pediatria polska 91 (2016) 301307

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Original research article/Artyku oryginalny

The clinical use of hypertonic saline/salbutamol in

treatment of bronchiolitis
Zastosowanie roztworu soli hipertonicznej w leczeniu zapalenia
oskrzelikw

Karolina Ratajczyk-Pekrul 1,*, Pawe Gonerko 1,

Jarosaw Peregud-Pogorzelski 2
1
Department of Pediatrics, Allergology and Pulmonology, Hospital of Zdroje, Szczecin, Poland
2
Department of Pediatric Oncology, Pomeranian Medical University, Szczecin, Poland

article info abstract

Article history: Aim: To compare the efcacy of nebulised 3% saline solution (with salbutamol) or 0.9%
Received: 25.02.2016 saline solution (with salbutamol) in the treatment of mild to moderate bronchiolitis.
Accepted: 14.04.2016 Methods: It was a randomised, double-blind trial. Seventy-eight children (up to 18 month
Available online: 23.04.2016 of life) with mild to moderate bronchiolitis hospitalised in Pediatric Unit Hospital of Zdroje
were enrolled. The infants received inhalation of salbutamol (0.15 mg/kg, max.
Keywords: 1.5 mg = 1.5 ml) dissolved in 3 ml 3% saline treatment group (n = 41), or 3 ml 0.9% saline

Bronchiolitis control group (n = 37). The therapy was repeated six times daily until discharge. The dura-

Hypertonic saline solution tion of hospital stay and rapidity of clinical improvement were assessed. Results: Taking

Salbutamol the signicance level specied at 0.05 into account, there were no statistically signicant

Respiratory syncytial virus differences in the length of hospital stay, with 3.06  1.613 days in the treatment group

Mucociliary clearance and 3.11  1.634 days in the control group (p = 0.43). Neither were observed statistically
signicant differences in clinical severity scores after 24, 48 and 72 h ( p24 = 0.192,
p48 = 0.425, p72 = 0.220). The positive rate for RSV was 53%. No signicant adverse
events, such as bronchospasm, were observed. Conclusions: Nebulised 3% saline (with
salbutamol) is not superior to 0.9% (with salbutamol) in the treatment of mild to moderate
bronchiolitis.
2016 Polish Pediatric Society. Published by Elsevier Sp. z o.o. All rights reserved.

toddlers, with viruses being the most common aetiological

Introduction factor among which respiratory syncytial virus (RSV) is
responsible for 7590% of infections. At the same time the
Bronchiolitis is the most frequent clinical manifestation of RSV infection is responsible for the most severe clinical
lower respiratory tract infection in small children and presentation of bronchiolitis [1, 2]. Typical symptoms are:

* Corresponding author at: Department of Pediatrics, Allergology and Pulmonology, Hospital of Zdroje, ul. Mczna 4, 70-780 Szczecin,
Poland. Tel.: +48 691961925.
E-mail address: krpekrul@wp.pl (K. Ratajczyk-Pekrul).
http://dx.doi.org/10.1016/j.pepo.2016.04.006
0031-3939/ 2016 Polish Pediatric Society. Published by Elsevier Sp. z o.o. All rights reserved.
302 pediatria polska 91 (2016) 301307
elongated expiration with the presence of wheezes and
crepitations in chest auscultation preceded by several days
of upper respiratory tract infection. In the course of the
disease the small bronchi are inamed, with oedema and
congestion of mucous and submucous membranes as well
as necrosis and exfoliation of respiratory syncytial cells
which leads to accumulation of a thick mucus in large
volume. All above mentioned changes lead to massive
bronchial obstruction, in which smooth muscle cells play a
minor part [3, 4].
It has been proven that the disturbance of mucociliary
transport plays a signicant role in pathogenesis of bron-
chiolitis, similarly as in cystic brosis and other chronic
respiratory tract disorders [5, 6].
Respiratory tract's epithelium is covered by liquid airway
surface layer (ASL), which is composed of two parts
external mucus layer (ML) and situated beneath it periciliary
layer (PCL). Effective mucociliary transport is dependant
mainly on the proper width of PCL (about 7 mm) which
ensures correct movement of the cilia. The role of ML is to
absorb and transport impurities and to regulate proper
hydration of PCL [6, 7].
Maintaining a constant, optimal composition of an ASL is
possible due to multiple conductance regulators localised on
the proximal end of epithelial cells [8]. Impaired function of
one of them cystic brosis transmembrane conductance
regulator (CFTR) is an underlying cause of cystic brosis.
As proposed by Mandelberg et al. [5], in RSV bronchiolitis
aside above-mentioned pathological changes, there is a dis-
turbed function of the channels that regulate ASL's composi-
tion which in consequence disrupts arrangement of ML/PCL
layers and leads to inappropriate mucociliary transport.
In vitro and clinical research have shown the benecial
inuence of concentrated saline nebulisations on mucoci-
liary transport, with the greatest inuence in patients with
cystic brosis [9]. This solution, due to its osmotic proper-
ties, draws water out from submucous membrane, reduces
oedema and restores appropriate composition of an ASL.
Additionally saline in hypertonic concentrations improves
rheological properties of the mucus, stimulates excretion of
PGE2 which promotes the movement of cilia and induces
cough to further clear the airways mechanically [1012].
Since 2002 several clinical studies have been published,
most of which positively evaluated the clinical effectiveness
of concentrated saline nebulisations (357%) in patients
with bronchiolitis [13]. The present publication is consecu-
tive to above-mentioned ones.
Table I Wang scalea
0 1
Respiratory rate <30 3145
Wheezing None Terminal expiratory or
only with stethoscope
Retraction None Intercostal only
General condition Normal
04 mild disease; 58 moderate disease; 912 severe disease.
a
Adapted from Wang et al. [14].
Methods
Patients
Children with clinical diagnosis of bronchiolitis were enrol-
led into the research. The main author was the only one to
qualify patients to take part in the study. Bronchiolitis was
diagnosed based on clinical symptoms: prolonged expira-
tion, wheezes and crepitations in patients with a few-day-
long history of viral infection of upper respiratory tract.
Additional criteria were: age 018 months of life, haemoglo-
bin oxygen saturation 95% or Wang Index 5 upon
admission (Table I) [14]. Pre-term babies <34 Hbd, children
with chronic cardiac or respiratory disease, immunological
deciencies, two or more episodes of bronchial obstruction,
children treated with systemic glucocorticosteroids, or ones
that did receive a hypertonic saline nebulisation in last
24 hrs prior to admission, or with saturation <85% were
excluded. Children with bronchial obstruction in history, but
not fullling any of the major (parental asthma medical
diagnosis, patient egzema medical diagnosis) and more
than one of the minor criteria (allergic rhinitis medical
diagnosis, eosinophilia 4%, wheezing apart from colds) of
Asthma Predictive Index (API) were qualied [15]. The
parents or legal guardians gave signed consent for their
children to participate in the study. The research was
approved by the local Bioethical Committee.
Study design
The research took place during two periods of seasonal
increase in bronchiolitis incidence in years 20112013, in the
Department of Pediatrics, Allergology and Pulmonology,
Hospital of Zdroje in Szczecin. For every patient a random
variable from a binomial distribution was generated by
a computer. Based on this number patient was given
a nebulisation. The number patient enlisted under was
known only to the personnel preparing the nebulisations,
and it was not revealed to the doctors and nurses taking
care of patient, or to legal guardians. The unblinding took
place after the research programme was completed.
Upon enrolling patients had to undergo: immunochroma-
tic test for RSV, throat cultures, complete blood count, CRP,
serum ions, urinalysis, arterial blood gas, A-P chest radio-
graph. All patients were examined twice a day in the
morning and in the evening. Patients were evaluated
2 3
4660 >60
Entire expiration or Inspiration and expiration
audible on expiration without stethoscope
without stethoscope
tracheosternal Nasal aming
Irritable, poor feeding, lethargic
 pediatria polska 91 (2016) 301307
according to Wang Criteria, and had saturation and heart
rate measured. Discharge qualication took place daily,
every morning and was conducted by the research's author.
Discharge criteria were as follows: Wang index 3 and
saturation of >95% without oxygen therapy for at least 24 h.
Discharged patients were recommended to continue 0.9%
saline nebulisations (max. 3 per day) with salbutamol if
needed.
Study drugs/intervention
Patients from researched group were nebulised with 3%
saline solution with salbutamol (Ventolin 0.1%, 0.15 mg/kg,
max. 1.5 mg = 1.5 ml) every 4 h from enrolment to the
moment they fullled criteria to be discharged home.
Patients from control group were given 0.9% saline solution
in nebulisation, also with salbutamol. Additional treatment
was administered according to clinical symptoms. Every
additional nebulisation was prepared according to the group
the patient was in. Nebulisations were given with nebuliser
with external air or oxygen supply with ow of 68 l/min.
End points
Endpoints evaluated in the research were: the length of
hospitalisation time from enrolment to fullling the
discharge criteria, clinical improvement index after 24,
48 and 72 h from enrolment. Clinical improvement index
was described by the absolute value of the difference
between Clinical Severity Scoring noted after 24, 48 and 72 h
(CSS24,48,72) and at the point of enrolment (CSS0). Mean
values of the endpoints were compared between the groups.
Statistical analysis
Statistical analysis was conducted with MS Ofce and IBM
SPSS Statistics (12.0) programmes. The endpoints observed
for researched groups were analysed by statistical tests for
the means of two populations. Commonly known two
sample z-test was employed to analyse continuous variables
while discrete variables were compared using test for
proportions in relatively small samples. As statistical signi-
cance level had been specied at 0.05 p-values below 0.05
were interpreted as statistically signicant for tests with
one sided critical areas (such as chi square test) whereas
only p-values below 0.025 were deemed signicant for two
tailed tests (e.g. based on normal distribution).
Results
A total number of 78 children were enrolled to take part in
research, 41 of whom were qualied into research group and
37 into control group (Fig. 1). The characteristics for both
groups were similar upon qualication (Tables II and III).
No statistically signicant difference in the hospitalisa-
tion period (p = 0.43) between control (3.11  1.634) and
research (3.06  1.613) group was noted. Clinical improve-
ment scores evaluated after 24, 48 and 72 h were not
statistically signicantly different (Table IV). It must be
303
mentioned that some patients were discharged before 72 hrs
of hospitalisation (9 patients from control and 17 from
researched group) Fig. 2. Assuming that last evaluation for
those, already discharged patients would not be worse than
last one done, nor would be higher than 3 (mod CSS72 = min
[CSS48;3]) additional analysis was made and no signicant
differences between both groups were observed (Table IV).
For seven of the enrolled patients researched illness was
a second episode of bronchial obstruction. All of those
patients were enrolled into researched group. Data analysis
after exclusion of those subjects has shown no differences
in the duration of hospitalisation (p = 0.492) and the impro-
vement speed for severity score (p24 = 0.459, p48 = 0.457,
p72 = 0.253, pmod72 = 0.317).
No clinically signicant side effects were observed. In
4 patients (2 from control and 2 from researched group)
a coarse voice was noted, with spontaneous improvement
within a few days. Two weeks after being discharged, two
patients returned to the Department with the symptoms of
gastro-enteral infection, one child from researched group
visited Paediatric A&E due to otitis media and was prescri-
bed antibiotics.
Discussion
In presented research no advantage of nebulised 3% saline
(with salbutamol) over nebulised 0.9% saline (with salbuta-
mol) in the treatment of bronchiolitis was observed. The
applied scheme of frequent nebulisations (every 4 h) made
caused the duration of hospitalisation for both groups (3.08
 1.48) was shorter than the mean period of hospitalisation
in the Department (6.42  2.84). Routinely only 3 nebulisa-
tions of 0.9% saline with salbutamol are administered in our
Department. The signicant limitation of this publication is
a small number of qualied patients. The reason for this
was the exclusion of patients treated with glucocorticoste-
roids, drugs frequently used in patients with dyspnoea due
to bronchiolitis.
Research done till present shows the superiority of
nebulised concentrated saline (frequently with salbutamol
or adrenaline) in the treatment of bronchiolitis. The 3%
concentration is the most frequently used. Keeping in mind
the mechanism in which concentrated solutions act in the
respiratory tract, the expected effect should be a resultant of
solution's concentration and volume, and is dependent on
the amount of NaCl delivered onto the respiratory epithe-
lium. Observations of patients with cystic brosis have
shown that therapeutic effect increases with the concentra-
tion of solution (and thus the mass of NaCl) [16, 17].
The clinical manifestation of bronchiolitis is a result of
the destructive inuence of viral infection on the respiratory
epithelium, which leads to disrupted mucociliary transport.
It can be assumed that only a particular severity is characte-
rised by such disturbance of mucociliary transport that it
would require replacing saline with its more concentrated
solutions to cure bronchiolitis. In this publication, severity
scoring and qualication for the research were evaluated
with Wang Scale and the values of saturation. The severity
according to Wang scale was respectively 7.68 and 7.86 for
304 pediatria polska 91 (2016) 301307

Fig. 1 Participant flow diagram

the research and control group, values similar to obtained by
previous researchers. The highest severity value was measu-
red in patients in publications of Luo et al. [18] and Miraglia
Del Giudice et al. [19] respectively 8.5 and 8.8 points [18, 19].
Those publications have shown the most positive effects
measured by shortened duration of hospitalisation for
concentrated solution as opposed to 0.9% saline. Those
values were lower in researches done in A&E those
publications show no superiority of hypertonic solution over
physiological one.
Assuming minimal bronchiolitis severity which causes
signicant mucociliary transport disturbances, we can also

Table II Patients characteristics at the entry to the study

Control group (37) Treatment group (41) p
Female 13 (36%) 19 (46%) 0.650
Age (months) 4.43 5.34 0.114
Breast feeding 15 (42%) 19 (46%) 0.837
Siblings 22 (61%) 24 (59%) 0.909
Atopya 10 (28%) 12 (29%) 0.942
Smoking 14 (39%) 17 (41%) 0.908
Wheezing in the past 0 (0%) 7 (17%) 0.184
RSV 20 (56%) 21 (51%) 0.849
CSS0 7.89 7.68 0.270
Haemoglobin oxygen saturation 93.39 94.12 0.104
Mean time from admission to enrollment (h) 4.22 5.37 0.207
Duration of symptoms at enrollment (day) 3.63 4.07 0.103
a
Atopy asthma, atopic dermatitis or allergic rhinitis in patient or in at least one of patient's siblings or parents, positive skin prick tests or
positive allergen specific Immunoglobulin E in patient's blood tests.
 pediatria polska 91 (2016) 301307
Table III Patients characteristics during the study
Control group (37)
Number of patients given antibiotic
Number of patients given systemic steroids
Number of patients given additional nebulisation
Number of patients given supplemental oxygen
Salbutamol nebulisation at the discharge
Table IV Clinical severity scorea
Mean 0.9% Mean 3% Standard deviation 0.9%
jCSS24 CSS0j 2.278 1.927
jCSS48 CSS0j 3.430 3.343
jCSS72 CSS0j 4.556 4.160
jmodCSS72 CSS0j 4.500 4.244
a
CSS clinical severity score, modCSS modified clinical severity score.
try to establish minimal effective mass and concentration of
NaCl needed for inducing recovery. On the other hand we
should remember that physiological concentrations of saline
are not ideal placebo, since their usage in particular volume
and in particular severity may cause benecial effect, which
was mentioned by Anil et al. [20]. The lowest effective dose of
NaCl in concentrated solution administered in bronchiolitis
was described by Sarrel 60 mg for patients in ambulatory
treatment [21]. In most publication the amount delivered to
respiratory epithelium was at least twice as large. In this
research 3 ml of 3% solution delivered 90 mg NaCl. Aside the
mass, the concentration of the solution is also meaningful,
since the water drawing abilities depend on it. The actual
concentrations used in paediatric research ranged from 1.7 to
7% [22]. In presented publication the actual concentration
after adding bronchodilating drug reached 2.2% for researched
group and 0.6% in control group. The concentration of 0.12%
is most likely the neutral one for mucociliary transport,
Fig. 2 Percentage of patients remaining in each group at 24
hourly intervals
305
Treatment group (41) p
5 5 0.913
3 2 0.877
2 2 0.949
7 6 0.981
34 27 0.669
Standard deviation 3% u  N(0.1) p
1.800 1.738 0.868 0.192
2.132 1.885 0.188 0.425
2.354 2.115 0.771 0.220
2.214 1.814 0.551 0.291
since no inuence on transport in research done with gamma
camera was proven [16]. Following theoretical assumption
NaCl mass, solution's concentration, difference in concentra-
tions between research and control groups and severity of the
illness all inuence the endpoint effect. This makes the
results of recently published article surprising, where authors
were comparing the effectiveness of 7% solution (3 ml)
administered with adrenaline 0.5 ml, 2.25% of epinephrine
with the effectiveness of 0.9% in treating bronchiolitis and no
superiority of the concentrated solution was shown [23].
As the in vivo and in vitro researches have shown the
benecial effect of nebulised concentrated solution with
increased hydration of ASL lasts relatively short (around
20 min) in healthy subjects. It, however, lasts longer in
patients with mutation of CFTR protein even as long as
240 min [24, 25]. This means that more frequent administra-
tions of nebulisations can increase total time of benecial
effects for ASL. Administering nebulisations 6 times a day,
as done in this research, could cause physiological concen-
tration to be effective, and diminish any difference in regard
to concentrated solution. Compared to previous publica-
tions, both groups were characterised by relatively short
duration of hospitalisation. Similar results with frequent
nebulisations (6 a day until discharge home) were obtained
by researchers from India [26].
This makes it crucial to take into consideration concen-
tration, volume and frequency of nebulisations the total
daily dose of NaCl.
In this publication RSV infection was conrmed by
immunochromatographic test in 51% of patients from
research group and 56% from control group. Similar
methods were used by other researchers, but they obtained
higher percentage of conrmed RSV infections (up to 80% in
most publications). It is possible that this lower percentage
may suggest other pathologic background in patients. On
the other hand enrolment of patients with second episode
of bronchial obstruction (7 patients from research group) did
not have any negative inuence on the duration of hospita-
lisation and the time of improvement.
Additional treatment (including systemic glucocorticoste-
roids) was necessary in a small percentage of patients.
Glucocorticosteroids in ambulatory treatment were one of
306 pediatria polska 91 (2016) 301307
the exclusion criteria, similarly to Al Ansari et al. publica-
tion [27]. This research has shown no superiority of 3%
solution over 0.9% one. On the other hand in research done
by Luo steroids were used in 70% of patients, and effects for
3% solution were very good, even when used without
bronchial dilating drug [28].
This research has conrmed the safety of 3% saline solution
with salbutamol in children with bronchiolitis, also in those
patients with consecutive bronchial obstruction episode.
Conclusion
Despite many doubts and lack of recommendations regarding
optimal doses, concentrations or frequency of inhalations,
concentrated saline solutions seem to be an effective and
safe method of treatment for children with bronchiolitis. At
present there is not enough data to conrm superiority of
concentrated solution over physiological one. In evaluation of
nebulisation's effectiveness it is crucial to take concentrations
and frequency determining total dose of NaCl into
consideration. At this stage it would be interesting to evaluate
3% solution without bronchial dilatators and effectiveness of
solutions with higher concentrations.
Authors contributions/Wkad autorw
PG, JP-P study design, data interpretation, acceptance of
nal manuscript version. KR-P study design, data collec-
tion, statistical analysis, data interpretation, acceptance of
nal manuscript version, literature search.
Conict of interest/Konikt interesu
None declared.
Financial support/Finansowanie
None declared.
Ethics/Etyka
The work described in this article has been carried out in
accordance with The Code of Ethics of the World Medical
Association (Declaration of Helsinki) for experiments invol-
ving humans; EU Directive 2010/63/EU for animal experi-
ments; Uniform Requirements for manuscripts submitted to
Biomedical journals.
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