Key Points
Question
Does the early use of nasal high-flow oxygen therapy in children aged 1 to 4 years with acute hypoxemic respiratory failure reduce the length of hospital stay compared with standard oxygen therapy?
Findings
In this randomized clinical trial that included 1567 children with acute hypoxemic respiratory failure, use of nasal high-flow oxygen therapy resulted in a median hospital stay of 1.77 days compared with 1.50 days in the standard oxygen therapy group, a difference that was statistically significant.
Meaning
Early use of nasal high-flow oxygen therapy in children aged 1 to 4 years with acute hypoxemic respiratory failure did not reduce the length of hospital stay compared with standard oxygen therapy.
Abstract
Importance
Nasal high-flow oxygen therapy in infants with bronchiolitis and hypoxia has been shown to reduce the requirement to escalate care. The efficacy of high-flow oxygen therapy in children aged 1 to 4 years with acute hypoxemic respiratory failure without bronchiolitis is unknown.
Objective
To determine the effect of early high-flow oxygen therapy vs standard oxygen therapy in children with acute hypoxemic respiratory failure.
Design, Setting, and Participants
A multicenter, randomized clinical trial was conducted at 14 metropolitan and tertiary hospitals in Australia and New Zealand, including 1567 children aged 1 to 4 years (randomized between December 18, 2017, and March 18, 2020) requiring hospital admission for acute hypoxemic respiratory failure. The last participant follow-up was completed on March 22, 2020.
Interventions
Enrolled children were randomly allocated 1:1 to high-flow oxygen therapy (n = 753) or standard oxygen therapy (n = 764). The type of oxygen therapy could not be masked, but the investigators remained blinded until the outcome data were locked.
Main Outcomes and Measures
The primary outcome was length of hospital stay with the hypothesis that high-flow oxygen therapy reduces length of stay. There were 9 secondary outcomes, including length of oxygen therapy and admission to the intensive care unit. Children were analyzed according to their randomization group.
Results
Of the 1567 children who were randomized, 1517 (97%) were included in the primary analysis (median age, 1.9 years [IQR, 1.4-3.0 years]; 732 [46.7%] were female) and all children completed the trial. The length of hospital stay was significantly longer in the high-flow oxygen group with a median of 1.77 days (IQR, 1.03-2.80 days) vs 1.50 days (IQR, 0.85-2.44 days) in the standard oxygen group (adjusted hazard ratio, 0.83 [95% CI, 0.75-0.92]; P < .001). Of the 9 prespecified secondary outcomes, 4 showed no significant difference. The median length of oxygen therapy was 1.07 days (IQR, 0.50-2.06 days) in the high-flow oxygen group vs 0.75 days (IQR, 0.35-1.61 days) in the standard oxygen therapy group (adjusted hazard ratio, 0.78 [95% CI, 0.70-0.86]). In the high-flow oxygen group, there were 94 admissions (12.5%) to the intensive care unit compared with 53 admissions (6.9%) in the standard oxygen group (adjusted odds ratio, 1.93 [95% CI, 1.35-2.75]). There was only 1 death and it occurred in the high-flow oxygen group.
Conclusions and Relevance
Nasal high-flow oxygen used as the initial primary therapy in children aged 1 to 4 years with acute hypoxemic respiratory failure did not significantly reduce the length of hospital stay compared with standard oxygen therapy.
Trial Registration
anzctr.org.au Identifier: ACTRN12618000210279
This randomized clinical trial compares the effect of early high-flow oxygen therapy vs standard oxygen therapy on length of hospital stay in children with acute hypoxemic respiratory failure.
Introduction
Respiratory illnesses are the most frequent reason for nonelective hospital admissions in children younger than 5 years of age, with a high global health burden.1,2,3 Acute hypoxemic respiratory failure is the common end point for many underlying specific diagnoses such as bronchiolitis, asthma, and pneumonia.4 In Australia and New Zealand in 2018, 38% of nonelective admissions to the intensive care unit (ICU) for children were due to acute hypoxemic respiratory failure.5 Although mortality due to acute hypoxemic respiratory failure improved in high-income countries, mortality remained between 13% in 2011 and 20% in 2017 in underresourced settings.6,7
There is an emerging trend to support respiration with methods other than standard oxygen therapy, particularly initially during the course of hospitalization with the aim of reducing the work of breathing and to potentially prevent progression of disease.8,9 Nasal high-flow oxygen therapy has evolved as a potential alternative to noninvasive ventilation.10,11 High-flow oxygen therapy can be used early in the disease process outside the ICU and requires little cooperation of the child.
A study performed between 2013 and 2016 in infants with hypoxia and bronchiolitis who were younger than 1 year of age showed that high-flow oxygen therapy demonstrated a lower rate for escalation of care compared with standard oxygen therapy, but there was no statistically significant difference in ICU admissions or length of hospital stay.12 Similarly, a pilot study conducted in 2016 and 2017 demonstrated that children and adolescents aged 0 to 16 years with acute hypoxemic respiratory failure managed with high-flow oxygen therapy had a lower rate of escalation of care compared with those receiving standard oxygen therapy, but there was no statistically significant difference in ICU admissions or length of hospital stay.13
Based on an absence of definitive evidence on the efficacy of high-flow oxygen therapy in children with hypoxemia without bronchiolitis, the Paediatric Acute Respiratory Studies 2 (PARIS 2) multicenter, randomized clinical trial was conducted to test the hypothesis that use of high-flow oxygen therapy in children with acute hypoxemic respiratory failure would reduce the length of hospital stay compared with standard oxygen therapy.
Methods
Study Design and Oversight
The PARIS 2 trial was an investigator-initiated randomized clinical trial to evaluate the role of high-flow oxygen therapy compared with standard oxygen therapy at 14 metropolitan and tertiary hospitals in Australia and New Zealand. The trial protocol was approved by the ethics committee at each hospital. The trial was overseen by a steering committee and an independent data and safety monitoring board. The trial protocol was published14 before enrollment was completed and appears in Supplement 1. The statistical analysis plan was uploaded on GitHub prior to completion of enrollment and appears in Supplement 2.
Participants
Children aged 1 to 4 years with acute hypoxemic respiratory failure were eligible if they presented to the emergency department and were subsequently admitted to an inpatient unit. Children were included in the trial if they fulfilled all 4 inclusion criteria: (1) were experiencing increased work in breathing due to acute respiratory disease, (2) had an ongoing oxygen requirement to maintain a prespecified oxygen saturation level, (3) had an increased respiratory rate of 35/min or higher, and (4) required admission to the hospital.
The majority of hospitals had an oxygen saturation as measured by pulse oximetry (Spo2) threshold set at 92% or greater; 1 hospital had a lower Spo2 threshold set at 90% or greater. Diagnoses leading to acute hypoxemic respiratory failure included pneumonia, pneumonitis, acute lower respiratory tract infection, reactive airway disease, and bronchiolitis (in children >12 months of age). Patients were classified into 2 groups using a pragmatic point-of-care definition: by presence of audible wheeze on auscultation (classified as obstructive airway disease) or by absence of wheeze (classified as nonobstructive airway disease).
Children with craniofacial abnormalities, upper airway obstruction, cyanotic heart disease, and those who required immediate higher-level care in the ICU or required noninvasive or invasive mechanical ventilation were excluded (the full list of exclusions appears in Supplement 1). As required by the Australian and New Zealand ethics committees, race and ethnicity were collected for each participant based on the patient registration form at admission to the hospital, generally based on fixed categories determined by the hospital. Written informed consent was obtained from all parents or guardians using either a prospective process or a retrospective deferred process (details appear in Supplement 1).
Randomization and Blinding
Children requiring hospital admission for acute hypoxemic respiratory failure were randomly allocated 1:1 to high-flow oxygen therapy or standard oxygen therapy (Figure 1). An online computer-generated randomization process with a sequence block size of 10 was used with stratification for each participating center and classification by presence of obstructive or nonobstructive disease. There was 1 center that used opaque and sealed envelopes.
Figure 1. Participant Flow Through the PARIS 2 Trial.
PARIS 2 indicates Paediatric Acute Respiratory Studies 2.
aThere were 4: (1) were experiencing increased work in breathing due to acute respiratory disease, (2) had an ongoing oxygen requirement to maintain a prespecified oxygen saturation level, (3) had an increased respiratory rate of 35/min or higher, and (4) required admission to the hospital.
bEven though consent was withdrawn, the data for this child remained in the study and analysis.
Blinding of the assigned treatment was not possible, given the visually obvious differences between the interventions. All investigators remained blinded and unaware of the trial outcome until the recruitment of all patients was completed and the outcome data were locked.
Trial Interventions
Prior to enrollment, children were initially treated with the hospital’s standard emergency department management for acute hypoxemic respiratory failure. This included burst-inhalation bronchodilator therapy for reactive airways, fluid bolus, and other medications. A child was eligible for enrollment if acute hypoxemic respiratory failure (Spo2 <90% or Spo2 <92% in room air) persisted, and a decision was made to admit the patient to the hospital.
The high-flow oxygen group received therapy using the AIRVO-2 high-flow system (Fisher & Paykel Healthcare) with nasal cannulas (OptiFlow Junior /2/2+[OJR41x/OJR520]). The applied flows were 2 L/kg/min for a body weight 0 kg to 12 kg, 30 L/min for 13 kg to 15 kg, 35 L/min for 16 kg to 30 kg, and 40 L/min for 31 kg to 50 kg.
The fraction of inspired oxygen (Fio2) for high-flow oxygen therapy was titrated to obtain an Spo2 in the range of 92% to 98% or an Spo2 in the range of 90% to 98% (for hospitals with lower saturation targets; additional information appears in eTable 1 in Supplement 3). During bronchodilator administration, high-flow oxygen therapy was stopped and standard oxygen therapy was provided.15 The flows remained unchanged until cessation of high-flow oxygen (no weaning of flows). Weaning of Fio2 to room air was permitted once the child was stable (as determined by the treating clinical team) to provide the lowest oxygen percentage to maintain an Spo2 of 90% or greater or an Spo2 of 92% or greater. High-flow oxygen therapy was stopped if Fio2 was equal to 0.21 and oxygen levels were in the expected range. Length of therapy in the high-flow oxygen group was defined as the time until high-flow oxygen therapy was ceased.
The standard oxygen group was placed on oxygen using subnasal cannula with flows up to 2 L/min to maintain an Spo2 of 90% to 98% or using a Hudson face mask (maximum of 8 L/min) or to maintain an Spo2 of 92% to 98%. Weaning of oxygen was permitted once the child was stable to provide the lowest oxygen percentage to maintain an Spo2 of 90% or greater or an Spo2 of 92% or greater.
Use of the alternative oxygen therapy from that assigned was permitted on clinical grounds of intolerance or the need to escalate therapy (decision made by the clinical team). Escalation of care was recommended if the oxygen requirement in the high-flow therapy group exceeded an Fio2 of 0.40 or 0.50 or the oxygen requirement in the standard oxygen group exceeded 2 L/min by nasal prong to maintain an Spo2 of 90% or greater or exceeded 8 L/min by face mask to maintain an Spo2 of 92% or greater. Tolerance of therapy was assessed using an unmarked 100-mm visual analog scale with both the parents and nursing staff recording the intensity of patient discomfort (range, no discomfort to maximal discomfort) at 2 separate intervals: at 1 hour and between 4 hours and 48 hours after starting the intervention.
Outcomes
The primary outcome was length of hospital stay (defined as the time from randomization to the time of hospital discharge or the time of death). There were 9 secondary outcomes, including length of oxygen therapy after randomization, the total length of hospital stay since presentation to the emergency department, the proportion of children receiving a change in oxygen therapy in general ward settings, the proportion of children requiring ICU admission or transfer to a hospital with pediatric ICU facilities, the proportion of children requiring care escalation to noninvasive or invasive ventilation, and adverse events. Further secondary outcomes were collected covering tolerance of the intervention with the visual analog scale and the clinical triggers that resulted in a therapy change.
A serious adverse event was defined as any event that was fatal, life-threatening, permanently disabling, incapacitating, or resulted in a prolonged hospital stay. We plan to report the secondary outcome of health care costs in an economic evaluation.
Sample Size Calculation
The primary hypothesis was that high-flow oxygen therapy reduces the length of hospital stay by 0.4 days. Because there is a relatively short median length of hospital stay for acute hypoxemic respiratory failure (2 days) in children,13 a mean difference of 9.6 hours (SD, 0.4 days) was chosen because it is both clinically meaningful to children and their families and it is meaningful to the health care system. Accordingly, a sample size of 1209 children was required to achieve a 2-tailed significance level of 5% and a power of 90%, assuming a median length of stay of 2.0 days and 1.6 days, and survival analysis as the primary method of analysis. To allow up to 20% nonadherence, 1512 children were required.
Statistical Analysis
The statistical analysis plan was reported and the full preliminary Stata analysis code (StataCorp) was uploaded on GitHub before completion of enrollment (also appears in Supplement 2). Patients were analyzed according to their randomization group.
The between-group difference with respect to the primary outcome measure (length of hospital stay) was assessed using a Cox proportional hazards model (the proportionality assumption was inspected visually using Kaplan-Meier plots and a log-log plot without clear evidence of divergence), and visually presented using a Kaplan-Meier plot. Both unadjusted and adjusted models were constructed; both models incorporated the treatment group as a fixed effect, with the adjusted model additionally including a stratification variable (obstructive vs nonobstructive airway disease) as a fixed effect and site as a random effect (ie, using a shared frailty model).
In addition, quantile regression with treatment group as a fixed effect was used to calculate the between-group difference and is presented alongside the 95% CIs. The adjusted model was used for the primary analysis. The hazard ratios (HRs) and 95% CIs are presented as an estimate of treatment effect and P values are reported for the adjusted model. Multiple imputation was preplanned for the primary outcome in the case of missing data; however, imputation was not done because there were no missing data related to hospital length of stay.
The secondary outcomes were analyzed using logistic regression (binary outcomes), linear regression (continuous normally distributed outcomes), and Cox regression (time-to-event outcomes). Unadjusted and adjusted effect estimates (site as a random effect and the stratification variable as a fixed effect) and the associated 95% CIs are provided. Because of the potential for type I error due to multiple comparisons, the findings for the analyses of the secondary outcomes should be interpreted as exploratory.
Preplanned subgroup analyses were undertaken to determine if the subgroups responded differently for children by presence vs absence of wheeze at hospital admission, presence vs absence of an obstructive airway disease diagnosis at hospital discharge, and by age of 1 year, 2 years, 3 years, and 4 years. Subgroup × treatment group interaction effects are reported for these subgroup analyses.
In addition, 2 preplanned sensitivity analyses addressing potentially subjective outcomes were undertaken. The outcomes investigated were: (1) the composite outcome of ICU admission or high-dependency care with presence of 3 or more of the aforementioned care escalation criteria present; and (2) the composite outcome of transfer to a tertiary hospital with presence of 3 or more of the care escalation criteria present.
A per-protocol analysis also was undertaken for the patients who remained on the initially allocated oxygen therapy (additional information appears in Supplement 2).
Statistical significance for the primary outcome was indicated by P = .05 and was determined with use of a 2-sided hypothesis test. No correction for multiple comparisons was applied in the evaluation of the secondary outcomes or for any of the other outcomes.
Results
Trial Sites and Participants
From December 18, 2017, to March 18, 2020, there were 3030 children who were screened and were eligible for the trial at the 14 participating emergency departments, of whom 1348 were not approached and 175 parents did not provide consent (eTable 1 in Supplement 3). A total of 1567 children (51% of eligible patients) were enrolled. Deferred consent after randomization was not provided by 29 parents in the high-flow oxygen group and 21 parents in the standard oxygen group, which left 753 children in the high-flow oxygen group and 764 in the standard oxygen group (Figure 1 and eFigure 1 in Supplement 3). The groups had similar baseline characteristics (Table 1). None of the children were lost to follow-up for assessment of the primary outcome. The last participant follow-up was completed on March 22, 2020.
Table 1. Characteristics of the Children, Their Families, and the Hospitals Involved in the PARIS 2 Trial.
| Characteristic | No. (%)a | |
|---|---|---|
| High-flow oxygen (n = 753) | Standard oxygen (n = 764) | |
| Age at randomization, median (IQR), y | 1.9 (1.4-3.0) | 1.9 (1.4-2.9) |
| Weight, median (IQR), kg | 12.7 (11.0-14.9) | 12.5 (10.9-14.9) |
| Sex | ||
| Female | 378 (50.2) | 354 (46.3) |
| Male | 375 (49.8) | 410 (53.7) |
| Race and ethnicityb | ||
| Aboriginal or Torres Strait Islander | 18 (2.4) | 21 (2.8) |
| Asian | 48 (6.4) | 47 (6.2) |
| Māori | 43 (5.7) | 43 (5.6) |
| Otherc | 72 (9.6) | 67 (8.8) |
| Pacific Islander | 44 (5.8) | 44 (5.8) |
| White | 249 (33.1) | 258 (33.8) |
| Unknownd | 279 (37.1) | 284 (37.2) |
| Medical history | ||
| Premature birth, No./total (%) | 121/718 (16.9) | 135/721 (18.7) |
| Neonatal respiratory support, No./total (%) | 104/699 (14.9) | 117/702 (16.7) |
| Noninvasive ventilation when the patient received neonatal respiratory support | 80 (10.6) | 92 (12.0) |
| Invasive ventilation when the patient received neonatal respiratory support | 34 (4.5) | 30 (3.9) |
| High-flow oxygen therapy when the patient received neonatal respiratory support | 25 (3.3) | 25 (3.3) |
| Hospital admission for respiratory disease | 410 (54.7) | 416 (54.8) |
| Intensive care unit admission for respiratory support | 93 (12.4) | 82 (10.8) |
| High-flow oxygen therapy during a prior hospital admission | 77 (10.3) | 72 (9.5) |
| Noninvasive ventilation during a prior hospital admission | 26 (3.5) | 19 (2.5) |
| Invasive ventilation during a prior hospital admission | 14 (1.9) | 14 (1.9) |
| Extracorporeal membrane oxygenation | 0 | 2 (2.4) |
| Chronic lung disease | 36 (4.8) | 29 (3.8) |
| Congenital heart disease | 11 (1.5) | 15 (2.0) |
| Wheeze | 482 (64.9) | 482 (63.1) |
| Family history of asthma, No./total (%) | 451/688 (65.6) | 417/688 (60.6) |
| Family history of allergy, No./total (%) | 288/649 (44.4) | 263/641 (41.0) |
| Viral testing and data collected at randomization | ||
| Attend childcare | 401 (53.3) | 396 (51.8) |
| Viral testing performede | 358 (47.5) | 364 (47.6) |
| No virus detected on nasopharyngeal aspirate | 133 (17.7) | 132 (17.3) |
| Had respiratory syncytial virus | 115 (15.3) | 109 (14.3) |
| Had >2 viruses | 42 (5.6) | 51 (6.7) |
| Had metapneumovirus | 33 (4.4) | 30 (3.9) |
| Had adenovirus | 21 (2.8) | 27 (3.5) |
| Had influenza | 22 (2.9) | 14 (1.8) |
| Stratification variable | ||
| Obstructive airway disease (wheeze present)f | 531 (70.5) | 535 (70.0) |
| Nonobstructive airway disease (wheeze absent) | 222 (29.5) | 229 (30.0) |
| Clinical diagnosis group | ||
| Asthma or reactive airways disease | 236 (31.3) | 255 (33.4) |
| Viral-induced wheeze | 177 (23.5) | 177 (23.2) |
| Pneumonia (bacterial or viral) | 108 (14.3) | 103 (13.5) |
| Pneumonitis | 95 (12.6) | 83 (10.9) |
| Bronchiolitis | 70 (9.3) | 72 (9.4) |
| Acute lower respiratory tract infectiong | 50 (6.6) | 51 (6.7) |
| Other nonobstructive airway disease | 3 (0.4) | 5 (0.7) |
| Acute respiratory distress syndromeh | 3 (0.4) | 2 (0.3) |
| Other obstructive airway disease | 2 (0.3) | 1 (0.1) |
| Aspiration | 1 (0.1) | 0 |
| Bronchiectasis | 0 | 0 |
| Other diagnosis group | 8 (1.1) | 15 (19.6) |
| Vital signs before enrollment | ||
| Heart rate, mean (SD), /min | 152 (21) | 152 (21) |
| Respiratory rate, mean (SD), /min | 48 (11) | 46 (10) |
| Spo2, median (IQR), % | 88 (86-89) | 88 (86-89) |
| Patients with an Spo2 <90% | 589 (78.2) | 586 (76.7) |
| Time from presentation to randomization, median (IQR), h | 2.88 (1.44-5.76) | 3.12 (1.44-5.52) |
| Time from onset of illness to presentation, median (IQR), h | 14.4 (7.2-28.8) | 14.4 (7.2-28.8) |
| Hospital characteristics | ||
| Had onsite intensive care unit | 667 (88.6) | 674 (88.2) |
| Location | ||
| Australia | 623 (82.7) | 632 (82.7) |
| New Zealand | 130 (17.3) | 132 (17.3) |
Abbreviations: PARIS 2, Paediatric Acute Respiratory Studies 2; Spo2, oxygen saturation as measured by pulse oximetry.
Unless otherwise indicated.
Reported by parents and recorded in the medical record.
African, Indian, and Japanese.
None recorded in the medical record.
Patients may have had 2 or more viruses that were detected.
Defined with the presence of a clinically audible wheeze on auscultation.
Diagnosed based on clinical suspicion without an x-ray or pathology measures.
Defined by the Australian and New Zealand Paediatric Intensive Care registry.5
Primary Outcome
The median length of hospital stay after randomization was significantly longer at 1.77 days (IQR, 1.03-2.80 days) in the high-flow oxygen group compared with 1.50 days (IQR, 0.85-2.44 days) in the standard oxygen group (adjusted HR, 0.83 [95% CI, 0.75-0.92]; P < .001) (Table 2, Figure 2, and eFigure 2 in Supplement 3). There was no significant difference in the effect in those with the presence vs absence of wheeze or by age groups (Table 2).
Table 2. Primary Outcome in All Patients and by Patient Subgroups.
| Median (IQR), d | Estimate of difference (95% CI) |
Unadjusted HR (95% CI) | Adjusted HR (95% CI) | P value | ||
|---|---|---|---|---|---|---|
| High-flow oxygen | Standard oxygen | |||||
| Primary outcome: length of hospital stay | ||||||
| All patients for time since randomization | (n = 753) 1.77 (1.03 to 2.80) |
(n = 764) 1.50 (0.85 to 2.44) |
0.27 (0.13 to 0.41) | 0.85 (0.77 to 0.94) | 0.83 (0.75 to 0.92) | <.001a |
| By wheeze | ||||||
| Present (n = 1066)b | 1.62 (0.92 to 2.58) | 1.43 (0.82 to 2.12) | 0.19 (0.03 to 0.34) | 0.86 (0.77 to 0.97) | 0.85 (0.75 to 0.96) | .71c |
| Absent (n = 451) | 2.20 (1.31 to 3.47) | 1.86 (0.93 to 2.97) | 0.340 (−0.003 to 0.690) | 0.82 (0.68 to 0.98) | 0.81 (0.67 to 0.98) | |
| By obstructive diseased | ||||||
| Present (n = 958)b | 1.53 (0.90 to 2.34) | 1.28 (0.77 to 2.02) | 0.24 (0.08 to 0.40) | 0.90 (0.80 to 1.03) | 0.87 (0.76 to 0.99) | .38c |
| Absent (n = 559) | 2.31 (1.29 to 3.79) | 1.93 (1.28 to 2.95) | 0.37 (0.03 to 0.70) | 0.82 (0.70 to 0.97) | 0.81 (0.68 to 0.96) | |
| By age at randomization, median (IQR)e | ||||||
| 1 y (n = 777)b | 1.87 (1.12 to 2.80) | 1.53 (0.95 to 2.61) | 0.33 (0.14 to 0.53) | 0.90 (0.78 to 1.04) | 0.84 (0.72 to 0.97) | .08f |
| 2 y (n = 372) | 1.62 (0.82 to 2.82) | 1.45 (0.73 to 2.30) | 0.17 (−0.15 to 0.48) | 0.90 (0.74 to 1.11) | 0.90 (0.73 to 1.11) | |
| 3 y (n = 189) | 1.74 (1.21 to 2.77) | 1.60 (0.77 to 2.30) | 0.15 (−0.26 to 0.56) | 0.79 (0.60 to 1.06) | 0.84 (0.62 to 1.14) | |
| 4 y (n = 149) | 1.47 (1.11 to 2.47) | 1.49 (0.68 to 2.25) | −0.009 (−0.490 to 0.470) | 0.56 (0.40 to 0.79) | 0.60 (0.42 to 0.85) | |
Abbreviation: HR, hazard ratio.
Adjusted for presence or absence of obstructive airway disease at randomization and study site.
Sample sizes larger than original group sizes because patients could switch treatment and receive high-flow oxygen or standard oxygen.
Associated with an interaction term and derived from an adjusted model.
Defined as a discharge diagnosis of reactive airway disease, asthma, or bronchiolitis.
Restricted to children aged 1 to 4 years (n = 1487).
Derived from the Wald test and an adjusted model.
Figure 2. Time to Discharge From Hospital Since Randomization.
The median length of the hospital stay and the median length of observation time was 1.77 days (IQR, 1.03-2.80 days) for the high-flow oxygen group and 1.50 days (IQR, 0.85-2.44 days) for the standard oxygen group in the intention-to-treat analysis.
Secondary Outcomes
Of the 9 prespecified secondary outcomes, 4 showed no significant difference. The median length of total hospital stay since presentation to the emergency department was 1.93 days (IQR, 1.21-2.94 days) in the high-flow oxygen group compared with 1.72 days (IQR, 1.03 to 2.68 days) in the standard oxygen group (adjusted HR, 0.82 [95% CI, 0.74 to 0.91]; Table 3). The median length of oxygen therapy after randomization was 1.07 days (IQR, 0.50-2.06 days) in the high-flow oxygen group compared with 0.75 days (IQR, 0.35-1.61 days) in the standard oxygen group (adjusted HR, 0.78 [95% CI, 0.70-0.86]; Table 3). There were 94 ICU admissions (12.5%) in the high-flow oxygen group compared with 53 ICU admissions (6.9%) in the standard oxygen group (adjusted odds ratio, 1.93 [95% CI, 1.35-2.75]; Table 3). A sensitivity analysis showed more ICU admissions in the high-flow oxygen group than in the standard oxygen group when ICU admissions were combined with 3 of 4 predetermined escalation criteria (adjusted odds ratio, 1.87 [95% CI, 1.20-2.90]; eTable 2 in Supplement 3).
Table 3. Secondary Outcomes, Complications, and Adverse Events.
| Secondary outcomes | No. (%)a | Estimate of difference (95% CI), %a |
Unadjusted OR (95% CI)a | Adjusted OR (95% CI)a,b | |
|---|---|---|---|---|---|
| High-flow oxygen (n = 753) | Standard oxygen (n = 764) | ||||
| Total length of hospital stay since presentation to the emergency department, median (IQR), d | 1.93 (1.21 to 2.94) | 1.72 (1.03 to 2.68) | 0.22 (0.09 to 0.35) | HR, 0.85 (0.77 to 0.94) | HR, 0.82 (0.74 to 0.91) |
| Length of oxygen therapy after randomization, median (IQR), d | 1.07 (0.50 to 2.06) | 0.75 (0.35 to 1.61) | 0.33 (0.20 to 0.46) | HR, 0.79 (0.71 to 0.87) | HR, 0.78 (0.70 to 0.86) |
| Escalation of care to an ICU | 94 (12.5) | 53 (6.9) | 5.5 (2.6 to 8.5) | 1.91 (1.34 to 2.72) | 1.93 (1.35 to 2.75) |
| Required noninvasive ventilation | 7 (7.4) | 6 (11.3) | |||
| Required invasive ventilation | 4 (4.3) | 0 | |||
| Required transfer to a tertiary hospital with onsite PICU, No./total (%)c | 2/85 (2.3) | 2/90 (2.2) | 0.1 (−4.3 to 4.5) | 1.05 (0.14 to 7.61) | 0.92 (0.13 to 6.75) |
| Change of allocated therapy and reason for the change d | |||||
| Change in oxygen therapy in general ward or emergency department | 323 (42.9) | 141 (18.5) | 24.4 (20.0 to 28.9) | 3.32 (2.63 to 4.19) | 3.42 (2.70 to 4.34) |
| Trigger of early-warning tool | 117 (15.5) | 111 (14.5) | 1.0 (−2.6 to 4.6) | 1.08 (0.82 to 1.43) | 1.09 (0.82 to 0.24) |
| Increased work of breathing | 33 (4.4) | 98 (12.8) | −8.4 (−11.2 to −5.6) | 0.31 (0.21 to 0.47) | 0.30 (0.20 to 0.46) |
| Decreased level of consciousness | 2 (0.3) | 2 (0.3) | 0 (−0.5 to 0.5) | 1.01 (0.14 to 7.22) | 1.01 (0.14 to 7.21) |
| Deterioration of cardiovascular function with impaired peripheral perfusion | 0 | 2 (0.3) | |||
| Clinician-directed treatment switch | 136 (18.1) | 123 (16.1) | 2.0 (−1.8 to 5.7) | 1.15 (0.88 to 1.50) | 1.15 (0.88 to 1.51) |
| Based on review by ICU team | 12 (1.6) | 27 (3.5) | −1.9 (−3.5 to 0.4) | 0.44 (0.22 to 0.88) | 0.43 (0.21 to 0.86) |
| Intolerance of allocated oxygen therapy | 92 (12.2) | 0 | |||
| Complications and adverse events | |||||
| Death | 1 (0.1) | 0 | |||
| Air leak syndrome, emergency intubation, cardiac arrest, or respiratory arrest | 0 | 0 | |||
| Nosebleed | 2 (0.3) | 0 | |||
Abbreviations: HR, hazard ratio; ICU, intensive care unit; OR, odds ratio; PICU, pediatric intensive care unit.
Unless otherwise indicated.
Adjusted for presence or absence of obstructive airway disease at randomization and study site.
Only includes those who were admitted to hospitals without onsite PICUs.
Multiple clinical reasons may have been recorded.
Tolerance of therapy, which was determined by the parents and the nursing staff, was measured at 1 hour and between 4 hours and 48 hours after starting the assigned oxygen therapy and did not show any significant between-group difference (eTable 3 in Supplement 3).
The per-protocol population included 834 children (336 in the high-flow oxygen group and 498 in the standard oxygen group) and showed similar results to the primary analysis with a longer length of hospital stay, longer length of oxygen therapy, and a greater proportion of ICU admissions in the high-flow oxygen group compared with the standard oxygen group (eFigure 3 and eTables 4-6 in Supplement 3).
Four adverse events were noted. There was 1 death in the high-flow oxygen group that was unrelated to treatment. None of these events were attributed to the interventions (Table 3).
The recruitment rate, hospital length of stay, and the results of sensitivity analysis for the per-protocol cohort appear in eTables 7-9 in Supplement 3. The physiological parameters prior to change in oxygen therapy for both trial groups and the time to crossover of oxygen therapy appear in eTable 10 in Supplement 3.
Clinical Management
Prior to enrollment of the 1567 children, 1467 (93.6%) received inhaled bronchodilators, 994 (63.4%) received steroids, and 631 (40.2%) were given antibiotics. In both groups, most children were started with the allocated treatment (714/753 [94.8%] in the high-flow oxygen group and 735/764 [96.2%] in the standard oxygen group), which occurred at a median time of 3.1 hours after presentation to the emergency department. There were 323 children (42.9%) in the high-flow oxygen group who crossed over and received standard oxygen therapy compared with 141 children (18.5%) in the standard oxygen group who crossed over and received high-flow oxygen therapy (adjusted odds ratio, 3.42 [95% CI, 2.70-4.34]; Table 3). The intervention crossovers were driven by triggers of an early-warning tool and clinician-directed treatment switches similarly in both groups, by intolerance of the allocated treatment more frequently in the high-flow oxygen group, and by increased work of breathing more frequently in the standard oxygen group (Table 3).
Discussion
In this multicenter, randomized clinical trial, children who received early high-flow oxygen therapy for mild to moderate acute hypoxemic respiratory failure had a significant longer stay in the hospital compared with children who received standard oxygen therapy. This significant difference was consistent for children presenting with obstructive airways disease (wheeze) and nonobstructive airways disease (no wheeze). A greater proportion of children in the high-flow oxygen group were admitted to the ICU and did not tolerate the assigned treatment compared with children in the standard oxygen group.
Consistent with the findings of a 2-center pilot study using the same intervention protocol, high-flow oxygen therapy yielded a longer length of stay by 0.2 days and a larger proportion of patients admitted to the ICU.13 However, the pilot study found significantly greater treatment failure in the standard oxygen group. The reason for this difference between the 2 studies is uncertain. Although the 2 studies had different recruitment ages, with the pilot study recruiting children aged 0 years to 16 years with acute hypoxemic respiratory failure (excluding infants <12 months of age with viral bronchiolitis), 82% of the children in the pilot study were in the same age range as the children in the current trial. Even though there were no significant differences in mean parental or staff comfort scores (as measured on a 100-mm visual analog scale, which this trial assessed at 1 hour and between 4 hours and 48 hours after starting the trial interventions), intolerance of treatment was more frequently cited for treatment failure in the high-flow oxygen group.
This multicenter trial does not explain why the length of oxygen therapy and hospital stay were prolonged in children allocated to high-flow oxygen therapy. There was a greater number of patients in the high-flow oxygen group who crossed over to standard oxygen therapy and this change to a second form of oxygen therapy may have prolonged time receiving oxygen therapy and thus a longer stay in the hospital. However, it seems unlikely that this factor accounts for these findings because the significant between-group differences in length of oxygen therapy and hospital stay were still apparent in the per-protocol analysis, which excluded all participants who switched oxygen therapies.
Slow weaning of oxygen therapy in pediatric patients, prolonging the length of the hospital stay, is well documented.16 Although the weaning protocol of oxygen therapy targeting an Spo2 of 92% to 98% (Supplement 1) was the same for both intervention groups, it is possible that greater familiarity with the weaning of standard oxygen resulted in the differences demonstrated. Alternatively, children randomized to high-flow oxygen therapy may have been unconsciously perceived by clinicians to be sicker by virtue of receiving a perceived higher level of respiratory support. This may have influenced the clinical team to be less aggressive with regard to weaning and thus artificially prolonging oxygen therapy, and ultimately length of stay. Similarly, the clinical team may have had a lower threshold for escalation of care to ICU admission. Regardless of the reason, the trial failed to find any benefit of starting high-flow oxygen therapy early during hospital management.
The trial was performed at 7 tertiary and 7 regional hospitals in Australia and New Zealand for a wide range of causes of acute hypoxemic respiratory failure, allowing generalizability of the study outcomes. It is unlikely that a learning effect contributed to the longer length of hospital stay because the participating hospitals were familiar with high-flow oxygen therapy after the previous high-flow oxygen trial in infants with bronchiolitis.
Limitations
This study has several limitations. First, the allocated oxygen therapy could not be blinded, which may have led to a bias in clinical decision-making to switch from the allocated oxygen therapy to the alternative oxygen therapy.
Second, a greater proportion of the children in the high-flow oxygen group were switched to standard oxygen than the children in the standard oxygen group who were switched to high-flow oxygen. The main reason for a switch in oxygen therapy in the high-flow oxygen group was intolerance of the high-flow oxygen therapy. The clinical triggers indicate that children were escalated from standard oxygen to high-flow oxygen based on progression of the disease, whereas a switch in the high-flow oxygen group to standard oxygen therapy occurred more often due to intolerance of the high-flow oxygen therapy. The comfort score measured at fixed intervals after randomization did not reflect the higher intolerance of the high-flow oxygen therapy because the measurement points did not align with the time of crossover.
Third, no clinical data during the weaning process were captured in the study. The same weaning process was used in infants with bronchiolitis in the previous randomized clinical trial,12 which did not show any significant difference in hospital length of stay. All of the staff working at the participating hospitals were familiar with the weaning process as per the previous randomized clinical trial and hence it is unlikely that a learning curve with the high-flow oxygen therapy contributed to an increased length of hospital stay.
Conclusions
Nasal high-flow oxygen used as the initial primary therapy in children aged 1 to 4 years with acute hypoxemic respiratory failure did not significantly reduce the length of hospital stay compared with standard oxygen therapy.
Section Editor: Christopher Seymour, MD, Associate Editor, JAMA (christopher.seymour@jamanetwork.org).
Trial protocol
Statistical analysis plan
eTable 1. Distribution of enrolled patients per site
eTable 2a. Results of sensitivity analyses for escalation of care
eTable 2b. Results of sensitivity analyses for primary outcome using discharge diagnosis
eTable 3. Tolerance measures
eTable 4. Characteristics of infants enrolled in PARIS 2 trial for per-protocol cohort
eTable 5. Primary outcome in the total trial cohort and subgroups for per-protocol cohort
eTable 6. Secondary outcomes in the total trial cohort for per-protocol cohort
eTable 7. Length of hospital stay since randomization (days) per site
eTable 8. Total length of hospital stay since presentation to emergency (days) per site
eTable 9. Results of sensitivity analyses for per-protocol cohort
eTable 10. Physiological parameters prior to change in oxygen therapy
eFigure 1. Recruitment graph
eFigure 2. Forest plot of primary outcome measure by site
eFigure 3. Kaplan-Meier curve for primary outcome in per protocol analysis
Data sharing statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol
Statistical analysis plan
eTable 1. Distribution of enrolled patients per site
eTable 2a. Results of sensitivity analyses for escalation of care
eTable 2b. Results of sensitivity analyses for primary outcome using discharge diagnosis
eTable 3. Tolerance measures
eTable 4. Characteristics of infants enrolled in PARIS 2 trial for per-protocol cohort
eTable 5. Primary outcome in the total trial cohort and subgroups for per-protocol cohort
eTable 6. Secondary outcomes in the total trial cohort for per-protocol cohort
eTable 7. Length of hospital stay since randomization (days) per site
eTable 8. Total length of hospital stay since presentation to emergency (days) per site
eTable 9. Results of sensitivity analyses for per-protocol cohort
eTable 10. Physiological parameters prior to change in oxygen therapy
eFigure 1. Recruitment graph
eFigure 2. Forest plot of primary outcome measure by site
eFigure 3. Kaplan-Meier curve for primary outcome in per protocol analysis
Data sharing statement