Supportive care remains the mainstay of therapy in bronchiolitis. Earlier studies suggest that helium-oxygen therapy may be beneficial, but evidence is limited. We aimed to compare efficacy of 2 treatment gases, Heliox and Airox (21% oxygen + 79% helium or nitrogen, respectively), on length of hospital treatment for bronchiolitis.
This was a multicenter randomized blinded controlled trial of 319 bronchiolitic infant subjects randomly assigned to either gas; 281 subjects completed the study (140 Heliox, 141 Airox), whose data was analyzed. Treatment was delivered via facemask (nasal cannula, if the facemask intolerant) ± continuous positive airway pressure (CPAP). Severe bronchiolitics received CPAP from the start. Primary end point was length of treatment (LoT) required to alleviate hypoxia and respiratory distress. Secondary end-points were proportion of subjects needing CPAP; CPAP (LoT); and change in respiratory distress score.
Analysis by intention to treat (all subjects); median LoT (inter-quartile range, days): Heliox 1.90 (1.08–3.17), Airox 1.87 (1.11–3.34), P = .41. Facemask tolerant subgroup: Heliox 1.46 (0.85–1.95), Airox 2.01 (0.93–2.86), P = .03. Nasal cannula subgroup: Heliox 2.51 (1.21–4.32), Airox 2.81 (1.45–4.78), P = .53. Subgroup started on CPAP: Heliox 1.55 (1.38–2.01), Airox 2.26 (1.84–2.73), P = .02. Proportion of subjects needing CPAP: Heliox 17%, Airox 19%, O.R. 0.87 (0.47–1.60), P = .76. Heliox reduced respiratory distress score after 8 hours (mixed models estimate, −0.1298; P < .001). The effect was greater for facemask compared with nasal cannula (mixed models estimate, 0.093; P = .04).
Heliox therapy does not reduce LoT unless given via a tight-fitting facemask or CPAP. Nasal cannula heliox therapy is ineffective.
We congratulate Chowdhury et al on their RCT comparing Heliox to Airox in infants with bronchiolitis(1). Previous studies investigating the use of Heliox in bronchiolitis have had limitations precluding any definitive conclusions regarding efficacy. The authors should be commended on their attention to study protocol and standardisation of interventions across sites. However, we have concerns regarding the methodology and analysis that question the recommendations made by the authors. We urge caution in interpretation of study findings.
It is unclear what stratification was used during randomisation. In addition, the labelling of intervention gases as cylinder A and B means that the study was only semi-blinded potentially exposing the study to assessment bias. It was pleasing to see the primary outcome as LoT that is less easily confounded than length of stay. However, the frequency of assessment throughout treatment was not specified.
Although the authors state that data was analysed by intention to treat, Figure 2 suggests that results were in fact based on a per protocol analysis. Patients discontinuing the intervention were excluded from final analysis, a significant oversight.
Though the study was powered to detect a reduction in LoT of 0.75 days between groups the author's main finding of a significant reduction in LoT in the Heliox arm (0.55 days) was only in the subgroup of FM tolerant children (30% of participants) for which the study was underpowered. In terms of statistical methods, there are inconsistencies between the statistics used to calculate the sample size and analysis for primary outcome (the former based on a comparison of means, and the latter a non-parametric test). The additional reduction in LoT in the RSV+ FM tolerant Heliox group is based on an even smaller sample (n=61). RSV testing is not routine in many institutions and results would not be available early enough to dictate management as proposed.
The data presented by the authors in Table 3 is confusing. The origin of all values is not immediately clear, and the total number of patients in subgroups do not match the overall numbers in each treatment arm. We also question the use of means and confidence intervals for summarising LoT given the skewed nature of this outcome.
The discussion is thorough and well balanced and the authors place their findings in the context of available literature. Given there was no evidence of an overall difference in LoT between Heliox and Airox groups it could be argued that their clinical recommendation regarding the use of Heliox in infants with bronchiolitis is overstated.
Despite the shortcomings to the study by Chowdhury and colleagues that preclude definitive recommendations at this stage, it is a valuable addition to the literature. The study provides encouraging preliminary results regarding the use of Heliox in certain subgroups of infants with bronchiolitis. We eagerly await the results of future adequately powered prospective randomised controlled studies as outlined by the authors to provide the definitive evidence needed that will lead to a change in current clinical management.
Suzi Reiss Hayley Hernstadt Joanna Lawrence Katherine Lee Laura Rodwell Tom Connell
1. Chowdhury MM, McKenzie SA, Pearson CC, Carr S, Pao C, Shah AR, et al. Heliox therapy in bronchiolitis: phase III multicenter double-blind randomized controlled trial. Pediatrics. 2013;131(4):661-9. Epub 2013/03/20.
Conflict of Interest:
None declared
We read with great interest: Heliox Therapy in Bronchiolitis: Phase III Multicenter Double-Blind Randomized Controlled Trial. Chaudry et al. deserve commendation for completing a multi-national, complex, and difficult study.
Their findings are consistent with some of our own recent results. (1) Of note, we suspect that their observation: "Heliox conferred no benefit over oxygen when delivered by nasal cannula at flow rates of < 3 LPM" was simply due to insufficient flow rate. Some centers report initiating therapy at 5-6 LPM high flow nasal cannula (HFNC) to deliver heliox inhalation effectively and then titrating upwards to 10 LPM based on clinical respiratory distress. (2) By setting a maximum of 3 LPM flow rate for nasal cannula delivery in their study, Chaudry et al. could have unintentionally biased the results toward showing less or no benefit from heliox delivered by nasal cannula.
In addition, two studies suggest that the clinical benefit of heliox inhalation by either face mask or nasal cannula may plateau at a clinical score (M-WCAS) = 3 after 60 minutes of therapy. (1,3) This plateau may reflect that patients have received optimal benefit from heliox therapy from both HFNC and face mask delivery systems. Inclusion of patients with an entry clinical score < 3 may have also unintentionally biased the results toward showing less or no benefit from heliox. Specifically, based on a median clinical score of 3 at entry for both groups and an interquartile range, the implication is that at least 25% of patients were recruited who may not benefit from heliox inhalation. Thus, these authors may have demonstrated lack of efficacy due to inclusion of mild bronchiolitis patients who could have been less likely to benefit.
Finally, the high failure rate of face mask delivery (which we agree is an excellent delivery method) is problematic. We agree that future studies may focus on optimal delivery methods that are tolerated well by these sick infants. A consistent theme in the heliox literature is that the sickest patients (often teetering on respiratory failure) appear to benefit the most. (4) Unfortunately, these patients are the most challenging to recruit in sufficient numbers for analysis in clinical trials.
Our neonatology colleagues have pioneered HFNC as well as CPAP technology and methods. Our severe bronchiolitis patients may appreciate us building on their outstanding work and explore optimal flow rates and delivery systems that are well tolerated.
In K. Kim, MD, MBA Kosair Children's Hospital University of Louisville School of Medicine Louisville, KY, USA
Shekhar Ventkataraman, MD Children's Hospital of Pittsburgh University of Pittsburgh Medical Center Pittsbrugh, PA, USA
1. Kim IK, Phrampus E, Sikes K, et al. Helium-Oxygen Therapy for Infants with Bronchiolitis. Archives Pediatrics & Adolescent Medicine, 2011 Dec; 165(12): 1115-1122. 2. Kim IK. Heliox Inhalation Therapy for Bronchiolitis. Available at http://heliox101.webnode.com. Accessed 4-25-13. 3. Martinon-Torres F, Rodr?guez-Nunez A, Martinon-Sanchez JM. Heliox therapy in infants with acute bronchiolitis. Pediatrics. 2002;109(1):68- 73. 4. Liet JM, Ducruet T, Gupta V, Cambonie G. Heliox inhalation therapy for bronchiolitis in infants. Cochrane Database Syst Rev. 2010; (4):CD006915
Conflict of Interest:
None declared