Aastma Anticolinergic

Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children (Review)
Plotnick L, Ducharme F
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2008, Issue 4 http://www.thecochranelibrary.com
Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 1 Admission. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.2. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 2 -(Change in % Pred FEV1 at 60 minutes after IB) +/- 15 minutes. . . . . . . . . . . . Analysis 1.3. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 3 - (Change in % Pred FEV1 at 120 minutes after IB) +/- 30 minutes. . . . . . . . . . . . Analysis 1.4. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 4 - (% Change in FEV1 at 60 minutes after IB) +/- 15 minutes. . . . . . . . . . . . . . Analysis 1.5. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 5 - (% Change in FEV1 at 120 minutes after IB) +/- 30 minutes. . . . . . . . . . . . . Analysis 1.6. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 6 % Change in Respiratory resistance at 60 minutes after IB +/- 15 minutes. . . . . . . . . Analysis 1.7. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 7 % Change in Respiratory resistance at 120 minutes after IB +/- 30 minutes. . . . . . . . . Analysis 1.8. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 8 Change in clinical score at 60 minutes +/- 15 minutes. . . . . . . . . . . . . . . . Analysis 1.9. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 9 Change in clinical score at 120 minutes +/- 30 minutes. . . . . . . . . . . . . . . . Analysis 1.10. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 10 O2 Saturation <95% at 60 minutes +/- 15 minutes. . . . . . . . . . . . . Analysis 1.11. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 11 O2 Saturation <95% at 120 minutes +/- 30 minutes. . . . . . . . . . . . . Analysis 1.12. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 12 Number of repeat treatments required after standard protocol prior to disposition. . . Analysis 1.13. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 13 Tremor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.14. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 14 Vomiting. . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.15. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 15 Nausea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.16. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 16 Need for corticosteroids in emergency department prior to disposition. . . . . . . Analysis 1.17. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 17 Relapse. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1 1 2 2 2 3 5 6 8 9 10 11 12 12 15 35 42 43 44 45 46 47 48 49 50 51 52 53 54 54 55 56 57
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Analysis 2.1. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL, Outcome 1 Admission. . . . . . . . . . . . . . . . . . . . Analysis 2.2. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL, Outcome 2 - (Change in % Pred FEV1 at 60 minutes after last IB) +/- 20 minutes. Analysis 2.4. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL, Outcome 4 - (% Change in FEV1 or PEFR at 60 minutes after last IB) +/- 15 minutes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.5. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL, Outcome 5 -( % Change in FEV1 or PEFR at 120 minutes after last IB) +/- 30 minutes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.7. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL, Outcome 7 Change in clinical score at 120 minutes +/- 30 minutes. . . . Analysis 2.8. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL, Outcome 8 O2 Saturation <95% at 60 minutes +/- 15 minutes. . . . . Analysis 2.10. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL, Outcome 10 Number of repeat treatments required after standard protocol prior to disposition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.11. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL, Outcome 11 Tremor. . . . . . . . . . . . . . . . . . . . Analysis 2.12. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL, Outcome 12 Vomiting. . . . . . . . . . . . . . . . . . . Analysis 2.13. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL, Outcome 13 Nausea. . . . . . . . . . . . . . . . . . . . Analysis 2.14. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL, Outcome 14 Need for corticosteroids in emergency department prior to disposition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.15. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL, Outcome 15 Relapse. . . . . . . . . . . . . . . . . . . . Analysis 3.1. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL, Outcome 1 2 to 3 inhalations required prior to disposition. . . . . . Analysis 3.2. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL, Outcome 2 >= 4 inhalations required prior to disposition. . . . . . . Analysis 3.3. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL, Outcome 3 Need for corticosteroids in emergency department prior to disposition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.4. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL, Outcome 4 Tremor. . . . . . . . . . . . . . . . . . . . Analysis 3.5. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL, Outcome 5 Vomiting. . . . . . . . . . . . . . . . . . . Analysis 3.6. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL, Outcome 6 Nausea. . . . . . . . . . . . . . . . . . . . Analysis 3.7. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL, Outcome 7 Admission. . . . . . . . . . . . . . . . . . . WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
58 59
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61 62 63
64 65 66 67
68 68 70 71
72 72 73 74 75 75 75 76 76 76
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[Intervention Review]
Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children
Laurie Plotnick1 , Francine Ducharme2
1 Department of Paedriatrics, The Montreal Childrens Hospital, McGill University, Montreal, Canada. 2 Department of Pediatrics, McGill University Health Centre, Montreal, Canada
Contact address: Laurie Plotnick, Department of Paedriatrics, The Montreal Childrens Hospital, McGill University, Room C538E, 2300 Tupper Street, Montreal, Quebec, H3H 1P3, Canada. drplotnick@sympatico.ca. Editorial group: Cochrane Airways Group. Publication status and date: Edited (no change to conclusions), published in Issue 4, 2008. Review content assessed as up-to-date: 24 April 2000. Citation: Plotnick L, Ducharme F. Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children. Cochrane Database of Systematic Reviews 2000, Issue 3. Art. No.: CD000060. DOI: 10.1002/14651858.CD000060. Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT Background Several randomized controlled trials have examined, with conicting results, the efcacy of the addition of anticholinergics to beta2 agonists in acute pediatric asthma. The pooling for a larger number of randomized controlled trials may provide not only greater power for detecting group differences and also provide better insight into the inuence of patients characteristics and treatment modalities on efcacy. Objectives The aims of this study were to estimate the therapeutic and adverse effects attributable to the addition of inhaled anticholinergics to beta2 agonists in acute pediatric asthma. Search strategy We searched MEDLINE (1966 to April 2000), EMBASE (1980 to April 2000), CINAHL (1982 to April 2000) and reference lists of studies. We also contacted drug manufacturers and trialists. Selection criteria Randomised trials comparing the combination of inhaled anticholinergics and beta2 agonists with beta2 agonists alone in children aged 18 months to 17 years with acute asthma. Data collection and analysis Assessments of trial quality and data extraction were done by two reviewers independently. Main results Of the 40 identied trials, 13 were relevant and eight of these were of high quality. The addition of a single dose of anticholinergic to beta2 agonists did not reduce hospital admission [RR=0.93 (95% CI: 0.65, 1.32)]. However, signicant group differences in lung function supporting the combination of anticholinergics and beta2-agonists were observed 60 minutes [SMD=0.57 (95% CI:0.21, 0.93)] and 120 minutes [SMD=0.53 (95% CI: 0.17, 0.90)] after the dose of anticholinergic. In contrast, the addition of multiple doses of anticholinergics to beta2 agonists reduced the risk of hospital admission by 25% [RR=0.75 (95% CI: 0.62,0.89)] in children with
Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1
predominantly moderate and severe exacerbations. Twelve (95% CI: 8, 32) children would need to be treated to avoid one admission. When restricting this strategy to children with severe exacerbations, seven (95% CI: 5, 20) children need to be treated to avoid an admission. At 60 minutes after the last anticholinergic inhalation, a weighted mean group difference of 9.68 in change in % predicted FEV1 [95% CI:5.70, 13.68] favoured anticholinergic use. In the two studies where anticholinergics were systematically added to every beta2 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. Authors conclusions A single dose of an anticholinergic agent is not effective for the treatment of mild and moderate exacerbations and is insufcient for the treatment of severe exacerbations. Adding multiple doses of anticholinergics to beta2 agonists appears safe, improves lung function and would avoid hospital admission in 1 of 12 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 with severe asthma exacerbation. There is no conclusive evidence for using multiple doses of anticholinergics in children with mild or moderate exacerbations.
PLAIN LANGUAGE SUMMARY Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children In an asthma attack, the airways (passages to the lungs) narrow from muscle spasms. Bronchodilators (reliever inhalers) relax the muscles in the airways, opening the airways so breathing is easier. Anti-cholinergic drugs can also affect these muscles, and so are sometimes used as well as bronchodilators when children have severe asthma attacks. The review of trials found using both drugs together improves outcomes for children with severe asthma attacks, although there is not enough evidence about effects for children with mild or moderate attacks. More research on possible adverse effects of the extra drug is needed, although it seems safe.
BACKGROUND
The initial management of acute pediatric asthma exacerbations in children focuses on the rapid relief of bronchospasm using inhaled or nebulized bronchodilators (BMA 1992; Boulet 1999; Guidelines, 1993; Mitchell 1992; Rachelefsky 1993; Warner 1989). Children who are incompletely responsive to bronchodilators require the addition of glucocorticoids (Scarfone 1993; Tal 1990). Beta2- agonists are clearly the most effective bronchodilators due to their rapid onset of action and the magnitude of achieved bronchodilation (Sears 1992 SVedmyr 1985). Anticholinergic agents, such as ipratropium bromide and atropine sulfate, have a slower onset of action and weaker bronchodilating effect, but may specifically relieve cholinergic bronchomotor tone and decrease mucosal edema and secretions (Chapman 1996; Gross 1988; Silverman 1990). Thus, the combination of inhaled anticholinergics with beta2 agonists may yield enhanced and prolonged bronchodilation. Several randomized controlled trials (RCTs) have examined, with conicting results, the efcacy of the addition of anticholinergics to beta2 agonists in acute pediatric asthma (Cook 1985, Guill 1987; Reisman 1988, Watson 1988). The conicting results were
attributed to differences in the asthma severity, intensity of anticholinergic treatment, co-intervention with glucocorticoids, and study power. The pooling for a larger number of RCTs may provide not only greater power for detecting group differences in hospital admission, but also better insight for the inuence of patients characteristics and treatment modalities on efcacy (Greenhalgh 1997; Peto 1995; Sackett 1995). A systematic review of RCTs published until 1992 concluded to a 12% greater improvement in % predicted FEV1 with anticholinergic use but with no reduction in hospital admission (Osmond 1995). Our previous Cochrane Review published in 1997 concluded to a signicant reduction in hospital admissions in schoolaged children with severe exacerbations receiving intensive anticholinergic treatment. Because three more trials have been published since our original Cochrane review, an update was required.
OBJECTIVES
The aim of this systematic review was to determine whether the addition of inhaled anticholinergics to beta2 agonists provides
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clinical improvement and affects the incidence of adverse effects in children with acute asthma exacerbations. Moreover, we wished to determine whether the intensity of treatment, severity of the exacerbation and concomitant use of glucocorticoids inuenced the magnitude of the effect attributable to inhaled anticholinergics.
5. Oxygen Saturation, 60 and 120 minutes after the last combined inhalation 6. Number of additional bronchodilator treatments required after the intervention/placebo protocol, prior to disposition 7. Need for systemic corticosteroids 8. Adverse effects such as nausea, vomiting and tremor 9. Relapse rate
METHODS Search methods for identication of studies Criteria for considering studies for this review
Electronic searches Types of studies All randomized controlled clinical trials conducted in an emergency department setting, comparing the combination of inhaled anticholinergic agents and beta2 agonists with short-acting beta2 agonists alone in the treatment of an acute unprovoked asthma exacerbation, were considered for this review. MEDLINE (1966 to April 2000), EMBASE (1980 to April 2000) and CINAHL (1982 to April 2000) were searched 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*].
Types of participants Children aged 18 months to 17 years presenting to an emergency department with an acute unprovoked (spontaneous) exacerbation of asthma.
Searching other resources Randomized controlled trials identied by the hand-searching of medical journals through the Cochrane Collaboration were surveyed using the same terms. Bibliographies of all trials and review articles identied above were checked to identify potentially relevant citations. Inquiries were made to Boehringer Ingelheim, producer of ipratropium bromide, regarding other published or unpublished trials conducted worldwide and supported by this company or its subsidiaries. Personal contact was made with trialists working in the eld of pediatric asthma to identify potentially relevant trials.
Types of interventions Treatment group: Single or repeated doses of nebulized or inhaled short-acting anticholinergic and beta2 agonists. Control group: Single or repeated doses of nebulized or inhaled placebo and short-acting beta2 agonists.
Types of outcome measures
Data collection and analysis

Primary outcomes
Hospital admission Selection of studies

Secondary outcomes
1. Change from baseline in %Predicted FEV1, 60 and 120 minutes after the last combined anticholinergic and beta2 agonist inhalation 2. Percent change from baseline in FEV1, 60 and 120 minutes after the last combined inhalation 3. Change from baseline in respiratory resistance, 60 and 120 minutes after the last combined inhalation 4. Change from baseline in clinical score, 60 and 120 minutes after the last combined inhalation
Each citation (title and abstract) identied through one of the above strategies was then reviewed by one reviewer and classied as denite, possible, or clearly not randomized controlled trial. The complete article of all citations identied as denite or possible randomized controlled trials was obtained, irrespective of language of publication. These were assessed independently by two reviewers to determine if the study met the inclusion criteria and, if so, to evaluate methodological quality and extract data. Reviewers were masked to the authors names and afliations, name of journal, date of publication, and sources of funding for the study. Disagreement between the reviewers was settled by consensus.
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Data extraction and management Two authors independently extracted data from eligible studies. For most outcomes, the data was stratied based on the use of corticosteroids (presence/absence/not described) as co-intervention. The need for corticosteroids was also added as an outcome for study protocols which left the choice of such co-intervention to the discretion of the treating physician. In this case, the addition of corticosteroids to the standard protocol is generally viewed as an indicator of poor patient response. In addition, whenever possible, studies were stratied based on the baseline severity of the patients (mild, moderate or severe asthma) using spirometry or clinical score. Assessment of risk of bias in included studies We have assessed the risk of bias for each study according to the allocation procedures and blinding. Each judgement is listed for each study in Characteristics of included studies. The methodological quality of each trial was assessed by two different methods. First, the quality of blinding was ranked using the Cochrane Approach and recorded under Allocation Concealment: A refers to adequate concealment, B refers to uncertainty about adequacy of concealment, C refers to clearly inadequate concealment. Jadads 5-point instrument was also used to evaluate the reported quality of randomization and blinding, and the description of withdrawals and dropouts. (Jadad 1995) This blind assessment has been shown to be valid and associated with high inter-rater reliability. Jadads score was recorded for each study under Table of included studies: Method (maximum=5, minimum=0). Inter-reviewer agreement in the assessment of methodological quality was calculated using the weighted kappa with quadratic means. Dealing with missing data The reviewers attempted to contact the rst author, or all coauthors in cases of non-response, of each RCT, by post, fax or e-mail, on at least three occasions to verify study methodology and extracted information and to provide additional data, if necessary. Data synthesis Data were entered into Review Manager software. Treatment effects for dichotomous outcomes were reported as pooled relative risks (RR) using the xed effect model (Greenland 1985) or, in case of heterogeneity, the random effect model (DerSimonian 1986). The Dersimonian and Laird model was applied to estimate the pooled absolute risk reduction and, therefore, estimate the number of patients needed to treat to prevent the adverse outcome of interest (DerSimonian 1986). For continuous outcomes, the weighted mean difference or the standardized weighted mean difference was used to estimate the
pooled effect size (Olkin 1995). The weighted mean difference was reported for pulmonary function tests using the same unit of measure: it is the weighted sum of each trials difference between the mean of the experimental and the control group, reported in the same scale as the pulmonary function test (Olkin 1995). The standardized mean difference, reported in standard deviation units, was used when the change in the same pulmonary function test was reported in different units (change in % predicted FEV1 and % change in FEV1): it is the weighted sum of each trials group mean difference divided by its pooled standard deviation (Hasselblad 1995). The contribution of each trial to the pooled estimate is proportional to the inverse of the variance (Robins 1986). Homogeneity of effect sizes were tested with the Dersimonian and Laird method with P=0.10 as the cut-off for signicance (DerSimonian 1986); heterogeneity was reported whenever identied. In an effort to detect possible biases, funnel plot symmetry was examined for trials contributing data to hospital admission (Egger 1997). The pooled effect sizes are presented with the 95% Condence Interval (CI). In order to evaluate the effect of baseline severity on the magnitude of response to the intervention, each study was also ranked numerically in increasing order of severity using the admission rate observed in the control group. The admission rate is reported in the user-dened order. If the admission rate for a particular study was not available, that study was not ranked. Ranking of severity based on admission rate in the control group corresponded very closely to ranking based on mean baseline % predicted FEV1 in the studies which reported it. Ranking on admission rate permitted the inclusion of studies which did not use spirometry or did not report mean baseline % predicted FEV1.
Subgroup analysis and investigation of heterogeneity Five factors were a priori believed to potentially inuence the magnitude and/or direction of the therapeutic response, namely the 1) intensity of anticholinergic treatment, 2) co-intervention with glucocorticoids, 3) severity of exacerbation, 4) methodological quality, and 5) publication status. RCTs were therefore grouped according to the intensity of anticholinergic protocol and, within each group, stratied on the presence/absence of systemic glucocorticoids. Whenever reported, the baseline percent predicted forced expiratory volume in 1 second (FEV1) and hospital admission rate in the control groups were recorded as indicators of severity and examined for their potential interaction with therapeutic effect.
Sensitivity analysis Sensitivity analyses were performed to examine the effect on results of excluding unpublished trials and those with poor methodological quality.
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RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
Results of the search Forty studies were reviewed in full text for possible inclusion; 37 studies were identied by the literature search and bibliographies and 3 studies were identied by contact with trialists. A total of 13 randomized controlled trials were selected for inclusion.
Included studies Trials were grouped according to the intensity of the anticholinergic protocol: trials testing the addition of a single dose of anticholinergic to the beta2 agonist inhalations were grouped under single dose protocol, trials testing multiple doses in a predetermined xed regimen were grouped under multiple dosexed protocol, while trials testing the systematic addition of anticholinergics to every beta2 agonist inhalation, leaving the number of inhalations determined by the patients needs, were named multiple dose-exible protocol. One trial, which tested two protocols, contributed to the rst two strata (Schuh 1995). With one exception (Guill 1987), ipratropium bromide was used as the anticholinergic agent. Five trials contributed data to the single dose protocol. The patients enrolled to this protocol were aged 3-17 years and varied from mild to severe asthma severity, based on spirometry and/ or clinical score. Two trials (Beck 1985; Schuh 1995) focused on children with severe exacerbations with a baseline FEV1 of <50% of predicted; the largest trial pertained to children with mild to moderate exacerbations (Ducharme 1998); the remaining trials failed to report severity (Cook 1985; Phanichyakam 1990). A single dose of 250 mcg of ipratropium bromide was added to multiple (2 to 6) doses of 2-agonists given every 20 to 30 min. There was no or variable use of systemic corticosteroid as cointervention. Seven trials contributed data to the multiple dose-xed protocol. The age range varied between 1 and 17 years. Most enrolled children had a moderate to severe exacerbation, but several trials reported data stratied on asthma severity. Asthma severity was dened on baseline by spirometry and/or clinical score: 5 trials contributed data to severe exacerbations, that is, baseline FEV1
<50% of predicted or clinical score 7 to 9 (Qureshi 1997; Qureshi 1998 (sev); Reisman 1988; Schuh 1995; Zorc 1999 (sev)); 2 trials contributed data to moderate to severe subgroup, i.e., FEV1 <70% of predicted (Watson, 1988, Peterson, 1996); 2 trials contributed data to the moderate subgroup, that is, baseline FEV1 50-70% of predicted or clinical score 4-6 (Qureshi, 1999, Zorc 1999 (mod)); 1 trial contributed data to the mild subgroup, that is, a clinical score of 1-3 (Zorc JJ 1999 (mil)). The treatment protocol varied across trials with 2 to 3 doses of ipratropium bromide (250 to 500 ug per dose) being administered with multiple (2 to 7) doses of 2agonists every 20 to 60 minutes. Most children received systemic corticosteroids as co-intervention. Two studies contributed data to the multiple dose-exible protocol. The age ranged between 13 months to 14 years old. One trial (Calvo 1998) enrolled children of various severity levels based on spirometry and/or clinical scores while the other trial (Guill 1987) failed to describe the severity of exacerbations. In this protocol a dose of inhaled atropine sulfate or ipratropium bromide (250 ug) was administered with every 2-agonist inhalation every 20 to 30 minutes until clinical response. Systemic corticosteroid use was either variable or not described. The most frequently reported outcomes were hospital admission rate and spirometric measurements in 9 trials; respiratory resistance measured by forced oscillation was used in the trial of children aged 3-17 years (Ducharme 1998); clinical scores were used for the youngest patients in four trials who were unable to perform spirometry (Calvo 1998; Cook 1985; Qureshi 1998 (mod)). 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. Excluded studies Twenty seven studies were excluded for the following reasons: studies dealing with infants (N=1), adults (N=5), hospitalized patients (N=4) or non-acute asthmatics (N=12); non-randomized control trials (N=4); and one study examining anticholinergics alone, not in combination with beta2 agonists.
Risk of bias in included studies

An overview of the risk of bias for the allocation and blinding procedures each study is given in Figure 1.
Figure 1. Methodological quality summary: review authors judgements about each methodological quality item for each included study.
The inter-rater agreement on methodological quality (Jadads score) was high (weighted kappa = 0.93). When scoring the quality of the studies, disagreement arose with one study (Cook 1985) and the quality score was easily achieved by consensus. Methodology of nine of the thirteen trials was conrmed by the authors (Calvo 1998; Cook 1985; Ducharme 1998; Guill 1987; Peterson 1996; Qureshi 1997; Qureshi 1998 (sev); Schuh 1995; Zorc 1999 (mod)) and most (N=8) were of high quality (Jadads quality score >=4) (see Table of Included Studies). Studies were ranked in increasing order of severity using the admission rate of the control group as user-dened order. The ranking varied from 0 to 0.53. Four studies were not ranked because admission rates were not provided (Beck 1985; Cook 1985, Guill 1987; Phanichyakam 1990). RANDOMIZATION Randomization was performed using computer-generated random numbers in four studies (Ducharme 1998; Guill 1987; Peterson 1996; Zorc JJ 1999 (mil)), tables of random numbers in three trials (Qureshi 1997; Qureshi 1998 (mod), Schuh 1995), 1 trial (Calvo 1998) used non-randomized consecutive assignment; and the remaining four studies failed to describe the method of randomization. Regarding means of allocation, nine studies used number-coded solutions supplied by the pharmacy (Beck 1985; Calvo 1998; Ducharme 1998; Peterson 1996; Qureshi 1997; Qureshi 1998 (sev); ;Reisman 1988; Schuh 1995, Zorc 1999 (sev)), one study used opaque consecutive numbered envelopes containing
assignment (Guill 1987) and three studies did not describe the means of allocation. BLINDING Eleven studies claimed double-blinding while the other two claimed triple-blinding (Ducharme 1998; Peterson 1996). Ten studies used an identical placebo in the control group, one study described a similarly-looking intervention and placebo solutions (Cook 1985), and two studies failed to provide details of the blinding (Phanichyakam 1990; Watson 1988). WITHDRAWAL/DROPOUT Ten studies reported the presence/absence of patient withdrawal or dropout and the reasons for the attrition if applicable (Calvo 1998; Cook 1985; Ducharme 1998; Guill 1987; Peterson 1996; Qureshi 1997; Qureshi 1998 (mod); Schuh 1995; Watson 1988; Zorc 1999 (sev)).
Effects of interventions
SINGLE DOSE PROTOCOLS (N=5) Five trials totaling 453 patients examined the efcacy of adding a single dose of 250ug ipratropium bromide to beta2-agonists. With regards to the primary endpoint, no reduction in hospital admission was observed when pooling two trials (allocating participants to three treatment-control comparisons) RR 0.93 95% CI 0.65 to 1.32, Figure 2; with no apparent heterogeneity. Both trials were published and of high methodological quality.
Figure 2. Forest plot of comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2AGONIST ALONE, outcome: 1.1 Admission.
Stratication on the presence/absence of co-intervention with corticosteroids suggested a trend towards a reduced risk of admission in children not so treated [RR 0.73 (0.46, 1.17)] as compared to those treated with systemic corticosteroids [RR 1.22 (0.69, 2.55)]. This suggests that co-intervention with corticosteroids may be a confounder for admission. Four trials examined response to treatment using pulmonary function tests. In the two trials reporting the % change in FEV1 a difference of 16.10% [95% CI: 5.54, 26.66]% between group means was documented at 60 minutes and of 17.49% (4.46, 30.53)% at 120 minutes after the inhalation of anticholinergics, both favouring anticholinergic use (Beck 1985; Phanichyakam 1990). However, when combining the three trials reporting change in lung function, either as change in % predicted FEV1 or % change from baseline FEV1, signicant improvement, equivalent to half a standard deviation in change, was still apparent at 60 minutes [standardized mean difference=0.57 (0.21, 0.93)] and at 120 minutes [standardized mean difference=0.53 (0.17, 0.90)] after the dose of anticholinergics (Beck 1985 Phanichyakam 1990; Schuh 1995). In the single trial examining the intervention in the two strata of children with mild to moderate exacerbations, the absence of group difference observed at 60 minutes [WMD=0.02
(-0.02,0.07)] and at 120 minutes [WMD=-0.01 ( -0.09, 0.07)] condently ruled out any important change in respiratory resistance due to treatment (Ducharme 1998).There were no signicant group differences in clinical score at 60 minutes [N= 2; WMD=-0.06 (-0.26, 0.14)] or 120 minutes [N=2; WMD = 0.13 (-0.22,0.48)], in oxygen saturation at 60 minutes [N=2; RR= 0.75 (0.55,1.01)] or 120 minutes [N=2; RR=1.10 (0.76,1.60)], in the need for additional inhalation(s) after the standard protocol prior to disposition to admission or discharge [N=2; RR= 1.05 (0.78,1.41): ] and relapse to additional care [N=2; RR=1.17 (0.56,2.45)]. The addition of a single dose of anticholinergics was not associated with increased tremor [N=2; RR =1.18 (0.72, 1.94)]. Due to the insufcient (<2 ) number of trials, data could not be aggregated for the change in % predicted FEV1 at 60 minutes and 120 minutes, the need for corticosteroids prior to disposition, rate of nausea and vomiting. When trials were rank-ordered on the admission rate in the control group (the user-dened order), no association between the direction or magnitude of response and baseline severity was apparent for any of the outcomes. MULTIPLE DOSES, FIXED PROTOCOLS (N=7)
Seven trials, totaling 1045 children, examined the effect of multiple doses of combined ipratropium bromide and beta2-agonists in a xed protocol. With the pooling of the six trials contributing data to this outcome, a 25% reduction in hospital admission rate was noted in favour of the combination therapy [RR 0.75 (95% CI 0.62 to 0.89), Figure 3] with no apparent heterogeneity. Twelve and a half (8, 32) patients would need to be treated with a multiple dose-xed protocol to prevent a single admission. There was no evidence of systematic bias identied by the measure of funnel plot asymmetry [intercept: 0.14(95% CI: -0.9, 1.4)]. Exclusion of the two smaller trials with lower quality scores (Reisman, 1988; Watson, 1998) did not affect the reduction in hospital admission rate attributable to combination therapy [RR=0.74 (0.62, 0.89)]. However, baseline severity greatly inuenced the reduction in hospital admission attributed to anticholinergics. In-
deed, when trials were rank-ordered by the admission rate (userdened order), greater prevention of admission was observed with trials with higher rates of admission in the control group. Similarly, when trials were stratied on reported baseline severity (based on % predicted FEV1 or clinical score), no signicant reduction were observed in children with mild [N=1, RR=1.46 (0.40, 5.31], moderate [N=2, RR=0.77 (0.48, 1.22)] or moderate to severe [N=2, RR=0.75 (0.45, 1.25)] exacerbations, although a protective trend was observed in the latter two categories. A signicant reduction was only observed in children with severe exacerbations [RR=0.71 (0.58, 0.89)] [exacerbations Qureshi 1997; Reisman 1988; Schuh 1995; and severe subgroups of Zorc 1999 (sev) and Qureshi 1998 (sev) ]. The number needed to treat with anticholinergics to prevent one admission among severe patients was 7 (95% CI: 5, 20).
Figure 3. Forest plot of comparison: 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL, outcome: 2.1 Admission.
Four trials reported response to treatment using change in % predicted FEV1: a weighted mean group difference of 9.68 [95% CI: 5.70, 13.68] in the change in % predicted FEV1 favouring anticholinergic use, was observed 60 minutes after the last anticholinergic inhalation. Two of these four trials also reported the magnitude of response in % change in FEV1; a signicant group difference in favour of anticholinergic use was noted 60 minutes after the last anticholinergic inhalation [WMD= 6.97 (1.60, 12.34)] (Watson 1988; Qureshi 1997). There was a signicant reduction in the need for additional inhalations after the standard protocol [N=2 trials, RR=0.81 (0.66, 0.99); random effect model], favouring combination therapy. The number needed to treat to prevent additional inhalation(s) in these two trials dealing with children with mild to severe exacerbations was 8 (95% CI: 5, 29). No group difference in relapse rate was observed [N=7; RR=0.86 (0.49,1.52)]. No data could be aggregated for lung function 120 minutes after the last dose of anticholinergics, clinical score, oxygen saturation, and need for systemic corticosteroids due to the insufcient number (<2) of trials reporting these outcomes. With regards to adverse effects, there was no group difference in the risk of nausea [N=3; RR=0.59 (0.30,1.14)], vomiting [N= 3; RR=1.03 (0.37,2.87)] or tremor [N=4; RR=1.01 (0.63,1.63)]. No heterogeneity was observed in the above comparisons unless specied otherwise. MULTIPLE DOSES, FLEXIBLE PROTOCOL (N=2) Analysis of the two trials which tested the administration of multiple inhalations of combined anticholinergic and b2-agonist until satisfactory clinical response did not reveal any signicant difference in the few reported outcomes (Guill 1987; Calvo 1998). There was a trend approaching signicance towards more patients requiring only 2 to 3 inhalations [N=2, RR=1.67 (95% CI: 0.98, 2.86)] and less patients requiring 4 or more inhalations [N=1, RR= 0.79 (95% CI: 0.61, 1.03)] with combination therapy as compared to beta2-agonists alone. No data could be aggregated for the need for systemic corticosteroids, admission or relapse due to the insufcient number (<2) of trials reporting these outcomes. There was no occurrence of nausea, vomiting, or tremor in either treatment groups in these two trials.
Single Dose Protocols

Trials examining the effect of the addition of a single dose of anticholinergics to beta2 agonists differed in several characteristics including age, severity of exacerbation, and co-intervention with glucocorticoids. These differences may explain the apparent divergence of individual trial results regarding hospital admission. Furthermore, the incomplete reporting of hospital admission and 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 with characteristics similar to those enrolled in the trials. The single study which examined children (aged 3 to 17 years) with mild to moderate asthma ruled out, with a narrow condence interval, any meaningful improvement in respiratory resistance attributable to anticholinergic use (Ducharme 1998). In contrast, trials that examined school aged children with severe asthma showed a signicant improvement in FEV1 60 minutes after the combined inhalation; a change that persisted at 120 minutes (Beck 1985; Schuh 1995). It is possible that differences in subjects age and baseline severity may be associated with various degrees of cholinergic induced bronchospasm. More trials in preschoolers and children with mild to moderate asthma are needed to conrm this hypothesis. Moreover, the sensitivity of response variables (change in % predicted FEV1, % change in FEV1, % change in respiratory resistance) to identify change as a result of treatment may vary. Finally, in contrast with current recommendations (Boulet 1999; NHLBI 1997; CAEP/CTS 1996; BMA 1992; Mitchell 1992; Rachelefsky 1993; Warner 1992) none of the trials involving children with severe exacerbations systematically added glucocorticoids to the inhalation regimen.
Multiple Dose-Fixed Protocols

Trials testing the addition of multiple doses of anticholinergics to beta2 agonists in a predetermined xed regimen were more homogeneous, focusing on school aged children (N=7) with severe exacerbations (N=5) and concomitant use of glucocorticoids (N= 4). A 25% reduction in hospital admission rate was attributable to combination therapy with no group difference in relapse rate among discharged patients. Twelve and a half patients would need to be treated with such a protocol to prevent one admission. The pooling of similar patients, mostly school-aged children with severe asthma, certainly contributed to the identication of this benet, as most of the individual trials did not have sufcient power to detect a group difference in admission rates. Baseline severity clearly inuenced the magnitude of benet expected of combination therapy; patients with mild to moderate exacerbations showing no reduction in hospital admission and those with severe exacerbations showing a 25 to 30% reduction in hospital admission. In fact, only 7 children with severe asthma need to be treated to prevent one admission. Insufcient power may have prevented the
10
DISCUSSION
The intensity of anticholinergic treatment protocol clearly inuenced 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 25% 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 generalizing results to all children with acute asthma.
identication of a signicant reduction in hospital admission in patients with moderate exacerbations (baseline FEV1 of 50-70% predicted or moderate clinical score or 25-30% admission rate in the control population). Regarding lung function, signicant group differences favouring the combination treatment were also observed, whether the response was expressed as change in % predicted FEV1 or as % change in FEV1 in trials examining children with baseline FEV1 of 30-70% of predicted. While modest, the extent of improvement in lung function is probably clinically meaningful as it was associated with a substantial reduction in hospital admissions. Three studies systematically administered glucocorticoids to all enrolled children (Qureshi 1997; Qureshi 1998 (sev); Zorc 1999 (sev)). All these studies showed favourable effects of the combination of multiple doses of anticholinergics and beta2 agonist that were sustained in the presence of glucocorticoids. Furthermore, in two trials which enrolled children with all spectrum of severity, the use of combination therapy resulted in a signicant 19% reduction in the need for additional inhalations after the xed protocol prior to disposition: In other words, 8 (95% CI: 5, 29) children would need to be treated with 2 to 3 doses of anticholinergics to prevent one or more additional inhalations.
Multiple Dose-Flexible Protocols

Two small trials examined the efcacy of systematically adding anticholinergics to every beta2 agonist inhalation, tailoring the number of inhalations to patients response. The systematic addition of anticholinergics to every inhalation was associated with a non-signicant trend towards reducing the number of inhalations needed. No data could be pooled regarding hospital admission or other measures of efcacy. Although this protocol most closely reects physicians treatment preference when dealing with children with mild to moderate asthma, more trials are required to conrm these trends before any conclusion can be drawn.
of study results to other countries should be considered, particularly with regards to the hospital admission. Large geographical variations in hospital admission rates have been predominantly attributed to differences in asthma severity, use of daily prophylaxis, intensity of emergency treatment, and admission criteria (Payne 1995; Homer 1996). Clearly, important international variations in these factors could inuence the anticipated response to treatment. Our thorough systematic search for published and unpublished trials resulted in identication of important trials, thus increasing the power and scope of the review (Cook 1993). Our review is strengthened by the direct conrmation of methodology and of extracted data with the authors of nine of thirteen trials. Nevertheless, the number and size of studies being pooled under each protocol remains small. Obviously, the present conclusions may be modied in the light of future trials. The present review summarizes the best evidence available to April 2000. This rst update identied 3 new trials not included in our rst Cochrane review published in 1997. Our conclusion regarding the single dose protocol remains unchanged due to the absence of new trials. With two additional trials in the multipledose xed protocol, we conrmed our prior ndings supporting the addition of multiple doses of anticholinergics to beta2-agonists for reducing hospital admission and improving lung function in children with severe exacerbations. A new nding indicates that the use of an intensive xed protocol also reduces the need for additional bronchodilator inhalations. However, it is unclear whether the avoidance of additional bronchodilator inhalations is mainly observed in the children with severe exacerbations or also pertains to children with moderate asthma. Despite a new trial contributing to the multiple dose exible protocol, no rm conclusion can be drawn regarding the systematic combination of anticholinergics and beta2-agonists in every inhalation, because of variation in reporting outcomes.
Side Effects
No apparent increase in the occurrence of nausea, vomiting or tremor were observed among 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.
AUTHORS CONCLUSIONS Implications for practice

The addition of multiple doses of anticholinergics to beta2 agonist inhalations is indicated in the initial management of children with severe exacerbations of asthma (<=55% of predicted FEV1). This intensive protocol improves lung function, reduces by 25% the risk of hospital admission and by 19% the need for additional bronchodilator inhalations. There is insufcient evidence supporting the use of this protocol in children with moderate exacerbations. In children with mild to moderate asthma exacerbations, there is no apparent benet from adding a single dose of anticholinergics to beta2-agonists. A single dose of anticholinergic is insufcient to avoid hospital admission in children with severe exacerbations.
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Strengths and Limitations

Like all systematic reviews, this meta-analysis is limited by the quality of existing data (Khan 1996). Fortunately, most trials (8/ 13) were of high quality. Exclusion of trials with lower reported methodological quality did not affect the conclusions. Funnel plot failed to identify any publication or other bias, although its sensitivity is somewhat limited by the small number trials. With 10 of the 13 trials originating from North America, the generalisability
Little evidence exists to support the systematic addition of anticholinergics to every beta2 agonist inhalation, irrespective of patients disease severity. The use of anticholinergics was not associated with increased in the following side effects, namely nausea, vomiting, and tremor. No comments regarding clinically important adverse effects, such as tachycardia or hypertension, can be made due to infrequent reporting.
more sensitive and reliable endpoints such as number of bronchodilator inhalations and oxygenation (during the emergency department treatment), duration of symptoms, functional status and quality of life (for discharged patients), and duration of hospitalization and duration of need for intensive (at <4-hour interval) bronchodilator inhalation (for hospitalized children). Finally there is a need for consistent reporting of baseline severity (with lung function or validated clinical score, whenever possible), glucocorticoid use, and admission and relapse rates.
Implications for research

Future trials should improve on three main aspects: interventions, choice of outcomes, and stratied reporting of results by asthma severity level. Firstly, because systematic glucocorticoids are now the standard treatment of children with severe exacerbations, they should be systematically given with beta2 agonists in future trials. In children with mild and moderate exacerbations, trials are needed to evaluate the potential benet of adding multiple doses of anticholinergics to beta2 agonist inhalations in a xed and/or exible (i.e., titrating the number of inhalations to patients response) protocol. Secondly, as admission and relapse are relatively gross measures of efcacy, subject to practice variation, future trials should include
ACKNOWLEDGEMENTS
No source of funding was available for this review. We thank the Cochrane Airways Review Group, namely Stephen Milan and Anna Bara, for the literature search and ongoing support and Dr Paul Jones for his constructive comments. We also thank Dr. Terry Klassen and Dr. David McGillivray for their invaluable suggestions and for Dr Francisco Noya for translating our correspondence to and from Spanish-speaking authors. We are indebted to the trials authors, namely Drs M.F. Guill, F.A. Qureshi, S. Schuh, K.P. Dawson, T. Klassen, J.J. Zorc and G.M. Calvo who cooperated enthusiastically to our requests for information.
REFERENCES
References to studies included in this review

Beck 1985 {published data only} Beck R. Use of ipratropium bromide by inhalation in the treatment of acute asthma in children. Clinical experience. Article in French [Utilisation du bromure dipratropium par voie inhalee pour le traitement de lasthme aigu chez lenfant]. Archives de Pediatrie 1995;2 Suppl(2):1458. Beck R, Robertson C, Galdes-Sebaldt M, Levison H. Combined salbutamol and ipratropium bromide by inhalation in the treatment of severe acute asthma. Journal of Pediatrics 1985;107:6058. Calvo 1998 {published data only} Calvo GM, Calvo AM, Marin HF, Moya GJ. Is it useful to add an anticholinergic treatment to beta2-adrenergic medication in acute asthma attack. Journal of Investigative Allergology Clinical Immunology 1998;8(1):304. Cook 1985 {published data only} Cook JJ, Fergusson DM, Dawson KP. Ipratropium and fenoterol in the treatment of acute asthma. Pharmatherapeutica 1985;4(6): 3836. Ducharme 1998 {unpublished data only} Ducharme FM, Davis GM. Randomized controlled trial of Ipratropium Bromide and frequent low doses of Salbutamol in the treatment of mild and moderate acute asthma. Journal of Pediatrics 1998;133(4):47985.
Guill 1987 {published data only} Guill MF, Maloney MJ, DuRant RH. Comparison of inhaled metaproterenol, inhaled atropine sulfate and their combination in treatment of children with acute asthma. Annals of Allergy 1987;59: 36771. Peterson 1996 {unpublished data only} Peterson R, Wensley D, Mitchell I, Klassen T, Lamarre J, Rivard G, et al.Boehringer Ingelheim Trial No 2442430, 3. 1994. Phanichyakam 1990 {published data only} Phanichyakam P, Kraisarin C, Sasisakulporn C. Comparison of Inhaled Terbutaline and Inhaled Terbutaline Plus Ipratropium Bromide in Acute Asthmatic Children. Asian Pacic Journal of Allergy and Immunology 1990;8:458. Qureshi 1997 {published data only} Qureshi FA, Zaritsky A, Lakkis H. Efcacy of Nebulized Ipratropium in Severe Asthmatic Children. Annals of Emergency Medicine 1997;29:20511. Qureshi 1998 (mod) {published data only} Qureshi F, Pestian J, Davis P, Zaritsky A. ffect of Nebulized Ipratropium on the Hospitalization Rates of Children with Asthma. New England Journal of Medicine 1998;339(15):10305. Qureshi 1998 (sev) {published data only} Qureshi F, Pestian J, Davis P, Zaritsky A. Effect of Nebulized Ipratropium on the Hospitalization Rates of Children with Asthma. New England Journal of Medicine 1998;339(15):103035.
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Reisman 1988 {published data only} Reisman J, Galdes-Sebaldt M, Kazim F, Canny G, Levison H. Frequent administration by inhalation of salbutamol and ipratropium bromide in the initial management of severe acute asthma in children. Journal of Allergy & Clinical Immunology 1988; 81:1620. Schuh 1995 {published data only} Schuh S, Johnson DW, Callahan S, Canny G, Levison H. Efcacy of frequent nebulized ipratropium added to frequent high-dose albuterol therapy in severe childhood asthma. Journal of Pediatrics 1995;126:63945. Watson 1988 {published data only} Watson WTA, Becker AB, Simmons FER. Comparison of Ipratropium Solution, Fenoterol Solution and Their Combination Administered by Nebulizer and Face Mask to Children with Acute Asthma. Journal of Allergy & Clinical Immunology 1988;82:10128. Zorc 1999 (mod) {published data only} Zorc JJ, Pusic MV, Ogborn CJ, Lebet R, Duggan AK. Ipratropium Bromide Added to Asthma treatment in the Pediatric Emergency Department. Pediatrics 1999;103(4):74852. Zorc 1999 (sev) {published data only} Zorc JJ, Pusic, MV, Ogborn CJ, Lebet R, Duggan AK. Ipratropium Bromide Added to Asthma Treatment in the Pediatric Emergency Department. Pediatrics 1999;103(4):74852. Zorc JJ 1999 (mil) {published data only} Zorc JJ, Pusic MV, Ogborn CJ, Lebet R, Duggan AK. Ipratropium Bromide Added to Asthma Treatment in the Pediatric Emergency Department. Pediatrics 1999;103(4):74852.
bromure dipatropium dans la crise dasthme de lenfant]. Archives de Pediatrie 1994;1:8792. DeStefano 1989 {published data only} DeStefano G, Bonetti S, Bonizzato C, Valletta EA, Piacentini GL, Boner AL. Additive effect of albuterol and ipatropium bromide in the treatment of bronchospasm in children. Annals of Allergy 1989; 65(4):2602. Ekwo 1978 {published data only} Ekwo E, Weinberger M. Evaluation of a program for the pharmacologic management of children with asthma. Journal of Allergy & Clinical Immunology 1978;61(4):2407. Freeman 1989 {published data only} Freeman J, Landau LI. The Effects of Ipatropium Bromide and Fenoterol Nebulizer Solutions in children with Asthma. Clinical pediatrics 1989;28(12):55660. Friberg 1989 {published data only} Friberg S, Graff-Lonnevig V. Ipatropium bromide (Atrovent) in childhood asthma: A cumulative dose-response study. Ann Allergy 1989;62:1314. Greenough 1986 {published data only} Greenough A, Loftus Bg, Pool J, Price JF. Response to bronchodilators assessed by lung mechanics. Archives of Disease in Childhood 1986;61:10203. Greenough A, Yuksel B, Everett L, Price JF. Inhaled ipratropium bromide and terbutaline in asthmatic children. Respiratory Medicine 1993;87:1114. Groggins 1981 {published data only} Groggins RC, Milner AD, Stokes GM. Bronchodilator effects of clemastine, ipratropium bromide, and salbutamol in preschool children with asthma. Archives of Disease in Childhood 1981;56: 3424. Hodges 1981 {published data only} Hodges IGC, Groggins RC, Milner AD, Stokes GM. Bronchodilator effect of inhaled ipratropium bromide in wheezy toddlers. Archives of Disease in Childhood 1981;56:72932. Lenney 1986 {published data only} Lenney W, Evans NAP. Nebulized Salbutamol and Ipatropium Bromide in Asthmatic Children. British Journal of Diseases of the Chest 1986;80:5965. Mann 1982 {published data only} Mann NP, Hiller EJ. Ipratropium bromide in children with asthma. Thorax 1982;37:724. Rayner 1987 {published data only} Rayner RJ, Cartlidge PHT, Upton CJ. Salbutamol and ipratropium in acute asthma. Archives of Disease in Childhood 1987;62:840841. Stokes 1983 {published data only} Stokes GM, Milner AD, Hodges IGC, Henry RL. Nebulised ipratropium bromide in wheezy infants and young children. European Journal of Respiratory Diseases 1983;64:4948. Storr 1986 {published data only} Storr J, Lenney W. Nebulised ipratropium and salbutamol in asthma. Archives of Disease in Childhood 1986;61:6023.
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References to studies excluded from this review

Boner 1987 {published data only} Boner AL, De Stefano G, Niero E, Vallone G, Gaburro D. Salbutamol and ipatropium bromide solution in the treatment of bronchospasm in asthmatic children. Annals of Allergy 1987;58: 548. Bratteby 1986 {published data only} Bratteby L-E, Foucard T, Lonnerholm G. Combined treatment with ipatropium bromide and beta-2-adrenoceptor agonists in childhood asthma. American Review of Respiratory Disease 1986;68: 23947. Caubet 1989 {published data only} Caubet Y. Comparison of the effectiveness and the tolerance of the dosing aerosols of Fenoterol/Ipatropium against Salbutamol in the asthmatic child. Article in French [Comparaison de lefcacite et de la tolerance des aerosols doseurs de lassociation Fenoterol/ Ipatropium contre le Salbutamol chez le grand enfant asthmatique]. La Revue de Pediatrie 1989;25(2):746. Davis 1984 {published data only} Davis A, Vickerson F, Worsley G, Mindorff C, Kazim F, Levison H. Determination of dose-response relationship for nebulized ipatropium in asthmatic children. Journal of Pediatrics 1984;Dec: 10025. Delacourt 1994 {published data only} Delacourt C, de Blic J, Lebourgeois M, Scheinmann P. Value of ipratropium bromide in asthma crisis in children [Interet du
Vichyanond 1990 {published data only} Vichyanond p, Sladek WA, Sur S, Hill MR, Szeer SJ, Nelson HS. Efcacy of Atropine Methylnitrate alone and in combination with Albuterol in children with asthma. Chest 1990;98:63742. Wilson 1984 {published data only} Wilson N, Dixon C, Silverman M. Bronchial responsiveness to hyperventilation in children with asthma:inhibition by ipratropium bromide. Thorax 1984;39:58893.
Jadad 1995 Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds JM, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized controlled trials: Is blinding necessary. Controlled Clinical Trials 1995;134:112. Khan 1996 Khan KS, Daya S, Jahad AR. The importance of quality of primary studies in producing unbiased systematic reviews. Archives of Internal Medicine 1996;156:6616. Mitchell 1992 Mitchell EA. Consensus on acute asthma management in children. Ad Hoc Pediatric Group. New Zealand Medical Journal 1992; Vol. 105:3535. NHLBI 1997 National Heart, Lung and Blood Institute. New NHLBI guidelines for the diagnosis and management of asthma. Lippincott Health Promotion Letter 1997;2:19. Olkin 1995 Olkin I. Statistical and theoretical considerations in meta-analysis. Journal of Clinical Epidemiology 1995 1995;48:13346.;48:13346. Osmond 1995 Osmond MH, Klassen TP. Efcacy of ipratropium bromide in acute childhood asthma - a meta-analysis. Academic Emergency Medicine 1995;2:6516. Payne 1995 Payne SM, Donahue C, Rappo P, McNamara JJ, Bass J, First L, et al.Variations in pediatric pneumonia and bronchitis/asthma admission rates. Is appropriateness a factor?. Archives of Pediatric and Adolescent Medicine 1995;149:1629. Peto 1995 Peto R, Collins R, Gray R. Large-scale randomized evidence: large, simple trials and overviews of trials. Journal of Clinical Epidemiology 1995;48:2340. Rachelefsky 1993 Rachelefsky GS, Warner JO. International consensus on the management of pediatric asthma: a summary statement. Pediatric Pulmonology. 1993; Vol. 15:1257. Robins 1986 Robins J, Breslow N, Greenland S. Estimators of the MantelHaenszel variance consistent in both sparse data and large-strata limiting models. Biometrics 1986;42:31123. Sackett 1995 Sackett DL. Applying overviews and meta-analyses at the bedside. Journal of Clinical Epidemiology 1995;48:616. Scarfone 1993 Scarfone RJ, Fuchs SM, Nager AL, Shane SA. Controlled trial of oral prednisone in the emergency department treatment of children with acute asthma. Pediatrics 1993;92:5138. Sears 1992 Sears MR. Clinical application of beta-agonists. Practical Allergy and Immunology 1992;7:98100. Silverman 1990 Silverman M. The role of anticholinergic antimuscarinic bronchodilator therapy in children. Lung 1990;168:3049.
14
Additional references
BMA 1992 British Medical Association. Asthma: a follow up statement from an international paediatric asthma consensus group. Archives of Diseases of Childhood. 1992; Vol. 67:2408. Boulet 1999 Boulet LP, Becker A, Berube D, Beveridge R, Ernst P. Canadian asthma consensus report, 1999. Canadian Medical Association Journal 1999;161(11 Suppl):S1S72. CAEP/CTS 1996 Beveridge RC, Grunfeld AF, Hodder RV, Verbeek PR. Guidelines for the emergency management of asthma in adults. Canadian Medical Association Journal 1996;155:2537. Chapman 1996 Chapman K. An international perspective on anticholinergic therapy. American Journal of Medicine 1996;100:24S. Cook 1993 Cook DJ, Guyatt GH, Ryan G, Clifton J, Buckingham L, Willan A, et al.Should unpublished data be included in meta-analyses? Current convictions and controversies. Journal of the American Medical Association 1993;269:274953. DerSimonian 1986 DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986 1986;7:17788.;7:17788. Egger 1997 Egger M, Smith GD, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ BMJ 1997;315: 629-34. 1997;315:62934. Greenhalgh 1997 Greenhalgh T. Papers that summarize other papers (systematic reviews and meta-analyses). British Medical Journal 1997;315: 6725. Greenland 1985 Greenland S, Robins JM. Estimation of a common effect parameter from sparse follow-up data. Biometrics 1985;41:5568. Gross 1988 Gross NJ. Ipratropium Bromide. New England Journal of Medicine 1988;8:48694. Hasselblad 1995 Hasselblad V, Hedges LV. Meta-analysis of screening and diagnostic tests. Psychol Bulletin 1995;117:16778. Homer 1996 Homer CJ, Szilagyi P, Rodewald L, Bloom SR, Greenspan P, Yazdgerdi S, et al.Does quality of care affect rates of hospitalization for childhood asthma?. Pediatrics 1996;98:1823.
Sim 1996 Sim I, Hlatky MA. Growing pains of meta-analysis. British Medical Journal 1996;313:7023. Stern 1997 Stern JM, SImes RJ. Publication bias: evidence of delayed publication in a cohort study of clinical research projects. British Medical Journal 1997;315:6405. SVedmyr 1985 Svedmyr N. A beta2-adrenergic agonist for use in asthma pharmacology, pharmacokinetics, clinical efcacy and adverse effects. Pharmacotherapy 1985;5:10926.
Tal 1990 Tal A, Levy N, Bearman JE. Methylprednisolone therapy for acute asthma in infants and toddlers: a controlled clinical trial. Pediatrics 1990;86:3506. Warner 1989 Warner JO, Gotz M, Landau LI, Levison H, Milner AD, Pedersen S, et al.Management of asthma: a consensus statement. Archives of Diseases of Childhood 1989;64:106579. Warner 1992 Warner JO. Asthma: a follow up statement from an international paediatric asthma consensus group. Archives of Diseases of Childhood. 1992; Vol. 67:2408. Indicates the major publication for the study
15
CHARACTERISTICS OF STUDIES Characteristics of included studies [ordered by study ID]

Beck 1985 Methods RANDOMIZATION - Method: not described - Means: number-coded solutions supplied by pharmacy BLINDING - double-blind; identical placebo WITHDRAWAL/DROPOUT - not described JADADs quality score=3 N = 25 AGE - 6-17.5 years old BASELINE SEVERITY - <50% Pred FEV1 COUNTRY - Canada OTHER - ability to perform spirometry consistently PROTOCOL - Fixed: 60 minutes - Observation period: 150 minutes total - Single dose anticholinergic TEST GROUP - Salbutamol 150 mcg/kg [(0.03ml/kg) max 5mg=1ml] then 50 mcg/kg (max 1.7mg) q20 minutes x6 + IB 250 mcg at 60 minutes (with 4th Salbutamol) CONTROL GROUP - Salbutamol 150 mcg/kg [(0.03ml/kg) max 5mg=1ml] then 50 mcg/kg (max 1.7mg) q20 minutes x 6 + placebo CO-INTERVENTION (other medications during study) - Systemic corticosteroids: not described - Theophylline : 6 in each group on regular theophylline; no mention if continued during study DEVICE - nebulizer PULMONARY FUNCTION TESTS - % Change in FEV1 VITAL SIGNS - pulse, blood pressure, respiratory rate ADVERSE EFFECTS - tremor, vomiting ADMISSION RELAPSE - within ? time Author (HL) contacted Conrmation by HL of methodology and data extraction - not obtained
Participants
Interventions
Outcomes
Notes
Risk of bias Item Adequate sequence generation? Authors judgement Unclear Description Described as randomised; other information not available
16
Beck 1985
(Continued)
Allocation concealment? Blinding? All outcomes Calvo 1998 Methods
Yes Yes
number-coded solutions supplied by pharmacy Identical placebo used
No RANDOMIZATION -Method:consecutive assignment - Means: number-coded solutions supplied by pharmacy BLINDING -double-blinding, identical placebo WITHDRAWAL/DROPOUTS - none JADADS quality score=3 N=80 AGE - 5-14 yo BASELINE SEVERITY - <80% Predicted PEF & Tal score >=5 COUNTRY - Chile PROTOCOL - Titrated to patient until symptoms controlled TEST GROUP - Salbutamol 200mcg + IB 40 mcg q15 minutes x 4 then q20 minutes x 3 CONTROL GROUP - Salbutamol 200mcg q15 minutes x 4 then q20 minutes x 3 CO-INTERVENTION (other medications used during study) - some patients received systemic corticosteroids (prednisone 1mg/kg/dose: max=40 mg) at 60 min after beginning treatment if no clinical or laboratory improvement DEVICE - inhalation PULMONARY FUNCTION TESTS - peak ow CLINICAL SCORE - Tal score VITAL SIGNS - pulse, respiratory rate ADVERSE EFFECTS - tremor, mydriatic reaction, dryness of the oral membrane, pharyngeal irritation, nausea, vomiting # PATIENTS NEEDING CORTICOSTEROIDS ADMISSION Author (GMC) contacted Conrmation by GMC of methodology and data extraction - obtained
Participants
Interventions
Outcomes
Notes
Risk of bias
Calvo 1998
(Continued)
Item Adequate sequence generation? Allocation concealment? Blinding? All outcomes Cook 1985 Methods
Authors judgement No No Yes
Description Consecutive assignment Number-coded solutions supplied by pharmacy Identical placebo
RANDOMIZATION - method and means not described BLINDING - double-blind; all solutions were 2.5 ml, no other details WITHDRAWAL/DROPOUT - described JADADs quality score=4 N = 30 AGE - 18 months - 12 years old BASELINE SEVERITY - moderately severe (not dened), excluded if needed iv medication COUNTRY - Australia PROTOCOL - Fixed: - Observation period: 120 minutes - Single dose TEST GROUP - Fenoterol 0.125 ml (1-4 y.o.)/0.25 ml (5-8 y.o.)/0.5 ml (9-12 y.o.) + IB 1 ml (1-4 y.o.)/1.5 ml (5-8 y.o.)/2.0 ml (9-12 y.o.) CONTROL GROUP - Fenoterol 0.125 ml (1-4 y.o.)/0.25 ml (5-8 y.o.)/0.5 ml (9-12 y.o.) + placebo CO-INTERVENTION (other medications used during study) - Systemic corticosteroids:- none - Other medications:- stopped DEVICE - nebulizer PULMONARY FUNCTION TESTS - Peak Flow Rates (not obtained routinely) CHANGE IN CLINICAL SCORE - Overall score of wheeze, air entry and respiratory distress VITAL SIGNS - pulse, respiratory rate NEED FOR REPEAT TREATMENTS AFTER STANDARD PROTOCOL PRIOR TO DISPOSITION Co-author (KPD) - contacted Conrmation by KPD of methodology - obtained Conrmation of data extraction - pending For change in clinical score, no values for t=0 minutes, therefore used t=5 minutes as baseline
Participants
Interventions
Outcomes
Notes
Risk of bias
Cook 1985
(Continued)
Item Adequate sequence generation?
Authors judgement Unclear
Description Described as randomised; other information not available Information not available Identical placebo
Allocation concealment? Blinding? All outcomes Ducharme 1998 Methods
Yes Yes
RANDOMIZATION - Method: computer-generated random numbers - Means: coded solutions BLINDING - triple blinding, identical placebo WITHDRAWAL/DROPOUT - none JADADs quality score=5 N = 298 AGE - 3-17 years old BASELINE SEVERITY - excluded patients requiring continuous Salbutamol COUNTRY - Canada OTHER - Ability to perform Respiratory Resistance (RFo) consistently PROTOCOL - Fixed: 60 minutes - Observation period: 210 minutes - Single dose TEST GROUP - Combination of: Salbutamol 0.15mg/kg q 1h + IB 250 mcg (single dose) OR Salbutamol 0.075mg/kg q30 minutes + IB 250mcg CONTROL GROUP - Combination of: Salbutamol 0.15mg/kg q 1h + placebo OR Salbutamol 0.075mg/kg q30 minutes + placebo CO-INTERVENTION (other medications used during study) - Systemic corticosteroids : at discretion of treating physician DEVICE: nebulizer PULMONARY FUNCTION TESTS - % Change in RFo CHANGE IN CLINICAL SCORE - Wheezing Score O2 SATURATION # REPEAT TREATMENTS REQUIRED AFTER STANDARD PROTOCOL PRIOR TO DISPOSITION VITAL SIGNS - pulse ADVERSE EFFECTS - tremor, vomiting, nausea
19
Participants
Interventions
Outcomes
Ducharme 1998
(Continued)
NEED FOR CORTICOSTEROIDS PRIOR TO DISCHARGE ADMISSION RELAPSE - within 72 hours ADMISSION RELAPSE ADVERSE EFFECTS - not described Notes Author (FMD) - contacted Conrmation by FMD of methodology and data extraction - obtained Factorial design - tested 2 interventions simultaneously (frequent low doses of Salbutamol & combination therapy with IB); no interaction observed between the 2 interventions
Risk of bias Item Adequate sequence generation? Allocation concealment? Blinding? All outcomes Guill 1987 Methods RANDOMIZATION - Method: computer-generated random numbers - Means: opaque consecutive numbered envelopes containing assignment BLINDING - double-blind, identical placebo WITHDRAWAL/DROPOUT- all participants completed the trial and were included in the analysis JADADs quality score=5 N = 35 participants, 44 visits AGE - 13 months - 12 years old BASELINE SEVERITY - not described COUNTRY - USA PROTOCOL - Titrated to patient until symptoms controlled or patient admitted TEST GROUP - Metaproterenol 0.2 ml (<12 y.o.)/0.3 ml (>=12 y.o.) + Atropine Sulfate 0.05-0.1 mg/kg (max 2 mg) CONTROL GROUP - Metaproterenol 0.2 ml (<12 y.o.)/0.3 ml (>=12 y.o.) CO-INTERVENTION (other medications used during study) - Systemic corticosteroids: not mentioned DEVICE - nebulizer Authors judgement Yes Yes Yes Description Computer-generated random numbers Coded solutions Identical placebo
Participants
Interventions
20
Guill 1987
(Continued)
Outcomes
PULMONARY FUNCTION TESTS - Change in %Predicted PEF CLINICAL SCORE - Pulmonary Index NUMBER OF REPEAT TREATMENTS REQUIRED PRIOR TO DISPOSITION ADVERSE EFFECTS - no details in study given but data conrmed ADMISSION - data not available RELAPSE - data not available Author (MFG) - contacted Conrmation by MFG of methodology and data extraction - obtained
Notes
Risk of bias Item Adequate sequence generation? Allocation concealment? Authors judgement Yes Yes Description Computer-generated random numbers Opaque consecutive numbered envelopes containing assignment Identical placebos used
Blinding? All outcomes Peterson 1996 Methods
Yes
RANDOMIZATION - Method: computer generated random numbers - Means: number-coded solutions supplied by the pharmacy BLINDING - triple-blinding, identical placebo WITHDRAWAL/DROPOUT - described JADADs quality score=5 N = 163 AGE - 5-12 years old BASELINE SEVERITY - <70% Predicted FEV1 COUNTRY - Canada OTHER - Ability to perform spirometry consistently N = 163 PROTOCOL - Fixed: 90 minutes - Observation period: 120 minutes total - Multiple doses TEST GROUP - Salbutamol 3 mg + IB 250 mcg q 45 min x 2 doses CONTROL GROUP - Salbutamol 3 mg q 45 min x 2 doses
21
Participants
Interventions
Peterson 1996
(Continued)
CO-INTERVENTION (other medications used during study) - additional inhalation of salbutamol + placebo/ipratropium at 90 min if FEV1 <85% of predicted. - Systemic corticosteroids: at discretion of treating physician - Other medications: documented DEVICE - nebulizer Outcomes PULMONARY FUNCTION TESTS - Change in %Predicted FEV1 - Change in Predicted PEF O2 SATURATION # REPEAT TREATMENTS REQUIRED AFTER STANDARD PROTOCOL PRIOR TO DISPOSITION VITAL SIGNS - blood pressure, pulse, respiratory rate ADVERSE EFFECTS - rash, dizziness, hyperkinesia, hypertonia, tremor, conjunctivitis, taste perversion, vomiting, abdominal pain, nausea, coughing, epistaxis, pneumonia, pneumothorax, asthma exacerbation, headache, chest pain, fever, pain, sinusitis, stridor, bacterial infection NEED FOR CORTICOSTEROIDS PRIOR TO DISPOSITION ADMISSION RELAPSE - within 72 hours Unpublished multicenter trial Co-investigator (TK) - contacted - granted permission to use unpublished data Conrmation by TK of methodology & data extraction - obtained
Notes
Risk of bias Item Adequate sequence generation? Allocation concealment? Authors judgement Yes Yes Description Computer generated random numbers Number-coded solutions supplied by the pharmacy Identical placebo
Blinding? All outcomes Phanichyakam 1990 Methods
Yes
RANDOMIZATION - Method and means not described BLINDING - double-blinding but not described WITHDRAWAL/DROPOUT - not described JADADs quality score=1 N = 20 AGE - 4-15 years old BASELINE SEVERITY - not specied
22
Participants
Phanichyakam 1990
(Continued)
COUNTRY - Thailand Interventions PROTOCOL - Fixed: 15 minutes - Observation period: 360 minutes total - Single dose TEST GROUP - Terbutaline 0.5 mg + IB 0.04 mg (15 minutes after terbutaline) x 1 dose CONTROL GROUP - Terbutaline 0.5 mg x 1 dose CO-INTERVENTION (other medications used during study) - not mentioned DEVICE - MDI with 750 cc volumetric spacer PULMONARY FUNCTION TESTS - % Change in FEV1 - % Change in PEF VITAL SIGNS - blood pressure, heart rate, respiratory rate ADVERSE EFFECTS - ocular, secretion-drying, facial-ushing Contact of three authors attempted - unsuccessful Conrmation of methodology and data extraction - not obtained
Outcomes
Notes
Risk of bias Item Adequate sequence generation? Authors judgement Unclear Description Described as randomised; no other information available Information not available Information not available
Allocation concealment? Blinding? All outcomes Qureshi 1997 Methods
Unclear Unclear
RANDOMIZATION - Method: table of random numbers - Means: number-coded solutions supplied by the pharmacy BLINDING - double-blinding, identical placebo WITHDRAWAL/DROPOUTS - none JADADs quality score=5 N=90 AGE - 6-18 yo BASELINE SEVERITY - <50% Predicted PEF COUNTRY - USA
23
Participants
Qureshi 1997
(Continued)
Interventions
PROTOCOL - Fixed:60 minutes - Observation period: 120 minutes total - Multiple doses TEST GROUP - Albuterol 0.15mg/kg/dose q30 min + Ipratropium 500 mcg at 0 & 60 minutes CONTROL GROUP - Albuterol 0.15mg/kg/dose q30 minutes + Saline at 0 & 60 minutes CO-INTERVENTION (other medications used during the study) - Systemic corticosteroids: all received oral steroids at 60 min. DEVICE - nebulizer PULMONARY FUNCTION TESTS - Change in Predicted FEV1 - Change in Predicted PEF O2 SATURATION VITAL SIGNS - blood pressure, heart rate, respiratory rate ADVERSE EFFECTS - increasing breathlessness, dry mouth, palpitations, blurred vision, dilatation of pupils, nausea, vomiting, mental confusion, dizziness, headache, back and chest pain # REPEAT TREATMENTS REQUIRED AFTER STANDARD PROTOCOL PRIOR TO DISPOSITION ADMISSION RELAPSE - within 48 hours Author (FQ) - contacted Conrmation by FQ of methodology and data extraction - obtained
Outcomes
Notes
Risk of bias Item Adequate sequence generation? Allocation concealment? Authors judgement Yes Yes Description Table of random numbers Number-coded solutions supplied by the pharmacy Identical placebo
Blinding? All outcomes
Yes
24
Qureshi 1998 (mod) Methods RANDOMIZATION - Method: table of random numbers - Means: number-coded solutions supplied by pharmacy BLINDING - double-blinding, identical placebo WITHDRAWAL/DROPOUTS - described JADADS quality score=5 N=163 AGE - 2-18 yo BASELINE SEVERITY- 50-70% PEFR or asthma score=8-11 COUNTRY - USA PROTOCOL - Fixed:60 minutes - Observation period: up to 248 minutes - Multiple doses TEST GROUP - Albuterol 2.5mg (<20kg)/ 5.0mg (=>20kg) q20 minutes x 3 & IB 500 mcg at 20 and 40 minutes CONTROL GROUP - Albuterol 2.5mg (<20kg)/ 5.0mg (=>20kg) q20 minutes x 3 & Saline at 20 and 40 minutes CO-INTERVENTION (other medications used during the study) - Systemic corticosteroids - all received oral steroids at 20 minutes DEVICE - nebulizer PULMONARY FUNCTION TESTS - % Change in PEFR CHANGE IN CLINICAL SCORE O2 SATURATION # NEBULIZER TXs UNTIL DISPOSITION TIME TO DISPOSITION VITAL SIGNS - pulse, respiratory rate ADMISSION RELAPSE Author (FQ) - contacted Conrmation by FQ of methodology and data extraction - obtained
Participants
Interventions
Outcomes
Notes
Risk of bias Item Adequate sequence generation? Allocation concealment? Authors judgement Yes Yes Description Table of random numbers Number-coded solutions supplied by pharmacy
25
Qureshi 1998 (mod)
(Continued)
Blinding? All outcomes Qureshi 1998 (sev) Methods
Yes
Identical placebo
RANDOMIZATION - Method: table of random numbers - Means: number-coded solutions supplied by pharmacy BLINDING - double-blinding, identical placebo WITHDRAWAL/DROPOUTS - described JADADS quality score=5 N=271 AGE - 2-18 yo BASELINE SEVERITY- <50% PEFR or asthma score=12-15 PROTOCOL - Fixed:60 minutes - Observation period: up to 248 minutes - Multiple doses TEST GROUP - Albuterol 2.5mg (<20kg)/ 5.0mg (=>20kg) q20 minutes x 3 & IB 500 mcg at 20 and 40 minutes CONTROL GROUP - Albuterol 2.5mg (<20kg)/ 5.0mg (=>20kg) q20 minutes x 3 & Saline at 20 and 40 minutes CO-INTERVENTION (other medications used during the study) - Systemic corticosteroids - all received oral steroids at 20 minutes DEVICE - nebulizer PULMONARY FUNCTION TESTS - % Change in PEFR CHANGE IN CLINICAL SCORE O2 SATURATION # NEBULIZER TXs UNTIL DISPOSITION TIME TO DISPOSITION VITAL SIGNS - pulse, respiratory rate ADMISSION, RELAPSE Author (FQ) - contacted Conrmation by FQ of methodology and data extraction - obtained
Participants
Interventions
Outcomes
Notes
Risk of bias Item Authors judgement Description

26
Qureshi 1998 (sev)
(Continued)
Adequate sequence generation? Allocation concealment? Blinding? All outcomes Reisman 1988 Methods
Yes Yes Unclear
Table of random numbers Number-coded solutions supplied by pharmacy Identical placebo
RANDOMIZATION - Method: not described - Means: number-coded solutions supplied by the pharmacy BLINDING - double-blinding, identical placebo WITHDRAWAL/DROPOUT - not fully described JADADs quality score=3 N = 24 AGE - 5-15 years old BASELINE SEVERITY - <=55% Pred FEV1 COUNTRY - Canada PROTOCOL - Fixed: 80 minutes - Observation period: 150 minutes total - Multiple doses TEST GROUP - Salbutamol 150 mcg/kg [(0.03ml/kg) max 5 mg=1ml)] then 50 mcg/kg q20 minutes x 6 + IB 250 mcg at 0, 40 and 80 minutes CONTROL GROUP - Salbutamol 150 mcg/kg [(0.03ml/kg) max 5 mg=1ml)] then 50 mcg/kg q20 minutes x 6 CO-INTERVENTION (other medications used during study) - Systemic corticosteroids : none - Theophylline : none DEVICE - nebulizer PULMONARY FUNCTION TESTS - Change in %Predicted FEV1 CHANGE IN WHEEZING SCORE ADVERSE EFFECTS - tremor, vomiting ADMISSION - described RELAPSE - not mentioned ADVERSE EFFECTS - Tremor Author (HL) - contacted Conrmation of methodology and data extraction - not obtained
Participants
Interventions
Outcomes
Notes
Risk of bias
27
Reisman 1988
(Continued)
Item Adequate sequence generation?
Authors judgement Unclear
Description Described as randomised; no other information available Number-coded solutions supplied by the pharmacy Identical placebo
Allocation concealment?
Yes
Blinding? All outcomes Schuh 1995 Methods
Yes
RANDOMIZATION - Method: table of random numbers - Means: number-coded solutions supplied by the pharmacy BLINDING - double-blind, identical placebo WITHDRAWAL/DROPOUT - described JADADs quality score=5 N = 120 AGE - 5-17 years old BASELINE SEVERITY - <50% Predicted FEV1 COUNTRY - Canada OTHER - ability to perform spirometry consistently N = 120 OTHER - included those able to perform PFTs reliably PROTOCOL - Fixed: 60 minutes - Observation period: 120 minutes total - Single and Multiple doses TEST GROUPS - Albuterol 0.15 mg/kg q 20 minutes x 3 + IB 250 mcg x 1 OR - Albuterol 0,15 mg/kg q 20 minutes x 3 + IB 250 mcg q20 minutes x 3 CONTROL GROUP - Albuterol 0.15mg/kg q20 minutes x 3 CO-INTERVENTION (other medications used during study) - Systemic corticosteroids: none - Other medications: no bronchodilators DEVICE - nebulizer PULMONARY FUNCTION TESTS - Change in %Predicted FEV1 OXYGEN SATURATION CHANGE IN CLINICAL SCORE - accessory muscle, wheeze, dyspnea and overall # REPEAT TREATMENTS REQUIRED AFTER STANDARD PROTOCOL PRIOR TO DISPOSITION
28
Participants
Interventions
Outcomes
Schuh 1995
(Continued)
VITAL SIGNS - heart rate, respiratory rate ADVERSE EFFECTS - nausea, tremor, conjunctivitis, coughing spasm with syncope NEED FOR CORTICOSTEROIDS PRIOR TO DISPOSITION ADMISSION - described RELAPSE - within 72 hours Notes Author (SS) contacted Conrmation of methodology and data extraction - obtained
Risk of bias Item Adequate sequence generation? Allocation concealment? Authors judgement Yes Yes Description Table of random numbers Number-coded solutions supplied by the pharmacy Identical placebo
Blinding? All outcomes Watson 1988 Methods
Yes
RANDOMIZATION - method and means not described BLINDING - double-blind, not described WITHDRAWAL/DROPOUT - none JADADs quality score=3 N = 31 AGE - 6-17 years old BASELINE SEVERITY - 30-70% Pred FEV1 COUNTRY - Canada OTHER - ability to perform spirometry consistently PROTOCOL - Fixed: 60 minutes - Observation period: 120 minutes total - Multiple doses TEST GROUP - Fenoterol 625 mcg + IB 250 mcg combined q60 minutes x 2 CONTROL GROUP - Fenoterol 625 mcg q 60 minutes x 2 CO-INTERVENTION (other medications usd during study) - Systemic corticosteroids: none - Theophylline: none DEVICE - nebulizer
Participants
Interventions
29
Watson 1988
(Continued)
Outcomes
PULMONARY FUNCTION TESTS - Change in %Predicted FEV1 - % Change in FEV1 OXYGEN SATURATION - no details given CHANGE IN CLINICAL SCORE - Pulmonary Index, no details given ADVERSE EFFECTS - tremor, no adverse effects but none other specied ADMISSION - described RELAPSE - not mentioned Author (WTAW) - contacted Conrmation by WTAW of methodology and data extraction - pending
Notes
Risk of bias Item Adequate sequence generation? Authors judgement Unclear Description Described as randomised; no other information available Information not available Information not available
Allocation concealment? Blinding? All outcomes Zorc 1999 (mod) Methods
Unclear Unclear
RANDOMIZATION - Method: computer generated random numbers - Means: number-coded solutions supplied by the pharmacy BLINDING - double-blind, identical placebo WITHDRAWAL/DROPOUT - described JADADs quality score=5 N=194 AGE - 1-17 years old BASELINE SEVERITY initial severity score of 4-6,excluded if required initial therapy in addition to the Critical Pathway - initial severity score was incomplete/missing for 14% of the total 427 participants of the full study COUNTRY - USA PROTOCOL - Fixed: 60 minutes - Observation period: up to 295 minutes - Multiple doses TEST GROUP - Albuterol 2.5mg (<20kg)/ 5.0mg (=>20kg) q20 minutes x 3 & IB 500 mcg at 20 and 40 minutes CONTROL GROUP
30
Participants
Interventions
Zorc 1999 (mod)
(Continued)
- Albuterol 2.5mg (<20kg)/ 5.0mg (=>20kg) q20 minutes x 3 & Saline at 20 and 40 minutes CO-INTERVENTION (other medications used during the study) - Systemic corticosteroids : all received oral steroids at 20 minutes DEVICE - nebulizer Outcomes # NEBULIZER TXs UNTIL DISPOSITION TIME TO DISPOSITION ADMISSION - to ward, to ICU RELAPSE Author (MP) - contacted Conrmation by MP of methodology and data extraction - obtained
Notes
Blinding? All outcomes Zorc 1999 (sev) Methods
Yes
RANDOMIZATION - Method: computer generated random numbers - Means: number-coded solutions supplied by the pharmacy BLINDING - double-blind, identical placebo WITHDRAWAL/DROPOUT - described JADADs quality score=5 N=51 AGE - 1-17 years old BASELINE SEVERITY - initial severity score of 7-9, excluded patients if respiratory failure or required initial therapy in addition to the Critical Pathway - initial severity score was incomplete/missing for 14% of the total 427 participants of the full study COUNTRY - USA PROTOCOL - Fixed: 60 minutes - Observation period: up to 295 minutes - Multiple doses TEST GROUP - Albuterol 2.5mg (<20kg)/ 5.0mg (=>20kg) q20 minutes x 3 &
31
Participants
Interventions
Zorc 1999 (sev)
(Continued)
IB 500 mcg at 20 and 40 minutes CONTROL GROUP - Albuterol 2.5mg (<20kg)/ 5.0mg (=>20kg) q20 minutes x 3 & Saline at 20 and 40 minutes CO-INTERVENTION (other medications used during the study) - Systemic corticosteroids: all received oral steroids at 20 minutes DEVICE - nebulizer Outcomes # NEBULIZER TXs UNTIL DISPOSITION TIME TO DISPOSITION ADMISSION - to ward, to ICU RELAPSE Author (MP) - contacted Conrmation by MP of methodology and data extraction - obtained
Notes
Blinding? All outcomes Zorc JJ 1999 (mil) Methods
Yes
RANDOMIZATION - Method: computer generated random numbers - Means: number-coded solutions supplied by the pharmacy BLINDING - double-blind, identical placebo WITHDRAWAL/DROPOUT - described JADADs quality score=5 N=117 AGE - 1-17 years old BASELINE SEVERITY - initial severity score of 1-3, excluded patients if required initial therapy in addition to the Critical Pathway - initial severity score was incomplete/missing for 14% of the total 427 participants of the full study COUNTRY - USA PROTOCOL - Fixed: 60 minutes - Observation period: up to 295 minutes - Multiple doses
32
Participants
Interventions
Zorc JJ 1999 (mil)
(Continued)
TEST GROUP - Albuterol 2.5mg (<20kg)/ 5.0mg (=>20kg) q20 minutes x 3 & IB 500 mcg at 20 and 40 minutes CONTROL GROUP - Albuterol 2.5mg (<20kg)/ 5.0mg (=>20kg) q20 minutes x 3 & Saline at 20 and 40 minutes CO-INTERVENTION (other medications used during the study) - Systemic corticosteroids: all received oral steroids at 20 minutes DEVICE - nebulizer Outcomes # NEBULIZER TXs UNTIL DISPOSITION TIME TO DISPOSITION ADMISSION - to ward, to ICU RELAPSE Author (MP) - contacted Conrmation by MP of methodology and data extraction - obtained
Notes
Blinding? All outcomes
Unclear
Characteristics of excluded studies [ordered by study ID]
Study Boner 1987 Bratteby 1986 Caubet 1989 Davis 1984 Delacourt 1994 DeStefano 1989
Reason for exclusion The study pertained to stable asthmatics. The study pertained to chronic asthmatics. The study pertained to chronic asthmatics. The study pertained to stable asthmatics. The study was not a randomized controlled trial. The study pertained to chronic asthmatics.
33
(Continued)
Ekwo 1978 Freeman 1989 Friberg 1989 Greenough 1986 Groggins 1981 Hodges 1981 Lenney 1986 Mann 1982 Rayner 1987 Stokes 1983 Storr 1986 Vichyanond 1990 Wilson 1984
The study was not a randomized controlled trial. The study pertained to patients who were already admitted. The study pertained to chronic asthmatics. The study pertained to chronic asthmatics. The study pertained to stable asthmatics. The study pertained to infants. The study pertained to chronic asthmatics. The study pertained to chronic asthmatics. The study pertained to patients who were already admitted. The study did not combine anticholinergic inhalations and beta2-agonist inhalations. The study pertained to patients who were already admitted. The study pertained to chronic asthmatics. The study pertained to non-acute asthmatics.
34
DATA AND ANALYSES
Comparison 1. ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE
Outcome or subgroup title 1 Admission 1.1 Co-intervention: Corticosteroids during study 1.2 Co-intervention: No corticosteroids 1.3 Corticosteroid use variable/not described 2 -(Change in % Pred FEV1 at 60 minutes after IB) +/- 15 minutes 2.1 Co-intervention: Corticosteroids during the previous 60 minutes 2.2 Co-intervention: No corticosteroids 2.3 Co-intervention: Corticosteroid use variable/ not described 3 - (Change in % Pred FEV1 at 120 minutes after IB) +/- 30 minutes 3.1 Co-intervention: Corticosteroids during the previous 120 minutes 3.2 Co-intervention: No corticosteroids 3.3 Corticosteroid use variable/ not described 4 - (% Change in FEV1 at 60 minutes after IB) +/- 15 minutes 4.1 Co-intervention: Corticosteroids during the previous 60 minutes 4.2 Co-intervention: No corticosteroids 4.3 Corticosteroid use variable/not described 5 - (% Change in FEV1 at 120 minutes after IB) +/- 30 minutes
No. of studies 2 1 2 0 1
No. of participants 378 171 207 0 76
Statistical method Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)
Effect size 0.93 [0.65, 1.32] 1.22 [0.69, 2.15] 0.73 [0.46, 1.17] Not estimable -6.6 [-13.73, 0.53]
Mean Difference (IV, Fixed, 95% CI)
Not estimable
1 0
76 0
Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)
-6.6 [-13.73, 0.53] Not estimable
74
-5.1 [-11.86, 1.66]
Not estimable
1 0 2
74 0 45
Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)
-5.1 [-11.86, 1.66] Not estimable -16.10 [-26.66, 5.54] Not estimable
0 2 2
0 45 45
Not estimable -16.10 [-26.66, 5.54] -17.49 [-30.53, 4.46]

35
5.1 Co-intervention: Corticosteroids during the previous 120 minutes 5.2 Co-intervention: No corticosteroids 5.3 Corticosteroid use variable/not described 6 % Change in Respiratory resistance at 60 minutes after IB +/- 15 minutes 6.1 Co-intervention: Corticosteroids during the previous 60 minutes 6.2 Co-intervention: No corticosteroids 6.3 Corticosteroid use variable/not described 7 % Change in Respiratory resistance at 120 minutes after IB +/- 30 minutes 7.1 Co-intervention: Corticosteroids during the previous 120 minutes 7.2 Co-intervention: No corticosteroids 7.3 Corticosteroid use variable/not described 8 Change in clinical score at 60 minutes +/- 15 minutes 8.1 Co-intervention: Corticosteroids during the previous 60 minutes 8.2 Co-intervention: No corticosteroids 8.3 Corticosteroid use variable/not described 9 Change in clinical score at 120 minutes +/- 30 minutes 9.1 Co-intervention: Corticosteroids during the previous 120 minutes 9.2 Co-intervention: No corticosteroids 9.3 Corticosteroid use variable/not described 10 O2 Saturation <95% at 60 minutes +/- 15 minutes 10.1 Co-intervention: Corticosteroids during the previous 60 minutes
Not estimable
0 2 1
0 45 294
Not estimable -17.49 [-30.53, 4.46] 0.02 [-0.02, 0.07]
70
-0.02 [-0.13, 0.09]
1 0 1
224 0 108
0.03 [-0.02, 0.08] Not estimable -0.01 [-0.09, 0.07]
47
0.02 [-0.12, 0.16]
1 0 2 1
61 0 370 68
Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)
-0.02 [-0.12, 0.08] Not estimable -0.06 [-0.26, 0.14] -0.23 [-0.66, 0.20]
2 0 1 1
302 0 105 44
-0.01 [-0.24, 0.22] Not estimable 0.13 [-0.22, 0.48] 0.32 [-0.17, 0.81]
1 0 2 1
61 0 376 70
Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
-0.06 [-0.55, 0.43] Not estimable 0.75 [0.55, 1.01] 0.84 [0.39, 1.79]
36
10.2 Co-intervention: No corticosteroids 10.3 Co-intervention: Corticosteroid use variable/not described 11 O2 Saturation <95% at 120 minutes +/- 30 minutes 11.1 Co-intervention: Corticosteroids during the previous 120 minutes 11.2 Co-intervention: No corticosteroids 11.3 Co-intervention: Corticosteroid use variable/not described 12 Number of repeat treatments required after standard protocol prior to disposition 12.1 0 treatments 12.2 >=1 additional treatment 13 Tremor 14 Vomiting 14.1 Co-intervention: Corticosteroids during study 14.2 Co-intervention: No corticosteroids 14.3 Corticosteroid use variable/not described 15 Nausea 15.1 Co-intervention: Corticosteroids during study 15.2 Co-intervention: No corticosteroids 15.3 Corticosteroid use variable/not described 16 Need for corticosteroids in emergency department prior to disposition 17 Relapse 17.1 Co-intervention: Corticosteroids upon discharge 17.2 Co-intervention: No corticosteroids 17.3 Corticosteroid use variable/not described
2 0
306 0
Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
0.73 [0.52, 1.01] Not estimable
2 1
185 47
1.10 [0.76, 1.60] 1.62 [0.75, 3.53]
2 0
138 0
0.97 [0.64, 1.49] Not estimable
Peto Odds Ratio (Peto, Fixed, 95% CI)
Subtotals only
2 2 2 1 1 1 0 1 1 1 0 1
328 328 105 292 65 227 0 241 59 182 0 298
Peto Odds Ratio (Peto, Fixed, 95% CI) Peto Odds Ratio (Peto, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
0.95 [0.61, 1.49] 1.08 [0.68, 1.71] 1.18 [0.72, 1.94] 0.64 [0.28, 1.45] 0.41 [0.02, 9.73] 0.67 [0.29, 1.55] Not estimable 0.54 [0.28, 1.06] 0.11 [0.01, 1.88] 0.69 [0.34, 1.38] Not estimable 0.92 [0.76, 1.12]
2 2 1 0
295 190 105 0
Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
1.17 [0.56, 2.45] 0.88 [0.32, 2.44] 1.62 [0.53, 4.94] Not estimable
37
Comparison 2. ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE FIXED PROTOCOL
Outcome or subgroup title 1 Admission 1.1 Co-intervention: Corticosteroids during study 1.2 Co-intervention: No corticosteroids 1.3 Corticosteroid use variable/not described 2 - (Change in % Pred FEV1 at 60 minutes after last IB) +/- 20 minutes 2.1 Co-intervention: Corticosteroids during the previous 60 minutes 2.2 Co-intervention: No corticosteroids 2.3 Corticosteroid use variable/not described 3 - (Change in % Pred FEV1 at 120 minutes after last IB) +/30 minutes 3.1 Co-intervention: Corticosteroids during the previous 120 minutes 3.2 Co-intervention: No corticosteroids 3.3 Corticosteroid use variable/not described 4 - (% Change in FEV1 or PEFR at 60 minutes after last IB) +/15 minutes 4.1 Co-intervention: Corticosteroids during the previous 60 minutes 4.2 Co-intervention: No corticosteroids 4.3 Corticosteroid use variable/not described 5 -( % Change in FEV1 or PEFR at 120 minutes after last IB) +/30 minutes 5.1 Co-intervention: Corticosteroids during the previous 120 minutes
No. of studies 10 6 3 1 4
No. of participants 1162 863 136 163 362
Statistical method Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)
Effect size 0.75 [0.62, 0.89] 0.73 [0.60, 0.91] 0.81 [0.49, 1.32] 0.75 [0.45, 1.25] -9.69 [-13.68, -5.70]
90
-9.5 [-14.89, -4.11]
2 1 0
109 163 0
-9.92 [-15.86, -3.98] Not estimable Not estimable
Not estimable
0 0 2
0 0 121
Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Std. Mean Difference (IV, Fixed, 95% CI)
Not estimable Not estimable -0.51 [-0.87, -0.14]
90
Std. Mean Difference (IV, Fixed, 95% CI)
-0.43 [-0.84, -0.01]
1 0 2
31 0 174
Std. Mean Difference (IV, Fixed, 95% CI) Std. Mean Difference (IV, Fixed, 95% CI) Std. Mean Difference (IV, Fixed, 95% CI)
-0.75 [-1.48, -0.02] Not estimable -0.02 [-0.32, 0.28]
174
Std. Mean Difference (IV, Fixed, 95% CI)
-0.02 [-0.32, 0.28]
38
5.2 Co-intervention: No corticosteroids 5.3 Corticosteroid use variable/not described 6 Change in clinical score at 60 minutes +/- 15 minutes 6.1 Co-intervention: Corticosteroids during the previous 60 minutes 6.2 Co-intervention: No corticosteroids 6.3 Corticosteroid use variable/not described 7 Change in clinical score at 120 minutes +/- 30 minutes 7.1 Co-intervention: Corticosteroids during the previous 120 minutes 7.2 Co-intervention: No corticosteroids 7.3 Corticosteroid use variable/not described 8 O2 Saturation <95% at 60 minutes +/- 15 minutes 8.1 Co-intervention: Corticosteroids during the previous 60 minutes 8.2 Co-intervention: No corticosteroids 8.3 Co-intervention: Corticosteroid use variable/not described 9 O2 Saturation <95% at 120 minutes +/- 30 minutes 9.1 Co-intervention: Corticosteroids during the previous 120 minutes 9.2 Co-intervention: No corticosteroids 9.3 Co-intervention: Corticosteroid use variable/not described 10 Number of repeat treatments required after standard protocol prior to disposition 10.1 0 treatments 10.2 >=1 treatment 11 Tremor 12 Vomiting
0 0 0 0
0 0 0 0
Std. Mean Difference (IV, Fixed, 95% CI) Std. Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)
Not estimable Not estimable Not estimable Not estimable
0 0 2 2
0 0 434 434
Not estimable Not estimable -0.36 [-0.67, -0.06] -0.36 [-0.67, -0.06]
0 0 1 0
0 0 79 0
Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
Not estimable Not estimable 0.60 [0.32, 1.09] Not estimable
1 0
79 0
0.60 [0.32, 1.09] Not estimable
0 0
0 0
Not estimable Not estimable
0 0
0 0
Not estimable Not estimable
Risk Ratio (M-H, Fixed, 95% CI)
Subtotals only
4 4 4 3
524 524 299 277
1.40 [1.13, 1.73] 0.83 [0.73, 0.93] 1.02 [0.63, 1.64] 1.03 [0.37, 2.87]
39
12.1 Co-intervention: Corticosteroids during study prior to vomiting 12.2 Co-intervention: No corticosteroids 12.3 Corticosteroid use variable/not described 13 Nausea 13.1 Co-intervention: Corticosteroids during study prior to vomiting 13.2 Co-intervention: No corticosteroids 13.3 Corticosteroid use variable/not described 14 Need for corticosteroids in emergency department prior to disposition 15 Relapse 15.1 Co-intervention: Corticosteroids upon discharge 15.2 Co-intervention: No corticosteroids 15.3 Corticosteroid use variable/not described
90
0.67 [0.12, 3.80]
1 1 3 1
24 163 334 90
0.59 [0.06, 5.68] 1.98 [0.37, 10.49] 0.59 [0.30, 1.14] 0.67 [0.12, 3.80]
1 1 1
81 163 81
Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
0.55 [0.26, 1.14] 0.99 [0.06, 15.53] Not estimable
8 5 2 1
616 441 55 120
0.86 [0.49, 1.53] 1.02 [0.45, 2.32] 0.79 [0.16, 3.90] 0.70 [0.28, 1.77]
Comparison 3. ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE TITRATRATION PROTOCOL

No. of studies 2 1 1 1 No. of participants 111 66 14 31
Outcome or subgroup title 1 2 to 3 inhalations required prior to disposition 1.1 Co-intervention: no corticosteroids 1.2 Co-intervention: Corticosteroids 1.3 Co-intervention: corticosteroid use variable/not described 2 >= 4 inhalations required prior to disposition 2.1 Co-intervention: no corticosteroids 2.2 Co-intervention: Corticosteroids
Statistical method Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
Effect size 1.67 [0.98, 2.87] 1.90 [0.89, 4.04] Not estimable 1.41 [0.66, 2.99]
1 1 1
80 66 14
0.74 [0.52, 1.04] 0.74 [0.52, 1.04] Not estimable

40
2.3 Co-intervention: corticosteroid use variable/not described 3 Need for corticosteroids in emergency department prior to disposition 4 Tremor 5 Vomiting 5.1 Co-intervention: Corticosteroids during study prior to vomiting 5.2 Co-intervention: No corticosteroids 5.3 Corticosteroid use variable/not described 6 Nausea 6.1 Co-intervention: Corticosteroids during study prior to vomiting 6.2 Co-intervention: No corticosteroids 6.3 Corticosteroid use variable/not described 7 Admission 7.1 Co-intervention: Corticosteroids during study 7.2 Co-intervention: No corticosteroids 7.3 Corticosteroid use variable/not described 8 Relapse 8.1 Co-intervention: Corticosteroids upon discharge 8.2 Co-intervention: No corticosteroids 8.3 Corticosteroid use variable/not described
Not estimable
80
0.56 [0.20, 1.51]
2 2 0
111 111 0
Not estimable Not estimable Not estimable
0 2 2 0
0 111 111 0
Not estimable Not estimable Not estimable Not estimable
0 2 1 1 1 0 0 0 0 0
0 111 80 14 66 0 0 0 0 0
Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
Not estimable Not estimable Not estimable Not estimable Not estimable Not estimable Not estimable Not estimable Not estimable Not estimable
41
Analysis 1.1. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 1 Admission.
Review: Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 1 Admission
Study or subgroup
Treatment n/N
Control n/N
Risk Ratio M-H,Fixed,95% CI
Weight
1 Co-intervention: Corticosteroids during study Ducharme 1998 21/86 17/85 39.5 % 1.22 [ 0.69, 2.15 ]
Subtotal (95% CI)

Total events: 21 (Treatment), 17 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.69 (P = 0.49) 2 Co-intervention: No corticosteroids Ducharme 1998 Schuh 1995
86
85
39.5 %
1.22 [ 0.69, 2.15 ]
2/70 17/39
7/57 19/41
17.8 % 42.7 %
0.23 [ 0.05, 1.08 ] 0.94 [ 0.58, 1.53 ]
Subtotal (95% CI)
109
98
60.5 %
0.73 [ 0.46, 1.17 ]
Total events: 19 (Treatment), 26 (Control) Heterogeneity: Chi2 = 3.17, df = 1 (P = 0.07); I2 =68% Test for overall effect: Z = 1.31 (P = 0.19) 3 Corticosteroid use variable/not described
Subtotal (95% CI)

Total events: 0 (Treatment), 0 (Control) Heterogeneity: not applicable Test for overall effect: not applicable
0.0 %
0.0 [ 0.0, 0.0 ]
Total (95% CI)
195
183
100.0 %
0.93 [ 0.65, 1.32 ]
Total events: 40 (Treatment), 43 (Control) Heterogeneity: Chi2 = 4.05, df = 2 (P = 0.13); I2 =51% Test for overall effect: Z = 0.43 (P = 0.67)
0.1 0.2
0.5
10
42
Analysis 1.2. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 2 -(Change in % Pred FEV1 at 60 minutes after IB) +/- 15 minutes.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 2 -(Change in % Pred FEV1 at 60 minutes after IB) +/- 15 minutes
Study or subgroup
Treatment N Mean(SD)
Control N Mean(SD)
Mean Difference IV,Fixed,95% CI
Weight
1 Co-intervention: Corticosteroids during the previous 60 minutes
Subtotal (95% CI)

Heterogeneity: not applicable Test for overall effect: not applicable
0.0 %
0.0 [ 0.0, 0.0 ]
2 Co-intervention: No corticosteroids Schuh 1995 36 -22.2 (17.4) 40 -15.6 (13.9) 100.0 % -6.60 [ -13.73, 0.53 ]
Subtotal (95% CI)

Heterogeneity: not applicable
36
40
100.0 %
-6.60 [ -13.73, 0.53 ]
Test for overall effect: Z = 1.81 (P = 0.070) 3 Co-intervention: Corticosteroid use variable/ not described
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
Total (95% CI)

36
40
100.0 %
-6.60 [ -13.73, 0.53 ]
Test for overall effect: Z = 1.81 (P = 0.070)
-10
-5
10
43
Analysis 1.3. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 3 - (Change in % Pred FEV1 at 120 minutes after IB) +/- 30 minutes.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 3 - (Change in % Pred FEV1 at 120 minutes after IB) +/- 30 minutes
Study or subgroup
Control N Mean(SD)
Weight
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
2 Co-intervention: No corticosteroids Schuh 1995 35 -18.2 (16.6) 39 -13.1 (12.5) 100.0 % -5.10 [ -11.86, 1.66 ]
Subtotal (95% CI)

35
39
100.0 %
-5.10 [ -11.86, 1.66 ]
Test for overall effect: Z = 1.48 (P = 0.14) 3 Corticosteroid use variable/ not described
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
Total (95% CI)

35
39
100.0 %
-5.10 [ -11.86, 1.66 ]
-10
-5
10
44
Analysis 1.4. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 4 - (% Change in FEV1 at 60 minutes after IB) +/- 15 minutes.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 4 - (% Change in FEV1 at 60 minutes after IB) +/- 15 minutes
Study or subgroup
Control N Mean(SD)
Weight
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
2 Co-intervention: No corticosteroids
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
3 Corticosteroid use variable/not described Beck 1985 Phanichyakam 1990 13 10 -20.4 (19.5) -36.4 (36) 12 10 -4.1 (6.2) -22 (38.3) 89.5 % 10.5 % -16.30 [ -27.47, -5.13 ] -14.40 [ -46.98, 18.18 ]
Subtotal (95% CI)
23
22
100.0 %
-16.10 [ -26.66, -5.54 ]
Heterogeneity: Chi2 = 0.01, df = 1 (P = 0.91); I2 =0.0% Test for overall effect: Z = 2.99 (P = 0.0028)
Total (95% CI)
23
22
100.0 %
-16.10 [ -26.66, -5.54 ]
-10
-5
10
45
Analysis 1.5. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 5 - (% Change in FEV1 at 120 minutes after IB) +/- 30 minutes.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 5 - (% Change in FEV1 at 120 minutes after IB) +/- 30 minutes
Study or subgroup
Control N Mean(SD)
Weight
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
2 Co-intervention: No corticosteroids
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
3 Corticosteroid use variable/not described Beck 1985 Phanichyakam 1990 13 10 -21.1 (22.7) -34.3 (25) 12 10 -3.2 (13.5) -18.5 (40.8) 80.7 % 19.3 % -17.90 [ -32.41, -3.39 ] -15.80 [ -45.46, 13.86 ]
Subtotal (95% CI)
23
22
100.0 %
-17.49 [ -30.53, -4.46 ]
Total (95% CI)
23
22
100.0 %
-17.49 [ -30.53, -4.46 ]
-10
-5
10
46
Analysis 1.6. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 6 % Change in Respiratory resistance at 60 minutes after IB +/- 15 minutes.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 6 % Change in Respiratory resistance at 60 minutes after IB +/- 15 minutes
Study or subgroup
Control N Mean(SD)
Weight
1 Co-intervention: Corticosteroids during the previous 60 minutes Ducharme 1998 31 -0.28 (0.26) 39 -0.26 (0.21) 14.9 % -0.02 [ -0.13, 0.09 ]
Subtotal (95% CI)

31
39
14.9 %
-0.02 [ -0.13, 0.09 ]
Test for overall effect: Z = 0.35 (P = 0.73) 2 Co-intervention: No corticosteroids Ducharme 1998 124 -0.27 (0.2) 100 -0.3 (0.16) 85.1 % 0.03 [ -0.02, 0.08 ]
Subtotal (95% CI)

124
100
85.1 %
0.03 [ -0.02, 0.08 ]
Test for overall effect: Z = 1.25 (P = 0.21) 3 Corticosteroid use variable/not described
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
Total (95% CI)
155
139
100.0 %
0.02 [ -0.02, 0.07 ]
Heterogeneity: Chi2 = 0.64, df = 1 (P = 0.42); I2 =0.0% Test for overall effect: Z = 1.02 (P = 0.31) Test for subgroup differences: Chi2 = 0.64, df = 1 (P = 0.42), I2 =0.0%
-10
-5
10
47
Analysis 1.7. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 7 % Change in Respiratory resistance at 120 minutes after IB +/- 30 minutes.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 7 % Change in Respiratory resistance at 120 minutes after IB +/- 30 minutes
Study or subgroup
Control N Mean(SD)
Weight
1 Co-intervention: Corticosteroids during the previous 120 minutes Ducharme 1998 22 -0.27 (0.23) 25 -0.29 (0.26) 31.8 % 0.02 [ -0.12, 0.16 ]
Subtotal (95% CI)

22
25
31.8 %
0.02 [ -0.12, 0.16 ]
Test for overall effect: Z = 0.28 (P = 0.78) 2 Co-intervention: No corticosteroids Ducharme 1998 36 -0.33 (0.21) 25 -0.31 (0.17) 68.2 % -0.02 [ -0.12, 0.08 ]
Subtotal (95% CI)

36
25
68.2 %
-0.02 [ -0.12, 0.08 ]
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
Total (95% CI)
58
50
100.0 %
-0.01 [ -0.09, 0.07 ]
-10
-5
10
48
Analysis 1.8. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 8 Change in clinical score at 60 minutes +/- 15 minutes.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 8 Change in clinical score at 60 minutes +/- 15 minutes
Study or subgroup
Control N Mean(SD)
1 Co-intervention: Corticosteroids during the previous 60 minutes Ducharme 1998 31 -0.58 (0.92) 37 -0.35 (0.86) -0.23 [ -0.66, 0.20 ]
Subtotal (95% CI)

31
37
-0.23 [ -0.66, 0.20 ]
Test for overall effect: Z = 1.06 (P = 0.29) 2 Co-intervention: No corticosteroids Ducharme 1998 Schuh 1995 121 39 -0.65 (0.85) 1.41 (0) 101 41 -0.64 (0.9) 1.12 (0) -0.01 [ -0.24, 0.22 ] 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)
160
142
-0.01 [ -0.24, 0.22 ]
Heterogeneity: Chi2 = 0.0, df = 0 (P = 1.00); I2 =0.0% Test for overall effect: Z = 0.08 (P = 0.93) 3 Corticosteroid use variable/not described
Subtotal (95% CI)

0.0 [ 0.0, 0.0 ]
Total (95% CI)
191
179
-0.06 [ -0.26, 0.14 ]
-10
-5
10
49
Analysis 1.9. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE, Outcome 9 Change in clinical score at 120 minutes +/- 30 minutes.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 9 Change in clinical score at 120 minutes +/- 30 minutes
Study or subgroup
Control N Mean(SD)
Weight
1 Co-intervention: Corticosteroids during the previous 120 minutes Ducharme 1998 21 -0.29 (0.72) 23 -0.61 (0.94) 49.9 % 0.32 [ -0.17, 0.81 ]
Subtotal (95% CI)

21
23
49.9 %
0.32 [ -0.17, 0.81 ]
Test for overall effect: Z = 1.27 (P = 0.20) 2 Co-intervention: No corticosteroids Ducharme 1998 35 -0.71 (0.83) 26 -0.65 (1.06) 50.1 % -0.06 [ -0.55, 0.43 ]
Subtotal (95% CI)

35
26
50.1 %
-0.06 [ -0.55, 0.43 ]
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
Total (95% CI)
56
49
100.0 %
0.13 [ -0.22, 0.48 ]
Heterogeneity: Chi2 = 1.15, df = 1 (P = 0.28); I2 =13% Test for overall effect: Z = 0.73 (P = 0.46) Test for subgroup differences: Chi2 = 1.15, df = 1 (P = 0.28), I2 =13%
-10
-5
10
50
Analysis 1.10. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2AGONIST ALONE, Outcome 10 O2 Saturation <95% at 60 minutes +/- 15 minutes.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 10 O2 Saturation <95% at 60 minutes +/- 15 minutes
Study or subgroup
Treatment n/N
Control n/N
Weight
1 Co-intervention: Corticosteroids during the previous 60 minutes Ducharme 1998 8/31 12/39 15.7 % 0.84 [ 0.39, 1.79 ]
Subtotal (95% CI)

31
39
15.7 %
0.84 [ 0.39, 1.79 ]
34/125 11/39
35/101 19/41
57.0 % 27.3 %
0.78 [ 0.53, 1.16 ] 0.61 [ 0.33, 1.11 ]
Subtotal (95% CI)
164
142
84.3 %
0.73 [ 0.52, 1.01 ]
Total events: 45 (Treatment), 54 (Control) Heterogeneity: Chi2 = 0.48, df = 1 (P = 0.49); I2 =0.0% Test for overall effect: Z = 1.90 (P = 0.057) 3 Co-intervention: Corticosteroid use variable/not described
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
Total (95% CI)
195
181
100.0 %
0.75 [ 0.55, 1.01 ]
Total events: 53 (Treatment), 66 (Control) Heterogeneity: Chi2 = 0.60, df = 2 (P = 0.74); I2 =0.0% Test for overall effect: Z = 1.92 (P = 0.055)
0.1 0.2
0.5
10
51
Analysis 1.11. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2AGONIST ALONE, Outcome 11 O2 Saturation <95% at 120 minutes +/- 30 minutes.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 11 O2 Saturation <95% at 120 minutes +/- 30 minutes
Study or subgroup
Treatment n/N
Control n/N
Weight
1 Co-intervention: Corticosteroids during the previous 120 minutes Ducharme 1998 10/22 7/25 19.6 % 1.62 [ 0.75, 3.53 ]
Subtotal (95% CI)

22
25
19.6 %
1.62 [ 0.75, 3.53 ]
14/36 14/37
8/26 18/39
27.8 % 52.5 %
1.26 [ 0.62, 2.56 ] 0.82 [ 0.48, 1.40 ]
Subtotal (95% CI)

Total events: 28 (Treatment), 26 (Control)
73
65
80.4 %
0.97 [ 0.64, 1.49 ]
Heterogeneity: Chi2 = 0.92, df = 1 (P = 0.34); I2 =0.0% Test for overall effect: Z = 0.12 (P = 0.90) 3 Co-intervention: Corticosteroid use variable/not described
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
Total (95% CI)

95
90
100.0 %
1.10 [ 0.76, 1.60 ]
Heterogeneity: Chi2 = 2.27, df = 2 (P = 0.32); I2 =12% Test for overall effect: Z = 0.51 (P = 0.61)
0.1 0.2
0.5
10
52
Analysis 1.12. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2AGONIST ALONE, Outcome 12 Number of repeat treatments required after standard protocol prior to disposition.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 12 Number of repeat treatments required after standard protocol prior to disposition
Study or subgroup
Treatment n/N
Control n/N
Peto Odds Ratio Peto,Fixed,95% CI
Weight
Peto Odds Ratio Peto,Fixed,95% CI
1 0 treatments Ducharme 1998 Cook 1985 98/156 10/15 90/142 11/15 91.4 % 8.6 % 0.98 [ 0.61, 1.56 ] 0.74 [ 0.16, 3.42 ]
Subtotal (95% CI)
171
157
100.0 %
0.95 [ 0.61, 1.49 ]
Total events: 108 (Treatment), 101 (Control) Heterogeneity: Chi2 = 0.12, df = 1 (P = 0.73); I2 =0.0% Test for overall effect: Z = 0.21 (P = 0.83) 2 >=1 additional treatment Ducharme 1998 Cook 1985 58/156 3/15 52/142 1/15 95.1 % 4.9 % 1.02 [ 0.64, 1.64 ] 3.05 [ 0.38, 24.18 ]
Subtotal (95% CI)
171
157
100.0 %
1.08 [ 0.68, 1.71 ]
Total events: 61 (Treatment), 53 (Control) Heterogeneity: Chi2 = 1.02, df = 1 (P = 0.31); I2 =2% Test for overall effect: Z = 0.33 (P = 0.74) Test for subgroup differences: Chi2 = 0.15, df = 1 (P = 0.70), I2 =0.0%
0.1 0.2
0.5
10
53
Analysis 1.13. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2AGONIST ALONE, Outcome 13 Tremor.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 13 Tremor
Study or subgroup
Treatment n/N
Control n/N 13/41 5/12
Weight
Schuh 1995 Beck 1985
14/39 7/13
70.9 % 29.1 %
1.13 [ 0.61, 2.09 ] 1.29 [ 0.56, 2.99 ]
Total (95% CI)
52
53
100.0 %
1.18 [ 0.72, 1.94 ]
0.1 0.2
0.5
10
Analysis 1.14. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2AGONIST ALONE, Outcome 14 Vomiting.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 14 Vomiting
Study or subgroup
Treatment n/N
Control n/N
Weight
Subtotal (95% CI)

Total events: 0 (Treatment), 1 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.55 (P = 0.58) 2 Co-intervention: No corticosteroids Ducharme 1998
29
36
10.0 %
0.41 [ 0.02, 9.73 ]
9/125
11/102
90.0 %
0.67 [ 0.29, 1.55 ]
Subtotal (95% CI)

Total events: 9 (Treatment), 11 (Control) Heterogeneity: not applicable
125
102
90.0 %
0.67 [ 0.29, 1.55 ]
0.1 0.2
0.5
10
(Continued . . . )
54
(. . .
Study or subgroup Treatment n/N 3 Corticosteroid use variable/not described Control n/N Risk Ratio M-H,Fixed,95% CI Weight
Continued) Risk Ratio
M-H,Fixed,95% CI
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
Total (95% CI)

154
138
100.0 %
0.64 [ 0.28, 1.45 ]
0.1 0.2
0.5
10
Analysis 1.15. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2AGONIST ALONE, Outcome 15 Nausea.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 15 Nausea
Study or subgroup
Treatment n/N
Control n/N
Weight
Subtotal (95% CI)

Total events: 0 (Treatment), 6 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.52 (P = 0.13) 2 Co-intervention: No corticosteroids Ducharme 1998
24
35
24.8 %
0.11 [ 0.01, 1.88 ]
12/98
15/84
75.2 %
0.69 [ 0.34, 1.38 ]
Subtotal (95% CI)

Total events: 12 (Treatment), 15 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.06 (P = 0.29)
98
84
75.2 %
0.69 [ 0.34, 1.38 ]
3 Corticosteroid use variable/not described
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
0.1 0.2
0.5
10
(Continued . . . )
55
(. . .
Study or subgroup Treatment n/N Test for overall effect: not applicable Control n/N Risk Ratio M-H,Fixed,95% CI Weight
M-H,Fixed,95% CI
Total (95% CI)
122
119
100.0 %
0.54 [ 0.28, 1.06 ]
0.1 0.2
0.5
10
Analysis 1.16. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2AGONIST ALONE, Outcome 16 Need for corticosteroids in emergency department prior to disposition.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 16 Need for corticosteroids in emergency department prior to disposition
Study or subgroup
Treatment n/N
Control n/N 85/142
Weight
Ducharme 1998
86/156
100.0 %
0.92 [ 0.76, 1.12 ]
Total (95% CI)

156
142
100.0 %
0.92 [ 0.76, 1.12 ]
Total events: 86 (Treatment), 85 (Control) Test for overall effect: Z = 0.83 (P = 0.41)
0.1 0.2
0.5
10
56
Analysis 1.17. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2AGONIST ALONE, Outcome 17 Relapse.
Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE Outcome: 17 Relapse
Study or subgroup
Treatment n/N
Control n/N
Weight
1 Co-intervention: Corticosteroids upon discharge Ducharme 1998 Schuh 1995 6/72 0/22 4/74 3/22 32.6 % 28.9 % 1.54 [ 0.45, 5.24 ] 0.14 [ 0.01, 2.61 ]
Subtotal (95% CI)

94
96
61.6 %
0.88 [ 0.32, 2.44 ]
Heterogeneity: Chi2 = 2.31, df = 1 (P = 0.13); I2 =57% Test for overall effect: Z = 0.24 (P = 0.81) 2 Co-intervention: No corticosteroids Ducharme 1998 9/61 4/44 38.4 % 1.62 [ 0.53, 4.94 ]
Subtotal (95% CI)

61
44
38.4 %
1.62 [ 0.53, 4.94 ]
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
Total (95% CI)
155
140
100.0 %
1.17 [ 0.56, 2.45 ]
0.1 0.2
0.5
10
57
Analysis 2.1. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2AGONIST ALONE - FIXED PROTOCOL, Outcome 1 Admission.
Comparison: 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL Outcome: 1 Admission
Study or subgroup
Treatment n/N
Control n/N
1 Co-intervention: Corticosteroids during study Zorc JJ 1999 (mil) Qureshi 1998 (mod) Zorc 1999 (mod) Zorc 1999 (sev) Qureshi 1997 Qureshi 1998 (sev) 6/60 8/79 18/98 7/22 9/36 51/136 4/57 9/84 25/96 12/29 14/31 71/135 1.43 [ 0.42, 4.79 ] 0.95 [ 0.38, 2.33 ] 0.71 [ 0.41, 1.21 ] 0.77 [ 0.36, 1.63 ] 0.55 [ 0.28, 1.10 ] 0.71 [ 0.54, 0.93 ]
Subtotal (95% CI)

431
432
0.73 [ 0.60, 0.91 ]
Heterogeneity: Chi2 = 2.19, df = 5 (P = 0.82); I2 =0.0% Test for overall effect: Z = 2.87 (P = 0.0041) 2 Co-intervention: No corticosteroids Reisman 1988 Schuh 1995 Watson 1988 2/11 15/40 0/16 3/13 19/41 0/15 0.79 [ 0.16, 3.90 ] 0.81 [ 0.48, 1.36 ] 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)

67
69
0.81 [ 0.49, 1.32 ]
Heterogeneity: Chi2 = 0.00, df = 1 (P = 0.98); I2 =0.0% Test for overall effect: Z = 0.85 (P = 0.40) 3 Corticosteroid use variable/not described Peterson 1996 19/82 25/81 0.75 [ 0.45, 1.25 ]
Subtotal (95% CI)

82
81
0.75 [ 0.45, 1.25 ]
Total (95% CI)

580
582
0.75 [ 0.62, 0.89 ]
0.1 0.2
0.5
10
58
Analysis 2.2. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2AGONIST ALONE - FIXED PROTOCOL, Outcome 2 - (Change in % Pred FEV1 at 60 minutes after last IB) +/20 minutes.
Comparison: 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL Outcome: 2 - (Change in % Pred FEV1 at 60 minutes after last IB) +/- 20 minutes
Study or subgroup
Control N Mean(SD)
1 Co-intervention: Corticosteroids during the previous 60 minutes Qureshi 1997 45 -33.6 (11.3) 45 -24.1 (14.6) -9.50 [ -14.89, -4.11 ]
Subtotal (95% CI)

45
45
-9.50 [ -14.89, -4.11 ]
Test for overall effect: Z = 3.45 (P = 0.00056) 2 Co-intervention: No corticosteroids Schuh 1995 Watson 1988 39 16 -23.4 (20.6) -89.3 (13.2) 39 15 -13.1 (12.5) -80 (14) -10.30 [ -17.86, -2.74 ] -9.30 [ -18.89, 0.29 ]
Subtotal (95% CI)
55
54
-9.92 [ -15.86, -3.98 ]
Heterogeneity: Chi2 = 0.03, df = 1 (P = 0.87); I2 =0.0% Test for overall effect: Z = 3.27 (P = 0.0011) 3 Corticosteroid use variable/not described Peterson 1996 82 -14.7 (0) 81 -13.9 (0) 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)

82
81
0.0 [ 0.0, 0.0 ]
Test for overall effect: Z = 0.0 (P < 0.00001)
Total (95% CI)
182
180
-9.69 [ -13.68, -5.70 ]
Heterogeneity: Chi2 = 0.04, df = 2 (P = 0.98); I2 =0.0% Test for overall effect: Z = 4.76 (P < 0.00001) Test for subgroup differences: Chi2 = 0.01, df = 1 (P = 0.92), I2 =0.0%
-10
-5
10
59
Analysis 2.4. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2AGONIST ALONE - FIXED PROTOCOL, Outcome 4 - (% Change in FEV1 or PEFR at 60 minutes after last IB) +/- 15 minutes.
Comparison: 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL Outcome: 4 - (% Change in FEV1 or PEFR at 60 minutes after last IB) +/- 15 minutes
Study or subgroup
Control N Mean(SD)
Std. Mean Difference IV,Fixed,95% CI
Weight
1 Co-intervention: Corticosteroids during the previous 60 minutes Qureshi 1997 45 -32.6 (11.7) 45 -26.8 (15.1) 75.4 % -0.43 [ -0.84, -0.01 ]
Subtotal (95% CI)

45
45
75.4 %
-0.43 [ -0.84, -0.01 ]
Test for overall effect: Z = 2.00 (P = 0.046) 2 Co-intervention: No corticosteroids Watson 1988 16 -63.6 (28.4) 15 -42.1 (27.5) 24.6 % -0.75 [ -1.48, -0.02 ]
Subtotal (95% CI)

16
15
24.6 %
-0.75 [ -1.48, -0.02 ]
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
Total (95% CI)
61
60
100.0 %
-0.51 [ -0.87, -0.14 ]
-10
-5
10
60
Analysis 2.5. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2AGONIST ALONE - FIXED PROTOCOL, Outcome 5 -( % Change in FEV1 or PEFR at 120 minutes after last IB) +/- 30 minutes.
Comparison: 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL Outcome: 5 -( % Change in FEV1 or PEFR at 120 minutes after last IB) +/- 30 minutes
Study or subgroup
Control N Mean(SD)
Weight
1 Co-intervention: Corticosteroids during the previous 120 minutes Qureshi 1998 (mod) Qureshi 1998 (sev) 22 65 26 (12) 32 (15) 25 62 29 (12) 31 (17) 26.8 % 73.2 % -0.25 [ -0.82, 0.33 ] 0.06 [ -0.29, 0.41 ]
Subtotal (95% CI)
87
87
100.0 %
-0.02 [ -0.32, 0.28 ]
Heterogeneity: Chi2 = 0.81, df = 1 (P = 0.37); I2 =0.0% Test for overall effect: Z = 0.13 (P = 0.89) 2 Co-intervention: No corticosteroids
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
Total (95% CI)
87
87
100.0 %
-0.02 [ -0.32, 0.28 ]
-10
-5
10
61
Analysis 2.7. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2AGONIST ALONE - FIXED PROTOCOL, Outcome 7 Change in clinical score at 120 minutes +/- 30 minutes.
Comparison: 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL Outcome: 7 Change in clinical score at 120 minutes +/- 30 minutes
Study or subgroup
Control N Mean(SD)
Weight
1 Co-intervention: Corticosteroids during the previous 120 minutes Qureshi 1998 (mod) Qureshi 1998 (sev) 79 136 -3.95 (1.18) -4.54 (2.05) 84 135 -3.65 (1.3) -4.07 (2.21) 64.0 % 36.0 % -0.30 [ -0.68, 0.08 ] -0.47 [ -0.98, 0.04 ]
Subtotal (95% CI)
215
219
100.0 %
-0.36 [ -0.67, -0.06 ]
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
Total (95% CI)
215
219
100.0 %
-0.36 [ -0.67, -0.06 ]
-10
-5
10
62
Analysis 2.8. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2AGONIST ALONE - FIXED PROTOCOL, Outcome 8 O2 Saturation <95% at 60 minutes +/- 15 minutes.
Comparison: 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL Outcome: 8 O2 Saturation <95% at 60 minutes +/- 15 minutes
Study or subgroup
Treatment n/N
Control n/N
Weight
Subtotal (95% CI)

Total events: 0 (Treatment), 0 (Control) Heterogeneity: not applicable Test for overall effect: not applicable 2 Co-intervention: No corticosteroids Schuh 1995
0.0 %
0.0 [ 0.0, 0.0 ]
11/40
18/39
100.0 %
0.60 [ 0.32, 1.09 ]
Subtotal (95% CI)

40
39
100.0 %
0.60 [ 0.32, 1.09 ]
Test for overall effect: Z = 1.67 (P = 0.094) 3 Co-intervention: Corticosteroid use variable/not described
Subtotal (95% CI)

0.0 %
0.0 [ 0.0, 0.0 ]
Total (95% CI)

40
39
100.0 %
0.60 [ 0.32, 1.09 ]
0.1 0.2
0.5
10
63
Analysis 2.10. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2AGONIST ALONE - FIXED PROTOCOL, Outcome 10 Number of repeat treatments required after standard protocol prior to disposition.
Comparison: 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL Outcome: 10 Number of repeat treatments required after standard protocol prior to disposition
Study or subgroup
Treatment n/N
Control n/N
Weight
1 0 treatments Zorc JJ 1999 (mil) Zorc 1999 (mod) Peterson 1996 Zorc 1999 (sev) 44/60 42/97 14/82 11/22 32/57 34/96 8/81 5/29 41.4 % 43.1 % 10.1 % 5.4 % 1.31 [ 0.99, 1.72 ] 1.22 [ 0.86, 1.74 ] 1.73 [ 0.77, 3.90 ] 2.90 [ 1.18, 7.13 ]
Subtotal (95% CI)
261
263
100.0 %
1.40 [ 1.13, 1.73 ]
Total events: 111 (Treatment), 79 (Control) Heterogeneity: Chi2 = 3.58, df = 3 (P = 0.31); I2 =16% Test for overall effect: Z = 3.08 (P = 0.0020) 2 >=1 treatment Zorc JJ 1999 (mil) Zorc 1999 (mod) Peterson 1996 Zorc 1999 (sev) 16/60 55/97 68/82 11/22 25/57 62/96 73/81 24/29 14.1 % 34.2 % 40.3 % 11.4 % 0.61 [ 0.36, 1.01 ] 0.88 [ 0.70, 1.10 ] 0.92 [ 0.81, 1.04 ] 0.60 [ 0.39, 0.95 ]
Subtotal (95% CI)
261
263
100.0 %
0.83 [ 0.73, 0.93 ]
0.1 0.2
0.5
10
64
Analysis 2.11. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2AGONIST ALONE - FIXED PROTOCOL, Outcome 11 Tremor.
Comparison: 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL Outcome: 11 Tremor
Study or subgroup
Treatment n/N
Control n/N 7/13 3/81 13/41 0/15
Risk Ratio M-H,Fixed,95% CI 1.01 [ 0.48, 2.12 ] 1.32 [ 0.30, 5.70 ] 0.95 [ 0.49, 1.82 ] 0.0 [ 0.0, 0.0 ]
Reisman 1988 Peterson 1996 Schuh 1995 Watson 1988
6/11 4/82 12/40 0/16
Total (95% CI)

149
150
1.02 [ 0.63, 1.64 ]
0.1 0.2
0.5
10
65
Analysis 2.12. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2AGONIST ALONE - FIXED PROTOCOL, Outcome 12 Vomiting.
Comparison: 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL Outcome: 12 Vomiting
Study or subgroup
Treatment n/N
Control n/N
Weight
1 Co-intervention: Corticosteroids during study prior to vomiting Qureshi 1997 2/45 3/45 43.8 % 0.67 [ 0.12, 3.80 ]
Subtotal (95% CI)

Total events: 2 (Treatment), 3 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.46 (P = 0.65) 2 Co-intervention: No corticosteroids Reisman 1988
45
45
43.8 %
0.67 [ 0.12, 3.80 ]
1/11
2/13
26.8 %
0.59 [ 0.06, 5.68 ]
Subtotal (95% CI)

11
13
26.8 %
0.59 [ 0.06, 5.68 ]
3 Corticosteroid use variable/not described Peterson 1996 4/82 2/81 29.4 % 1.98 [ 0.37, 10.49 ]
Subtotal (95% CI)

82
81
29.4 %
1.98 [ 0.37, 10.49 ]
Total (95% CI)

138
139
100.0 %
1.03 [ 0.37, 2.87 ]
0.1 0.2
0.5
10
66
Analysis 2.13. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2AGONIST ALONE - FIXED PROTOCOL, Outcome 13 Nausea.
Comparison: 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL Outcome: 13 Nausea
Study or subgroup
Treatment n/N
Control n/N
Weight
1 Co-intervention: Corticosteroids during study prior to vomiting Qureshi 1997 2/45 3/45 15.9 % 0.67 [ 0.12, 3.80 ]
Subtotal (95% CI)

Total events: 2 (Treatment), 3 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.46 (P = 0.65) 2 Co-intervention: No corticosteroids Schuh 1995
45
45
15.9 %
0.67 [ 0.12, 3.80 ]
8/40
15/41
78.7 %
0.55 [ 0.26, 1.14 ]
Subtotal (95% CI)

40
41
78.7 %
0.55 [ 0.26, 1.14 ]
3 Corticosteroid use variable/not described Peterson 1996 1/82 1/81 5.3 % 0.99 [ 0.06, 15.53 ]
Subtotal (95% CI)

82
81
5.3 %
0.99 [ 0.06, 15.53 ]
Total (95% CI)
167
167
100.0 %
0.59 [ 0.30, 1.14 ]
0.1 0.2
0.5
10
67
Analysis 2.14. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2AGONIST ALONE - FIXED PROTOCOL, Outcome 14 Need for corticosteroids in emergency department prior to disposition.
Comparison: 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL Outcome: 14 Need for corticosteroids in emergency department prior to disposition
Study or subgroup
Treatment n/N
Control n/N 41/41
Risk Ratio M-H,Fixed,95% CI 0.0 [ 0.0, 0.0 ]
Schuh 1995
40/40
Total (95% CI)

Total events: 40 (Treatment), 41 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P < 0.00001)
40
41
0.0 [ 0.0, 0.0 ]
0.1 0.2
0.5
10
Analysis 2.15. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2AGONIST ALONE - FIXED PROTOCOL, Outcome 15 Relapse.
Comparison: 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE - FIXED PROTOCOL Outcome: 15 Relapse
Study or subgroup
Treatment n/N
Control n/N
1 Co-intervention: Corticosteroids upon discharge Qureshi 1998 (mod) Zorc 1999 (sev) Qureshi 1997 Schuh 1995 Qureshi 1998 (sev) 1/71 1/15 1/36 1/25 7/85 2/75 0/17 0/31 3/22 4/64 0.53 [ 0.05, 5.70 ] 3.38 [ 0.15, 77.12 ] 2.59 [ 0.11, 61.49 ] 0.29 [ 0.03, 2.62 ] 1.32 [ 0.40, 4.31 ]
Subtotal (95% CI)

232
209
1.02 [ 0.45, 2.32 ]
0.1 0.2
0.5
10
(Continued . . . )
68
(. . .
Study or subgroup Treatment n/N Reisman 1988 Watson 1988 2/11 0/16 Control n/N 3/13 0/15 Risk Ratio M-H,Fixed,95% CI
M-H,Fixed,95% CI 0.79 [ 0.16, 3.90 ] 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)

27
28
0.79 [ 0.16, 3.90 ]
Heterogeneity: Chi2 = 0.0, df = 0 (P = 1.00); I2 =0.0% Test for overall effect: Z = 0.29 (P = 0.77) 3 Corticosteroid use variable/not described Peterson 1996 7/63 9/57 0.70 [ 0.28, 1.77 ]
Subtotal (95% CI)

63
57
0.70 [ 0.28, 1.77 ]
Total (95% CI)

322
294
0.86 [ 0.49, 1.53 ]
0.1 0.2
0.5
10
69
Analysis 3.1. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL, Outcome 1 2 to 3 inhalations required prior to disposition.
Comparison: 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL Outcome: 1 2 to 3 inhalations required prior to disposition
Study or subgroup
Treatment n/N
Control n/N
1 Co-intervention: no corticosteroids Calvo 1998 15/35 7/31 1.90 [ 0.89, 4.04 ]
Subtotal (95% CI)

Total events: 15 (Treatment), 7 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.66 (P = 0.097) 2 Co-intervention: Corticosteroids Calvo 1998
35
31
1.90 [ 0.89, 4.04 ]
0/5
0/9
0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)

0.0 [ 0.0, 0.0 ]
3 Co-intervention: corticosteroid use variable/not described Guill 1987 9/16 6/15 1.41 [ 0.66, 2.99 ]
Subtotal (95% CI)

16
15
1.41 [ 0.66, 2.99 ]
Total (95% CI)

56
55
1.67 [ 0.98, 2.87 ]
0.1 0.2
0.5
10
70
Analysis 3.2. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL, Outcome 2 >= 4 inhalations required prior to disposition.
Comparison: 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL Outcome: 2 >= 4 inhalations required prior to disposition
Study or subgroup
Treatment n/N
Control n/N
1 Co-intervention: no corticosteroids Calvo 1998 20/35 24/31 0.74 [ 0.52, 1.04 ]
Subtotal (95% CI)

Total events: 20 (Treatment), 24 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.73 (P = 0.084) 2 Co-intervention: Corticosteroids Calvo 1998
35
31
0.74 [ 0.52, 1.04 ]
5/5
9/9
0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)

0.0 [ 0.0, 0.0 ]
3 Co-intervention: corticosteroid use variable/not described
Subtotal (95% CI)

0.0 [ 0.0, 0.0 ]
Total (95% CI)

40
40
0.74 [ 0.52, 1.04 ]
0.1 0.2
0.5
10
71
Analysis 3.3. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL, Outcome 3 Need for corticosteroids in emergency department prior to disposition.
Comparison: 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL Outcome: 3 Need for corticosteroids in emergency department prior to disposition
Study or subgroup
Treatment n/N
Control n/N 9/40
Weight
Calvo 1998
5/40
100.0 %
0.56 [ 0.20, 1.51 ]
Total (95% CI)

40
40
100.0 %
0.56 [ 0.20, 1.51 ]
Total events: 5 (Treatment), 9 (Control) Test for overall effect: Z = 1.15 (P = 0.25)
0.1 0.2
0.5
10
Analysis 3.4. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL, Outcome 4 Tremor.
Comparison: 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL Outcome: 4 Tremor
Study or subgroup
Treatment n/N
Control n/N 0/40 0/15
Risk Ratio M-H,Fixed,95% CI 0.0 [ 0.0, 0.0 ] 0.0 [ 0.0, 0.0 ]
Calvo 1998 Guill 1987
0/40 0/16
Total (95% CI)

56
55
0.0 [ 0.0, 0.0 ]
Heterogeneity: Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0% Test for overall effect: Z = 0.0 (P < 0.00001)
0.1 0.2
0.5
10
72
Analysis 3.5. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL, Outcome 5 Vomiting.
Comparison: 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL Outcome: 5 Vomiting
Study or subgroup
Treatment n/N
Control n/N
1 Co-intervention: Corticosteroids during study prior to vomiting
Subtotal (95% CI)

Total events: 0 (Treatment), 0 (Control) Heterogeneity: not applicable Test for overall effect: not applicable 2 Co-intervention: No corticosteroids
0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)

Total events: 0 (Treatment), 0 (Control) Heterogeneity: not applicable Test for overall effect: not applicable 3 Corticosteroid use variable/not described Calvo 1998 Guill 1987
0.0 [ 0.0, 0.0 ]
0/40 0/16
0/40 0/15
0.0 [ 0.0, 0.0 ] 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)

56
55
0.0 [ 0.0, 0.0 ]
Total (95% CI)

56
55
0.0 [ 0.0, 0.0 ]
0.1 0.2
0.5
10
73
Analysis 3.6. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL, Outcome 6 Nausea.
Comparison: 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL Outcome: 6 Nausea
Study or subgroup
Treatment n/N
Control n/N
1 Co-intervention: Corticosteroids during study prior to vomiting
Subtotal (95% CI)

Total events: 0 (Treatment), 0 (Control) Heterogeneity: not applicable Test for overall effect: not applicable 2 Co-intervention: No corticosteroids
0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)

Total events: 0 (Treatment), 0 (Control) Heterogeneity: not applicable Test for overall effect: not applicable 3 Corticosteroid use variable/not described Calvo 1998 Guill 1987
0.0 [ 0.0, 0.0 ]
0/40 0/16
0/40 0/15
0.0 [ 0.0, 0.0 ] 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)

56
55
0.0 [ 0.0, 0.0 ]
Total (95% CI)

56
55
0.0 [ 0.0, 0.0 ]
0.1 0.2
0.5
10
74
Analysis 3.7. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL, Outcome 7 Admission.
Comparison: 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE - TITRATRATION PROTOCOL Outcome: 7 Admission
Study or subgroup
Treatment n/N
Control n/N
1 Co-intervention: Corticosteroids during study Calvo 1998 0/5 0/9 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)

Total events: 0 (Treatment), 0 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P < 0.00001) 2 Co-intervention: No corticosteroids Calvo 1998
0.0 [ 0.0, 0.0 ]
0/35
0/31
0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)

Total events: 0 (Treatment), 0 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P < 0.00001) 3 Corticosteroid use variable/not described
35
31
0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)

0.0 [ 0.0, 0.0 ]
Total (95% CI)

40
40
0.0 [ 0.0, 0.0 ]
0.1 0.2
0.5
10
WHATS NEW
Last assessed as up-to-date: 24 April 2000.
Date 22 July 2008
Event Amended
Description Converted to new review format.
75
HISTORY
Protocol rst published: Issue 1, 1996 Review rst published: Issue 2, 1997
Date 25 April 2000
Event New citation required and conclusions have changed
Description Substantive amendment
DECLARATIONS OF INTEREST
Dr Ducharme and Dr Plotnick received some travel support from Boehringer Ingelheim to attend national and international conferences.
SOURCES OF SUPPORT Internal sources

NHS Research and Development, UK.
External sources
No sources of support supplied
INDEX TERMS Medical Subject Headings (MeSH)

Administration, Inhalation; Adrenergic beta-Agonists [administration & dosage; therapeutic use]; Asthma [ drug therapy]; Cholinergic Antagonists [administration & dosage; therapeutic use]; Drug Therapy, Combination; Randomized Controlled Trials as Topic
MeSH check words

Child; Humans
76

Aastma Anticolinergic

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Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children (Review)

Types of outcome measures

Data collection and analysis

Hospital admission Selection of studies

Risk of bias in included studies

Single Dose Protocols

Multiple Dose-Fixed Protocols

Multiple Dose-Flexible Protocols

AUTHORS CONCLUSIONS Implications for practice

Strengths and Limitations

Implications for research

References to studies included in this review

References to studies excluded from this review

CHARACTERISTICS OF STUDIES Characteristics of included studies [ordered by study ID]

Allocation concealment? Blinding? All outcomes Calvo 1998 Methods

number-coded solutions supplied by pharmacy Identical placebo used

Authors judgement No No Yes

Description Consecutive assignment Number-coded solutions supplied by pharmacy Identical placebo

Item Adequate sequence generation?

Authors judgement Unclear

Allocation concealment? Blinding? All outcomes Ducharme 1998 Methods

Blinding? All outcomes Peterson 1996 Methods

Blinding? All outcomes Phanichyakam 1990 Methods

Allocation concealment? Blinding? All outcomes Qureshi 1997 Methods

Blinding? All outcomes

Qureshi 1998 (mod)

Blinding? All outcomes Qureshi 1998 (sev) Methods

Risk of bias Item Authors judgement Description

Qureshi 1998 (sev)

Yes Yes Unclear

Table of random numbers Number-coded solutions supplied by pharmacy Identical placebo

Item Adequate sequence generation?

Authors judgement Unclear

Blinding? All outcomes Schuh 1995 Methods

Blinding? All outcomes Watson 1988 Methods

Allocation concealment? Blinding? All outcomes Zorc 1999 (mod) Methods

Zorc 1999 (mod)

Blinding? All outcomes Zorc 1999 (sev) Methods

Zorc 1999 (sev)

Blinding? All outcomes Zorc JJ 1999 (mil) Methods

Zorc JJ 1999 (mil)

Blinding? All outcomes

Characteristics of excluded studies [ordered by study ID]

DATA AND ANALYSES

Comparison 1. ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE

No. of participants 378 171 207 0 76

Mean Difference (IV, Fixed, 95% CI)

-6.6 [-13.73, 0.53] Not estimable

Mean Difference (IV, Fixed, 95% CI)

-5.1 [-11.86, 1.66]

Mean Difference (IV, Fixed, 95% CI)

Mean Difference (IV, Fixed, 95% CI)

Not estimable -16.10 [-26.66, 5.54] -17.49 [-30.53, 4.46]

Mean Difference (IV, Fixed, 95% CI)

Not estimable -17.49 [-30.53, 4.46] 0.02 [-0.02, 0.07]

Mean Difference (IV, Fixed, 95% CI)

-0.02 [-0.13, 0.09]

0.03 [-0.02, 0.08] Not estimable -0.01 [-0.09, 0.07]

Mean Difference (IV, Fixed, 95% CI)

0.02 [-0.12, 0.16]

0.73 [0.52, 1.01] Not estimable

1.10 [0.76, 1.60] 1.62 [0.75, 3.53]

0.97 [0.64, 1.49] Not estimable