Abstract
Background
Due to its low density properties, helium‐oxygen mixtures have the potential to decrease the work of breathing and possibly avoid the need for intubation and mechanical ventilation in patients with respiratory failure.
Objectives
To determine the effect of the addition of helium/oxygen mixtures (heliox) to standard medical care during ventilated and non‐ventilated acute exacerbations of COPD.
Search methods
Randomized controlled trials were identified from the Cochrane Airways Review Group asthma Register. Primary authors and experts were contacted. References from included and excluded studies, known reviews and texts were also searched.
Selection criteria
Studies were selected for inclusion if they compared treatment with heliox to placebo (oxygen or air) in randomized controlled trials in adults with an exacerbation of COPD.
Data collection and analysis
Data from all trials were combined using the Review Manager (version 4.1). We planned to perform: 1) random effects weighted mean difference (WMD), with 95% confidence intervals (95% CI), 2) Homogeneity of effect sizes with the Dersimonian and Laird method with p<0.1 as the cut point for significance, and 3) sensitivity analysis on different helium‐oxygen mixtures (80/20 vs 70/30), and 4) methodological quality (Jadad score >2 vs. <3). An update search conducted in September 2002 identified one further excluded study.
Main results
Four studies, all published between 1997 and 2000 met the inclusion criteria. Two studies compared heliox‐oxygen vs. air‐oxygen in decompensated COPD patients who were not ventilated. One study was performed in mechanical ventilated patients and one in patients undergoing noninvasive pressure support ventilation (NIPSV). Data could be obtained for only two of the studies. One was a randomized crossover study of 70:30 helium‐oxygen vs air‐oxygen that involved nineteen patients with acute severe COPD, hospitalized in an intensive care unit for NIPSV . In the patients receiving heliox, arterial PCO2 fell more; WMD 0.8 kPa (95% CI 0.26, ‐1.34). The second was a trial involving 47 patients with acute COPD, who presented to an Emergency Department, randomized to receive updraft nebulization of albuterol and ipratropium bromide using 80% helium and 20% oxygen or compressed air as the driving gas. Treatments were administered at 0, 20, 40, and 120 minutes after randomization. There were no significant differences in the change of FEV1 and FVC between the two groups by either the 1 or 2 hours point, although a small improvement in FEF 25‐75 was significantly greater in the heliox group than in the air group.
Authors' conclusions
There is currently insufficient evidence to support the use of helium‐oxygen mixtures to treat acute exacerbations of COPD in either ventilated or non‐ventilated patients. Suitably designed randomised controlled trials with the endpoint being the avoidance of mechanical ventilation may be justified.
Plain language summary
Helium‐oxygen mixture for the treatment of exacerbations of chronic obstructive pulmonary disease
Mixtures of helium and oxygen (heliox) may make breathing easier, but there is not enough evidence from trials to show whether these mixtures can relieve attacks of COPD (chronic obstructive pulmonary disease).
Background
As early as 1935 helium and oxygen mixtures (heliox) were introduced to the medical community for treatment of airway obstruction (Barach 1935). There was a resurgence in interest in heliox in the 1980's for the treatment of acute asthma. Due to their low density with respect to air, heliox mixtures have the potential to decrease airway resistance and therefore decrease the work of breathing in situations associated with increased airway resistance. Thus, heliox treatment may benefit patients suffering from obstructive lesions of the larynx, trachea, and airways. Additionally, the deposition of inhaled particles in a heliox mixture was shown to be improved, with a greater percentage of particle retention in the lung (Anderson 1993). This suggests that one of the beneficial effects of heliox in situations of reactive airway disease may be the improved deposition of aerosolized bronchodilators.
On the other hand, Hess 1999 concluded that the inhaled mass of albuterol decreased significantly when the nebulizer was powered with heliox rather than air. The authors recommended that the flow to power the nebulizer should be increased when heliox is used. Patients with chronic obstructive pulmonary disease (COPD) have increased resistance to flow due to narrowing of the airways by edema and mucous, and loss of lung collagen, and this increased resistance to flow results in greater work of breathing. It can be expected that breathing a high mixture of helium (>60%) would result in lower resistance to flow, and in a decrease in work of breathing. Research on patients with stable COPD (Swidwa 1985) has demonstrated a decrease in lung hyperinflation (as measured by a fall in functional residual capacity by 15%). This would be expected to place the respiratory muscles at a better mechanical advantage and decrease the work of breathing. Indeed, a significant decline in VCO2 was also noted supporting a reduced work of breathing. Lastly, there was a small but significant fall in the PaCO2. These findings lend support to the therapeutic use of heliox in patients with COPD. Thus, helium‐oxygen mixtures have the potential to stabilize patients with acute respiratory failure who might otherwise require intubation and mechanical ventilation. However, little is unknown regarding the use of heliox in treating patients with acute exacerbations of COPD.
Objectives
The objective of this systematic review was to determine the effect of the addition of heliox to standard medical care during acute COPD exacerbations, as measured by pulmonary function and clinical endpoints.
Methods
Criteria for considering studies for this review
Types of studies
Only randomized, single or double blind, placebo controlled trials (either parallel group or crossover) were considered for inclusion.
Types of participants
Participants should be adults ( >18 years of age) with a clinical diagnosis COPD (according to accepted criteria such as those published by the ATS) experiencing an exacerbation of their COPD, presenting to emergency rooms or other acute care settings. Studies involving patients exclusively with asthma were not included. Studies involving both COPD and asthmatic patients were considered if patients with COPD could be separately analyzed by review the study or through correspondence with the authors. COPD patients requiring mechanical or noninvasive ventilation at presentation were included.
Types of interventions
All patients must have been treated with either helium‐oxygen or air‐oxygen administered in random order. Study co‐interventions such as the use of corticosteroids and other drugs were monitored and would form subgroup comparisons when possible. Also, different helium‐oxygen mixtures (80/20, 70/30, 60/40), and duration of heliox administration would be considered in subgroup analysis.
Types of outcome measures
Primary outcomes
The primary outcome measures were changes in peak expiratory flow (PEF; absolute and percent of predicted), forced expiratory volume in the first second (FEV1; absolute and percent of predicted)
Secondary outcomes
Additional outcomes were: 1) Symptom score/symptoms/signs (wheezing, shortness of breath, dyspnea, accessory muscle use) 2) Physiological measures: PaO2, SaO2, tidal volume, minute ventilation, inspiratory time and vital signs 3 ) Side effects/adverse effects 4) Clinical outcomes: need for mechanical ventilation, admissions to the hospital. The timing of assessment was before, during, and 15‐30 minutes after breathing heliox.
Assessments included up to 6 hours of treatment.
Search methods for identification of studies
Electronic searches
A search was carried out using the Cochrane Airways group "COPD RCT" register, derived from a search of EMBASE, MEDLINE, and CINAHL for the years 1966 to 2000. In addition, hand searching of the 20 most productive respiratory care journals was completed and relevant RCTs were added to the register, including those published in languages other than English. Search of this register was completed using the following terms:
(((Emerg* OR acute OR exacerbat*) AND (COPD OR Emphysema OR Chronic bronchitis OR bronchitis OR CAL OR COAD)) AND ((Heliox OR Helium) AND Oxygen))
An advanced search of CENTRAL, the Cochrane Controlled Trials Register was completed using the above search strategy.
Searching other resources
Authors of all studies were contacted to locate other unpublished or "in progress" studies which meet the inclusion criteria. References from included studies and any identified reviews were searched for citations. Also we contacted companies that sell heliox or delivery systems for it.
Data collection and analysis
Selection of studies
Titles, abstracts, and citations were independently reviewed by the two reviewers (GJR and CR) 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 kappa statistic values. Any disagreement over inclusion was resolved by a third reviewer (CVP) and consensus.
Data extraction and management
Two reviewers (GJR and CR) would independently extracted data from included trials and enter results into the Cochrane Collaboration software program (Review Manager). Data extraction included the following items:
Population: age, gender, number of patients studied, patient demographics, withdrawals
Intervention: agent, dose, route of delivery, and duration of therapy
Control: concurrent treatments (beta‐agonist, ipratropium bromide, corticosteroids, and aminophylline)
Outcomes: Pulmonary function measures (FEV1 and PEF), symptom score/symptoms (wheezing, shortness of breath, dyspnea, accessory muscle use), physiological measures (PaO2, SaO2, tidal volume, minute ventilation, inspiratory time and vital signs), side effects/adverse effects, clinical outcomes (need for mechanical ventilation, admissions to the hospital)
Design: method of randomization and allocation concealment.
Assessment of risk of bias in included studies
Two reviewers (GJR and CR) assessed the methodological quality of the included trials using two methods. First, using the Cochrane approach to assessment of allocation concealment: 1) Grade A: Adequate concealment; 2) Grade B: Uncertain; 3) Grade C: Clearly inadequate concealment. Second, each study was assessed for validity on a 0‐5 scale, by the method of Jadad (Jadad 1995): 1) Was the study described as randomized? (1=yes, 0=no); 2) Was the study described as double‐blind? (1=yes, 0=no); 3) Was there a description of withdrawals and drop outs? (1=yes, 0=no); 4) Was the method of randomisation well described and appropriate? (1=yes, 0=no); 5) Was the method of double‐blinding well described and appropriate? (1=yes, 0=no); 6) Deduct 1 point if methods of randomisation or blinding were inappropriate. Inter‐rater reliability was measured for both quality scales by using kappa statistics.
Assessment of heterogeneity
For pooled effects, heterogeneity would be tested using the Breslow‐Day test; with p<0.1 considered as statistically significant.
Data synthesis
All included trials would be combined using the Review Manager (version 4.1). For continuous variables the results of individual studies would be calculated as random effects weighted mean difference (WMD) or standardized mean difference (SMD), with 95% Confidence Intervals (CI). All similar studies would be pooled using random effects WMD/SMD and 95% CIs. For dichotomous variables, a random effects relative risk (RR) with 95% CI would be calculated for individual studies. All similar studies would be pooled using random effects RR and 95% CIs.
Sensitivity analysis
Sensitivity analysis would be performed using:
Co‐interventions with corticosteroids vs. none
Different helium‐oxygen mixtures (80/20, vs. 70/30 or 60/40)
Duration of heliox administration (long vs. short)
Methodological quality (concealment Grade A vs. Grades B & C, or Jadad score >2 vs. <3)
Random effects vs. fixed effects modelling
Results
Description of studies
Results of the search
Three‐hundred and forty two articles were identified in this search. Of these, the reviewers selected eighteen papers about the use of heliox‐oxygen in airflow obstruction as potentially eligible.
Included studies
We selected four studies (Gerbeaux 1997; Jolliet 1999; Onn 1999; de Boisblanc 2000) published between 1997 and 2000. One study was from France, one from Israel, one from Switzerland, and one from USA. The studies compared heliox‐oxygen vs. air‐oxygen in decompensated COPD non‐ventilated patients, (two studies), in mechanical ventilated patients (one study), and in noninvasive pressure support ventilated patients (one study). Two studies were available in abstract form only, and attempts to contact the authors were unsuccessful so it was not possible to include data from these studies in the meta‐analysis (Gerbeaux 1997; Onn 1999). Therefore, we extracted data from two studies (Jolliet 1999; de Boisblanc 2000). An update search conducted in September 2002 identified one excluded study (Gerbeaux 2001).
The Jolliet et al study (Jolliet 1999) was designed to test the hypothesis that, in decompensated COPD, noninvasive pressure support ventilation (NIPSV) using a 70:30 helium:oxygen mixture instead of 70:30 air:oxygen mixture could reduce dyspnea and improve ventilatory variables, gas exchange and haemodynamic tolerance. The study involved 19 severe COPD decompensated patients (FEV1 0.83 L, PCO2 7.3 kPa). The protocol sequence was: 45 min of NIPSV with air:oxygen or helium:oxygen, no ventilation for 45 min, and 45 min of NIPSV with air:oxygen or helium:air. On the other hand, deBoisblanc et al. (de Boisblanc 2000) performed a randomized trial to determine whether the bronchodilator effects of albuterol and ipratropium bromide are greater if updraft nebulization is driven by 80% helium and 20% oxygen than if driven by compressed room air during the treatment of an acute exacerbation of COPD disease. Treatments were given at 0, 20, 40 and 120 minutes after randomization. The study involved 47 COPD decompensated patients (FEV1 40% of predicted), PaCO2 7.3 kPa).
Excluded studies
Nine articles were excluded because they mainly involved acute asthma patients (Shiue 1989Gluck 1990Kass 1995; Manthous 1995; Carter 1996; Kudukis 1997; Verbeek 1998; Henderson 1999; Kass 1999); five were excluded due to: 1) no randomized trials on COPD decompensated patients (Diehl 1999; Esquinas 2000; Jaber 2000); 2) helium‐oxygen was tested in stable COPD patients (Swidwa 1985); and 3) letter with anecdotal evidence (Polito 1995). See Characteristics of excluded studies.
Risk of bias in included studies
The first manuscript (Jolliet 1999) presented a randomized, crossover design. Its methodological quality was high (Jadad score=3), but it did not report the use of concealment allocation. On the other hand, the second one (de Boisblanc 2000) showed a randomized design; its methodological quality was low (Jadad=2), and it did not report concealment allocation. Full manuscripts were not available on two studies (Gerbeaux 1997; Onn 1999), so they were not rated.
Effects of interventions
In Jolliet 1999, air:oxygen and helium:oxygen both decreased respiratory rate and increased tidal volume and minute ventilation. Both gases increased total respiratory cycle time and decreased the inspiratory/total time ratio, the reduction in the latter being significantly greater with helium:oxygen (Change in Ti/Ttot ‐0.27 (SD 0.1) for helium v. ‐0.23 (SD 0.07) for air , p<0.05). Peak inspiratory flow rate increased more with helium:oxygen. PaO2 increased with both gases, whereas PaCO2, decreased more with helium:oxygen (mean fall in PaCO2 of ‐7.2 kPa (SD 0.9) with helium v. ‐6.4 SD 0.8 with air, p<0.05). Dyspnea score (Borg scale) decreased more with helium:oxygen than with air:oxygen, (mean change ‐1.8 points (SD 1.1) on helium and ‐0.8 points (SD 0.9) on air, p<0.05). No clinical outcome data such as duration of non‐invasive ventilation, or need for intubation and mechanical ventilation were available
In the second randomized trial (de Boisblanc 2000) there were no significant differences in the change of FEV1 and FVC between the two groups by either the 1 or 2 hours point. However, the small improvement in FEF 25‐75 was significantly greater in the heliox group than in the air group ( increase with Heliox 15% (95% CI 8% to 21%) and with air 7% (95% CI 4% to 11%), p=0.05). The authors concluded that these data do not support the routine use of heliox as a driving gas for nebulization of bronchodilators in acute exacerbations of COPD.
Discussion
To date, we could find only two adequate studies investigating the use of heliox to treat acute exacerbations of airway obstruction due to COPD. These studies included non‐ventilated and noninvasively ventilated patients. The data suggest that heliox can improve gas exchange and reduce symptoms in patients receiving non‐invasive ventilation for respiratory failure due to exacerbations of COPD, but it has little additional benefit in non‐ventilated acute COPD patients.
The improvement in arterial PCO2 was small, but could be sufficient to avoid the need for intubation and mechanical ventilation in some patients. There are, however, no published data to support this conclusion. Suitably designed randomised controlled trials with the endpoint being the avoidance of mechanical ventilation may be justified.
Authors' conclusions
Implications for practice.
We conclude that currently, there is not enough evidence to support the use of helium‐oxygen mixtures to treat acute exacerbations of COPD in either ventilated or non‐ventilated patients.
Implications for research.
Questions regarding the treatment of acute COPD exacerbations with heliox remain unanswered:
Larger randomized and controlled studies are needed to clarify its efficacy
These studies are needed to allow sub‐group analyses (severity, clearly defined and based on presenting pulmonary function results and response to initial beta‐agonist and/or anticholinergic therapy whenever possible, different helium‐oxygen mixtures, and duration of heliox administration).
Studies are required to examine the effect of heliox with specific co interventions (i.e. corticosteroids and other drugs).
Future research 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.
Feedback
Quality of the review
Summary
I find it surprising that the Cochrane Library have published a review that concludes that there is insufficient evidence to justify Heliox. If the purpose of the Cochrane library is as stated to synthesise a plethora of articles (so that we do not have to), then why has Rodrigo et al reviewed a subject with only 2 papers and concluded that there is currently not enough data to review!
As to interpretation of the results of the two papers; That Heliox does not alter lung function is not surprising given that Heliox does not treat the underlying obstruction. The fact that PCO2 does fall with the use of Heliox is significant, and I please refer intensivists to Gerbeaux et al Crit Care Med 2001 29:2322‐2324 Use of Heliox in patients with severe exacerbations of COPD, before making any decisions on use.
I certify that I have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of my criticisms.
Contributors
Paul Simpson.
What's new
| Date | Event | Description |
|---|---|---|
| 25 July 2008 | Amended | Converted to new review format. |
History
Protocol first published: Issue 1, 1999 Review first published: Issue 2, 2000
| Date | Event | Description |
|---|---|---|
| 7 November 2000 | New citation required and conclusions have changed | Substantive amendment |
Acknowledgements
The authors wish to acknowledge the assistance of Stephen Milan, Anna Bara, and Jane Dennis of the Cochrane Airways Review Group. We would also like to acknowledge the assistance of the following corresponding authors: Stephen Mette, Laurent Brochard and Jesse B. Hall. Finally, the assistance of Professor Paul Jones (Cochrane Airways Review Group Coordinating Editor) was greatly appreciated.
Data and analyses
Comparison 1. Nonivasive ventilation using helium ‐O2 vs air‐O2.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Dyspnea decrease (Borg scale) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2 Tidal volume (mL) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3 Inspiratory/Total time ratio | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4 Peak inspiratory flow rate (L/min) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5 PaO2 (KPa) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 7 PaCO2 (KPa) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 8 pH | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 9 Heart rate (/min) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected |
1.1. Analysis.
Comparison 1 Nonivasive ventilation using helium ‐O2 vs air‐O2, Outcome 1 Dyspnea decrease (Borg scale).
1.2. Analysis.
Comparison 1 Nonivasive ventilation using helium ‐O2 vs air‐O2, Outcome 2 Tidal volume (mL).
1.3. Analysis.
Comparison 1 Nonivasive ventilation using helium ‐O2 vs air‐O2, Outcome 3 Inspiratory/Total time ratio.
1.4. Analysis.
Comparison 1 Nonivasive ventilation using helium ‐O2 vs air‐O2, Outcome 4 Peak inspiratory flow rate (L/min).
1.5. Analysis.
Comparison 1 Nonivasive ventilation using helium ‐O2 vs air‐O2, Outcome 5 PaO2 (KPa).
1.7. Analysis.
Comparison 1 Nonivasive ventilation using helium ‐O2 vs air‐O2, Outcome 7 PaCO2 (KPa).
1.8. Analysis.
Comparison 1 Nonivasive ventilation using helium ‐O2 vs air‐O2, Outcome 8 pH.
1.9. Analysis.
Comparison 1 Nonivasive ventilation using helium ‐O2 vs air‐O2, Outcome 9 Heart rate (/min).
Comparison 2. Nebulisation of albuterol and ipatropium using Heliox vs Air.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 FEV1 (change in % predicted) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2 FEF 25‐75 (change in % predicted) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected |
2.1. Analysis.
Comparison 2 Nebulisation of albuterol and ipatropium using Heliox vs Air, Outcome 1 FEV1 (change in % predicted).
2.2. Analysis.
Comparison 2 Nebulisation of albuterol and ipatropium using Heliox vs Air, Outcome 2 FEF 25‐75 (change in % predicted).
Characteristics of studies
Characteristics of included studies [ordered by study ID]
de Boisblanc 2000.
| Methods | Design: Prospective, randomized | |
| Participants | Randomized: 50 Eligible: 250 Completed: 47 Majors exclusions: non‐availability of one of the investigators or significant co‐morbid condition | |
| Interventions | Setting: Emergency Department Interventions: a nebulization of bronchodilators (albuterol and ipratropium bromide) using either 80% helium and 20% oxygen or compressed room air as the driving gas. | |
| Outcomes | Outcome: pulmonary function (FEV1, FVC, FEF25‐75) as % of predicted | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | Third party randomisation |
Jolliet 1999.
| Methods | Design: Prospective, randomized, crossover. Method of randomization: not stated | |
| Participants | Eligible: 25 Randomized: 20 Completed: 19 Majors exclusions: pneumothorax, severe respiratory failure or haemodynamic instability, with high probability of imminent intubation, hypoxaemia requiring an inspired oxygen fraction >0.3, impaired consciousness. Patients with severe COPD (FEV1=0.83) after initial stabilization. | |
| Interventions | Setting:Medical intensive care unit, university tertiary care center. Interventions: Noninvasive pressure support ventilation was administered: 45 min with air:oxygen or helium:oxygen (70:30). | |
| Outcomes | Outcomes included were: dyspnea, respiratory rate, tidal volume, peak inspiratory flow, minute ventilation, inspiratory time, respiratory cycle duration, pH, alveolo‐arterial O2 difference, PaO2, PaCO2, systemic arterial pressure, and heart rate. | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | Information not available |
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Carter 1996 | Acute asthma patients |
| Diehl 1999 | Abstract. Nonrandomized trial |
| Dorfman unpublished | Acute asthma patients |
| Esquinas 2000 | Abstract. Nonrandomized trial |
| Gerbeaux 2001 | Retrospective analysis over 18 months |
| Gluck 1990 | Acute asthma patients Nonrandomized trial |
| Henderson 1999 | Acute asthma patients |
| Jaber 2000 | Nonrandomized trial. |
| Kass 1995 | Acute asthma patients Nonrandomized trial |
| Kass 1999 | Acute asthma patients |
| Kudukis 1997 | Acute asthma patients |
| Manthous 1995 | Acute asthma patients Nonrandomized trial |
| Polito 1995 | Letter. Anecdotal evidence |
| Shiue 1989 | Acute asthma patients Nonrandomized trial |
| Swidwa 1985 | Stable COPD patients. Nonrandomized trial. |
| Verbeek 1998 | Acute asthma patients Nonrandomized trial |
Contributions of authors
GR: Protocol initiation and development, assessed search results, data extraction, entry and analysis, interpretation and write‐up CR: Protocol initiation and development, assessed search results, data extraction, entry and analysis, interpretation and write‐up CP: Protocol initiation and development, assessed search results, data extraction, entry and analysis, interpretation and write‐up BR: Protocol initiation and development, assessed search results, data extraction, entry and analysis, interpretation and write‐up EHW: Editorial support throughout
Sources of support
Internal sources
Departamento de Emergencia Hospital Central de las FF.AA, Uruguay.
External sources
Garfield Weston Foundation, UK.
Declarations of interest
The authors who have been involved in this review have done so without any known conflicts of interest. They are neither involved with the primary studies nor affiliated with any company that produces heliox.
Edited (no change to conclusions)
References
References to studies included in this review
de Boisblanc 2000 {published data only}
- Boisblanc BP, DeBleiux P, Resweber S, Fusco EE. 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. Critical Care Medicine 2000;28:3177‐80. [DOI] [PubMed] [Google Scholar]
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