Inhaled hyperosmolar agents for bronchiectasis

Hart, Anna and Sugumar, Karnam and Milan, Stephen and Fowler, Stephen J. and Crossingham, Iain (2014) Inhaled hyperosmolar agents for bronchiectasis. Cochrane Database of Systematic Reviews. ISSN 1469-493X

Abstract

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. Objectives To determine whether inhaled hyperosmolar substances are effective in the treatment of bronchiectasis. Search 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. Selection criteria Any randomised controlled trial (RCT) using hyperosmolar inhalation in patients with bronchiectasis not caused by cystic fibrosis. Data collection and analysis Two review authors assessed studies for suitability. We used standard methods recommended by The Cochrane Collaboration. Main 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. Authors' 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 Plain language summary Inhaled hyperosmolar agents for bronchiectasis Review question We wanted to know if inhaled hyperosmolar agents - treatments which help people cough up sputum - may be helpful for people with bronchiectasis. We only included trials on people who had bronchiectasis and who did not have cystic fibrosis. Therefore we are unable to draw any conclusions for people with cystic fibrosis. Background Bronchiectasis is a lung condition that usually develops after a series of lung problems (such as childhood infections, problems in the lung structure, tuberculosis, and cystic fibrosis). A lot of mucus (phlegm) collects in the lungs, causing discomfort and the need to cough it up. The phlegm also collects bacteria, which can add to breathing difficulties and make people very ill by causing recurring lung infections that are difficult to clear with antibiotics. Breathing in (inhaling) hypertonic saline (salt solutions with a greater salt content than blood) liquids may help clear this mucus, as may the drug mannitol (inhaled in dry powder form). This is because the concentrated salt or sugar (mannitol) draws water into the mucus in the lung and makes it thinner and easier to cough out. Study characteristics 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. Key results 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. Quality of the evidence 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.