Papers
Should inhaled anticholinergics be added to 
2
agonists for treating acute childhood and adolescent asthma? A
systematic review
Laurie H Plotnick a Division
of Pediatric Emergency Medicine, Department of Pediatrics, Montreal
Children's Hospital, McGill University, Montreal, Quebec H3H 1P3,
Canada, b Department
of Pediatrics, Montreal Children's Hospital
Correspondence to: Dr
Ducharme fduccpr{at}mch.mcgill.ca
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Abstract |
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 Introduction
Subjects and methods
Results
Discussion
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Objectives To estimate the therapeutic and adverse
effects of addition of inhaled anticholinergics to 
2
agonists in acute asthma in children and adolescents.
Design Systematic review of randomised
controlled trials of children and adolescents taking 2
agonists for acute asthma with or without the addition of inhaled
anticholinergics.
Main outcome measures Hospital admission,
pulmonary function tests, number of nebulised treatments, relapse, and
adverse effects.
Results Of 37 identified trials, 10 were relevant and
six of these were of high quality. The addition of a single dose of
anticholinergic to 2 agonist did not reduce hospital
admission (relative risk 0.93, 95% confidence interval 0.65 to 1.32).
However, significant group differences in lung function supporting the combination treatment were observed 60 minutes (standardised mean difference 
0.57, 0.93 to 0.21) and 120 minutes (0.53,
0.90 to 0.17) after the dose of anticholinergic. In contrast, the addition of multiple doses of anticholinergics to 2
agonists, mainly in children and adolescents with severe exacerbations, reduced the risk of hospital admission by 30% (relative risk 0.72, 0.53 to 0.99). Eleven (95% confidence interval 5 to 250) children would need to be treated to avoid one admission. A parallel improvement in lung function (standardised mean difference 0.66, 0.95 to 0.37) was noted 60 minutes after the last combined inhalation. In
the single study where anticholinergics were systematically added to
every 2 agonist inhalation, irrespective of asthma
severity, no group differences were observed for the few available
outcomes. There was no increase in the amount of nausea, vomiting, or
tremor in patients treated with anticholinergics.
Conclusions Adding multiple doses of anticholinergics
to 2 agonists seems safe, improves lung function, and
may avoid hospital admission in 1 of 11 such treated patients. Although multiple doses should be preferred to single doses of anticholinergics, the available evidence only supports their use in school aged children
and adolescents with severe asthma exacerbation.
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Key messages
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55% of predicted FEV1)| |
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The initial management of acute asthma exacerbations in children
and adolescents focuses on the rapid relief of bronchospasm with
inhaled or nebulised bronchodilators.1-6 Young people who are not responsive to bronchodilators require the addition of glucocorticoids.
7 8
2 agonists are the
most effective of the bronchodilators owing to their rapid onset of
action and the extent of achieved bronchodilation.
9 10
Anticholinergic agents, such as ipratropium bromide and atropine
sulphate, have a slower onset of action and weaker bronchodilating
effect than 2 agonists but may relieve cholinergic
bronchomotor tone and decrease mucosal oedema and
secretions.11-13 Thus the combination of inhaled
anticholinergics with 2 agonists may yield enhanced and
prolonged bronchodilation.
Several randomised controlled trials have examined the efficacy of the
addition of anticholinergics to 2 agonists for treating acute asthma in children and adolescents.14-17
Conflicting results from these trials were attributed to differences in
the severity of the asthma, intensity (number of doses) of
anticholinergic treatment, cointervention with glucocorticoids, and
study power. A systematic review of randomised controlled trials
published up to 1992 concluded that there was a 12% greater
improvement in percentage predicted forced expiratory volume in 1 second (FEV1) with anticholinergic use but no reduction in
hospital admission.18 As several new trials have been
completed since 1992, the conclusions of the original review may need
revision.19-21 The pooling of a larger number of
randomised controlled trials may provide not only greater power for
detecting group differences in hospital admission but also better
insight into the influence of patients' characteristics and treatment
modalities on efficacy of treatment.22-24
We aimed to determine whether the addition of inhaled anticholinergics
to 2 agonists leads to clinical improvement and affects the incidence of adverse effects in children and adolescents with acute
asthma exacerbations. We also wanted to determine whether the intensity
of treatment, severity of the exacer- bation, and concomitant use
of glucocorticoids influenced the extent of the effect attributable to
inhaled anticholinergics.
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Literature search and identification of trials
We used five search strategies to identify potentially relevant
trials. Firstly, we searched Medline (1966-97), Embase (1980-97), and
Cinahl (1982-97) databases using the following MeSH, full text, and
keyword terms: [asthma, wheez*, or respiratory sounds] and [random*, trial*, placebo*, comparative study,
controlled study, double-blind, single-blind] and
[child* or infan* or adolescen* or
pediatr* or paediatr*] and [emergenc*
or acute*], and [ipratropium* or
anticholinerg* or atropin*]. Secondly, we
identified randomised controlled trials by hand searching medical
journals identified through the Cochrane Collaboration, using the same
terms. Thirdly, we checked bibliographies of all trials and review
articles identified from the databases and medical journals to
determine potentially relevant citations. Fourthly, we made inquiries
to Boehringer Ingelheim, producer of ipratropium bromide, regarding
other published or unpublished trials conducted worldwide and supported
by the company or its subsidiaries. Finally, we contacted trialists
working on childhood and adolescent asthma to identify potentially
relevant trials.
Study selection
Criteria for considering trials included: (a)
randomised controlled clinical trials conducted in an emergency
department setting; (b) unprovoked asthma exacerbation
in children aged 18 months to 17 years; (c) single or
multiple doses of inhaled short acting anticholinergics combined with
2 agonists compared with 2 agonists alone; (d) admission to hospital as primary outcome, and
change in pulmonary function tests, need for additional bronchodilator inhalations, relapse rate, and adverse effects as secondary outcome.
Methodological quality
The methodological quality of each trial was assessed using
Jadad's instrument.25 This instrument evaluates the
quality of randomisation and blinding and reasons for withdrawal on a score of 0 (worst) to 5 (best).
Statistical analyses
Treatment effects for dichotomous outcomes were reported as pooled
relative risks with the fixed effect model26 or, in case of heterogeneity, the random effect model.27 The
Dersimonian and Laird model was used to estimate the pooled absolute
risk reduction and therefore estimate the number of patients needed to
treat to prevent the adverse outcome of interest.27 For
continuous outcomes, the weighted mean difference or the standardised
weighted mean difference was used to estimate the pooled effect
size.28 The weighted mean difference was reported for
pulmonary function tests using the same unit of measure: the weighted
sum of each trial's difference between the mean of the experimental
and the control group, reported on the same scale as the pulmonary
function test.28 The standardised mean difference,
reported in SD units, was used when the change in the same pulmonary
function test was reported in different units (change in percentage
predicted FEV1 and percentage change in FEV1):
the weighted sum of each trial's group mean difference divided by its
pooled SD.29 The contribution of each trial to the pooled
estimate is proportional to the inverse of the variance.30
Homogeneity of effect sizes were tested with the Dersimonian and Laird
method with P=0.10 as the cut off point for
significance27; heterogeneity was reported whenever
identified. To detect possible biases, funnel plot symmetry was
examined for trials contributing data to hospital
admission.31 The pooled effect sizes are presented with
the 95% confidence interval.
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A total of 37 studies were reviewed in full text for possible inclusion; 34 were identified from the literature search and bibliographies, and three were identified by contact with trialists. Twenty seven studies were excluded for the following reasons: studies dealt with infants (n=1), adults (n=5), hospitalised patients (n=4), or non-acute asthma (n=12); non-randomised controlled trials (n=4); and anticholinergics alone were studied (n=1). A total of 10 randomised controlled trials were selected for inclusion.
Trials were grouped according to the intensity of the anticholinergic
protocol: trials testing the addition of a single dose of
anticholinergic to 2 agonist inhalations were grouped
under single dose protocol, trials testing multiple doses in a
predetermined fixed regimen were grouped under multiple dose fixed
protocol, while a single trial testing the systematic addition of
anticholinergics to every 2 agonist inhalation,
leaving the number of inhalations determined by the patient's
needs, was named multiple dose flexible protocol (table 1). One trial,
which tested two protocols, contributed to the first two
strata.19 With one exception,14 the
anticholinergic agent used was ipratropium bromide. Cointervention with
glucocorticoids was infrequent even in trials focusing on children and
adolescents with severe exacerbations. Most trials considered children
and adolescents with severe exacerbations, one study considered
children and adolescents with mild to moderate asthma,21
and the remainder failed to describe the baseline severity of their
patients. Two of the largest trials, both of which reported no
beneficial effect from the addition of anticholinergics to
2 agonists, have not yet been published in full text (R
Peterson, personal communication).21 Methodology of six of
the 10 trials was confirmed by the authors (Peterson,
1996)
14 15 19-21
; most were of high quality (Jadad's quality score=5) (table 2). The main outcome variable was spirometric measurements in seven trials, all in school aged children; respiratory resistance measured by forced oscillation was used in the trial of
children and adolescents aged 3-17 years21; clinical
scores were used for the youngest patients in two
trials.
14 15
Not all trials considered each outcome. The
reporting of adverse and side effects was variable. Adverse effects
such as hypertension or tachycardia were reported so infrequently that
they could not be considered in this review. Side effects such as
nausea, vomiting, and tremor, which may interfere with patients'
compliance, were extracted whenever
reported.
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Single dose protocols
Five trials totalling 453 patients examined the efficacy of adding
a single dose of 250 µg ipratropium bromide to 2
agonists. No reduction in hospital admission was observed when pooling
the two trials reporting this outcome (relative risk 0.93, 95%
confidence interval 0.65 to 1.32) (fig 1). As these two trials were of
high methodological quality, this factor did not influence the results. Exclusion of the unpublished study, which focused exclusively on
children and adolescents with mild to moderate exacerbations, did not
alter the conclusion. There was no evidence of systematic bias
identified by the measure of funnel plot asymmetry (intercept 1.5, 25 to 30).
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0.57, 0.93
to 0.21) and at 120 minutes (0.53, 0.90 to 0.17) after the
dose of anticholinergics (fig 2).
19 32 33
In the single
trial examining the intervention in children with mild to moderate
exacerbations, the absence of group difference observed at 60 minutes
(0.10, 0.13 to 0.33) and at 120 minutes (0.02, 0.36 to 0.40)
confidently ruled out any important change in respiratory resistance
due to treatment (fig 2).21 No reduction in relapse rate
(1.17, 0.56 to 2.45) was observed. The addition of a single dose of
anticholinergics was not associated with increased vomiting (0.66, 0.30 to 1.44) or tremor (0.98, 0.88 to 1.10), but there was an apparent
reduction in nausea (0.55, 0.33 to 0.91).
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Multiple dose fixed protocols
Five trials, totalling 366 children, examined the effect of
multiple doses of combined ipratropium bromide and 2
agonists in a fixed protocol. Pooling of the four trials contributing
data to this outcome showed a 30% reduction in hospital admission rate in favour of the combination treatment (0.72, 0.53 to 0.99; fig 1) (R
Peterson, personal communication).
16 19 20
Eleven (95% confidence interval 5 to 250) patients would need to be treated with a
multiple dose fixed protocol to prevent a single admission. Exclusion
of the two smaller trials with lower quality scores
16 17
did not affect the reduction in hospital admission rate attributable to
combination treatment (0.72, 0.52 to 0.99) due to their small weights
in the summary estimate. Similarly, exclusion of the unpublished trial
did not affect the extent of reduction in hospital admission rate,
although the significance level was affected (0.70, 0.47 to 1.05).
There was no evidence of systematic bias identified by the funnel plot
(intercept 0.22, 0.35 to 0.80). No group difference in relapse rate
was observed (0.68, 0.31 to 1.51).
0.66, 0.95 to 0.37). The limited
spectrum of baseline severity of patients enrolled in these five trials
did not permit a meaningful analysis of tendency to examine the
potential influence of baseline severity on extent of response. There
was no significant group difference in the occurrence of side effects
such as nausea (0.59, 0.30 to 1.14), vomiting (1.03, 0.37 to 2.87), and
tremor (1.02, 0.63 to 1.64).
Multiple dose flexible protocol
Analysis of the single trial in which multiple inhalations of
combined atropine sulphate and 2 agonist were given to
31 patients until a satisfactory clinical response was achieved did not
show any significant difference in the few reported
outcomes.14 There was no apparent impact on the number of
inhalations required before discharge (one inhalation: relative risk
0.67, 0.27 to 1.66; two inhalations: 1.25, 0.57 to 2.75; three
inhalations: 2.82, 0.12 to 64.39), although there was a tendency
towards more inhalations in the intervention group. There was no group
difference in the occurrence of tremor (0/15 versus 0/16).
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The intensity of anticholinergic treatment protocol influenced the extent of treatment response in terms of reduction in hospital admission. Whereas no group difference was observed in patients treated with a single dose of anticholinergics, a 30% reduction in hospital admission was observed in patients treated with multiple doses. However, important differences other than the intensity of anticholinergic treatment exist between trials to explain these apparent divergent conclusions. Therefore trials' characteristics should be carefully considered before generalising results to all children and adolescents with acute asthma.
Single dose protocols
Trials examining the effect of the addition of a single dose of
anticholinergics to 2 agonists differed in several
characteristics including age, severity of exacerbation, and
cointervention with glucocorticoids. These differences may explain the
apparent divergence of individual trial results regarding hospital
admission. Furthermore, the incomplete reporting of hospital admission
and the use of various pulmonary function tests reduced the effective
sample size of patients that could be pooled. Interpretation of results obtained from pooling trials under the single dose protocol must therefore be made with caution and be limited to children and adolescents with characteristics similar to those enrolled in the
trials. The single study which examined children and adolescents (age
range 3 to 17 years) with mild to moderate asthma ruled out, with a
narrow confidence interval, any meaningful improvement in respiratory
resistance attributable to anticholinergic use.21 In
contrast, trials that examined school aged children with severe asthma
showed a significant improvement in FEV1 60 minutes after the combined inhalation; a change that persisted at 120 minutes.
19 32
It is possible that differences in
subjects' age and baseline severity may be associated with various
degrees of cholinergic induced bronchospasm. More trials in preschool
children and children and adolescents with mild to moderate asthma are
needed to confirm this hypothesis. Moreover, the sensitivity of
response variables (change in percentage predicted FEV1,
percentage change in FEV1, percentage change in respiratory
resistance) to identify change as a result of treatment may vary.
Finally, in contrast with current recommendations,
1 3-6 34
none of the trials of children
and adolescents with severe exacerbations systematically added
glucocorticoids to the inhalation regimen. Whether this would have
improved lung function remains to be proved.
Multiple dose fixed protocols
Trials testing the addition of multiple doses of
anticholinergics to 2 agonists in a predetermined fixed
regimen were more homogeneous, focusing on school aged children and
adolescents (n=5) with severe exacerbations (n=3) and infrequent
concomitant use of glucocorticoids (n=4). A 30% reduction in hospital
admission rate was attributable to combination treatment. Eleven
patients would need to be treated with such a protocol to prevent one
admission. The pooling of similar patients, mostly school aged children
and adolescents with severe asthma, certainly contributed to the
identification of this benefit, as none of the individual trials had
sufficient power to detect a group difference in admission rates. Yet,
because of the relative homogeneity of the trials and the inability to obtain data stratified on severity, it is impossible to separate the
effects of multiple dosing from that of baseline severity. Regarding
lung function, significant group differences favouring the combination
treatment were also observed, whether the response was expressed as
change in percentage predicted FEV1 or as percentage change
in FEV1. While modest, the extent of improvement in lung function is probably clinically meaningful as it was associated with a
substantial reduction in hospital admissions. In a single study,
glucocorticoids were systematically given to all enrolled patients.20 Although the trial reported the largest
reduction in hospital admission, more trials are needed to confirm that the favourable effect of combined multiple doses of anticholinergics and 2 agonist will be sustained in the presence of
glucocorticoids in children and adolescents with severe exacerbations.
Multiple dose flexible protocols
A single small trial examined the efficacy of systematically
adding anticholinergics to every 2 agonist
inhalation, tailoring the number of inhalations to patients'
response. This protocol did not seem to reduce the number of
inhalations needed. No data were provided on hospital admission.
Although this protocol most closely reflects physicians' treatment
preference when dealing with children and adolescents with mild to
moderate asthma, little evidence exists at present to support its use.
Further trials are therefore needed before any conclusion can be drawn
about the protocol's efficacy.
Side effects
No apparent increase in the occurrence of nausea, tremor, or
vomiting was observed in subjects treated with either the single or
multiple dose protocols. Clinically important adverse effects, such as
tachycardia or hypertension, were reported too infrequently to permit
any analyses.
Strengths and limitations
Like all systematic reviews this meta-analysis is limited by the
quality of existing data.35 Fortunately, six out of 10 trials were of high quality. Exclusion of trials with lower reported methodological quality did not affect the conclusions. Interestingly, the two trials with the largest sample sizes and thus the greater power, failed to detect any group differences in lung function and
hospital admission. Although they both had excellent quality scores,
they remain unpublished. Clearly, publication bias exists in this
area.36 Exclusion of these two unpublished trials, one of
the single dose and one of the multiple dose fixed protocol, did not
affect conclusions, only the significance level. Although somewhat
insensitive when used for a small number of pooled trials, funnel plot
statistics failed to identify any major differences between trials.
With eight of the 10 trials originating from North America, the
generalisability of study results to other countries should be
considered, particularly regarding hospital admission. Although
variations in hospital admission rates have been documented, these
variations have been predominantly attributed to differences in asthma
severity, daily prophylaxis, intensity of emergency treatment, and
admission criteria.
37 38
Clearly, important international
variations in these factors could influence the anticipated response to
treatment.
Design and reporting of trials
Trials should improve on three main aspects: interventions,
choice of outcomes, and reporting of results. Firstly, because systemic
glucocorticoids are now the standard treatment of children and
adolescents with severe exacerbations they should be systematically given with 2 agonists in future trials. Conversely, in
children and adolescents with mild to moderate exacerbations trials are needed to evaluate the potential benefit of systematically adding anticholinergics to every 2 agonist inhalation,
titrating the number of inhalations to patients' response. Secondly,
as admission and relapse rates are relatively gross measures of
efficacy, subject to practice variation, future trials should include
more sensitive and reliable endpoints such as quality of life, duration
of hospitalisation, and duration of symptoms following discharge.
Finally, there is a need for consistent reporting of baseline severity,
glucocorticoid use, and admission and relapse rates.
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Acknowledgments |
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We thank the Cochrane Airways Review Group, namely Stephen Milan and Anna Tomato, for the literature search and ongoing support, and Dr Paul Jones and Dr Fred Wolf for their constructive comments. We also thank Dr Terry Klassen and Dr David McGillivray, the trials' authors, namely Dr MF Guill, FA Qureshi, S Schuh, KP Dawson, and T Klassen, and Ms Judith Marshall for preparation of the manuscript.
Contributors: FMD initiated and coordinated the formulation of the primary hypothesis, designed the protocol, and participated in the identification and selection of studies, methodology assessment, data extraction, data analysis and interpretation, and writing of the paper; she will act as guarantor for the paper. LHP participated in the study selection, methodology assessment, data extraction, correspondence with authors, data analysis and interpretation, and writing of the paper.
Funding: None.
Conflict of interest: None.
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(Accepted 6 July 1998)
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Rapid Responses:
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- Ipratropium reduces hospitalization in severe asthma
- Arno Zaritsky, et al.
bmj.com, 12 Oct 1998 [Full text] - High doses of ipratropio in acute asthma
- Gustavo Rodrigo
bmj.com, 21 Oct 1998 [Full text]
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