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Mucolytics for bronchiectasis

  1. Mark Wilkinson1,
  2. Karnam Sugumar2,
  3. Stephen J Milan3,*,
  4. Anna Hart4,
  5. Alan Crockett5,
  6. Iain Crossingham6

Editorial Group: Cochrane Airways Group

Published Online: 2 MAY 2014

Assessed as up-to-date: 19 JUN 2013

DOI: 10.1002/14651858.CD001289.pub2


How to Cite

Wilkinson M, Sugumar K, Milan SJ, Hart A, Crockett A, Crossingham I. Mucolytics for bronchiectasis. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD001289. DOI: 10.1002/14651858.CD001289.pub2.

Author Information

  1. 1

    University Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster, UK

  2. 2

    Royal Preston Hospital, Lancashire Teaching Hospitals NHS Trust, Department of Paediatrics, Preston, UK

  3. 3

    Lancaster University, Lancaster Health Hub, Lancaster, UK

  4. 4

    Lancaster University, Lancaster Medical School, Clinical Research Hub, Lancaster, Lancashire, UK

  5. 5

    University of South Australia, School of Health Sciences, Adelaide, South Australia, Australia

  6. 6

    Royal Blackburn Hospital, Blackburn, Lancashire, UK

*Stephen J Milan, Lancaster Health Hub, Lancaster University, Lancaster, UK. s.milan@lancaster.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 2 MAY 2014

SEARCH

 

Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 
Summary of findings for the main comparison. Bromhexine compared with placebo for bronchiectasis

Bromhexine compared with placebo for bronchiectasis

Patient or population: patients with bronchiectasis
Settings: community
Intervention: bromhexine
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboBromhexine

Frequency and duration of exacerbationsSee commentSee commentSee commentSee commentN/AOutcome not reported

HospitalisationsSee commentSee commentSee commentSee commentN/AOutcome not reported

Adverse events0 per 100 32.2 per 100

(0.05 to 11.7)
OR 2.93
(0.12 to 73.97)
88
(1 study)
⊕⊕⊝⊝
low1,2

Health-related quality of lifeSee commentSee commentSee commentSee commentSee commentOutcome not reported

Symptoms difficulty in expectoration

Follow-up: 16 days
Absolute values not reportedAbsolute values not reportedMD -0.53

(-0.81 to -0.25)
88
(1 study)
⊕⊕⊝⊝
low1,2

DeathsSee commentSee commentSee commentSee commentSee commentOutcome not reported

Lung function

FEV1

Follow-up: 13 days
Mean FEV1 in the control group was 1614 mLMean FEV1 in the intervention groups was 184 mL higher
(149.75 lower to 517.75 higher)
MD 184.00

(-149.75 to 517.75)
88
(1 study)
⊕⊕⊝⊝
low1,2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1One point deducted to reflect risk of bias assessment of randomisation (judged as unclear risk of bias).
2One point deducted to reflect imprecision in the estimate, with data coming from only one trial, leading to low event rate and wide confidence intervals.
3Assumed risk is based on the control group (N = 43) of the one trial reporting adverse events.

 Summary of findings 2 5 mg RhDNase compared with placebo for bronchiectasis

 Summary of findings 3 Erdosteine versus no treatment for bronchiectasis

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of the condition

Bronchiectasis is predominantly an acquired disease process that represents the end stage of a variety of unrelated pulmonary insults and antecedent events. It is defined in anatomical terms as persistent and irreversible dilatation and distortion of medium-sized bronchi. Focal or diffuse forms of bronchial disease also predispose to the development of bronchiectasis. Bronchial obstruction due to varied and unrelated causes (e.g. aspiration of foreign bodies, carcinoma, extrinsic compression by surrounding enlarged lymph nodes, inspissated viscid secretions) can cause obstructive or localised forms of bronchiectasis. Diffuse bronchiectasis is usually associated with previous widespread pneumonic damage (e.g. pertussis and measles pneumonia, severe influenza and varicella pneumonia, necrotising bacterial pneumonias due to Klebsiella, Staphylococcus aureus, Pseudomonas and anaerobic infections), chronic granulomatous disease (e.g. tuberculosis, sarcoidosis, histoplasmosis, coccidioidomycosis), hypersensitivity and immunodeficiency disorders (e.g. congenital or acquired ahypogammaglobulinaemia) or genetic syndromes (e.g. cystic fibrosis, tracheobronchomegaly, bronchial cartilage deficiency, Kartagener's syndrome, Young's syndrome, immotile cilia disease). Many of these conditions predispose to recurrent lower respiratory infection as a result of poor tracheobronchial clearance. It has been suggested that with widespread use of high-resolution computed tomography, more bronchiectasis diagnoses are being made (Goeminne 2010), and mucus clearance along with antimicrobial therapy remains an integral part of management of the condition (Stafler 2010).

 

Description of the intervention

Several agents are known to alter the physical or chemical characteristics of sputum such that removal of sputum from the airway becomes easier. These drugs are collectively known as mucolytics. The precise mechanism of action of many of these drugs is not known (Cotgreave 1987; Rogers 2007) but may include breaking down large molecules within the mucus to reduce viscosity and reducing the biological activity of various proteins (Zafarullah 2003). Attempts have been made to classify mucoactive drugs (Balsamo 2010) as true mucolytics (thin mucus), expectorants (work by inducing cough) and mucokinetics (increase mucus transport within the lungs), but in practice these drugs probably work through several of these mechanisms simultaneously (Tomkiewicz 1995).

The mechanism of action of recombinant human DNase (RhDNase or dornase alfa) is known. This is a mucolytic that enzymatically degrades the long chains of DNA derived from neutrophils that are a constituent of the pus that can form a considerable part of the mucus in infected lungs (Henke 2007).

Mucolytics may be given orally or parenterally. Alternatively, some, such as recombinant human DNase (RhDNase), are delivered directly to the lungs by nebulisation and inhalation.

National guidelines (BTS 2010; TSANZ 2010) consider RhDNase to be contraindicated in non–cystic fibrosis (CF) bronchiectasis following a trial that reported deleterious effects on both lung function and exacerbation rate in adults (O'Donnell 1998). By extrapolation from this study, the same recommendation has been given for children with non-CF bronchiectasis. Based primarily on an earlier version of this Cochrane review (Crockett 2001), guidelines in the Southern hemisphere (TSANZ 2010) recommend against the use of mucoactive drugs including mucolytics in bronchiectasis.

 

How the intervention might work

Bronchiectasis is a disease characterised by excessive mucus production and retention. By reducing the viscosity of mucus, mucolytics may aid clearance of sputum from the airways. Removal of mucus plugs from small and medium-sized airways allows recruitment of the associated lung and hence improvement in spirometric measures of lung function. Retained sputum could potentially act as a culture medium for bacteria (Stockley 1995), leading to recurrent or persistent chest infection. By enhancing mucus removal, this risk is reduced.

 

Why it is important to do this review

It is important to gain further clarity on the clinical benefits and adverse events associated with ingested or inhaled mucolytics in the treatment of bronchiectasis.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

To determine whether ingested or inhaled mucolytics are effective in the treatment of patients with bronchiectasis.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We included randomised trials comparing treated and untreated groups of participants with bronchiectasis.

 

Types of participants

Adults with a diagnosis of bronchiectasis, but not cystic fibrosis.

 

Types of interventions

Intervention group: any mucolytic given by nebuliser or orally in single or repeated doses alone or in combination with glucocorticosteroids, beta2-agonists (long- or short-acting or both) or xanthine bronchodilators.

Control group: single or repeated doses of nebulised or oral placebo combined with glucocorticosteroids, beta2-agonists or xanthine bronchodilators.

Important co-interventions: physical interventions (physiotherapy) and drugs that increase mucociliary clearance (beta2-agonists) or change viscoelastic characteristics of sputum (corticosteroids).

 

Types of outcome measures

 

Primary outcomes

  • Frequency and duration of exacerbations.
  • Hospitalisations.
  • Adverse events.

 

Secondary outcomes

  • Mortality.
  • Symptoms: cough, sputum volume and ease of expectoration, wheeze, dyspnoea.
  • Lung function.
  • In vitro characteristics of sputum.
  • Measurement of tracheobronchial clearance.
  • Health-related quality of life (e.g. Short Form (SF)-36, St George's Respiratory Questionnaire (SGRQ)).

 

Search methods for identification of studies

 

Electronic searches

We identified trials from the Cochrane Airways Group Specialised Register (CAGR), which is maintained by the Trials Search Co-ordinator for the Group. The Register contains trial reports identified through 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 (please see Appendix 1 for further details). We searched all records in the CAGR using the search strategy in Appendix 2.

We also conducted a search of ClinicalTrials.gov (www.ClinicalTrials.gov) and the World Health Organization (WHO) trials portal (www.who.int/ictrp/en/). We searched all databases from their inception to June 2013, with no restriction on language of publication.

 

Searching other resources

Full publications of all references identified as randomised controlled trials (RCTs) or unclear were obtained and reviewed independently by two review authors (SJM, MW). Reference lists of all identified RCTs were checked to identify potentially relevant citations. The international headquarters of Boehringer Ingelheim, the pharmaceutical company that produces bromhexine, was contacted. Enquiries regarding other published or unpublished studies known and/or supported by this company or its subsidiaries were made so that these results could be included in our review. Finally, personal contact was made with colleagues and trialists working in the field of bronchiectasis to ask them to identify potentially relevant trials. In addition, all identified papers and reviews were handsearched for further references, and study authors were contacted to ask whether they could identify any unpublished or missed trials.

 

Data collection and analysis

 

Selection of studies

MW and IC independently screened the identified references using the abstract, title and medical subject heading (MeSH) terms, and independently assessed studies for potential relevance. At the next stage, using the full text of the potentially relevant studies, the same review authors (MW and IC) independently selected trials for inclusion in the review. Had disagreements arisen, we planned to involve an independent third party adjudicator (SJM); however, this was not necessary.

 

Data extraction and management

Data for included trials were extracted independently by two review authors (SJM and MW) and were entered into the software programme of The Cochrane Collaboration (Review Manager (RevMan)) by SJM. Data entry was checked by AH.

 

Assessment of risk of bias in included studies

Two review authors (SJM and MW) assessed the trials with respect to selection bias, performance and detection bias, attrition bias, reporting bias and other potential sources of bias using the ’Risk of bias’ tool of The Cochrane Collaboration (Higgins 2011).

 

Measures of treatment effect

For dichotomous variables, we expressed data as odds ratios (ORs) with 95% confidence intervals (CIs). Data for continuous variables were reported as mean differences (MDs) with 95% CIs or as standardised mean differences (SMDs) with 95% CIs in analyses for which it was necessary to pool data from different measures.

 

Unit of analysis issues

The unit of analysis was the participant.

 

Dealing with missing data

We planned to contact study authors if outcome data or information on trial design was missing; however, this issue did not arise.

 

Assessment of heterogeneity

We tested heterogeneity among pooled estimates using the Der-Simonian and Laird method; we considered a P value < 0.05 as the threshold for statistical significance. Heterogeneity was assessed at first by visual inspection of forest plots. The Chi2 test was similarly considered (P value < 0.10) but was interpreted with caution owing to the low power associated with this test. I2 was also considered and was interpreted in relation to the following guidance (Higgins 2011).

  • 0% to 40%: might not be important.
  • 30% to 60%: may represent moderate heterogeneity.
  • 50% to 90%: may represent substantial heterogeneity.
  • 75% to 100%: shows considerable heterogeneity.

When we encountered heterogeneity according to the above mentioned criteria, we applied fixed-effect and random-effects models and commented on differences, reporting the random-effects model in the review.

 

Assessment of reporting biases

We planned to examine publication bias by using funnel plots if we had included an adequate number of trials (10 or more) aggregated in a single meta-analysis. We recognise that an asymmetrical funnel plot can reflect heterogeneity, outcome reporting bias and small-study effects and therefore is not necessarily a reflection of publication bias.

 

Data synthesis

 

Summary of findings table

We created a 'Summary of findings' table using the following outcomes.

Primary

  • Frequency and duration of exacerbations.
  • Hospitalisations.
  • Adverse events.

Secondary

  • Health-related quality of life.
  • Symptoms: cough, sputum volume and ease of expectoration, wheeze, dyspnoea.
  • Mortality.
  • Lung function.

We used 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 that contributed data to the meta-analyses for prespecified outcomes. We applied methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) by using GRADEpro software. We justified all decisions to downgrade or upgrade the quality of studies by using footnotes and included comments to aid readers' understanding of the review when necessary.

 

Subgroup analysis and investigation of heterogeneity

Subgroup and sensitivity analyses were performed by pooling absolute and relative data to include sufficient studies at each time point. In these cases, we calculated individual and pooled statistics as SMDs and 95% CIs using a random-effects model. Subgroup analysis was performed using the following subgroups.

 

Sensitivity analysis

We planned to conduct sensitivity analyses by comparing random-effects versus fixed-effect modelling if issues of significant heterogeneity arose. However this was not necessary.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of studies

 

Results of the search

Thirty-six reports were identified in the June 2013 searches; they included the three studies already identified in the previous version of this review (Crockett 2001). Identified studies were independently evaluated against the inclusion criteria by MW and IC, and four studies were judged as appropriate for inclusion (details are provided in Characteristics of included studies). Thirty-two reports were excluded (details provided in Characteristics of excluded studies).

See Figure 1 for a study flow diagram.

 FigureFigure 1. Study flow diagram.

 

Included studies

Four RCTs were identified, with a total of 528 participants who were randomly assigned (504 completed the study). Details are provided in Characteristics of included studies. Only one study (Olivieri 1991) compared oral bromhexine versus placebo in the treatment of acute exacerbations of bronchiectasis (88 participants were randomly assigned, with 21 participants withdrawing from the study; participants in both treatment arms received an antibiotic (ceftazidine 1 g, intramuscular (IM), twice daily) for the first week of the 15-day trial, and the choice of antibiotic was not based on microbiological assessment). All participants in this trial were suffering from an acute infective exacerbation of bronchiectasis, with morning cough and purulent sputum. Another study (Crisafulli 2007) (30 participants randomly assigned, with no participants withdrawing from the study) compared oral erdosteine and physiotherapy versus physiotherapy alone over a 15-day period. Participants were over 55 years of age and were non-smokers or ex-smokers with moderate airflow obstruction and stable disease.

The remaining two studies compared RhDNase versus placebo. Wills 1996, a 14-day trial with 61 participants (all completed the study, but three had treatment interrupted), included participants who were in a stable state, with moderate airflow obstruction, and compared two doses of RhDNase (2.5 mg and 5 mg) versus placebo. The largest study (O'Donnell 1998), with 349 participants (of whom 346 completed the study), also included participants who were in a stable state and compared 2.5 mg aerosolised RhDNase twice daily versus placebo for 24 weeks. Participants had a mean age of 60 years, with daily sputum production and airflow limitation. Attempts to obtain more detailed information from the included studies were unsuccessful.

 

Excluded studies

Thirty-two reports were excluded (details in Characteristics of excluded studies). Twelve (38%) reports described participants with a variety of respiratory conditions, and data were not reported separately for those with bronchiectasis; a further 12 (38%) reports were excluded, as the intervention was not a mucolytic agent. An additional five (16%) reports were excluded, as the participants had a diagnosis other than bronchiectasis, and two (6%) reports were excluded on the basis of having a non-randomised design. The remaining trial (3%) was excluded, as the mucolytic agent was not compared with placebo/no treatment.

 

Risk of bias in included studies

 

Allocation

All four included studies were assessed as unclear in terms of allocation concealment bias (Figure 2). In terms of random sequence generation, one trial (Crisafulli 2007) was assessed as having low risk of bias, and the remaining three studies were judged to be unclear in this respect.

 FigureFigure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

 

Blinding

The risk of performance and detection bias in three included studies (O'Donnell 1998; Olivieri 1991; Wills 1996) was judged to be low (Figure 3). Crisafulli 2007 was an unblinded study in which erdosteine and physiotherapy versus physiotherapy alone were compared. The risk of performance bias was evaluated as high; however outcomes were assessed by personnel blinded and not directly associated with the study administration, and detection bias was therefore rated as low.

 FigureFigure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Incomplete outcome data

Only two of the four included studies were assessed as having low risk of bias in terms of attrition bias (O'Donnell 1998; Wills 1996), whereas the risk of attrition bias in Olivieri 1991 was regarded as high, and in Crisafulli 2007, the risk of attrition bias was judged as unclear.

 

Selective reporting

All four included studies were assessed as unclear in terms of reporting bias.

 

Other potential sources of bias

All four included studies were assessed as unclear in terms of other potential sources of bias.

 

Effects of interventions

See:  Summary of findings for the main comparison Bromhexine compared with placebo for bronchiectasis;  Summary of findings 2 5 mg RhDNase compared with placebo for bronchiectasis;  Summary of findings 3 Erdosteine versus no treatment for bronchiectasis

 

Bromhexine versus placebo

One study of 15 days' duration compared bromhexine versus placebo (Olivieri 1991). Primary outcomes, exacerbations and hospitalisations were not reported. No significant difference was noted between bromhexine and placebo in terms of adverse events (OR 2.93, 95% CI 0.12 to 73.97;  Analysis 1.1).

As for secondary outcomes, no deaths were reported. Symptoms were reported in terms of "difficulty in expectoration," sputum production, cough score and sputum quality. Difficulty in expectoration was significantly improved in the bromhexine-treated participants at day 10 (MD -0.45, 95% CI -0.89 to -0.03) and day 16 (MD -0.53, 95% CI -0.81 to -0.25). Our GRADE assessments of the quality of evidence in this trial produced a rating of low ( Summary of findings for the main comparison).

The percentage change in sputum production was greater in the bromhexine group at days seven, 10 and 16 (MD -21.5, 95% CI -38.9 to -4.1 at day 16). The cough score was significantly reduced at day 13 (MD -0.48, 95% CI -0.89 to -0.06). The quality of sputum was improved at both day 13 and day 16 (MD -0.45, 95% CI -0.87 to -0.034 at day 13). The analyses reported above were conducted by the authors of the previous version of this review (Crockett 2001), and additional data were supplied by the trial author (Olivieri 1991).

No significant difference between bromhexine and placebo in forced expiratory volume in one second (FEV1) was noted at seven days (MD 108.60 mL, 95% CI -242.38 to 459.58;  Analysis 1.2) or at 13 days (MD 184.00 mL, 95% CI -149.75 to 517.75;  Analysis 1.2). The analysis of auscultatory findings provided in the trial report indicated an advantage for bromhexine; however insufficient details of the analysis are provided to clarify whether the advantage was evident at day 16 (the final day) or, on average, throughout the trial.

 

RhDNase (5 mg) versus placebo

One trial of two weeks' duration compared 5 mg RhDNase versus placebo (Wills 1996). Our GRADE assessments of the quality of evidence in this trial produced a rating of low ( Summary of findings 2). No significant differences were reported between RhDNase (5 mg) and placebo with respect to the numbers of participants requiring hospitalisation for infective exacerbation (OR 5.54, 95% CI 0.25 to 123.08;  Analysis 2.1). The table of adverse events in the trial report provides numbers of incidents of adverse events, rather than numbers of participants experiencing adverse events; for this reason we have not entered the data using RevMan software. The authors of the trial report described no significant differences between RhDNase (5 mg) and placebo in terms of most of the 19 reported adverse events, with the only exception being the incidence of influenza syndrome as diagnosed by participants, with more occurrences reported in the RhDNase arm.

In terms of secondary outcomes, no deaths occurred and no symptoms were reported. No significant difference in FEV1 (MD 2.10 L, 95% CI -2.90 to 7.10;  Analysis 2.2) or percentage change in forced vital capacity (FVC) (MD -2.00, 95% CI -6.16 to 2.16;  Analysis 2.3) was observed at day 15 of this trial. A significant difference favouring placebo over RhDNase (5 mg) was observed (MD -3.20, 95% CI -6.30 to -0.10;  Analysis 2.4) in relation to the change between baseline and day 15 on the immediate activities component of the functional status questionnaire quality of life assessment. No other significant differences were observed in the other quality of life measures ( Analysis 2.4) nor in sputum colour ( Analysis 2.5).

 

RhDNase (2.5 mg) versus placebo

One study of two weeks' duration compared 2.5 mg RhDNase versus placebo (Wills 1996). Our GRADE assessments of the quality of evidence in this trial produced a rating of low. No participants in the RhDNase (2.5 mg) or placebo arms were hospitalised for infective exacerbation. Again, we did not perform an analysis of the adverse events, as they were reported as numbers of events rather than as numbers of people experiencing one or more events.

Neither percentage change in FEV1 (MD 2.10 L, 95% CI -2.95 to 7.15;  Analysis 3.2) nor percentage change in FVC (MD -2.40, 95% CI -6.42 to 1.62;  Analysis 3.3) was significantly different between groups. Only one significant difference between RhDNase (2.5 mg) and placebo was reported in changes from baseline on components of the functional status questionnaire quality of life assessment ( Analysis 3.4), and this involved the dyspnoea component, favouring RhDNase (2.5 mg) (MD 1.70, 95% CI 0.17 to 3.23;  Analysis 3.4). No significant difference in sputum colour was reported ( Analysis 3.5).

An additional, considerably longer, study of 24 weeks' duration compared 2.5 mg RhDNase versus placebo (O'Donnell 1998). Results were generally reported in a format that could not be included in the meta-analyses.

The study authors reported that the RhDNase group had a higher but non-significant protocol-defined exacerbation rate of 0.66 exacerbations per participant per 168 days compared with 0.56 exacerbations per participant in the placebo group (risk ratio (RR) 1.17, 95% CI 0.85 to 1.65). The RhDNase group also had a higher non–protocol-defined exacerbation rate than the placebo group (RR 2.01, 95% CI 1.15 to 3.50), and when both of these types of exacerbations were combined, a significant increase in occurrence was noted in the RhDNase group (RR 1.35, 95% CI 1.01 to 1.79). RhDNase had a statistically significant negative effect (P value ≤ 0.05) on FEV1, (mean percentage decline -1.7% in the placebo group and -3.6% in the RhDNase group; confidence intervals were not included in the trial report). Hospitalisation rates were increased in the RhDNase group (0.21 in the placebo group vs 0.39 in the treated group; RR 1.85, confidence intervals were not included in the trial report). Placebo-treated participants used antibiotics less (44.1 vs 56.9 days; P value ≤ 0.05; confidence intervals were not included in the trial report) and steroids less (23.4 vs 29.4 days; P value ≤ 0.05; confidence intervals were not included in the trial report) when compared with participants given RhDNase.

No significant difference in the incidence of adverse events was reported between control and study groups. However, the study authors report higher levels of antibodies to RhDNase in the treatment group (OR 28.19, 95% CI 3.77 to 210.85;  Analysis 3.7).

 

Erdosteine versus no treatment

One study of 15 days' duration compared erdosteine versus no treatment (Crisafulli 2007). Our primary outcomes of exacerbations, hospital admissions and adverse events were not reported.

In terms of secondary outcomes, no deaths were reported. The impact on mucus density was evaluated in  Analysis 4.1. No significant differences between erdosteine and control were seen at five days (MD -0.07, 95% CI -0.41 to 0.27), 10 days (MD -0.27, 95% CI -0.68 to 0.14) or 15 days (MD -0.27, 95% CI -0.63 to 0.09). Similarly, for mucus purulence ( Analysis 4.2), no significant differences between erdosteine and control were noted at five days (MD -0.03, 95% CI -0.36 to 0.30) and 10 days (MD -0.20, 95% CI -0.58 to 0.18); however, the significant difference at 15 days indicated benefit for erdosteine versus control (MD -0.47, 95% CI -0.79 to -0.15). No significant differences were described between erdosteine and control at five days (MD -0.13, 95% CI -0.62 to 0.36), 10 days (MD 0.20, 95% CI -0.28 to 0.68) or 15 days (MD 0.40, 95% CI -0.03 to 0.83) in terms of mucus volume production ( Analysis 4.3). By applying GRADE criteria, review authors evaluated the quality of evidence on these outcomes as low ( Summary of findings 3).

A significant difference was indicated between erdosteine and control in change from baseline to day 15 for FEV1 (mL) (MD 200.00, 95% CI 39.97 to 360.03;  Analysis 4.4), but no significant difference was noted for FEV1 %predicted (MD 4.50, 95% CI -3.11 to 12.11;  Analysis 4.5). Similarly, a significant difference was observed between erdosteine and control in change from baseline to day 15 for FVC (mL) (MD 300.00, 95% CI 27.48 to 572.52;  Analysis 4.6) but not for FVC %predicted (MD 8.90, 95% CI -2.55 to 20.35;  Analysis 4.7). Again, by applying GRADE criteria, review authors evaluated the quality of evidence on these outcomes as low.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Summary of main results

Only four trials could be included in this review, and the results of one of the trials could not be entered into the meta-analysis, as no standard deviations were available. It was not possible to combine the other three trials in an overall analysis because they used different drugs in different clinical settings. Scant data were reported on the primary outcomes of interest to this review and on outcomes important to the patient, such as quality of life.

The study by Olivieri 1991 tested the efficacy of adding bromhexine hydrochloride to an antibiotic during an acute infective exacerbation. The test dose chosen, 30 mg orally three times per day, is higher than the dose currently used in conventional medical practice. The drug was effective in improving sputum expectoration after ten days' treatment in participants with an acute exacerbation of bronchiectasis. It further reduced sputum production at seven, 10 and 16 days. It reduced cough significantly at only one time point and improved quality of sputum on days 13 and 16. The FEV1 remained unchanged throughout the trials.

The clinical conclusions derived from these data are that oral bromhexine at a dose above the usual recommended level can be effective in changing sputum production and clearance during an acute infective exacerbation. This effect was seen after only seven days of treatment. It is impossible to judge whether concurrent use of bromhexine with the antibiotic ceftazidine introduced a synergistic interaction.

A recommendation for widespread use of bromhexine in bronchiectasis cannot be made on the basis of one trial alone, and it is clear that further well-designed randomised controlled studies are required to evaluate the role of this agent.

Two trials (O'Donnell 1998; Wills 1996) compared nebulised RhDNase versus placebo in participants with chronic bronchiectasis. Wills 1996 was a two-week study, whereas O'Donnell 1998 ran for 24 weeks. Only one of the two trials (Wills 1996) considered RhDNase at 5 mg, and no important significant differences favouring RhDNase versus placebo were observed. Both trials evaluated nebulised RhDNase at a lower dose (2.5 mg), and the only significant difference between RhDNase (2.5 mg) and placebo reported in Wills 1996 was change from baseline in the dyspnoea component of the functional status questionnaire quality of life assessment, favouring the RhDNase (2.5 mg) arm. In the 24-week trial (O'Donnell 1998), the study authors reported a higher incidence of exacerbations and hospital admissions in the RhDNase arm and higher levels of antibodies to RhDNase in the treatment group; stronger evidence would be required to justify its use outside of a clinical trial.

Erdosteine combined with physiotherapy slightly improved sputum purulence and small but clinically useful changes in spirometry over a 15-day period compared with physiotherapy alone (Crisafulli 2007). No significant improvements were seen at earlier time points. This trial included 30 participants, all older than 55 years, with stable disease and at least moderate airflow limitation. This single, small trial provides insufficient evidence on its own to advocate the use of erdosteine, and further studies are required.

Randomised controlled trials are needed to examine the role of the other available mucolytics in stable bronchiectasis and in the subset of patients experiencing exacerbations.

 

Overall completeness and applicability of evidence

Only three trials (with a total of 498 participants) provided data to this review, and opportunities for aggregation of the data were very limited. Several studies included a small number of participants with bronchiectasis in samples including participants with a range of respiratory conditions, and it was not possible to isolate the bronchiectasis data in those trials (details provided in Characteristics of excluded studies). The overall completeness and applicability of data eligible for inclusion in this review are therefore limited to three very different studies, with only one considering the comparison of bromhexine versus placebo (Olivieri 1991; N = 88), one comparing RhDNase versus placebo over a period of two weeks (Wills 1996; N = 61) and another comparing RhDNase versus placebo over a period of 24 weeks (O'Donnell 1998; N = 349),

 

Quality of the evidence

In terms of random sequence generation, three trials (O'Donnell 1998; Olivieri 1991; Wills 1996) were evaluated as unclear, and one (Crisafulli 2007) was judged as low risk. All four were judged to have unclear risk with respect to allocation concealment. On performance bias, three trials (O'Donnell 1998; Olivieri 1991; Wills 1996) were assessed as low risk, and one (Crisafulli 2007) was assessed as high risk. In terms of blinding of personnel, all four trials were judged to be at low risk of bias (detection bias).

 

Potential biases in the review process

The support provided by the Cochrane Airways Review Group in identification of potentially relevant trials is of a very high order; nevertheless, uncertainties regarding study selection bias or publication bias are inevitably a concern in all reviews. Failure to identify unpublished trials may lead to an incomplete estimation of mucolytic agents. Whilst a comprehensive search of the published literature for potentially relevant clinical trials was conducted without language restrictions using a systematic search strategy to minimise the likelihood of bias, we recognise the possibility that additional unpublished trials may have been missed.

 

Agreements and disagreements with other studies or reviews

The availability of data in this update is similar to that in the previous version of this review (Crockett 2001), and we have added only one small trial (Crisafulli 2007) (N = 30) comparing erdosteine and physiotherapy versus physiotherapy alone; however it has been possible to include several additional analyses in the update.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 

Implications for practice

Little evidence is available to recommend the routine use of mucolytics in bronchiectasis. However, bromhexine treatment for longer than seven days at a high dose has been reported to produce some beneficial changes in sputum production and clearance during an acute exacerbation. This finding is based on one rather old trial (Olivieri 1991) that included only 88 participants. Lung function was not altered with this drug, and quality of life and other outcome measures were not examined. No trial evidence exists at all for its use for longer than about two weeks.

Erdosteine in combination with physiotherapy showed a small benefit in spirometric parameters and sputum purulence after 15 days compared with physiotherapy alone. This finding comes from one small trial in stable older participants with mucus hypersecretion, which did not use a placebo (Crisafulli 2007).

Evidence is insufficient to allow a firm recommendation for either agent.

Evidence has suggested possible harm and no evidence of benefit from RhDNase in non-CF bronchiectasis. This drug should not be used routinely in this condition.

 
Implications for research

Further randomised controlled trials of mucolytics in adults and children with non-CF bronchiectasis are clearly needed. These should examine short-term use of mucolytics with or instead of antibiotics to reduce exacerbation duration and long-term effects of mucolytics on exacerbation frequency and lung function.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

The authors of the original version of this review acknowledged the support of the Cochrane Airways Review Group staff (Steve Milan, Anna Bara and Jane Dennis) in identifying trials from the register and in obtaining copies of the papers, as well as editorial support from Dr Peter Gibson, Australian Co-ordinator of the Cochrane Airways Review Group. Anna Bara provided extra support in teaching us the correct way to use RevMan. They also thanked Professors Tom Petty and Dario Olivieri for responding to correspondence and supplying additional data to allow assessment of whether some studies should be included.

In the 2013 update, we would particularly like to acknowledge the contributions of Josephine M Cranston, John H Alpers, Karen M Latimer, authors of the original version of this review (Crockett 2001), and the excellent support and assistance received from Emma Welsh, Liz Stovold and Emma Jackson of the Cochrane Airways Review Group, together with greatly appreciated guidance from Chris Cates (Cochrane Airways Review Group Co-ordinating Editor). We would also like to thank Diogo Bugano, Federica Davolio, Zhirajr Mokini Poturljan and Uwe Wollina for help with translation of non–English language studies. We are grateful to Yoshinori Hasegawa for providing helpful clarification of non-availability of bronchiectasis participants' data from Itoh 1984. The support provided by librarians Judith Scammel, Jane Appleton and Hilary Garrett at St Georges University London is also very much appreciated.

Michael Greenstone was the Editor of this review and commented critically on the review.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
Download statistical data

 
Comparison 1. Bromhexine versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Adverse events1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 FEV1 (mL)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    2.1 At 7 days
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 At 13 days
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 2. 5 mg RhDNase versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Hospitalisations for infective exacerbations1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 % change FEV1 at day 151Mean Difference (IV, Fixed, 95% CI)Totals not selected

 3 % change FVC at day 151Mean Difference (IV, Fixed, 95% CI)Totals not selected

 4 Quality of Life1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    4.1 Cough and congestion
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.2 Dyspnoea
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.3 Basic activity limitations
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.4 Intermediate activity limitations
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.5 Emotional well-being
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.6 Fatigue
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.7 Not able to carry out usual activities
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.8 Days stayed in bed
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.9 Perception of overall health
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Sputum colour1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 6 Deaths1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 3. 2.5 mg RhDNase versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Hospitalisations for infective exacerbations1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 % change FEV1 at day 151Mean Difference (IV, Fixed, 95% CI)Totals not selected

 3 % change FVC at day 151Mean Difference (IV, Fixed, 95% CI)Totals not selected

 4 Quality of life1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    4.1 Cough and congestion
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.2 Dyspnoea
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.3 Basic activity limitations
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.4 Intermediate activity limitations
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.5 Emotional well-being
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.6 Fatigue
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.7 Not able to carry out usual activities
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.8 Days stayed in bed
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.9 Perception of overall health
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Sputum colour1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 6 Deaths2390Odds Ratio (M-H, Fixed, 95% CI)3.09 [0.32, 29.98]

 7 Antibodies to RhDNase1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 4. Erdosteine versus no treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mucus density1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    1.1 Day five
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Day 10
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Day 15
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Mucus purulence1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    2.1 Day five
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 Day 10
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.3 Day 15
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Mucus volume production1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    3.1 Day five
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 Day 10
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.3 Day 15
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Change in FEV1 (mL) at day 151Mean Difference (IV, Fixed, 95% CI)Totals not selected

 5 Change in FEV1 %Pred at day 151Mean Difference (IV, Fixed, 95% CI)Totals not selected

 6 Change in FVC (mL) at day 151Mean Difference (IV, Fixed, 95% CI)Totals not selected

 7 Change in FVC %Pred at day 151Mean Difference (IV, Fixed, 95% CI)Totals not selected

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

 

Electronic searches: core databases


DatabaseFrequency of search

CENTRAL (The Cochrane Library)Monthly

MEDLINE (Ovid)Weekly

EMBASE (Ovid)Weekly

PsycINFO (Ovid)Monthly

CINAHL (EBSCO)Monthly

AMED (EBSCO)Monthly



 

 

Handsearches: core respiratory conference abstracts


ConferenceYears searched

American Academy of Allergy, Asthma and Immunology (AAAAI)2001 onwards

American Thoracic Society (ATS)2001 onwards

Asia Pacific Society of Respirology (APSR)2004 onwards

British Thoracic Society Winter Meeting (BTS)2000 onwards

Chest Meeting2003 onwards

European Respiratory Society (ERS)1992, 1994, 2000 onwards

International Primary Care Respiratory Group Congress (IPCRG)2002 onwards

Thoracic Society of Australia and New Zealand (TSANZ)1999 onwards



 

 

MEDLINE search strategy used to identify trials for the CAGR

 

Bronchiectasis search

1. exp Bronchiectasis/

2. bronchiect$.mp.

3. bronchoect$.mp.

4. kartagener$.mp.

5. (ciliary adj3 dyskinesia).mp.

6. (bronchial$ adj3 dilat$).mp.

7. or/1-6

 

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1-7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases

 

Appendix 2. Search strategy for the Cochrane Airways Group Register

 

2013 update

#1 BRONCH:MISC1

#2 MeSH DESCRIPTOR Bronchiectasis Explode All

#3 bronchiect*

#4 #1 or #2 or #3

#5 MeSH DESCRIPTOR Expectorants

#6 mucolytic*

#7 "mucociliary clearance"

#8 N-acetylcysteine

#9 bromhexine

#10 S-carboxymethylcysteine

#11 ambroxol

#12 sobrerol

#13 "iodinated glycerol"

#14 "human DNase"

#15 RhDNase

#16 Bromhexine

#17 #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16

#18 #4 and #17

[Note; in search line #1, MISC1 denotes the field where the reference has bene coded for condition, in this case, bronchiectasis]

 

Previous versions

Mucolytic* or "mucociliary clearance" or N-acetylcysteine or bromhexine or S-carboxymethylcysteine or ambroxol or sobrerol or "iodinated glycerol" or "human DNase" or RhDNase or Bromhexine

[Limited to bronchiectasis records]

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Last assessed as up-to-date: 19 June 2013.


DateEventDescription

23 October 2014AmendedTypo in summary of findings table edited



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Protocol first published: Issue 1, 1997
Review first published: Issue 2, 2000


DateEventDescription

30 September 2013New citation required and conclusions have changedOne new study added to the previous version of this review (Crockett 2001). Methodology updated (including new full risk of bias assessment). GRADE and risk of bias assessments added to the review. Review redrafted

19 June 2013New search has been performedNew literature search run

19 January 2010New search has been performedLiterature search re-run; no new studies identified.

8 August 2008AmendedConverted to new review format.

10 October 2000New citation required and conclusions have changedSubstantive amendment



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

In the original version of this review (Crockett 2001), AC initiated the study. AC and KL reviewed the trials. JC and Anna Bara were responsible for data entry and analysis. All review authors were involved in the discussion and in interpretation of the results. AC, KL and JC wrote the paper. AC is guarantor for the study.

In the 2013 update, MW, IC, KS, AC and SJM updated the background. MW and IC independently selected studies for inclusion. SJM and MW independently extracted data and completed risk of bias assessments. SJM and AH updated the results section. The results, risk of bias and summary of findings sections were completed by SJM and AH. SJM provided summary of findings tables and figures. SJM updated the methods section. AH, MW, IC, KS, AC and SJM completed the Discussion and Conclusions.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Internal sources

  • NHS Research and Development, UK.
  • National Institute for Health Research, UK.

 

External sources

  • No sources of support supplied

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

In the 2013 update of this review, we defined primary and secondary outcomes. We brought the review up to date using current methodological standards consistent with Higgins 2011.

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Crisafulli 2007 {published data only}
  • Crisafulli E, Coletti O, Costi S, Zanasi E, Lorenzi C, Lucic S, et al. Effectiveness of erdosteine in elderly patients with bronchiectasis and hypersecretion: a 15-day, prospective, parallel, open-label, pilot study. Clinical Therapeutics 2007;29(9):2001-9.
O'Donnell 1998 {published data only}
Olivieri 1991 {published data only}
  • Olivieri D, Ciaccia A, Marangio E, Marsico S, Todisco T, Del Vita M. Role of bromhexine in exacerbations of bronchiectasis. Double-blind randomized multicenter study versus placebo. Respiration 1991;58(3-4):117-21. [: 4900100000003559]
Wills 1996 {published data only}
  • Wills PJ, Wodehouse T, Corkery K, Mallon K, Wilson R, Cole PJ. Short-term recombinant human DNase in bronchiectasis. Effect on clinical state and in vitro sputum transportability. American Journal of Respiratory and Critical Care Medicine 1996;154(2 Pt 1):413-7. [: 4900100000005313]

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Alberto 1968 {published data only}
  • Alberto S, Colongo PG, Brusasco L, Frigerio G. [Studies of the clinical and respiratory functional effects of a mucolytic-antibiotic preparation in chronic bronchopulmonary diseases. Controlled double-blind single code studies] [Studi sugli effetti clinici e sulla funzionalità respiratoria di un preparato mucolitico-antibiotico nelle affezioni croniche broncopolmonari. Ricerca controllata doppio-cieca a codifica singola]. Minerva Medica 1968;59(53):2995-3002.
Balzano 1973 {published data only}
  • Balzano E, De Gaetani G. [D1-sobrerol in the treatment of acute and chronic bronchopulmonary phlogoses]. [Italian] [Il dl sobrerolo nel trattamento delle flogosi broncopolmonari acute e croniche]. Minerva Medica 1973;64(37):1995-2002.
Bateman 1971 {published data only}
Benjamin 1971 {published data only}
  • Benjamin C. The use and efficacy of mucolytic agents. South African Medical Journal 1971; Vol. 45, issue 34:948-52.
Bergogne 1985 {published data only}
  • Bergogne Berezin E, Berthelot G, Kafe HP, Dournovo P. Influence of a fluidifying agent (bromhexine) on the penetration of antibiotics into respiratory secretions. International Journal of Clinical Pharmacology Research 1985;5(5):341-4.
Bradley 2011 {published data only}
  • Bradley JM, Treacy K, O'Neill B, McCourt F, Green L, Gardner E, et al. A randomised double blind 13 week crossover trial of hypertonic saline (HTS) (6%) vs isotonic saline (ITS) (0.9%) in patients with bronchiectasis [Abstract]. Thorax 2011;66(Suppl 4):A49 [S106].
Cobbin 1971 {published data only}
Currie 1988 {published data only}
Daviskas 1999 {published data only}
  • Daviskas E, Anderson SD, Eberl S, Chan HK, Bautovich G, Anderson S, et al. Inhalation of dry powder mannitol improves clearance of mucus in patients with bronchiectasis. American Journal of Respiratory and Critical Care Medicine 1999;159(6):1843-8. [: 4900100000008890]
Fadda 2001 {published data only}
  • Fadda G. Oral neltenexine in patients with obstructive airways diseases: an open, randomised, controlled comparison versus sobrerol. Minerva Medica 2001;92(4):269-75. [: 4900100000011117]
Germouty 1988 {published data only}
  • Germouty J, Jirou-Najou JL. Clinical trial of ambroxol in 2 different dosage programs in 120 patients with bronchiectasis. [Portuguese]. Revista Brasileira de Clinica E Terapeutica 1988;17(1-2):33-6.
Ghiringhelli 1981 {published data only}
  • Ghiringhelli G. Feprazone plus bromhexine in treatment of flare-ups of chronic bronchopathies. [Italian]. Archivio Di Medicina Interna 1981;33(2):157-68.
Hasani 1994 {published data only}
  • Hasani A, Pavia D, Spiteri MA, Yeo CT, Agnew JE, Clarke SW, et al. Regional mucus transport following unproductive cough and forced expiration technique in patients with airways obstruction. European Respiratory Journal 1994;105(5):1420-5.
Hasani 1994A {published data only}
Itoh 1984 {published data only}
  • Itoh K, Kounou O, Morise M, Iwakura M, Misutani N, Katayama T, et al. Clinical effects of proteinase, sfericase (AI-794), on chronic bronchitis and similar diseases. International Journal of Clinical Pharmacology, Therapy, and Toxicology 1984;22(1):32-8.
Kawashima 1989 {published data only}
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Kossmagk 1980 {published data only}
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Sahay 1982 {published data only}
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Serisier 2013 {published data only}
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Stafanger 1988 {published data only}
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Taskar 1992 {published data only}
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Yalçin 2006 {published data only}

Additional references

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Balsamo 2010
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Cotgreave 1987
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