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Meta-Analysis
. 2013 Aug 21;2013(8):CD000060.
doi: 10.1002/14651858.CD000060.pub2.

Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of acute asthma in children

Benedict Griffiths  1 , Francine M Ducharme
Affiliations
Meta-Analysis

Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of acute asthma in children

Benedict Griffiths et al. Cochrane Database Syst Rev. .

Abstract

Background: There are several treatment options for managing acute asthma exacerbations (sustained worsening of symptoms that do not subside with regular treatment and require a change in management). Guidelines advocate the use of inhaled short acting beta2-agonists (SABAs) in children experiencing an asthma exacerbation. 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. Therefore, the combination of inhaled anticholinergics with SABAs may yield enhanced and prolonged bronchodilation.

Objectives: To determine whether the addition of inhaled anticholinergics to SABAs provides clinical improvement and affects the incidence of adverse effects in children with acute asthma exacerbations.

Search methods: We searched MEDLINE (1966 to April 2000), EMBASE (1980 to April 2000), CINAHL (1982 to April 2000) and reference lists of studies of previous versions of this review. We also contacted drug manufacturers and trialists. For the 2012 review update, we undertook an 'all years' search of the Cochrane Airways Group's register on the 18 April 2012.

Selection criteria: Randomized parallel trials comparing the combination of inhaled anticholinergics and SABAs with SABAs alone in children (aged 18 months to 18 years) with an acute asthma exacerbation.

Data collection and analysis: Two review authors independently assessed trial quality and extracted data. We used the GRADE rating system to assess the quality of evidence for our primary outcome (hospital admission).

Main results: Twenty trials met the review eligibility criteria, generated 24 study comparisons and comprised 2697 randomised children aged one to 18 years, presenting predominantly with moderate or severe exacerbations. Most studies involved both preschool-aged children and school-aged children; three studies also included a small proportion of infants less than 18 months of age. Nine trials (45%) were at a low risk of bias. Most trials used a fixed-dose protocol of three doses of 250 mcg or two doses of 500 mcg of nebulized ipratropium bromide in combination with a SABA over 30 to 90 minutes while three trials used a single dose and two used a flexible-dose protocol according to the need for SABA.The addition of an anticholinergic to a SABA significantly reduced the risk of hospital admission (risk ratio (RR) 0.73; 95% confidence interval (CI) 0.63 to 0.85; 15 studies, 2497 children, high-quality evidence). In the group receiving only SABAs, 23 out of 100 children with acute asthma were admitted to hospital compared with 17 (95% CI 15 to 20) out of 100 children treated with SABAs plus anticholinergics. This represents an overall number needed to treat for an additional beneficial outcome (NNTB) of 16 (95% CI 12 to 29).Trends towards a greater effect with increased treatment intensity and with increased asthma severity were observed, but did not reach statistical significance. There was no effect modification due to concomitant use of oral corticosteroids and the effect of age could not be explored. However, exclusion of the one trial that included infants (< 18 months) and contributed data to the main outcome, did not affect the results. Statistically significant group differences favoring anticholinergic use were observed for lung function, clinical score at 120 minutes, oxygen saturation at 60 minutes, and the need for repeat use of bronchodilators prior to discharge from the emergency department. No significant group difference was seen in relapse rates.Fewer children treated with anticholinergics plus SABA reported nausea and tremor compared with SABA alone; no significant group difference was observed for vomiting.

Authors' conclusions: Children with an asthma exacerbation experience a lower risk of admission to hospital if they are treated with the combination of inhaled SABAs plus anticholinergic versus SABA alone. They also experience a greater improvement in lung function and less risk of nausea and tremor. Within this group, the findings suggested, but did not prove, the possibility of an effect modification, where intensity of anticholinergic treatment and asthma severity, could be associated with greater benefit.Further research is required to identify the characteristics of children that may benefit from anticholinergic use (e.g. age and asthma severity including mild exacerbation and impending respiratory failure) and the treatment modalities (dose, intensity, and duration) associated with most benefit from anticholinergic use better.

PubMed Disclaimer

Conflict of interest statement

Francine Ducharme has received travel support, research funds and fees for speaking from Novartis, Taketa (formally Nycomed) and Merck Frosst Inc and served on an advisory board for Novartis.

Figures

1
1
Methodological quality summary: review authors' judgments about each methodological quality item for each included study.
2
2
Forest plot of comparison: 1 Anticholinergic and short‐acting beta2‐agonists versus short‐acting beta2‐agonists alone (all protocols), outcome: 1.1 Primary outcome: hospital admissions.
3
3
In the children on short‐acting beta2‐agonists only, 23 people out of 100 were admitted to hospital, compared with 17 (95% CI 15 to 20) out of 100 for children on short‐acting beta2‐agonists plus anticholinergics.
4
4
Funnel plot of analysis 1.1.
1.1
1.1. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 1 Primary outcome: hospital admissions.
1.2
1.2. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 2 Primary outcome: hospital admissions subgrouped by trial protocol.
1.3
1.3. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 3 Primary outcome: hospital admissions subgrouped by review authors' judgment of trial report.
1.4
1.4. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 4 Primary outcome: hospital admissions subgrouped by control group event rate (tertiles).
1.5
1.5. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 5 Primary outcome: hospital admissions subgrouped by co‐intervention of corticosteroid.
1.6
1.6. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 6 Change from baseline in % predicted FEV1, 60 minutes after the last of IB.
1.7
1.7. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 7 Change from baseline in % predicted FEV1, 120 minutes after last IB.
1.8
1.8. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 8 % Change in FEV1 or PEFR at 60 minutes after last IB (± 15 minutes).
1.9
1.9. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 9 % Change in FEV1 or PEFR at 120 minutes after last IB (± 30 minutes).
1.10
1.10. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 10 % Change in respiratory resistance at 60 minutes after IB (± 15 minutes).
1.11
1.11. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 11 % Change in respiratory resistance at 120 minutes after IB (± 30 minutes).
1.12
1.12. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 12 Change in clinical score at 120 minutes (± 30 minutes).
1.13
1.13. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 13 Need for repeat bronchodilator treatment after standard protocol prior to disposition.
1.14
1.14. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 14 O2 saturation < 95% at 60 minutes (± 15 minutes).
1.15
1.15. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 15 O2 saturation < 95% at 120 minutes (± 30 minutes).
1.16
1.16. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 16 Need for corticosteroids in emergency department prior to disposition.
1.17
1.17. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 17 Tremor.
1.18
1.18. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 18 Vomiting.
1.19
1.19. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 19 Nausea.
1.20
1.20. Analysis
Comparison 1 Anticholinergic and beta2‐agonists versus beta2‐agonists alone (all protocols), Outcome 20 Relapse.
See this image and copyright information in PMC

Update of

Comment in

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