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.