Gustavo J. Rodrigo, MD; Carlos Rodrigo, MD; Charles V. Pollack, MD; and Brian Rowe, MD, MSc, CCFP (EM)

Transcription

1 Use of Helium-Oxygen Mixtures in the Treatment of Acute Asthma* A Systematic Review Gustavo J. Rodrigo, MD; Carlos Rodrigo, MD; Charles V. Pollack, MD; and Brian Rowe, MD, MSc, CCFP (EM) Study objective: To determine the effect of the addition of heliox to standard medical care on the course of acute asthma. Design: Systematic review of randomized and nonrandomized prospective, controlled trials of children and adults that compared heliox to placebo when used in conjunction with other standard acute treatments. Main outcome measures: Pulmonary function tests, hospital admissions, physiologic measures, side effects, and clinical outcomes. Results: Seven trials were selected for inclusion, with a total of 392 patients with acute asthma. Six studies involved adults, and one study dealt solely with children. The main outcome variable was spirometric measurements (peak expiratory flow or FEV 1 ) in six trials. Two studies evaluated the effect of heliox on airways resistance. No significant differences were demonstrated between heliox or oxygen/air groups (standardized mean difference [SMD], 0.20; 95% confidence interval [CI], 0.91 to 0.51; p 0.6). However, the four studies that used heliox to deliver nebulized therapy showed a nonsignificant increase in pulmonary function (SMD, 0.21; 95% CI, 0.43 to 0.01; p 0.06). In two studies of the same subgroup, heliox mixtures produced a significantly greater increase of heart rate than oxygen/air (weighted mean difference, 9.0; 95% CI, 1.27 to 16.8; p 0.02). However, the four studies that used heliox to deliver nebulized therapy reported a nonsignificant difference in hospital admissions (odds ratio, 1.07; 95% CI, 0.46 to 2.48; p 0.9). Overall, heliox appears to be safe and well tolerated. Conclusions: The existing evidence does not provide support for the administration of heliumoxygen mixtures to emergency department patients with moderate-to-severe acute asthma. However, these conclusions are based on between-group comparisons and small studies, and these results should be interpreted with caution. (CHEST 2003; 123: ) Key words: acute asthma; emergency treatment; heliox; helium; oxygen; status asthmaticus Abbreviations: CI confidence interval; ED emergency department; OR odds ratio; PEF peak expiratory flow; SMD standardized mean difference; WMD weighted mean difference Helium and oxygen mixtures (heliox) have been used sporadically in respiratory medicine for decades. For example, as early as 1935, heliox was *From the Departamento de Emergencia (Dr. G. Rodrigo), Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay; Unidad de Cuidado Intensivo (Dr. C. Rodrigo), Asociación Española 1a de Socorros Mutuos, Montevideo, Uruguay; Department of Emergency Medicine (Dr. Pollack), Pennsylvania Hospital, Philadelphia, PA; and Division of Emergency Medicine (Dr. Rowe), University of Alberta, Edmonton, Alberta, Canada. Manuscript received May 21, 2002; revision accepted September 12, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( permissions@chestnet.org). Correspondence to: Gustavo J. Rodrigo, MD, Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Av. 8 de Octubre 3020, Montevideo 11600, Uruguay; gurodrig@ adinet.com.uy. introduced to the medical community for treatment of upper and lower airway obstruction. 1 The interest in heliox for treatment of asthma became prominent in the 1980s when deaths from asthma began to rise. Due to their low density with respect to air (80% helium/20% oxygen mixture has a density approximately one third that of air), heliox mixtures have the For editorial comment see page 675 potential to decrease airway resistance and therefore decrease the work of breathing in those situations associated with increased airway resistance. Thus, they may provide benefit to patients with obstructive lesions of the larynx, trachea, and airways. Additionally, research using heliox mix- CHEST / 123 / 3/ MARCH,

2 tures has demonstrated a greater percentage of lung particle retention and a large delivery of albuterol from both metered-dose inhalers and nebulizers. 2,3 This suggests that one of the beneficial effects of heliox use in reactive airway diseases may include improved deposition of aerosolized bronchodilators. 4,5 Heliox has also been recommended as a useful adjunct in the adult patient with severe asthma, both during spontaneous ventilation as well as during mechanical ventilation. 6 9 Reports describing the use of heliox in children with asthma also provide conflicting results, with some failing 10 and others showing a benefit. 11 However, much of the evidence arises from either small trials or uncontrolled studies. Fortunately, controlled trials comparing the effectiveness of heliox to oxygen for -agonist therapy have recently been performed. 12,13 Much is unknown regarding the use of heliox in acute asthma. 14 First, without controlled studies, the effect of heliox is difficult to assess. Second, the duration of administration and optimal helium/oxygen mixture remain undetermined. Finally, the cost of treatment is relatively high. Given the abovementioned controversies, the need for a systematic review exists. However, to date no systematic reviews on this topic have been published, and it is not surprising that heliox use is variable and institution specific. Despite the lapse of 60 years since its use was first proposed, the role of heliox in treating patients with acute severe asthma is unclear. The objective of this systematic review was to determine the effect of the addition of heliox to standard medical care on the course of acute asthma, as measured by pulmonary function and clinical end points. Materials and Methods Search Strategy for Identification of Studies A search was carried out using five search strategies to identify potentially relevant trials. Firstly, we searched MEDLINE (1966 through 2002), EMBASE (1980 through 2002), and CINAHL (1982 through 2002) databases using the following medical subject headings, full text, and keyword terms: Emerg* OR acute asthma OR status asthmaticus OR severe asthma AND heliox OR helium AND oxygen. Secondly, an advanced search of the Cochrane Controlled Trials Register was completed using the above-mentioned search strategy. Thirdly, references from included studies, reviews, and texts were searched for citations. Fourthly, authors of the studies were contacted to locate other unpublished or in progress studies that met the inclusion criteria. Finally, a hand searching of the 20 most productive respiratory care journals was completed. Criteria Selection Only controlled (randomized or nonrandomized) prospective trials were considered for inclusion. Both parallel group and crossover designs were considered. Studies including either children or adult ( 18 years of age) patients presenting to an emergency department (ED) or equivalent care settings for treatment of acute asthma were considered for inclusion in the review. Age formed one of the subgroups examined in the review. All study participants had a clinical diagnosis of acute asthma exacerbation (according to accepted criteria such as those published by the American Thoracic Society 15 ); studies involving solely patients with COPD were excluded. Studies including both COPD and asthmatic patients were to be considered if patients with acute asthma could be separately analyzed by reviewing of the study or through correspondence with the authors. Studies involving acute asthma patients requiring mechanical ventilation at presentation were also excluded. Only studies comparing treatment with inhaled heliox to control (oxygen or air) were considered. Study co-interventions such as corticosteroids and other drugs were monitored and formed planned subgroup comparisons when possible. Different helium-oxygen mixtures (80/20, 70/30, 60/40) and duration of heliox administration were considered in subgroup analysis. Methods of the Review Titles, abstracts, and citations were independently reviewed by two reviewers (G.J.R., C.R.) to assess potential relevance for full review. From the full text, both reviewers independently assessed studies for inclusion based on the criteria for population, intervention, study design, and outcomes. Agreement was measured using statistics and any disagreement over study inclusion was resolved by a third reviewer (C.V.P. or B.R.) and consensus. Data extraction included the following items: (1) population: age, gender, number of patients studied, patient demographics, withdrawals; (2) intervention: agent, dose, route of delivery, and duration of therapy; (3) control: concurrent treatments; (4) outcomes; and (5) design: method of randomization and allocation concealment. Methodologic Quality The methodologic quality of each trial was evaluated using the instrument of Jadad et al. 16 This instrument assesses the quality of randomization and blinding and reasons for withdrawal on a score of 0 (worst) to 5 (best). Statistical Methods For continuous outcomes, the results of individual studies were calculated as a random effects weighted mean difference (WMD) or standardized mean difference (SMD). 17 The WMD was reported for variables using the same unit of measure: the weighted sum of the difference of each trial between the mean of the experimental and the control group, reported on the same scale. The SMD, reported in SD units, was used when the change in the same pulmonary function test was reported in different units: the weighted sum of the group mean difference of each trial divided by its pooled SD. 18 The contribution of each trial to the pooled estimate was proportional to the inverse of the variance. 19 Homogeneity of effect sizes were tested with the method of DerSimonian and Laird 20 with p 0.1 as the cut point for significance. The pooled effect sizes were presented with the 95% confidence interval (CI). Sensitivity analysis was performed using: age (adults vs chil- 892 Reviews

3 dren), different helium-oxygen mixtures (80/20 vs 70/30), and methodologic quality (Jadad score 3 vs 3). The primary outcome measures were changes in peak expiratory flow (PEF) [absolute and percentage of predicted PEF] and FEV 1 (absolute and percentage of predicted FEV 1 ). Additional outcomes included the following: (1) physiologic measures: heart and respiratory rates, Pao 2, arterial oxygen saturation, pulsus paradoxus, and vital signs; (2) side effects/adverse effects; and (3) clinical outcomes: need for mechanical ventilation and admissions to the hospital. The timing of assessment was during breathing heliox (15 to 60 min) and assessments included up to 6 h of treatment in the ED. The meta-analysis was performed with Metaview 4.1 (Cochrane Review Manager; Cochrane Collaboration, Oxford, UK). Results The initial search produced 89 potentially relevant citations. Of these, 21 studies were reviewed in full text for possible inclusion. Fourteen studies were excluded for the following reasons: noncontrolled trials, 7,8,21,22 hospitalized patients, 10 patients receiving mechanical ventilation, 23 anecdotal evidence, 24,25 patients with COPD, patients with bronchiolitis, 30 and out-of-hospital setting. 31 A total of seven controlled, prospective trials conducted in North America were selected for inclusion (Table 1). 9,11 13,32 34 One study might not have been peer reviewed because it was published as a correspondence. 33 The two reviewers independently agreed on the studies to be included and excluded in all cases. Six studies involved adults, 9,12,13,32 34 and one study involved children. 11 All studies reported moderate-to-severe reductions in the mean pulmonary function measures at presentation. For example, mean pretreatment PEFs were reported as follows: 43% predicted, to 42% predicted, L/min, L/min, 32 and 40% predicted. 34 Inhaled albuterol and corticosteroids were used in all trials. The seven studies included in the review were not similar. Four of them evaluated the effect of heliox when it was used to deliver nebulized therapy. 12,13,33,34 In these studies, heliox was used to aerosolized medications, but patients were able to entrain air; the patients were not breathing pure heliox. These studies were designed primarily to determine whether nebulizer therapy driven by heliox was more effective than nebulizer therapy driven by air/oxygen. The other three studies 9,11,32 assessed the effect of replacing the airoxygen mixture in the lungs with a heliox mixture. These three studies were designed to wash out the air in the lungs and replace the gas mixture flowing through the airways with helium and oxygen. They evaluated the effect of heliox on airways resistance. In four studies, patients received a helium-oxygen mixture of 80/20 9,11,13,33 ; all others used the 70/30 mixture. The duration of heliox therapy was between 15 min and 480 min. Six studies were randomized, controlled trials, 11 13,32 34 and only one study was a nonrandomized, prospective, controlled study. 9 The seven studies included a total of 392 patients. Using the Jadad method, two studies reported a score of 3. Overall, the methodologic quality was rated as low. There was excellent agreement between quality scores of the two reviewers for the six trials ( 1.0). Six trials examined response to treatment using pulmonary function tests (PEF, FEV 1 ). 9,12,13,32 34 There do appear to be unresolved issues concerning PEF measurements in patients breathing helium-oxygen mixtures, because helium is lighter than nitrogen. In three of the articles included here, 12,32,33 PEF was measured with a peak flowmeter and the authors did not report correction for gas density. By contrast, in two studies included here, 9,11 PEF measurements made breathing heliox needed to be corrected by a factor of 1.32 when measured using a peak flowmeter. Spirom- Table 1 Characteristics of Trials Included in the Review* Trials Design Patients, No. (Age Range, yr) Mean Baseline Severity Quality Score Helium-O 2 Mixture -Agonist Protocol Dorfman et al 33 R 39 (18 55) 70% PEF 1 80/20 Alb IB NEB continuous Henderson et al 12 R, SB 204 (18 65) 50% PEF 2 70/30 Alb 5 mg NEB 3 Kass and Terregino 32 R 23 (18 50) 200 L/min PEF 2 70/30 Alb 5 mg NEB 1 Kress et al 13 R, SB 45 (18 50) 50% FEV /20 Alb 5 mg NEB 3 Kudukis et al 11 R, DB 18 (16 mo 17 yr) 3 80/20 Alb NEB continuous Manthous et al 9 NR 27 (21 66) 250 L/min PEF 1 80/20 Alb 5 mg NEB 1 Rose et al 34 R, DB 18 (18 55) 40% PEF 4 70/30 Alb NEB continuous *Alb Albuterol; IB ipratropium bromide; NEB nebulized; NR nonrandomized; R randomized; DB double blind; SB single blind. CHEST / 123 / 3/ MARCH,

4 eters were used for the two trials in this review, 12,13 which should not require correction since they are volumetric devices. Two of the three studies designed to wash out the air in the lungs and replace it with helium and oxygen presented pulmonary function measures. 9,32 Results were pooled at 15 to 20 min after the start of treatment. No significant differences were demonstrated between heliox or oxygen/air groups (SMD, 0.20; 95% CI, 0.91 to 0.51; p 0.6) [Fig 1]. The test of heterogeneity was not significant (p 0.2). In two trials of this subgroup, 11,31 heliox mixtures produced a nonsignificantly diminution of heart rate than did oxygen/air (WMD, 10.0; 95% CI, 21.7 to 1.54, p 0.09; , p 0.02). However, the four trials that used heliox to deliver nebulized therapy, 12,13,33,34 showed a nonsignificant increase in pulmonary function at 30 to 120 min after treatment (SMD, 0.21; 95% CI, 0.43 to 0.01; p 0.06). No significant heterogeneity was demonstrated (p 0.5). In two studies of the same subgroup, 13,33 heliox mixtures produced significantly greater increase of heart rate than oxygen/air (WMD, 9.0; 95% CI, 1.27 to 16.8; p 0.02); however, there was significant heterogeneity ( , p 0.005). Sensitivity analysis was not performed because we found only one children s study and two trials with Jadad score 3. Hospital Admissions The four studies that used heliox to deliver nebulized therapy 12,13,33,34 reported hospital admissions (Fig 2); no significant differences were identified between patients treated with heliox or oxygen/air at the end of the study period (odds ratio [OR], 1.07; 95% CI, 0.46 to 2.48, p 0.9; , p 0.26). Other Outcomes With regard to additional outcomes, two studies that evaluated the effect of heliox on airways resistance reported pulsus paradoxus. 9,11 We found a significant difference in favor of heliox mixtures for decreasing pulsus paradoxus (WMD, 6.40; 95% CI, 10.5 to 2.20, p 003; , p 0.2). Finally, adverse effects were reported in two trials; in the study by Henderson et al, 12 one patient became hypoxic while receiving the 70/30 heliox mix, and the study by Dorfman et al 33 reported only one helioxtreated patient who experienced dizziness during the intervention. Discussion This systematic review has attempted to incorporate the best available evidence on heliox use in patients with acute asthma. We found five randomized trials and one prospective, nonrandomized, placebo-controlled clinical trial that compared heliox to other forms of standard care. There was only one study in children. Several important conclusions arise from the analysis. Overall, the addition of heliox to standard medical care during the course of acute asthma is not more effective, in terms of pulmonary function, than a comparison delivery with air or oxygen. However, the review found two types of studies. The pooled analysis from the studies that evaluated the effect of heliox on airway resistance Figure 1. Pooled SMDs in lung function, after treatment with inhaled heliox (treatment group) or oxygen/air (control group). SMD represents difference in means between groups displayed on SD units. Width of horizontal line represents 95% CI around point estimate (gray square). Size of point estimate represents relative weight (percentage of weight) of each trial in the pooled summary estimate (diamond). 894 Reviews

5 Figure 2. Pooled ORs of hospital admissions comparing treatment with inhaled heliox (treatment group) or oxygen/air (control group). A logarithmic scale was used for plotting the ORs. Width of horizontal line represents 95% CI around point estimate (black square). Size of point estimate represents relative weight (percentage of weight) of each trial in the pooled summary estimate (diamond). Vertical line is line of no effect (OR, 1.0). revealed that there are not significant differences between groups. However, the studies that used heliox to deliver nebulized therapy showed a trend toward an increase in pulmonary function, suggesting that heliox could be more effective than oxygen/ air in delivering inhaled particles of -agonists to the distal airways. The significant increase of heart rate that showed these studies supports this presumption, although this result was heterogeneous between studies. However, at the end of the study period, no significant differences were identified between patients treated with heliox or oxygen/air in hospital admissions. With regard to additional outcomes, two studies (one adult and one pediatric) that assessed the effect of heliox on airways reported a significant difference in favor of heliox mixtures for decreasing pulsus paradoxus. If we considered pulsus paradoxus as an indirect measure of the work of breathing, this result suggested some benefit. However, this finding is based in only two trials (one nonrandomized); consequently, this information should be interpreted with caution. There was insufficient information to pool other outcomes or side effects, so no firm conclusions regarding adverse effects can be drawn. In one study, one patient became hypoxic while receiving the 70/30 heliox mixture. Overall, heliox appears to be safe and well tolerated in the mixtures used in these studies to treat acute asthma. Strengths and Limitations Our analysis is subject to the general problems of meta-analysis. There is a possibility of publication bias in this meta-analysis. For example, by missing unpublished trials, we may be providing an inaccurate estimation of the effect of heliox treatment. However, a comprehensive search of the published literature for potentially relevant studies was conducted, using a systematic strategy to avoid bias. This was followed by attempts to contact corresponding and first authors. There is also a possibility of study selection bias. However, we employed two independent reviewers, and we feel confident that the studies excluded were done so for consistent and appropriate reasons. Like all systematic reviews, this meta-analysis is limited by the quality of existing research and how the data are reported. Only two of included trials were considered high quality. Interestingly, the trial with the largest sample size 12 failed to detect any difference between groups in lung function. However, this study used a 70/30 heliox mixture and did not describe its heliox delivery system in detail. Finally, the number and size of studies included was small. So, the current conclusions may be modified by the publication of results from larger trials. Implications for Practice The existing evidence fails to demonstrate that the administration of helium-oxygen mixtures to ED adult patients with moderate-to-severe asthmatic exacerbations alters outcomes. We would conclude at this time that there is a lack of evidence to support the role of heliox in the initial treatment of acute asthma adult patients. With only one study in children, there are not enough data to establish the role of heliox in this age group. Implications for Research Many questions regarding the treatment of acute asthma with heliox remain unanswered; most importantly, larger and more definitive controlled studies are needed to clarify the efficacy. Additional studies are needed to confirm the subgroup findings from this review suggesting a possible benefit of heliox when it was used to deliver nebulized therapy. In future studies, severity must be clearly defined and based on presenting pulmonary function results and response to initial -agonist therapy whenever possible. Specifically, we need to perform studies that assess the effect CHEST / 123 / 3/ MARCH,

6 of heliox in acute asthma patients who fail to respond to the ED treatment (to prevent intubation). Studies involving children need to be performed to determine the effect of heliox in this age group. Further studies are required to examine the effect of heliox based on the prior inhaled steroid use in patients presenting to the ED with an asthma exacerbation. The effect of treatment may differ based on inhaled steroid use, and the answer to this question remains unclear. Inhaled steroids are increasingly employed, and the development of high-dose inhaled steroids with lower systemic activity suggests that this would be an important area for future research. Future research on acute asthma must concentrate on well-defined outcomes which may lead to more informative reviews. More specifically, criteria for discharge and reporting of lung function test data in a systematic fashion would assist in further work. Finally, better description of the methodology would also be beneficial. References 1 Barach AL. The use of helium in the treatment of asthma and obstructive lesions in the larynx and trachea. Ann Intern Med 1935; 9: Anderson M, Svartengren M, Bylin G, et al. Deposition in asthmatics of particles inhaled in air or in helium-oxygen. Am Rev Respir Dis 1993; 147: Goode ML, Fink JB, Dhand R, et al. Improvement in aerosol delivery with helium-oxygen mixtures during mechanical ventilation. Am J Respir Crit Care Med 2000; 163: Hess DR, Acosta FI, Ritz RH, et al. The effect of heliox on nebulizer function using a -agonist bronchodilator. Chest 1999; 115: Habib DM, Garner SS, Brandeburg S. Effect of heliumoxygen on delivery of albuterol in pediatric volume cycled lung model. Pharmacotherapy 1999; 19: Shiue ST, Gluck EH. The use of helium-oxygen mixtures in the support of patients with status asthmaticus and respiratory acidosis. J Asthma 1989; 26: Gluck EH, Onorato DJ, Castriotta R. Helium-oxygen mixtures in intubated patients with status asthmaticus and respiratory acidosis. Chest 1990; 98: Kass JE, Castriotta RJ. Heliox therapy in acute severe asthma. Chest 1995; 107: Manthous CA, Hall JB, Melmed A, et al. Heliox improves pulsus paradoxus and peak expiratory flow in nonintubated patients with severe asthma. Am J Respir Crit Care Med 1995; 151: Carter ER, Webb CR, Moffitt DR. Evaluation of heliox in children hospitalized with acute severe asthma: a randomized crossover trial. Chest 1996; 109: Kudukis TM, Manthous CA, Schmidt GA, et al. Inhaled helium-oxygen revisted: effect of inhaled helium-oxygen during the treatment of status asthmaticus in children. J Pediatr 1997; 130: Henderson SO, Acharya P, Kilaghbian T, et al. Use of heliox driven nebulizer therapy in the treatment of acute asthma. Ann Emerg Med 1999; 33: Kress JP, Noth I, Gehlbach BK, et al. The utility of albuterol nebulized with heliox during acute asthma exacerbations. Am J Respir Crit Care Med 2002; 165: Manthous C, Morgan S, Pohlman A, et al. Heliox in the treatment of airflow obstruction: a critical review of the literature. Respir Care 1997; 42: American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987; 136: Jadad AR, Moore RA, Carrol D, et al. Assessing the quality of reports of randomized controlled trials: is blinding necessary? Control Clin Trials 1995; 134: Olkin I. Statistical and theoretical considerations in metaanalysis. Clin Epidemiol 1995; 48: Hasselblad V, Hedges LV. Meta-analysis of screening and diagnostic tests. Psychol Bull 1995; 117: Robins J, Breslow N, Greenland S. Estimators of the Mantel- Haenszel variance consistent in both sparse data and largestrata limiting models. Biometrics 1986; 42: DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: Shiue ST, Gluck EH. The use of helium-oxygen mixtures in the support of patients with status asthmaticus and respiratory acidosis. J Asthma 1989; 26: Verbeek PR, Chopra A. Heliox does not improve FEV 1 in acute asthma patients. J Emerg Med 1998; 16: Shaeffer EM, Pohlman A, Morgan S, et al. Oxygenation in status asthmaticus improves during ventilation with heliumoxygen. Crit Care Med 1999; 27: Polito A, Fessler H. Heliox in respiratory failure from obstructive lung disease. N Engl J Med 1995; 332: Austran F. Heliox inhalation in status asthmaticus and respiratory acidemia: a brief report. Heart Lung 1996; 25: Swidwa DM, Montenegro HD, Goldman MD, et al. Heliumoxygen breathing in severe chronic obstructive pulmonary disease. Chest 1985; 87: Jolliet P, Tassaux D, Thouret JM, et al. Beneficial effects of helium:oxygen vs air:oxygen noninvasive pressure support in patients with decompensated chronic obstructive pulmonary disease. Crit Care Med 1999; 27: deboisblanc BP, DeBleiux P, Resweber S, et al. Randomized trial of the use of heliox as a driving gas for updraft nebulization of bronchodilators in the emergency treatment of acute exacerbations of chronic obstructive pulmonary disease. Crit Care Med 2000; 28: Jaber S, Fodil R, Carlucci A, et al. Noninvasive ventilation with helium-oxygen in acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 161: Hollman G, Shen G, Zeng L, et al. Helium-oxygen improves clinical asthma scores in children with acute bronchiolitis. Crit Care Med 1998; 26: L Her E, Monchi M, Joly B, et al. Helium-oxygen breathing in the early emergency care of acute severe asthma: a randomized pilot study. Eur J Emerg Med 2000; 7: Kass EJ, Terregino CA. The effect of heliox in acute severe asthma: a randomized controlled trial. Chest 1999; 116: Dorfman TA, Shipley ER, Burton JH, et al. Inhaled heliox does not benefit ED patients with moderate to severe asthma. Am J Emerg Med 2000; 18: Rose JS, Panacek EA, Miller P. Prospective randomized trial of heliox-driven continuous nebulizers in the treatment of asthma in the emergency department. J Emerg Med 2002; 22: Reviews