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Inhaled hyperosmolar agents for bronchiectasis

  1. Anna Hart1,
  2. Karnam Sugumar2,
  3. Stephen J Milan3,*,
  4. Stephen J Fowler4,5,
  5. Iain Crossingham6

Editorial Group: Cochrane Airways Group

Published Online: 12 MAY 2014

Assessed as up-to-date: 2 APR 2014

DOI: 10.1002/14651858.CD002996.pub3


How to Cite

Hart A, Sugumar K, Milan SJ, Fowler SJ, Crossingham I. Inhaled hyperosmolar agents for bronchiectasis. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD002996. DOI: 10.1002/14651858.CD002996.pub3.

Author Information

  1. 1

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

  2. 2

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

  3. 3

    St George's, University of London, Population Health Sciences and Education, London, UK

  4. 4

    University Hospital of South Manchester, University of Manchester, NIHR Respiratory and Allergy Clinical Research Facility, Manchester, UK

  5. 5

    Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK

  6. 6

    Royal Blackburn Hospital, Blackburn, Lancashire, UK

*Stephen J Milan, Population Health Sciences and Education, St George's, University of London, London, UK. s.milan@lancaster.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 12 MAY 2014

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Summary of findings    [Explanations]

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

 
Summary of findings for the main comparison. Inhaled mannitol versus placebo for bronchiectasis

Inhaled mannitol versus placebo for bronchiectasis

Patient or population: patients with bronchiectasis
Settings: community
Intervention: Inhaled mannitol

Comparison: placebo

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

Assumed riskCorresponding risk

PlaceboInhaled mannitol versus placebo

Exacerbations

Exacerbation rate per year.

Follow-up: 12 months
See commentSee commentRR 0.92

(0.78 to 1.08)
461

(1 study)
⊕⊕⊕⊝

moderate1
These data for this study are unpublished and were presented in summarised form the European Respiratory Society Conference 2013

Hospitalisations

Number of participants experiencing one of more hospitalisations.

Follow-up: 12 months
See commentSee commentRR 0.61

(0.34, 1.09)
461

(1 study)
⊕⊕⊕⊝

moderate1
These data for this study are unpublished and were presented in summarised form the European Respiratory Society Conference 2013

Adverse events

Follow-up: 12 weeks (Bilton 2013) and 12 months (NCT00669331)
894 per 1000890 per 1000
(837 to 927)
OR 0.96
(0.61 to 1.51)
804
(2 studies)
⊕⊕⊕⊝

moderate2
Bilton: "In both cohorts, most AEs were unrelated to study treatment. " There was also no significant difference between the two conditions with respect to SAEs OR 0.79 [0.52, 1.19]

MortalitySee commentSee commentSee commentSee commentSee commentNo deaths reported in any study

Health-related quality of life measured on the SGRQ

Scale from 0 to 100. Low on the scale is better.

Follow-up: 2 weeks (Daviskas 2004), 12 weeks (Bilton 2013) and 12 months (NCT00669331)
The mean change from baseline in the SGRQ total score in the intervention groups was
-2.05 standard deviations higher
(-3.69 lower to -0.40 higher)
MD -2.05

(-3.69 to -0.40)
840

(3 studies)
⊕⊕⊕⊝

moderate2

Symptoms

Bronchiectasis Symptoms Questionnaire Follow-up: 12 weeks
The mean symptom score was 28.4The mean symptom score was 1.20 lower (3.91 lower to 1.51 higher]MD -1.20 (-3.91 to 1.51)343

(1 study)
⊕⊕⊕⊝

moderate3

Lung function

FEV1 (L)

Follow-up: 12 weeks
The mean FEV1 was 1.95 LThe mean change in FEV1 was 0.03 L lower (0.10 lower to 0.16 higher)MD 0.03 (-0.10, 0.16)343

(1 study)
⊕⊕⊕⊝

moderate3

*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; MD: mean difference; OR: Odds ratio; SGRQ: St George's Respiratory Questionairre

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 (-1 limitations) One point deducted based on risk of bias assessment of trial NCT00669331
2 (-1 inconsistency) One point deducted to reflect the variability among the included studies with respect to risk of bias
3 (-1 limitations) One point deducted based on risk of bias assessment of trial Bilton 2013

 Summary of findings 2 Hypertonic saline versus isotonic saline for bronchiectasis

 

Background

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

Description of the condition

Bronchiectasis is a disorder of the lungs characterised by irreversible dilatation of the bronchi. It is the end result of a number of different insults to the lungs. These include inherited diseases of the lungs’ defence mechanisms, such as ciliary dyskinesia and primary immunodeficiencies, congential structural lung abnormalities and acquired problems, such as the aftermath of tuberculosis or childhood respiratory infection, large airway obstruction and chronic inflammatory conditions (for example, rheumatoid arthritis). Many cases of bronchiectasis are idiopathic (Anwar 2013). Cystic fibrosis is the cause of the majority of cases of severe bronchiectasis (Sly 2013), however the management of cystic fibrosis-related bronchiectasis is considered separately in other reviews.

Impaired lung defences, changes in mucus consistency and mechanical obstruction of the bronchi all lead to a higher risk of lung infection and associated damage and dilatation of the bronchi. This dilatation in turn promotes mucus retention, leading to further and more protracted pulmonary infection and hence, a vicious cycle of disease progression.

The true population prevalence of bronchiectasis is unknown (Frey 2007; Shoemark 2007). Weycker 2005 suggested the prevalence could be as high as 270 cases per 100,000 in the over 75s. Bronchiectasis frequently complicates other respiratory diseases, such as chronic obstructive pulmonary disease (COPD) where its presence is an independent predictor of mortality (Martinez 2013).

Diagnosis is by high resolution computed tomography of the thorax (Bonavita 2012) in patients with symptoms of chronic or recurrent pulmonary suppuration.

 

Description of the intervention

Inhaled hyperosmolar agents are used in conditions, such as non-cystic fibrosis bronchiectasis, cystic fibrosis, COPD and asthma (Daviskas 1996; Elkins 2006a; Pavia 1978). The aim of treatment is to facilitate tracheo-bronchial mucous clearance. The first documented use of such a strategy was in 1978 using nebulised 1.21 M saline (approximately 7% saline) (Pavia 1978). Since then concentrations from 3% to 14.4% (Daviskas 1996; Robinson 1997) have been used in various studies. Various devices have been used to drive the nebulisation, from air-driven small-volume chambers, as typically used for delivering nebulised bronchodilators in asthma, through to low- and high-volume ultrasonic devices. The nebulisation process can be somewhat cumbersome and time consuming. Inhaled dry powder mannitol, which was developed initially as a bronchial challenge agent in asthma, is being increasingly used as an alternative. It is delivered from capsules via a purpose-designed inhaler device.

National guidelines on the diagnosis and management of bronchiectasis from several countries (BTS 2010; TSANZ 2010) generally ignore hyperosmolar agents on the grounds of insufficient evidence to make a positive recommendation. Anecdotally however hyperosmolar agents, particularly hypertonic saline, are increasingly prescribed in clinical practice.

 

How the intervention might work

The key clinical feature of bronchiectasis is chronic mucus hypersecretion, mucus retention or both. These are central to the vicious cycle of disease progression described above, causing the characteristic chronic productive cough and predisposing to recurrent lower respiratory tract infections. One of the central tenets of treatment for bronchiectasis is therefore the application of strategies to facilitate mucus clearance. This includes chest clearance manoeuvres instigated and taught by specialist respiratory physiotherapists (Pasteur 2010). Such clearance is however hindered both by the volume but also the viscosity of the sputum.

Whilst the specific clinically relevant mechanism has not been elucidated, hyperosmolar agents are used principally to reduce sputum viscosity and therefore ease chest clearance. When inhaled they are deposited in the airway, and the consequence of their hyperosmolarity in theory is that they draw fluid from the airway epithelium onto the mucosal surface and hence into contact with the mucous (Wills 2006). This then has the effect of both loosening the mucous and making it less viscous (Shibuya 2003; Wills 1997) which (particularly when used together with effective chest clearance techniques) will facilitate expectoration (Daviskas 2001; Kellett 2005).

One potential disadvantage of such agents occurs where there might be an asthmatic element to the bronchiectasis, such as in allergic bronchopulmonary aspergillosis. Inhaled hyperosmolar agents also have the effect of desiccating airway inflammatory cells, disrupting the cell membrane and causing release of bronchoconstricting and pro-inflammatory mediators, such as histamine and leukotrienes. This may cause significant acute bronchoconstriction, and hence it is recommended that a supervised test dose be administered with spirometry or peak expiratory flow (PEF) measurements before and after (Pasteur 2010). Those at risk of bronchial hyperresponsiveness should be pre-treated with an inhaled bronchodilator (Pasteur 2010).

Potential non-mucolytic mechanisms for the benefit of hypertonic saline could arise from its relative pro- and anti-inflammatory effects. Recent in vitro studies suggest that high concentrations of salt induce type 17 helper T lymphocytes, which in turn produce the antibacterial cytokines interleukins 17, 21 and 22 (Kleinewietfeld 2013; Wu 2013). It also may also have beneficial antiinflammatory effects by decreasing local interleukin 8 levels (Reeves 2011).

 

Why it is important to do this review

Clinically bronchiectasis manifests as chronic mucus production, along with a variable amount of airflow limitation. Mucus hypersecretion is a distressing symptom. Mucus plugging (obstruction of small- or medium-sized airways with mucus) can cause breathlessness and hypoxia. Inhaled hyperosmolar agents should in theory draw water into the airways, particularly the airway surface layer of fluid (Enderby 2007). This has the effect of improving ciliary function, of making sputum thinner, more watery and easier to cough out, and of stimulating cough (Elkins 2006), thus improving mucus clearance and the reducing risk of mucus plugging. If inhaled hyperosmolar agents are able to reduce these effects to a clinically significant degree in vivo, they would be useful drugs in the treatment of non-cystic fibrosis bronchiectasis.

 

Objectives

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

To determine whether inhaled hyperosmolar treatments are effective in the treatment of bronchiectasis.

 

Methods

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

Criteria for considering studies for this review

 

Types of studies

Any randomised trial comparing treated and untreated patients with bronchiectasis.

 

Types of participants

People with bronchiectasis of any cause except cystic fibrosis.

 

Types of interventions

Inhalation of any hyperosmolar substance, either single dose or more prolonged treatment.

 

Types of outcome measures

 

Primary outcomes

  • Frequency and duration of exacerbations
  • Hospitalisations
  • Adverse events

 

Secondary outcomes

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

 

Search methods for identification of studies

 

Electronic searches

We identified trials from the Cochrane Airways Group's 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 WHO trials portal (www.who.int/ictrp/en/). We searched all databases from their inception up to April 2014, with no restriction on language of publication.

 

Searching other resources

We searched all reference lists of available primary studies and review articles to identify other potentially relevant citations.

 

Data collection and analysis

 

Selection of studies

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

 

Data extraction and management

Data for included trials were extracted independently by two review authors (AH and IC) and entered into The Cochrane Collaboration's software program (Review Manager (RevMan)).

 

Assessment of risk of bias in included studies

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

 

Measures of treatment effect

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

 

Unit of analysis issues

The unit of analysis was the patient.

 

Dealing with missing data

We planned to contact authors if outcome data or information on trial design were missing; this was necessary in just one case Chandra 2008 and we are awaiting a response.

 

Assessment of heterogeneity

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

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

 

Assessment of reporting biases

We planned to examine publication bias 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 asymmetric funnel plot can reflect heterogeneity, outcome reporting bias and small-study effects and may therefore not necessarily reflect publication bias.

 

Data synthesis

 

'Summary of findings' table

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

  • Frequency and duration of exacerbations
  • Hospitalisations
  • Adverse events
  • Mortality
  • Symptoms: cough, sputum volume and ease of expectoration, wheeze, dyspnoea
  • Lung function
  • Health-related quality of life (e.g. SF-36 and St George's Respiratory Questionnaire (SGRQ)

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 which contribute data to the meta-analyses for the prespecified outcomes. We used methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEpro software. We justified all decisions to down- or up-grade the quality of studies using footnotes and included comments to aid reader's understanding of the review where necessary.

 

Subgroup analysis and investigation of heterogeneity

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

  • Dose (160 mg, 320 mg and 480 mg). This was feasible with the available data only the in inhaled mannitol versus no treatment comparison) As data were used in each subgroup from the same trial, the data from the subgroups were not aggregated.
  • Time (three, six and 12 months). This was feasible with the available data only in the hypertonic saline versus isotonic saline comparison. Again as data were used in each subgroup from the same trial, the data from the subgroups were not aggregated.

 

Sensitivity analysis

Sensitivity analyses were performed by comparing random-effects versus fixed-effect modelling.

 

Results

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

Description of studies

 

Results of the search

Thirty-six reports were identified in the searches up to April 2014 (Figure 1). They were independently evaluated against the inclusion criteria and 22 reports of 11 studies were judged as appropriate for inclusion (details are provided in Characteristics of included studies). Fourteen studies were excluded and they were added to the two identified in the previous version of the review to bring the total to 16.

 FigureFigure 1. Study flow diagram.

 

Included studies

Eleven studies involving 1021 participants met our eligibility criteria; two (Daviskas 1999; Daviskas 2004) of the 11 were identified in the previous version of this review (Wills 2006). We found trials on three separate comparisons: inhaled mannitol versus placebo (five studies), inhaled mannitol versus no treatment (two studies) and hypertonic saline versus isotonic saline (four studies).

 

Inhaled mannitol versus placebo

Five studies on 883 participants (number of participants analysesd) compared inhaled mannitol with placebo (Bennoor 2012 (N = 50, Bilton 2013 (N = 343), Chandra 2008 (N = 12), Daviskas 2004 (N = 17), NCT00669331 (N = 461)). Only one of the five studies (Daviskas 2004) was of cross-over design and the others were parallel group trials.

Only one of the five trials was single blind (Bennoor 2012); the remaining four were double-blind studies (Bilton 2013; Chandra 2008; Daviskas 2004; NCT00669331). Study duration varied between 12 days and 12 months (Bennoor 2012 12 days, Bilton 2013 12 weeks, Chandra 2008 12 weeks, Daviskas 2004 two weeks and NCT00669331 12 months). There was also variation among the doses used in the studies. In Bilton 2013 the comparison was between inhaled 320 mg mannitol versus placebo twice daily. In Bennoor 2012 400 mg mannitol (10 capsules) or placebo was inhaled via rotahaler daily and in Daviskas 2004 the comparison was 400 mg inhaled mannitol versus placebo twice daily. In NCT00669331 mannitol 400 mg twice daily for 52 weeks was compared with matched control 10 capsules twice a day for 52 weeks. Chandra 2008 also used twice daily mannitol inhalation, however the dose is not specified in the trial report.

 

Inhaled mannitol versus no treatment

Two small cross-over studies involving 25 participants) reported this comparison (Daviskas 1999, N = 11; Daviskas 2008 N = 14. In Daviskas 1999 approximately 300 mg inhaled dry powder mannitol was delivered via approximately nine capsules and Daviskas 2008 used 160 mg, 320 mg or 480 mg of mannitol.

 

Hypertonic saline versus isotonic saline

Four studies with 113 participants compared hypertonic saline versus isotonic saline ( Bradley 2011 (N = 19), Kellett 2005 (N = 24), Kellet 2011 (N = 30), Nicolson 2012 (N = 40)). Three of the four studies were cross-over design (Bradley 2011; Kellett 2005; Kellet 2011) and Nicolson 2012 was a 12-month parallel group trial. Only one of the studies Kellet 2011 was single blind; the remaining three were double blind. There was considerable variation among the durations of these trials: Bradley 2011 was a 13-week trial with treatment for four weeks and a two-week washout between treatments,

Kellett 2005 used a single treatment of 10 to 20 minutes in a four-week trial; Kellet 2011 was a eight-month trial with treatments for three months and Nicolson 2012 ran for 12 months. There was relatively little variation among the interventions. Bradley 2011 used twice daily nebulised hypertonic saline (6%) masked with quinine sulfate for isotonic saline versus twice daily isotonic saline (0.9%) (nebulised) masked with quinine sulfate for hypertonic saline. In Kellett 2005 the comparison was between hyperosmolar saline - 7% after nebulised terbutaline versus normal saline after nebulised terbutaline. Kellet 2011 used 4 mL hypertonic saline (7%) once day versus 4 mL isotonic saline (0.9%) once day, and Nicolson 2012 compared hypertonic saline (6%) - 5 mL twice a day via a nebuliser for 12 months versus isotonic saline.

 

Excluded studies

Sixteen studies were excluded for the following reasons: 11 (69%) did not include a hyperosmolar agent, four (25%) were not randomised and the remaining study (6%) did not include patients with bronchiectasis (full details provided in Characteristics of excluded studies).

 

Risk of bias in included studies

 

Allocation

Two studies Kellett 2005; Nicolson 2012 were judged to be at low risk of bias in terms of random sequence generation, and the remaining nine studies were considered as unclear risk. In terms of allocation concealment only Nicolson 2012 was judged to be low risk of bias, and in the remaining 10 studies the risk was evaluated as unclear (Figure 2).

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

 

Blinding

In terms of performance bias, three studies were judged as low risk (Bilton 2013, Kellett 2005; Nicolson 2012). In five studies the risk was considered to be unclear (Bradley 2011; Chandra 2008; Daviskas 1999; Daviskas 2004; NCT00669331) and in the remaining three the risk was evaluated as high (Bennoor 2012; Daviskas 2008; Kellet 2011). On detection bias, two studies were judged as low (Kellett 2005; Nicolson 2012). The level of risk was viewed as unclear in seven (Bilton 2013; Bradley 2011; Chandra 2008; Daviskas 2008; Daviskas 2004; Kellet 2011; NCT00669331). In the following two studies the risk was judged to be high (Bennoor 2012; Daviskas 1999).

 

Incomplete outcome data

Only five studies (Bilton 2013; Kellet 2011; Kellett 2005; NCT00669331; Nicolson 2012) were judged to be low risk in terms of attrition bias, and only one Bradley 2011, was judged to be in the high risk of bias category. The remaining five (Bennoor 2012; Chandra 2008; Daviskas 1999; Daviskas 2008; Daviskas 2004) were considered as unclear in this respect Figure 3.

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

 

Selective reporting

Three studies (Bilton 2013; Daviskas 1999; Nicolson 2012) were evaluated as low risk in terms of reporting bas. The remaining eight (Bennoor 2012; Bradley 2011; Chandra 2008; Daviskas 2008; Daviskas 2004; Kellet 2011; Kellett 2005; NCT00669331) were considered as unclear on this measure.

 

Other potential sources of bias

In this category all 11 studies were evaluated as unclear.

 

Effects of interventions

See:  Summary of findings for the main comparison Inhaled mannitol versus placebo for bronchiectasis;  Summary of findings 2 Hypertonic saline versus isotonic saline for bronchiectasis

 

Inhaled mannitol versus placebo

Five studies (combined N = 883) compared mannitol versus placebo: Bennoor 2012 (50 participants), Chandra 2008 (12 participants), Bilton 2013 (362 participants randomised and 343 analysed), Daviskas 2004 (17 participants) and NCT00669331 (461 participants). Only one of the six studies Daviskas 2004 was a cross-over design and Bennoor 2012, Bilton 2013, Chandra 2008 and NCT00669331 were parallel group trials. Personal communication with Dr Bilton confirmed that people on placebo in NCT00669331 were given 50 mg of mannitol (intended as a non-therapeutic dose), and there is a possibility that this may have led to conservative estimates of the treatment effects. In most cases the results presented in the trial reports were not in a format that enabled the data to be entered into RevMan for the purposes of meta-analysis and are therefore reported narratively here. The quality of evidence for this comparison where GRADE assessments were applied was moderate ( Summary of findings for the main comparison).

 
Exacerbations

The only data available from the included trials for this outcome were provided by NCT00669331, a C trial with 461 participants, and reported as exacerbation rate per year. There was an 8% reduction (risk ratio (RR) 0.92 95% confidence interval (CI) 0.78 to 1.08) in favour of mannitol, however this was not significant. These data for this study are unpublished and were presented at the European Respiratory Society Conference 2013.

However, the median time to first exacerbation was significantly different between the two groups (median: 165 versus 124 days for mannitol and placebo respectively (hazard ratio (HR) 0.78, 95% CI 0.63 to 0.96, P = 0.022, NCT00669331).

There was also a significant difference in favour of mannitol (RR 0.76, 95% CI 0.58 to 1.00, P = 0.0496) for the number of days on antibiotics for pulmonary exacerbations (NCT00669331). We acknowledge that time to first exacerbation and antibiotics for pulmonary exacerbations, per se, were not prespecified in our planned outcomes for this review. However, we are including this additional information as these outcomes are so very closely linked to our prespecified outcome of exacerbations.

 
Hospital admissions

Data for this outcome were provided by one trial on 461 participants (NCT00669331), as hospitalisations due to pulmonary exacerbations. There was no significant difference between the two groups (RR 0.61, 95% CI 0.34 to 1.09, P = 0.093).

 
Mortality

Only one study reported deaths (Bilton 2013). They reported 2/241 deaths in the mannitol-treated group, but stated that they were not related to study treatment.

 
Health-related quality of life

Three trials on 821 participants reported St George's Respiratory Questionnaire (SGRQ) data (Bilton 2013, Daviskas 2004, NCT00669331). The direction of scaling on the SGRQ indicates that a score of 100 represents worst possible quality of life and zero represents best possible quality of life. There was a significant difference in favour of mannitol on SGRQ total scores (mean difference (MD) -2.05; 95% CI -3.69 to -0.40  Analysis 1.1). There were considerable differences in duration of the three trials (Bilton 2013 12 weeks, Daviskas 2004 two weeks and NCT00669331 52 weeks), but low heterogeneity (I2 very near zero). The difference between the two groups is less than four points which is generally regarded as the minimum clinically important difference (MCID) for SGRQ total scores in COPD studies (Jones 2005) and the lower confidence limit is smaller than that threshold (-3.69); whether this MCID may also hold for bronchiectasis studies is unclear.

In separate analyses of component scores, data were available from only Bilton 2013 and Daviskas 2004. There were no significant differences between mannitol versus placebo on symptoms component (MD -1.42; 95% CI -5.12 to 2.28  Analysis 1.2) and activity component (MD -0.84; 95% CI -3.95 to 2.28  Analysis 1.3); however there was a significant difference in favour of mannitol on impact component scores (MD -3.16; 95% CI -5.77 to -0.55  Analysis 1.4). In view of the high level of heterogeneity (I² = 58%) on the impact component scores analysis we used a random-effects model and on that basis the significant difference was not observed (MD -2.21; 95% CI -5.92 to 1.49  Analysis 1.4); we therefore conclude that the significant effect on impact scores reported in Wills 2006 should be viewed with caution in light of the data now available from Bilton 2013.

However, in a recent parallel group study of 50 patients with stable bronchiectasis Bennoor 2012 reported a significant reduction from baseline in SGRQ symptom scores and impact scores but did not provide any summary data. There was no difference between the two groups with respect to SGRQ activity scores. With regard to total SGRQ scores and dyspnoea scores, there was a significant advantage in favour of mannitol (P < 0.001). These results were not reported in a format that enabled us to include the study in the meta-analyses.

Bilton 2013 reported no significant difference in cough score between mannitol and placebo for Leicester Cough Questionnaire (LCQ) data (MD 0.00; 95% CI -0.81 to 0.81,  Analysis 1.5).

 
Symptoms

One trial on 343 participants (Bilton 2013) reported no significant difference between mannitol and placebo for Bronchiectasis Symptoms Questionnaire data (MD -1.20; 95% CI -3.91 to 1.51,  Analysis 1.6).

In Daviskas 2004 symptom scores were reported as a domain of the SGRQ (see above).

 
Lung function

There was no significant difference in FEV1 % predicted between mannitol versus placebo (% predicted FEV1 2.70; 95% CI -8.53 to 13.93,  Analysis 1.7) in Daviskas 2004 or in FEV1 (L) at 12 weeks (MD 0.03; 95% CI -0.10 to 0.16  Analysis 1.8). There were also no significant or clinically important differences in Chandra 2008 with respect to changes from baseline in FEV1 in people on either mannitol or placebo, and it was not possible to aggregate these data with those from other studies .

At 12 weeks, in Bilton 2013, there was no significant difference between mannitol versus placebo with respect to FVC (MD 0.04; 95% CI -0.15 to 0.23  Analysis 1.14) or FEF25-75 ((MD 0.07; 95% CI -0.09 to 0.23  Analysis 1.10). However, Bennoor 2012 reported a significant differential improvement in FVC (P < 0.039) and FEF25-75 (P < 0.045) on day 12; these results were not reported in a manner that enabled us to aggregate these data with other studies.

 
Sputum volume

Bilton 2013 reported a significant difference between the mannitol and placebo in the 24-hour sputum weight from baseline, noting a significant reduction in weight of sputum expectorated in the placebo group and not in those on mannitol (MD 4.32; 95% CI 1.60 to 7.04  Analysis 1.11), and this was interpreted by the authors in relation to the higher antibiotic use in the placebo group.

However in Bennoor 2012, there was no significant difference in sputum volume between the mannitol and placebo arms. No summary statistics were provided and it was therefore not possible to combine these results with those from other studies.

 
Antibiotic use

The difference between the mannitol and placebo groups in Bilton 2013 was not significant (odds ratio (OR) 0.72; 95% CI 0.46 to 1.14  Analysis 1.12).

 
Incremental shuttle walk test

Bilton 2013 reported no significant difference between mannitol versus placebo in the incremental shuttle walk test at week 12 (MD 18.70; 95% CI -20.50 to 57.90  Analysis 1.13).

 
Adverse events and serious adverse events

Bilton 2013 and NCT00669331 reported no significant difference between mannitol and placebo in either adverse events (OR 0.96; 95% CI 0.61 to 1.51  Analysis 1.9) or serious adverse events (OR 0.79; 95% CI 0.52 to 1.19  Analysis 1.15). The number of adverse events was high in Bilton (placebo: 80% versus mannitol: 82%), but most adverse events were unrelated to the treatment.

Bennoor 2012 reported that two patients in the mannitol group experienced dry mouths and four reported headache, fatigue and chest pain; it is unclear from the trial report whether the participants experiencing dry mouths were included among the four others and we are therefore reporting this narratively. No adverse events were reported in the placebo group.

 

Inhaled mannitol versus no treatment

Two small cross-over studies (N = 25) compared inhaled mannitol versus no treatment: Daviskas 1999 (11 participants) and Daviskas 2008 (14 participants). In Daviskas 2008 and Daviskas 1999 no treatment is referred to in the trial report as baseline (please see Characteristics of included studies). Data from both studies were not reported in a format that enabled us to enter them into a meta-analysis.

 
Exacerbations

There were no data available from the included trials for this outcome.

 
Hospital admissions

There were no data available from the included trials for this outcome.

 
Lung function

There were data available from only one of the included trials for this outcome Daviskas 2008. The radioaerosol deposition was consistent with the FEV1 % predicted being similar on all study days (76.7 (SD) 3.6; 76.5 (SD) 3.7; 77.0 (SD) 3.7; 76.0 (SD) 3.4 and 76.6 (SD) 3.7% for baseline, control, 160, 320 and 480 mg mannitol, respectively; P > 0.4).

 
Mortality

No deaths were reported.

 
Mucus clearance

Data were provided by two very small cross-over studies: Daviskas 1999 (11 participants) and Daviskas 2008 (14 participants). The latter suggests dose response effects (with 160, 320 and 480 mg mannitol) in mucus clearance from the whole right lung when compared to no treatment over 75 minutes; each of the three doses produced significantly more mucus clearance at that time point versus a no treatment condition, with 480 mg producing significantly more mucus clearance than 160 mg (P < 0.0001). The difference between treatment and no treatment was: 160 mg condition: 12.0% mean clearance P < 0.01, 320 mg condition: 16.8% mean clearance P < 0.001 and 480 mg condition: 21.9% mean clearance P < 0.001).

In Daviskas 1999, only one dose was used (reported as approximately 300 mg) and the difference between treatment and no treatment was 22.3% mean clearance over 75 minutes (P < 0.0001).

Data are included in Daviskas 1999 and Daviskas 2008 to provide further clarity in relation to mucus clearance in the right central, right intermediate and right peripheral areas. These findings need to be interpreted with caution in view of the very small sample, however - in addition to benefits in clearance in the whole right lung and intermediate and central areas - they do indicate that a significant advantage for mannitol in mucus clearance in the peripheral region over longer time periods (from 30 to 75 minutes after the start of the dose). At this stage, in view of the paucity of data, these impressions are in need of further clarification with larger studies and serve largely as hypotheses for further investigations.

 

Hypertonic saline versus isotonic saline

The quality of evidence for the comparison hypertonic saline versus isotonic saline was moderate ( Summary of findings 2). Four studies (N = 113) compared hypertonic saline versus isotonic saline (Bradley 2011, N = 19, Kellett 2005 N = 24, Kellet 2011, N = 30, Nicolson 2012, N = 40). Three of the four studies Bradley 2011, Kellett 2005, Kellet 2011 were cross-over design and the data were not reported in a format that enabled us to include them in meta-analyses. Nicolson 2012 was a 12-month parallel group trial.

 
Exacerbations

One cross-over study (Kellet 2011) demonstrated a significant difference between hypertonic saline versus isotonic saline with respect to this outcome (P < 0.05). The rate of exacerbations in the hypertonic saline group (2.14 exacerbations/year) was less than half the rate in the isotonic saline group (4.85 exacerbations/year).

However this finding was not supported by Nicolson 2012, where there were no significant differences between hypertonic saline versus isotonic saline on exacerbations (over 12 months), exacerbations requiring antibiotics, number of exacerbation days or number of exacerbation days requiring antibiotics. Median number of exacerbations (inter-quartile range (IQR)) were 1 (zero to 4) for isotonic saline and 3 (zero to 6) for hypertonic saline (P = 0.24).

 
Hospital admissions

In Nicolson 2012 there was no significant difference between hypertonic saline versus isotonic saline with respect to hospital admissions (P = 0.34) or hospital days (P = 0.36). Four (10%) participants had hospital admissions, three in the isotonic saline group were in hospital for three, five and 61 days respectively and one participant in the hypertonic saline group was in hospital for 68 days.

 
Health-related quality of life

In Nicolson 2012 there was no significant difference between hypertonic saline versus isotonic saline with respect to SRGQ symptoms scores at three, six or 12 months  Analysis 2.1; SGRQ activity scores at three, six or 12 months  Analysis 2.2; or SGRQ impact scores at three, six or 12 months  Analysis 2.3. Data for total SGRQ scores were not reported. In the same study there was no significant difference between hypertonic saline versus isotonic saline with respect to LCQ physical scores at three, six or 12 months  Analysis 2.4; there was no significant difference between hypertonic saline versus isotonic saline with respect to LCQ psychological scores at six and 12 months, although there was a modest significant difference at three months (MD 0.90; 95% CI 0.12 to 1.68). At this time point however in the isotonic saline group the LCQ psychological domain score improved from 3.9 to 5.0 (a 1.1 unit change) and the hypertonic saline group score improved from 4.7 to 5.9 (1.2 unit change). The difference in change score (0.1 units) is therefore neither statistically nor clinically significant.  Analysis 2.5. There were no differences between hypertonic saline versus isotonic saline with respect to LCQ social scores at three six or 12 months  Analysis 2.6. Data for total LCQ scores were not reported.

However, an additional comparison between hypertonic saline versus isotonic saline is provided in a small cross-over study with 19 participants by Bradley 2011. Significant benefits in favour of hypertonic saline were observed in the physical domain of the LCQ ( -0.8 (SD 0.9); P = 0.01) and the respiratory symptoms domain of the Quality of Life Questionnaire-Bronchiectasis, QOL-B ( -11.6 (SD 17.7); P = 0.03) .

Kellet 2011 reported that significant changes were seen for St George’s Respiratory Quality of Life (global score) and in terms of the subscales of symptoms and impact, but did not reach statistical significance for the activity subscale. Graphs, but no data, were provided.

 
Mortality

No deaths were reported.

 
Lung function

Kellet 2011 reported a significant advantage for hypertonic saline versus isotonic saline in change from baseline in FEV1 % (MD 13.30; P < 0.01) and FVC (MD 10.51; P < 0.01).

Bradley 2011 report that hypertonic saline had an effect on FEV1; the effect size being an unspecified value between 0.01 and 0.14.

In terms of FEV (L), there was no significant benefit for hypertonic saline versus isotonic saline at three, six or twelve months in Nicolson 2012 ( Analysis 2.7); similarly, there were no differences between the two groups at these time points on FVC  Analysis 2.8 or FEF 25-75  Analysis 2.9. However there was a benefit for hypertonic saline versus isotonic saline in FVC % change from pre-treatment baseline in Kellet 2011 (MD 10.51; 95% CI 2.36 to 18.66 Analysis 2.10).

In Kellett 2005 there was no significant differences in FEV1 (P = 0.12) or FVC (P = 0.23) between hypertonic saline versus isotonic saline; these data were reported in a format that did not provide an opportunity for aggregation with other studies. The median, (inter-quartile) values were: FEV1 2.0, (1.25 to 2.40) hypertonic saline versus 1.85, (1.36 to 2.20) isotonic saline, and FVC 2.50, (1.79 to 3.08) hypertonic saline versus 2.55, (1.91 to 2.94) isotonic saline.

 
Sputum weight/volume

In Kellett 2005 sputum weights were significantly different between the isotonic saline median 3.17 g, (IQR 1.45 to 6.25) and hypertonic saline median 5.3 g, (IQR 2.97 to 9.33) arms. Ease of expectoration as measured on a 10 cm VAS scale was significantly lower with hypertonic saline, median 2.40 cm, (IQR 1.43 to 5.40) than isotonic saline median 5.20 cm, (IQR 2.75 to 8.38).

In Nicolson 2012 participants in both the hypertonic and isotonic saline groups improved over the course of the 12-month trial with only 15% having a positive sputum culture, in either group, at that point; these data were reported in a format that did not provide an opportunity for aggregation with other studies.

Bradley 2011 report that hypertonic saline had an effect on sputum; the effect size being an unspecified value between 0.01 and 0.14 .

Kellet 2011 reported "improvements in sputum viscosity and ease of expectoration (visual analogue scale)" in the conference abstract and abstract of the published trial report but gave no data.

 
Antibiotic use

In a cross-over study Kellet 2011 has demonstrated a significant difference between hypertonic saline versus isotonic saline with respect to this outcome (P < 0.05). The level of antibiotic use in the hypertonic saline group (2.4 courses per year) was less than half the level in the isotonic saline group (5.4 courses per year).

Nicolson 2012 reported no significant difference (P = 0.77) in the number of exacerbation days requiring antibiotics.

 
Cough

In Nicolson 2012, there were no significant differences between groups in cough frequency reported by VAS at three (P = 0.39), six (P = 0.17) or 12 months (P = 0.60).

 
Adverse events

There were reportedly no significant differences in the occurrence of adverse events between people in the hypertonic saline versus isotonic saline groups in Bradley 2011, but no data were reported.

Nicolson 2012 reported three adverse events in the hypertonic saline group: chest tightness during inhalation which resolved with treatment of an underlying acute exacerbation in one participant. An episode of hypertension was reported by another participant and this was resolved without further intervention, and was unrelated to the intervention in the view of the patient's physician. Both patients remained in the trial without incident to the completion of the study. An episode of rapid atrial fibrillation requiring attendance at the emergency department was experienced by a third participant and the saline inhalation was ceased prior to the three-month assessment. There were no adverse events in the isotonic saline group. The difference between the two groups was not significant (OR 8.20; 95% CI 0.40 to 169.90  Analysis 2.10).

 

Discussion

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

Summary of main results

In one relatively large trial, mannitol significantly extended the time to first bronchiectasis exacerbation from just over four months to around five and a half months. This translated into a trend towards a reduction in annual exacerbations with mannitol but did not reach conventional significance. The number of days patients spent taking antibiotics for exacerbations of bronchiectasis was also significantly reduced, though overall use of courses of antibiotics was probably unchanged.

The effect of mannitol on sputum volume is unclear. Bilton 2013 reported a reduction in sputum volume in the placebo group, whereas sputum production was maintained in the mannitol group. Bennoor 2012 reported no difference in sputum production between the mannitol and placebo arms. The clinical implications of sputum production differ in different patients. A reduction in expectorated sputum volume may reflect either a reduction in chronic bronchial sepsis or increased infection due to retained secretions. For some, but not all, patients sputum expectoration is a troubling symptom and changes in sputum expectoration need interpreting in this light.

Despite changes in the number of exacerbations, respiratory related quality of life was not clinically improved in those taking mannitol. These were, by and large, patients with long standing chronic illness and quality of life was not systematically recorded during exacerbations so this may be due to the timing of quality of life assessments. Alternatively it may be that such patients have adapted their lifestyles so that chest exacerbations do not dramatically impair their quality of life. Quality of life was generally assessed by means of the SGRQ. This includes questions on cough. The relationship between hyperosmolar therapy and cough may be complex. Hyperosmolar agents are directly irritant to the lungs and thus stimulate coughing in the short term, worsening some symptom elements of the SGRQ. However, they may also change the characteristics of the cough. Consequent thinner mucus might make cough less painful or embarrassing and thus improve these elements of the SGRQ and improved mucus clearance may reduce overall cough in the medium or long term. It is possible that quality of life is being modified by these therapies without overall improvement. Individual SGRQ question level data were not available.

On the whole, no dramatic effects of mannitol on lung function were noted. Potentially mannitol could have improved spirometry by reducing the amount of mucus plugging in the small airways (and thus increasing the effective small airway diameter). Mannitol can trigger bronchoconstriction so a detrimental effect on spirometry was also possible. With the exception of NCT00669331, patients in the included trials were selected as having relatively normal spirometry before inclusion as well as not having a large reduction in spirometry during a mannitol provocation test so large changes in spirometry would be surprising in these groups. A significant effect (good or bad) in those with abnormal baseline spirometry is not excluded by these studies. Spirometric data have not yet been reported for NCT00669331, though significant bronchospasm was not observed as an adverse outcome.

Inhaled mannitol did not appear to cause many adverse events. Lung function did not decrease as might have been expected and Bilton 2013 reported no significant difference in the rates of adverse events between mannitol and placebo. Bennoor 2012 described a number of symptoms in patients taking mannitol but severity and causality were unclear.

Two very small studies (Daviskas 1999; Daviskas 2008) looked at mannitol against no treatment. In one (Daviskas 2008), lung function was reported as unchanged, though the methodology used (radioisotope deposition not spirometry) was unusual. Both studies suggested a dose response effect with greater radioisotope evidence of sputum movement with increasing doses of mannitol. The small scale, preliminary nature of these studies should be noted, along with their use of a measurement technique not widely used in clinical practice.

Two of the four included studies that investigated the use of nebulised hypertonic versus isotonic saline (Kellet 2011; Nicolson 2012) contributed data on exacerbation rates, antibiotic use and/or hospitalisations. The studies of Bradley 2011 and Kellett 2005 were too short to assess an effect on exacerbation frequency, hospitalisations or antibiotic use, the former with a four-week treatment period, and the latter comparing the effect of four different single-dose treatment regimens.

The Nicolson 2012 and Kellet 2011 studies provide contrasting results. Whilst Nicholson found that treatment with both isotonic and hypertonic saline resulted in a very large drop in exacerbation frequency over the year of the study, there was no difference between the treatments. Likewise, there were no differences in number or length of hospital admissions. In contrast Kellet 2011 reported a statistically significant and clinically important reduction in exacerbations in the hypertonic saline group (annualised exacerbation rate 2.1 for hypertonic saline, 4.9 for isotonic saline), with a comparable reduction in use of antibiotics (annualised rate 2.4) versus isotonic saline (5.4). As noted below, these differences in impact between the two studies were also seen on many other shared outcomes, and likely to be due at least in part to significant methodological differences between the studies.

The strong impact of both treatments on outcomes in the Nicholson study merits further consideration. The pre-study exacerbation rate data were collected retrospectively and so relied presumably on patient recall. To patients the usual definition of an exacerbation would likely include the requirement for antibiotics and/or hospital admission, and probably last for more than a day. It is not possible therefore to directly relate this rate to the multiple definitions applied prospectively during the study period (i.e. the retrospective baseline definition of exacerbation was not the same as any of the prospective definitions). Nevertheless, the reported rates certainly imply a large benefit of study participation in both groups, also reflected in the very low requirement for antibiotics (median 0.5 courses per year in the isotonic saline group; 1.0 per year in the hypertonic saline group). The median “pre-study” exacerbation rate was five per annum, but during the study there were only a median one to two “exacerbation days requiring antibiotics” for the group as a whole. This fairly dramatic finding (and the similar findings in this study relating to quality of life as discussed below) could be explained by the benefit that could be obtained by participating in a study which provides relatively frequent medical review, and possibly more importantly the potential for increased self-awareness related to the disease process. Volunteers were all nebulising twice daily and filling in daily diaries reporting their symptoms, and 85% were using chest clearance techniques. It is also possible that retrospective recall overestimates exacerbation rate. The third potential contributing issue (applicable to all studies here) is that isotonic saline in fact is not really a placebo in this context and may have benefits by increasing airway hydration, with further benefit possibly conferred by the respiratory manoeuvres that participants were instructed to undertake during nebulisation. The Nicholson paper also did not select patients on the basis of features that could theoretically confer a differential benefit of hypertonic saline, such as frequent exacerbators or those with large volumes of sticky sputum. It is therefore possible that any potential signal due to “between-treatment” difference was overwhelmed by the benefit of study participation. One interesting finding of the Nicholson study was that at the end of the study far more patients in the hypertonic saline group chose to stay on their study medication long term than in the isotonic saline group. The exact numbers are not clear; it is stated in the results that six chose to remain on isotonic saline, whereas 23 stayed on hypertonic saline, but this latter is likely to be a typographical error as only 20 participants used hypertonic saline during the trial, and in the discussion section “nearly three-quarters” of the group were said to have remained on this treatment.

The Kellet 2011 study, which demonstrated significant benefits for hypertonic saline, is described as single blind, as the study medicines were presented in specific ampoules identifiable to the study team. In addition the adequacy of patient-blinding was not checked (as it was in the Nicholson study), and it seems very likely that volunteers could taste a clear difference between 7% and 0.9% saline, especially as all patients had a test dose of hypertonic saline at the beginning of the study, and with the cross-over design all patients received both treatments allowing direct comparison during the study. Another difference between the Nicolson 2012 and Kellet 2011 studies was that the former gave nebulised saline twice daily, the latter once only. The definition of exacerbation was different in the Kellet 2011 study and required contact with a primary or secondary care physician for a deterioration in bronchiectasis-related symptoms. Again, retrospective baseline exacerbation rate data were used, but not required for the primary treatment comparison because of the cross-over design. It is also worth noting that this study excluded patients colonised with Pseudomonas aeruginosa, for unexplained reasons. Such patients represent a subgroup in bronchiectasis with poor outcomes Evans 1996; Martinez 2007, and who might potentially benefit from mucolytic therapy, so their exclusion here is difficult to explain.

Nicholson and colleagues assessed health-related quality of life using the general respiratory SGRQ and cough-specific LCQ. As for exacerbations, a large clinically relevant improvement in all domains of both measures occurred during the study with both strengths of saline, with no difference between treatment groups. On the other hand, Kellet 2011 reported statistically and clinically significant improvements in SGRQ total scores and symptom and impact domains. Potential explanations for this are discussed above.

Bradley 2011 reported a statistically and clinically relevant improvement in the physical domain of the LCQ with hypertonic versus isotonic saline, as well as in the respiratory symptoms domain of the QOL-B, although this latter quality of life questionnaire has not been validated and the minimal important difference is not known. However, multiple comparisons were performed in a small number of participants in this feasibility study, with no adjustment for multiple testing, hence the probability of these being false-positive findings is not known.

In the Nicolson 2012 study, mean lung function was very good at baseline, for example mean FEV1 was 80% predicted in the isotonic saline group and 85% predicted in the hypertonic saline group, which may have lead to a ceiling effect explaining the minimal, although statistically significant, 90 mL improvement in both groups. No differences were seen between groups. Again a contrast is provided by the Kellet 2011 study, which investigated the use of hypertonic saline in bronchiectasis patients with more severe disease than Nicholson at least in terms of lung function, with mean FEV1 66% predicted. This paper reports a significant benefit of hypertonic over isotonic saline, with a 15% improvement in FEV1 following three months treatment with the former compared to a 2% improvement with the latter, with a similar-sized effect difference on FVC also.

The limited data available from the Bradley 2011 abstract do not enable the size of effect on FEV1 to be calculated, nor whether the change was statistically significant, whilst Kellett 2005 reported no improvement in lung function after a single dose of hypertonic saline versus isotonic saline.

No effects on sputum weight or volume were reported in the Nicholson paper, although the frequency of positive sputum cultures in both groups improved over the year of the study, with no between-group difference. Kellet 2011 reported unquantified benefits of hypertonic over isotonic saline on sputum viscosity and ease of expectoration in the abstract of their article, but no further results are given in the main results section. No meaningful interpretation of the effect of hypertonic saline on sputum is possible from the limited data available from the Bradley 2011 abstract.

Kellett 2005 looked at the effect of single dose isotonic or hypertonic saline in combination with chest clearance (active cycle of breathing technique) in patients who specifically reported “thick, sticky” sputum, and expectorating small volumes (less than 10 g per day), but who nevertheless had required at least one antibiotic course over the preceding six months. The outcomes of this study were particularly focused on the acute effect of first-dose of saline solutions on sputum parameters, and hence, whilst they provide useful data in this regard, they cannot be extrapolated to longer-term effects. In addition, the study’s objective was to perform a four-way comparison (the other two treatment schedules were chest clearance alone and nebulised bronchodilator plus chest clearance) and hence the comparison of outcomes between hypertonic and isotonic saline was performed post-hoc, with the variables grouped in multiple ways, and again with no adjustment for multiple-testing. With these qualifications, single dose hypertonic saline use was associated with increase sputum weight, decreased viscosity, and improved ease of expectoration when compared with isotonic saline.

In the Nicolson 2012 study, two patients reported side effects considered potentially due to hypertonic saline; one with transient chest tightness, which was relieved after treatment for an exacerbation, and another with atrial fibrillation which resulted in withdrawal from the study (NB all participants inhaled 200 mcg salbutamol prior to saline nebulisation). There were no adverse reactions noted in the isotonic saline group. Bradley 2011 reported no difference in side effects between the hypertonic and isotonic saline treatment groups. Two of the 32 patients screened for the Kellet 2011 study were excluded because of bronchial hyperresponsiveness to the test dose of hypertonic saline. Adverse events during the study period are not reported.

 

Overall completeness and applicability of evidence

Whilst the five studies (combined N = 883) comparing mannitol versus placebo provide more clarity in this area than was available in the previous version of this review, the opportunities for the aggregation of data were limited. Data comparing hypertonic saline with isotonic saline were, by comparison, relatively sparse and there were even more obvious limitations for meta-analyses. Over the last seven years since the last update of this review (Wills 2006), a number of new studies have been published, however one very recent large study comparing mannitol with placebo over a 12-month period NCT00669331 has yet to be published in full. The data available from that study at the time of completing this update are limited to those presented at a recent international conference.

 

Quality of the evidence

In terms of random sequence generation only two trials (Kellett 2005; Nicolson 2012) were considered to be at low risk of bias (selection bias); both trials compared hypertonic saline with isotonic saline, had adequate randomisation procedures, and all five trials comparing mannitol versus placebo (or no treatment) had issues with their randomisation procedure, which undermine our confidence in the results. The risk of bias for the remaining nine trials was evaluated as unclear as details of the random sequence generation were not described in the trial report. In terms of the blinding of participants and personnel, only three trials (Bilton 2013; Kellett 2005; Nicolson 2012) were judged to be at low risk of bias (performance bias), and only one of those trials compared mannitol with placebo (or no treatment).

 

Potential biases in the review process

The Cochrane Airways Group provides exceptional support in the identification of potentially relevant trials; however, concerns regarding study selection bias or publication bias are an issue in this review as with any other. We are mindful that a failure to identify unpublished trials may lead to an incomplete estimation of hyperosmolar agents. Even though an extensive search of the published literature, without language restrictions, for potentially relevant clinical trials was undertaken using a systematic search strategy to minimise the likelihood of bias, we acknowledge that additional unidentified trials may still be undetected. We note that improvements in the standardisation of reporting would facilitate the opportunities to draw comparisons among trials.

 

Agreements and disagreements with other studies or reviews

The availability of data in this update is considerable when compared to the previous version of this review Wills 2006 and the number of included studies has increased from two to 11. Whereas the previous review highlighted the paucity of evidence in this area, we now note that five studies (combined N = 883) compared mannitol versus placebo, enabling us to assess the clinical benefits of hyperosmolar agents over periods up to 12 months. Whilst a paucity of evidence remains in relation to some important outcomes, and we note that there is still a need for more information from randomised studies in relation to exacerbations and hospitalisations in particular, the additional nine trials available to this version of the review have provided considerably more clarity than was available hitherto in this important area.

 

Authors' conclusions

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

 

Implications for practice

Inhaled mannitol increases time to infective exacerbation in patients with bronchiectasis, without improving respiratory quality of life. It has a role in reducing exacerbations and antibiotic use in those with normal or mild to moderately impaired spirometry. Its safety has not been studied in patients with severe lung function impairment.

For hypertonic saline, the two full studies published to date that describe chronic dosing and hence could help guide clinical practice have produced conflicting results, which is likely due to their different patient groups and study designs. The magnitude of the effect size in the Kellet 2011 study on important endpoints including exacerbation rates, antibiotic use, lung function and quality of life suggest that there might be a clinically relevant effect of hypertonic saline in similar patients, despite the methodological concerns arising mainly from the potentially inadequate blinding. On the other hand, the results of Nicolson 2012 suggest that hypertonic saline does not confer any clear benefit over isotonic saline when it is introduced to treatment in those with physiologically mild disease.

Future larger scale studies should focus on targeting those with established disease and poor lung function, whilst addressing the potential bias associate with inadequate blinding.

 
Implications for research

Larger, more long-term studies into the use of inhaled hyperosmolar agents in bronchiectasis are now starting to appear. Future studies should focus on those with impaired spirometry and consider using health economy important measures such as hospitalisation rate and antibiotic usage. Long-term studies of hyperosmolar agents in patients with early bronchiectasis and relatively normal spirometry are also justified to see if these agents can prevent progression to impaired lung function.

 

Acknowledgements

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

The authors of the original version of this review acknowledged the support the Cochrane Airways Group staff, particularly Steve Milan, Toby Lasserson, Liz Arnold and Karen Blackhall for their help with the software and in trial identification, and their gratitude to Prof E Daviskas and Dr. S Anderson of the Royal Prince Alfred Hospital and Prof. P Cole of the Brompton Hospital for their personal communications.

In the 2013 update we would particularly like to acknowledge the contribution of Peter J Wills and Michael Greenstone, authors on the original version of this review and the excellent support and assistance received from Emma Welsh, Liz Stovold and Emma Jackson of the Cochrane Airways Review group, together with the greatly appreciated guidance received from Chris Cates (Cochrane Airways Review Group Co-ordinating Editor). We are indebted to Dr D Bilton for additional information. The support provided by librarians Judith Scammel, Jane Appleton and Hilary Garrett at St Georges University London is also greatly appreciated.

 

Data and analyses

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

 
Comparison 1. Inhaled mannitol versus placebo

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

 1 Change from baseline in health-related quality of life (SGRQ). Total3Mean Difference (Fixed, 95% CI)-2.05 [-3.69, -0.40]

    1.1 2 Weeks
1Mean Difference (Fixed, 95% CI)-6.0 [-13.59, 1.59]

    1.2 12 Weeks
1Mean Difference (Fixed, 95% CI)-1.27 [-3.69, 1.15]

    1.3 12 months
1Mean Difference (Fixed, 95% CI)-2.4 [-4.76, -0.04]

 2 Change from baseline in health-related quality of life (SGRQ). Symptoms2377Mean Difference (Fixed, 95% CI)-1.42 [-5.12, 2.28]

    2.1 2 Weeks
134Mean Difference (Fixed, 95% CI)-7.1 [-18.53, 4.33]

    2.2 12 Weeks
1343Mean Difference (Fixed, 95% CI)-0.76 [-4.67, 3.15]

 3 Change from baseline in health-related quality of life (SGRQ). Activity2Mean Difference (Fixed, 95% CI)-0.84 [-3.95, 2.28]

    3.1 2 Weeks
1Mean Difference (Fixed, 95% CI)-1.2 [-7.53, 5.13]

    3.2 12 Weeks
1Mean Difference (Fixed, 95% CI)-0.72 [-4.30, 2.86]

 4 Change from baseline in health-related quality of life (SGRQ). Impact2Mean Difference (Fixed, 95% CI)-3.16 [-5.77, -0.55]

    4.1 2 Weeks
1Mean Difference (Fixed, 95% CI)-9.8 [-18.66, -0.94]

    4.2 12 Weeks
1Mean Difference (Fixed, 95% CI)-2.53 [-5.26, 0.20]

 5 Leicester Cough Questionnaire score after 12 weeks1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 6 Bronchiectasis Symptoms Questionnaire score at week 121Mean Difference (IV, Fixed, 95% CI)Totals not selected

 7 Change in FEV1 (% predicted)1% predicted FEV1 (Fixed, 95% CI)Totals not selected

 8 FEV1 (L) at 12 weeks1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 9 Adverse events2804Odds Ratio (M-H, Fixed, 95% CI)0.96 [0.61, 1.51]

 10 FEF25-75(L/s) after 12 weeks1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 11 Change in 24 hr sputum weight from baseline1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 12 Antibiotic use1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 13 Incremental Shuttle Walk (metres) at week 121Mean Difference (IV, Fixed, 95% CI)Totals not selected

 14 FVC (L) at 12 weeks1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 15 Serious adverse events2804Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.52, 1.19]

 
Comparison 2. Hypertonic saline versus isotonic saline

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

 1 SGRQ Symptom1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    1.1 3 months
140Mean Difference (IV, Fixed, 95% CI)-8.5 [-20.48, 3.48]

    1.2 6 months
140Mean Difference (IV, Fixed, 95% CI)6.40 [-5.93, 18.73]

    1.3 12 months
140Mean Difference (IV, Fixed, 95% CI)1.60 [-12.53, 15.73]

 2 SGRQ Activity1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 3 months
140Mean Difference (IV, Fixed, 95% CI)4.40 [-11.49, 20.29]

    2.2 6 months
140Mean Difference (IV, Fixed, 95% CI)2.60 [-11.86, 17.06]

    2.3 12 months
140Mean Difference (IV, Fixed, 95% CI)2.70 [-13.11, 18.51]

 3 SGRQ Impact1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    3.1 3 months
140Mean Difference (IV, Fixed, 95% CI)-0.40 [-12.03, 11.23]

    3.2 6 months
140Mean Difference (IV, Fixed, 95% CI)-0.80 [-9.71, 8.11]

    3.3 12 months
140Mean Difference (IV, Fixed, 95% CI)4.40 [-7.50, 16.30]

 4 Leicester Cough Questionnaire Physical1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    4.1 3 months
140Mean Difference (IV, Fixed, 95% CI)0.40 [-0.22, 1.02]

    4.2 6 months
140Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.88, 0.68]

    4.3 12 months
140Mean Difference (IV, Fixed, 95% CI)-0.20 [-0.95, 0.55]

 5 Leicester Cough Questionnaire Psychological1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 3 months
140Mean Difference (IV, Fixed, 95% CI)0.90 [0.12, 1.68]

    5.2 6 months
140Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.85, 0.65]

    5.3 12 months
140Mean Difference (IV, Fixed, 95% CI)0.20 [-0.63, 1.03]

 6 Leicester Cough Questionnaire Social1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    6.1 3 months
140Mean Difference (IV, Fixed, 95% CI)0.5 [-0.34, 1.34]

    6.2 6 months
140Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.82, 0.62]

    6.3 12 months
140Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.85, 0.65]

 7 FEV1 (L)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    7.1 3 months
140Mean Difference (IV, Fixed, 95% CI)0.13 [-0.43, 0.69]

    7.2 6 months
140Mean Difference (IV, Fixed, 95% CI)0.17 [-0.40, 0.74]

    7.3 12 months
140Mean Difference (IV, Fixed, 95% CI)0.19 [-0.37, 0.75]

 8 FVC1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    8.1 3 months
140Mean Difference (IV, Fixed, 95% CI)0.05 [-0.63, 0.73]

    8.2 6 months
140Mean Difference (IV, Fixed, 95% CI)0.10 [-0.57, 0.77]

    8.3 12 months
140Mean Difference (IV, Fixed, 95% CI)0.11 [-0.57, 0.79]

 9 FEF25-751Mean Difference (IV, Fixed, 95% CI)Subtotals only

    9.1 3 months
140Mean Difference (IV, Fixed, 95% CI)0.12 [-0.52, 0.76]

    9.2 6 months
140Mean Difference (IV, Fixed, 95% CI)0.16 [-0.57, 0.89]

    9.3 12 months
140Mean Difference (IV, Fixed, 95% CI)0.29 [-0.35, 0.93]

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

 

Appendices

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

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

 

Electronic searches: core databases


DatabaseFrequency of search

CENTRAL (The Cochrane Library)Monthly

MEDLINE (Ovid)Weekly

EMBASE (Ovid)Weekly

PsycINFO (Ovid)Monthly

CINAHL (EBSCO)Monthly

AMED (EBSCO)Monthly



 

 

Handsearches: core respiratory conference abstracts


ConferenceYears searched

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

American Thoracic Society (ATS)2001 onwards

Asia Pacific Society of Respirology (APSR)2004 onwards

British Thoracic Society Winter Meeting (BTS)2000 onwards

Chest Meeting2003 onwards

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

International Primary Care Respiratory Group Congress (IPCRG)2002 onwards

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



 

 

MEDLINE search strategy used to identify trials for the CAGR

 

Bronchiectasis search

1. exp Bronchiectasis/

2. bronchiect$.mp.

3. bronchoect$.mp.

4. kartagener$.mp.

5. (ciliary adj3 dyskinesia).mp.

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

7. or/1-6

 

Filter to identify RCTs

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

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

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1-7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

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

 

Appendix 2. Search strategy for the Cochrane Airways Group Register

 

2013 update

#1 BRONCH:MISC1

#2 MeSH DESCRIPTOR Bronchiectasis Explode All

#3 bronchiect*

#4 #1 or #2 or #3

#5 MeSH DESCRIPTOR Mannitol Explode 1 2

#6 MeSH DESCRIPTOR Saline Solution, Hypertonic

#7 MeSH DESCRIPTOR Sodium Chloride

#8 "sodium chloride"

#9 NaCl

#10 mannitol

#11 osmolality

#12 osmolarity

#13 hyperosmolar

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

#15 #4 and #14

[In search line #1, MISC1 denotes the field in which the reference has been coded for condition, in this case, bronchiectasis]

 

Previous versions

"sodium chloride" OR NaCl OR mannitol OR osmolality OR osmolarity OR hyperosmolar

[Limited to bronchiectasis records]

 

What's new

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

Last assessed as up-to-date: 2 April 2014.


DateEventDescription

2 April 2014New search has been performedNew literature search run.

2 April 2014New citation required and conclusions have changedReview updated. The previous version of this review included two trials (28 participants), and now includes 11 trials (1021) participants.

'Summary of findings' tables added, review text redrafted, risk of bias updated.



 

History

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

Protocol first published: Issue 2, 2000
Review first published: Issue 1, 2001


DateEventDescription

28 July 2008AmendedConverted to new review format.

17 January 2006New citation required and conclusions have changedSubstantive amendment



 

Contributions of authors

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

In the original version of this review Wills 2006, the contribution of authors was as follows: PW: Initiation of the protocol, assessment of search results, quality assessment, data extraction, interpretation/discussion. MG: Editorial support, interpretation/discussion.

In the 2013 update SF, IC, KS and SM updated the background. KS and IC independently selected studies for inclusion. AH and IC independently extracted data. SM entered the data and AH checked data entry. The results, 'Risk of bias' and 'Summary of findings' sections were completed by SM, IC and AH. SM updated the methods section. AH, SF, IC, KS and SM completed the Discussion and Conclusions.

Chris Cates was the contact editor for this review and critically commented on it.

 

Declarations of interest

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

None known.

 

Sources of support

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

Internal sources

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

 

External sources

  • No sources of support supplied

 

Differences between protocol and review

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

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

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Bennoor 2012 {published data only}
  • Bennoor KS, Afreen KF, Hossain MA, Mahmud AM, Hassan MR. Inhaled mannitol in patients with bronchiectasis: effect on lung function and health status [Abstract]. Respirology 2012;17(Suppl 2):49 [423]. [CRS-ID: 4900100000073916]
Bilton 2013 {published data only}
  • Safety and efficacy of bronchitol in bronchiectasis. http://ClinicalTrials.gov/show/NCT00277537 (accessed 6 November 2013).
  • Bilton D, Daviskas E, Anderson SD, Kolbe J, King G, Stirling RG, et al. Phase 3 randomized study of the efficacy and safety of inhaled dry powder mannitol for the symptomatic treatment of non-cystic fibrosis bronchiectasis. Chest 2013;144(1):215–25.
  • Bilton D, Daviskas E, Jaques A, Anderson S, Charlton B. A randomised placebo-controlled trial of inhaled mannitol in patients with bronchiectasis [Abstract]. European Respiratory Society Annual Congress, Berlin, Germany, October 4-8. 2008:[P602]. [CRS-ID: 4900100000023582]
  • Bilton D, Daviskas E, Jaques A, Anderson SD, Charlton B. A randomised, placebo-controlled trial of inhaled mannitol in patients with bronchiectasis [Abstract]. American Thoracic Society International Conference, May 15-20, 2009, San Diego. 2009:A3221 [Poster #E21]. [CRS-ID: 4900100000053774]
  • Daviskas E. A new approach to treatment of difficult bronchiectasis [Abstract]. Respirology 2007;12(Suppl 4):A99. [CRS-ID: 4900100000021916]
  • Daviskas E, Bilton D, Jaques A, Anderson S, Charlton B. A randomised, placebo -controlled trial of inhaled mannitol in patients with bronchiectasis [Abstract]. Respirology (Carlton, Vic.) 2009;14(Suppl 1):A29. [CRS-ID: 4900100000024188]
Bradley 2011 {published data only}
  • Bradley JM, Treacy K, O'Neill B, McCourt F, Green L, Gardner E, et al. A randomised double blind 13 week crossover trial of hypertonic saline (HTS) (6%) vs isotonic saline (ITS) (0.9%) in patients with bronchiectasis [Abstract]. Thorax 2011;66(Suppl 4):A49 [S106]. [CRS-ID: 4900100000054250]
  • NCT01112410. Hypertonic saline (6%) versus isotonic saline (0.9%) in bronchiectasis. http://ClinicalTrials.gov/show/NCT01112410 (accessed 6 November 2013).
Chandra 2008 {published data only}
  • Chandra AR, Jones AS, King GG. Effects of inhaled mannitol treatment on airway wall dimensions measured by HRCT in patients with bronchiectasis [Abstract]. American Thoracic Society International Conference, May 16-21, 2008, Toronto. 2008:Poster #121. [CRS-ID: 4900100000023010]
Daviskas 1999 {published data only}
  • Daviskas E, Anderson S, Eberl S, Kim Chan H, Bautovich G. Inhalation of dry powder mannitol improves clearance of mucus in patients with bronchiectasis. American Journal of Respiratory and Critical Care Medicine 1999;159(6):1843-8.
Daviskas 2004 {published data only}
  • Daviskas E, Turton JA, Anderson SD, Young IV, Young IH, Lassig A, et al. A placebo controlled trial with inhaled mannitol improves health related quality of life in patients with bronchiectasis. European Respiratory Journal 2004;24(Suppl 48):707s.
  • Goldman MD, Daviskas E, Turton JA, Anderson SD. Inhaled mannitol improves lung function assessed by forced oscillation in a placebo controlled trial in patients with bronchiectasis. European Respiratory Journal 2004;24(Suppl 48):470s.
Daviskas 2008 {published data only}
  • Daviskas E, Anderson SD, Eberl S, Young IH. Effect of increasing doses of mannitol on mucus clearance in patients with bronchiectasis. European Respiratory Journal 2008;31(4):765-72. [CRS-ID: 4900100000024228]
Kellet 2011 {published data only}
  • Kellett F, Niven R. Nebulised 7 % hypertonic sodium chloride improves lung function and airway clearance in non cystic fibrosis bronchiectasis [Abstract]. European Respiratory Society Annual Congress, Barcelona, Spain, September 18-22. 2010:[P4587]. [CRS-ID: 4900100000026056]
  • Kellett F, Robert NM. Nebulised 7% hypertonic saline improves lung function and quality of life in bronchiectasis. Respiratory Medicine 2011;105(12):1831-5. [CRS-ID: 4900100000056247]
Kellett 2005 {unpublished data only}
  • Kellett F, Niven RM, Redfern J. Double blind trial of hyperosmolar saline as an adjunct to physiotherapy in patients with bronchiectasis. European Respiratory Journal 2001;18(Suppl 33):484s. [CRS-ID: 4900100000015089]
  • Kellett F, Redfern J, Niven RM. Evaluation of nebulised hypertonic saline (7%) as an adjunct to physiotherapy in patients with stable bronchiectasis. Respiratory Medicine 2005;99(1):27-31.
NCT00669331 {published data only}
  • Bilton D, Tino G, Barker A, Chambers D, DeSoyza A, Dupont L, et al. Inhaled mannitol for non-cystic fibrosis bronchiectasis:Results of a 12 month, multi-centre, double-blind, controlled study. ERS Annual Conference September 7-11 2013, Barcelona. 2013.
  • NCT00669331. Inhaled mannitol as a mucoactive therapy for bronchiectasis. http://ClinicalTrials.gov/show/NCT00669331 (accessed 6 November 2013).
Nicolson 2012 {published data only}
  • NCT00484263. The long term effect of inhaled hypertonic saline (6%) in patients with non cystic fibrosis bronchiectasis. http://ClinicalTrials.gov/show/NCT00484263 (accessed 6 November 2013).
  • Nicolson CHH, Stirling RG, Borg BM, Button BM, Wilson JW, Holland AE. The long term effect of inhaled hypertonic saline 6% in non-cystic fibrosis bronchiectasis. Respiratory Medicine 2012;106(5):661-7. [CRS-ID: 4900100000056481]

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Briffa 2009 {published data only}
  • Briffa PJ, Anderson SD, Burton DL, Young IH. Prevention of airway narrowing following mannitol inhalation in subjects with bronchiectasis [Abstract]. Respirology 2009;14(Suppl 1):A1. [CRS-ID: 4900100000024129]
Briffa 2011 {published data only}
Daviskas 2001 {published data only}
Daviskas 2003 {published data only}
  • Daviskas E, Anderson SD, Gomes K, Briffa P, Cochrane B, Chan K, et al. Increase in health status after 12 days treatment with inhaled mannitol in patients with bronchiectasis. European Respiratory Journal 2003;22(Suppl 45):430s.
Daviskas 2010 {published data only}
  • Daviskas E, Anderson SD, Eberl S, Young IH. Beneficial effect of inhaled mannitol and cough in asthmatics with mucociliary dysfunction. Respiratory Medicine 2010;104(11):1645-53. [CRS-ID: 4900100000025884]
Harrison 1983 {published data only}
  • Harrison AC, Fleming J, Rea HH, Harris EA. Bronchial hyper-reactivity in bronchiectasis. Australian and New Zealand Journal of Medicine 1983;13(5):544. [CRS-ID: 4900100000008522; : 4900100000008522]
Murray 2011 {published data only}
  • Murray MP, Govan JRW, Doherty CJ, Simpson AJ, Wilkinson TS, Chalmers JD, et al. A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis. American Journal of Respiratory and Critical Care Medicine 2011;183(4):491-9. [CRS-ID: 4900100000026211]
NCT00105183 {published data only}
  • NCT00105183. EZ-2053 in the prophylaxis of acute pulmonary allograft rejection. http://ClinicalTrials.gov/show/NCT00105183 (accessed 6 November 2013).
NCT00730977 {published data only}
  • NCT00730977. A pilot study to investigate administration of mannitol via a novel dry powder inhaler device. http://ClinicalTrials.gov/show/NCT00730977 Vol. (accessed 6 November 2013).
NCT00749866 {published data only}
  • NCT00749866. Long term nebulised gentamicin in patients with bronchiectasis. http://ClinicalTrials.gov/show/NCT00749866 (accessed 6 November 2013).
NCT01076491 {published data only}
  • NCT01076491. High dose inhaled mannitol study. http://ClinicalTrials.gov/show/NCT01076491 Vol. (accessed 6 November 2013).
NCT01313624 {published data only}
  • NCT01313624. A study to see if AZLI (an inhaled antibiotic) is effective in treating adults with non-CF bronchiectasis - AIR-BX1. http://ClinicalTrials.gov/show/NCT01313624 (accessed 6 November 2013).
NCT01314716 {published data only}
  • NCT01314716. A study to see if AZLI (an inhaled antibiotic) is effective in treating adults with non-CF bronchiectasis - AIR-BX2. http://ClinicalTrials.gov/show/NCT01314716 (acessed 6 November 2013).
NCT01677403 {published data only}
  • NCT01677403. A study to access safety and efficacy of nebulized tobramycin in patients with bronchiectasis. http://clinicaltrials.gov/show/NCT01677403 (accessed 6 November 2013).
Serisier 2013 {published data only}
  • Serisier DJ, Martin ML, McGuckin MA, Lourie R, Chen AC, Brain B, et al. Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: The BLESS randomized controlled trial. JAMA 2013;309(12):1260-7.
Sutton 1988 {published data only}
  • Sutton PP, Gemmell HG, Innes N, Davidson J, Smith FW, Legge JS, et al. Use of nebulised saline and nebulised terbutaline as an adjunct to chest physiotherapy. Thorax 1988;43(1):57-60. [CRS-ID: 4900100000018041]

Additional references

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Anwar 2013
  • Anwar GA, McDonnell MJ, Worthy SA, Bourke SC, Afolabi G, Lordan J, et al. Phenotyping adults with non-cystic fibrosis bronchiectasis: A prospective observational cohort study. Respiratory Medicine 2013;107(7):1001–7.
Bonavita 2012
BTS 2010
  • Pasteur MC, Bilton D, Hill AT (on behalf of the British Thoracic Society Bronchiectasis (non-CF) Guideline Group:a sub-group of the British Thoracic Society Standards of Care Committee). BTS Guideline for non-CF Bronchiectasis. http://www.brit-thoracic.org.uk/Guidelines/Bronchiectasis-Guideline-non-CF.aspx (accessed 6 November 2013).
Daviskas 1996
  • Daviskas E, Anderson SD, Gonda I, Eberl S, Meikle S, Seale JP, et al. Inhalation of hypertonic saline aerosol enhances mucociliary clearance in asthmatic and healthy subjects. European Respiratory Journal 1996;9(4):725-32.
Elkins 2006
Elkins 2006a
  • Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB, et al. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. New England Journal of Medicine 2006;354(3):229-40.
Enderby 2007
Evans 1996
Frey 2007
  • Frey JG. Bronchiectasis: a reemerging disease. Revue Médicale Suisse 2007;3(99):477-8, 480-3.
Higgins 2011
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1. The Cochrane Collaboration, Available from www.cochrane-handbook.org (accessed 10/12/2013)., updated March 2011.
Jones 2005
  • Jones PW. St Georges Respiratory Questionnaire:MCID. COPD 2005;2(1):75-9.
Kleinewietfeld 2013
  • Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 2013;496(7446):518-22.
Martinez 2007
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