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
Data files
Oct 09, 2024 version files 286.12 KB
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README.md
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repository_HFNC_x_NIV.xlsx
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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 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 < 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.
README: 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)
Methods
Materials and methods
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 < 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 cmH2O, IPAP 8 to 12 cmH2O) and adjustment through clinical evaluation. Frequency of rescue breathing, and asynchronies was not registered. 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 of age admitted for bronchiolitis that progressed to mild to moderate respiratory distress (WDF score < 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 (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 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 > 60 bpm (in children up to 1 year old) or > 40 bpm (in children aged 1 to 2 years), or a heart rate > 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.
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 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 H0: p1−p2=δ. 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 - <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 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]