CD001289 PDF

Cochrane Database of Systematic Reviews
Mucolytics for bronchiectasis (Review)

Wilkinson M, Sugumar K, Milan SJ, Hart A, Crockett A, Crossingham I
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.
www.cochranelibrary.com

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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Figure 2.
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Figure 3.
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ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Bromhexine versus placebo, Outcome 1 Adverse events.
. . . . . . . . . . .
Analysis 1.2. Comparison 1 Bromhexine versus placebo, Outcome 2 FEV1 (mL).
. . . . . . . . . . . .
Analysis 2.1. Comparison 2 5 mg RhDNase versus placebo, Outcome 1 Hospitalisations for infective exacerbations. .
Analysis 2.2. Comparison 2 5 mg RhDNase versus placebo, Outcome 2 % change FEV1 at day 15. . . . . . .
Analysis 2.3. Comparison 2 5 mg RhDNase versus placebo, Outcome 3 % change FVC at day 15. . . . . . . .
Analysis 2.4. Comparison 2 5 mg RhDNase versus placebo, Outcome 4 Quality of Life. . . . . . . . . . .
Analysis 2.5. Comparison 2 5 mg RhDNase versus placebo, Outcome 5 Sputum colour. . . . . . . . . . .
Analysis 2.6. Comparison 2 5 mg RhDNase versus placebo, Outcome 6 Deaths. . . . . . . . . . . . . .
Analysis 3.1. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 1 Hospitalisations for infective exacerbations.
Analysis 3.2. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 2 % change FEV1 at day 15. . . . . . .
Analysis 3.3. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 3 % change FVC at day 15. . . . . . .
Analysis 3.4. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 4 Quality of life. . . . . . . . . . .
Analysis 3.5. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 5 Sputum colour. . . . . . . . . . .
Analysis 3.6. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 6 Deaths. . . . . . . . . . . . .
Analysis 3.7. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 7 Antibodies to RhDNase. . . . . . .
Analysis 4.1. Comparison 4 Erdosteine versus no treatment, Outcome 1 Mucus density. . . . . . . . . . .
Analysis 4.2. Comparison 4 Erdosteine versus no treatment, Outcome 2 Mucus purulence. . . . . . . . . .
Analysis 4.3. Comparison 4 Erdosteine versus no treatment, Outcome 3 Mucus volume production. . . . . . .
Analysis 4.4. Comparison 4 Erdosteine versus no treatment, Outcome 4 Change in FEV1 (mL) at day 15. . . . .
Analysis 4.5. Comparison 4 Erdosteine versus no treatment, Outcome 5 Change in FEV1 %Pred at day 15. . . .
Analysis 4.6. Comparison 4 Erdosteine versus no treatment, Outcome 6 Change in FVC (mL) at day 15. . . . .
Analysis 4.7. Comparison 4 Erdosteine versus no treatment, Outcome 7 Change in FVC %Pred at day 15. . . . .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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[Intervention Review]
Mucolytics for bronchiectasis

Mark Wilkinson1 , Karnam Sugumar2 , Stephen J Milan3 , Anna Hart4 , Alan Crockett5 , Iain Crossingham6
1 University Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster, UK. 2 Department of Paediatrics, Royal Preston Hospital,
Lancashire Teaching Hospitals NHS Trust, Preston, UK. 3 Lancaster Health Hub, Lancaster University, Lancaster, UK. 4 Lancaster
Medical School, Clinical Research Hub, Lancaster University, Lancaster, UK. 5 School of Health Sciences, University of South Australia,
Adelaide, Australia. 6 Royal Blackburn Hospital, Blackburn, UK
Contact address: Stephen J Milan, Lancaster Health Hub, Lancaster University, Lancaster, UK. s.milan@lancaster.ac.uk.
Editorial group: Cochrane Airways Group.
Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 5, 2014.
Review content assessed as up-to-date: 19 June 2013.
Citation: 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.
ABSTRACT
Background
Bronchiectasis is predominantly an acquired disease process that represents the end stage of a variety of unrelated pulmonary insults.
It is defined as persistent irreversible dilatation and distortion of medium-sized bronchi. It has been suggested that with widespread
use of high-resolution computed tomography, more bronchiectasis diagnoses are being made. Patients diagnosed with bronchiectasis
frequently have difficulty expectorating sputum. Sputum therefore is retained in the lungs and may become infected, leading to further
lung damage. Mucolytic agents target hypersecretion or changed physiochemical properties of sputum to make it easier to clear. One
drug, recombinant human DNase, breaks down the DNA that is released at the site of infection by neutrophils.
Mucus clearance along with antimicrobial therapy remains an integral part of bronchiectasis management. Chest physiotherapy along
with mucolytic agents is commonly used in practice without clear supportive evidence.
Objectives
To determine whether ingested or inhaled mucolytics are effective in the treatment of patients with bronchiectasis.
Search methods
We searched the Cochrane Airways Group Specialised Register and reference lists of relevant articles. We contacted experts in the field
and drug companies. Searches were current as of June 2013.
Selection criteria
Randomised trials of mucolytic treatment in people with bronchiectasis but not cystic fibrosis.
Data collection and analysis
Data extraction was performed independently by two review authors. Study authors were contacted for confirmation.
Main results
Four trials (with a combined total of 528 adult participants) were included, but almost none of the data from these studies could be
aggregated in a meta-analysis.
One trial (with 88 participants) compared bromhexine versus placebo. Compared with placebo, high doses of bromhexine with
antibiotics eased difficulty in expectoration (mean difference (MD) -0.53, 95% confidence interval (CI) -0.81 to -0.25 at 16 days); the
quality of the evidence was rated as low. A reduction in sputum production was noted with bromhexine (MD -21.5%, 95% CI -38.9
to -4.1 at day 16); again the quality of the evidence was rated as low. No significant differences between bromhexine and placebo were
observed with respect to reported adverse events (odds ratio (OR) 2.93; 95% CI 0.12 to 73.97), and again the quality of the evidence
was rated as low.
In a single small, blinded but not placebo-controlled trial of older (> 55 years) participants with stable bronchiectasis and mucus
hypersecretion, erdosteine combined with physiotherapy over a 15-day period improved spirometry and sputum purulence more
effectively compared with physiotherapy alone. The spirometric improvement was small (MD 200 mL in forced expiratory volume in
one second (FEV1 ) and 300 mL in forced vital capacity (FVC)) and was apparent only at day 15, not at earlier time points.
The remaining two studies (with a combined total of 410 participants) compared recombinant human DNase (RhDNase) versus
placebo. These two studies were very different (one was a two-week study of 61 participants, and the other ran for 24 weeks and
included 349 participants), and the opportunity for combining data from the two studies was very limited. Compared with placebo,
recombinant human DNase showed no difference in FEV1 or FVC in the smaller study but showed a significant negative effect on
FEV1 in the larger and longer study. For reported adverse events, no significant differences between recombinant human DNase and
placebo were noted. In all of the above comparisons of recombinant human DNase versus placebo, the quality of the evidence was
judged to be low.
Authors conclusions
Given the harmful effects of recombinant human DNase in one trial and no evidence of benefit, this drug should be avoided in noncystic fibrosis bronchiectasis, except in the context of clinical trials. Evidence is insufficient to permit evaluation of the routine use
of other mucolytics for bronchiectasis. High doses of bromhexine coupled with antibiotics may help with sputum production and
clearance, but long-term data and robust clinical outcomes are lacking. Similarly, erdosteine may be a useful adjunct to physiotherapy
in stable patients with mucus hypersecretion, but robust longer-term trials are required.
Generally, clinical trials in children on the use of various mucolytic agents are lacking. As the number of agents available on the market,
such as RhDNase, acetylcysteine and bromhexine, is increasing, improvement of the evidence base is needed.
PLAIN LANGUAGE SUMMARY

Mucolytic drugs (to help make phlegm easier to cough up) for people with bronchiectasis
Review question: This review considered the question of whether mucolytics may be helpful for people with bronchiectasis who do
not also have cystic fibrosis. Studies of participants with cystic fibrosis were not included in this review, and we are unable to draw any
conclusions on this treatments relevance to people with cystic fibrosis.
Background: Bronchiectasis is a lung condition that usually develops after a series of lung problems (such as childhood infections,
problems in lung structure, tuberculosis and cystic fibrosis). A lot of mucus (phlegm) collects in the lungs, causing discomfort and the
need to cough it up. The phlegm also collects bacteria, which can add to breathing difficulties. Mucolytic drugs break down phlegm,
which can make it easier to cough up.
Study characteristics: Four studies (with a total of 528 participants) were identified that met the inclusion criterion of comparing
mucolytic treatment versus no mucolytic treatment. All studies were conducted in adults. One study considered bromhexine versus
placebo, two compared RhDNase versus placebo (one for a period of two weeks and the other over a period of 24 weeks) and the
fourth compared erdosteine with physiotherapy versus physiotherapy alone in elderly patients. The small number of studies available
for review and their different designs meant that only descriptions of the individual studies were possible with very limited opportunities
for combining the studies in single analyses.
Key results: No strong evidence is available to support the use of these drugs in people with bronchiectasis (from causes other than
cystic fibrosis); however it is not possible to draw any clear conclusions, as so few studies have been reported.
Quality of the evidence: Details of the way patients were allocated to receive or not receive mucolytics were not clearly described in
any of the four studies. This was considered carefully in the review in relation to our level of uncertainty in interpreting the results.
When this is taken into account, together with the imprecision of the results, estimates of the usefulness of mucolytics as treatment
were generally judged to be of low quality in relation to (non-cystic fibrosis) bronchiectasis.


S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Bromhexine compared with placebo for bronchiectasis

Patient or population: patients with bronchiectasis
Settings: community
Intervention: bromhexine
Comparison: placebo
Outcomes
Illustrative comparative risks* (95% CI)
Assumed risk
Corresponding risk
Placebo
Bromhexine
Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence

(GRADE)
Comments
Frequency and duration See comment

of exacerbations
See comment
See comment
See comment
N/A
Outcome not reported
Hospitalisations
See comment
See comment
See comment
See comment
N/A
Adverse events
0 per 100 3
2.2 per 100

(0.05 to 11.7)
OR 2.93
(0.12 to 73.97)
88
(1 study)

low1,2
See comment
See comment
See comment
See comment
Symptoms difficulty in Absolute values not re- Absolute values not re- MD -0.53
expectoration
ported
ported
(-0.81 to -0.25)
Follow-up: 16 days
88
(1 study)

low1,2
Deaths
See comment
See comment
See comment
Lung function
FEV1
Follow-up: 13 days
Mean FEV1 in the control Mean FEV1 in the inter- MD 184.00

group was 1614 mL
vention groups was 184 (-149.75 to 517.75)
mL higher
(149.75 lower to 517.75
higher)
88
(1 study)

low1,2
Health-related quality of See comment

life
See comment
See comment

*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.
1 One
point deducted to reflect risk of bias assessment of randomisation (judged as unclear risk of bias).
point deducted to reflect imprecision in the estimate, with data coming from only one trial, leading to low event rate and wide
confidence intervals.
3 Assumed risk is based on the control group (N = 43) of the one trial reporting adverse events.
2 One
BACKGROUND
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 mediumsized 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, Kartageners
syndrome, Youngs 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).
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 (ODonnell 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.
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
OBJECTIVES
To determine whether ingested or inhaled mucolytics are effective
in the treatment of patients with bronchiectasis.
METHODS
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.
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

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
Georges Respiratory Questionnaire (SGRQ)).
Selection of studies
Search methods for identification 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.
Electronic searches
Data extraction and management
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
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 DerSimonian 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.
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 randomeffects versus fixed-effect modelling if issues of significant heterogeneity arose. However this was not necessary.
Assessment of reporting biases
RESULTS
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.
Description of studies
Data synthesis
Summary of findings table

We created a Summary of findings table using the following outcomes.
Primary
Frequency and duration of exacerbations.
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). Thirtytwo reports were excluded (details provided in Characteristics of
excluded studies).
See Figure 1 for a study flow diagram.

Figure 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 (ODonnell 1998), with 349 participants (of whom 346 completed the study), also included partici-
pants 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.
Figure 2. Risk of bias graph: review authors judgements about each risk of bias item presented as
percentages across all included studies.

10
Blinding
The risk of performance and detection bias in three included studies (ODonnell 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.

11
Figure 3. Risk of bias summary: review authors judgements about each risk of bias item for each included
study.

12
Incomplete outcome data

Only two of the four included studies were assessed as having low
risk of bias in terms of attrition bias (ODonnell 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.

13
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 (ODonnell 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.

14

A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
5 mg RhDNase compared with placebo for bronchiectasis

Settings: community
Intervention: 5 mg RhDNase*
Comparison: placebo
Outcomes
Assumed risk
Corresponding risk
Placebo
5 mg RhDNase
Relative effect
(95% CI)
No. of participants
(studies)

(GRADE)
Comments
Hospitalisations for infective exacerbations reported, see below

of exacerbations
See comment
See comment
See comment
See comment
Hospitalisations for in- 0 per 100 3

fective exacerbations
Follow-up: 15 days
10 per 100
(1.2 to 31.7)
OR 5.54
(0.25 to 123.08)
40
(1 study)

low1,2
Adverse events
See comment
See comment
See comment
See comment
See comment
The authors of the trial report there were no significant differences between
RhDNase (5 mg) versus
placebo on most of the 19
reported adverse events
with the only exception
being the incidence of influenza syndrome as diagnosed by the participants, with more occurrences in the RhDNase
arm
15


life
Symptoms
sputum Mean sputum
colour
score was 3.2
Scale used not reported
See comment
See comment
colour Mean sputum colour in MD 0.28 (-0.04 to 0.60)

the intervention groups
was
0.28 higher
(0.04 lower to 0.6 higher)
Deaths
Follow-up: 15 days
See comment
See comment
See comment
Lung function
% change FEV1
Follow-up: 15 days
Mean change on placebo Mean % change FEV1 at MD 2.10 (-2.90 to 7.10)

was -0.5%
day 15 in the intervention
groups was
2.1% higher
(2.95 lower to 7.15
higher)
See comment
See comment
40
(1 study)

low1,2
We cannot interpret this

finding since the difference is not statistically
significant and we do not
know what scale sputum
colour was measured on
See comment
See comment
40
(1 study)

low1,2
CI: Confidence interval; OR: Odds ratio.
The
review also reports data for 2.5 mg RhDNase; no hospital admissions and no differences in FEV1 , quality of life, sputum colour or
deaths were reported.
1 One point deducted to reflect risk of bias assessment of randomisation (judged as unclear risk of bias).
2
One point deducted to reflect imprecision in the estimate, with data coming from only one trial, leading to wide confidence intervals.
3 Assumed risk is based on the control group (N = 20) of the one trial reporting adverse events.
16

Erdosteine versus no treatment for bronchiectasis

Settings: community
Intervention: erdosteine versus no treatment
Outcomes
Assumed risk
Corresponding risk
No treatment
Erdosteine
Relative effect
(95% CI)
No. of participants
(studies)

(GRADE)
Comments

of exacerbations
See comment
See comment
See comment
See comment
Hospitalisations for in- See comment

fective exacerbations
See comment
See comment
See comment
See comment
Adverse events
See comment
See comment
See comment
See comment
See comment

life
See comment
See comment
See comment
See comment
Symptoms
Mean mucus production Mean mucus volume pro- MD 0.40
mucus volume produc- 0.93 mL
duction day 15 in the in- (-0.03 to 0.83)
tion
tervention groups was
Follow-up: 15 days
0.4 mL higher
(0.03 lower to 0.83
higher)
30
(1 study)

low1,2
Deaths
See comment
See comment
30
(1 study)

low1,2
See comment
See comment
See comment
Lung function change in Mean change on placebo Mean change in FEV1 at MD 200 mL (40 to 360)
FEV1 (L) at day 15
was 0 mL
day 15 in the intervention
groups was
200 mL higher
17

(40 to 360 mL higher)

CI: Confidence interval.
1
One point deducted to reflect risk of bias assessment (unblinded study).

point deducted to reflect imprecision (data contributed by one small study).
2 One
18
DISCUSSION
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 (ODonnell 1998; Wills 1996) compared nebulised
RhDNase versus placebo in participants with chronic bronchiectasis. Wills 1996 was a two-week study, whereas ODonnell 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 (ODonnell 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 (ODonnell 1998; N =
349),

In terms of random sequence generation, three trials (ODonnell
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 (ODonnell 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.

19
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.
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
AUTHORS CONCLUSIONS
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
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 nonavailability 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.
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References to studies included in this review
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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,
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Olivieri 1991 {published data only}

Olivieri D, Ciaccia A, Marangio E, Marsico S, Todisco
T, Del Vita M. Role of bromhexine in exacerbations of
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ODonnell 1998 {published data only}

ODonnell AE, Barker AF, Ilowite JS, Fick RB. Treatment
of idiopathic bronchiectasis with aerosolized recombinant
Wills 1996 {published data only}

Wills PJ, Wodehouse T, Corkery K, Mallon K, Wilson
R, Cole PJ. Short-term recombinant human DNase

20
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sputum transportability. American Journal of Respiratory
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Germouty J, Jirou-Najou JL. Clinical trial of ambroxol
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Ghiringhelli 1981 {published data only}
Ghiringhelli G. Feprazone plus bromhexine in treatment of
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Balzano E, De Gaetani G. [D1-sobrerol in the treatment
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SW, et al. Regional mucus transport following unproductive
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Bateman 1971 {published data only}

Bateman PP. A new mucolytic, bromhexine (bisolvon). A
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Benjamin 1971 {published data only}

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Bergogne Berezin E, Berthelot G, Kafe HP, Dournovo
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Bradley 2011 {published data only}
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L, Gardner E, et al. A randomised double blind 13
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[Abstract]. Thorax 2011;66(Suppl 4):A49 [S106].
Cobbin 1971 {published data only}
Cobbin DM, Elliott FM, Rebuck AS. The mucolytic agent
bromhexine (Bisolvon) in chronic lung disease: a doubleblind crossover trial. Australian and New Zealand Journal of
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Currie 1988 {published data only}
Currie DC, Greenstone M, Pavia D, Agnew JE, Pellow P,
Clarke SW, et al. Efficacy of mucoregulatory agents in
Youngs syndrome. Thorax 1988;43(6):4801.
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
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Itoh 1984 {published data only}

Itoh K, Kounou O, Morise M, Iwakura M, Misutani N,
Katayama T, et al. Clinical effects of proteinase, sfericase
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Kawashima 1989 {published data only}
Kawashima K, Yamamoto H, Kadoya M, Kato M, Nata
T, Iida E, et al. Clinical role of Branhamella catarrhalis
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Kellett 2005 {published data only}
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of nebulised hypertonic saline (7%) as an adjunct to
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Respiratory Medicine 2005;99(1):2731.
Kossmagk 1980 {published data only}
Kossmagk R. Ultrasonic aerosol apparatus hire system
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bronchiectasia. [German]. Zeitschrift Fur Erkrankungen der
Atmungsorgane 1980;155(1):1257.
Loukides 1998 {published data only}
Loukides S, Kharitonov S, Wodehouse T, Cole PJ,
Barnes PJ. Effect of arginine on mucociliary function in
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Mareels J. A long term tolerance trial of bromhexine. Acta
Therapeutica 1983;9(3):30515.

21
Marthin 2007 {published data only}

Marthin JK, Mortensen J, Pressler T, Nielsen KG.
Pulmonary radioaerosol mucociliary clearance in diagnosis
of primary ciliary dyskinesia. Chest 2007;132(3):96676.
[4900100000021265]
Noone 1999 {published data only}
Noone PG, Bennett WD, Regnis JA, Zeman KL, Carson
JL, King M, et al. Effect of aerosolized uridine-5triphosphate on airway clearance with cough in patients
with primary ciliary dyskinesia. American Journal of
Respiratory and Critical Care Medicine 1999;160(1):1449.
[4900100000006450]
Patterson 2007 {published data only}
Patterson JE, Hewitt O, Kent L, Bradbury I, Elborn
JS, Bradley JM. Acapella versus usual airway clearance
during acute exacerbation in bronchiectasis: a randomized
crossover trial. Chronic Respiratory Disease 2007;4(2):6774.
Sahay 1982 {published data only}
Sahay JN, Chatterjee SS, Ingram DF. The effect of methyl
cysteine (Visclair) in respiratory diseases. A pilot study.
Clinical Trials Journal 1982;19(3):13743.
Serisier 2013 {published data only}
Serisier DJ, Martin ML, McGuckin MA, Lourie R,
Chen AC, Brain B, et al. Effect of long-term, lowdose erythromycin on pulmonary exacerbations among
patients with non-cystic fibrosis bronchiectasis: the BLESS
randomized controlled trial. JAMA 2013; Vol. 309, issue
12:12607.
Stafanger 1988 {published data only}
Stafanger G, Garne S, Howitz P, Morkassel E, Koch C. The
clinical effect and the effect on the ciliary motility of oral
N-acetylcysteine in patients with cystic fibrosis and primary
ciliary dyskinesia. The European Respiratory Journal 1988;1
(2):1617. [4900100000002512]
Tambascio 2011 {published data only}
Tambascio J, de Souza LT, Lisboa RM, Passarelli RDCV,
de Souza HCD, Gastaldi AC. The influence of Flutter
VRP1 components of mucus transport of patients with
bronchiectasis. Respiratory Medicine 2011;105(9):131621.
Taskar 1992 {published data only}
Taskar VS, Sharma RR, Goswami R, John PJ, Mahashur
AA. Effect of bromhexine on sputum amoxycillin levels in
lower respiratory infections. Respiratory Medicine 1992;86
(2):15760. [4900100000003765]
Tsang 2003 {published data only}
Tsang SMH, Jones AYM, Tsang SM H, Jones AYM. Postural
drainage or flutter device in conjunction with breathing and
coughing compared to breathing and coughing alone in
improving secretion removal and lung function in patients
with acute exacerbation of bronchiectasis. A pilot study.
Hong Kong Physiotherapy Journal 2003;21:2936.
Verstraeten 1979 {published data only}
Verstraeten JM. Mucolytic treatment in chronic obstructive
lung disease: double-blind comparative clinical trial with Nacetylcysteine, bromhexine and placebo. Acta Tuberculosea
et Pneumologica Belgica 1979;70(1):7180.
Wong 2012 {published data only}

Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey
H, et al. Azithromycin for prevention of exacerbations in
non-cystic. Lancet 2012;380(9842):6607.
Yalin 2006 {published data only}
Yalin E, Kiper N, Ozelik U, Do ru D, Firat P, Sahin A,
et al. Effects of clarithromycin on inflammatory parameters
and clinical conditions in children with bronchiectasis.
Journal of Clinical Pharmacy and Therapeutics 2006;31(1):
4955.
Additional references
Balsamo 2010
Balsamo R, Lanata L, Egan CG. Mucoactive drugs.
European Respiratory Review 2010;19(116):127-33.
BTS 2010
Pasteur MC, Bilton D, Hill AT. BTS guideline for non-CF
bronchiectasis. www.brit-thoracic.org.uk/LinkClick.aspx?
link=496&tabid=69 (accessed 15 November 2013).
Cotgreave 1987
Cotgreave I, Eklund A, Larsson K, Moldus P. No
penetration of orally administered N-acetylcysteine into
bronchoalveolar lavage fluid. European Journal of Respiratory
Diseases 1987;70(2):737.
Goeminne 2010
Goeminne P, Dupont L. Non-cystic fibrosis bronchiectasis:
diagnosis and management in 21st century. Postgraduate
Medical Journal 2010;86:493501.
Henke 2007
Henke MO, Ratjen F. Mucolytics in cystic fibrosis.
Paediatric Respiratory Reviews 2007;8(1):24-9.
Higgins 2011
Higgins JPT, Green S (editors). Cochrane Handbook for
Systematic Reviews of Interventions Version 5.1 [updated
March 2011]. The Cochrane Collaboration, 2011.
www.cochrane-handbook.org.
Review Manager (RevMan) [Computer program]
Copenhagen: The Nordic Cochrane Centre, The
Cochrane Collaboration. Review Manager (RevMan). 5.2.
Copenhagen: The Nordic Cochrane Centre, The Cochrane
Collaboration, 2012.
Rogers 2007
Rogers DF. Mucoactive agents for airway mucus
hypersecretory diseases. Respiratory Care 2007;52(9):117697.
Stafler 2010
Stafler P, Carr S. Non cystic fibrosis bronchiectasis:
its diagnosis and management. Archives of Diseases in
Childhood. Education and Practice Edition 2010;95:7382.
Stockley 1995
Stockley RA. Role of inflammation in respiratory tract
infections. American Journal of Medicine 1995;99(6):8S13S.

22
Tomkiewicz 1995
Tomkiewicz RP, App EM, De Sanctis GT, Coffiner M,
Maes P, Rubin BK, et al. A comparison of a new mucolytic
N-acetylcysteine l-lysinate with N-acetylcysteine: airway
epithelial function and mucus changes in dog. Pulmonary
Pharmacology 1995;8(6):259-65.
Zafarullah 2003
Zafarullah M, Li WQ, Sylvester J, Ahmad M. Molecular
mechanisms of N-acetylcysteine actions. Cellular and
Molecular Life Sciences 2003;60(1):620.
References to other published versions of this review
TSANZ 2010
TSANZ and the Lung Foundation. Chronic suppurative
lung disease and bronchiectasis in children and adults 2010.
http://www.lungfoundation.com.au/professional-resources/
guidelines/ (accessed 15 November 2013).
Crockett 2001
Crockett A, Cranston JM, Alpers JH, Latimer KM.
Mucolytics for bronchiectasis. Cochrane Database of
Systematic Reviews 2001, Issue 1. [DOI: 10.1002/
14651858.CD001289]
Indicates the major publication for the study

23
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Crisafulli 2007
Methods
Prospective, randomised, parallel, open-label, pilot study
Participants
Participants over 55 years of age with focal or diffuse bronchiectasis (with or without
chronic airflow limitation), with no current smoking status
Thirty participants (15 in erdosteine group and 15 in control group)
Males: erdosteine group 11 (73 %), control group 10 (67 %)
Mean age: erdosteine group 70 (SD 13.6), control group 71 (SD 9.3)
FEV1 %predicted, erdosteine group 50.8 (SD 20.7), control group 43.9 (SD 12.5)
Diagnosis of bronchiectasis based on a confirmed computerised tomography scan and
previously recorded diagnostic criteria findings. Participants consecutively enrolled and
randomly assigned into two groups
Included participants in stable condition, having daily sputum production > 30 mL but
with no evidence of ongoing exacerbation, as confirmed by medical history report and
physical examination
Patients excluded if they used antibiotics, mucolytics, systemic steroids or antitussive
drugs, or if they reported a change in long-term medications in the four weeks before
commencement of the study. Patients with a medical history of hypersensitivity to erdosteine, diabetes, liver failure or cancer were also excluded from the study
Participants were enrolled in the hospitals rehabilitation programme based on joint
criteria of the American Thoracic Society and the European Respiratory Society
Interventions
PO erdosteine 225 mg twice daily and routine chest physiotherapy versus routine chest
physiotherapy alone
Outcomes
Primary end point of the study was to establish the effectiveness (in terms of subjective semi-quantitative score of sputum characteristics) of erdosteine used adjunctive to
routine chest physiotherapy in the study population. Secondary end point was to assess physiological changes associated with the treatment regimen. Measurements were
assessed in all enrolled participants at 5-day time points: 0 (baseline), 5, 10, and 15 days
after randomisation
Notes
15-Day trial
All study drugs provided by Laboratori Baldacci SpA, Pisa, Italy
Risk of bias
Bias
Authors judgement
Support for judgement
Random sequence generation (selection Low risk

bias)
Randomisation sequence achieved by selecting from an eight-block number table
Allocation concealment (selection bias)
Not specified in trial report
Unclear risk

24
Crisafulli 2007
(Continued)
Blinding of participants and personnel High risk

(performance bias)
All outcomes
Open-label study
Blinding of outcome assessment (detection Low risk

bias)
All outcomes
All measurements assessed by personnel

blinded and not directly associated with
study administration
Incomplete outcome data (attrition bias)

All outcomes
Unclear risk
No withdrawals reported
Selective reporting (reporting bias)
Unclear risk
No apparent indication of selective reporting
Other bias
Unclear risk
No other indication of bias
ODonnell 1998
Methods
Double-blind, randomised, placebo-controlled, multi-centre study
Participants
Adult outpatients in stable condition with idiopathic bronchiectasis from 23 centres in

North America, Great Britain and Ireland
RhDNase group of 173 participants randomly assigned (172 completed), control group
176 participants randomly assigned (174 completed)
Mean age: RhDNase group 60 years, control group 60 years (standard deviations not
provided in trial report)
Men: RhDNase group 60 (35%), control group 72 (41%)
Baseline lung function: mean FEV1 L RhDNase group 1.34, control group 1.43 (standard deviations not provided in trial report)
Baseline lung function: mean % predicted FEV1 RhDNase group 50.76%, control group
52.05% (standard deviations not provided in trial report)
Inclusion criteria:
Radiographic (one of the following four criteria):
Standard chest radiograph compatible with bronchiectasis
Chest CT showing ectasia of peripheral bronchi, fluid-filled airways or
thickening of the mucosa
Contrast bronchography compatible with bronchiectasis
Bacterial pneumonia localised to same lobe or segment
Daily purulent sputum production > 15 mL for most days in the three months
before enrolment
Sweat chloride level < 60 mEq/L
Reproducible spirometry demonstrating FEV1 > 30% and < 80% predicted for
age, sex and height
Exclusion criteria:
Any deterioration in pulmonary status that caused a change in antibiotic,
corticosteroid or bronchodilator regimen or any hospitalisation within 14 days before
randomisation
History of major hemoptysis requiring interventional therapy or transfusion

25
ODonnell 1998
(Continued)
within 180 days of randomisation. Active allergic bronchopulmonary aspergillosis,

active mycobacterium tuberculosis or atypical mycobacterial infection
Cystic fibrosis, tracheostomy and non-dermal malignancy within past two years.
Pregnant and lactating women not enrolled. Participants having used any
investigational drug within 28 days of randomisation
Interventions
Run-in: three times clinical evaluation before drug administration

Aerosolised 1.0 mg/mL RhDNase in 2.5 mL of excipient (150 mM NaC1, 1.5 mM
calcium chloride pH 6.0) (2.5 mg of aerosolised RhDNase twice daily) versus excipient
alone (twice daily) for 24 weeks
All participants continued to receive usual care
Active drug or placebo solution delivered by Marquest Acorn II Nebuliser (Marquest,
Inglewood, CO) powered by compressor (De Vilbiss Pulmo Aide; DeVilbiss, Somerset,
PA)
Outcomes
Primary outcomes: incidence of pulmonary exacerbations and mean percentage change

in FEV1 from baseline
Secondary outcomes: % change in FVC, health-related quality of life, adverse events
Total of 5 visits over the study period. FEV1 ; quality of life and dyspnoea recorded at each
visit; treatment FEV1 recorded as mean of all FEV1 on treatment. Total of exacerbations
recorded over the duration of the study
Notes
24-Week trial
RhDNase provided by Genentech, San Francisco
Risk of bias
Bias
Authors judgement
Random sequence generation (selection Unclear risk

bias)
Not reported
Not reported
Unclear risk
Blinding of participants and personnel Low risk

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind and CT scans analysed by radiologists outside the study

All outcomes
Two placebo-treated participants (one with

self limited haemoptysis and one with sinus
symptoms) and one RhDNase-treated participant with increased sputum production
withdrew from the study
Low risk

26
ODonnell 1998
(Continued)
Unclear risk
Other bias
Unclear risk
Olivieri 1991
Methods
Double-blind, randomised, multi-centre study (four-centre study)
Participants
Data collected from four Italian university departments of lung disease

Adult participants with acute bronchiectasis with morning cough and > 20 mL of sputum.
Bronchiectasis confirmed by bronchography and/or CT scan
Bromhexine group, 45; placebo group, 43 (data on FEV1 outcomes and percentage
change in mean sputum volume not available from 21 participants)
Mean age: bromhexine group 49.5 (2.6), range 20 to 71, Placebo group 54.3 (2.3), range
20 to 70
Men: bromhexine group 29 (64%), placebo group 28 (65%)
Baseline lung function: mean FEV1 L (SD), bromhexine group 1.67 (0.11), placebo
group 1.65 (0.14)
Inclusion criteria:
Adults, during an exacerbation of bronchiectasis with morning cough,
expectorating > 20 mL purulent sputum
Exclusion criteria:
Severe liver, kidney or heart disease. Pregnant or nursing women. Surgical patients
Interventions
Randomisation after three-day washout period (no mucolytics, beta2 -agonists, corticoids
and/or antibiotics)
Bromhexine 30 mg three times daily
Placebo three times daily
(first week on ceftazidine 1 g intramuscular injection antibiotic)
Outcomes
Clinical evaluation of cough, auscultatory findings and difficulty of expectoration using

an arbitrary four-point scale with semi-quantitative scores. FEV1 . Rating scale of drug
tolerability . Clinical parameters recorded at days 4, 7, 10, 13 and 16. FEV1 at days 7
and 13
Notes
15-Day trial
A co-author on the trial (M Del Vita) based in the Medical Department at Boehringer
Ingelheim Italia
Risk of bias
Bias
Authors judgement

bias)


Not reported
27
Unclear risk
Not reported

(performance bias)
All outcomes
Double-blind with matching placebo

bias)
All outcomes
Double-blind with matching placebo

All outcomes
High risk
Only 67 participants contributed data to

the FEV1 and % change in mean sputum volume after 10 days of treatment outcomes. Trial report does not clarify why
data on these outcomes are available for
only 76% of participants
Unclear risk
No apparent indication of selective reporting bias
Other bias
Unclear risk
Wills 1996
Methods
Double-blind, randomised, placebo-controlled trial
Participants
Single-centre study (Royal Brompton Hospital, London, UK)

Adult participants with moderate or severe bronchiectasis of more than one lobe, confirmed by bronchography or CT scan
61 participants between 33 and 72 years of age
Men: 28 (46%)
Randomly assigned to three groups (details of ages and number of men in each group
not reported):
Group 1 bd dosing 20, Group 2 od dosing 21, Group 3 placebo 20
Baseline lung function: mean % predicted FEV1 (SE): Group 1 bd dosing 56.1 (4.9),
Group 2 od dosing 61.2 (4.9), Group 3 placebo 63.9 (5.4)
Inclusion criteria:
Participants with stable moderate or severe bronchiectasis of more than one lobe
confirmed by bronchography or CT scanning, who did not have cystic fibrosis, active
tuberculosis or lung cancer
Participants had to be able to perform pulmonary function tests reproducibly and
had to have FVC greater than 40% of predicted, with FEV1 /FVC less than 75%
Pulse oximetry required to show oxygen saturation greater than 90%
Disease state stable at enrolment with no hospitalisation or change in antibiotic,
steroid or bronchodilator therapy in previous 14 days
Participants had to be producing > 5 mL of sputum daily
None receiving other investigational drugs or regular opiates
Women with reproductive potential had to be using adequate contraceptive
measures
Exclusion criteria:

28
Wills 1996
(Continued)
People with asthma or > 10% sputum eosinophilia, CF, lung cancer or
mycobacterial disease excluded
Interventions
Visited site three times in five days to ensure that entry criteria were met
First dose administered in hospital and a 14-day treatment period followed at home
At end of the trial period, each participant re-attended 28 days later (28 days after day
14)
No treatment changes in 14 days before randomisation
RhDNase 2.5 mg in 2.5 mL twice daily versus RhDNase once daily and excipient placebo
once daily versus excipient placebo twice daily
Acorn II nebuliser (Marquest Medical) driven by Pulmo-Aide compressor (DeVilbiss)
Outcomes
Primary outcome: effect on FEV1

Secondary outcomes: effect on FVC, quality of life (functional status questionnaire);
safety evaluation; sputum transportability; VAS of breathlessness; sputum assessment
and exacerbations (exacerbations data not reported)
Data collected at days 15 and 28
Notes
14-Day trial
Two study authors recipients of grants from Genentech
Risk of bias
Bias
Authors judgement

bias)
Not reported
Not reported
Unclear risk

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind

All outcomes
Low risk
All participants completed all scheduled

visits
Unclear risk
Other bias
Unclear risk
No other clear indication of bias

Treatment interrupted in 3 participants:
Consent withdrawn after an infective
exacerbation developed
Dyspnoea occurred

29
Wills 1996
(Continued)
Hospitalisation occurred and study

drug was inadvertently discontinued
All 3 were in the RhDNase twice-daily
group
Three hospitalisations of two participants
for infective exacerbations-both were in the
RhDNase twice-daily group
Abbreviations: bd: twices daily; CT: computed tomography; FEV1: forced expiratory volume in one second; FVC: forced vital capacity;
od: once daily; RhDNase: recombinant human DNase; SD: standard deviation; VAS: visual analogue scale.
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Alberto 1968
The study combined participants with chronic bronchitis, emphysema, asthma, cor pulmonale and bronchiectasis. Separate data from the bronchiectasis participants in this sample were not reported
Balzano 1973
Not a randomised controlled trial. 55 participants with various respiratory diagnoses on single treatment
Bateman 1971
Participants did not have a diagnosis of bronchiectasis
Benjamin 1971
Bergogne 1985
The study combined participants with chronic bronchitis and bronchiectasis. Separate data from the bronchiectasis participants in this sample were not reported
Bradley 2011
Not a mucolytic agent (hypertonic saline is not defined as a mucolytic by our prespecified entry criteria)
Cobbin 1971
Only two of fifteen participants treated had a diagnosis of bronchiectasis
Currie 1988
Mucolytic agent not compared with placebo/no treatment
Daviskas 1999
Not a mucolytic agent
Fadda 2001
Germouty 1988
Ghiringhelli 1981
The study combined participants with various respiratory diagnoses. Separate data from the one bronchiectasis
participant in this sample were not reported
Hasani 1994

30
(Continued)
Hasani 1994A
Itoh 1984
The study combined participants with chronic bronchitis, bronchiectasis, pulmonary tuberculosis, bronchial
asthma, pulmonary pyosis, pulmonary emphysema, pulmonary fibrosis, pulmonary cancer, pneumonia and
pleurisy. Separate data from the bronchiectasis participants in this sample were not reported
Kawashima 1989
Not a randomised controlled trial and not a mucolytic agent
Kellett 2005
Not a mucolytic agent (hypertonic saline is not defined as a mucolytic by our prespecified entry criteria)
Kossmagk 1980
The study combined participants with various respiratory diagnoses. Separate data from the bronchiectasis
participants in this sample were not reported
Loukides 1998
Focus of study is ciliary beat frequency, not a measure of mucolysis
Mareels 1983
The study combined participants with acute bronchitis and chronic bronchitis. Only one participant had a
diagnosis of bronchiectasis. Data from the three groups were not reported separately
Marthin 2007
Noone 1999
Intervention not used as a mucolytic agent but to enhance cilia function, changing the consistency/secretion of
mucin
Patterson 2007
Sahay 1982
The study combined five bronchiectasis participants (four completed) in sample of 36 participants with various
respiratory diseases. Separate data from the bronchiectasis participants in this sample were not reported
Serisier 2013
Stafanger 1988
The study combined participants with cystic fibrosis and primary ciliary dyskinesia. Unclear in the trial report
whether the primary ciliary dyskinesia participants also had a diagnosis of bronchiectasis
Tambascio 2011
Taskar 1992
The study combined participants with bronchiectasis, COPD, lung abscess. Separate data from the bronchiectasis
participants in this sample were not reported
Tsang 2003
Verstraeten 1979
Only two of 60 participants included in the study had a diagnosis of bronchiectasis. One participant was treated
with bromhexine, the other with N-acetyl-cysteine
Wong 2012
Yalin 2006

31
DATA AND ANALYSES
Comparison 1. Bromhexine versus placebo
Outcome or subgroup title

1 Adverse events
2 FEV1 (mL)
2.1 At 7 days
2.2 At 13 days
No. of
studies
No. of
participants
1
1
1
1
Statistical method
Odds Ratio (M-H, Fixed, 95% CI)
Mean Difference (IV, Fixed, 95% CI)
Effect size
Totals not selected
Totals not selected
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
Comparison 2. 5 mg RhDNase versus placebo

1 Hospitalisations for infective
exacerbations
2 % change FEV1 at day 15
3 % change FVC at day 15
4 Quality of Life
4.1 Cough and congestion
4.2 Dyspnoea
4.3 Basic activity limitations
4.4 Intermediate activity
limitations
4.5 Emotional well-being
4.6 Fatigue
4.7 Not able to carry out usual
activities
4.8 Days stayed in bed
4.9 Perception of overall
health
5 Sputum colour
6 Deaths
No. of
studies
No. of
participants
Statistical method
Effect size
Totals not selected
1
1
1
1
1
1
1

Totals not selected

Totals not selected
Totals not selected
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
1
1
1

0.0 [0.0, 0.0]

0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
1
1

0.0 [0.0, 0.0]

0.0 [0.0, 0.0]
1
1

Totals not selected

Totals not selected

32
Comparison 3. 2.5 mg RhDNase versus placebo

1 Hospitalisations for infective
exacerbations
2 % change FEV1 at day 15
3 % change FVC at day 15
4 Quality of life
4.1 Cough and congestion
4.2 Dyspnoea
4.3 Basic activity limitations
4.4 Intermediate activity
limitations
4.5 Emotional well-being
4.6 Fatigue
4.7 Not able to carry out usual
activities
4.8 Days stayed in bed
4.9 Perception of overall
health
5 Sputum colour
6 Deaths
7 Antibodies to RhDNase
No. of
studies
No. of
participants
Statistical method
Effect size
Totals not selected
1
1
1
1
1
1
1

Totals not selected

Totals not selected
Totals not selected
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
1
1
1

0.0 [0.0, 0.0]

0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
1
1

0.0 [0.0, 0.0]

0.0 [0.0, 0.0]

Totals not selected

3.09 [0.32, 29.98]
Totals not selected
1
2
1
390
Comparison 4. Erdosteine versus no treatment

1 Mucus density
1.1 Day five
1.2 Day 10
1.3 Day 15
2 Mucus purulence
2.1 Day five
2.2 Day 10
2.3 Day 15
3 Mucus volume production
3.1 Day five
3.2 Day 10
3.3 Day 15
4 Change in FEV1 (mL) at day 15
5 Change in FEV1 %Pred at day
15
6 Change in FVC (mL) at day 15
7 Change in FVC %Pred at day 15
No. of
studies
No. of
participants
Statistical method
Effect size
1
1
1
1
1
1
1
1
1
1
1
1
1
1

Totals not selected

0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
Totals not selected
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
Totals not selected
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
Totals not selected
Totals not selected
1
1

Totals not selected

Totals not selected

33
Analysis 1.1. Comparison 1 Bromhexine versus placebo, Outcome 1 Adverse events.

Review:
Comparison: 1 Bromhexine versus placebo

Outcome: 1 Adverse events
Study or subgroup
Bromhexine
Placebo
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
1/45
0/43
Olivieri 1991
2.93 [ 0.12, 73.97 ]
0.01
0.1
10
Favours Bromhexine
100
Favours Placebo
Analysis 1.2. Comparison 1 Bromhexine versus placebo, Outcome 2 FEV1 (mL).

Review:
Comparison: 1 Bromhexine versus placebo

Outcome: 2 FEV1 (mL)
Study or subgroup
Mean
Difference
Control
Mean
Difference
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
34
1740.4 (712.5423)
33
1631.8 (751.9633)
108.60 [ -242.38, 459.58 ]
34
1797.8 (693.8833)
33
1613.8 (699.6877)
184.00 [ -149.75, 517.75 ]
1 At 7 days
Olivieri 1991
2 At 13 days
Olivieri 1991
-500
-250
Favours Bromhexine

250
500
Favours Placebo
34
Analysis 2.1. Comparison 2 5 mg RhDNase versus placebo, Outcome 1 Hospitalisations for infective
exacerbations.
Review:
Comparison: 2 5 mg RhDNase versus placebo

Outcome: 1 Hospitalisations for infective exacerbations
Study or subgroup
5 mg rhDNase
Placebo
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
2/20
0/20
Wills 1996
5.54 [ 0.25, 123.08 ]
0.01
0.1
Favours rhDNase
10
100
Favours placebo
Analysis 2.2. Comparison 2 5 mg RhDNase versus placebo, Outcome 2 % change FEV1 at day 15.
Review:

Outcome: 2 % change FEV1 at day 15
Study or subgroup
Wills 1996
5 mg rhDNase
Mean
Difference
Placebo
Mean(SD)
Mean(SD)
20
1.6 (7.6026)
20
-0.5 (8.4971)
IV,Fixed,95% CI
IV,Fixed,95% CI
2.10 [ -2.90, 7.10 ]
-10
-5
Favours Placebo

Mean
Difference
10
Favours rhDNase
35
Analysis 2.3. Comparison 2 5 mg RhDNase versus placebo, Outcome 3 % change FVC at day 15.
Review:

Outcome: 3 % change FVC at day 15
Study or subgroup
5 mg rhDNase
Wills 1996
Mean
Difference
Placebo
Mean(SD)
Mean(SD)
20
1.1 (6.7082)
20
3.1 (6.7082)
Mean
Difference
IV,Fixed,95% CI
IV,Fixed,95% CI
-2.00 [ -6.16, 2.16 ]
-10
-5
Favours Placebo
10
Favours rhDNase
Analysis 2.4. Comparison 2 5 mg RhDNase versus placebo, Outcome 4 Quality of Life.

Review:

Outcome: 4 Quality of Life
Study or subgroup
5 mg rhDNase
Mean
Difference
Placebo
Mean
Difference
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
20
1.5 (3.1305)
20
1 (3.5777)
0.50 [ -1.58, 2.58 ]
20
0 (4.0249)
20
0 (2.6833)
0.0 [ -2.12, 2.12 ]
20
0 (1.3416)
20
-0.3 (0.8944)
0.30 [ -0.41, 1.01 ]
20
-1.5 (5.8138)
20
1.7 (4.0249)
-3.20 [ -6.30, -0.10 ]
20
0.1 (2.2361)
20
0.2 (1.3416)
-0.10 [ -1.24, 1.04 ]
1 Cough and congestion

Wills 1996
2 Dyspnoea
Wills 1996
3 Basic activity limitations
Wills 1996
4 Intermediate activity limitations
Wills 1996
5 Emotional well-being
Wills 1996
6 Fatigue
-1
-0.5
Favours placebo
0.5
Favours rhDNase
(Continued . . . )

36
(. . .
Study or subgroup
5 mg rhDNase
Wills 1996
Mean
Difference
Placebo
Continued)
Mean
Difference
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
20
-1 (2.6833)
20
0.9 (3.5777)
-1.90 [ -3.86, 0.06 ]
20
0.3 (0.8944)
20
-0.1 (0.8944)
0.40 [ -0.15, 0.95 ]
20
0.1 (0.4472)
20
-0.1 (0.4472)
0.20 [ -0.08, 0.48 ]
20
-0.4 (2.2361)
20
0.3 (1.3416)
-0.70 [ -1.84, 0.44 ]
7 Not able to carry out usual activities

Wills 1996
8 Days stayed in bed
Wills 1996
9 Perception of overall health
Wills 1996
-1
-0.5
0.5
Favours placebo
Favours rhDNase
Analysis 2.5. Comparison 2 5 mg RhDNase versus placebo, Outcome 5 Sputum colour.

Review:

Outcome: 5 Sputum colour
Study or subgroup
Wills 1996
5 mg rhDNase
Mean
Difference
Placebo
Mean(SD)
Mean(SD)
20
3.48 (0.4919)
20
3.2 (0.5367)
IV,Fixed,95% CI
IV,Fixed,95% CI
0.28 [ -0.04, 0.60 ]
-0.5
-0.25
Favours rhDNase

Mean
Difference
0.25
0.5
Favours Placebo
37
Analysis 2.6. Comparison 2 5 mg RhDNase versus placebo, Outcome 6 Deaths.

Review:

Outcome: 6 Deaths
Study or subgroup
5 mg rhDNase
Placebo
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
0/20
0/20
Wills 1996
Not estimable
0.01
0.1
Favours rhDNase
10
100
Favours placebo
Analysis 3.1. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 1 Hospitalisations for infective
exacerbations.
Review:
Comparison: 3 2.5 mg RhDNase versus placebo

Outcome: 1 Hospitalisations for infective exacerbations
Study or subgroup
Wills 1996
2.5 mg rhDNase
Placebo
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
0/20
0/20
Not estimable
0.01
0.1
Favours rhDNase

10
100
Favours placebo
38
Analysis 3.2. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 2 % change FEV1 at day 15.
Review:

Outcome: 2 % change FEV1 at day 15
Study or subgroup
2.5 mg rhDNase
Wills 1996
Mean
Difference
Placebo
Mean(SD)
Mean(SD)
21
1.6 (11.4564)
20
-0.5 (8.4971)
Mean
Difference
IV,Fixed,95% CI
IV,Fixed,95% CI
2.10 [ -4.05, 8.25 ]
-10
-5
Favours Placebo
10
Favours rhDNase
Analysis 3.3. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 3 % change FVC at day 15.
Review:

Outcome: 3 % change FVC at day 15
Study or subgroup
Wills 1996
2.5 mg rhDNase
Mean
Difference
Placebo
Mean(SD)
Mean(SD)
21
0.7 (6.4156)
20
3.1 (6.7082)
IV,Fixed,95% CI
IV,Fixed,95% CI
-2.40 [ -6.42, 1.62 ]
-10
-5
Favours placebo

Mean
Difference
10
Favours rhDNase
39
Analysis 3.4. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 4 Quality of life.
Review:

Outcome: 4 Quality of life
Study or subgroup
2.5 mg rhDNase
Mean
Difference
Placebo
Mean
Difference
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
21
0.3 (3.6661)
20
1 (3.5777)
-0.70 [ -2.92, 1.52 ]
21
1.7 (2.291)
20
0 (2.683)
1.70 [ 0.17, 3.23 ]
21
0.2 (1.3748)
20
-0.3 (0.8944)
0.50 [ -0.21, 1.21 ]
21
1 (3.2078)
20
1.7 (4.0249)
-0.70 [ -2.93, 1.53 ]
21
-0.6 (2.2913)
20
0.2 (1.3416)
-0.80 [ -1.94, 0.34 ]
21
-1.1 (3.6661)
20
0.9 (3.5777)
-2.00 [ -4.22, 0.22 ]
21
0.1 (0.4583)
20
-0.1 (0.8944)
0.20 [ -0.24, 0.64 ]
21
0.01 (0.4583)
20
-0.1 (0.4472)
0.11 [ -0.17, 0.39 ]
21
-0.3 (0.9165)
20
0.3 (1.3416)
-0.60 [ -1.31, 0.11 ]
1 Cough and congestion

Wills 1996
2 Dyspnoea
Wills 1996
3 Basic activity limitations
Wills 1996
4 Intermediate activity limitations
Wills 1996
5 Emotional well-being
Wills 1996
6 Fatigue
Wills 1996
7 Not able to carry out usual activities
Wills 1996
8 Days stayed in bed
Wills 1996
9 Perception of overall health
Wills 1996
-4
-2
Favours placebo

Favours rhDNase
40
Analysis 3.5. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 5 Sputum colour.
Review:

Outcome: 5 Sputum colour
Study or subgroup
2.5 mg rhDNase
Wills 1996
Mean
Difference
Placebo
Mean(SD)
Mean(SD)
21
3.4 (0.5041)
20
3.2 (0.5367)
Mean
Difference
IV,Fixed,95% CI
IV,Fixed,95% CI
0.20 [ -0.12, 0.52 ]
-0.5
-0.25
0.25
0.5
Analysis 3.6. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 6 Deaths.

Review:

Outcome: 6 Deaths
Study or subgroup
ODonnell 1998
2.5 mg rhDNase
Placebo
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
3/173
1/176
0/21
0/20
194
196
Wills 1996
Total (95% CI)
Weight
Odds Ratio
M-H,Fixed,95% CI
100.0 %
3.09 [ 0.32, 29.98 ]

Not estimable
100.0 %
3.09 [ 0.32, 29.98 ]
Total events: 3 (2.5 mg rhDNase), 1 (Placebo)

Heterogeneity: not applicable
Test for overall effect: Z = 0.97 (P = 0.33)
Test for subgroup differences: Not applicable
0.01
0.1
Favours rhDNase
10
100
Favours placebo

41
Analysis 3.7. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 7 Antibodies to RhDNase.
Review:

Outcome: 7 Antibodies to RhDNase
Study or subgroup
2.5 mg rhDNase
Placebo
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
24/173
1/176
ODonnell 1998
28.19 [ 3.77, 210.85 ]
0.005
0.1
Favours rhDNase
10
200
Favours placebo
Analysis 4.1. Comparison 4 Erdosteine versus no treatment, Outcome 1 Mucus density.

Review:
Comparison: 4 Erdosteine versus no treatment

Outcome: 1 Mucus density
Study or subgroup
Erdosteine
Mean
Difference
Control
Mean
Difference
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
15
1.6 (0.48)
15
1.67 (0.48)
-0.07 [ -0.41, 0.27 ]
15
1.13 (0.51)
15
1.4 (0.63)
-0.27 [ -0.68, 0.14 ]
15
0.8 (0.56)
15
1.07 (0.45)
-0.27 [ -0.63, 0.09 ]
1 Day five
Crisafulli 2007
2 Day 10
Crisafulli 2007
3 Day 15
Crisafulli 2007
-1
-0.5
Favours erdosteine

0.5
Favours control
42
Analysis 4.2. Comparison 4 Erdosteine versus no treatment, Outcome 2 Mucus purulence.

Review:

Outcome: 2 Mucus purulence
Study or subgroup
Erdosteine
Mean
Difference
Control
Mean
Difference
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
15
1 (0.53)
15
1.03 (0.37)
-0.03 [ -0.36, 0.30 ]
15
0.6 (0.63)
15
0.8 (0.41)
-0.20 [ -0.58, 0.18 ]
15
0.33 (0.48)
15
0.8 (0.41)
-0.47 [ -0.79, -0.15 ]
1 Day five
Crisafulli 2007
2 Day 10
Crisafulli 2007
3 Day 15
Crisafulli 2007
-1
-0.5
Favours erdosteine
0.5
Favours control
Analysis 4.3. Comparison 4 Erdosteine versus no treatment, Outcome 3 Mucus volume production.
Review:

Outcome: 3 Mucus volume production
Study or subgroup
Erdosteine
Mean
Difference
Control
Mean
Difference
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
IV,Fixed,95% CI
15
0.47 (0.64)
15
0.6 (0.73)
-0.13 [ -0.62, 0.36 ]
15
1.07 (0.59)
15
0.87 (0.74)
0.20 [ -0.28, 0.68 ]
15
1.33 (0.48)
15
0.93 (0.7)
0.40 [ -0.03, 0.83 ]
1 Day five
Crisafulli 2007
2 Day 10
Crisafulli 2007
3 Day 15
Crisafulli 2007
-1
-0.5
Favours erdosteine

0.5
Favours control
43
Analysis 4.4. Comparison 4 Erdosteine versus no treatment, Outcome 4 Change in FEV1 (mL) at day 15.
Review:

Outcome: 4 Change in FEV1 (mL) at day 15
Study or subgroup
Crisafulli 2007
Erdosteine
Mean
Difference
Control
Mean(SD)
Mean(SD)
15
200 (300)
15
0 (100)
Mean
Difference
IV,Fixed,95% CI
IV,Fixed,95% CI
200.00 [ 39.97, 360.03 ]
-500
-250
Favours control
250
500
Favours erdosteine
Analysis 4.5. Comparison 4 Erdosteine versus no treatment, Outcome 5 Change in FEV1 %Pred at day 15.
Review:

Outcome: 5 Change in FEV1 %Pred at day 15
Study or subgroup
Crisafulli 2007
Erdosteine
Mean
Difference
Control
Mean(SD)
Mean(SD)
15
5.8 (13.3)
15
1.3 (7)
IV,Fixed,95% CI
IV,Fixed,95% CI
4.50 [ -3.11, 12.11 ]
-100
-50
Favours control

Mean
Difference
50
100
Favours erdosteine
44
Analysis 4.6. Comparison 4 Erdosteine versus no treatment, Outcome 6 Change in FVC (mL) at day 15.
Review:

Outcome: 6 Change in FVC (mL) at day 15
Study or subgroup
Crisafulli 2007
Erdosteine
Mean
Difference
Control
Mean(SD)
Mean(SD)
15
300 (500)
15
0 (200)
Mean
Difference
IV,Fixed,95% CI
IV,Fixed,95% CI
300.00 [ 27.48, 572.52 ]
-500
-250
Favours control
250
500
Favours erdosteine
Analysis 4.7. Comparison 4 Erdosteine versus no treatment, Outcome 7 Change in FVC %Pred at day 15.
Review:

Outcome: 7 Change in FVC %Pred at day 15
Study or subgroup
Crisafulli 2007
Erdosteine
Mean
Difference
Control
Mean(SD)
Mean(SD)
15
9.5 (20.8)
15
0.6 (8.9)
IV,Fixed,95% CI
IV,Fixed,95% CI
8.90 [ -2.55, 20.35 ]
-100
-50
Favours control

Mean
Difference
50
100
Favours erdosteine
45
APPENDICES
Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register
(CAGR)
Electronic searches: core databases
Database
Frequency 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
Conference
Years 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 Meeting
2003 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

46
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]

47
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]
WHATS NEW
Last assessed as up-to-date: 19 June 2013.
Date
Event
Description
23 October 2014
Amended
Typo in summary of findings table edited
HISTORY
Protocol first published: Issue 1, 1997
Review first published: Issue 2, 2000
Date
Event
Description
30 September 2013
New citation required and conclusions have changed
One 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 2013
New search has been performed
New literature search run
19 January 2010
New search has been performed
Literature search re-run; no new studies identified.
8 August 2008
Amended
Converted to new review format.
10 October 2000
New citation required and conclusions have changed
Substantive amendment

48
CONTRIBUTIONS OF AUTHORS
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
None known.
SOURCES OF SUPPORT
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

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.
INDEX TERMS
Medical Subject Headings (MeSH)
Anti-Bacterial Agents [therapeutic use]; Bromhexine [therapeutic use]; Bronchiectasis [ therapy]; Deoxyribonucleases [therapeutic
use]; Drug Therapy, Combination; Expectorants [ therapeutic use]; Randomized Controlled Trials as Topic; Recombinant Proteins
[therapeutic use]; Thioglycolates [therapeutic use]; Thiophenes [therapeutic use]
MeSH check words

Humans

49

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Cochrane Database of Systematic Reviews

Mucolytics for bronchiectasis (Review)

Wilkinson M, Sugumar K, Milan SJ, Hart A, Crockett A, Crossingham I.

Mucolytics for bronchiectasis (Review)

Mucolytics for bronchiectasis (Review)

Mucolytics for bronchiectasis

PLAIN LANGUAGE SUMMARY

Mucolytics for bronchiectasis (Review)

Mucolytics for bronchiectasis (Review)

Bromhexine compared with placebo for bronchiectasis

Illustrative comparative risks* (95% CI)

Quality of the evidence

Frequency and duration See comment

Outcome not reported

Outcome not reported

2.2 per 100

Mean FEV1 in the control Mean FEV1 in the inter- MD 184.00

Health-related quality of See comment

Outcome not reported

Outcome not reported

Mucolytics for bronchiectasis (Review)

Description of the condition

How the intervention might work

Why it is important to do this review

Description of the intervention

Criteria for considering studies for this review

Mucolytics for bronchiectasis (Review)

Frequency and duration of exacerbations.

searched all databases from their inception to June 2013, with no

Searching other resources

Data collection and analysis

Search methods for identification of studies

MW and IC independently screened the identified references using

Data extraction and management

We identified trials from the Cochrane Airways Group Specialised

Assessment of risk of bias in included studies

Mucolytics for bronchiectasis (Review)

Measures of treatment effect

Assessment of reporting biases

We planned to examine publication bias by using funnel plots if

Summary of findings table

Results of the search

Mucolytics for bronchiectasis (Review)

Figure 1. Study flow diagram.

Mucolytics for bronchiectasis (Review)

Four RCTs were identified, with a total of 528 participants who

pants who were in a stable state and compared 2.5 mg aerosolised

Risk of bias in included studies

Mucolytics for bronchiectasis (Review)

Mucolytics for bronchiectasis (Review)

Mucolytics for bronchiectasis (Review)

Incomplete outcome data

Bromhexine versus placebo

One study of 15 days duration compared bromhexine versus

No significant difference between bromhexine and placebo in

RhDNase (5 mg) versus placebo

RhDNase (2.5 mg) versus placebo

Mucolytics for bronchiectasis (Review)

Neither percentage change in FEV1 (MD 2.10 L, 95% CI -2.95

reported between control and study groups. However, the study

Erdosteine versus no treatment

One study of 15 days duration compared erdosteine versus no

Mucolytics for bronchiectasis (Review)