Inhaled anti‐cholinergics for prolonged non‐specific cough in children
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the effectiveness of inhaled anti‐cholinergics in treating children with non‐specific cough.
Background
Cough is a very common symptom of respiratory disease and the commonest symptom for presentation to family doctors [Britt 2002]. The definition of chronic cough in children varies from longer than 3‐6 weeks and its prevalence ranges from 3% in Dutch school children [Spee‐van 1998] to 35% in South African children [Nriagu 1999]. The reporting of isolated cough in questionnaires is however unreliable [Brunekreef 1992] and prevalence figures are very likely to be inaccurate.
Non‐specific cough is defined as non‐productive cough in the absence of identifiable respiratory disease or known aetiology [Chang 2001]. Children with a history of nonspecific cough are commonly seen in paediatric practice. The majority have no signs of other current disease processes. In the absence of research to guide clinical practice, these children are treated with a variety of therapies: antibiotics, cough suppressants, anti‐histamines, decongestants, bronchodilators, sodium cromoglycate, inhaled corticosteroids and oral corticosteroids, sometimes resulting in significant side effects [Thomson 2002].
These children present a major management problem and cause considerable anxiety to parents. The desire by patients and medical practitioners to treat cough is reflected in the wide use of over‐the‐counter (OTC) medications for coughs and colds and the frequent prescription of antibiotics for upper respiratory tract infection [McManus 1997]. Many children with non‐specific cough are treated with asthma type medications (corticosteroids and/or bronchodilators). However, any beneficial effects of these interventions have not been clearly described.
A Cochrane review on the use of beta2‐agonists for acute bronchitis focused on acute cough (undefined time frame) in both adults and children. The reviewers concluded that use of beta2‐agonists confers no benefit in the absence of airflow obstruction [Smucny 2001]. This present review instead focuses on prolonged non‐specific cough in children. This condition is most likely to differ from acute bronchitis with respect to the duration of cough (>3 weeks) and quality of cough (non‐productive).
Objectives
To determine the effectiveness of inhaled anti‐cholinergics in treating children with non‐specific cough.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials comparing inhaled anti‐cholinergics with a placebo medication.
Types of participants
All trials which included children under 18 years of age with prolonged (3 or more weeks) non‐specific cough (dry and non‐productive cough without any other respiratory symptom, sign or systemic illness). An a priori subgroup analysis is planned for children < 7 years of age.
Exclusion criteria: cough related to mycoplasma, pertussis and chlamydia, presence of underlying cardio‐respiratory condition, current or recurrent wheeze (>2 episodes), presence of other respiratory symptoms (productive cough, haemoptysis, dyspnoea), presence of other respiratory signs (clubbing, chest wall deformity, respiratory noises such as wheeze on auscultation and other adventitious sounds), presence of any sign of systemic illness (failure to thrive, aspiration, neurological or developmental abnormality), presence of lung function abnormality.
Types of interventions
All randomised controlled comparisons of anti‐cholinergics versus placebo medication in the management of non‐specific cough. Trials only comparing two or more asthma medications without a placebo comparison group will not be included. Two separate treatment regimes will be evaluated:
i) Inhaled anticholinergics by metered dose inhaler (with or without spacer device),
ii) Inhaled anticholinergics by nebuliser
Trials that included the use of other medications or interventions were included if all participants had equal access to such medications or interventions.
Types of outcome measures
Attempts will be made to obtain data on at least one of the following outcome measures:
Primary outcome:
a) proportions of participants who were not cured or not substantially improved at follow up (clinical failure).
Secondary outcomes:
b) proportions of participants who were not cured at follow up,
c) proportions of participants who not substantially improved at follow up,
d) mean difference in cough indices (cough diary, cough frequency, cough scores),
e) proportions experiencing adverse effects, eg. tremor, behavioral changes (side effects),
f) proportions experiencing complications eg. requirement for medication change.
g) proportions of participants expressing preference for medication or placebo.
h) proportions of parent/carers expressing preference for medication or placebo.
The proportions of participants who failed to improve on treatment and the mean clinical improvement will be determined using the following hierarchy of assessment measures (ie. where two or more assessment measures are reported in the same study, the outcome measure that is listed first in the hierarchy will be used).
i) Objective measurements of cough indices (cough frequency, cough receptor sensitivity, cough amplitude).
ii) Symptomatic (Likert scale, visual analogue scale, level of interference of cough, cough diary) ‐ assessed by the child.
iii) Symptomatic (Likert scale, visual analogue scale, level of interference of cough, cough diary) ‐ assessed by the parents/careres.
iv) Symptomatic (Likert scale, visual analogue scale, level of interference of cough, cough diary) ‐ assessed by clinicians.
v) Airway markers consistent with infection or inflammation.
Search methods for identification of studies
The following topic search strategy will used to identify the relevant randomised controlled trials listed on the electronic databases: (cough [MeSH] OR cough [text word] OR bronchitis [MeSH] OR bronchitis [text word]) AND (bronchodilator [MeSH] OR bronchodilator [text word] or anti cholinergic [MeSH] OR anti‐cholinergic [text word] OR ipratropium [text word] OR ipratropium bromide [text word]). A similar strategy will be used with the electronic database EMBASE.
Trials will be identified from the following sources:
1. The Cochrane Controlled Trials Register (which includes the Airways Collaborative Review Group Specialised Trials Register).
2. MEDLINE 1999‐2003 accessed via PubMed. Topic search strategy combined with the following terms to identify randomised controlled trials: clinical trial [ptyp] OR "clinical trial*"[text word] OR random*[text word] OR "double‐blind"[text word] OR "double blind"[text word] OR "single‐blind"[text word] OR "single blind"[text word] OR placebo*[text word] .
3. OLDMEDLINE accessed via the National Library of Medicine Gateway. Topic search strategy combined with the following terms to identify randomised controlled trials: random: OR "double‐blind" OR "double blind" OR "single‐blind" OR "single blind" OR placebo: OR "clinical trial:" OR "drug therapy".
4. EMBASE 1997‐2003 accessed via Science Direct. Topic search strategy combined with the following terms to identify randomised controlled trials: clinical trial! OR random! OR "double‐blind" OR "double blind" OR "single‐blind" OR "single blind" OR placebo!
5. The list of references in relevant publications.
6. Written communication with the authors of trials included in the review.
7. Written communication with major pharmaceutical companies (with offices in Australia) that manufacture anti cholinergic medications.
Data collection and analysis
Retrieval of studies: From the title, abstract, or descriptors, two reviewers (ABC, PM) will independently review literature searches to identify potentially relevant trials for full review. Searches of bibliographies and texts will be conducted to identify additional studies. From the full text using specific criteria, the same two reviewers will independently select trials for inclusion. Agreement will be measured using kappa statistics. Disagreement will be resolved by consensus or third party adjudication (M McKean).
Trials that satisfy the inclusion criteria will be reviewed and the following information recorded: study setting, year of study, source of funding, patient recruitment details (including number of eligible children), inclusion and exclusion criteria, randomisation and allocation concealment method, numbers of participants randomised, blinding (masking) of participants, care providers and outcome assessors, dose and type of anti‐cholinergic therapy, duration of therapy, co‐interventions, numbers of patients not followed up, reasons for withdrawals from study protocol (clinical, side‐effects, refusal and other), details on side‐effects of therapy, and whether intention‐to‐treat analyses were possible. Data will be extracted on the outcomes described previously. Further information will be requested from the authors where required.
Studies included in the review will undergo quality assessment performed independently by all reviewers. Four components of quality will be assessed:
1. Allocation concealment. Trials will be scored as: Grade A: Adequate concealment, Grade B: Unclear, Grade C: Clearly inadequate concealment. (Grade A = high quality).
2. Blinding. Trials will be scored as: Grade A: Participant and care provider and outcome assessor blinded, Grade B: Outcome assessor blinded, Grade C: Unclear, Grade D: No blinding of outcome assessor (Grade A, B = high quality).
3. Reporting of participants by allocated group. Trials will be scored as: Grade A: The progress of all randomised children in each group described, Grade B: Unclear or no mention of withdrawals or dropouts, Grade C: The progress of all randomised children in each group clearly not described. (Grade A = high quality).
4. Follow‐up. Trials will be scored as: Grade A: Outcomes measured in >90% (where withdrawals due to complications and side‐effects are categorised as treatment failures), Grade B: Outcomes measured in 80‐90%, Grade C: Unclear, Grade D: Outcomes measured in <80%. (Grade A = high quality).
Each study will also be assessed using a 1 to 5 scale described by Jadad et al [Jadad 1996] and summarised as follows:
Was the study described as randomised? (1=yes; 0=no)
Was the study described as double blind? (1=yes; 0=no)
Was there a description of withdrawals and dropouts? (1=yes; 0=no)
Was the method of randomisation clearly described and appropriate? (1=yes; 0=no)
Was the method of double blinding well described and appropriate? (1=yes; >0=no)
While only the allocation concealment quality assessment will be displayed in the meta‐analysis figures, all assessments will be included in the "Characteristics of included studies" table. Inter‐reviewer reliability for the identification of high quality studies for each component will be measured by the Kappa statistic.
For the dichotomous outcome variables of each individual study, relative and absolute risk reductions will be calculated using a modified intention‐to‐treat analysis. This analysis assumes that children not available for outcome assessment have not improved (and probably represents a conservative estimate of effect). An initial qualitative comparison of all the individually analysed studies will examine whether pooling of results (meta‐analysis) is reasonable. This will take into account differences in study populations, inclusion/exclusion criteria, interventions, outcome assessment, and estimated effect size.
The results from studies that met the inclusion criteria and reported any of the outcomes of interest will be included in the subsequent meta‐analyses. The summary weighted risk ratio and 95% confidence interval (fixed effects model) will be calculated using the inverse of the variance of each study result for weighting (Cochrane statistical package, REVMAN version 4.1). The number needed to treat will be calculated using the summary odds ratio and the average control event rate described in the relevant studies. The cough indices will be assumed to be normally distributed continuous variables so the mean difference in outcomes can be estimated (weighted mean difference). If studies reported outcomes using different measurement scales, the standardised mean difference will be estimated. Any heterogeneity between the study results will be described and tested to see if it reached statistical significance using a chi‐squared test. The 95% confidence interval estimated using a random effects model will be included whenever there are concerns about statistical heterogeneity.
An a priori sub‐group analysis is planned for children less than 7 years of age. Sensitivity analyses are planned to assess the impact of the potentially important factors on the overall outcomes: a) study quality; b) study size; c) variation in the inclusion criteria; d) differences in the medications used in the intervention and comparison groups; e) differences in outcome measures; and f) analysis by "treatment received" rather than "intention‐to‐treat".
