title: Inhaled hyperosmolar agents for bronchiectasis.
abstract: BACKGROUND
  Mucus retention in the lungs is a prominent feature of bronchiectasis. The stagnant mucus becomes chronically colonised with bacteria, which elicit a host neutrophilic response. This fails to eliminate the bacteria, and the large concentration of host-derived protease may contribute to the airway damage. The sensation of retained mucus is itself a cause of suffering, and the failure to maintain airway sterility probably contributes to the frequent respiratory infections experienced by many patients.Hypertonic saline inhalation is known to accelerate tracheobronchial clearance in many conditions, probably by inducing a liquid flux into the airway surface, which alters mucus rheology in a way favourable to mucociliary clearance. Inhaled dry powder mannitol has a similar effect. Such agents are an attractive approach to the problem of mucostasis, and deserve further clinical evaluation.
  
  
  OBJECTIVE
  To determine whether inhaled hyperosmolar substances are effective in the treatment of bronchiectasis.
  
  
  METHODS
  We searched the Cochrane Airways Group Specialised Register, trials registries, and the reference lists of included studies and review articles. Searches are current up to April 2014.
  
  
  METHODS
  Any randomised controlled trial (RCT) using hyperosmolar inhalation in patients with bronchiectasis not caused by cystic fibrosis.
  
  
  METHODS
  Two review authors assessed studies for suitability. We used standard methods recommended by The Cochrane Collaboration.
  
  
  RESULTS
  Eleven studies met the inclusion criteria of the review (1021 participants).Five studies on 833 participants compared inhaled mannitol with placebo but poor outcome reporting meant we could pool very little data and most outcomes were reported by only one study. One 12-month trial on 461 participants provided results for exacerbations and demonstrated an advantage for mannitol in terms of time to first exacerbation (median time to exacerbation 165 versus 124 days for mannitol and placebo respectively (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.63 to 0.96, P = 0.022) and number of days on antibiotics for bronchiectasis exacerbations was significantly better with mannitol (risk ratio (RR) 0.76, 95%CI 0.58 to 1.00, P = 0.0496). However, exacerbation rate per year was not significantly different between mannitol and placebo (RR 0.92 95% CI 0.78 to 1.08). The quality of this evidence was rated as moderate. There was also an indication, from only three trials, again based on moderate quality evidence, that mannitol improves health-related quality of life (mean difference (MD) -2.05; 95% CI -3.69 to -0.40). An analysis of adverse events data, also based on moderate quality evidence, revealed no difference between mannitol and placebo (OR 0.96; 95% CI 0.61 to 1.51). Two additional small trials on 25 participants compared mannitol versus no treatment and the data from these studies were inconclusive.Four studies (combined N = 113) compared hypertonic saline versus isotonic saline. On most outcomes there were conflicting results and the opportunities for the statistical aggregation of data from studies was very limited. It is not possible to draw robust conclusions for this comparison and judgments should be reserved until further data are available.
  
  
  CONCLUSIONS
  There is an indication from a single, large, unpublished study that inhaled mannitol increases time to first exacerbation in patients with bronchiectasis. In patients with near normal lung function, spirometry does not change dramatically with mannitol and adverse events are not more frequent than placebo. Further investigation is required in a patient population with impaired lung function.It is not possible to draw firm conclusions regarding the effect of nebulised hypertonic saline due to significant differences in the methodology, patient groups, and findings amongst the limited data available. The data suggest that it is unlikely to have benefit over isotonic saline in patients with milder disease, and hence future studies should test its use in those with more severe disease.
authors.affiliation: Lancaster Medical School, Clinical Research Hub, Lancaster University, Lancaster, Lancashire, UK, LA1 4TB.
authors.forename: Anna
authors.initials: A
authors.lastname: Hart
authors.forename: Karnam
authors.initials: K
authors.lastname: Sugumar
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Milan
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Fowler
authors.forename: Iain
authors.initials: I
authors.lastname: Crossingham
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001987:Bronchiectasis / Q000188:drug therapy*; D018592:Cross-Over Studies; D006304:Health Status; D006801:Humans; D006982:Hypertonic Solutions / Q000008:administration & dosage*; D008353:Mannitol / Q000008:administration & dosage*; D009079:Mucociliary Clearance; D009994:Osmolar Concentration; D011208:Powders; D016032:Randomized Controlled Trials as Topic
chemical_list: D000900:Anti-Bacterial Agents; D006982:Hypertonic Solutions; D011208:Powders; D008353:Mannitol