European Journal of Cardiovascular Medicine

Bronchiolitis remains the leading cause of hospitalization in infants under one year of age worldwide. The disease, most commonly triggered by respiratory syncytial virus (RSV), produces small-airway inflammation, mucus plugging, and variable hypoxemic respiratory failure. Supportive care—hydration, feeding support, and oxygen supplementation when indicated—constitutes the cornerstone of management. Despite decades of clinical experience, optimal noninvasive respiratory support strategies continue to evolve, particularly for infants who present with moderate work of breathing and hypoxemia.

High-flow nasal cannula (HFNC) technology delivers heated, humidified air–oxygen mixtures at flow rates that often exceed the patient’s inspiratory demand. Physiologically, HFNC confers several potential benefits relevant to bronchiolitis: (1) washout of nasopharyngeal dead space, improving CO₂ clearance; (2) reduced inspiratory resistance by supplying high flow with stable FiO₂; (3) generation of low, flow-dependent distending pressure (usually 2–6 cm H₂O) that may counter small-airway collapse; (4) improved mucociliary function due to optimized humidity/temperature; and (5) improved comfort and feeding tolerance compared with tight-fitting interfaces. These mechanisms, demonstrated in physiologic studies and clinical observations, provided the rationale for HFNC’s rapid clinical adoption.

The clinical evidence base for HFNC in infant bronchiolitis has expanded substantially over the past decade. Two pivotal randomized controlled trials (RCTs) deserve mention. Franklin et al. (NEJM 2018) conducted a multicenter RCT in Australia and New Zealand enrolling infants treated outside the ICU, showing that HFNC reduced treatment escalation versus SOT (standard nasal cannula/face mask) when used as an early therapy in hypoxemic bronchiolitis. Importantly, that trial allowed rescue crossover to HFNC in the SOT arm for persistent distress/hypoxemia, reflecting real-world practice. [1,4,13,17] An earlier RCT—Kepreotes et al. (2017)—reported similar findings in moderate bronchiolitis presenting to the ED, although conducted at a single center with open-label design; HFNC reduced treatment failure compared with SOT. [1,9] Subsequent meta-analyses and Cochrane updates have concluded that HFNC likely reduces the need for escalation and may shorten duration of oxygen therapy and hospital stay by modest margins, with no clear increase in adverse events when appropriately monitored. [3,6,]

While trials and reviews provide high-level evidence, practice variation remains pronounced. Some centers initiate HFNC in nearly all hypoxemic infants; others reserve it for those who fail SOT. This heterogeneity partly reflects concerns regarding resource utilization and overuse (e.g., prolonged therapies, PICU transfers for monitoring) in the absence of clear criteria for starting and weaning HFNC. Recent quality improvement (QI) collaboratives demonstrate that standardized criteria can safely reduce unnecessary HFNC initiation and duration without compromising outcomes—underscoring that how HFNC is implemented matters as much as whether it is used. [2,5]

Guidelines historically emphasized minimal interventions and discouraged ineffective therapies (bronchodilators, epinephrine trials, hypertonic saline in the ED), but have offered limited, evolving guidance on HFNC. The 2014 AAP bronchiolitis guideline predates most large HFNC RCTs, focusing on oxygen thresholds and supportive care. In practice, many hospitals have adapted local pathways to incorporate HFNC following key trials. Updated systematic reviews and summaries (e.g., Cochrane; AAFP synopsis) now suggest HFNC is reasonable for moderate hypoxemic bronchiolitis when SOT is insufficient or in lieu of SOT in selected settings, with typical starting flows of 1–2 L/kg/min and careful weaning. [6,10]

Against this backdrop, we designed a 2019 prospective, pragmatic randomized study in a high-volume Indian tertiary pediatric center to evaluate HFNC’s effect on escalation of care and clinically meaningful secondary outcomes, using a real-world protocol aligned with contemporary RCTs. Recognizing the importance of implementation, we integrated standardized initiation and weaning criteria, bedside nursing protocols, and feeding guidance. We also prespecified safety assessments, including monitoring for barotrauma, nasal trauma, and abdominal distension.

Our primary hypothesis was that early HFNC in infants with moderate bronchiolitis and hypoxemia would reduce escalation of care compared with SOT. Secondary hypotheses were that HFNC would shorten time to clinical stability, reduce oxygen duration, and be safe without increasing adverse events. We further situated our results within the broader evidence base through a narrative synthesis and discussion of policy-relevant issues, including QI initiatives to minimize overuse and optimize value.

Study design and setting

We conducted a prospective, open-label, pragmatic randomized controlled study from January 1 to December 31, 2019 in the pediatric emergency department and inpatient pediatric wards of a tertiary care teaching hospital. The study protocol was approved by the institutional ethics committee; written informed consent was obtained from guardians.

Participants:

 Eligible were infants 1–12 months with a clinical diagnosis of bronchiolitis (first episode of wheeze/crackles following an upper respiratory prodrome), moderate work of breathing (retractions, tachypnea), and SpO₂ 88–92% on room air. Exclusion criteria included immediate need for intubation, chronic lung disease, hemodynamically significant congenital heart disease, craniofacial anomalies incompatible with nasal cannulas, prior enrollment, nosocomial bronchiolitis, or shock requiring vasoactive support.

Randomization and allocation:

Participants were randomized 1:1 to HFNC or SOT using computer-generated variable-size blocks and sealed opaque envelopes. Masking was not possible. Interventions: The HFNC arm received heated, humidified air–oxygen via age-appropriate nasal cannula at an initial flow of 2 L/kg/min (max 20 L/min) with FiO₂ titrated to SpO₂ 92–96%; flow adjustments (1.5–2.5 L/kg/min) were allowed based on clinical response. The SOT arm received standard low-flow oxygen (nasal prongs up to 2 L/min or headbox) with FiO₂ titrated to the same SpO₂ targets.

Weaning and escalation:

Stability criteria were SpO₂ ≥92% on FiO₂ ≤0.30, reduced retractions, and age-appropriate respiratory rate for ≥4 hours. Weaned FiO₂ in 0.05–0.10 steps to 0.21 before reducing HFNC flow by 0.5–1 L/kg/min every 2–4 hours. Rescue/escalation criteria included persistent hypoxemia (SpO₂ <90% on FiO₂ ≥0.40), apnea, worsening distress, or clinician concern; escalation options were CPAP/NIV or PICU transfer. Rescue crossover from SOT to HFNC was permitted as clinically indicated (Franklin et al. [4]; Kepreotes et al. [5]).

Outcomes:

The primary outcome was escalation of care (composite of PICU transfer for respiratory support upgrade, initiation of CPAP/NIV, or endotracheal intubation). Secondary outcomes included time to clinical stability, hospital LOS, duration of oxygen therapy, feeding interruption, device-related adverse events, pneumothorax, and readmission within 7 days.

Sample size and statistical analysis:

Assuming escalation rates of 30% with SOT and 15% with HFNC (absolute difference 15%), α=0.05 and 80% power required 186 participants; we enrolled 200 to allow for attrition. Analyses were intention-to-treat. Categorical comparisons used chi-square or Fisher’s exact tests; continuous variables used t-tests or Mann–Whitney U tests as appropriate. Risk differences and ratios with 95% confidence intervals were reported. A multivariable logistic regression assessed predictors of escalation (covariates: age, weight, baseline respiratory rate, baseline RDAI score, and randomized arm). Time-to-event outcomes used Kaplan–Meier plots and log-rank tests; p<0.05 considered significant.

 Table 1 presents baseline characteristics of infants randomized to High-Flow Nasal Cannula (HFNC, n=100) and Standard Oxygen Therapy (SOT, n=100). Both groups were comparable, indicating successful randomization.The mean age was ~5 months in both groups (HFNC: 5.1 ± 2.8 vs. SOT: 5.0 ± 2.9 months, p=0.84). Male sex distribution was nearly identical (59% vs. 61%, p=0.77). Mean weight was similar (6.5 ± 1.6 kg vs. 6.4 ± 1.7 kg, p=0.69).Respiratory severity at enrollment showed no differences: respiratory rate averaged 62 vs. 63 breaths/min (p=0.46), median SpO₂ was 90% in both groups (p=0.55), and RDAI scores were equal (median 8, IQR 6–10, p=0.98).Feeding mode (oral/nasogastric: 58/42 vs. 56/44, p=0.76) and RSV positivity (50% vs. 48%, p=0.78) were also balanced.

Table 1. Baseline Characteristics of Enrolled Infants

Table 2 summarizes the primary and secondary outcomes comparing High-Flow Nasal Cannula (HFNC) with Standard Oxygen Therapy (SOT) in enrolled infants. The primary outcome, escalation of care, occurred significantly less often in the HFNC group (12%) compared to the SOT group (28%), corresponding to a risk difference of −16% (95% CI −27 to −5, p=0.004). This demonstrates that HFNC substantially reduced the need for advanced respiratory support.

Regarding secondary outcomes, HFNC was associated with faster recovery. The median time to clinical stability was 22 hours with HFNC versus 30 hours with SOT (hazard ratio 1.42, p=0.002). Similarly, the median hospital stay was modestly shorter in the HFNC group (2.6 days vs. 3.1 days, p=0.03). Oxygen therapy duration was reduced by about eight hours in HFNC recipients (28 vs. 36 hours, p=0.01). Feeding interruption was also shorter in the HFNC group (median 10 vs. 12 hours, p=0.04), suggesting improved tolerance and earlier resumption of enteral feeding.Safety outcomes were reassuring: adverse events were rare and comparable between groups (4% HFNC vs. 3% SOT, p=0.70), with no serious complications reported. Readmission within seven days was similarly low (2% vs. 3%, p=0.65)

Table 2. Primary and Secondary Clinical Outcomes

Table 3 presents the results of a multivariable logistic regression analysis evaluating predictors of escalation of care in infants with bronchiolitis. After adjusting for age, weight, respiratory rate, and baseline severity, the use of High-Flow Nasal Cannula (HFNC) was independently associated with a significantly lower risk of escalation compared to Standard Oxygen Therapy (SOT). The adjusted odds ratio (aOR) for HFNC was 0.35 (95% CI: 0.17–0.71, p=0.004), indicating a 65% reduction in the odds of requiring advanced respiratory support.

Other predictors showed meaningful associations. Baseline respiratory rate was a significant risk factor; for every 5 breaths per minute increase, the odds of escalation rose by 18% (aOR 1.18, 95% CI: 1.02–1.38, p=0.03). Similarly, higher clinical severity at presentation, as measured by the Respiratory Distress Assessment Instrument (RDAI), predicted escalation. For every 2-point increase in RDAI score, the odds increased by 22% (aOR 1.22, 95% CI: 1.01–1.49, p=0.04).

In contrast, age and weight were not statistically significant predictors, with aORs close to unity (p=0.49 and p=0.31, respectively)

Table 3. Multivariable Logistic Regression for Escalation of Care

This single-center pragmatic randomized trial conducted during 2019 indicates that early initiation of HFNC in infants with moderate hypoxemic bronchiolitis reduces escalation of care compared with Standard Oxygen Therapy (SOT). Beyond the primary outcome, HFNC was associated with faster clinical recovery—shorter time to stability, reduced oxygen exposure, and modestly shorter length of stay—without an uptick in significant adverse events. These findings reinforce earlier randomized evidence and systematic reviews supporting HFNC as an effective escalation strategy for moderate bronchiolitis (Franklin et al. [4]; Kepreotes et al. [5]; Lin et al. [6]; Beggs et al. [7]; Cochrane Review [8]).

Interpretation in context: The observed absolute risk reduction in escalation (16%) closely mirrors results reported in multicenter trials. Franklin et al. [4] found a lower rate of treatment escalation with HFNC in a large trial that enrolled infants outside intensive care settings; their pragmatic allowance for rescue crossover was replicated in our protocol to align with real-world practice and ethical equipoise. Kepreotes et al. [5] similarly reported lower treatment failure with HFNC in an ED-based randomized study. Meta-analyses consolidate these findings, indicating a consistent benefit of HFNC over SOT for escalation endpoints, while effects on LOS and oxygen duration are smaller and more heterogeneous—likely because discharge timing depends on variables beyond respiratory physiology, such as feeding tolerance and social readiness (Cochrane Review [8]; Zalek et al. [2]).

Mechanisms of benefit: HFNC plausibly improves outcomes via a combination of physiologic effects. High flows wash out nasopharyngeal dead space, diminishing CO₂ rebreathing and lowering ventilatory drive in infants who often breathe rapidly and shallowly. Flow-dependent pressure may splint small airways and reduce dynamic airway collapse, while warmed humidification enhances mucociliary clearance and patient comfort—factors that may permit earlier feeding and reduce the work of breathing (Zalek et al. [2]; Bučan et al. [3]). These mechanisms explain why HFNC tends to improve clinical distress scores and reduce the need for escalation in multiple trials.

Safety considerations: Serious complications associated with HFNC—such as pneumothorax—are uncommon in randomized and observational series. We observed no pneumothoraces and only minor interface-related events. Adherence to safe practice (appropriate cannula sizing, careful monitoring of saturations and work of breathing, and conservative feeding thresholds) likely mitigates the small risks that exist (Franklin et al. [4]; Cochrane Review [8]; Zalek et al. [2]).

Implementation and value: The clinical effectiveness of HFNC is well supported, but its value depends on targeted use. Quality improvement studies have emphasized that indiscriminate HFNC initiation for mild disease or failure to wean appropriately can drive unnecessary monitoring, increased nurse workload, and higher costs without improving outcomes (Cavayas et al. [9]; Riese et al. [10]; Hinkle et al. [11]). Our local pathway included explicit initiation thresholds, nurse-driven weaning, and early reassessment, which likely limited overuse while delivering clinical benefit. In resource-limited settings, pairing HFNC adoption with protocolized pathways is especially important to ensure cost-effectiveness and equitable access.

Comparative positioning: For infants with mild hypoxemia and minimal distress, SOT remains appropriate. HFNC is an intermediate, well-tolerated step that reduces progression to CPAP/NIV and invasive ventilation in moderate cases. CPAP/NIV remains essential for severe disease or HFNC failure, delivering greater positive pressure support albeit with potential tolerance issues; head-to-head evidence suggests comparable failure rates but differences in tolerance and nursing requirements (Nair et al. [12]; Beggs et al. [7]). Our pragmatic algorithm—HFNC as initial escalation with predefined triggers for CPAP/NIV—balances clinical efficacy with comfort and resource stewardship.

Franklin et al. provided correspondence and a detailed protocol supplement that explain trial conduct, rescue-crossover procedures, and prespecified analyses (Franklin et al. [13]; Franklin et al. [15]). The ClinicalTrials.gov entry (NCT02737280) documents registry details and primary/secondary endpoints for HFNC trials, useful for protocol verification [14]. Systematic-review resources (the Cochrane Library review and its patient summary) synthesize randomized evidence and conclude that HFNC reduces treatment escalation or failure with modest effects on length of stay and oxygen duration (Cochrane Library [16]; Cochrane patient summary [20]). The Bottom Line summary distills key clinician-facing points from the NEJM trial for bedside interpretation [17]. The PARIS-2 trial (JAMA 2023) and related abstracts expand understanding of HFNC across a broader pediatric population and provide complementary data to infant-focused studies (PARIS-2 Investigators [18]; Kepreotes et al. [19]). Finally, recent implementation and weaning guidance emphasizes nurse-driven, stepwise FiO₂-first weaning and explicit start/stop thresholds to limit overuse while preserving benefit (Jones et al. [21])

Strengths and limitations:

 Strengths of current include pragmatic design, standardized criteria, intention-to-treat analysis, and outcomes relevant to families and systems. Limitations include single-center setting (limiting generalizability), open-label design (inherent to device studies), and partial RSV testing. Although escalation policies were protocolized, clinician discretion may have introduced variability. We did not perform capnography or blood gases routinely; thus, physiologic mechanisms were inferred rather than measured.

In this pragmatic randomized study of infants with moderate bronchiolitis, HFNC reduced escalation of care, shortened time to stability and oxygen duration, and was safe compared with SOT. These findings, consistent with large RCTs and meta-analyses, support HFNC as a first-line escalation strategy when implemented with protocolized initiation and weaning. Systems should pair adoption with QI frameworks to ensure appropriate, value-aligned use.

Author Contributions

ZK, PP, and SB contributed to the conception and design of the study. ZK was responsible for data acquisition, while PP performed statistical analysis and interpretation. SB assisted in drafting the manuscript and critically revising it for important intellectual content. All authors reviewed and approved the final version and agree to be accountable for the integrity of the work.

Funding and Disclosures

This study received no external financial support. The authors declare that they have no competing interests.

Ethics

The study protocol was reviewed and approved by the Institutional Ethics Committee (DMHS/IEC-2019/110/045). Written informed consent was obtained from the parents or legal guardians of all enrolled participants prior to inclusion.

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