DOI: 10.5061/dryad.4xgxd25jh
title: Data from a randomized controlled trial: Comparison between high-flow nasal cannula (HFNC) therapy and noninvasive ventilation (NIV) in children with acute respiratory failure by bronchiolitis

description: 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 &lt; 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 mechanical ventilation
 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 were allocated to the HFNC
 group (136 randomized and 10 excluded). The median age was 2.5 (1-6)
 months in the NIV group 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 were intubated 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 &lt; 0.0001). There was no significant
 difference in the PICU LOS or sedation duration. Sedation requirement,
 hospital LOS and invasive 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 caused by
 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.
description: <strong>Materials and methods</strong>
 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 was approved later because some formatting and data
 adjustments were required. 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 before the data were
 collected by the physician responsible for starting the
 protocol. Patients admitted with a diagnosis of mild to
 moderate acute respiratory distress (Wood-Downes-Férres score &lt; 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 potentially
 eligible 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 kit of 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. After the protocol was completed, all records were gathered,
 and the data were transferred to a digital dataset. Each patient receiving
 NIV or HFNC therapy was transferred to 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 initial inspiratory positive airway
 pressure (IPAP) and expiratory positive airway pressure (EPAP) values were
 defined according to the institutional protocol (BiPAP – bilevel positive
 air pressure: EPAP 4 to 6 cmH<sub>2</sub>O, IPAP 8 to 12
 cmH<sub>2</sub>O) and adjustment through clinical evaluation.
 Frequency of rescue breathing, and asynchronies was not registered. In
 both groups, a binasal prong was used. FiO<sub>2</sub> 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 of age admitted for bronchiolitis
 that progressed to mild to moderate respiratory distress (WDF score
 &lt; 8 points) during hospitalization. Bronchiolitis was clinically
 defined 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 ³ 8 points), gestational age less
 than 35 weeks, bronchopulmonary dysplasia, cyanotic congenital heart
 disease or hemodynamic repercussion, liver disease, neuromuscular disease,
 or tracheostomy. Infants with a positive viral panel result for
 SARS-CoV-2, those whose parents refused to participate in this study and
 those with missing fulfilled forms were also excluded.
 Vital signs, WDF score, peripheral oxygen saturation
 (SpO<sub>2</sub>), and FiO<sub>2</sub> 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
 and depended 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 and 4, seasonal
 coronaviruses (types OC43, HKU1, NL63 and 229E), human adenovirus, human
 enterovirus, human rhinovirus, SARS-CoV-2 and human bocavirus.
 The criteria for indicating HFNC/NIV therapy failure and the need
 for mechanical ventilation were signs of severe respiratory distress (WDF
 score of 8 to 14 points), a respiratory rate &gt; 60 bpm (in children
 up to 1 year old) or &gt; 40 bpm (in children aged 1 to 2 years), or a
 heart rate &gt; 160 bpm. For this study, crossover was not allowed,
 and patients who experienced therapy failure were intubated. Although the
 intervention could not be masked, all the investigators remained unaware
 of the partial 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 and clinical judgment. 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 the mortality
 rate. The hospital's epidemiological data and the
 reasons for hospitalization classified by the International Classification
 of Diseases (ICD-10 J21 – acute bronchiolitis) recorded at admission were
 retrospectively collected from the patients’ electronic medical records.
 The purpose was to determine the fraction of study participants, the
 primary reason for intensive care and the need for invasive mechanical
 ventilation. Data on the enteral feeding duration and antibiotic
 administration were also obtained retrospectively.
 <strong>Statistical analysis</strong>
 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 carried out in Brazil. Considering the success rate, 252
 patients (126 in each group) were needed to exclude a difference of 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
 for the primary outcome. The Farrington-Manning method for rate
 differences tests the null hypothesis of <em>H0​:
 p1​−p2​=δ</em>. The rejection of the null hypothesis allows the
 conclusion that the rate of success in group one is at least the rate 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
 and NIV 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 - &lt;0.5), moderate effect (d = 0.5 -
 &lt;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 Statistical Computing, Vienna, Austria).
 [31] The interrater reliability of the WDF score was
 not evaluated. The standard method was applied for missing data, which is
 the analysis of complete cases not using any replacement or imputation
 technique. [32] The percentages of missing data for each period were as
 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 and abstracts were applied for text structuring. [33,
 34]
description: # Data from a randomized controlled trial: Comparison between high-flow
 nasal cannula (HFNC) therapy and noninvasive ventilation (NIV) in children
 with acute respiratory failure by bronchiolitis This dataset contains
 information on each patient randomized to the study. The first row
 describes the variables registered. From the second row onwards, each of
 them represents the variables of a unique patient that include indirect
 data, values ​​found during the period on high-flow or NIV and also during
 hospitalization that were used for statistical analysis between the
 groups. *Column legends:* Plot_ID: identifier for study plot Gn: gender
 (male = 0, female = 1) Ag: age ranges in months (e.g. 7 was replaced with
 6-8) We: weight ranges in kilograms (e.g. 7,5 was replaced with 6-8) PW:
 previous weezing (n = no, y = yes) PRH: previous respiratory
 hospitalization (n = no, y = yes) Em: protocol finalization at emergency
 department (n = no, y = yes) Trn: external transfer after intubation (n =
 no, y = yes) Gr: group randomized (NIV = noninvasive ventilation, HFNC =
 high-flow nasal cannula) VP: viral panel (RSV = respiratory syncytial
 virus, Bo = bocavirus, SC = seasonal coronavirus, Pa = parainfluenza, Ad =
 adenovirus, Me = metapneumovirus, RE = rhino/enterovirus, NA = sample not
 available) It: intubation TD: HFNC/NIV duration in hours \_0 (e.g. HR_0) =
 heart rate at protocol initiation \_2 (e.g. HR_2) = heart rate after 2h of
 protocol initiation \_6 (e.g. HR_6) = heart rate after 6h of protocol
 initiation \_12 (e.g. HR_12) = heart rate after 12h of protocol initiation
 \_24 (e.g. HR_24) = heart rate after 24h of protocol initiation \_48 (e.g.
 HR_48) = heart rate after 48h of protocol initiation \_72 (e.g. HR_72) =
 heart rate after 72h of protocol initiation \_96 (e.g. HR_96) = heart rate
 after 96h of protocol initiation HR: heart rate RR: respiratory rate SpO2:
 peripheral oxygen saturation WD: Wood-Downes-Férres score FiO2: fraction
 of inspired oxygen L/min: liters per minute (HFNC) IPAP: inspiratory
 positive airway pressure (NIV) EPAP: expiratory positive airway pressure
 (NIV) SDu: sedation duration (in days) ETu: enteral tube duration (in
 days) NPI: nasal pressure injury (n = no, y = yes) PLOS: PICU length of
 stay ranges in days (e.g. 7 was replaced with 6-8) HLOS: hospital length
 of stay ranges in days (e.g. 7 was replaced with 6-8) MV: mechanical
 ventilation duration (in days) ATB: antibiotic requirement (n = no, y =
 yes) PIM: Pediatric Index of Mortality De: death (n = no, y = yes) pf:
 protocol finalized md: missing data nc: not calculated negative: viral
 panel with no virus identified After data curation, some adjustments were
 done to facilitate dataset comprehension and to respect data sharing for
 human subjects: 1\) Blank spaces have been eliminated 2\) The
 identification of each column has been adjusted according to the standards
 and described in detail in the README 3\) In the viral panel column = the
 "+" symbol has been eliminated and the results have been
 separated by commas 4\) For protocols that have already been finalized,
 the letter "x" has been replaced by "pf" to facilitate
 understanding 5\) Column “Age”, "We", PLOS and HLOS: the
 specific age (in months), weight (in kilograms), PICU length of stay (in
 days) and hospital length of stay (in days) were replaced with the
 respectively ranges (e.g. 6 was replaced with 0-5) 6\) For gender, male
 (“m”) and female (“f”) were replaced by 0 (male) and 1 (female). 7\) Empty
 cell was filled with "nc" and the number "10" was
 transferred to the appropriate column Z 8\) "sr" was has been
 replaced by "md" (missing data)