EXPERT OPINION ON NEWER

APPROACHES AND EMERGING

TRENDS IN MUCUS
MANAGEMENT
 Overview: Mucus-Quantity/Quality

Mucus flow Surfactant layer

Cough or air flow

Mucus gland
Mucus gland

Int J Chron Obstruct Pulmon Dis. 2014; 9: 139–150

Excessive mucus production and
associated complications

N Engl J Med. 2010 Dec 2; 363(23): 2233–2247.

 Mucus hypersecretion
plays an important
role and is an
important
pathophysiological
and clinical
manifestation of the
following airway
diseases……

ACUTE
BRONCHIECTASIS CYSTIC FIBROSIS
BRONCHIOLITIS
 Treatment Options for Airway mucus clearance

Airway clearance therapy Pharmacological- Mucoactives

Breathing Autogenic Mechanical Mucoregulators Mucokinetics-

techniques drainage devices Expectorants - Carbocysteine Bronchodilators,
and macrolides ambroxol.
- Hypertonic
Saline
Mucolytics-
NAC, dornase
alpha, etc.
International journal of chronic obstructive pulmonary disease 13 (2018): 399.
 Overview of
Hypertonic saline
 Hypertonic saline (HS) is a concentrated sterile
solution of sodium chloride (NaCl) in water

The concentration of NaCl is greater than that of

physiologic saline or normal saline (0.9% NaCl)
 Mechanism of hypertonic saline
OTHER MODES OF ACTION
PREDOMINANT
Disrupts the structure of the mucus
Decreases the viscoelasticity of gel
the airway secretions better to
ease their clearance from the
Stimulates movement of cilia
airways
Causes sputum induction and
Breaks the ionic bonds within
cough which helps clear the
the mucus gel
sputum outside of the bronchi and
thus improve airway obstruction.
Increases the depth of the Absorbs water from the mucosa
airway surface liquid layer and submucosa and reduces
edema of the airway wall
FLOW PROPERTIES MADE MORE FAVORABLE AND THEREBY
IMPROVES MUCUS CLEARANCE J R Soc Med 2011: 104: S2–S5
Respiratory care 52.9 (2007): 1176-1197
 Clinical efficacy of
Nebulized Hypertonic
saline
 ACUTE BRONCHIOLITIS

• Systematic review of 11 randomized trials involving 1033 infants with mild to moderate
acute viral bronchiolitis.
• Children up to 24 months of age diagnosed with acute bronchiolitis

• Nebulised 3% hypertonic saline alone versus nebulised 0.9% saline.

• Nebulised 3% hypertonic saline plus bronchodilator versus nebulised 0.9% saline.
Studies • Nebulised 3% hypertonic saline plus bronchodilator versus nebulised 0.9% saline plus same
included bronchodilator.
• Nebulised 3% hypertonic saline alone or plus bronchodilator versus standard treatment.

Cochrane Database of Systematic Reviews 2013, Issue 7.

Art. No.: CD006458
Key outcomes
1. Length of hospital stay: Nebulised 3% saline had a statistically significant shorter
mean length of hospital stay.

Hypertonic saline versus 0.9% saline:

length of hospital stay (days)

Represents 22.7%
reduction
P < 0.0001

Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD006458

2. Clinical severity scores: Lower mean clinical severity score (post treatment) in the nebulized
hypertonic saline group

(0.88, 1.32 and 1.51 lower on day 1, day 2 and day 3 as compared to nebulized 0.9% saline group respectively)

Shorter duration of respiratory signs and symptoms with

3. Time for the resolution of symptoms/signs 3% nebulized
(pooled mean difference of -1.19 days, P < 0.00001).

4. Adverse events: No significant adverse events reported with hypertonic saline inhalation.

Conclusion:
 Nebulised 3% hypertonic saline may significantly reduce the length of hospital stay among
infants hospitalised with non-severe acute viral bronchiolitis and improve the clinical
severity score in both outpatient and inpatient populations.
 Nebulised 3% hypertonic saline used in conjunction with bronchodilators should be
considered an effective and safe treatment for infants with mild to moderate acute viral
bronchiolitis.

Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD006458

Prospective study of hospitalized children (N=99) with acute bronchiolitis (aged 2 to 24
months)

Treatment groups: Group A: Nebulized 3% hypertonic saline (4 ml)

Group B: Nebulized 0.9% normal saline (4 ml)
Group C: Nebulized salbutamol in a dose of 0.15 mg/kg body weight (minimum dose 1 mg) in
normal saline to make a total volume of 4 ml using an oxygen flow rate of 8 L/min.

Perspectives in clinical research 7.2 (2016): 88.

 Key 1. Clinical severity score: Significant
Before
treatment
After
treatment
Outcomes reduction (p<0.05) in the CS scores in Treatment Mean ± SD Mean ± SD
3% hypertonic saline group Group A 5.9 ± 1.5 1.0 ± 1.1
Group B 5.1 ± 2.3 1.9 ± 1.1
Group C 5.5 ± 1.0 3.3 ± 0.5

Length of hospital stay (days)

2. Length of hospital stay (LOS): Treatment Mean ± SD P-
Reduction in the LOS with 3% hypertonic value
saline Group A 3.4 ± 1.7 0.001
Group B 3.7 ± 1.9
Group C 4.9 ± 1.4

Conclusion:
 Nebulized 3% hypertonic saline (without additional bronchodilators) is an effective and safe
treatment for nonasthmatic, moderately ill patients with acute bronchiolitis in terms of reducing
the CS scores and length of hospital stay as compared to 0.9% saline and salbutamol in 0.9%
saline.
Perspectives in clinical research 7.2 (2016): 88.
 Randomized controlled trial of 90 children (aged 1 month to 2 years)

Treatment groups: Group 1: 3 ml of 7% nebulized hypertonic saline

Group 2: 3 ml of 0.9% nebulized normal saline with 0.3 ml salbutamol

Key Outcomes
Duration of Treatment Groups P-
oxygen value
therapy Group 1 Group 2
1. Duration of oxygen supplementation: (hypertonic (normal saline+
Patients in hypertonic saline group saline) salbutamol)
required a significantly shorter duration of
oxygen therapy (p = 0.009)
Mean ± SD 12.53 ± 3.58 20.25 ± 4.15 0.009*
(hours)
Bangladesh Journal of Child Health 43.2 (2019): 80-84.
 Mean clinical Group 1 Group 2 P- value
severity score (hypertonic (normal
2. Clinical severity score: Reduction
saline) saline+
was much earlier in children who Salbutamol)
received 7% nebulized hypertonic
N= 45
saline.
At baseline 7.9 8.6 0.061
At 12 hours 6.8 7.6 0.074
At 24 hours 3.8 4.9 0.041*
At 48 hours 1.4 3.1 0.012*
At 72 hours 1.3 2.1 0.081

Length of hospital Treatment Groups P- value

stay Group 1 Group 2
3. LOS: Significantly shorter LOS (hypertonic (normal
(p<.001) was much earlier in children saline) saline+
who received 7% nebulized hypertonic salbutamol)
saline.
Mean ± SD (hours) 56.36 ± 12.33 71.07 ± < 0.001*
13.48

Conclusion: 7% hypertonic saline was found to be more effective than 0.9% normal saline with salbutamol
in terms of reducing clinical severity, length of hospital stays and duration of oxygen therapy.
Bangladesh Journal of Child Health 43.2 (2019): 80-84.
BRONCHIECTASIS

Single blind, randomised, placebo controlled, cross-over study of 7% hypertonic

saline compared to 0.9% normal saline in patients (N=32) with non-CF
bronchiectasis

Key
Outcomes
Parameters 7% 0.9% P value
Hypertonic Normal
1. Changes in lung function: A significant saline saline
improvement in both parameters of lung FEV1 % 15.1 1.8 < 0.01
change
function was observed in favor of 7%
FVC % 11.23 0.72 < 0.01
hypertonic saline change

Respiratory medicine 105.12 (2011): 1831-1835.

2. SGRQ score: Significant changes were seen
in terms of the sub-scales of symptoms and
impact in the hypertonic saline group (p<0.05)

3. Antibiotic usage: Significantly lower in the hypertonic saline group vs. normal saline group (2.4 vs. 5.4
courses per patient per year)
4. Emergency health care utilization visits: Significantly reduction in hypertonic saline group as compared to
the normal saline group (2.1 vs. 4.9 events per patient per year)

Conclusion:
Regular use of 7% hypertonic saline improves lung function, quality of life and health
care utilisation in non-cystic fibrosis bronchiectasis patients.

Respiratory medicine 105.12 (2011): 1831-1835.

 A randomized cross-over study of 150
days in children (N=52) with non-CF
bronchiectasis

Patients were divided into two treatment groups: test arm (3 ml of 3% hypertonic saline) and
control arm (conventional physiotherapy)

Key Outcomes
 Significantly higher mean improvement was seen in the hypertonic saline group as compared to
the control group in the following lung function parameters;

1. FEV1: During the first phase (14.15 ± 5.50 vs. 5.04 ± 5.55, p=0.001) as well as the second phase
(10.81±5.51 vs. 3.54 ±5.13, p=0.001)
2. FVC: In the first phase (13.77±5.73 vs. 7.54±4.90, p=0.001) and the second phase (9.42 ± 7.00 vs.
4.42 ± 4.00, p=0.003)
Pediatric Pulmonology (2020).
3. Number of exacerbations/child/year

 Significantly lesser number of exacerbations were seen in the hypertonic saline group vs the
control group during phase 1
2.50±0.64 vs. 7.80±1.05, p=0.001

 Also, lesser number of exacerbations was seen during phase II of the study but was not
significant.

3.90±0.74 vs. 6.20±0.77, p=0.074

Conclusion: In Children with non-CF bronchiectasis

Hypertonic Saline (3% NaCl) nebulisation prior to chest physiotherapy significantly improves FEV1 and
FVC .
The reduction in the frequency of exacerbation was also found to be significant with hypertonic saline
nebulization compared to conventional physiotherapy.
Incorporating hypertonic saline nebulization into airway clearance technique is an effective strategy to
improve lung volumes and morbidity in children with non-CF bronchiectasis.
Pediatric Pulmonology (2020).
CYSTIC FIBROSIS

Systematic review of 17 trials (966 participants, aged 4 months to 63 years)

Key outcomes 3.44 % significantly higher mean change in FEV1, P = 0.015

Mean lung clearance index (LCI) was 1.03 lower

(*LCI-It is a measure of abnormalities of smaller airways to detect
early signs of lung injury in CF)

• Regular use of nebulised 7% hypertonic saline resulted in an improvement in lung function

• Also, an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults.
Cochrane Database of Systematic Reviews 2018, Issue 9. Art. No.: CD001506.
 164 patients with stable cystic fibrosis who were at
least six years old were randomly assigned to inhale 4
ml of either 7% hypertonic saline or 0.9 percent
(isotonic saline control) saline twice daily for 48 weeks.

Key Outcomes
1. Rate of change in lung function from
baseline:
• Hypertonic-saline group had significantly higher
FVC (by 82 ml) and FEV1 (by 68 ml) values from
the baseline
• Hypertonic saline was not associated with
worsening bacterial infection or inflammation.

New England Journal of Medicine 354.3 (2006): 229-240.

2. Incidence of pulmonary
exacerbations
• Hypertonic saline group had
significantly higher percentage of
patients without exacerbations (76 %
vs. 62 % in the control group;
P=0.03)

• The time in which participants

remained free of exacerbations was
significantly longer in the hypertonic
saline group (41% vs. 16%, P <0.001)
(Figure B)

New England Journal of Medicine 354.3 (2006): 229-240.

 Use of Hypertonic Saline in Sputum Induction
• Non-invasive, simple, cost effective and safe procedure to
collect respiratory secre­tions from lung airways for diagnosis
of various respiratory diseases.
osmolarity of the airway lining
fluid
vascular permeability in the
Mechanism
bronchial mucosa
Induces production of mucus by
submucosal glands.
Concentration of hypertonic saline
used for sputum induction in
different studies ranges from 0.9–7%
with duration of nebulization mostly
for 15–20 min.
Ultrasonic nebulisers are
recommended for this procedure
Pretreatment with a bronchodilator
(Salbutamol - 200–400 µg (2–4) puffs
from MDI is recommended to prevent
excessive bronchoconstriction
Lung India 23.2 (2006): 82.
European Respiratory Journal 2002 20: 3s-8s
 GUIDELINE
RECOMMENDATIONS
As per European Respiratory Society (ERS) nebulization with Hypertonic saline solutions are
reportedly more effective than normal saline in inducing sputum.

The Centers for Disease Control and Prevention (CDC) guidelines mentions that for “patients
unable to cough up sputum, deep sputum-producing coughing may be induced by inhalation
of an aerosol of warm, sterile, hypertonic saline (3%– 5%).”

National Institute for Health & Care Excellence (NICE) advices that the key feature of sputum
induction is inhalation of a nebulized hypertonic saline solution

Sputum induction guidelines by the New South Wales Health (NSW) recommends that
patients should be nebulized with 3% hypertonic saline solution for expectoration of
respiratory secretions and diagnostic purposes.
1. erj.ersjournals.com/content/20/37_suppl/3s
2. cdc.gov
3. nice.org.uk
4. health.nsw.gov.au
 Safety of Nebulized Hypertonic Saline

Safe and well tolerated in No significant adverse events

patients with were reported when used for
bronchiolitis, any indications
bronchiectasis and cystic - Commonly reported-
fibrosis in the clinical exacerbation of cough and
studies bronchospasm (mild and
resolved spontaneously)

Should not be administered

Caution is necessary in
patients with congestive
heart failure or renal
insufficiency
Rare cases of bronchospasm
immediately after using
reported.
other inhaled medications
Caution is necessary in
(e.g., nebulised antibiotics,
patients with hypersensitive
dornase alpha, inhaled
bronchial system
corticosteroids).