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* 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.
Correspondence to: Gustavo J. Rodrigo, MD, Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Av. 8 de Octubre 3020, Montevideo 11600, Uruguay; e-mail: gurodrig{at}adinet.com.uy.
| Abstract |
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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 FEV1) 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 helium-oxygen 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.
Key Words: acute asthma emergency treatment heliox helium oxygen status asthmaticus
| Introduction |
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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 above-mentioned 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 |
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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 Society15
); 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 Laird20
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 children), 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 FEV1 (absolute and percentage of predicted FEV1). Additional outcomes included the following: (1) physiologic measures: heart and respiratory rates, PaO2, 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 |
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In four studies, patients received a helium-oxygen mixture of 80/209
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
12
13
32
33
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, FEV1).9 12 13 32 33 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. Spirometers 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;
2 = 4.99, p = 0.02).
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2 = 11.9, 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 therapy12
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;
2 = 3.92, p = 0.26).
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2 = 1.36, 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 al33
reported only one heliox-treated patient who experienced dizziness during the intervention. | Discussion |
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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 size12 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 ß-agonist therapy whenever possible. Specifically, we need to perform studies that assess the effect 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.
| Footnotes |
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Received for publication May 21, 2002. Accepted for publication September 12, 2002.
| References |
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