Abstract: 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. There is an indication from a single, large, unpublished study that inhaled mannitol increases time to first exacerbation in patients with bronchiectasis.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

Plain-language summary: We found 11 randomised controlled trials on 1021 participants that compared inhaled hyperosmolar agents versus no mucolytic treatment. Five studies compared inhaled mannitol versus placebo (with a total of 883 participants) and two very small studies (with a total of just 25 participants) compared inhaled mannitol with no treatment. We also found four studies (with a total of 113 participants) that compared hypertonic saline with isotonic (normal) saline. For the comparison between mannitol and placebo only one study (a 12-month trial with 461 participants) provided information on the number of people who had an exacerbation (or flare up) over the course of a year. This study showed that people who were treated with mannitol had 8% fewer exacerbations on average compared with placebo. Overall, we felt the quality of this evidence was moderate and new trials would be likely to change either how effective we think the treatment is or how confident we are about it. Three trials assessed the effect of mannitol on health-related quality of life, and again the quality of the evidence was rated as moderate. An analysis of adverse events data, also based on moderate quality evidence, revealed no difference between mannitol and placebo The trials comparing hypertonic saline with isotonic saline had conflicting results for most of the outcomes of interest. Because we were unable to combine the data, it is not possible to draw robust conclusions for this comparison and judgments should be reserved until further data are available. Our analysis of adverse events between hypertonic saline versus isotonic saline showed no significant difference however this was based on a single study and the quality of the evidence was moderate. Details of how the patients in the trials were allocated to receive mannitol or not was clearly described in only one of the studies, and similarly only one of the hypertonic saline versus isotonic saline studies provided this information. The general lack of information on this point was considered carefully in the review in relation to our level of uncertainty in interpreting the results. Taking this into account, the quality of evidence was generally regarded as moderate both for the mannitol and hypertonic saline studies.