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Sputum retention is a distressing feature of non-cystic fibrosis bronchiectasis and has been shown to contribute to the vicious cycle of infection seen in this disease. In a previous study we demonstrated that nebulised 7% hypertonic saline was both safe and effective in this patient population. Patients with a clinical diagnosis of non-cystic fibrosis bronchiectasis, confirmed by HRCT, were entered into a randomised single blind cross-over study to evaluate 0.9% sodium chloride (IS) and 7% hypertonic saline (HS). Following a 4 week run in patients received a random order active HS or IS daily for 3 months. A 4 week wash-out phase was included between phases. We report lung function, quality of life, and health care utilisation responses. 32 patients mean age 56.6 years (SD 14.6), 16 male, were recruited of which 28 were randomised and completed the study. Lung function (%change from baseline) improved in HS vs. IS (FEV1: 15.1, 1.8 p<0.01; FVC: 11.2, 0.7 p<0.01. SGRQ improved significantly from baseline (HS 6.0, IS 1.2; p<0.05). There were reductions in annualised antibiotic usage (HS 2.4, IS 5.4 courses per patient per year), annualised emergency health care utilisation visits were reduced (HS 2.1, IS 4.9 events per patient per year). There were also improvements in sputum viscosity and ease of expectoration (visual analogue scale). Regular use of 7% hypertonic saline improves lung function, quality of life and health care utilisation in non-cystic fibrosis bronchiectasis patients.
This creates favourable conditions for bacterial colonisation and proliferation within the respiratory tract, which then directly affects the ciliary beating and co-ordination, disrupting the epithelium itself.
Targeting sodium transportation has attractions. The principle polymer components of sputum, including sputum gels and mucins are negatively charged. Therefore, concentration changes of the major ions, sodium and chloride; influence the degree of hydration and physical properties of the sputum.
This principle has been demonstrated in cystic fibrosis where the predominant ion transport abnormality in the airway epithelium appears to be an increased rate of sodium absorption and decreased permeability to chloride. This occurs as a result of a defective gene which is responsible for compiling a transmembrane regulator protein.
The use of nebulised “normal” (0.9% isotonic) saline (IS), as a method of enhancing mucociliary clearance has become a clinically accepted adjunct to physiotherapy in the treatment of many chronic lung conditions but it has little scientific evidence on which to base its use.
We have previously demonstrated the potential safety and possible efficacy of hypertonic saline used as a single dose in patients with non-CF bronchiectasis, which has led to pragmatic use of this therapy in our centre.
The aim of this study was to determine the effectiveness of daily 7% hypertonic saline in improving markers of bronchiectasis, including physiology, quality of life, infection rate and subjective markers of sputum viscosity and ease of expectoration, over a 3 month treatment period when compared to 0.9% saline.
Patients chronically colonised with pseudomonas were excluded from the trial.
The study was a single blind, randomised, placebo controlled, cross-over study. At screening patients were required to undertake a challenge to 7% HS, to demonstrate tolerability as confirmed by a fall in FEV1 of less than 10% from pre-challenge levels. Following a four week run in, baseline data was collected and patients were randomised to receive either 7% HS (4 ml nebulised once daily) or placebo (0.9% IS 4 ml nebulised once daily). Each treatment phase lasted 3 months, with efficacy measures, collected at the end of each 3 month cycle. After the first treatment (active or placebo), there followed a 4 week wash-out phase, repeat baseline measures and cross-over to receive 3 months placebo (IS), or active 7% (HS) (see Fig. 1 – trial design).
Adult patients over the age of 18, with a pre-existent diagnosis of bronchiectasis, as confirmed by a high resolution CT scan (performed within the last 4 years), were considered for this study. Exclusion criteria were any severe medical condition that excluded the use of HS, an expected broncho-constrictor response to a 7% challenge to HS, such as evidence or history of bronchial reactivity, use of nebulised antibiotics or maintenance oral antibiotics or previous use of nebulised hypertonic saline.
Other than exclusion criteria, participants were allowed to continue all chronic medication but were requested to keep a diary and report if medication changed during the course of the study. The primary and secondary care physicians responsible for the patients were requested to keep all medication stable, but were advised to give medications for exacerbations as they perceived appropriate. No changes were made to other medications during the trial.
Changes in absolute FEV1 and FVC were calculated as percent change in absolute value from pre-treatment phase to post treatment phase. The comparison between these changes during active and placebo phases was the a-prioiri primary end-points.
All measures were made by a single operator using a single calibrated, dry wedge bellows spirometer. FEV1 and FVC were measured, using the best of 3 forced manoeuvres fulfilling the American Thoracic Society criteria.
Quality of life measures were made using the St George’s respiratory Quality of Life Questionnaire. Self-completed questionnaires were performed before and after each treatment phase. A clinically relevant change was considered to be 4 for total score. End-points included the global score change during active and placebo phases, as well as scores for the sub-scales of symptoms, activity and impact.
Health care utilisation/exacerbation
Two separate measures of health care utilisation were calculated. These were rescue antibiotic use, which was either a course of antibiotics prescribed by the primary care, secondary provider or self-prescribed from a “rescue pack” present as part of normal care for that individual. From the latter oral or intravenous antibiotic courses were included.
Annualised exacerbation rates were any unscheduled primary or secondary care events, which led to provision of rescue medication, either steroids or antibiotics, accident and emergency attendance or hospitalisations. Due to the presence of rescue packs for self-prescribed antibiotics, antibiotic use could be more frequent than exacerbations within the study.
Data was collected prospectively during the 3 month active or placebo phases. For baseline data, the response to the questions to the individual for retrospective recall of:- “In the last 12 months how many times have you had to go to your GP or hospital with your chest, how many courses of antibiotics and or antibiotics have you had?”. The patients were prompted only if unsure about medication names.
Sputum viscosity was assessed subjectively by the investigator using a “pourability grade” previously described.
Patients were asked to report their subjective view of the sputum ease of expectoration for the 24 h preceding each clinic visit using a visual analogue scale (1–10). This data was collected at the end of run-in, active and placebo phases.
All patients provided written informed consent to participate in this project which was approved by the South Manchester Local Research and Ethics committee.
All data was analysed using SPSS statistical package. For lung function percent change from pre-phase baseline was calculated as geometric mean and 95% confidence intervals determined. St Georges Respiratory Questionnaire data, paired student T tests were used for comparison of change across treatment phases.
32 patients were screened for the trial, 2 were excluded in run-in due to hyper-responsiveness to hypertonic saline challenge (30 had no fall in FEV1 as defined by a fall from baseline of greater than 10%). 30 patients were randomised, 2 withdrew, 1 due to a new medical diagnosis (laryngeal cancer) and one due to failure to comply with study visits, prior to commencing phase 1. 28 patients represented the study population (per protocol).
Fourteen males (mean age (60.36 years) and 14 females (mean age 60.43) completed the study.
Table 1 presents the demographic details of the study population.
Table 2 presents the primary end-point data of change in FEV1 and FVC during active and placebo phases. A significant improvement in both parameters was seen in favour of HS when compared to IS. Analysis has demonstrated no order effect of treatment.
Table 2Changes in lung function over treatment periods (% change from pre-treatment baseline).
Significant changes were seen for St George’s Respiratory Quality of Life (global score) and in terms of the sub-scales of symptoms and impact, but did not reach statistical significance for activity (Fig. 2).
There were reductions in health care utilisations, when comparing the prospectively collected data between active and placebo phases. Retrospectively collected data suggested there were low levels of antibiotic use/exacerbations prior to the study compared to active phases during the study (Table 3). Reasons for this are discussed below.
Table 3Outcome of exacerbations/health care utilization.
It is possible therefore, that administration of a concentrated sodium chloride solution would increase mucociliary clearance. This has been demonstrated in bronchiectasis where the application of HS to the surface of the respiratory epithelium increased the amount of sodium and chloride in the airway surface liquid. As a result, the osmotic gradient increased and water was attracted back onto the airway surface, thus rehydrating the periciliary fluid and mucus layer.
The study has limitations, primarily in the single blind nature of the study. At the time of performing this study, we could not get a producer to provide normal saline in glass ampoules or HS in plastic ampoules. Patients were unaware of which solution was the active one. HS was provided in brown glass ampoules containing 4 ml of colourless solution. IS was provided in 4 ml plain plastic ampoules. Whilst we did not tell the subjects which solution was which, it is possible that trial volunteers could have done research to identify, which solutions are provided and for which there was existing information of benefit. The improvements in objectively collected data such as lung function, practitioner provided confirmation of prescription of steroids/exacerbations, suggests the findings are real.
It would be theoretically possible that season of year could influence the outcome measure of exacerbations especially as the treatment phases for the cross-over design were only 3 months. Patients were recruited over a 6 month period from September to March. The random allocation of patients to 7% HS or NS for the first 3 month treatment phase largely excludes any such bias and an analysis of order effect showed no difference.
We have already confirmed and published on the safety and efficacy of a single dose of hypertonic saline in non-CF bronchiectasis delivered to the airways.
showed that increasing concentrations (0.9–12%) of sodium chloride, improved mucociliary clearance. Effects appeared to be dose dependent i.e. improved mucociliary clearance was seen with increasing concentrations of sodium chloride. Significantly Robinson
found that HS, up to a concentration of 12%, did not induce a clinically significant change in FEV1. Although a transient fall occurred in some patients it recovered either spontaneously, or following inhalation of a bronchodilator. Our study has shown 2 of 32 patients were unable to tolerate HS without a fall in FEV1 of more than 10%.
The situation may not be the same in asthma because Schoeffel
showed a 20% fall in FEV1 with HS (2.7% and 3.6%), and no reduction in FEV1 with normal saline (0.3% and 0.9%). Thus variability in airway response to saline may occur in different disease pathologies and supports the controlled administration of saline in clinical practice.
the greatest mucolytic effects were seen with 7% hypertonic saline when compared to 0.9% and 14.4%. Hypertonic saline has been shown to be effective in cystic fibrosis in both the long and short term. In a study of therapy over 48 weeks (n=164), 7% saline showed an improvement compared to 0.9% in both FEV1 and FVC (p=0.03) and significantly fewer infections (p=0.02).
It was shown to be more effective than DNase in newborns with atelectasis and reduced both admissions and respiratory distress in broncholitis.
Our findings add to the existing literature on the potential benefits of hypertonic saline and particularly support the use of daily HS in patients with non-CF bronchiectasis. The findings of significant improvements in lung physiology are unusual in non-CF bronchiectasis and the extended duration of benefit is encouraging.
This study has demonstrated the clinical benefit of daily nebulised 7% HS in stable non-CF bronchiectasis. A multi-centre double blind study is now required to support continued long term treatment in non-cystic fibrosis bronchiectasis, and to establish if beneficial in other lung pathologies.
Conflict of interest
FK has no shares or pecuniary interest in any company who will benefit from any results published in this paper.
In the last 5 years, FK has received between £1k and £5k in lecture fees from Forest pharmaceuticals presenting at national and international meetings.
RN has no shares or pecuniary interest in any company who will benefit from any findings/results of the published data.
In the last 5 years RN has received sponsorship for lecturing at international/ national meetings from the following companies.
Boehringer Ingelheim <£1k
RN has received sponsorship or unrestricted travel grants to attend international academic meetings by the following pharmaceutical companies in the last 5 years.