Systematic Review and Meta-Analysis Medicine ®

3% nebulized hypertonic saline versus normal

saline for infants with acute bronchiolitis
A systematic review and meta-analysis of randomized
controlled trials
Jin-Feng Yu, MMa, Yan Zhang, MMb, Zhan-Bo Liu, MMc, Jing Wang, MBa, Li-Ping Bai, MBa,* 

Abstract
Background: This study evaluated the efficacy and safety of 3% nebulized hypertonic saline (NHS) in infants with acute
bronchiolitis (AB).
Methods: We systematically searched the PUBMED, EMBASE, Cochrane Library, China National Knowledge Infrastructure
Database, WANFANG, and VIP databases from inception to June 1, 2022. We included randomized controlled trials comparing
NHS with 0.9% saline. Outcomes included the length of hospital stay (LOS), rate of hospitalization (ROH), clinical severity score
(CSS), rate of readmission, respiratory distress assessment instrument, and adverse events. RevMan V5.4 software was used for
statistical analysis.
Results: A total of 27 trials involving 3495 infants were included in this study. Compared to normal saline, infants received 3%
NHS showed better outcomes in LOS reduction (MD = −0.60, 95% CI [−1.04, −0.17], I2 = 92%, P = .007), ROH decrease (OR
= 0.74, 95% CI [0.59, 0.91], I2 = 0%, P = .005), CSS improvement at day 1 (MD = −0.79, 95% CI [−1.23, −0.34], I2 = 74%, P <
.001), day 2 (MD = −1.26, 95% CI [−2.02, −0.49], I2 = 91%, P = .001), and day 3 and over (MD = −1.27, 95% CI [−1.92, −0.61],
I2 = 79%, P < .001), and respiratory distress assessment instrument enhancement (MD = −0.60, 95% CI [−0.95, −0.26], I2 = 0%,
P < .001). No significant adverse events related to 3% NHS were observed.
Conclusion: This study showed that 3% NHS was better than 0.9% normal saline in reducing LOS, decreasing ROH, improving
CSS, and in enhancing the severity of respiratory distress. Further studies are needed to validate these findings.
Abbreviations: AB = acute bronchiolitis, AEs = adverse events, CI = confidence interval, CSS = clinical severity score, LOS
= length of hospital stay, MD = mean difference, NHS = nebulized hypertonic saline, NS = normal saline, RCTs = randomized
controlled trials, RDAI = respiratory distress assessment instrument, ROH = rate of hospitalization, ROR = rate of readmission,
RR = risk ratio.
Keywords: acute bronchiolitis, efficacy, infant, meta-analysis, nebulized hypertonic saline, safety, systematic review

1. Introduction Presently, management of AB mainly consists of supportive

Acute bronchiolitis (AB) is the most common lower respiratory
tract infection in infants under 2 years of age and is a major cause
of hospitalization.[1–3] Studies have reported that such disorders
could affect more than 68% of infants and neonates younger
than 1 year old.[4,5] It has also been reported to be mainly caused
by respiratory syncytial virus.[6–9] It often manifests as excessive
coughing with tachypnea, fever, acute wheezing, and even signs
of respiratory distress.[10] Thus, it is imperative to treat infants
with this condition.
care, supplemental oxygen, adequate hydration, mechanical
ventilatory support, antibiotics, corticosteroids, chest physio-
therapy, magnesium sulfate, and nebulized hypertonic saline
(NHS).[11–21] Previous studies have reported that NHS can benefit
infants with AB.[21–47] It has been reported that NHS can induce
osmotic flow of water into the lung mucosa, rehydrate airway
surface lipid, increase mucosa cilia function, and enhance air-
way obstruction by clearing sputum outside of the bronchi.[48–52]
Although a variety of clinical studies have investigated the
efficacy of NHS in the management of infants with AB,[21–47]

This study was supported by Heilongjiang Provincial Higher Education
Fundamental Business Expenses Research Project (2019-KYYWFMY-0020). The
supporter did not involve in this study.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are
available from the corresponding author on reasonable request.
a
Department of Pediatric Medicine, Hongqi Hospital Affiliated to Mudanjiang
Medical University, Mudanjiang, China, b Department of Hematology, Hongqi
Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, China, c
Department of Computer, Hongqi Hospital Affiliated to Mudanjiang Medical
University, Mudanjiang, China.
*Correspondence: Li-Ping Bai, Department of Pediatric Medicine, Hongqi Hospital
Affiliated to Mudanjiang Medical University, No. 5 Tongxiang Street, Aiming
District, Mudanjiang 157011, China (e-mail: jianwu2678@yeah.net).
Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open-access article distributed under the terms of the Creative
Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is
permissible to download, share, remix, transform, and buildup the work provided
it is properly cited. The work cannot be used commercially without permission
from the journal.
How to cite this article: Yu J-F, Zhang Y, Liu Z-B, Wang J, Bai L-P. 3% nebulized
hypertonic saline versus normal saline for infants with acute bronchiolitis: A
systematic review and meta-analysis of randomized controlled trials. Medicine
2022;101:43(e31270).
Received: 14 June 2022 / Received in final form: 16 September 2022 / Accepted:
19 September 2022
http://dx.doi.org/10.1097/MD.0000000000031270

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Yu et al.  •  Medicine (2022) 101:43Medicine
their findings are inconsistent. In addition, 5 previous simi-
lar systematic review addressed this issue.[53–57] However, they
included pretty low quality trials, which may benefit their con-
clusions. Furthermore, 2 latest high quality trials[29,41] had pub-
lished after the most recent review.[54] Thus, it is very necessary
to carry out an updated systematic review to explore this topic.
Therefore, this study summarizes the latest evidence to system-
atically evaluate the efficacy and safety of 3% NHS for infants
with AB.
2. Methods
2.1. Ethical statement
This systematic review did not analyze individual data, thus no
ethical approval was needed.
2.2. Eligibility criteria
We included randomized controlled trials (RCTs) that compared
3% NHS with 0.9% saline. Children under 24 months of age
who were diagnosed with AB were eligible for inclusion, regard-
less of their region, race, and gender. Patients in the treatment
group received 3% NHS and the participants in the control
group received 0.9% normal saline (NS). Outcomes included
the length of hospital stay (LOS), rate of hospitalization (ROH),
clinical severity score (CSS), rate of readmission (ROR), respira-
tory distress assessment instrument (RDAI), and adverse events
(AEs). Other studies were excluded, such as duplications, animal
studies, reviews, non-clinical studies, and quasi-RCTs. Studies
with insufficient essential data were also excluded.
2.3. Search strategy and study selection
This systematic review systematically retrieved potential studies
from PUBMED, EMBASE, Cochrane Library, China National
Knowledge Infrastructure Database, WANFANG, and VIP data-
bases from inception to June 1, 2022. We also searched for other
literature sources, such as the reference lists of relevant reviews.
We searched all records in English and Chinese. We used the fol-
lowing search terms: (“bronchiolitis” OR “acute wheezing” OR
“respiratory syncytial virus”) AND (“pediatrics” OR “infant”
OR “child”) AND (“3% saline” OR “hypertonic saline” OR
“saline solution” OR “0.9% saline”).
Upon retrieval of the search results, duplicates were removed.
Titles and abstracts of potential records were scanned by 2 inde-
pendent authors, followed by a full-paper reading to include
the associated potential articles against the eligibility criteria.
Any differences were resolved by a third senior author through
discussion.
2.4. Data extraction
Two authors independently extracted data from the included
trials using a standardized collection form. Any divergence
was settled down by a third senior author through discussion
or consultation. We extracted data associated with publication
information (such as title, region, and first author), patient char-
acteristics (such as age, sex, and ethnicity), study design (such as
sample size, details of randomization, allocation, and blinding),
intervention and control, and outcomes.
2.5. Risk of bias assessment
Two authors independently examined the risk of bias in the
included trials using the Cochrane risk of bias tool.[58,59] The
quality of each study was rated as high, unclear, or low risk of
bias in 7 aspects. Any discrepancies were determined by a third
senior author through discussion or consultation.
2
2.6. Statistical analysis
RevMan 5.4 software (The Nordic Cochrane Centre, The
Cochrane Collaboration, Copenhagen, Denmark) was used for sta-
tistical analysis. All discontinuous data are presented as risk ratios
(RR) and 95% confidence intervals (CI). All continuous data were
calculated as the mean difference (MD) and 95% CI. Statistical
heterogeneity across studies was assessed using the Higgins I² test
with cutoff point of 50%. I² ≤ 50% showed acceptable heteroge-
neity among the studies, and a fixed-effects model was utilized to
synthesize the data. I² > 50% suggested the existence of substan-
tial heterogeneity across trials, and a random-effects model was
used to pool the data. A meta-analysis and subgroup analysis was
performed if substantial heterogeneity was identified among the
results. We also reported the outcome results as a narrative sum-
mary if the data could not be pooled.
3. Results
3.1. Study selection
A total of 790 associated records were identified in both the
electronic databases and other sources. After removing dupli-
cates, the topics, abstracts, and full-text articles were screened,
and 506 studies were excluded. Finally, 27 articles involving
3495 patients met the eligibility criteria. The study selection
process is shown in Figure 1.
3.2. Study characteristics
The characteristics of the 27 included trials are summarized in
Table 1. The basic features of the studies were as follows: first
author, year of publication, location, sample size, age, details
of the intervention and control, and outcomes. These cases
came from 14 different regions: Qatar, France, Turkey, the UK,
Portugal, the USA, Canada, Bangladesh, Switzerland, Nepal,
China, Japan, India, and Israel. The intervention and control
arms received 3% NHS and 0.9% NS, respectively.
3.3. Study quality assessment
The methodological quality of the 27 included RCTs is shown
in Figure 2. All 27 trials had random sequence generation and
provided adequate information on incomplete outcomes, selec-
tive reporting, and other bias.[21–47] Twenty studies reported suf-
ficient information on allocation concealment,[3–32,36,38–45,47] and
18 RCTs elaborated the blinding of participants and person-
nel clearly.[21–23,25–28,30–32,36,39–45,47] All trials described blinding of
outcome assessments, except for 10 studies,[24,28,29,33–35,37,38,40,46]
which provided insufficient information.
3.4. Effects of 3% NHS on infants with AB
3.4.1. Reduction in LOS.  LOS was the most reported outcome
(18 of 27 studies).[21,22,24,25,28,29,31,34–41,43,45,46] Meta-analysis results
showed that there were significant differences (MD = −0.60, 95%
CI [−1.04, −0.17], I2 = 92%, P = .007; Fig. 3).[21,22,24,25,28,29,31,34–
41,43,45,46]
The subgroup analysis was performed according to the
location of China (MD = −1.86, 95% CI [−2.15, −1.57], I2 = 36%,
P < .001; Fig. 3)[34–36,46] and other regions (MD = −0.19, 95% CI
[−0.37, −0.01], I2 = 28%, P = .04; Fig. 3).[21,22,24,25,28,29,31,37–41,43,45]
3.4.2. Decrease in ROH.  Seven studies involving 1590 patients
assessed the ROH. There were significant difference on ROH
(OR = 0.74, 95% CI [0.59, 0.91], I2 = 0%, P = .005)[22,23,25,27,32,42,47]
(Fig. 4).
3.4.3. Improvement in CSS.  Six trials evaluated CSS[21,25,34,36,42,45]
(Fig. 5). Meta-analysis results showed significant improvement
Yu et al.  •  Medicine (2022) 101:43www.md-journal.com
in CSS on day 1 (MD = −0.79, 95% CI [−1.23, −0.34], I2 = 74%,
P < .001),[21,25,34,36,42,45] day 2 (MD = −1.26, 95% CI [−2.02,
−0.49], I2 = 91%, P = .001),[21,25,34,36,42,45] and day 3 and over (MD
= −1.27, 95% CI [−1.92, −0.61], I2 = 79%, P < .001).[25,34,36,42,45]
3.4.4. Change in ROR.  Eight studies were included with 1097
infants. The meta-analysis results did not show significant
differences in ROR (OR = 0.77, 95% CI [0.51, 1.16], I2 = 27%,
P = .21; Fig. 6).[21,23,24,26,27,29,30,44]
Figure 1.  Flow diagram of study selection.
3
3.4.5. Change in RDAI.  5 trials involving 1369 infants assessed
RDAI.[22,26,27,32,47] The meta-analysis results showed significant
difference in RDAI (MD = −0.60, 95% CI [−0.95, −0.26], I2 =
0%, P < .001; Fig. 7).[22,26,27,32,47]
3.4.6. AEs. A total of 17 studies reported AEs[21–24,26,30,33–
(Table 1). These were cough, vomiting, diarrhea,
36,38,40,42,43,45–47]
Figure 2.  Risk of bias summary.
Yu et al.  •  Medicine (2022) 101:43Medicine
Figure 3.  Meta-analysis of length of hospital stay.
agitation, rhinorrhea, hoarse voices, and vigorous crying.
Fortunately, all AEs were resolved, and all infants completed
the study.
4. Discussion
This study summarizes the latest clinical evidence to assess the
efficacy and safety of 3% NHS in the treatment of infants with
AB. A total of 27 RCTs involving 3495 infants were included in
the analysis. The methodological quality of the trials was gen-
erally acceptable.
Five previous studies[48–52] investigated the efficacy of NHS
in the management of bronchiolitis. One study explored the
association between nebulized epinephrine and hypertonic
saline in infants with AB.[48] The other 4 studies[54–57] focused on
assessing the efficacy of NHS for AB. However, their findings
4
are inconsistent.[48,54–57] In addition, 2 high-quality RCTs[29,41]
were published after the most recent review.[54] Based on a pre-
vious study, this study updated the findings and provided the
latest evidence for 3% NHS in infants with AB. The findings of
the present study are partly consistent with those of previous
studies.[54–57]
In this study, the meta-analysis results showed significant
differences between the 2 management strategies in terms of
LOS reduction, ROH decrease, CSS improvement, and RDAI
enhancement. This indicates that the efficacy of 3% NHS is bet-
ter than that of 0.9% NS in the treatment of infants with AB.
As for AEs, although 17 studies reported it, all of them were
resolved well, and all infants completed the study.
This systematic review and meta-analysis had several lim-
itations. First, some trials had small sample sizes, which may
have restricted their efficacy and safety. Second, 4 studies
reported a high risk of bias in allocation concealment, blinding
Yu et al.  •  Medicine (2022) 101:43www.md-journal.com

Figure 4.  Meta-analysis of rate of hospitalization.

Figure 5.  Meta-analysis of clinical severity score.

of participants, researchers, and outcome assessment, which Author contributions

may limit their effects on the present findings. Third, some
meta-analyses had substantial heterogeneity, which may not
have sufficiently verified the effects of the modality. Therefore,
the present findings should be interpreted cautiously and future
studies should determine their frequency and duration.
5. Conclusion
In conclusion, this study showed that 3% NHS was superior to
0.9% NS in terms of reducing LOS, decreasing ROH, improving
CSS, and reducing the severity of respiratory distress. Further
studies are warranted to confirm the present findings.
Conceptualization: Jing Wang, Li-Ping Bai, Yan Zhang, Zhan-Bo
Liu.
Data curation: Jin-Feng Yu, Jing Wang, Li-Ping Bai, Yan Zhang,
Zhan-Bo Liu.
Formal analysis: Jin-Feng Yu, Li-Ping Bai, Zhan-Bo Liu.
Funding acquisition: Li-Ping Bai.
Investigation: Li-Ping Bai.
Methodology: Jin-Feng Yu, Jing Wang, Li-Ping Bai, Yan Zhang.
Project administration: Li-Ping Bai.
Resources: Jin-Feng Yu, Jing Wang, Yan Zhang, Zhan-Bo Liu.
Software: Jin-Feng Yu, Jing Wang, Yan Zhang, Zhan-Bo Liu.
Supervision: Li-Ping Bai.

5
Yu et al.  •  Medicine (2022) 101:43Medicine

Figure 6.  Meta-analysis of rate of re-admission.

Figure 7.  Meta-analysis of respiratory distress assessment instrument.

Table 1
General characteristics of included studies.
Study Location Sample size (T/C) Age (mo, T/C) Intervention Control Outcomes

Al-Ansari 2010[21] Qatar 58/56 T: 3.8 ± 2.8; C: 3.3 ± 2.4 3% NHS + epinephrine 0.9% NS + epinephrine LOS, CSS, ROR, AEs
Angoulvant 2017[22] France 385/387 T: 3 (median);C: 3 (median) 3% NHS 0.9% NS LOS, ROH, RDAI, AEs
Anil 2010[23] Turkey 39/38 9.5 ± 5.3 3% NHS + epinephrine 0.9% NS + epinephrine ROH, CSS, ROR, AEs
Everard 2014[24] UK 142/149 T: 3.3 ± 2.6; C: 3.4 ± 2.8 3% NHS + standard care 0.9% NS + standard care LOS; ROR, RDAI, AEs
Flores 2016[25] Portugal 33/35 T: 3.3 ± 2.4; C: 3.8 ± 2.5 3% NHS + salbutamol 0.9% NS + salbutamol LOS; CSS
Florin 2014[26] USA 31/31 T: 7.5 ± 5.1; C: 6.1 ± 3.6 3% NHS 0.9% NS ROH, RDAI, AEs
Grewal 2009[27] Canada 23/23 T: 5.6 ± 4.0; C: 4.4 ± 3.4 3% NHS + epinephrine 0.9% NS + epinephrine ROH, ROR, RDAI
Islam 2018[28] Bangladesh 45/45 5.4 3% NHS 0.9% NS LOS, CSS
Jaquet-Pilloud 2020[29] Switzerland 61/59 T: 7.7(6.4, 9.1); C: 7.5(6.2, 8.9) 3% NHS + standard care 0.9% NS + standard care LOS, ROR
Khanal 2015[30] Nepal 50/50 T: 9.8 ± 5.0; C: 9.5 ± 4.2 3% NHS + epinephrine 0.9% NS + epinephrine CSS, ROR, AEs
Kuzik 2007[31] Canada 45/46 4.7 ± 4.2 3% NHS 0.9% NS LOS
Kuzik 2010[32] Canada 44/44 8.9 (average) 3% NHS + salbutamol 0.9% NS + salbutamol ROH, RDAI
Li 2014[33] China 42/42 T: 6.7 (median); C: 7.6 (median) 3% NHS 0.9% NS CSS, AEs
Lin 2018[34] China 142/149 3–24 3% NHS 0.9% NS LOS, CSS, AEs
Liu 2014[35] China 142/149 2–24 3% NHS 0.9% NS LOS, AEs
Luo 2011[36] China 57/55 T: 5.9 ± 4.1; C: 5.8 ± 4.3 3% NHS 0.9% NS LOS, CSS, AEs
Mahesh Kumar2013[37] India 20/20 5.9 ± 3.8 3% NHS + albuterol 0.9% NS + albuterol LOS, CSS,
Morikawa 2018[38] Japan 63/65 4.3 3% NHS + salbutamol 0.9% NS + salbutamol LOS; CSS; AEs
Ojha 2014[39] Nepal 28/31 8.5 ± 5.0 3% NHS 0.9% NS LOS, CSS,
Pandit 2013[40] India 51/49 NR 3% NHS + adrenaline 0.9% NS + adrenaline LOS, RDAI, AEs
Pandit 2022[41] Bangladesh 50/50 NR 3% NHS 0.9% NS LOS
Sarrell 2002[42] Israel 33/32 12.5 ± 6.0 3% NHS + terbutaline 0.9% NS + terbutaline ROH, CSS, AEs
Sharma 2013[43] India 125/123 8.5 ± 5.0 3% NHS + salbutamol 0.9% NS + salbutamol LOS, CSS, AEs
Silver 2015[44] USA 93/97 4.2 (mean) 3% NHS 0.9% NS ROR
Tal 2006[45] Israel 21/20 2.6 ± 1.0 3% NHS + epinephrine 0.9% NS + epinephrine LOS, CSS, AEs
Wang 2014[46] China 20/20 T: 11.6 ± 2.0; C: 11.6 ± 2.0 3% NHS + dexamethasone 0.9% NS + dexamethasone LOS, AEs
Wu 2014[47] USA 211/197 T: 6.5 ± 5.1; C: 6.4 ± 5.3 3% NHS 0.9% NS ROH, RDAI, AEs
0.9% NS = 0.9% normal saline, 3% NHS = 3% nebulized hypertonic saline, AEs = adverse events, C = control group, CSS = clinical severity score, LOS = length of hospital stay, NR = not report, RDAI =
respiratory distress assessment instrument, ROH = rate of hospitalization, ROR = rate of re-admission, T = treatment group.

6
Yu et al.  •  Medicine (2022) 101:43www.md-journal.com
Validation: Jin-Feng Yu, Jing Wang, Li-Ping Bai, Yan Zhang,
Zhan-Bo Liu.
Visualization: Jin-Feng Yu, Jing Wang, Li-Ping Bai, Yan Zhang,
Zhan-Bo Liu.
Writing – original draft: Jin-Feng Yu, Li-Ping Bai, Yan Zhang,
Zhan-Bo Liu.
Writing – review & editing: Jin-Feng Yu, Jing Wang, Li-Ping Bai,
Yan Zhang, Zhan-Bo Liu.
References
[1] Falahi S, Sayyadi H, Abdoli A, et al. The prevalence of human bocavirus
in <2-year-old children with acute bronchiolitis. New Microbes New
Infect. 2020;37:100736.
[2] Ralston SL, Lieberthal AS, Meissner HC, et al. Clinical practice guide-
line: the diagnosis, management, and prevention of bronchiolitis.
Pediatrics. 2014;134:e1474–502.
[3] Chou T, Chen EY, Liu YY, et al. A comparison study: Treat acute
bronchiolitis infants with hypertonic saline by small volume jet neb-
ulizer and portable vibrating-mesh nebulizer. In B57.PEDIATRIC
INFECTION. American Thoracic Society 2018; A3685.
[4] Meissner HC. Selected populations at increased risk from respiratory
syncytial virus infection. Pediatr Infect Dis J. 2003;22:S40–4; discus-
sion S44.
[5] Shi T, McAllister DA, O’Brien KL, et al. Global, regional, and national
disease burden estimates of acute lower respiratory infections due to
respiratory syncytial virus in young children in 2015: a systematic
review and modelling study. Lancet. 2017;390:946–958.
[6] De Paulis M, Oliveira DBL, Thomazelli LM, et al. The importance of
viral load in the severity of acute bronchiolitis in hospitalized infants.
Clinics (Sao Paulo). 2021;76:e3192.
[7] Petat H, Gajdos V, Angoulvant F, et al. High frequency of viral
Co-detections in acute bronchiolitis. Viruses. 2021;13:990.
[8] Guitart C, Alejandre C, Torrús I, et al. Impact of a modification of the
clinical practice guide of the American Academy of Pediatrics in the
management of severe acute bronchiolitis in a pediatric intensive care
unit. Med Intensiva (Engl Ed). 2021;45:289–97.
[9] Ghazaly M, Nadel S. Overview of prevention and management of acute
bronchiolitis due to respiratory syncytial virus. Expert Rev Anti Infect
Ther. 2018;16:913–28.
[10] Fretzayas A, Moustaki M. Etiology and clinical features of viral bron-
chiolitis in infancy. World J Pediatr. 2017;13:293293-–299.
[11] Juliana A, Plötz FB, Achten N, et al. .Requirement of respiratory sup-
port in acute bronchiolitis in infants is linked to endothelial and neu-
trophil activation. Pediatr Pulmonol. 2021;56:3908–15.
[12] Tortosa F, Izcovich A, Carrasco G, et al. High-flow oxygen nasal can-
nula for treating acute bronchiolitis in infants: a systematic review and
meta-analysis. Medwave. 2021;21:e8190.
[13] Jat KR, Dsouza JM, Mathew JL. Continuous positive airway pressure
(CPAP) for acute bronchiolitis in children. Cochrane Database Syst
Rev. 2022;4:CD010473.
[14] Chandelia S, Kumar D, Chadha N, et al. Magnesium sulphate for treat-
ing acute bronchiolitis in children up to two years of age. Cochrane
Database Syst Rev. 2020;12:CD012965.
[15] Roqué I Figuls M, Giné-Garriga M, et al. Chest physiotherapy for
acute bronchiolitis in paediatric patients between 0 and 24 months old.
Cochrane Database Syst Rev. 2012;2:CD004873.
[16] Almeida-Junior AA, da Silva MT, Almeida CC, et al. Relationship
between physiologic deadspace/tidal volume ratio and gas exchange
in infants with acute bronchiolitis on invasive mechanical ventilation.
Pediatr Crit Care Med. 2007;8:372–7.
[17] Hartog K, Ardura-Garcia C, Hammer J, et al. Acute bronchiolitis in
Switzerland - Current management and comparison over the last two
decades. Pediatr Pulmonol. 2022;57:734–43.
[18] Chen IL, Huang HC, Chang YH, et al. Effect of antibiotic use
for acute bronchiolitis on new-onset asthma in children. Sci Rep.
2018;8:6090.
[19] McCallum GB, Plumb EJ, Morris PS, et al. Antibiotics for persistent
cough or wheeze following acute bronchiolitis in children. Cochrane
Database Syst Rev. 2017;8:CD009834.
[20] Kua KP, Lee SWH. Systematic review and meta-analysis of the effi-
cacy and safety of combined epinephrine and corticosteroid therapy for
acute bronchiolitis in infants. Front Pharmacol. 2017;8:396.
[21] Al-Ansari K, Sakran M, Davidson BL, et al. Nebulized 5% or 3%
hypertonic or 0.9% saline for treating acute bronchiolitis in infants. J
Pediatr. 2010;157:630–4, 634.e1.
7
[22] Angoulvant F, Bellettre X, Milcent K, et al. Effect of nebulized hyper-
tonic saline treatment in emergency departments on the hospitalization
rate for acute bronchiolitis: a randomized clinical trial. JAMA Pediatr.
2017;171:e171333.
[23] Anil AB, Anil M, Saglam AB, et al. High volume normal saline alone
is as effective as nebulized salbutamol-normal saline, epinephrine-nor-
mal saline, and 3% saline in mild bronchiolitis. Pediatr Pulmonol.
2010;45:41–7.
[24] Everard ML, Hind D, Ugonna K, et al. SABRE: a multicentre ran-
domised control trial of nebulised hypertonic saline in infants hospital-
ised with acute bronchiolitis. Thorax. 2014;69:1105–12.
[25] Flores P, Mendes AL, Neto AS. A randomized trial of nebulized 3%
hypertonic saline with salbutamol in the treatment of acute bronchiol-
itis in hospitalized infants. Pediatr Pulmonol. 2016;51:418–25.
[26] Florin TA, Shaw KN, Kittick M, et al. Nebulized hypertonic saline for
bronchiolitis in the emergency department: a randomized clinical trial.
JAMA Pediatr. 2014;168:664–70.
[27] Grewal S, Ali S, McConnell DW, et al. A randomized trial of nebu-
lized 3% hypertonic saline with epinephrine in the treatment of acute
bronchiolitis in the emergency department. Arch Pediatr Adolesc Med.
2009;163:1007–12.
[28] Islam KT, Mollah AH, Matin A, et al. Comparative efficacy of nebu-
lized 3% hypertonic saline versus 0.9% Normal saline in children with
acute bronchiolitis. Bangladesh J Child Health. 2018;42:130–7.
[29] Jaquet-Pilloud R, Verga ME, Russo M, et al. Nebulised hypertonic
saline in moderate-to-severe bronchiolitis: a randomised clinical trial.
Arch Dis Child. 2020;105:236–40.
[30] Khanal A, Sharma A, Basnet S, et al. Nebulised hypertonic saline (3%)
among children with mild to moderately severe bronchiolitis--a double
blind randomized controlled trial. BMC Pediatr. 2015;15:115.
[31] Kuzik BA, Al-Qadhi SA, Kent S, et al. Nebulized hypertonic saline in
the treatment of viral bronchiolitis in infants. J Pediatr. 2007;151:266–
70, 270.e1.
[32] Kuzik BA, Flavin MP, Kent S, et al. Effect of inhaled hypertonic saline
on hospital admission rate in children with viral bronchiolitis: a ran-
domized trial. CJEM. 2010;12:477–84.
[33] Li G, Zhao J. Effectiveness of inhaled hypertonic saline in children with
bronchiolitis. Zhonghua Er Ke Za Zhi. 2014;52:607–10.
[34] Lin JH, Chen CX, Jiang SL. Therapeutic effect of 3% sodium chlo-
ride solution for injection on bronchiolitis in infants. Maternal Child
Health Care China. 2018;33:3222–4.
[35] Liu TY, Li YC. Clinical observation of 80 cases of infantile Bronchiolitis
treated with hypertonic saline nebulized inhalation. Med J Chin
People’s Health. 2014;26:56–7.
[36] Luo Z, Fu Z, Liu E, et al. Nebulized hypertonic saline treatment in
hospitalized children with moderate to severe viral bronchiolitis. Clin
Microbiol Infect. 2011;17:1829–33.
[37] Mahesh Kumar KB, Karunakara BP, Manjunath MN, et al.
Aerosolised hypertonic saline in hospitalized young children with
acute bronchiolitis: a randomized controlled clinical trial. J Pediatric
Sci. 2013;5:e174.
[38] Morikawa Y, Miura M, Furuhata MY, et al. Nebulized hypertonic
saline in infants hospitalized with moderately severe bronchiolitis due
to RSV infection: a multicenter randomized controlled trial. Pediatr
Pulmonol. 2018;53:358–65.
[39] Ojha AR, Mathema S, Sah S, et al. A comparative study on use of 3%
saline versus 0.9% saline nebulization in children with bronchiolitis. J
Nepal Health Res Counc. 2014;12:39–43.
[40] Pandit S, Dhawan N, Thakur D. Utility of hypertonic saline in the
management of acute bronchiolitis in infants: a randomised controlled
study. Int J Clin Pediatr. 2013;2:24–9.
[41] Pandit P, Hoque MA, Pandit H, et al. Efficacy of nebulized hypertonic
saline (3%) versus normal saline and salbutamol in treating acute
bronchiolitis in a tertiary hospital: a randomized controlled trial.
Mymensingh Med J. 2022;31:295–303.
[42] Sarrell EM, Tal G, Witzling M, et al. Nebulized 3% hypertonic saline
solution treatment in ambulatory children with viral bronchiolitis
decreases symptoms. Chest. 2002;122:2015–20.
[43] Sharma BS, Gupta MK, Rafik SP. Hypertonic (3%) saline vs 0.93%
saline nebulization for acute viral bronchiolitis: a randomized con-
trolled trial. Indian Pediatr. 2013;50:743–7.
[44] Silver AH, Esteban-Cruciani N, Azzarone G, et al. 3% hypertonic
saline versus Normal saline in inpatient bronchiolitis: a randomized
controlled trial. Pediatrics. 2015;136:1036–43.
[45] Tal G, Cesar K, Oron A, et al. Hypertonic saline/epinephrine treatment
in hospitalized infants with viral bronchiolitis reduces hospitalization
stay: 2 years experience. Isr Med Assoc J. 2006;8:169–73.
Yu et al.  •  Medicine (2022) 101:43Medicine
[46] Wang YJ. Therapeutic effect of atomization inhalation of different
concentrations of saline on infants with bronchiolitis. Chin Pract Med.
2014;9:118–9.
[47] Wu S, Baker C, Lang ME, et al. Nebulized hypertonic saline for bron-
chiolitis: a randomized clinical trial. JAMA Pediatr. 2014;168:657–63.
[48] Shoseyov D, Bibi H, Shai P, et al. Treatment with hypertonic versus
normal saline nasal wash of pediatric chronic sinusitis. Allergy Clin
Immunol. 1998;101:602–5.
[49] Everard ML, Hind D, Ugonna K, et al. Saline in acute bronchiolitis RCT
and economic evaluation: hypertonic saline in acute bronchiolitis - ran-
domised controlled trial and systematic review. Health Technol Assess.
2015;19:1–130.
[50] Wang YH, Yang CP, Ku MS, et al. Efficacy of nasal irrigation in the
treatment of acute sinusitis in children. Int J Pediatr Otorhinolaryngol.
2009;73:1696–701.
[51] Heikkila P, Renko M, Korppi M. Hypertonic saline inhalations in bron-
chiolitis-a cumulative meta-analysis. Pediatr Pulmonol. 2018;53:233–42.
[52] Grewal S, Goldman RD. Hypertonic saline for bronchiolitis in infants.
Can Fam Phys. 2015;61:531–3.
[53] Pereira RA, Oliveira de Almeida V, Zambrano M, et al. Effects of nebu-
lized epinephrine in association with hypertoni c saline for infants with
acute bronchiolitis: a systematic review and meta-analysis. Health Sci
Rep. 2022;5:e598.
[54] Hsieh CW, Chen C, Su HC, et al. Exploring the efficacy of using
hypertonic saline for nebulizing treatment in children with bronchi-
olitis: a meta-analysis of randomized controlled trials. BMC Pediatr.
2020;20:434.
[55] Zhang L, Mendoza-Sassi RA, Wainwright C, et al. Nebulised hyper-
tonic saline solution for acute bronchiolitis in infants. Cochrane
Database Syst Rev. 2017;12:CD006458.
[56] Maguire C, Cantrill H, Hind D, et al. Hypertonic saline (HS) for acute
bronchiolitis: systematic review and meta-analysis. BMC Pulm Med.
2015;15:148.
[57] Zhang L, Mendoza-Sassi RA, Klassen TP, et al. Nebulized hyper-
tonic saline for acute bronchiolitis: a systematic review. Pediatrics.
2015;136:687–701.
[58] Higgins JPT, Thompson SG, Deeks JJ, et al. Measuring inconsistency in
meta-analysis. BMJ. 2003;327:557–60.
[59] Higgins JPT, Green S. (editors). Cochrane Handbook for Systematic
Reviews of Interventions Version 5.1.0 [updated March 2011]. The
Cochrane Collaboration. 2011. Available at handbook.cochrane.org
[access date May 20, 2022].