Board(IRB) of the hospital (Hospital Municipal Infantil Menino Jesus Research Ethics
Committee; approval number 39509820.0.0000.5639, 11/24/2020).
Consent for publication
Written informed consent was obtained from a parent and/or legal guardian
before the data were collected by the physician responsible for starting theprotocol.
Competing interests
The authors declare no competing interests.
Author details
1
Pediatric Intensive Care Unit, Hospital Municipal Infantil Menino Jesus,São Paulo, São Paulo, Brazil
2
Microbiology Department, Universidade de São Paulo, São Paulo, SãoPaulo, Brazil
3
Hospital Israelita Albert Einstein, São Paulo, São Paulo, Brazil
4
Pediatric Intensive Care Unit, GRAAC, Universidade Federal de São Paulo,São Paulo, São Paulo, Brazil
5
Pediatric Intensive Care Unit, Instituto da Criança, Universidade de São
Paulo, São Paulo, São Paulo, Brazil
Received: 15 June 2024 / Accepted: 5 September 2024

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53. Santos ACEZ. Forthcoming (2024). Comparison between high-flow nasal cannula (HFNC) therapy and noninvasive ventilation (NIV) in children with acuterespiratory failure by bronchiolitis: Dataset from a randomized controlled trial[Dataset]. Dryad. https://doi.org/10.5061/dryad.4xgxd25jh

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