Nebulised hypertonic saline solution for acute bronchiolitis in infants

Linjie Zhang, Raúl A Mendoza-Sassi, Claire Wainwright, Terry P Klassen, Linjie Zhang, Raúl A Mendoza-Sassi, Claire Wainwright, Terry P Klassen

Abstract

Background: Airway oedema (swelling) and mucus plugging are the principal pathological features in infants with acute viral bronchiolitis. Nebulised hypertonic saline solution (≥ 3%) may reduce these pathological changes and decrease airway obstruction. This is an update of a review first published in 2008, and previously updated in 2010 and 2013.

Objectives: To assess the effects of nebulised hypertonic (≥ 3%) saline solution in infants with acute bronchiolitis.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily, Embase, CINAHL, LILACS, and Web of Science on 11 August 2017. We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 8 April 2017.

Selection criteria: We included randomised controlled trials and quasi-randomised controlled trials using nebulised hypertonic saline alone or in conjunction with bronchodilators as an active intervention and nebulised 0.9% saline, or standard treatment as a comparator in children under 24 months with acute bronchiolitis. The primary outcome for inpatient trials was length of hospital stay, and the primary outcome for outpatients or emergency department trials was rate of hospitalisation.

Data collection and analysis: Two review authors independently performed study selection, data extraction, and assessment of risk of bias in included studies. We conducted random-effects model meta-analyses using Review Manager 5. We used mean difference (MD), risk ratio (RR), and their 95% confidence intervals (CI) as effect size metrics.

Main results: We identified 26 new trials in this update, of which 9 await classification due to insufficient data for eligibility assessment, and 17 trials (N = 3105) met the inclusion criteria. We included a total of 28 trials involving 4195 infants with acute bronchiolitis, of whom 2222 infants received hypertonic saline.Hospitalised infants treated with nebulised hypertonic saline had a statistically significant shorter mean length of hospital stay compared to those treated with nebulised 0.9% saline (MD -0.41 days, 95% CI -0.75 to -0.07; P = 0.02, I² = 79%; 17 trials; 1867 infants) (GRADE quality of evidence: low). Infants who received hypertonic saline also had statistically significant lower post-inhalation clinical scores than infants who received 0.9% saline in the first three days of treatment (day 1: MD -0.77, 95% CI -1.18 to -0.36, P < 0.001; day 2: MD -1.28, 95% CI -1.91 to -0.65, P < 0.001; day 3: MD -1.43, 95% CI -1.82 to -1.04, P < 0.001) (GRADE quality of evidence: low).Nebulised hypertonic saline reduced the risk of hospitalisation by 14% compared with nebulised 0.9% saline among infants who were outpatients and those treated in the emergency department (RR 0.86, 95% CI 0.76 to 0.98; P = 0.02, I² = 7%; 8 trials; 1723 infants) (GRADE quality of evidence: moderate).Twenty-four trials presented safety data: 13 trials (1363 infants, 703 treated with hypertonic saline) did not report any adverse events, and 11 trials (2360 infants, 1265 treated with hypertonic saline) reported at least one adverse event, most of which were mild and resolved spontaneously.

Authors' conclusions: Nebulised hypertonic saline may modestly reduce length of stay among infants hospitalised with acute bronchiolitis and improve clinical severity score. Treatment with nebulised hypertonic saline may also reduce the risk of hospitalisation among outpatients and emergency department patients. However, we assessed the quality of the evidence as low to moderate.

Conflict of interest statement

Linjie Zhang: None known. Raúl A Mendoza‐Sassi: None known. Claire Wainwright: received travel grants from the North American Cystic Fibrosis Foundation and the European Cystic Fibrosis Society, travel and accommodation expenses from Novartis Pharmaceuticals and Vertex Pharmaceuticals, and travel and accommodation expenses from the University of Miami; has served as a consultant for/an advisory board member for Vertex Pharmaceuticals; has previously and is currently receiving grants or grants pending from the National Health and Medical Research Council (Australia), and has previously and currently is receiving funds from Vertex Pharmaceuticals for site costs associated with clinical trial participation and has previously received funds from Ablynx, and Novo Nordisk Phamaceuticals for site participation in clinical trials; and her institution has previously received payment for her providing lectures from Novartis Pharmaceuticals and Vertex Pharmaceuticals. None of the declared benefits were received in relation to this review or review topic or scope. Terry P Klassen: None known.

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Funnel plot of the weighted mean difference (WMD) of length of hospital stay (days) against its standard error. The circles represent risk estimates of each study, and the black vertical line represents the pooled effect estimate. Dashed lines represent pseudo‐95% confidence limits. Egger test (P = 0.29) suggests no small‐study effects.
1.1. Analysis
1.1. Analysis
Comparison 1 Hypertonic saline versus normal saline (0.9%), Outcome 1 Length of hospital stay (days).
1.2. Analysis
1.2. Analysis
Comparison 1 Hypertonic saline versus normal saline (0.9%), Outcome 2 Rate of hospitalisation.
1.3. Analysis
1.3. Analysis
Comparison 1 Hypertonic saline versus normal saline (0.9%), Outcome 3 Clinical severity score (post‐treatment) at day 1.
1.4. Analysis
1.4. Analysis
Comparison 1 Hypertonic saline versus normal saline (0.9%), Outcome 4 Clinical severity score (post‐treatment) at day 2.
1.5. Analysis
1.5. Analysis
Comparison 1 Hypertonic saline versus normal saline (0.9%), Outcome 5 Clinical severity score (post‐treatment) at day 3.
1.6. Analysis
1.6. Analysis
Comparison 1 Hypertonic saline versus normal saline (0.9%), Outcome 6 Rate of re‐admission.
1.7. Analysis
1.7. Analysis
Comparison 1 Hypertonic saline versus normal saline (0.9%), Outcome 7 Time for resolution of symptoms/signs.
1.8. Analysis
1.8. Analysis
Comparison 1 Hypertonic saline versus normal saline (0.9%), Outcome 8 Radiological assessment score.

References

References to studies included in this review Al‐Ansari 2010 {published data only}

    1. Al‐Ansari K, Sakran M, Davidson BL, Sayyed RE, Mahjoub H, Ibrahim K. Nebulized 5% or 3% hypertonic or 0.9% saline for treating acute bronchiolitis in infants. Journal of Pediatrics 2010;157(4):630‐4.
Angoulvant 2017 {published data only}
    1. Angoulvant F, Bellêttre X, Milcent K, Teglas JP, Claudet I, Guen CG, et al. Effect of nebulized hypertonic saline treatment in emergency departments on the hospitalization rate for acute bronchiolitis: a randomized clinical trial. JAMA Pediatrics 2017;171(8):e171333. [DOI: 10.1001/jamapediatrics.2017.1333]
Anil 2010 {published data only}
    1. Anil AB, Anil M, Saglam AB, Cetin N, Bal A, Aksu N. High volume normal saline alone is as effective as nebulized salbutamol‐normal saline, epinephrine‐normal saline, and 3% saline in mild bronchiolitis. Pediatric Pulmonology 2010;45(1):41‐7.
Everard 2014 {published data only}
    1. Everard ML, Hind D, Ugonna K, Freeman J, Bradburn M, Cooper CL, et al. SABRE: a multicentre randomised control trial of nebulised hypertonic saline in infants hospitalised with acute bronchiolitis. Thorax 2014;69(12):1105‐12. [DOI: 10.1136/thoraxjnl-2014-205953]
Flores 2016 {published data only}
    1. Flores P, Mendes AL, Neto AS. A randomized trial of nebulized 3% hypertonic saline with salbutamol in the treatment of acute bronchiolitis in hospitalized infants. Pediatric Pulmonology 2016;51(4):418‐25. [DOI: 10.1002/ppul.23306]
Florin 2014 {published data only}
    1. Florin TA, Shaw KN, Kittick M, Yakscoe S, Zorc JJ. Nebulized hypertonic saline for bronchiolitis in the emergency department: a randomized clinical trial. JAMA Pediatrics 2014;168(7):664–70.
Grewal 2009 {published data only}
    1. Grewal S, Ali S, McConnell DW, Vandermeer B, Klassen TP. A randomized trial of nebulized 3% hypertonic saline with epinephrine in the treatment of acute bronchiolitis in the emergency department. Archives of Pediatrics & Adolescent Medicine 2009;163(11):1007‐12.
Ipek 2011 {published data only}
    1. Ipek IO, Yalcin EU, Sezer RG, Bozaykut A. The efficacy of nebulized salbutamol, hypertonic saline and salbutamol/hypertonic saline combination in moderate bronchiolitis. Pulmonary Pharmacology & Therapeutics 2011;24(6):633‐7.
Jacobs 2014 {published data only}
    1. Jacobs JD, Foster M, Wan J, Pershad J. 7% hypertonic saline in acute bronchiolitis: a randomized controlled trial. Pediatrics 2014;133(1):e8–13.
Khanal 2015 {published data only}
    1. Khanal A, Sharma A, Basnet S, Sharma PR, Gami FC. Nebulised hypertonic saline (3%) among children with mild to moderately severe bronchiolitis ‐ a double blind randomized controlled trial. BMC Pediatrics 2015;15:115. [DOI: 10.1186/s12887-015-0434-4]
Köse 2016 {published data only}
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Kuzik 2007 {published data only}
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Li 2014 {published data only}
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Luo 2010 {published data only}
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Luo 2011 {published data only}
    1. Luo Z, Fu Z, Liu E, Xu X, Fu X, Peng D, et al. Nebulized hypertonic saline treatment in hospitalized children with moderate to severe viral bronchiolitis. Clinical Microbiology and Infection 2011;17(12):1829‐33.
Mahesh Kumar 2013 {published data only}
    1. Mahesh Kumar KB, Karunakara BP, Manjunath MN, Mallikarjuna HB. Aerosolised hypertonic saline in hospitalized young children with acute bronchiolitis: a randomized controlled clinical trial. Journal of Pediatric Sciences 2013;5(1):e174.
Mandelberg 2003 {published data only}
    1. Mandelberg A, Tal G, Witzling M, Someck E, Houri S, Balin A, et al. Nebulized 3% hypertonic saline solution treatment in hospitalized infants with viral bronchiolitis. Chest 2003;123(2):481‐7.
Miraglia Del Giudice 2012 {published data only}
    1. Miraglia Del Giudice M, Saitta F, Leonardi S, Capasso M, Niglio B, Chinellato I, et al. Effectiveness of nebulized hypertonic saline and epinephrine in hospitalized infants with bronchiolitis. International Journal of Immunopathology and Pharmacology 2012;25(2):485‐91.
NCT01238848 {unpublished data only}
    1. NCT01238848. Efficacy of nebulized hypertonic saline in the treatment of acute bronchiolitis [A randomized controlled trial to evaluate efficacy of nebulized hypertonic saline vs. normal saline in the treatment of hospitalized children with bronchiolitis]. (first received 11 November 2010).
Ojha 2014 {published data only}
    1. Ojha AR, Mathema S, Sah S, Aryal UR. A comparative study on use of 3% saline versus 0.9% saline nebulization in children with bronchiolitis. Journal of Nepal Health Research Council 2014;12(26):39–43.
Pandit 2013 {published data only}
    1. Pandit S, Dhawan N, Thakur D. Utility of hypertonic saline in the management of acute bronchiolitis in infants: a randomized controlled study. International Journal of Clinical Pediatrics 2013;2(1):24–9.
Ratajczyk‐Pekrul 2016 {published data only}
    1. Ratajczyk‐Pekrul K, Gonerko P, Peregud‐Pogorzelski J. The clinical use of hypertonic saline/salbutamol in treatment of bronchiolitis. Pediatria Polska 2016;91(4):301‐7.
Sarrell 2002 {published data only}
    1. Sarrell EM, Tal G, Witzling M, Someck E, Houri S, Cohen HA, et al. Nebulized 3% hypertonic saline solution treatment in ambulatory children with viral bronchiolitis decreases symptoms. Chest 2002;122(6):2015‐20.
Sharma 2013 {published data only}
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Tal 2006 {published data only}
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Teunissen 2014 {published data only}
    1. Teunissen J, Hochs AH, Vaessen‐Verberne A, Boehmer AL, Smeets CC, Brackel H, et al. The effect of 3% and 6% hypertonic saline in viral bronchiolitis: a randomised controlled trial. European Respiratory Journal 2014;44(4):913–21.
Tinsa 2014 {published data only}
    1. Tinsa F, Abdelkafi S, Bel Haj I, Hamouda S, Brini I, Zouari B, et al. A randomized, controlled trial of nebulized 5% hypertonic saline and mixed 5% hypertonic saline with epinephrine in bronchiolitis. La Tunisie Medicale 2014;92(11):674‐7.
Wu 2014 {published data only}
    1. Wu S, Baker C, Lang ME, Schrager SM, Liley FF, Papa C, et al. Nebulized hypertonic saline for bronchiolitis: a randomized clinical trial. JAMA Pediatrics 2014;168(7):657‐63.
References to studies excluded from this review Al‐bahadily 2017 {published data only}
    1. Al‐bahadily AJM, Al‐Omrani AAM, Atiya AA. Hypertonic 3% saline in comparison with 0.9% (normal) saline in treatment of acute bronchiolitis. International Journal of Pediatrics 2017;5(1):4209‐16.
Amirav 2005 {published data only}
    1. Amirav I, Oron A, Tal G, Cesar K, Ballin A, Houri S, et al. Aerosol delivery in RSV bronchiolitis: hood or face‐mask?. Journal of Pediatrics 2005;147(5):627‐31.
Bagus 2012 {published data only}
    1. Bagus SI, Putu SP. Efficacy of nebulized hypertonic saline and albuterol combination for the management of acute bronchiolitis: a randomized, double‐blind controlled trial. Paediatric Respiratory Reviews 2012;13(Suppl 1):S76.
Bueno Campaña 2014 {published data only}
    1. Bueno Campaña M, Olivares Ortiz J, Notario Muñoz C, Rupérez Lucas M, Fernández Rincón A, Patiño Hernández O, et al. High flow therapy versus hypertonic saline in bronchiolitis: randomised controlled trial. Archives of Disease in Childhood 2014;99(6):511‐5.
Flores‐González 2015 {published data only}
    1. Flores‐González JC, Matamala‐Morillo MA, Rodríguez‐Campoy P, Pérez‐Guerrero JJ, Serrano‐Moyano B, Comino‐Vazquez P, et al. Epinephrine improves the efficacy of nebulized hypertonic saline in moderate bronchiolitis: a randomised clinical trial. PLoS ONE 2015;10(11):e0142847.
Flores‐González 2016 {published data only}
    1. Flores‐González JC, Dominguez‐Coronel MT, Matamala Morillo MA, Aragón Ramírez M, García Ortega RM, Dávila Corrales FJ, et al. Does nebulized epinephrine improve the efficacy of hypertonic saline solution in the treatment of hospitalized moderate acute bronchiolitis? A double blind, randomized clinical trial. Minerva Pediatrica 2016;68(2):81‐8.
Guomo 2007 {published data only}
    1. Guomo R, Cossettini M, Saretta F, Fasoli L, Guerrera T, Canciani M. Efficacy of hypertonic saline solution in infants with acute bronchiolitis. European Respiratory Journal 2007;30(Suppl):E3016.
Gupta 2016 {published data only}
    1. Gupta HV, Gupta VV, Kaur G, Baidwan AS, George PP, Shah JC, et al. Effectiveness of 3% hypertonic saline nebulization in acute bronchiolitis among Indian children: a quasi experimental study. Perspectives in Clinical Research 2016;7(2):88‐93.
Kuzik 2010 {published data only}
    1. Kuzik BA, Flavin MP, Kent S, Zielinski D, Kwan CW, Adeleye A, et al. Effect of inhaled hypertonic saline on hospital admission rate in children with viral bronchiolitis: a randomized trial. Canadian Journal of Emergency Medicine 2010;12(6):477‐84.
Malik 2015 {published data only}
    1. Malik G, Singh A, Singh K, Pannu MS, Singh P, Banga S, et al. A comparative study to assess the effects of nebulised 3% hypertonic saline, 0.9% normal saline and salbutamol in management of acute bronchiolitis among Indian children. Journal of Evolution of Medical and Dental Sciences 2015;4(21):3662‐8.
Nenna 2014 {published data only}
    1. Nenna R, Papoff P, Moretti C, Angelis D, Battaglia M, Papasso S, et al. Seven percent hypertonic saline ‐ 0.1% hyaluronic acid in infants with mild‐to‐moderate bronchiolitis. Pediatric Pulmonology 2014;49(9):919‐25.
Silver 2015 {published data only}
    1. Silver AH, Esteban‐Cruciani N, Azzarone G, Douglas LC, Lee DS, Liewehr S, et al. 3% hypertonic saline versus normal saline in inpatient bronchiolitis: a randomized controlled trial. Pediatrics 2015;136(6):1036‐43.
Tribastone 2003 {published data only}
    1. Tribastone AD. Nebulized 3% saline effective for viral bronchiolitis. Journal of Family Practice 2003;52(5):359‐60.
References to studies awaiting assessment CTRI/2010/091/003065 {unpublished data only}
    1. CTRI/2010/091/003065. A clinical trial to study the effect of nebulized hypertonic saline as compared to normal saline in infants and children with bronchiolitis [Study of nebulized hypertonic saline in the treatment of bronchiolitis in infants and children]. (first received 1 November 2011).
EudraCT2009‐014758‐14 {unpublished data only}
    1. EudraCT2009‐014758‐14. Nebulised hypertonic (3%) saline in the treatment of bronchiolitis [Does nebulised hypertonic (3%) saline reduce the duration of hospital admission in infants with bronchiolitis?]. (first received 17 March 2010).
NCT00677729 {unpublished data only}
    1. NCT00677729. Hypertonic saline to reduce hospital admissions in bronchiolitis [Inhaled hypertonic saline to reduce hospital admissions in infants with viral bronchiolitis (HS in ER study)]. (first received 2 May 2008).
NCT01777347 {unpublished data only}
    1. NCT01777347. Efficacy of 3% hypertonic saline in acute viral bronchiolitis (GUERANDE) [3% hypertonic saline to reduce hospitalization rate in acute viral bronchiolitis: a randomized double blind clinical trial]. (first received 14 November 2012).
NCT01834820 {unpublished data only}
    1. NCT01834820. Epinephrine, dexamethasone, and hypertonic saline in bronchiolitis, randomised clinical trial of efficacy and safety [Pilot study: epinephrine, dexamethasone, and hypertonic saline in children with bronchiolitis, randomised clinical trial of efficacy and safety]. (first received 15 January 2013).
NCT02029040 {unpublished data only}
    1. NCT02029040. Nebulized 3% hypertonic saline in the treatment of acute bronchiolitis [A randomized trial of nebulized 3% hypertonic saline in the treatment of acute bronchiolitis in the emergency department]. (first received 3 January 2014).
NCT02045238 {unpublished data only}
    1. NCT02045238. Inhaled hypertonic saline use in the emergency department to treat acute viral bronchiolitis [Study of the effect of inhaled 3% hypertonic saline compared with normal saline (0.9%) for the treatment of acute viral bronchiolitis in a short stay ward]. (first received 22 January 2014).
NCT02233985 {unpublished data only}
    1. NCT02233985. Nebulized 3% hypertonic saline solution treatment of bronchiolitis in infants [A randomized trial of nebulized 3% hypertonic saline with salbutamol in the treatment of acute bronchiolitis in pediatric hospital]. (first received 7 May 2014).
NCT02834819 {unpublished data only}
    1. NCT02834819. Nebulized 3% hypertonic saline vs. standard of care in patients with bronchiolitis [A randomized controlled trial of nebulized 3% hypertonic saline vs. standard of care in patients with bronchiolitis]. (first received 15 July 2016).
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