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Respiratory Medicine (2011) 105, 1831e1835

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/rmed

Nebulised 7% hypertonic saline improves lung


function and quality of life in bronchiectasis
Fiona Kellett a,*, Niven M. Robert b
a
b

Stockton Heath and Lymm Physiotherapy Practice, Respiratory Medicine, Stockton Heath Warrington, UK
University of Manchester and University Hospital South Manchester, UK

Received 12 February 2011; accepted 24 July 2011


Available online 22 October 2011

KEYWORDS
Hypertonic saline;
Lung function;
Quality of life;
Bronchiectasis

Summary
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.
2011 Elsevier Ltd. All rights reserved.

Introduction
In bronchiectasis, sputum retention is a distressing symptom
and arguably the most important factor in maintaining the
vicious cycle of respiratory infection,1 inflammation and

further sputum production, resulting in impaired quality of


life and increased morbidity and mortality.2
Many factors act to impair efficient mucociliary clearance,
including infection, increased mucus production, abnormal
mucus composition, ciliary slowing, and loss of ciliated cells.3

* Corresponding author. Tel.: 44 1925261508.


E-mail address: fee@kellett.plus.com (F. Kellett).
0954-6111/$ - see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.rmed.2011.07.019

1832
It has been suggested that inflammation and infection
causes the normal co-ordinated beat pattern of the cilia to
become dyskinetic4,5 Bacterial infection can also alter the
composition of mucus, with the viscosity increasing due to
an increase in DNA content.3 As a result of increased
viscosity, mucus becomes detached from the cilia and
mucociliary transport is impaired.6 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.3,7 Chronic bacterial colonisation, which elicits a host
neutrophilic response, may result in large concentrations of
host-derived protease contributing to airway damage.8
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.9
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.10 As a result sputum in cystic fibrosis has high
visco-elastic properties which impair mucociliary clearance. Altering the composition and ciliary transportability
of sputum has beneficial impact.4,11
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.1
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.12 However,
supporting long term data is limited.

Methodology
Aims
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.

Trial design
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,

F. Kellett, N.M. Robert


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
e trial design).

Study population
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.

End-points
Primary end-points
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.14

Secondary end-points
Quality of life
Quality of life measures were made using the St Georges
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

Lung function and quality of life in bronchiectasis

1833
Group A

0.9% saline

Recruitment

1 month wash out

7 % saline

wash out

Randomisation

1 month run in

End

7 % saline

1 month wash out

0.9% saline

wash out

Group B
Time -28
(days)

+90

+120

Figure 1

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
Sputum viscosity was assessed subjectively by the investigator using a pourability grade previously described.12,15
Ease of expectoration
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 (1e10). This data
was collected at the end of run-in, active and placebo
phases.
Ethics
All patients provided written informed consent to participate in this project which was approved by the South
Manchester Local Research and Ethics committee.
Statistical analysis
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.

Results
32 patients were screened for the trial, 2 were excluded in
run-in due to hyper-responsiveness to hypertonic saline

+210

+240

Study design.

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.
Significant changes were seen for St Georges Respiratory Quality of Life (global score) and in terms of the subscales 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.

Discussion
In non-CF bronchiectasis, the concentration of saline is
higher than in CF, but below both the plasma concentration
and the optimum for transportability of sputum.11 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
Table 1

Demographic data of study population.


N Z 28

Sex (% male)
Age (SD)
FEV1% predicted (SD)
FVC % predicted (SD)
Exacerbations in last 12 months
SD Z Standard deviation.

14 (50%)
56.6 (14.6)
66.4 (26.1)
77.8 (23.4)
2.6

1834

F. Kellett, N.M. Robert

Table 2

Changes in lung function over treatment periods (% change from pre-treatment baseline).

Phase

Active (HS)

Placebo (NS)

P value

FEV1% change (95% C.I.)


FVC % change (95% C.I.)

15.1 (8.2;22.0)
11.23 (8.6;13.9)

1.8 (8.9;10.7)
0.72 (7.4;8.9)

<0.01
<0.01

18

p<0.05

0.9 IS
7% HS

16
14

SGRQ Score

12
10

n.s.

p<0.05

p<0.05

6
4
2
0
-2

symptoms

activity

impact

Total

Figure 2 Changes in St Georges Respiratory Quality of Life


Questionnaire for active and placebo phases.

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.11,13
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
Table 3

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.12 The data in this
study are also in keeping with existing published data on
the use of hypertonic saline and are in the same order of
magnitude as those seen within the safety study.
In patients with cystic fibrosis (15 adults and 43 children), 6% HS was shown to increase FEV1 and sputum
expectoration, over a 2 week period, when compared to
IS.16 A subjective improvement in the ease of performing
chest physiotherapy following HS was also reported.
In patients with cystic fibrosis, Robinson17 showed that
increasing concentrations (0.9e12%) 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 Robinson17 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
Schoeffel18 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.
In a study of both asthma and cystic fibrosis19 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 Z 164), 7% saline showed an improvement compared to
0.9% in both FEV1 and FVC (p Z 0.03) and significantly
fewer infections (p Z 0.02).20
In a trial of 24 patients with cystic fibrosis treated with
nebulised 7% HS 4 times daily, Donaldson et al.,21 demonstrated a sustained benefit in (>8 h) mucus clearance

Outcome of exacerbations/health care utilization.

Annualised antibiotic use n/year


Annualised exacerbations n/year

Baseline
retrospective
recall

Active
prospective

Placebo
prospective

P value active:
placebo

2.11
2.60

2.43
2.14

5.43
4.85

<0.05
<0.05

Lung function and quality of life in bronchiectasis


(p Z 0.02) and improved FEV1 (p Z 0.02) when compared to
baseline
Hypertonic saline is increasingly being used in paediatric
medicine in the treatment of both bronchiolitis22 and
atelectasis.23 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 multicentre 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.
GSK 1ke5k
Astra-Zeneca 1ke5k
Novartis 1ke5k
Boehringer Ingelheim <1k
Chiesi 1ke5k
RN has received sponsorship or unrestricted travel grants
to attend international academic meetings by the following
pharmaceutical companies in the last 5 years.
GSK, Astra Zeneca, Novartis, Boehringer Ingelheim.

Supplementary data
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.rmed.
2011.07.019.

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