High-flow nasal cannula for respiratory support in children with severe asthma attack: a systematic review and meta-analysis
Article information
Abstract
Background
Adjunctive therapies, including high-flow nasal cannula (HFNC) and bilevel positive airway pressure, have been explored to manage severe asthma attacks and avoid invasive ventilation. HFNC has gained interest as a potential alternative. This review evaluated and compared outcomes of HFNC with conventional oxygen therapy or other non-invasive ventilation (NIV) in severe asthma.
Methods
A comprehensive search of PubMed/Medline, Scopus, Cochrane Library, and gray literature identified studies published between August 25, 2014, and August 25, 2024. A random-effects meta-analysis was performed, and results were presented in a forest plot. Study quality was assessed using the Cochrane Risk of Bias tool (ROB-2) and Newcastle-Ottawa Scale. The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and was registered in PROSPERO (CRD42024558656).
Results
Nine studies with 14,606 subjects were included. HFNC showed a trend toward improved pulmonary scores, though not statistically significant (P>0.05). Pediatric intensive care unit (PICU) admission and need for escalation of support did not significantly differ from standard oxygen therapy or other NIV. HFNC was associated with a modest but significant increase in readmission (odds ratio, 3.14; 95% CI, 1.07–9.24; P=0.04). PICU length of stay was comparable across groups, and mortality among HFNC-treated patients remained <1%. Overall evidence quality was very low to low.
Conclusions
HFNC did not demonstrate superior outcomes over conventional oxygen therapy and other NIV. Evidence remains limited and of low quality, highlighting the need for further high-quality studies.
INTRODUCTION
Asthma is a chronic respiratory illness characterized by airway inflammation, leading to bronchoconstriction, increased mucus production, and breathing difficulties [1]. It is one of the most prevalent chronic childhood respiratory disorders, affecting around 9%–14% of the global population and 4%–6% of children and adolescents in Indonesia [2-4]. According to disability-adjusted life years, childhood asthma is a leading cause of morbidity within the 5–14 year age group, ranking among the top 10 contributors to disability burden in this population, especially in low-to-middle income countries [5,6].
Severe acute asthma exacerbation, which typically develops as a result of exposure to an external agent or poor adherence to therapy, is the most prevalent reason for a pediatric emergency department (ED) visit, accounting for nearly 5%–15% of all visits [7,8]. This is a potentially life-threatening disorder that frequently results in admission to a pediatric intensive care unit (PICU) [9]. Research on the incidence of severe asthma exacerbations among children in primary care indicates that approximately 0.4% (4 per 1,000) of asthmatic children experience a serious exacerbation annually. Furthermore, children with a prior severe exacerbation have a 25% risk of recurrence within the following year [10,11].
Treatment of severe acute asthma exacerbations in children with β2-agonists, anticholinergics, corticosteroids, and oxygen supplementation may not resolve airway blockage, necessitating adjuvant therapy [12]. Non-invasive ventilation (NIV) including continuous positive airway pressure (CPAP); bilevel positive airway pressure (BiPAP); or heated, humidified high-flow nasal cannula (HFNC) may be used for respiratory support in children with status asthmaticus in cases of standard treatment failure [13,14]. These modalities are used to avoid invasive mechanical ventilation associated with complications such as pneumothorax, ventilator-related comorbidities, and disrupted cardiopulmonary interactions [15,16].
HFNC has emerged as an alternative respiratory support to non-invasive positive-pressure ventilation in the neonatal intensive care unit. It is widely used to treat acute respiratory failure in newborns, infants, and children [17-19]. HFNC therapy enhances patient comfort and oxygenation through well-established physiological mechanisms. These mechanisms include reducing inspiratory resistance, eliminating dead space within the nasopharyngeal region, and minimizing oxygen dilution [20,21]. The literature supports the safe and effective use of HFNC therapy in managing various pediatric illnesses, including viral bronchiolitis, pneumonia, and even heart failure [22,23].
Despite the growing application of HFNC therapy, strong clinical evidence supporting its use across all clinical settings has yet to be fully established. Additionally, concerns exist regarding the possibility of HFNC delaying initiation of more established and effective ventilation strategies [24,25]. This potential risk necessitates further investigation, particularly in children with severe asthma. One review study provided a brief explanation of the potential benefits of HFNC therapy for severe asthma attacks based on published literature, but results were not quantitatively measured [26]. Therefore, we aimed to summarize the efficacy of HFNC in pediatric severe acute asthma exacerbations based on a systematic review of the literature and meta-analysis of relevant data. In particular, we compared the clinical outcomes of HFNC therapy to those of standard oxygen therapy or other non-invasive ventilatory support measures such as CPAP and BiPAP.
MATERIALS AND METHODS
Protocol Registration and Approval
Results are reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria [27]. This study synthesized data from electronic databases. Hence, institutional review board approval was not required. The protocol was recorded in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42024558656).
Eligibility Criteria
Both randomized and non-randomized controlled trials and observational studies were considered suitable for inclusion in further analysis. Studies lacking full-text availability were excluded, along with reviews, case reports/series, commentary articles, conference abstracts, and book sections. The study population comprised patients aged 18 years and younger with moderate-to-severe asthma attacks (pulmonary index score 6 or above) refractory to initial standard therapy (inhaled salbutamol and ipratropium bromide, systemic corticosteroids). No restrictions were imposed based on race, socioeconomic status, religion, geographic location, or underlying health conditions. The intervention was use of HFNC for respiratory support compared with standard oxygen therapy or other available NIVs, such as CPAP or BiPAP. Outcomes of interest were improvement of pulmonary score, PICU admission and readmission rates, need for additional respiratory support, and mortality rate.
Search Strategy, Sources, and Study Selection
A comprehensive literature search was conducted across multiple databases, including PubMed/Medline, Scopus, Cochrane Library, and gray literature repositories such as Google Scholar, WorldCat, and clinical trial registries. Articles published from August 25, 2014, to August 25, 2024, were included in the search. Search terms were ("severe asthma" OR "critical asthma" OR "status asthmaticus" OR "asthma exacerbation" OR "asthma attack") AND ("high flow nasal cannula" OR "HFNC") AND ("pediatrics" OR "children" OR "adolescent") along with relevant Medical Subject Headings (MeSH) terms if applicable. No publication date and language restrictions were applied. Additionally, a snowball search method was employed to identify relevant articles by screening citations of published review articles aligned with the research topic and objectives.
The search process was independently conducted by three authors, followed by article screening using the keywords. Duplicate articles were removed, and the remaining articles were screened based on title and abstract to identify potentially eligible manuscripts. Full-text articles meeting the eligibility criteria underwent a thorough evaluation for data synthesis. Reasons for excluding studies were recorded, and discrepancies were resolved through consensus. All selection procedures were carried out manually by the authors, and this process is summarized in Figure 1.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart. This diagram summarizes the search strategy and selection process applied to include articles eligible for this meta-analysis.
Data Extraction
Three reviewers independently extracted data from the articles selected during screening. In cases of disagreement, consensus was reached through discussion. Extracted data included (1) first author and publication year; (2) geographical region of the study; (3) study design; (4) sample size; (5) baseline characteristics (age, sex, clinical parameters, blood gas values); (6) diagnosis; (7) setting; and (8) outcomes of interest. All data extraction procedures were conducted manually by the reviewers.
Risk of Bias Assessment and Confidence in Cumulative Evidence
Version 2 of the Cochrane Risk of Bias tool (ROB-2) and Newcastle-Ottawa Scale (NOS) was used to determine the quality of the included studies [28,29]. Four researchers independently judged the methodological quality of each study manually, with any discrepancies resolved through consensus. Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was used to assess confidence in the cumulative evidence [30]. Judgment was based on study limitations, consistency, directness, imprecision, and/or reporting bias. Overall certainty of the evidence was reported as high, moderate, low, or very low quality.
Data Synthesis, Presentation, and Statistical Analysis
Meta-analysis using a random-effects model was conducted, and the results are presented in a forest plot. The studies listed in the forest plot were sorted in alphabetical order. Statistical significance was determined at a threshold of P<0.05. Heterogeneity of included studies was assessed using Cochrane’s Q Test and Higgins I2 statistics. Subgroup analysis was conducted to determine possible causes of heterogeneity. A funnel plot was used for visual assessment of publication bias. An asymmetric funnel plot indicates the possibility of publication bias. The Begg and Mazumdar Rank Correlation Test and Egger’s Test of the Intercept were also used to assess the presence of publication bias. Any missing data required for the analysis were retrieved by contacting the corresponding author of the article. Furthermore, a sensitivity analysis was performed to confirm the robustness of this meta-analysis by excluding studies with a high risk of bias. All statistical tests were performed using Review Manager version 5.4 [31]. When meta-analysis could not be conducted, a narrative synthesis evaluating clinical outcomes reported in the included studies was performed instead. The findings of the included studies are presented in a table, and the studies listed were sorted alphabetically by last name of the first author.
RESULTS
Search Results
After conducting an extensive literature search, 398 studies were identified and screened based on their titles and abstracts. Following this initial screening, 22 studies were assessed for eligibility. Ultimately, nine studies were included in the review [13,25,32-38]. The search flowchart and study selection process are shown in Figure 1.
Characteristics of the Included Studies
Nine studies were included in the analysis, two randomized controlled trials and seven cohort studies. Studies were conducted in the United States (four studies), Spain (four studies), and Paraguay (one study) and enrolled children and adolescents aged 18 years or younger with moderate-to-severe asthma exacerbations (pulmonary score >5) that did not respond to initial standard therapy. Most subjects were male. Included studies were conducted in various settings, mainly in the PICU, followed by the ED and inpatient ward. The initial flow rate of HFNC ranged from 0.5–2 L/kg/min to maintain an oxygen saturation of 93% or higher. All except one study with suspicion of bias due to randomization of the process and selection of the reported results were judged to be of good quality. Detailed characteristics of the included studies are provided in Table 1, and bias assessment results are provided in Table 2 and Figure 2.
Characteristics of the included studies
Risk of bias assessment - Newcastle Ottawa scale
Risk of bias assessment using the Cochrane risk of bias tool.
Meta-analysis
Patients in the HFNC group (48.43%) tended to have greater improvements in pulmonary scores than those receiving standard oxygen therapy, but this difference was not significant (odds ratio [OR], 1.53; 95% CI, 0.44–5.27; I2=66%; P=0.50) (Figure 3A). As many as 14.5% of patients using HFNC, either in the ED or pediatric ward, required admission to the PICU. However, we did not find any significant difference in outcomes compared with those treated with standard oxygen therapy (OR, 3.34; 95% CI, 0.26–43.52; I2=92%; P=0.36) (Figure 3B). Patients in the HFNC group (3.2%) were more likely to be readmitted to PICU/hospital wards after being discharged (OR, 3.14; 95% CI, 1.07–9.24; I2=0%; P=0.04) (Figure 3C). Typical PICU length of stay for the HFNC and conventional oxygen therapy groups ranged from 2 to 3 days, while those of other NIV groups ranged from 2 to 5 days.
Efficacy of high-flow nasal cannula (HFNC) for severe asthma attacks. The horizontal line indicates the 95% CI of a study. Squares represent the results of a study. Square size varies according to the weight of a particular study. The diamond at the bottom of the plot represents the pooled analysis of all included studies. The outer edges of the diamond indicate the CIs. (A) Improvement of pulmonary score. (B) Admission to pediatric intensive care unit (PICU). (C) Readmission post-discharge. (D) Escalation of ventilatory support (vs. standard oxygen therapy). (E) Escalation of ventilatory support (vs. other non-invasive ventilation). df: degree of freedom; I2: test of heterogeneity; M-H: Mantel-Haenszel; CPAP: continuous positive airway pressure; BiPAP: bilevel positive airway pressure.
We observed that a subset of patients treated with HFNC (10.5%) required escalation of respiratory support. This effect was not significantly different from that of standard oxygen therapy (OR, 1.78; 95% CI, 0.76–4.19; I2=94%; P=0.19) (Figure 3D) or the NIV method CPAP/BiPAP (OR, 5.98; 95% CI, 0.77–46.23; I2=57%; P=0.09) (Figure 3E). The mortality rate of subjects treated with HFNC was no higher than 1%.
Confidence in the Cumulative Evidence
This meta-analysis included both randomized controlled trials and observational studies, which initially provided low- to high-quality evidence. Most studies were considered to be of good quality, and bias was considered unlikely. We detected substantial heterogeneity in our analysis, except for the readmission rate after discharge. Two analyses showed a wide confidence interval that raised concerns about the precision of the current study. No serious indirectness that could affect the results in their entirety was found. Publication bias could not be evaluated as fewer than 10 studies were included. Hence, the evidence generated from this meta-analysis was judged to be very-low to low, as outlined in Table 3.
GRADE evidence profile
DISCUSSION
HFNC has been proposed as an alternative respiratory support in pediatric acute respiratory distress due to its physiological advantages, such as washout of nasopharyngeal dead spaces, reducing inspiratory resistance, improving mucociliary function, reducing metabolic work related to gas conditioning, and providing low-level positive distending pressure [20,21]. In pediatric asthma, these mechanisms theoretically may mitigate bronchospasm, enhance secretion clearance, and improve ventilation-perfusion mismatch. However, these proposed benefits are largely based on extrapolated physiological data or evidence from other respiratory conditions, such as bronchiolitis or pneumonia [17,22].
Our meta-analysis did not show significant improvements in pulmonary scores or PICU admission rates compared to standard oxygen therapy when HFNC therapy was used in pediatric EDs or wards. The pathophysiology of severe asthma includes marked bronchospasm, airway inflammation, mucus impaction, and dynamic hyperinflation, resulting in elevated airway resistance and intrinsic positive end-expiratory pressure (auto-PEEP) [21,22]. While HFNC delivers warmed, humidified gas with low-level flow-dependent PEEP (typically 2–6 cm H2O), this is often insufficient to overcome the degree of air trapping and respiratory muscle load seen in severe asthma [20]. Unlike CPAP or BiPAP, HFNC does not offer adjustable inspiratory pressure or ventilatory assistance, limiting its capacity to reduce CO2 retention and respiratory fatigue [39-41]. These physiological constraints may explain the absence of significant clinical improvement observed in our pooled outcomes, despite the theoretical benefits of HFNC such as improved oxygenation and mucociliary clearance [21,22].
This meta-analysis also demonstrated that HFNC did not significantly reduce the need for escalation to CPAP, BiPAP, or intubation in pediatric asthma patients across ED, ward, and PICU settings. The introduction of HFNC therapy in the pediatric ED decreased the intubation rates for children with acute respiratory failure [42]. Another study reported that implementing HFNC therapy in PICUs was linked to lower intubation rates, with failure rates ranging from 25% to 30% [19,43]. While HFNC is generally well tolerated and simple to administer, these advantages do not inherently translate to clinical efficacy in preventing deterioration. Moreover, clinical predictors such as persistent hypercapnia or lack of respiratory rate improvement have been associated with HFNC failure in children with acute respiratory conditions, including status asthmaticus [44,45]. Subjects from the HFNC group included in the analysis had elevated pCO2 levels, which might decrease the clinical efficacy of HFNC. We also observed a modest but significant increase in readmission among HFNC-treated patients in the PICU setting. This finding may reflect early reliance on HFNC in patients with more severe presentations or delayed escalation to more effective respiratory support.
Given the established role of CPAP and BiPAP in reducing intubation and improving ventilation in children with status asthmaticus, we compared HFNC directly with these modalities. CPAP and BiPAP offer consistent airway pressure and ventilatory support, which are especially beneficial in patients with high airway resistance and CO2 retention [14,16]. HFNC, in contrast, provides only passive support and variable pressure delivery [14,16]. Although it may be easier to administer and better tolerated in mild-to-moderate cases, its non-inferiority in severe asthma has not been conclusively demonstrated, as reported in our meta-analysis. Murphy and Kessel [41] reported that, while HFNC did not result in significant improvements in respiratory rate among subjects with status asthmaticus, it remained comparable to BiPAP within the pre-defined non-inferiority limit of 20%. Several studies have compared CPAP and HFNC for both initiating (“step-up”) and weaning (“step-down”) respiratory support. HFNC was shown to be non-inferior to CPAP in the step-up setting, but failed to demonstrate non-inferiority in step-down care, particularly among younger, chronically ill, or sedated children [39,40].
This meta-analysis has several limitations that warrant consideration. First, substantial heterogeneity was observed across outcomes, likely due to variations in study design, patient populations, clinical settings (ED, ward, PICU), and HFNC initiation criteria. Second, imprecision was evident in some analyses, as reflected by wide confidence intervals, partly due to the small sample sizes in certain studies. Additionally, the limited number of randomized controlled trials and the predominance of retrospective observational designs may have introduced bias and limited the strength of causal inference. Finally, as the number of included studies was fewer than 10, formal assessment of publication bias could not be performed. Future high-quality, multicenter trials are needed to better define the role of HFNC in pediatric severe asthma and to strengthen the evidence base. Currently, two registered randomized clinical trials have yet to announce their findings [46,47]. These trials might offer valuable insights in addition to the findings of this meta-analysis.
In our meta-analysis, the physiological advantages offered by HFNC therapy did not translate into significantly improved clinical outcomes in pediatric severe asthma. The absence of consistent, asthma-specific physiological data such as changes in dynamic hyperinflation, CO2 clearance, or inspiratory effort limited our ability to establish a strong causal link. Further rigorous studies are warranted to delineate specific clinical scenarios where HFNC might offer distinct benefits and to more robustly determine the comparative efficacy of HFNC compared to other NIV options.
KEY MESSAGES
▪ high-flow nasal cannula (HFNC) therapy does not exhibit superiority to standard oxygen therapy and other non-invasive ventilation modalities for treating severe asthma attacks.
▪ Future high-quality, multicenter trials are needed to better define the role of HFNC in pediatric severe asthma and to strengthen the evidence base.
Notes
CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was reported.
FUNDING
None.
ACKNOWLEDGMENTS
None.
AUTHOR CONTRIBUTIONS
Conceptualization: GM, MIR. Data curation: GM, MIR, AD, NA. Formal analysis: GM, MIR, AD, NA. Methodology: GM, MIR, AD, NA. Project administration: GM, MIR, AD, NA. Visualization: GM, MIR, AD, NA Writing – original draft: GM, MIR, AD, NA. Writing – review & editing: GM, MIR, AD, NA. All authors read and agreed to the published version of the manuscript.