Addition of inhaled anticholinergics to beta2‐agonists for children with acute asthma in hospital
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy and safety of adding anticholinergics to β2‐agonists as inhaled or nebulized therapy in children hospitalised for an acute asthma exacerbation. Moreover, we wish to investigate the characteristics of patients or therapy, if any, that would influence the magnitude of response attributable to the addition of anticholinergics.
Background
Description of the condition
One of the main goals in the management of acute asthma exacerbations in children is to achieve a rapid reversal of airflow obstruction (NAEPP 2011). This is best achieved using inhaled or nebulized short‐acting β2‐agonists (Camargo 2003; Karpel 1997) which are most effective bronchodilators due to their rapid onset of action and the magnitude of achieved bronchodilation (Sears 1992; Svedmyr 1985). Systemic corticosteroids should be added early in the course of treatment to patients who have moderate or severe exacerbations or to children who fail to respond promptly and completely to bronchodilators (Rechelefsky 2003; Rowe 2004).
Description of the intervention
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, with the slower but prolonged onset of action, anticholinergics can work as complementary treatment with β2‐agonists and may yield enhanced bronchodilation.
Several trials have explored the role of ipratropium bromide in the emergency department setting. One systematic review of randomised controlled trials concluded that the addition of multiple doses of inhaled anticholinergic agents to β2‐agonist therapy in the initial treatment of children with acute asthma exacerbations was safe and efficacious with most of the effect observed in those with severe asthma exacerbations (Plotnick 2008). Indeed, there is no apparent benefit in children presenting with mild to moderate asthma exacerbations (Plotnick 2008). The addition of multiple doses of inhaled anticholinergic agents to β2‐agonists was also shown to be cost‐effective (Lord 1999).
How the intervention might work
To our knowledge, two trials have assessed the efficacy of adding ipratropium bromide to β2‐agonists after the emergency department treatment period, that is, in children hospitalised for an acute asthma exacerbation (Craven 2001; Goggin 2001). Both trials independently could not demonstrate benefit conferred by the addition of anticholinergics. Consequently, national and international asthma guidelines currently recommend that inhaled anticholinergics should not be used in hospitalised children with acute asthma (GINA 2011; NAEPP 2011). Yet, in several institutions, anticholinergics are used for a certain period of time after admission of children, particularly, but not only, in those admitted to the ICU.
Why it is important to do this review
The difference in practice between institutions, termed practice variation, underlines a gap between recommended and observed care or care gap. In absence of an identified systematic review, we believe a Cochrane review would clarify the evidence accumulated to date regarding the role of anticholinergics in the management of children hospitalised for an acute asthma exacerbation.
Objectives
To assess the efficacy and safety of adding anticholinergics to β2‐agonists as inhaled or nebulized therapy in children hospitalised for an acute asthma exacerbation. Moreover, we wish to investigate the characteristics of patients or therapy, if any, that would influence the magnitude of response attributable to the addition of anticholinergics.
Methods
Criteria for considering studies for this review
Types of studies
We will include all randomised controlled trials.
Types of participants
We will include children aged 1 to 18 years hospitalised for an acute asthma exacerbation.
Types of interventions
Intervention: Nebulized or inhaled anticholinergics with short‐acting β2‐agonists
Comparison: Nebulized or inhaled short‐acting β2‐agonists alone
Co‐interventions, such as systemic corticosteroids are anticipated and permitted, provided they are similar in both groups and do not form part of the randomised treatment.
Types of outcome measures
Primary outcomes
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Duration of hospital stay
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Serious adverse events
Secondary outcomes
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Duration of stay in intensive care unit (ICU) (for those admitted to the ICU)
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Admission to the ICU (for those admitted on the wards)
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Ventilation assistance
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Need for supplemental asthma therapy (for example aminophylline)
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Duration of the need for supplemental oxygen
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Time to short‐acting β2‐agonists spaced at 4 hours or more
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Change from baseline in asthma severity measured as lung function, symptoms or clinical scores
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Relapse rate within 72 hours of discharge from hospital
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Adverse health effects
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Withdrawal rate, namely overall withdrawals, withdrawals due to poor control of symptoms or deterioration, and withdrawals due to adverse effects
Search methods for identification of studies
Electronic searches
We will identify trials from the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO and handsearching of respiratory journals and meeting abstracts (see Appendix 1 for further details). We will search all records in the CAGR coded as "asthma" using the strategy in Appendix 2.
There will be no restriction on type or language of publication and the database will be searched from the date of inception to the present.
Searching other resources
We will check the reference lists of all identified RCTs to identify potentially relevant citations. We will check the web sites of international headquarters of pharmaceutical companies producing anticholinergics for reports of relevant completed trials. We will also explore the ClinicalTrials.gov web site for relevant clinical trials.
Data collection and analysis
Two reviewers (KV and BFC) will independently extract data and disagreement will be dealt with by consensus or through the input of a third reviewer (FMD). When necessary, we will contact authors of included studies to provide important missing data.
Selection of studies
Two reviewers (KV and BFC) will independently review each abstract and annotate them as: 1) RCT; 2) clearly not an RCT; or 3) unclear. We will obtain the publications of references identified as either RCTs or unclear, and two authors will review the full‐text trial reports independently. We will resolve disagreement with by consensus or the input of a third reviewer (FMD)
Data extraction and management
Two review authors (KV and BFC) will independently extract data and disagreement will be dealt with by consensus or with the input of a third reviewer (FMD), if needed.
Assessment of risk of bias in included studies
We will assess methodological quality of the eligible trials using the Cochrane Collaboration 'risk of bias' tool based on:
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random sequence generation;
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allocation concealment;
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blinding of participants and personnel;
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blinding of outcome assessment;
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incomplete outcome data;
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selective outcome reporting; and
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other bias
Quality assessment will be performed independently by two reviewers. We will resolve disagreement with by consensus or the input of a third reviewer.
Measures of treatment effect
We will calculate treatment effects for dichotomous variables as relative risk (RR) or risk difference (RD), or both with 95% confidence intervals (CI). We will assume equivalence if the relative risk estimate and its 95% CI fall between 0.9 and 1.1. For continuous outcomes, such as lung function tests, we will calculate pooled statistics as mean differences (MD), or standardised mean differences (SMD) as indicated and report 95 %CI. We will summarise differences between groups in event rates using rate ratios.
Unit of analysis issues
The unit of analysis will be the patient. If a trial has more than one intervention or control group, we will consider additional comparisons, if appropriate. If two comparisons used the same group twice as comparator, we will halve the number of participants in the control group to avoid over‐representation. For dichotomous outcomes, we would halve the control group numerator and denominator.
Dealing with missing data
Where possible, we will contact investigators or study sponsors to obtain missing numerical outcome data or data in a different format to accumulate data in the review. We will not impute for missing data.
Assessment of heterogeneity
Homogeneity between included studies being pooled will be tested with the DerSimonian and Laird method, and P > 0.10 or an I2 > 40 % will be used as the cut‐off level for significance. If heterogeneity is suggested by one or both methods, random‐effects model will be applied to the summary estimates. Unless specified otherwise, the fixed effect model will be used.
Assessment of reporting biases
We will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce a serious bias, we will perform a sensitivity analysis to explore the impact of including such studies in the overall assessment of results.
Data synthesis
Data will be reported with their 95 %CI. We will perform meta‐analysis using RevMan 5.1.
Subgroup analysis and investigation of heterogeneity
Subgroup analyses will be performed to explore possible reasons for heterogeneity of study results on the main outcome. A priori defined subgroups will be based on:
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Admission site (hospital wards versus intensive care unit)
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Age (preschool children versus school aged children)
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Intensity of anticholinergic treatment
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Co‐intervention with systemic corticosteroids (yes or no)
Sensitivity analysis
For the primary outcome, we will perform sensitivity analyses to determine the effect of publication status (abstracts or web reports only versus full text papers) and methodological quality. We will perform sensitivity analyses for publication status by removing the unpublished data and for methodological quality by removing trials not meeting the following criteria: clearly reported and acceptable random sequence generation, reported and acceptable double‐blinding, and low and balanced attrition in both groups.
Summary of findings table
We will create a summary of findings table using the two primary outcomes and the following secondary outcomes: duration of stay in ICU; admission to the ICU; adverse effects; change from baseline in lung function. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it relates to the studies which contribute data to the meta‐analyses for the pre‐specified outcomes. We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011) and GRADEpro software. We will justify all decisions to down‐ or up‐grade the quality of studies using footnotes and make comments to aid reader's understanding of the review where necessary.
