Inhaled mannitol for cystic fibrosis - Cochrane Library

Inhaled mannitol for cystic fibrosis (Protocol) Thornton J, Murray CS, Elkins M, Dwyer T

This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2010, Issue 8 http://www.thecochranelibrary.com

Inhaled mannitol for cystic fibrosis (Protocol) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . ABSTRACT . . . . . . . . . BACKGROUND . . . . . . . OBJECTIVES . . . . . . . . METHODS . . . . . . . . . REFERENCES . . . . . . . . APPENDICES . . . . . . . . HISTORY . . . . . . . . . . CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST .

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[Intervention Protocol]

Inhaled mannitol for cystic fibrosis Judith Thornton1 , Clare S Murray2 , Mark Elkins3 , Tiffany Dwyer3 1 Primary

Care Research Group, University of Manchester, Manchester, UK. 2 Respiratory Group School of Translational Medicine, University of Manchester, Manchester, UK. 3 Department of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, Australia Contact address: Judith Thornton, Primary Care Research Group, University of Manchester, 5th Floor, Williamson Building, Oxford Road, Manchester, M13 9PT, UK. [email protected]. [email protected]. Editorial group: Cochrane Cystic Fibrosis and Genetic Disorders Group. Publication status and date: New, published in Issue 8, 2010. Citation: Thornton J, Murray CS, Elkins M, Dwyer T. Inhaled mannitol for cystic fibrosis. Cochrane Database of Systematic Reviews 2010, Issue 8. Art. No.: CD008649. DOI: 10.1002/14651858.CD008649. Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT This is the protocol for a review and there is no abstract. The objectives are as follows: To assess whether inhaled dry powder mannitol is well tolerated and whether it improves the respiratory function, reduces respiratory exacerbations and improves the quality of life of people with CF.

BACKGROUND

Description of the condition Cystic fibrosis (CF) is caused by a gene defect on the long arm of chromosome 7 which encodes for a transmembrane-regulating protein called the cystic fibrosis transmembrane conductance regulator (CFTR) (Dinwiddie 2000). The CFTR is primarily a chloride ion channel but is also involved in the regulation of other membrane channels and transport of molecules which may be important in mucociliary clearance and innate defence mechanisms (McAuley 2000). The interaction of CFTR with the epithelial sodium channel is also important and it is up-regulated in CF. Thus, defective CFTR in CF causes reduced chloride secretion and excess absorption of sodium across the epithelia and leading to thickened secretions in organs such as the pancreas and lung (McAuley 2000). These viscous secretions lead to airway obstruction, infection and chronic inflammation in a vicious cycle resulting in progressive lung damage with bronchiectasis and eventual

respiratory failure (Dinwiddie 2000). Lung disease remains the most common cause of death in people with CF (Robinson 2001). Liou developed and validated a five-year survivorship model of CF that identified eight characteristics of the disease in addition to forced expiratory volume at one second (FEV1 ) as a percentage of predicted normal that together accurately predict survival including: age; sex; weight-for-age z score; pancreatic sufficiency; diabetes mellitus; Staphylococcus aureus infection; Burkerholderia cepacia infection; and annual number of acute pulmonary exacerbations (Liou 2001). Several agents are used to clear secretions from the airways of people with CF. These agents include inhaled n-acetylcysteine, hypertonic saline and recombinant human deoxyribonuclease (dornase alfa) (Bye 2007; Nash 2009). A Cochrane Review demonstrated that dornase alfa reduces pulmonary exacerbations and improves lung function (Jones 2010). A second Cochrane Review showed that although regular treatment with hypertonic saline led to only modest improvements in lung function in adults and children, there were substantial reductions in pulmonary exacer-


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bations (Wark 2009). Although acetylcysteine has been used as a mucolytic drug in CF for many years, a Cochrane Review found little evidence for any beneficial effect (Nash 2009). These three treatments have to be given using a nebuliser, which can be timeconsuming, inconvenient and unpopular with patients. The effectiveness, safety, burden of care and adherence to nebulised therapy is being examined in a Cochrane Review (Hughes 2009). In addition, dornase alfa is expensive; in a study in children, daily dornase alfa was more effective than hypertonic saline but significantly increased healthcare costs (Suri 2002). Jones et al, noted that in cost analyses of a second study in adults and children, healthcare costs relating to respiratory tract infections were less in the treated participants but this cost saving did not offset the cost of therapy itself (Jones 2010). Inhaled dry powder mannitol is now being investigated as an alternative treatment for airway clearance.

Description of the intervention Mannitol is a dry powder contained in 40 mg capsules for inhalation. It is inhaled orally via a breath-activated hand-held inhalation device. Clinical studies have used varying doses of mannitol (315 mg to 635 mg) but generally around 400 mg (10 capsules) twice daily has been administered. Since mannitol is inhaled as a dry powder, it does not require a nebuliser. However, it is not as rapid as many dry powder medications because the dose is divided into multiple capsules which must be loaded and inhaled individually.

inhaled mannitol improved airway clearance (Wills 2008); these findings were supported by additional studies (Daviskas 1997; Daviskas 2001; Daviskas 2002; Daviskas 2005). An initial shortterm safety and efficacy study suggested mannitol may improve lung function in people with CF (Jaques 2008). A subsequent phase II study comparing the medium-term efficacy of mannitol with dornase alfa showed mannitol to be at least as effective as dornase alfa in improving FEV1 in children with CF (Minasian 2010). Phase III trials in CF are now in progress. In addition, the dry powder formulation of mannitol may be more convenient and easier to use compared with established agents which require delivery via a nebuliser; anecdotal reports suggest that once individuals become familiar with the technique, administration time for inhaled mannitol compares well with the time taken to administer nebulised dornase alfa. Thus, the evidence in CF should be combined and presented in a systematic review. This need is reinforced by the granting of orphan drug status for mannitol in both the USA and Europe and by the UK National Institute for Health and Clinical Excellence (NICE) considering a review of the use of mannitol in CF.

OBJECTIVES To assess whether inhaled dry powder mannitol is well tolerated and whether it improves the respiratory function, reduces respiratory exacerbations and improves the quality of life of people with CF.

How the intervention might work Mannitol is a naturally occurring six-carbon monosaccharide (sugar alcohol) which is not actively transported and is poorly absorbed after inhalation (Anderson 1997). It appears to act by inducing an influx of water into the airway lumen and evidence from in vitro and animal studies suggests a number of mechanisms by that may increase mucociliary clearance, including improving hydration of airway secretions and reducing sputum viscosity (Bye 2007). However, Daviskas examined ex vivo sputum and was only able to demonstrate an improvement in hydration with no substantial change in viscoelasticity (Daviskas 2010). An additional suggested mechanism of action is stimulating release of mediators that increase ciliary beat frequency (Brannan 2003; Wanner 1983). Regardless of the exact mechanism by which it is achieved, mannitol increases mucociliary clearance in people with CF (Robinson 1999).

Why it is important to do this review Inhaled dry powder mannitol is in commercial development for the treatment of CF and bronchiectasis. A Cochrane Review of inhaled hyperosmolar agents in people with bronchiectasis identified two randomised controlled trials (RCTs) and demonstrated that

METHODS

Criteria for considering studies for this review

Types of studies Randomised controlled trials (RCTs). Types of participants Adults (16 years old and over) and children (under 16 years old) with CF (diagnosed clinically and by sweat or genetic testing and including all degrees of disease severity). Types of interventions We plan to compare orally inhaled dry powder mannitol with either placebo, active inhaled comparators (for example, hypertonic saline or dornase alfa) or with no treatment. All doses and regimens of mannitol administration will be included. Studies of all durations of treatment and follow up will be included.


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Types of outcome measures

Primary outcomes

1. Quality of life as measured by a validated tool such as Cystic Fibrosis Questionnaire-Revised version (CFQ-R (Quittner 2009) and Cystic Fibrosis Quality of Life Questionnaire (CFQoL (Gee 2000)) 2. Lung function i) forced expiratory volume in one second (FEV1 ) (in litres or per cent predicted) ii) forced vital capacity (FVC) (in litres or per cent predicted) iii) forced expiratory flow between 25% and 75% expired volume (FEF25−75 ) (in litres or per cent predicted) 3. Pulmonary exacerbations i) number of participants free of pulmonary exacerbations ii) time to next pulmonary exacerbation

Secondary outcomes

1. Adverse effects relating to treatment i) type and number of adverse events defined as follows: a) mild (not requiring extra treatment); b) moderate (requiring extra treatment); c) severe (life-threatening or requiring hospitalisation). ii) number of participants who ceased inhalations because of poor tolerability e.g. cough or bronchoconstriction 2. Time off school or work 3. Need for additional non-routine antibiotics i) intravenous ii) oral iii) nebulised 4. Hospitalisations i) number of hospitalisations ii) duration 5. Assessment of symptoms (including cough, sputum volume, ease of expectoration and dyspnoea) 6. Sputum microbiology (change in numbers of pathogens, emergence of new pathogens) 7. Burden of treatment (using a validated measure)

Search methods for identification of studies

Electronic searches We will identify relevant studies from the Group’s Cystic Fibrosis Trials Register.

The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (Clinical Trials) (updated each new issue of The Cochrane Library), quarterly searches of MEDLINE, a search of EMBASE to 1995 and the prospective handsearching of two journals - Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work is identified by searching the abstract books of three major cystic fibrosis conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all searching activities for the register, please see the relevant sections of the Cochrane Cystic Fibrosis and Genetic Disorders Group Module.

Searching other resources We plan to check the reference lists of any studies identified for further relevant studies. We shall also contact primary authors of identified trials and research institutions or biotech companies for unpublished studies.

Data collection and analysis

Selection of studies Three authors (JT, CM and TD) will independently review all potential studies for inclusion. These three authors will examine the title and abstract of potential publications to remove those that do not meet inclusion criteria (e.g. single case reports, reviews etc). They will then examine the full text publications of the remaining studies to determine if they meet the eligibility criteria. If they are unable to reach agreement regarding the determination of eligibility by discussion, they will resolve this by approaching the fourth author to act as arbiter (ME). Authors will examine publications potentially eligible for inclusion for duplication by comparing author, institution, study detail (intervention, dosing, timing etc) and participant demographics.

Data extraction and management Three authors (JT, CM and TD) will independently extract study characteristics and outcome data from the studies onto a standard data extraction form. If there is disagreement, they will resolve this by approaching the fourth author (ME) to act as arbiter. We will report data at one month, three months and one year. If any studies have followed participants beyond one year, we will also report these data. The following comparisons will be undertaken: mannitol versus no treatment; mannitol versus placebo; mannitol versus n-acetylcysteine; mannitol versus hypertonic saline; and mannitol versus dornase alfa.


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Assessment of risk of bias in included studies The authors will assess the risk of bias using the ’Risk of bias’ assessment tool as documented in section 8.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Low and high risk of bias will be defined as in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Sequence generation The authors will determine if the allocation sequence was adequately generated. An adequate generation of the allocation sequence constitutes a low risk of bias, inadequate generation constitutes a high risk of bias and if it is unclear how the sequence was generated, this constitutes an unclear risk of bias. Allocation concealment The authors will determine if the allocation sequence was adequately concealed. An adequate concealment of the allocation sequence constitutes a low risk of bias, inadequate concealment constitutes a high risk of bias and if it is unclear how allocation was concealed, this constitutes an unclear risk of bias. Blinding (or masking) of participants, personnel and outcome assessors The authors will assess whether knowledge of the allocated intervention was adequately prevented during the study. If knowledge of allocation was adequately prevented this constitutes a low risk of bias, if knowledge of allocation was not adequately prevented this constitutes a high risk of bias and if it is unclear whether knowledge of allocation was adequately concealed, this constitutes an unclear risk of bias. Incomplete outcome data The authors will assess whether incomplete outcome data were adequately addressed. For example, if missing data from a large proportion of the total number of participants were a result of participants dropping out of one arm of the study (e.g. the mannitol arm), this would constitute a high risk of bias. However, if there are small numbers of participants with missing data spread evenly across the study arms, then this would constitute a low risk of bias. If it is unclear how the the issue of incomplete outcome data was addressed, this constitutes an unclear risk of bias. Selective outcome reporting The authors will assess whether reports of the study are free of suggestions of selective outcome reporting. If the study appears to be free of selective outcome reporting this constitutes a low risk of bias, evidence of selective outcome reporting constitutes a high risk of bias and if it is unclear whether there is selective outcome reporting, this constitutes an unclear risk of bias. Other potential sources of bias The authors will assess whether the study was apparently free of other problems that could put it at high risk of bias. For example, we plan to report on whether the investigators performed a sample size calculation, for which outcome(s) and the method used.

Measures of treatment effect

For binary (dichotomous) outcome measures, we aim to calculate a pooled estimate of treatment effect for each outcome across studies using risk ratio (RR) where appropriate and the corresponding 95% confidence intervals (CIs). For continuous outcome measures, we will calculate a pooled estimate of treatment effect by calculating the mean difference (MD) and the corresponding 95% CIs. Where possible, if standard errors (SE) are reported, these will be converted to standard deviations (SD). When analysing count data, we will decide whether to treat this as dichotomous, continuous, time-to-an-event or as a rate. Although we accept that it is preferable to decide how count data will be analysed in advance, we think our choice will be determined by the format of the available data and thus can not be decided until most studies have been reviewed. We plan to analyse such data as described in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2008). We plan to analyse time-to-event data (e.g. time to next pulmonary exacerbation) using the hazard ratio and 95% CIs. Where studies measure data longitudinally, we plan to base our analysis on the final time-point results which is a common method used in Cochrane Reviews (Jones 2005). We accept that this analysis would treat the data as independent, although in reality they are not. However, methods are not yet available to carry out a meta-analysis of aggregate longitudinal data, unless we are able to obtain any individual patient data. Unit of analysis issues When conducting a meta-analysis combining results from crossover studies we plan to use the methods recommended by Elbourne (Elbourne 2002). However, if only limited data are available, we will only be able to either use the first-arm data only or to treat the cross-over studies as if they are parallel studies. Elbourne states that this approach will produce conservative results as it does not take into account within-patient correlation (Elbourne 2002). Also each participant will appear in both the treatment and control group, so the two groups will not be independent. We do not plan to combine data from parallel trials with data from cross-over trials; these will be analysed separately. Dealing with missing data In the event of missing, incomplete, or unclear data we will contact the original investigators. If we do not obtain the necessary data for analysis, we will report the studies in a narrative way. Assessment of heterogeneity We plan to assess the degree of heterogeneity between studies using the I2 statistic (Higgins 2003). This measure describes the percentage of total variation across studies that are caused by heterogeneity rather than by chance (Higgins 2003). The values of


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I2 lie between 0% and 100%, and a simplified categorization of heterogeneity that we plan to use is of low (I2 value of less than 25%), moderate (I2 value of between 25 and 50%), and high (I2 value of over 50%) (Higgins 2003). Assessment of reporting biases We will assess reporting bias among the studies using the funnel plot method discussed in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). If asymmetry is present, we will explore possible causes including publication bias, methodological quality, and true heterogeneity.

Subgroup analysis and investigation of heterogeneity If we find significant heterogeneity (over 50%) and there are sufficient studies included in the review, we will investigate the possible causes further by performing the following subgroup analyses: • age: children (under 16 years) and adult (16 years and over); • sex; • disease severity: FEV1 % predicted over 90%, 70% to 90%, 40% to 69%, under 40%); • dornase alfa: participants using or not using dornase alfa; • infection with Pseudomonas aeruginosa.

Data synthesis We will enter data extracted from included studies into RevMan 5 (RevMan 2008). If no significant heterogeneity is identified, we plan to compute pooled estimates of the treatment effect for each outcome under a fixed-effect model. If we find significant heterogeneity, we will compute pooled estimates of the treatment effect for each outcome using a random-effects model.

Sensitivity analysis We will also test the robustness of our results through a sensitivity analysis on the basis of the methodological quality of the included studies, for example, unpublished studies, small studies, allocation concealment, assessor blinding, and loss to follow-up on the results.

REFERENCES

Additional references Anderson 1997 Anderson SD, Brannan J, Spring J, Spalding N, Rodwell LT, Chan K, Gonda I, Walsh A, Clark AR. A New Method For Bronchial-provocation Testing inAsthmatic Subjects Using a Dry Powder of Mannitol. American Journal of Respiratory and Critical Care Medicine 1997;156:758–765. Brannan 2003 Brannan JD, Gulliksson M, Anderson SD, Chew N, Kumlin M. Evidence of mast cell activation and leukotriene release after mannitol inhalation. European Respiratory Journal 2003;22(3):491–6. Bye 2007 Bye PTP, Elkins MR. Other mucoactive agents for cystic fibrosis. Paediatric Respiratory Reviews 2007;8(1):30–9. Daviskas 1997 Daviskas E, Anderson SD, Brannan JD, Chan H-K, Eberl S, Bautovich G. Inhalation of dry powder mannitol increases mucociliary clearance. European Respiratory Journal 1997; 10(11):2449–54. Daviskas 2001 Daviskas E, Anderson SD, Eberl S, Chan H-K, Young IH. The 24-h effect of mannitol on the clearance of mucus in patients with bronchiectasis. Chest 2001;119:414–421. Daviskas 2002 Daviskas E, Anderson SD, Eberl S, Chan H-K, Young IH, Seale JP. Effects of terbutaline in combination with

mannitol on mucociliary clearance. European Respiratory Journal 2002;20(6):1423–9. Daviskas 2005 Daviskas E, Anderson SD, Gomes K, Briffa P, Cochrane B, Chan H-K, et al.Inhaled mannitol for the treatment of mucociliary dysfunction in patients with bronchiectasis: effect on lung function, health status and sputum. Respirology 2005;10(1):46–56. Daviskas 2010 Daviskas E, Anderson SD, Jaques A, Charlton B. Inhaled mannitol improves the hydration and surface properties of sputum in patients with cystic fibrosis. Chest 2010;137(4): 861–8. Deeks 2008 Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 9: Analysing data and undertaking meta-analyses. In: Higgins JPT, Green S (editors). Cochrane Handbook of Systematic Reviews of Interventions. Version 5.0.0 (updated February 2008). The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org. Dinwiddie 2000 Dinwiddie R. Pathogenesis of lung disease in cystic fibrosis. Respiration 2000;67:3–8. Elbourne 2002 Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington HV, Vail A. Meta-analyses involving crossover trials: methodological issues. International Journal of Epidemiology 2002;31(1):140–9.


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Gee 2000 Gee L, Abbott J, Conway S, Etherington C, Webb A. Development of a disease specific health related quality of life measure for adults and adolescents with cystic fibrosis. Thorax 2000;55(11):946–54.

Nash 2009 Nash EF, Stephenson A, Ratjen A, Tullis E. Nebulized and oral thiol derivatives for pulmonary disease in cystic fibrosis. Cochrane Database of Systematic Reviews 2009, Issue 1. [DOI: 10.1002/14651858.CD007168.pub2]

Higgins 2003 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327 (7414):557–60.

Quittner 2009 Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest 2009;135 (6):1610–8.

Higgins 2008 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org. Hughes 2009 Hughes T, Mills N, Whitaker P. Nebuliser devices for drug delivery in cystic fibrosis. Cochrane Database of Systematic Reviews 2009, Issue 1. [DOI: 10.1002/ 14651858.CD007639] Jaques 2008 Jaques A, Daviskas E, Turton JA, McKay K, Cooper P, Stirling RG, Robertson CF, Bye TP, LeSouef PN, Shadblot B, Sanderson SD, Charlton B. Inhaled mannitol improves lung function in cystic fibrosis. Chest 2008;133:1388–1396. Jones 2005 Jones AP, Riley R, Williamson PR, Whitehead A. Metaanalysis of longitudinal data. Royal Statistical Society Annual Conference. 2005. Jones 2010 Jones AP, Wallis C, Kearney CE. Dornase alfa for cystic fibrosis. Cochrane Database of Systematic Reviews 2010, Issue 3. [DOI: 10.1002/14651858.CD001127.pub2.] Liou 2001 Liou G, Adler FR, FitzSimmons SC, Cahill BC, Hibbs JR, Marshall BC. Predictive 5-year survivorship model of cystic fibrosis. American Journal of Epidemiology 2001;153: 345–352. McAuley 2000 McAuley DF, Elborn JS. Cystic fibrosis: basic science. Paediatric Respiratory Reviews 2000;1(2):93–100. Minasian 2010 Minasian C, Wallis C, Metcalfe C, Bush A. Comparison of inhaled mannitol, daily rhDNase and a combination of both in children with cystic fibrosis: a randomised trial. Thorax 2010;65:51–56.

RevMan 2008 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008. Robinson 1999 Robinson M, Daviskas E, Eberl S, Baker J, Chan H-K, Anderson SD, et al.The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study. European Respiratory Journal 1999;14(3):678–85. Robinson 2001 Robinson P. Cystic Fibrosis. Thorax 2001;56(3):237–41. Suri 2002 Suri R, Grieve R, Normand C, Metcalfe C, Thompson S, Wallis C, et al.Effects of hypertonic saline, alternate day and daily rhDNase on healthcare use, costs and outcomes in children with cystic fibrosis. Thorax 2002;57(10):841–6. Wanner 1983 Wanner A, Maurer D, Abraham WM, Szepfalusi Z, Sielczak M. Effects of chemical mediators of anaphylaxis on ciliary function. Journal of Clinical Immunology 1983;72(6): 663–7. Wark 2009 Wark P, McDonald VM. Nebulised hypertonic saline for cystic fibrosis. Cochrane Database of Systematic Reviews 2009, Issue 2. [DOI: 10./1461002/14651858.CD001506.pub3] Wills 2008 Wills PJ, Greenstone M. Inhaled hyperosmolar agents for bronchiectasis. Cochrane Database of Systematic Reviews 2008, Issue 2. [DOI: 10.1002/ 14651858.CD002996.pub2] ∗ Indicates the major publication for the study


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APPENDICES

Appendix 1. Glossary

Term

Explanation

bronchiectasis

a congenital or acquired disorder of the large bronchi of the lungs, characterized by permanent, abnormal dilation and destruction of bronchial walls. In this condition some of the bronchi and bronchioles have lost their elasticity and have expanded and filled with fluid. It may be caused by recurrent inflammation or infection of the airways

bronchiolar

to do with the fine, thin-walled, tubular extensions of a bronchus

ciliary beat frequency

the rate at which the cilia beat (cilia are fine hair-like projections from certain kinds of cells; they line the respiratory tract and move in rhythmic unison to “sweep” away fluids and particles within the lungs)

epithelial

to do with the outside layer of cells that covers all the free, open surfaces of the body including the skin and mucous membranes

hyperosmolar agents

agents causing the abnormal increase in the concentration of a solution, especially a body fluid, as occurs in dehydration

mucins

a group of glycoproteins found especially in the secretions of mucous membranes

mucociliary clearance

the movement of the mucous covering of the surface of the respiratory tract by the beating of cilia: rapid, forward (effective) stroke and slow, return (recovery) stroke

mucolytic

capable of dissolving, digesting, or liquefying mucus

rheological

to do with the change in form and the flow of matter, including elasticity, viscosity, and plasticity

tracheobronchial clearance

clearance of the trachea and bronchi

HISTORY Protocol first published: Issue 8, 2010


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CONTRIBUTIONS OF AUTHORS

Roles and responsibilities TASK

WHO WILL UNDERTAKE THE TASK?

Protocol stage: draft the protocol

JT CM ME TD

Review stage: select which trials to include

JT CM TD

Review stage: if necessary, arbitrate on which trials to include

ME

Review stage: extract data from trials

JT CM TD

Review stage: enter data into RevMan

JT

Review stage: carry out the analysis

JT CM

Review stage: interpret the analysis

JT CM

Review stage: draft the final review

JT CM

Review stage: comment on the final review

ME, TD

Update stage: update the review

JT CM ME TD

DECLARATIONS OF INTEREST Dr Murray is principal investigator and Dr Thornton was pharmacist for a clinical trial of inhaled mannitol in children with CF. Dr Thornton’s main employment is with NICE (Clinical Practice); NICE (Technology Appraisals) are considering an appraisal of mannitol in CF.


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