Nebulized hypertonic saline treatment in hospitalized children with

moderate to severe viral bronchiolitis

Z. Luo, Z. Fu, E. Liu, X. Xu, X. Fu, D. Peng, Y. Liu, S. Li, F. Zeng and X. Yang
Respiratory Department, Childrens Hospital, Chong Qing Medical University, Chongqing, China
Abstract
The objective of this study was to determine the efcacy and safety of frequently inhaled nebulized hypertonic saline (HS) in infants with
moderate to severe bronchiolitis. One hundred and twenty-six infants were randomized to receive either nebulized 3% hypertonic saline
(HS) or 0.9% normal saline (NS), but only 112 patients completed the whole study. Cough, wheezing, pulmonary physical signs, clinical
severity scores and the hospital length of stay (LOS) were recorded. The wheezing remission time was 4.8 1.0 days in the NS group and
3.6 0.9 days in the HS group (p <0.01). The cough remission time was 5.5 0.9 days in the NS group and 4.3 0.7 days in the HS group
(p <0.01). The moist crackles disappeared at 6.2 0.7 days in the NS group and at 4.4 0.9 days in the HS group (p <0.01). The clinical
severity scores decreased more signicantly in the HS group than in the NS group on each day within 96 h after enrolment (p <0.01). The
LOS decreased from 6.4 1.4 days in the NS group to 4.8 1.2 days in the HS group (p <0.01). The treatment was well tolerated, with
no adverse effects attributable to nebulized HS. The conclusions are that frequently inhaled HS relieved symptoms and signs faster than
NS, and shortened LOS signicantly for infants with moderate to severe bronchiolitis, without apparent adverse effects.
Keywords: Bronchiolitis, hypertonic saline solution, RSV
Original Submission: 17 January 2010; Revised Submission: 30 May 2010; Accepted: 17 June 2010
Editor: M. Drancourt
Article published online: 15 July 2010
Clin Microbiol Infect 2011; 17: 18291833
10.1111/j.1469-0691.2010.03304.x
Corresponding author and reprint requests: Z. Luo, Respira-
tory Department, Childrens Hospital, Chongqing Medical University,
Chongqing, 400014, China
E-mail: luozhengxiu816@163.com
Introduction
Bronchiolitis is infection of the bronchial and bronchiolar epi-
thelium, which is mainly caused by respiratory syncytial virus
(RSV). The primary treatment remains largely supportive, with
mechanical ventilatory support as needed [1]. Other types of
treatment remain controversial [1,2]. It has been shown that
nebulized hypertonic saline (HS) decreases the hospital length
of stay (LOS) as compared with normal saline (NS) among
infants hospitalized with viral bronchiolitis [3,4]. We and other
researchers demonstrated that nebulized HS and bronchodila-
tors decreased symptoms and LOS for infants with mild to
moderate viral bronchiolitis [57]. Both of the aforemen-
tioned studies used three times per day dosing, which is signi-
cantly less than the three to six times per hour regimens often
used to children in respiratory distress [810]. Children with
moderate to severe bronchiolitis have difculty in breathing.
Frequently inhaled nebulized HS reduced the LOS for infants
with moderately severe bronchiolitis [3]. The present study
was performed to investigate frequently inhaled nebulized HS
for moderate to severe bronchiolitis in a prospective, random-
ized, double-blind, controlled fashion. The primary objective
was to compare the symptoms, signs, clinical severity scores
and the LOS of these infants with those of a control group of
infants receiving frequently inhaled nebulized NS.
Materials and Methods
Patients
Infants aged <24 months with a rst episode of wheezing
admitted to the Childrens Hospital, Chongqing Medical Uni-
versity in China for the treatment of moderate to severe
bronchiolitis were eligible for the study. The patients were
ranked as moderately to severely ill according to the clinical
score system, as follows [11]. (i) respiratory rate: 0 points,
<30 breaths/min; 1 point, 3145 breaths/min; 2 points, 46
60 breaths/min; 3 points, >60 breaths/min. (ii) Wheezing:
0 points, none; 1 point, terminal expiratory or heard only
2011 The Authors
Journal Compilation 2011 European Society of Clinical Microbiology and Infectious Diseases
ORIGINAL ARTICLE INFECTIOUS DISEASES
with a stethoscope; 2 points, entire expiration or audible on
expiration without a stethoscope; 3 points, inspiration and
expiration without a stethoscope. (iii) Retractions: 0 points,
none; 1 point, intercostal only; 2 points, tracheosternal;
3 points, severe with nasal aring. (iv) General condition:
0 points, normal; 3 points, irritable, lethargic, poor feeding.
Regarding the clinical total score, the disease severity can be
divided into the following ranks: 04.9 points, mild; 5
8.9 points, moderate; and 912 points, severe disease.
Exclusion criteria
The exclusion criteria were as follows: age >24 months, pre-
vious episode of wheezing, chronic cardiac and pulmonary
disease, immunodeciency, accompanying respiratory failure,
requiring mechanical ventilation, inhaling the nebulized 3%
HS solution 12 h before treatment, and prematurity, with
birth at <34 weeks of gestation.
Study design
Infants with moderate to severe bronchiolitis were assessed
within 2 h for entry into the study. If inclusion/exclusion cri-
teria were satised, then informed consent was obtained.
Patients were randomized to receive 4 mL of a solution con-
taining either HS or NS. The random code was generated by
computer. The code was concealed in a sealed, opaque enve-
lope until the child was recruited. The solution was adminis-
tered in a double-blind fashion every 2 h for three doses,
followed by every 4 h for ve doses, followed by every 6 h
until discharge [3]. Each of the two groups received the
same supportive and comprehensive treatments, including
sputum aspiration, waterelectrolyte balance maintenance
and oxygen therapy. All inhaled treatments were delivered
to infants from standard air-compressed nebulizers (PARI
Corporation, Starnford, Germany). Patients were examined
at the time of study entry and every 12 h after enrolment.
No detectable differences in colour, smell or other physical
properties existed between HS and NS. The identities of the
solution were not available to the investigators, nurses or
parents. The decisions to discharge babies were made by
attending physicians when the patients had experienced no
respiratory symptoms and signs during the past 12 h. The
attending physicians were also blind to the solution.
Sample and method for detecting RSV
DNA was extracted from 200 lL of airway aspirate with the
QIAamp DNA Mini kit (Qiagen, MD, USA), and samples
were eluted in 200 lL of AE buffer. Viral antigen was analy-
sed for RSV by direct uorescent assay (D3 direct uores-
cent assay Respiratory Viruses Screening & ID Kit;
Diagnostic Hybrids, Hannover, Germany).
Ethics
The study was approved by the ethics and human research
committees of the Childrens Hospital, Chongqing Medical
University. Written informed consent was obtained from at
least one parent of each infant before enrolment.
Observation and evaluation
We evaluated these patients symptoms (cough, wheezing,
hoarse voice, vomiting, diarrhoea, general condition), signs
(temperature, respiratory rate, heart rate, retraction, pulmo-
nary signs, heart sounds) every 12 h after enrolment. We
recorded the clinical severity scores every 12 h after enrol-
ment, the day when cough, wheezing and pulmonary moist
crackles disappeared, and the LOS.
Statistical analyses
SPSS edition 11.5 was used to analyse all the data. Chi-
square tests were used to compare categorical variables.
One-way analysis of variance (ANOVA) was used for the
continuous variables. The mean standard deviation (x s)
expresses the central trend of the data. A p-value <0.05 was
considered to be statistically signicant.
Results
Participants ow and baseline data
One hundred and thirty-ve patients with moderate to
severe bronchiolitis were recruited from November 2008 to
November 2009 at the Childrens Hospital, Chongqing Medi-
cal University, but only 112 patients completed the whole
study (Fig. 1). Among the 112 patients, 57 were enrolled in
the HS group (32 males; 25 females), with an average age of
5.9 4.1 months and a disease course of 3.4 1.7 days.
Fifty-ve participants were in the NS group (31 males; 24
females), with an average age of 5.8 4.3 months and a dis-
ease course of 3.2 1.4 days. No signicant differences
existed between the two groups (summarized in Table 1).
Outcomes of therapeutic effects
In the HS group, as compared with the NS group, the time
required for wheezing and coughing relief was reduced by
1.2 days on average, the moist crackles vanished 1.8 days
earlier, and the LOS decreased by 1.6 days (Table 2). The
clinical severity scores at baseline were 8.8 1.1 in the HS
group and 8.5 1.5 in the NS group. The clinical severity
scores in the HS group on the rst, second, third and fourth
days were 5.7 1.5, 3.5 1.1, 2.4 0.9 and 1.7 0.6,
respectively. In the NS group, the clinical severity scores on
the rst, second, third and fourth days were 7.3 1.7,
1830 Clinical Microbiology and Infection, Volume 17 Number 12, December 2011 CMI
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Journal Compilation 2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 17, 18291833
5.9 1.5, 4.1 1.1 and 3.1 0.7, respectively. The clinical
severity scores decreased more signicantly in the HS group
than in the NS group on each day within 96 h after enrol-
ment (Fig. 2).
Adverse events
All participants tolerated therapy without apparent adverse
effects and were eventually discharged after achieving full
recovery. No infants were withdrawn by the medical staff
because of clinical deterioration or the need for intensive-
care support. The coughing and wheezing never worsened
over the course of the treatment. Although ve infants had
hoarse voices, only two of these infants were receiving HS,
and the hoarse voice disappeared after 34 days.
Discussion
Bronchiolitis is the most common lower respiratory tract
infection in infants. Wheezing is the primary clinical symp-
tom. The use of inhaled HS to treat viral bronchiolitis was
rst reported in 2003 [5], and the evidence in favour was
135 patients with moderate to severe ill bronchiolitis were recruited
9 childrens parents refused to
participate in the study
126 patients participated in the study
64 patients in the treatment group 62 patients in the control group
57 patients
completed
the whole
study
55 patients
completed the
whole study
7 patients
discharged
within 12 h
after enrolment
7 patients
discharged
within 12 h
after enrolment
FIG. 1. Flow diagram of the study.
TABLE 1. Comparison of basic clinical information between
the two groups
Basic information
NS group
(n = 55)
HS group
(n = 57) p-Value
Female/male 77.4 78.1 0.98
Age (months) 5.8 4.3 5.9 4.1 0.71
Duration of wheezing
on admission (days)
3.2 1.4 3.4 1.7 0.77
Systemic glucocorticoid
use before admission, no. (%)
35 (77.8) 43 (75.4) 0.82
Clinical score on admission 8.5 1.5 8.8 1.1 0.42
RSV detection rate (%) 40 (72.7%) 42 (73.7%) 0.91
HS, hypertonic saline; NS, normal saline; RSV, respiratory syncytial virus.
TABLE 2. Comparison of symptoms, signs and hospital
length of stay (LOS) between the two groups (x s)
Group
Sample
size
Wheezing
relief
(days)
Cough
relief
(days)
Moist
crackles
vanished
(days)
LOS
(days)
HS group 57 3.6 0.9 4.3 0.7 4.4 0.9 4.8 1.2
NS group 55 4.8 1.0 5.5 0.9 6.2 0.7 6.4 1.4
t-Value 4.372 4.915 8.011 4.566
p-Value <0.01 <0.01 <0.01 <0.01
HS, hypertonic saline; NS, normal saline.
9
8
7
6
5
4
3
2
1
0
0 1 2 3 4
10
Days of hospitalization
Study group
Control group
C
l
i
n
i
c
a
l

s
c
o
r
e
s
FIG. 2. Clinical severity scores vs. hospitalization days in the two
groups.
CMI Luo et al. Nebulized hypertonic saline treatment in hospitalized children 1831
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Journal Compilation 2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 17, 18291833
strengthened with the publication of a 2-year extension of
the original study [6]. We previously demonstrated that neb-
ulized HS and salbutamol decreased the clinical symptoms
more quickly and shortened the LOS for infants with mild to
moderate bronchiolitis [7]. The current study demonstrated
that frequently inhaled HS is an effective treatment for
infants with moderate to severe bronchiolitis. It took less
time to relieve symptoms and pulmonary signs: 1.2 days on
average for wheezing and cough alleviation, and 1.8 days for
pulmonary moist crackles to vanish. The clinical severity
scores decreased more signicantly in the HS group than in
the NS group on each day within 96 h after hospitalization.
The LOS was reduced by 1.6 days, from 6.4 1.4 to
4.8 1.2 days. In our study, patients were discharged when
the patients had experienced no respiratory symptoms and
signs during the past 12 h, whereas in other studies, the dis-
charge criteria were clinical score <4 and S
a
O
2
of at least
95% in room air for 4 h, so the LOS in our study is longer
than in other studies, where the LOS was typically 36 days.
A normal height of the periciliary liquid is crucial for nor-
mal airway mucociliary clearance. RSV infection depletes the
mucous layer water content, damages the airway surface
liquid epithelium, and reduces the height of the periciliary
liquid and clearance of mucus [12]. HS may reverse some of
the pathophysiological abnormalities in viral bronchiolitis.
In vitro, HS increases airway surface thickness, decreases epi-
thelial oedema, improves mucus elasticity and viscosity
[13,14], accelerates the transport rates of mucus [14,15],
and improves clearance of mucus [16]. In vivo, HS increases
the rate of mucociliary transport, even in normal subjects
[17]. HS breaks the ionic bonds within the mucous gel and
reduces oedema of the airway wall in viral bronchiolitis
[5,18], causes sputum induction and cough, helps to clear the
sputum, and improves airway obstruction [5]. In this trial,
we did not detect the actual mechanisms. HS improves
mucociliary function and promotes the elimination of mucus,
thereby reducing the adhesion of the virus and consequent
airway inammation reaction, as well as the risk of a second-
ary bacterial infection. However, further investigation is
needed to verify these assumptions.
The pathology of bronchiolitis is peribronchiolar mononu-
clear inltration, epithelial cell necrosis, sub-mucosal oedema
and an increase in the rate of mucous secretion, and there-
fore an increase in the mucin/water ratio [19], which causes
relative a reduction in the airway surface liquid [20]. The
pathophysiology of bronchiolitis is quite distinct from that of
asthma; these patients are less, if at all, responsive to bron-
chodilators [8]. Nebulized HS alone is safe for infants with
moderately severe bronchiolitis [3]. In the current study, we
demonstrated that HS is safe for infants with moderate to
severe bronchiolitis; there were no apparent adverse effects
attributable to frequently inhaled HS. Patients nished the
entire treatment without bronchospasm, cough or wheezing
aggravation.
In summary, inhaled HS is efcient and safe for infants
with moderate to severe bronchiolitis.
Transparency Declaration
All authors declare no potential conicts of interest.
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