Mucolytics For Bronchiectasis (Review) : Cochrane

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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 14
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Analysis 1.1. Comparison 1 Bromhexine versus placebo, Outcome 1 Adverse events. . . . . . . . . . . . 34
Analysis 1.2. Comparison 1 Bromhexine versus placebo, Outcome 2 FEV1 (mL). . . . . . . . . . . . . 34
Analysis 2.1. Comparison 2 5 mg RhDNase versus placebo, Outcome 1 Hospitalisations for infective exacerbations. . 35
Analysis 2.2. Comparison 2 5 mg RhDNase versus placebo, Outcome 2 % change FEV1 at day 15. . . . . . . 35
Analysis 2.3. Comparison 2 5 mg RhDNase versus placebo, Outcome 3 % change FVC at day 15. . . . . . . . 36
Analysis 2.4. Comparison 2 5 mg RhDNase versus placebo, Outcome 4 Quality of Life. . . . . . . . . . . 36
Analysis 2.5. Comparison 2 5 mg RhDNase versus placebo, Outcome 5 Sputum colour. . . . . . . . . . . 37
Analysis 2.6. Comparison 2 5 mg RhDNase versus placebo, Outcome 6 Deaths. . . . . . . . . . . . . . 38
Analysis 3.1. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 1 Hospitalisations for infective exacerbations. 38
Analysis 3.2. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 2 % change FEV1 at day 15. . . . . . . 39
Analysis 3.3. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 3 % change FVC at day 15. . . . . . . 39
Analysis 3.4. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 4 Quality of life. . . . . . . . . . . 40
Analysis 3.5. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 5 Sputum colour. . . . . . . . . . . 41
Analysis 3.6. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 6 Deaths. . . . . . . . . . . . . 41
Analysis 3.7. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 7 Antibodies to RhDNase. . . . . . . 42
Analysis 4.1. Comparison 4 Erdosteine versus no treatment, Outcome 1 Mucus density. . . . . . . . . . . 42
Analysis 4.2. Comparison 4 Erdosteine versus no treatment, Outcome 2 Mucus purulence. . . . . . . . . . 43
Analysis 4.3. Comparison 4 Erdosteine versus no treatment, Outcome 3 Mucus volume production. . . . . . . 43
Analysis 4.4. Comparison 4 Erdosteine versus no treatment, Outcome 4 Change in FEV1 (mL) at day 15. . . . . 44
Analysis 4.5. Comparison 4 Erdosteine versus no treatment, Outcome 5 Change in FEV1 %Pred at day 15. . . . 44
Analysis 4.6. Comparison 4 Erdosteine versus no treatment, Outcome 6 Change in FVC (mL) at day 15. . . . . 45
Analysis 4.7. Comparison 4 Erdosteine versus no treatment, Outcome 7 Change in FVC %Pred at day 15. . . . . 45
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 49
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Mucolytics for bronchiectasis (Review) i

[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.
Mucolytics for bronchiectasis (Review) 1
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 non-
cystic 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 treatment’s 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.

Mucolytics for bronchiectasis (Review) 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) Relative effect No. of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Assumed risk Corresponding risk
Placebo Bromhexine
Frequency and duration See comment See comment See comment See comment N/A Outcome not reported
of exacerbations
Hospitalisations See comment See comment See comment See comment N/A Outcome not reported
Adverse events 0 per 100 3 2.2 per 100 OR 2.93 88 ⊕⊕

(0.05 to 11.7) (0.12 to 73.97) (1 study) low1,2
Health-related quality of See comment See comment See comment See comment See comment Outcome not reported
life
Symptoms difficulty in Absolute values not re- Absolute values not re- MD -0.53 88 ⊕⊕
expectoration ported ported (-0.81 to -0.25) (1 study) low1,2
Follow-up: 16 days
Deaths See comment See comment See comment See comment See comment Outcome not reported
Lung function Mean FEV1 in the control Mean FEV1 in the inter- MD 184.00 88 ⊕⊕
FEV1 group was 1614 mL vention groups was 184 (-149.75 to 517.75) (1 study) low1,2
Follow-up: 13 days mL higher
(149.75 lower to 517.75
higher)
4
*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).
2 One 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.
5
BACKGROUND 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 di-
Description of the condition rectly to the lungs by nebulisation and inhalation.
National guidelines (BTS 2010; TSANZ 2010) consider RhD-
Bronchiectasis is predominantly an acquired disease process that
Nase to be contraindicated in non-cystic fibrosis (CF) bronchiec-
represents the end stage of a variety of unrelated pulmonary in-
tasis following a trial that reported deleterious effects on both lung
sults and antecedent events. It is defined in anatomical terms as
function and exacerbation rate in adults (O’Donnell 1998). By
persistent and irreversible dilatation and distortion of medium-
extrapolation from this study, the same recommendation has been
sized bronchi. Focal or diffuse forms of bronchial disease also pre-
given for children with non-CF bronchiectasis. Based primarily
dispose to the development of bronchiectasis. Bronchial obstruc-
on an earlier version of this Cochrane review (Crockett 2001),
tion due to varied and unrelated causes (e.g. aspiration of for-
guidelines in the Southern hemisphere (TSANZ 2010) recom-
eign bodies, carcinoma, extrinsic compression by surrounding en-
mend against the use of mucoactive drugs including mucolytics
larged lymph nodes, inspissated viscid secretions) can cause ob-
in bronchiectasis.
structive or localised forms of bronchiectasis. Diffuse bronchiec-
tasis is usually associated with previous widespread pneumonic
damage (e.g. pertussis and measles pneumonia, severe influenza
and varicella pneumonia, necrotising bacterial pneumonias due to How the intervention might work
Klebsiella, Staphylococcus aureus, Pseudomonas and anaerobic infec- Bronchiectasis is a disease characterised by excessive mucus pro-
tions), chronic granulomatous disease (e.g. tuberculosis, sarcoido- duction and retention. By reducing the viscosity of mucus, mu-
sis, histoplasmosis, coccidioidomycosis), hypersensitivity and im- colytics may aid clearance of sputum from the airways. Removal of
munodeficiency disorders (e.g. congenital or acquired ahypogam- mucus plugs from small and medium-sized airways allows recruit-
maglobulinaemia) or genetic syndromes (e.g. cystic fibrosis, tra- ment of the associated lung and hence improvement in spiromet-
cheobronchomegaly, bronchial cartilage deficiency, Kartagener’s ric measures of lung function. Retained sputum could potentially
syndrome, Young’s syndrome, immotile cilia disease). Many of act as a culture medium for bacteria (Stockley 1995), leading to
these conditions predispose to recurrent lower respiratory infection recurrent or persistent chest infection. By enhancing mucus re-
as a result of poor tracheobronchial clearance. It has been suggested moval, this risk is reduced.
that with widespread use of high-resolution computed tomogra-
phy, more bronchiectasis diagnoses are being made (Goeminne
2010), and mucus clearance along with antimicrobial therapy re- Why it is important to do this review
mains an integral part of management of the condition (Stafler
2010). 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 char-
acteristics of sputum such that removal of sputum from the air- OBJECTIVES
way becomes easier. These drugs are collectively known as mu-
To determine whether ingested or inhaled mucolytics are effective
colytics. The precise mechanism of action of many of these drugs
in the treatment of patients with bronchiectasis.
is not known (Cotgreave 1987; Rogers 2007) but may include
breaking down large molecules within the mucus to reduce vis-
cosity and reducing the biological activity of various proteins
(Zafarullah 2003). Attempts have been made to classify mucoac- METHODS
tive drugs (Balsamo 2010) as true mucolytics (thin mucus), ex-
pectorants (work by inducing cough) and mucokinetics (increase
mucus transport within the lungs), but in practice these drugs Criteria for considering studies for this review
probably work through several of these mechanisms simultane-
ously (Tomkiewicz 1995).
The mechanism of action of recombinant human DNase (RhD- Types of studies
Nase or dornase alfa) is known. This is a mucolytic that enzymat- We included randomised trials comparing treated and untreated
ically degrades the long chains of DNA derived from neutrophils groups of participants with bronchiectasis.

Types of participants searched all databases from their inception to June 2013, with no
Adults with a diagnosis of bronchiectasis, but not cystic fibrosis. restriction on language of publication.
Types of interventions
Searching other resources
Intervention group: any mucolytic given by nebuliser or orally in
single or repeated doses alone or in combination with glucocorti- Full publications of all references identified as randomised con-
costeroids, beta2 -agonists (long- or short-acting or both) or xan- trolled trials (RCTs) or unclear were obtained and reviewed inde-
thine bronchodilators. pendently by two review authors (SJM, MW). Reference lists of all
Control group: single or repeated doses of nebulised or oral placebo identified RCTs were checked to identify potentially relevant ci-
combined with glucocorticosteroids, beta2 -agonists or xanthine tations. The international headquarters of Boehringer Ingelheim,
bronchodilators. the pharmaceutical company that produces bromhexine, was con-
Important co-interventions: physical interventions (physiother- tacted. Enquiries regarding other published or unpublished stud-
apy) and drugs that increase mucociliary clearance (beta2 -agonists) ies known and/or supported by this company or its subsidiaries
or change viscoelastic characteristics of sputum (corticosteroids). 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 po-
Types of outcome measures tentially relevant trials. In addition, all identified papers and re-
views were handsearched for further references, and study authors
were contacted to ask whether they could identify any unpublished
Primary outcomes
or missed trials.
• Frequency and duration of exacerbations.
• Hospitalisations.
• Adverse events.
Data collection and analysis
Secondary outcomes
• Mortality.
• Symptoms: cough, sputum volume and ease of
Selection of studies
expectoration, wheeze, dyspnoea.
• Lung function. MW and IC independently screened the identified references using
• In vitro characteristics of sputum. the abstract, title and medical subject heading (MeSH) terms, and
• Measurement of tracheobronchial clearance. independently assessed studies for potential relevance. At the next
• Health-related quality of life (e.g. Short Form (SF)-36, St stage, using the full text of the potentially relevant studies, the
George’s Respiratory Questionnaire (SGRQ)). 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,
Search methods for identification of studies this was not necessary.
Electronic searches Data extraction and management

We identified trials from the Cochrane Airways Group Specialised Data for included trials were extracted independently by two re-
Register (CAGR), which is maintained by the Trials Search Co-or- view authors (SJM and MW) and were entered into the software
dinator for the Group. The Register contains trial reports identified programme of The Cochrane Collaboration (Review Manager
through systematic searches of bibliographic databases including (RevMan)) by SJM. Data entry was checked by AH.
the Cochrane Central Register of Controlled Trials (CENTRAL),
MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, and
handsearching of respiratory journals and meeting abstracts (please
Assessment of risk of bias in included studies
see Appendix 1 for further details). We searched all records in the
CAGR using the search strategy in Appendix 2. Two review authors (SJM and MW) assessed the trials with respect
We also conducted a search of to selection bias, performance and detection bias, attrition bias,
ClinicalTrials.gov (www.ClinicalTrials.gov) and the World Health reporting bias and other potential sources of bias using the ’Risk
Organization (WHO) trials portal (www.who.int/ictrp/en/). We of bias’ tool of The Cochrane Collaboration (Higgins 2011).

Measures of treatment effect • Hospitalisations.
For dichotomous variables, we expressed data as odds ratios (ORs) • Adverse events.
with 95% confidence intervals (CIs). Data for continuous variables Secondary
were reported as mean differences (MDs) with 95% CIs or as • Health-related quality of life.
standardised mean differences (SMDs) with 95% CIs in analyses • Symptoms: cough, sputum volume and ease of
for which it was necessary to pool data from different measures. expectoration, wheeze, dyspnoea.
• Mortality.
Unit of analysis issues • Lung function.
The unit of analysis was the participant. We used the five GRADE considerations (study limitations, con-
sistency of effect, imprecision, indirectness and publication bias)
to assess the quality of a body of evidence as it relates to the studies
Dealing with missing data
that contributed data to the meta-analyses for prespecified out-
We planned to contact study authors if outcome data or informa- comes. We applied methods and recommendations described in
tion on trial design was missing; however, this issue did not arise. Section 8.5 and Chapter 12 of the Cochrane Handbook for System-
atic Reviews of Interventions (Higgins 2011) by using GRADEpro
Assessment of heterogeneity software. We justified all decisions to downgrade or upgrade the
We tested heterogeneity among pooled estimates using the Der- quality of studies by using footnotes and included comments to
Simonian and Laird method; we considered a P value < 0.05 as the aid readers’ understanding of the review when necessary.
threshold for statistical significance. Heterogeneity was assessed at
first by visual inspection of forest plots. The Chi2 test was similarly Subgroup analysis and investigation of heterogeneity
considered (P value < 0.10) but was interpreted with caution owing Subgroup and sensitivity analyses were performed by pooling ab-
to the low power associated with this test. I2 was also considered solute and relative data to include sufficient studies at each time
and was interpreted in relation to the following guidance (Higgins point. In these cases, we calculated individual and pooled statistics
2011). as SMDs and 95% CIs using a random-effects model. Subgroup
• 0% to 40%: might not be important. analysis was performed using the following subgroups.
• 30% to 60%: may represent moderate heterogeneity.
• 50% to 90%: may represent substantial heterogeneity.
• 75% to 100%: shows considerable heterogeneity. Sensitivity analysis
We planned to conduct sensitivity analyses by comparing random-
When we encountered heterogeneity according to the above men-
effects versus fixed-effect modelling if issues of significant hetero-
tioned criteria, we applied fixed-effect and random-effects mod-
geneity arose. However this was not necessary.
els and commented on differences, reporting the random-effects
model in the review.
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) aggre-
gated in a single meta-analysis. We recognise that an asymmetrical Description of studies
funnel plot can reflect heterogeneity, outcome reporting bias and
small-study effects and therefore is not necessarily a reflection of
publication bias. Results of the search
Thirty-six reports were identified in the June 2013 searches; they
Data synthesis included the three studies already identified in the previous ver-
sion of this review (Crockett 2001). Identified studies were in-
dependently evaluated against the inclusion criteria by MW and
Summary of findings table IC, and four studies were judged as appropriate for inclusion (de-
We created a ’Summary of findings’ table using the following out- tails are provided in Characteristics of included studies). Thirty-
comes. two reports were excluded (details provided in Characteristics of
Primary excluded studies).
• Frequency and duration of exacerbations. See Figure 1 for a study flow diagram.

Figure 1. Study flow diagram.

pants who were in a stable state and compared 2.5 mg aerosolised
Included studies
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
Four RCTs were identified, with a total of 528 participants who
from the included studies were unsuccessful.
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 Excluded studies
treatment of acute exacerbations of bronchiectasis (88 participants
Thirty-two reports were excluded (details in Characteristics of
were randomly assigned, with 21 participants withdrawing from
excluded studies). Twelve (38%) reports described participants
the study; participants in both treatment arms received an an-
with a variety of respiratory conditions, and data were not reported
tibiotic (ceftazidine 1 g, intramuscular (IM), twice daily) for the
separately for those with bronchiectasis; a further 12 (38%) reports
first week of the 15-day trial, and the choice of antibiotic was not
were excluded, as the intervention was not a mucolytic agent. An
based on microbiological assessment). All participants in this trial
additional five (16%) reports were excluded, as the participants
were suffering from an acute infective exacerbation of bronchiec-
had a diagnosis other than bronchiectasis, and two (6%) reports
tasis, with morning cough and purulent sputum. Another study
were excluded on the basis of having a non-randomised design.
(Crisafulli 2007) (30 participants randomly assigned, with no par-
The remaining trial (3%) was excluded, as the mucolytic agent
ticipants withdrawing from the study) compared oral erdosteine
was not compared with placebo/no treatment.
and physiotherapy versus physiotherapy alone over a 15-day pe-
riod. Participants were over 55 years of age and were non-smokers
or ex-smokers with moderate airflow obstruction and stable dis- Risk of bias in included studies
ease.
The remaining two studies compared RhDNase versus placebo.
Wills 1996, a 14-day trial with 61 participants (all completed the Allocation
study, but three had treatment interrupted), included participants All four included studies were assessed as unclear in terms of allo-
who were in a stable state, with moderate airflow obstruction, cation concealment bias (Figure 2). In terms of random sequence
and compared two doses of RhDNase (2.5 mg and 5 mg) versus generation, one trial (Crisafulli 2007) was assessed as having low
placebo. The largest study (O’Donnell 1998), with 349 partici- risk of bias, and the remaining three studies were judged to be
pants (of whom 346 completed the study), also included partici- 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.

Blinding
The risk of performance and detection bias in three included stud-
ies (O’Donnell 1998; Olivieri 1991; Wills 1996) was judged to be
low (Figure 3). Crisafulli 2007 was an unblinded study in which er-
dosteine and physiotherapy versus physiotherapy alone were com-
pared. The risk of performance bias was evaluated as high; how-
ever outcomes were assessed by personnel blinded and not directly
associated with the study administration, and detection bias was
therefore rated as low.

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

No significant difference between bromhexine and placebo in
Incomplete outcome data
forced expiratory volume in one second (FEV1 ) was noted at seven
Only two of the four included studies were assessed as having low days (MD 108.60 mL, 95% CI -242.38 to 459.58; Analysis 1.2) or
risk of bias in terms of attrition bias (O’Donnell 1998; Wills 1996), at 13 days (MD 184.00 mL, 95% CI -149.75 to 517.75; Analysis
whereas the risk of attrition bias in Olivieri 1991 was regarded as 1.2). The analysis of auscultatory findings provided in the trial re-
high, and in Crisafulli 2007, the risk of attrition bias was judged port indicated an advantage for bromhexine; however insufficient
as unclear. 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.
Selective reporting
All four included studies were assessed as unclear in terms of re-
porting bias. RhDNase (5 mg) versus placebo
One trial of two weeks’ duration compared 5 mg RhDNase ver-
Other potential sources of bias sus placebo (Wills 1996). Our GRADE assessments of the qual-
ity of evidence in this trial produced a rating of low (Summary
All four included studies were assessed as unclear in terms of other
of findings 2). No significant differences were reported between
potential sources of bias.
RhDNase (5 mg) and placebo with respect to the numbers of par-
ticipants requiring hospitalisation for infective exacerbation (OR
Effects of interventions 5.54, 95% CI 0.25 to 123.08; Analysis 2.1). The table of adverse
See: Summary of findings for the main comparison Bromhexine events in the trial report provides numbers of incidents of adverse
compared with placebo for bronchiectasis; Summary of findings events, rather than numbers of participants experiencing adverse
2 5 mg RhDNase compared with placebo for bronchiectasis; events; for this reason we have not entered the data using RevMan
Summary of findings 3 Erdosteine versus no treatment for software. The authors of the trial report described no significant
bronchiectasis 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,
Bromhexine versus placebo with more occurrences reported in the RhDNase arm.
One study of 15 days’ duration compared bromhexine versus In terms of secondary outcomes, no deaths occurred and no symp-
placebo (Olivieri 1991). Primary outcomes, exacerbations and toms were reported. No significant difference in FEV1 (MD 2.10
hospitalisations were not reported. No significant difference was L, 95% CI -2.90 to 7.10; Analysis 2.2) or percentage change in
noted between bromhexine and placebo in terms of adverse events forced vital capacity (FVC) (MD -2.00, 95% CI -6.16 to 2.16;
(OR 2.93, 95% CI 0.12 to 73.97; Analysis 1.1). Analysis 2.3) was observed at day 15 of this trial. A significant
As for secondary outcomes, no deaths were reported. Symptoms difference favouring placebo over RhDNase (5 mg) was observed
were reported in terms of “difficulty in expectoration,” sputum (MD -3.20, 95% CI -6.30 to -0.10; Analysis 2.4) in relation to the
production, cough score and sputum quality. Difficulty in expec- change between baseline and day 15 on the immediate activities
toration was significantly improved in the bromhexine-treated par- component of the functional status questionnaire quality of life
ticipants at day 10 (MD -0.45, 95% CI -0.89 to -0.03) and day assessment. No other significant differences were observed in the
16 (MD -0.53, 95% CI -0.81 to -0.25). Our GRADE assessments other quality of life measures (Analysis 2.4) nor in sputum colour
of the quality of evidence in this trial produced a rating of low (Analysis 2.5).
(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 - RhDNase (2.5 mg) versus placebo
38.9 to -4.1 at day 16). The cough score was significantly reduced One study of two weeks’ duration compared 2.5 mg RhDNase ver-
at day 13 (MD -0.48, 95% CI -0.89 to -0.06). The quality of sus placebo (Wills 1996). Our GRADE assessments of the quality
sputum was improved at both day 13 and day 16 (MD -0.45, 95% of evidence in this trial produced a rating of low. No participants
CI -0.87 to -0.034 at day 13). The analyses reported above were in the RhDNase (2.5 mg) or placebo arms were hospitalised for
conducted by the authors of the previous version of this review infective exacerbation. Again, we did not perform an analysis of
(Crockett 2001), and additional data were supplied by the trial the adverse events, as they were reported as numbers of events
author (Olivieri 1991). rather than as numbers of people experiencing one or more events.

Neither percentage change in FEV1 (MD 2.10 L, 95% CI -2.95 reported between control and study groups. However, the study
to 7.15; Analysis 3.2) nor percentage change in FVC (MD -2.40, authors report higher levels of antibodies to RhDNase in the treat-
95% CI -6.42 to 1.62; Analysis 3.3) was significantly different be- ment group (OR 28.19, 95% CI 3.77 to 210.85; Analysis 3.7).
tween 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 Erdosteine versus no treatment
assessment (Analysis 3.4), and this involved the dyspnoea com- One study of 15 days’ duration compared erdosteine versus no
ponent, favouring RhDNase (2.5 mg) (MD 1.70, 95% CI 0.17 treatment (Crisafulli 2007). Our primary outcomes of exacerba-
to 3.23; Analysis 3.4). No significant difference in sputum colour tions, hospital admissions and adverse events were not reported.
was reported (Analysis 3.5). In terms of secondary outcomes, no deaths were reported. The
An additional, considerably longer, study of 24 weeks’ duration impact on mucus density was evaluated in Analysis 4.1. No sig-
compared 2.5 mg RhDNase versus placebo (O’Donnell 1998). nificant differences between erdosteine and control were seen at
Results were generally reported in a format that could not be five days (MD -0.07, 95% CI -0.41 to 0.27), 10 days (MD -0.27,
included in the meta-analyses. 95% CI -0.68 to 0.14) or 15 days (MD -0.27, 95% CI -0.63 to
The study authors reported that the RhDNase group had a higher 0.09). Similarly, for mucus purulence (Analysis 4.2), no signifi-
but non-significant protocol-defined exacerbation rate of 0.66 ex- cant differences between erdosteine and control were noted at five
acerbations per participant per 168 days compared with 0.56 ex- days (MD -0.03, 95% CI -0.36 to 0.30) and 10 days (MD -0.20,
acerbations per participant in the placebo group (risk ratio (RR) 95% CI -0.58 to 0.18); however, the significant difference at 15
1.17, 95% CI 0.85 to 1.65). The RhDNase group also had a higher days indicated benefit for erdosteine versus control (MD -0.47,
non-protocol-defined exacerbation rate than the placebo group 95% CI -0.79 to -0.15). No significant differences were described
(RR 2.01, 95% CI 1.15 to 3.50), and when both of these types between erdosteine and control at five days (MD -0.13, 95% CI
of exacerbations were combined, a significant increase in occur- -0.62 to 0.36), 10 days (MD 0.20, 95% CI -0.28 to 0.68) or 15
rence was noted in the RhDNase group (RR 1.35, 95% CI 1.01 days (MD 0.40, 95% CI -0.03 to 0.83) in terms of mucus volume
to 1.79). RhDNase had a statistically significant negative effect production (Analysis 4.3). By applying GRADE criteria, review
(P value ≤ 0.05) on FEV1 , (mean percentage decline -1.7% in authors evaluated the quality of evidence on these outcomes as low
the placebo group and -3.6% in the RhDNase group; confidence (Summary of findings 3).
intervals were not included in the trial report). Hospitalisation A significant difference was indicated between erdosteine and con-
rates were increased in the RhDNase group (0.21 in the placebo trol in change from baseline to day 15 for FEV1 (mL) (MD 200.00,
group vs 0.39 in the treated group; RR 1.85, confidence intervals 95% CI 39.97 to 360.03; Analysis 4.4), but no significant dif-
were not included in the trial report). Placebo-treated participants ference was noted for FEV1 %predicted (MD 4.50, 95% CI -
used antibiotics less (44.1 vs 56.9 days; P value ≤ 0.05; confi- 3.11 to 12.11; Analysis 4.5). Similarly, a significant difference was
dence intervals were not included in the trial report) and steroids observed between erdosteine and control in change from baseline
less (23.4 vs 29.4 days; P value ≤ 0.05; confidence intervals were to day 15 for FVC (mL) (MD 300.00, 95% CI 27.48 to 572.52;
not included in the trial report) when compared with participants Analysis 4.6) but not for FVC %predicted (MD 8.90, 95% CI -
given RhDNase. 2.55 to 20.35; Analysis 4.7). Again, by applying GRADE criteria,
No significant difference in the incidence of adverse events was review authors evaluated the quality of evidence on these outcomes
as low.

Mucolytics for bronchiectasis (Review) 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
Placebo 5 mg RhDNase
Frequency and duration See comment See comment See comment See comment See comment Hospitalisations for in-
of exacerbations fective exacerbations re-
ported, see below
Hospitalisations for in- 0 per 100 3 10 per 100 OR 5.54 40 ⊕⊕

fective exacerbations (1.2 to 31.7) (0.25 to 123.08) (1 study) low1,2
Follow-up: 15 days
Adverse events See comment See comment See comment See comment See comment The authors of the trial re-
port there were no signif-
icant differences between
RhDNase (5 mg) versus
placebo on most of the 19
reported adverse events
with the only exception
being the incidence of in-
fluenza syndrome as di-
agnosed by the partici-
pants, with more occur-
rences in the RhDNase
arm
15
life
Symptoms sputum Mean sputum colour Mean sputum colour in MD 0.28 (-0.04 to 0.60) 40 ⊕⊕ We cannot interpret this
colour score was 3.2 the intervention groups (1 study) low1,2 finding since the differ-
Scale used not reported was ence is not statistically
0.28 higher significant and we do not
(0.04 lower to 0.6 higher) know what scale sputum
colour was measured on
Follow-up: 15 days
Lung function Mean change on placebo Mean % change FEV1 at MD 2.10 (-2.90 to 7.10) 40 ⊕⊕
% change FEV1 was -0.5% day 15 in the intervention (1 study) low1,2
Follow-up: 15 days groups was
2.1% higher
(2.95 lower to 7.15
higher)
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
No treatment Erdosteine
Frequency and duration See comment See comment See comment See comment See comment Outcome not reported
of exacerbations
Hospitalisations for in- See comment See comment See comment See comment See comment Outcome not reported
fective exacerbations
Adverse events See comment See comment See comment See comment See comment Outcome not reported
life
Symptoms Mean mucus production Mean mucus volume pro- MD 0.40 30 ⊕⊕

mucus volume produc- 0.93 mL duction day 15 in the in- (-0.03 to 0.83) (1 study) low1,2
tion tervention groups was
Follow-up: 15 days 0.4 mL higher
(0.03 lower to 0.83
higher)
Lung function change in Mean change on placebo Mean change in FEV1 at MD 200 mL (40 to 360) 30 ⊕⊕
FEV1 (L) at day 15 was 0 mL day 15 in the intervention (1 study) low1,2
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).
2 One point deducted to reflect imprecision (data contributed by one small study).
18
DISCUSSION 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
Summary of main results advocate the use of erdosteine, and further studies are required.
Randomised controlled trials are needed to examine the role of
Only four trials could be included in this review, and the results
the other available mucolytics in stable bronchiectasis and in the
of one of the trials could not be entered into the meta-analysis,
subset of patients experiencing exacerbations.
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 Overall completeness and applicability of
on outcomes important to the patient, such as quality of life. evidence
The study by Olivieri 1991 tested the efficacy of adding bromhex-
ine hydrochloride to an antibiotic during an acute infective exac- Only three trials (with a total of 498 participants) provided data
erbation. The test dose chosen, 30 mg orally three times per day, is to this review, and opportunities for aggregation of the data were
higher than the dose currently used in conventional medical prac- very limited. Several studies included a small number of partici-
tice. The drug was effective in improving sputum expectoration pants with bronchiectasis in samples including participants with
after ten days’ treatment in participants with an acute exacerbation a range of respiratory conditions, and it was not possible to iso-
of bronchiectasis. It further reduced sputum production at seven, late the bronchiectasis data in those trials (details provided in
10 and 16 days. It reduced cough significantly at only one time Characteristics of excluded studies). The overall completeness and
point and improved quality of sputum on days 13 and 16. The applicability of data eligible for inclusion in this review are there-
FEV1 remained unchanged throughout the trials. fore limited to three very different studies, with only one consider-
The clinical conclusions derived from these data are that oral ing the comparison of bromhexine versus placebo (Olivieri 1991;
bromhexine at a dose above the usual recommended level can be N = 88), one comparing RhDNase versus placebo over a period of
effective in changing sputum production and clearance during an two weeks (Wills 1996; N = 61) and another comparing RhDNase
acute infective exacerbation. This effect was seen after only seven versus placebo over a period of 24 weeks (O’Donnell 1998; N =
days of treatment. It is impossible to judge whether concurrent 349),
use of bromhexine with the antibiotic ceftazidine introduced a
synergistic interaction.
A recommendation for widespread use of bromhexine in
Quality of the evidence
bronchiectasis cannot be made on the basis of one trial alone, and
it is clear that further well-designed randomised controlled studies In terms of random sequence generation, three trials (O’Donnell
are required to evaluate the role of this agent. 1998; Olivieri 1991; Wills 1996) were evaluated as unclear, and
Two trials (O’Donnell 1998; Wills 1996) compared nebulised one (Crisafulli 2007) was judged as low risk. All four were judged
RhDNase versus placebo in participants with chronic bronchiec- to have unclear risk with respect to allocation concealment. On
tasis. Wills 1996 was a two-week study, whereas O’Donnell 1998 performance bias, three trials (O’Donnell 1998; Olivieri 1991;
ran for 24 weeks. Only one of the two trials (Wills 1996) con- Wills 1996) were assessed as low risk, and one (Crisafulli 2007)
sidered RhDNase at 5 mg, and no important significant differ- was assessed as high risk. In terms of blinding of personnel, all
ences favouring RhDNase versus placebo were observed. Both tri- four trials were judged to be at low risk of bias (detection bias).
als 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 qual-
Potential biases in the review process
ity of life assessment, favouring the RhDNase (2.5 mg) arm. In The support provided by the Cochrane Airways Review Group in
the 24-week trial (O’Donnell 1998), the study authors reported a identification of potentially relevant trials is of a very high order;
higher incidence of exacerbations and hospital admissions in the nevertheless, uncertainties regarding study selection bias or publi-
RhDNase arm and higher levels of antibodies to RhDNase in the cation bias are inevitably a concern in all reviews. Failure to iden-
treatment group; stronger evidence would be required to justify tify unpublished trials may lead to an incomplete estimation of
its use outside of a clinical trial. mucolytic agents. Whilst a comprehensive search of the published
Erdosteine combined with physiotherapy slightly improved spu- literature for potentially relevant clinical trials was conducted with-
tum purulence and small but clinically useful changes in spirom- out language restrictions using a systematic search strategy to min-
etry over a 15-day period compared with physiotherapy alone imise the likelihood of bias, we recognise the possibility that ad-
(Crisafulli 2007). No significant improvements were seen at earlier ditional unpublished trials may have been missed.

Agreements and disagreements with other children with non-CF bronchiectasis are clearly needed. These
studies or reviews should examine short-term use of mucolytics with or instead of
antibiotics to reduce exacerbation duration and long-term effects
The availability of data in this update is similar to that in the previ-
of mucolytics on exacerbation frequency and lung function.
ous 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.
ACKNOWLEDGEMENTS
The authors of the original version of this review acknowledged
AUTHORS’ CONCLUSIONS the support of the Cochrane Airways Review Group staff (Steve
Milan, Anna Bara and Jane Dennis) in identifying trials from the
Implications for practice register and in obtaining copies of the papers, as well as edito-
rial support from Dr Peter Gibson, Australian Co-ordinator of
Little evidence is available to recommend the routine use of mu-
the Cochrane Airways Review Group. Anna Bara provided extra
colytics in bronchiectasis. However, bromhexine treatment for
support in teaching us the correct way to use RevMan. They also
longer than seven days at a high dose has been reported to pro-
thanked Professors Tom Petty and Dario Olivieri for responding
duce some beneficial changes in sputum production and clearance
to correspondence and supplying additional data to allow assess-
during an acute exacerbation. This finding is based on one rather
ment of whether some studies should be included.
old trial (Olivieri 1991) that included only 88 participants. Lung
function was not altered with this drug, and quality of life and In the 2013 update, we would particularly like to acknowledge the
other outcome measures were not examined. No trial evidence ex- contributions of Josephine M Cranston, John H Alpers, Karen M
ists at all for its use for longer than about two weeks. Latimer, authors of the original version of this review (Crockett
Erdosteine in combination with physiotherapy showed a small 2001), and the excellent support and assistance received from
benefit in spirometric parameters and sputum purulence after 15 Emma Welsh, Liz Stovold and Emma Jackson of the Cochrane
days compared with physiotherapy alone. This finding comes from Airways Review Group, together with greatly appreciated guid-
one small trial in stable older participants with mucus hypersecre- ance from Chris Cates (Cochrane Airways Review Group Co-or-
tion, which did not use a placebo (Crisafulli 2007). dinating Editor). We would also like to thank Diogo Bugano, Fed-
erica Davolio, Zhirajr Mokini Poturljan and Uwe Wollina for help
Evidence is insufficient to allow a firm recommendation for either with translation of non-English language studies. We are grateful
agent. to Yoshinori Hasegawa for providing helpful clarification of non-
Evidence has suggested possible harm and no evidence of benefit availability of bronchiectasis participants’ data from Itoh 1984.
from RhDNase in non-CF bronchiectasis. This drug should not The support provided by librarians Judith Scammel, Jane Apple-
be used routinely in this condition. ton and Hilary Garrett at St Georges University London is also
very much appreciated.
Implications for research Michael Greenstone was the Editor of this review and commented
Further randomised controlled trials of mucolytics in adults and critically on the review.
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crossover trial. Chronic Respiratory Disease 2007;4(2):67–74.
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Sahay JN, Chatterjee SS, Ingram DF. The effect of methyl bronchiectasis. www.brit-thoracic.org.uk/LinkClick.aspx?
cysteine (Visclair) in respiratory diseases. A pilot study. link=496&tabid=69 (accessed 15 November 2013).
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Serisier DJ, Martin ML, McGuckin MA, Lourie R, penetration of orally administered N-acetylcysteine into
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diagnosis and management in 21st century. Postgraduate
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de Souza HCD, Gastaldi AC. The influence of Flutter March 2011]. The Cochrane Collaboration, 2011.
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Verstraeten 1979 {published data only} Childhood. Education and Practice Edition 2010;95:73–82.
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guidelines/ (accessed 15 November 2013). ∗
Indicates the major publication for the study

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 er-
dosteine, diabetes, liver failure or cancer were also excluded from the study
Participants were enrolled in the hospital’s 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 subjec-
tive semi-quantitative score of sputum characteristics) of erdosteine used adjunctive to
routine chest physiotherapy in the study population. Secondary end point was to as-
sess 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 Randomisation sequence achieved by se-
bias) lecting from an eight-block number table
Allocation concealment (selection bias) Unclear risk Not specified in trial report

Crisafulli 2007 (Continued)
Blinding of participants and personnel High risk Open-label study

(performance bias)
All outcomes
Blinding of outcome assessment (detection Low risk All measurements assessed by personnel
bias) blinded and not directly associated with
All outcomes study administration
Incomplete outcome data (attrition bias) Unclear risk No withdrawals reported

All outcomes
Selective reporting (reporting bias) Unclear risk No apparent indication of selective report-
ing
Other bias Unclear risk No other indication of bias
O’Donnell 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 (stan-
dard 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

O’Donnell 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
Random sequence generation (selection Unclear risk Not reported

bias)
Allocation concealment (selection bias) Unclear risk Not reported
Blinding of participants and personnel Low risk Double-blind

(performance bias)
All outcomes
Blinding of outcome assessment (detection Low risk Double-blind and CT scans analysed by ra-
bias) diologists outside the study
All outcomes
Incomplete outcome data (attrition bias) Low risk Two placebo-treated participants (one with
All outcomes self limited haemoptysis and one with sinus
symptoms) and one RhDNase-treated par-
ticipant with increased sputum production
withdrew from the study

O’Donnell 1998 (Continued)
ing
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)

Blinding of participants and personnel Low risk Double-blind with matching placebo
(performance bias)
All outcomes
Blinding of outcome assessment (detection Low risk Double-blind with matching placebo
bias)
All outcomes
Incomplete outcome data (attrition bias) High risk Only 67 participants contributed data to
All outcomes the FEV1 and % change in mean spu-
tum volume after 10 days of treatment out-
comes. Trial report does not clarify why
data on these outcomes are available for
only 76% of participants
ing bias
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, con-
firmed 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:

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)
Blinding of participants and personnel Low risk Double-blind

(performance bias)
All outcomes
Blinding of outcome assessment (detection Low risk Double-blind

bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk All participants completed all scheduled
All outcomes visits
ing
Other bias Unclear risk No other clear indication of bias

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

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 bronchiec-
tasis. 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 Participants did not have a diagnosis of bronchiectasis
Bergogne 1985 The study combined participants with chronic bronchitis and bronchiectasis. Separate data from the bronchiec-
tasis 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 Participants did not have a diagnosis of bronchiectasis
Germouty 1988 Participants did not have a diagnosis of bronchiectasis
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 Participants did not have a diagnosis of bronchiectasis

(Continued)
Hasani 1994A Not a mucolytic agent
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 Not a mucolytic agent
Noone 1999 Intervention not used as a mucolytic agent but to enhance cilia function, changing the consistency/secretion of
mucin
Patterson 2007 Not a mucolytic agent
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 Not a mucolytic agent
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 Not a mucolytic agent
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 Not a mucolytic agent
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 Not a mucolytic agent
Yalçin 2006 Not a mucolytic agent

DATA AND ANALYSES
Comparison 1. Bromhexine versus placebo
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Adverse events 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
2 FEV1 (mL) 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
2.1 At 7 days 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.2 At 13 days 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
Comparison 2. 5 mg RhDNase versus placebo
No. of No. of
1 Hospitalisations for infective 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
exacerbations
2 % change FEV1 at day 15 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
3 % change FVC at day 15 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
4 Quality of Life 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
4.1 Cough and congestion 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.2 Dyspnoea 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.3 Basic activity limitations 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.4 Intermediate activity 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
limitations
4.5 Emotional well-being 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.6 Fatigue 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.7 Not able to carry out usual 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
activities
4.8 Days stayed in bed 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.9 Perception of overall 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
health
5 Sputum colour 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
6 Deaths 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected

Comparison 3. 2.5 mg RhDNase versus placebo
No. of No. of
1 Hospitalisations for infective 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
exacerbations
2 % change FEV1 at day 15 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
3 % change FVC at day 15 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
4 Quality of life 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
4.1 Cough and congestion 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.2 Dyspnoea 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.3 Basic activity limitations 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.4 Intermediate activity 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
limitations
4.5 Emotional well-being 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.6 Fatigue 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.7 Not able to carry out usual 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
activities
4.8 Days stayed in bed 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.9 Perception of overall 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
health
5 Sputum colour 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
6 Deaths 2 390 Odds Ratio (M-H, Fixed, 95% CI) 3.09 [0.32, 29.98]
7 Antibodies to RhDNase 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
Comparison 4. Erdosteine versus no treatment
No. of No. of
1 Mucus density 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
1.1 Day five 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.2 Day 10 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
2 Mucus purulence 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
3 Mucus volume production 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
4 Change in FEV1 (mL) at day 15 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
5 Change in FEV1 %Pred at day 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
15
6 Change in FVC (mL) at day 15 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
7 Change in FVC %Pred at day 15 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected

Analysis 1.1. Comparison 1 Bromhexine versus placebo, Outcome 1 Adverse events.
Review: Mucolytics for bronchiectasis
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
Olivieri 1991 1/45 0/43 2.93 [ 0.12, 73.97 ]
0.01 0.1 1 10 100

Favours Bromhexine Favours Placebo
Analysis 1.2. Comparison 1 Bromhexine versus placebo, Outcome 2 FEV1 (mL).
Comparison: 1 Bromhexine versus placebo
Outcome: 2 FEV1 (mL)
Mean Mean
Study or subgroup Control Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 At 7 days
Olivieri 1991 34 1740.4 (712.5423) 33 1631.8 (751.9633) 108.60 [ -242.38, 459.58 ]
2 At 13 days
Olivieri 1991 34 1797.8 (693.8833) 33 1613.8 (699.6877) 184.00 [ -149.75, 517.75 ]
-500 -250 0 250 500

Favours Bromhexine Favours Placebo

Analysis 2.1. Comparison 2 5 mg RhDNase versus placebo, Outcome 1 Hospitalisations for infective
exacerbations.
Comparison: 2 5 mg RhDNase versus placebo
Outcome: 1 Hospitalisations for infective exacerbations
Study or subgroup 5 mg rhDNase Placebo Odds Ratio Odds Ratio

Wills 1996 2/20 0/20 5.54 [ 0.25, 123.08 ]
0.01 0.1 1 10 100

Favours rhDNase Favours placebo
Analysis 2.2. Comparison 2 5 mg RhDNase versus placebo, Outcome 2 % change FEV1 at day 15.
Outcome: 2 % change FEV1 at day 15
Mean Mean
Study or subgroup 5 mg rhDNase Placebo Difference Difference
Wills 1996 20 1.6 (7.6026) 20 -0.5 (8.4971) 2.10 [ -2.90, 7.10 ]
-10 -5 0 5 10
Favours Placebo Favours rhDNase

Analysis 2.3. Comparison 2 5 mg RhDNase versus placebo, Outcome 3 % change FVC at day 15.
Outcome: 3 % change FVC at day 15
Mean Mean
Wills 1996 20 1.1 (6.7082) 20 3.1 (6.7082) -2.00 [ -6.16, 2.16 ]
-10 -5 0 5 10
Analysis 2.4. Comparison 2 5 mg RhDNase versus placebo, Outcome 4 Quality of Life.
Outcome: 4 Quality of Life
Mean Mean
1 Cough and congestion

Wills 1996 20 1.5 (3.1305) 20 1 (3.5777) 0.50 [ -1.58, 2.58 ]
2 Dyspnoea
Wills 1996 20 0 (4.0249) 20 0 (2.6833) 0.0 [ -2.12, 2.12 ]
3 Basic activity limitations

Wills 1996 20 0 (1.3416) 20 -0.3 (0.8944) 0.30 [ -0.41, 1.01 ]
4 Intermediate activity limitations

Wills 1996 20 -1.5 (5.8138) 20 1.7 (4.0249) -3.20 [ -6.30, -0.10 ]
5 Emotional well-being
Wills 1996 20 0.1 (2.2361) 20 0.2 (1.3416) -0.10 [ -1.24, 1.04 ]
6 Fatigue
-1 -0.5 0 0.5 1
Favours placebo Favours rhDNase
(Continued . . . )

(. . . Continued)
Mean Mean
Wills 1996 20 -1 (2.6833) 20 0.9 (3.5777) -1.90 [ -3.86, 0.06 ]
7 Not able to carry out usual activities

Wills 1996 20 0.3 (0.8944) 20 -0.1 (0.8944) 0.40 [ -0.15, 0.95 ]
8 Days stayed in bed

Wills 1996 20 0.1 (0.4472) 20 -0.1 (0.4472) 0.20 [ -0.08, 0.48 ]
9 Perception of overall health

Wills 1996 20 -0.4 (2.2361) 20 0.3 (1.3416) -0.70 [ -1.84, 0.44 ]
-1 -0.5 0 0.5 1
Analysis 2.5. Comparison 2 5 mg RhDNase versus placebo, Outcome 5 Sputum colour.
Outcome: 5 Sputum colour
Mean Mean
Wills 1996 20 3.48 (0.4919) 20 3.2 (0.5367) 0.28 [ -0.04, 0.60 ]
-0.5 -0.25 0 0.25 0.5

Favours rhDNase Favours Placebo

Analysis 2.6. Comparison 2 5 mg RhDNase versus placebo, Outcome 6 Deaths.
Outcome: 6 Deaths
Study or subgroup 5 mg rhDNase Placebo Odds Ratio Odds Ratio

Wills 1996 0/20 0/20 Not estimable
0.01 0.1 1 10 100

Analysis 3.1. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 1 Hospitalisations for infective
exacerbations.
Comparison: 3 2.5 mg RhDNase versus placebo
Outcome: 1 Hospitalisations for infective exacerbations
Study or subgroup 2.5 mg rhDNase Placebo Odds Ratio Odds Ratio

0.01 0.1 1 10 100


Analysis 3.2. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 2 % change FEV1 at day 15.
Outcome: 2 % change FEV1 at day 15
Mean Mean
Study or subgroup 2.5 mg rhDNase Placebo Difference Difference
Wills 1996 21 1.6 (11.4564) 20 -0.5 (8.4971) 2.10 [ -4.05, 8.25 ]
-10 -5 0 5 10
Analysis 3.3. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 3 % change FVC at day 15.
Outcome: 3 % change FVC at day 15
Mean Mean
Wills 1996 21 0.7 (6.4156) 20 3.1 (6.7082) -2.40 [ -6.42, 1.62 ]
-10 -5 0 5 10

Analysis 3.4. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 4 Quality of life.
Outcome: 4 Quality of life
Mean Mean
1 Cough and congestion

Wills 1996 21 0.3 (3.6661) 20 1 (3.5777) -0.70 [ -2.92, 1.52 ]
2 Dyspnoea
Wills 1996 21 1.7 (2.291) 20 0 (2.683) 1.70 [ 0.17, 3.23 ]
3 Basic activity limitations

Wills 1996 21 0.2 (1.3748) 20 -0.3 (0.8944) 0.50 [ -0.21, 1.21 ]
4 Intermediate activity limitations

Wills 1996 21 1 (3.2078) 20 1.7 (4.0249) -0.70 [ -2.93, 1.53 ]
5 Emotional well-being
Wills 1996 21 -0.6 (2.2913) 20 0.2 (1.3416) -0.80 [ -1.94, 0.34 ]
6 Fatigue
Wills 1996 21 -1.1 (3.6661) 20 0.9 (3.5777) -2.00 [ -4.22, 0.22 ]
7 Not able to carry out usual activities

Wills 1996 21 0.1 (0.4583) 20 -0.1 (0.8944) 0.20 [ -0.24, 0.64 ]
8 Days stayed in bed

Wills 1996 21 0.01 (0.4583) 20 -0.1 (0.4472) 0.11 [ -0.17, 0.39 ]
9 Perception of overall health

Wills 1996 21 -0.3 (0.9165) 20 0.3 (1.3416) -0.60 [ -1.31, 0.11 ]
-4 -2 0 2 4

Analysis 3.5. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 5 Sputum colour.
Outcome: 5 Sputum colour
Mean Mean
Wills 1996 21 3.4 (0.5041) 20 3.2 (0.5367) 0.20 [ -0.12, 0.52 ]
-0.5 -0.25 0 0.25 0.5
Analysis 3.6. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 6 Deaths.
Outcome: 6 Deaths
Study or subgroup 2.5 mg rhDNase Placebo Odds Ratio Weight Odds Ratio
O’Donnell 1998 3/173 1/176 100.0 % 3.09 [ 0.32, 29.98 ]
Total (95% CI) 194 196 100.0 % 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 1 10 100


Analysis 3.7. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 7 Antibodies to RhDNase.
Outcome: 7 Antibodies to RhDNase
Study or subgroup 2.5 mg rhDNase Placebo Odds Ratio Odds Ratio

O’Donnell 1998 24/173 1/176 28.19 [ 3.77, 210.85 ]
0.005 0.1 1 10 200

Analysis 4.1. Comparison 4 Erdosteine versus no treatment, Outcome 1 Mucus density.
Comparison: 4 Erdosteine versus no treatment
Outcome: 1 Mucus density
Mean Mean
Study or subgroup Erdosteine Control Difference Difference
1 Day five
Crisafulli 2007 15 1.6 (0.48) 15 1.67 (0.48) -0.07 [ -0.41, 0.27 ]
2 Day 10
Crisafulli 2007 15 1.13 (0.51) 15 1.4 (0.63) -0.27 [ -0.68, 0.14 ]
3 Day 15
Crisafulli 2007 15 0.8 (0.56) 15 1.07 (0.45) -0.27 [ -0.63, 0.09 ]
-1 -0.5 0 0.5 1
Favours erdosteine Favours control

Analysis 4.2. Comparison 4 Erdosteine versus no treatment, Outcome 2 Mucus purulence.
Outcome: 2 Mucus purulence
Mean Mean
1 Day five
Crisafulli 2007 15 1 (0.53) 15 1.03 (0.37) -0.03 [ -0.36, 0.30 ]
2 Day 10
Crisafulli 2007 15 0.6 (0.63) 15 0.8 (0.41) -0.20 [ -0.58, 0.18 ]
3 Day 15
Crisafulli 2007 15 0.33 (0.48) 15 0.8 (0.41) -0.47 [ -0.79, -0.15 ]
-1 -0.5 0 0.5 1
Analysis 4.3. Comparison 4 Erdosteine versus no treatment, Outcome 3 Mucus volume production.
Outcome: 3 Mucus volume production
Mean Mean
1 Day five
Crisafulli 2007 15 0.47 (0.64) 15 0.6 (0.73) -0.13 [ -0.62, 0.36 ]
2 Day 10
Crisafulli 2007 15 1.07 (0.59) 15 0.87 (0.74) 0.20 [ -0.28, 0.68 ]
3 Day 15
Crisafulli 2007 15 1.33 (0.48) 15 0.93 (0.7) 0.40 [ -0.03, 0.83 ]
-1 -0.5 0 0.5 1

Analysis 4.4. Comparison 4 Erdosteine versus no treatment, Outcome 4 Change in FEV1 (mL) at day 15.
Outcome: 4 Change in FEV1 (mL) at day 15
Mean Mean
Crisafulli 2007 15 200 (300) 15 0 (100) 200.00 [ 39.97, 360.03 ]
-500 -250 0 250 500

Favours control Favours erdosteine
Analysis 4.5. Comparison 4 Erdosteine versus no treatment, Outcome 5 Change in FEV1 %Pred at day 15.
Outcome: 5 Change in FEV1 %Pred at day 15
Mean Mean
Crisafulli 2007 15 5.8 (13.3) 15 1.3 (7) 4.50 [ -3.11, 12.11 ]
-100 -50 0 50 100


Analysis 4.6. Comparison 4 Erdosteine versus no treatment, Outcome 6 Change in FVC (mL) at day 15.
Outcome: 6 Change in FVC (mL) at day 15
Mean Mean
Crisafulli 2007 15 300 (500) 15 0 (200) 300.00 [ 27.48, 572.52 ]
-500 -250 0 250 500

Analysis 4.7. Comparison 4 Erdosteine versus no treatment, Outcome 7 Change in FVC %Pred at day 15.
Outcome: 7 Change in FVC %Pred at day 15
Mean Mean
Crisafulli 2007 15 9.5 (20.8) 15 0.6 (8.9) 8.90 [ -2.55, 20.35 ]
-100 -50 0 50 100


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

MEDLINE search strategy used to identify trials for the CAGR
Bronchiectasis search
1. exp Bronchiectasis/
2. bronchiect$.mp.
3. bronchoect$.mp.
4. kartagener$.mp.
5. (ciliary adj3 dyskinesia).mp.
6. (bronchial$ adj3 dilat$).mp.
7. or/1-6
Filter to identify RCTs

1. exp “clinical trial [publication type]”/
2. (randomised or randomised).ab,ti.
3. placebo.ab,ti.
4. dt.fs.
5. randomly.ab,ti.
6. trial.ab,ti.
7. groups.ab,ti.
8. or/1-7
9. Animals/
10. Humans/
11. 9 not (9 and 10)
12. 8 not 11
The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases
Appendix 2. Search strategy for the Cochrane Airways Group Register
2013 update
#1 BRONCH:MISC1
#2 MeSH DESCRIPTOR Bronchiectasis Explode All
#3 bronchiect*
#4 #1 or #2 or #3
#5 MeSH DESCRIPTOR Expectorants
#6 mucolytic*
#7 “mucociliary clearance”
#8 N-acetylcysteine
#9 bromhexine
#10 S-carboxymethylcysteine
#11 ambroxol
#12 sobrerol
#13 “iodinated glycerol”
#14 “human DNase”
#15 RhDNase
#16 Bromhexine
#17 #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16
#18 #4 and #17
[Note; in search line #1, MISC1 denotes the field where the reference has bene coded for condition, in this case, bronchiectasis]

Previous versions
Mucolytic* or “mucociliary clearance” or N-acetylcysteine or bromhexine or S-carboxymethylcysteine or ambroxol or sobrerol or
“iodinated glycerol” or “human DNase” or RhDNase or Bromhexine
[Limited to bronchiectasis records]
WHAT’S NEW
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 (in-
cluding 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

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


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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

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

Mucolytics for bronchiectasis (Review)

Mucolytics for bronchiectasis (Review) i

Mucolytics for bronchiectasis

Editorial group: Cochrane Airways Group.

PLAIN LANGUAGE SUMMARY

Mucolytics for bronchiectasis (Review) 3

Bromhexine compared with placebo for bronchiectasis

Patient or population: patients with bronchiectasis

Assumed risk Corresponding risk

Adverse events 0 per 100 3 2.2 per 100 OR 2.93 88 ⊕⊕

GRADE Working Group grades of evidence.

Description of the intervention

Mucolytics for bronchiectasis (Review) 6

Electronic searches Data extraction and management

Mucolytics for bronchiectasis (Review) 7

Assessment of reporting biases RESULTS

Mucolytics for bronchiectasis (Review) 8

Mucolytics for bronchiectasis (Review) 9

Mucolytics for bronchiectasis (Review) 10

Mucolytics for bronchiectasis (Review) 11

Mucolytics for bronchiectasis (Review) 12

Mucolytics for bronchiectasis (Review) 13

Mucolytics for bronchiectasis (Review) 14

5 mg RhDNase compared with placebo for bronchiectasis

Patient or population: patients with bronchiectasis

Assumed risk Corresponding risk

Hospitalisations for in- 0 per 100 3 10 per 100 OR 5.54 40 ⊕⊕

GRADE Working Group grades of evidence.

Erdosteine versus no treatment for bronchiectasis

Patient or population: patients with bronchiectasis

Assumed risk Corresponding risk

Symptoms Mean mucus production Mean mucus volume pro- MD 0.40 30 ⊕⊕

(40 to 360 mL higher)

GRADE Working Group grades of evidence.

Mucolytics for bronchiectasis (Review) 19

Mucolytics for bronchiectasis (Review) 23

Characteristics of included studies [ordered by study ID]

Methods Prospective, randomised, parallel, open-label, pilot study

Notes 15-Day trial

Bias Authors’ judgement Support for judgement

Mucolytics for bronchiectasis (Review) 24

Blinding of participants and personnel High risk Open-label study

Incomplete outcome data (attrition bias) Unclear risk No withdrawals reported

Other bias Unclear risk No other indication of bias

Methods Double-blind, randomised, placebo-controlled, multi-centre study

Mucolytics for bronchiectasis (Review) 25

within 180 days of randomisation. Active allergic bronchopulmonary aspergillosis,

Interventions Run-in: three times clinical evaluation before drug administration

Notes 24-Week trial

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not reported

Allocation concealment (selection bias) Unclear risk Not reported

Blinding of participants and personnel Low risk Double-blind

Mucolytics for bronchiectasis (Review) 26

Other bias Unclear risk No other indication of bias

Methods Double-blind, randomised, multi-centre study (four-centre study)

Notes 15-Day trial

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not reported