Efficacy of 3% hypertonic saline in bronchiolitis: A meta‑analysis
- Authors:
- Published online on: June 18, 2019 https://doi.org/10.3892/etm.2019.7684
- Pages: 1338-1344
Abstract
Introduction
Bronchiolitis, a common lower respiratory tract infection in infants, is the primary reason of hospitalization of infants in developed and developing countries (1). This disease is characterized by wheezing, cough and tachypnea. Cases mostly present among the infants aged 1–6 months. It usually occurs in early spring and winter seasons (2).
It is estimated that 1 in 5 infants each year suffers respiratory infection caused by respiratory syncytial virus (RSV) (3). The mortality rate is 0.5–1.5% among hospitalized infants, but increases to 3–4% for infants with potential pulmonary or cardiac diseases (4). This is a frustrating condition for physicians managing bronchiolitis, as most cases are not responsive to treatment (5). At present, treatment for this disease is primarily supportive with the administration of bronchodilators (6,7), steroids (8,9) and antibiotics (10), which show little benefit.
It has been established that 3% hypertonic solution (3% HS) solution absorbs water from the submucosa, subsequently resolving edema and thereby improving mucociliary function (11). Data from in vitro and in vivo experiments have indicated that HS accelerates the transport rates of mucus (12,13). It has been demonstrated that inhalation of nebulized 3% HS may improve immediate and long-term clearance of small airways in infants with bronchiolitis (14–16). However, the functional mechanism remains unknown. HS has been suggested to facilitate the removal of inspissated mucus, disruption of mucus strand and reduction of mucosal edema (17,18). HS is usually administered with a bronchodilator to decrease the risk of bronchospasm caused by HS (19). Certain studies have suggested that nebulized 3% HS is useful for infants with bronchiolitis (14,20–24); however, certain studies have reported no beneficial efficacy of HS in bronchiolitis (25–27).
The present meta-analysis was performed to provideadditional insight on this topic. A total of 23 eligible articles were selected. Duration of hospitalization, clinical severity score (CSS) and re-admission rates were analyzed to determine the efficacy of 3% HS compared with NS. The results provided information regarding the clinical application of 3% HS in bronchiolitis.
Materials and methods
Search strategy
Articles were accessed using the Pubmed (from 1966 to March 2018; http://www.ncbi.nlm.nih.gov/PubMed) and MEDLINE (from 1966 to March 2018; http://wwwcf.nlm.nih.gov/serials/journals/index.cfm) databases. The Cochrane Central Register of Controlled Trials (CENTRAL; http://www.cochranelibrary.com/central) was also used. The following terms were used: ‘Bronchiolitis’ OR ‘respiratory syncytial virus’ OR ‘RSV’ OR ‘acute wheezing’ AND ‘3% saline’. The search focused on human studies and had no language restrictions. Concurrently, additional articles were obtained via references of obtained reviews.
Inclusion criteria
The included studies were selected based on the following criteria: i) The studies were designed as randomized controlled trials (RCTs); ii) the studies investigated the efficacy of 3% HS in bronchiolitis; iii) they included a comparison in efficacy between 3% HS and normal saline (NS; 0.9% saline) was performed; and iv) they examined length of stay, CSS score, or re-admission rates.
Data extraction
A total of 2 independent authors reviewed all obtained articles, scanned the full texts, selected eligible articles according to the inclusion criteria and carefully extracted the data. Baseline characteristics of the included trials were identified, including name of first author, publication year, number of patients in each group, the drugs used and their doses. The primary outcomes were the re-admission rates, duration of hospital stay and the CSS score.
Statistical analysis
All statistical analyses were completed with State 12.0 software (Stata Corp LLC, College Station, TX, USA). The weighted mean difference (WMD) with 95% confidence interval (95% CI) was used to pool continuous data of length of stay. Standard mean difference (SMD) with 95% CI was used to pool data of CSS score. Relative risk (RR) with 95% CI was calculated to examine the association between 3% HS and re-admission. Heterogeneity was evaluated by I2 and P-values. The potential publication bias was assessed with the Begg's funnel plot method and Egger's regression quality of included studies was evaluated according to the modified Jadad scale score (28). P<0.05 was considered to indicate a statistically significant difference.
Results
Literature search and study selection
A total of 79 relevant articles were identified from Pubmed and MEDLINE databases. CENTRAL was also used. Of these, 31 articles were excluded, as they were review articles (n=22) or case reports (n=9). Then, the full-texts of the 48 remaining articles were extracted and examined carefully. A total of 15 articles revealed non-relevant outcomes and 10 articles provided no available data; therefore, 23 articles were included. The detailed selection process is demonstrated in Fig. 1. Information concerning the study population, the intervention type, HS dosage, additional medication and outcomes of each study are summarized in Table I. All 23 studies were double-blinded RCTs (14,15,20–25,27,29–42). Jadad scores of each study are presented in Table II.
Effects on the length of stay
A total of 14RCTs were included to analyze the duration of hospitalization (Fig. 2). The pooled data revealed that infants treated with HS nebulizers exhibited shorter periods of hospitalization compared with those treated by NS nebulizers (WMD=−0.43; 95% CI=−0.70, −0.15). Subgroup analysis of additional medications demonstrated that HS nebulizer with epinephrine may significantly decrease the length of hospital stay, with a WMD=−0.62 (95% CI=−0.90, −0.33).
Effects on CSS score
A total of 8RCTs provided data of CSS scores on the first day of treatment (Fig. 3). Compared with the NS nebulizer, HS nebulizers significantly decreased CSS scores on the first day of treatment (SMD=−0.58; 95% CI=−0.85, −0.31). Then, 7RCTs provided data of CSS scores on the second day of treatment. The results demonstrated that there was statistically significant difference in CSS scores between HS and NS nebulizers on the second day (SMD=−0.92; 95% CI=−1.36, −0.49). A total of 7RCTs provided data of CSS scores on the third day of treatment. The pooled results indicated a lower CSS score in the 3% HS group compared with the control group (SMD=−0.93; 95% CI=−1.55, −0.32).
Effects on re-admission
A total of 5RCTs analyzed the effects of HS nebulizers on the re-admission rate. The pooled outcome indicated a beneficial effect of HS nebulizers on decreasing re-admission rate compared with NS nebulizers (RR=0.93; 95% CI=0.70, 1.23; Fig. 4).
Sensitivity analysis and publication bias
A sensitivity analysis was performed to evaluate the effects of the methodological quality of each trial on the pooled results. The results indicated that the pooled results were robust. The funnel plot appeared to be symmetric and no potential publication bias was observed (Fig. 5; Begg's, P=0.133; Egger's, P=0.576, hospital stay).
Discussion
Bronchiolitis is one of the most common lower respiratory tract infections in infants (43,44). The pathophysiology of bronchiolitis is different from that of asthma. It involves infection of the bronchiolar epithelium, characterized by the sloughing and necrosis of epithelial cells, edema, peribronchiolar mononuclear infiltration and secretion of mucus. These changes result in the obstruction of flow in the small and large airways, causing hyperinflation, wheezing and atelectasis (45,46).
Antiviral agents are available for bronchiolitis; however, they are not routinely prescribed due to unconfirmed efficacy. Ribavirin is the only specific drug used to treat RSV infection; however, its efficacy was not been significant (47–50). Studies using glucocorticoids to treat bronchiolitis demonstrated negative effects (51,52). In addition, the application of β2-agonists may confer short-term improvement in infants with bronchiolitis, in particular the application of epinephrine (53–55). However, no significant effects have been observed in other types of β2-agonists (46,56).
Previous studies have demonstrated that inhaled HS is a promising therapy (24,26). As stated previously, RSV infection results in edema, necrosis and sloughing of the respiratory epithelium, causing obstruction of the small and large airways. HS may decrease the edema extent of airways through drawing fluid from adventitial and submucosal spaces. This increased fluid may contribute to a loosening of inspissated mucous and improvement of mucociliary clearance. The patients with bronchiectasis demonstrated a significant increase in weight of expectorated sputum and decrease in sputum viscosity (57,58). Concurrently, it has been suggested that nasal HS may alleviate the symptoms of chronic rhinosinusitis. Previously, certain studies revealed the benefit of HS in decreasing respiratory distress (15,20,34,59) and length of stay (21,22–24) among infants with bronchiolitis.
However, there are inconsistent data concerning the efficacy of 3% HS in bronchiolitis. The study by Teunissen et al (35) demonstrated that 3% HS was safe for bronchiolitis; however, it did not decrease the length of stay orduration of supplemental oxygen required in infant hospitalization due to bronchiolitis. Sharma et al (27) revealed that the CSS in 3 and 0.9% saline groups were not significantly different. The mean length of hospital stay was 63.93±22.43 h in the 3% saline group and 63.51±21.27 h in 0.9% saline group (P=0.878). Therefore, nebulized 3% HS was not superior to 0.9% saline in infants with diagnosed bronchiolitis. Pandit et al (36) reached a similar conclusion: Nebulization with HS + adrenaline and normal saline +adrenaline were equally effective in the treatment of bronchiolitis in infants. Our analysis, based on 23 studies, demonstrated that 3% HS was more effective compared with 0.9% NS in decreasing the length of hospitalization, CSS score and rate of re-admission. Compared with individual articles, the pooled results were much more credible.
However, there were limitations in the present study. Firstly, significant heterogeneity was observed in the analysis of length of stay. Although subgroup analysis of supplemental medication was performed, heterogeneity was observed in subgroup analysis of β2 agonists (P<0.001) and 3% HS-only treatment (P<0.001). This may be due to the differences in patient characteristics, severity of bronchiolitis and performance of individual physicians. Secondly, only 3% HS was analyzed and other concentrations of HS were not considered; comprehensive analysis should therefore be preformed to confirm the efficacy of HS.
In conclusion, 3% HS is superior to normal saline (0.9% saline) in decreasing length of stay, CSS score and rate of re-admission in cases of infant bronchiolitis.
Acknowledgements
The authors would like to thank the authors of the original studies included in this meta-analysis.
Funding
No funding was received.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Authors' contributions
ZYW designed the study. ZYW and XDL screened the literature. ZYW and ALS extracted the data from the literature. ZYW and XQF conducted the meta-analysis and wrote the manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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