Download Use of Helium-Oxygen Mixtures in the Treatment of Acute Asthma*

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 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], ⴚ 0.20; 95% confidence
interval [CI], ⴚ 0.91 to 0.51; p ⴝ 0.6). However, the four studies that used heliox to deliver
nebulized therapy showed a nonsignificant increase in pulmonary function (SMD, ⴚ 0.21; 95%
CI, ⴚ 0.43 to 0.01; p ⴝ 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 ⴝ 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 ⴝ 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; 123:891– 896)
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
and oxygen mixtures (heliox) have been
H elium
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, 2002.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
[email protected]).
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@
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-
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CHEST / 123 / 3 / MARCH, 2003
891
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 failing10 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.
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).
Materials and Methods
Statistical 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.
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 chil-
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dren), different helium-oxygen mixtures (80/20 vs 70/30), and
methodologic quality (Jadad score ⬎ 3 vs ⱕ 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
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,26 –29 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,33 39 to 42% predicted,12
⬍ 150 L/min,9 ⬍ 200 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
studies9,11,32 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 80/209,11,13,33; 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,11–13,32–34 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
ⱖ 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).9,12,13,32–34
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*
Design
Patients, No.
(Age Range, yr)
Quality
Score
Helium-O2
Mixture
Dorfman et al
R
39 (18–55)
⬍ 70% PEF
1
80/20
Henderson et al12
R, SB
204 (18–65)
⬍ 50% PEF
2
70/30
Kass and Terregino32
R
23 (18–50)
⬍ 200 L/min PEF
2
70/30
Kress et al13
R, SB
45 (18–50)
⬍ 50% FEV1
1
80/20
Kudukis et al11
Manthous et al9
R, DB
NR
18 (16 mo–17 yr)
27 (21–66)
⬍ 250 L/min PEF
3
1
80/20
80/20
Rose et al34
R, DB
18 (18–55)
⬍ 40% PEF
4
70/30
Trials
33
Mean Baseline
Severity
␤-Agonist Protocol
Alb ⫹ IB
NEB continuous
Alb 5 mg
NEB ⫻ 3
Alb 5 mg
NEB ⫻ 1
Alb 5 mg
NEB ⫻ 3
Alb NEB continuous
Alb 5 mg
NEB ⫻ 1
Alb NEB continuous
*Alb ⫽ Albuterol; IB ⫽ ipratropium bromide; NEB ⫽ nebulized; NR ⫽ nonrandomized; R ⫽ randomized; DB ⫽ double blind; SB ⫽ single
blind.
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893
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; ␹2 ⫽ 4.99, 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 (␹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 ⱖ 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).
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; ␹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 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).
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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.
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
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
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
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CHEST / 123 / 3 / MARCH, 2003
895
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.
14
15
16
17
18
19
20
21
22
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22:133–137
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