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Three Part Question

In [infants with acute viral bronchiolitis] is [nebulised hypertonic saline] effective in [improving symptoms, reducing admission rate, or reducing length of stay]

Clinical Scenario

A 4 month old infant presents to the ED with a 2 day history of coryza and cough. His mother reports he has become breathless over the last 24 hours and is no longer feeding as well as usual. You make a clinical diagnosis of bronchiolitis. You are aware that bronchodilators are not recommended in bronchiolitis but are keen to give some treatment. You wonder if hypertonic saline is effective.

Search Strategy

Medline
Embase
Cochrane Database of Systematic Reviews
Clinical Trials.gov
Medline and Embase : (exp *bronchiolitis, viral/ OR exp *bronchiolitis OR bronchiolit*.af OR exp *RESPIRATORY SYNCYTIAL VIRUSES/ OR exp *RESPIRATORY SYNCYTIAL VIRUS INFECTIONS/ OR exp *RESPIROVIRUS INFECTIONS/ OR exp *RESPIRATORY TRACT INFECTIONS/ OR exp *PARAMYXOVIRIDAE INFECTIONS/ OR exp *INFLUENZA, HUMAN/ OR exp *ADENOVIRIDAE/ OR (infant* adj5 wheeze).af OR (wheez* adj5 bronchi*).af)AND ( (hypertonic AND saline).af OR exp *SALINE SOLUTION, HYPERTONIC/ OR exp *SODIUM CHLORIDE/ OR saline.af OR (3% ADJ saline).af OR (3% ADJ sodium AND chloride).af OR (3% ADJ NaCl).af OR (3 AND percent ADJ sodium AND chloride).af OR (3 AND percent ADJ NaCl).af OR (3 AND percent ADJ saline).af) AND (exp *"NEBULIZERS AND VAPORIZERS"/ OR exp *AEROSOLS/ OR exp *RESPIRATORY THERAPY/ OR nebulis*.af OR nebuliz*.af OR exp *ADMINISTRATION, INHALATION/ OR exp *AEROSOLS/ OR inhal*.af

Search Outcome

2 meta analyses incorporating 11 RCTs.
20 RCTs in total of which 11 included in meta-analysis and not discussed seperately

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Zhang et al 2013 Brazil	Meta analysis of 11 RCTS, total patients 1090, 560 of whome received hypertonic saline (3% HS n=503, 5% HS n=57). 500 inpatients (5 trials); 65 outpatients (1 trial); 525 ED patients (4 trials)	Meta analysis of 11 RCTs of Nebulised hypertonic saline (3%) with or without broncho-dilators	Length of stay	Mean difference -1.15 days (95% CI -1.49 to -0.82)
			Clinical Severity score post treatment	Day 1 Mean difference -0.88 (95%CI -1.36 to -0.39) p=0.0004 Day 2 Mean difference -1.32 (95%CI -2.00 to -0.64) p=0.001 Day 3 Mean difference -1.51 (95%CI -1.88 to -1.14) p<0.00001
Yen-Ju Chen y, Wen-Li Lee y, Chuang-Ming Wang, 2014 Taiwan	Meta Analysis of 11 RCTs, including total of 1070 patients.	Meta analysis of 11 RCTs, includes 7 of the same papers as Zhang et al.	Duration of hospital admission	WMD=-0.96 (95% CI -1.38 to -0.54) p<0.001	Sample size of included trials generally small and 6 did not use intention to treat analysis.
			Rate of hospital Admissions	Risk Ratio 0.59 (95% CI 0.37-0.93) p=0.02
			Effect on rate of readmission	Risk ratio=1.08 (95% CI=0.68-1.73; p=0.74
			Effect on clinical severity score: Day 1	WMD= -0.77 (95% CI -1.31- -0.24) p=0.005
			Day 2	WMD= -0.85 (95% CI -1.30- -0.39) p<0.001
			Day 3	WMD= -1.36 (95% CI -1.70- -1.02) p<0.001
Miraglia Del Giudice M, Saitta, F, Leonardi S, Capasso M, Niglio C, Chinellato I, Decimo F, et al 2012 Italy	106 Hospitalised infants < 2 years with bronchiolitis	Double blinded Randomised controlled trial of 6 hrly nebulised 0.9% vs 3% saline (both with epinephrine)	Length of stay	3% : 4.9 +/- 1.3 days vs. 0.9%: 5.6 +/-1.6 p<0.05	No power calculation performed 3 patients withdrew consent after randomisation- not clear if intention to treat or per protocol analysis used or reasons for withdrawal
			Clinical severity score	Day 1: 8.8 +/- 1.5 vs. 8.5 +/-1.4 p=NS Day 2: 8.3 +/- 1.7 vs. 7.4 +/- 1.6 p<0.005 Day 3: 7.7 +/- 1.6 vs. 6.6 +/-1.6 p<0.005
Sharma B; Gupta M, Rafik S 2013 India	250 Infants 1-24 months hospitalised with bronchiolitis with clinical severity score 3-6 (moderate)	Randomised double blinded controlled trial nebulised with 4ml 3% or 0.9% saline (both with 2.5mg salbutamol) at 4 hourly intervals	Length of stay	HS: 63.93h +/- 22.43 vs. NS: 63.51 +/- 21.27 p=0.878	Details of 2 patients withdrawn from NS arm not given. Per protocol analysis used
			Clinical severity scores	No significant difference between groups
Ojha A, Mathema S, Sah S, Aryal U 2014 Nepal	72 Infants aged 45 days to 2 years hospitalised with bronchiolitis. Mean age 8.56 months	Double blind randomised controlled trial of nebulised 4ml 0.9% vs. 3% saline administered three times daily	Length of stay	NS: 44.82 (+/-23.15) vs. HS: 43.60 (+/- 28.25) p=0.86	Small trial, underpowered as although appropriate number recruited, 13 withdrew before completion. Per protocol analysis used.
			Duration of oxygen supplementation	NS: 34.50 (+/-26.03) vs HS: 32.50 (+/-20.44) p=0.85
			Time for normalisation of clinical score	NS: 38.34 (+/-26.67) vs. HS:36.79 (+/-19.53) p=0.80
Everard M, Hind D, Ugonna K, Freeman J, Bradburn M, Cooper C, Cross E, Maguire C, Cantrill H, et al 2014 UK	317 Infants under 1 year of age admitted with bronchiolitis and requiring oxygen therapy	Open multicentre parallel group pragmatic RCT in 10 UK hospitals. Usual care vs. 3% hypertonic saline 4 hourly	Time to 'fit for discharge'	Hazard ratio 0.95 (95%CI 0.75-1.20)	Non blinded.
			Time to discharge	Hazard ratio 0.97 (95% CI 0.76-1.23)
Teunissen J, Hochs A, Vaessen-Verbene A, Boehmer A, Smeets C, Brackel H, van Gent R, et al 2014 Netherlands	292 infants (median age 3.4 mo) hospitalised with bronchiolitis enrolled, 242 completed study	Multicentre double blind randomised controlled trial, comparing nebulised 6%, 3% and 0.9% saline (all with salbutamol)	Length of stay	6%; 70 h (IQR69) vs. 3%: 69 h (IQR 57) vs. 53h (IQR 52) p=0.29	Large number of withdrawals
Wu S, Baker C, Lang M, Schrager S, Liley F, Papa C, Mira V, Balkian A, Mason W 2014 USA	408 children under 24 months presenting to the ED of 2 tertiary children's hospitals	Double blind randomized controlled trial over 3 consecutive bronchiolitis seasons. 4ml 3% vs 0.9% saline up to 3 times in the ED and then 8 hourly if admitted. Patients premedicated with albuterol.	Admission rate	HS: 28.9% vs NS: 42.6%. OR 0.49 (95% CI 0.28-0.86)
			Length of stay	HS: 3.16d vs. 3.92 d p=0.24
Florin T; Shaw K; Kittick M; Yakscoe S; Zorc J 2014 USA	62 patients aged 2-24 months with first episode bronchiolitis and RDAI 4-15 (moderate-severe)	Double blinded randomised controlled trial. 3% vs 0.9% saline administered once in the ED. Both groups treated with albuterol before trial intervention.	Change in RDAI (reduction=improvement)	HS: -1 vs NS: -5 p:0.01	Small trial. Short observation period
Flores-Gonzales J, Comino-Vazquez P, Rodriquez-Campoy P, Jiminez-Gomez G, Matamala-Morillo M, et al 2014 Spain	389 patients with moderate acute bronchiolitis.	Data on 181 (group 0) collected retrospectively treated with 0.9% saline (+ bronchodilators) and 208 (group 1) prospectively treated with 3% saline (+ bronchodilators).	PICU admission rate	Group 0: 17.8% vs. Group 1:12.5% p=0.146	Before and after study, unblinded. Corticosteroids and antibiotics both used.
			PICU length of stay	Group 0: 5.91 vs Group 1: 3.76 p=0.859
			Mechanical ventilation rate	25% vs 24% p=0.931
Jacobs J, Foster M, Wan J, Pershad J 2014 USA	101 infants with moderate to severe acute bronchiolitis	Prospective double blind randomized controlled trial of 7% vs 0.9% saline, both with epinephrine	Change in severity score	HS: 2.6 (=/-1.9) vs NS: 2.4 (=/-2.3) Diff in means 0.21(95% CI -0.61-1.03) p=0.61
			Admission rate	HS: 42% vs. NS: 49%. OR 0.76 (95% CI 0.35-1.7)

Comment(s)

Bronchiolitis is a common presentation to Emergency Departments and paediatric units in the winter months and effective treatment is very limited. Bronchiolitis may occur due to infection with a range of viruses, most commonly respiratory syncytial virus (RSV). The pathophysiology is substantially different from that in older patients with wheeze which may explain the lack of benefit from bronchodilator therapy. In bronchiolitis, small airway obstruction occurs as a result of bronchiolar inflammation, leading to a combination of mucosal oedema, mucus plugging and sloughing of necrotic bronchiolar mucosa within the narrow bronchiolar lumen. It is suggested that hypertonic saline may reduce mucosal oedema, rehydrate the airway surface liquid, disrupt ionic bonds within mucus plugs and encourage expectoration. The included trials are all of reasonable quality although some are relatively small, however most use a physiologically active placebo (0.9% saline) and many also use some form of bronchodilator, which are generally accepted to be ineffective in bronchiolitis. Since the most recent meta-analysis in 2014 which was supportive of hypertonic saline therapy in bronchiolitis, a further 9 RCTs have been published, 7 of which demonstrated no advantage of hypertonic saline over 0.9% saline. The SABRE trial, which is the only trial to date to avoid the use of a potentially physiological placebo did not demonstrate any benefit from hypertonic saline. Overall it seems likely that, although there may be a benefit to the use of hypertonic saline, the clinical effect is small, hence the conflicting results of the 20 RCTs to date.

Clinical Bottom Line

Hypertonic saline is safe and may be a useful therapy for patients with acute bronchiolitis, however clinical effects appear relatively small and the main focus should remain on providing quality supportive care.

References

1. Zhang L, Mendoza- Sassi R, Wainwright C, Klassen T. Nebulized hypertonic saline solution for acute bronchiolitis in infants Cochrane Database of Systematic Reviews 2013; CD:006458
2. Yen-Ju Chen y, Wen-Li Lee y, Chuang-Ming Wang, Nebulized Hypertonic Saline Treatment Reduces Both Rate and Duration of Hospitalization for Acute Bronchiolitis in Infants: An Updated Meta-analysis Pediatrics and Neonatology 2014; 55 (6); 431-438
3. Miraglia Del Giudice M, Saitta, F, Leonardi S, Capasso M, Niglio C, Chinellato I, Decimo F, et al Effectiveness of hypertonic saline and epinephrine in hospitalised infants with bronchiolitis International Journal of Immunopathology and Pharmacology 2012; 25(2);485-91
4. Sharma B; Gupta M, Rafik S Hypertonic (3%) Saline Vs 0.9% Saline Nebulization for Acute Viral Bronchiolitis: A randomized controlled trial Indian Pediatrics 2013; 50(8);743-7
5. Ojha A, Mathema S, Sah S, Aryal U A comparative study on the use of 3% saline versus 0.9% saline nebulization in children with bronchiolitis Journal of Nepal Health Research Council 2014; 12(26); 39-43
6. Everard M, Hind D, Ugonna K, Freeman J, Bradburn M, Cooper C, Cross E, Maguire C, Cantrill H, et al SABRE: a multicentre randomised control trial of nebulised hypertonic saline in infants hospitalised with acute bronchiolitis Thorax 2014; 69(12);1105-12
7. Teunissen J, Hochs A, Vaessen-Verbene A, Boehmer A, Smeets C, Brackel H, van Gent R, 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
8. Wu S, Baker C, Lang M, Schrager S, Liley F, Papa C, Mira V, Balkian A, Mason W Nebulized hypertonic saline for bronchiolitis: a randomized controlled trial JAMA Pediatrics 2014; 168(7):657-63
9. Florin T; Shaw K; Kittick M; Yakscoe S; Zorc J Nebulized hypertonic saline for bronchiolitis in the Emergency Department: a randomized controlled trial JAMA Pediatrics 2014; 168(7):664-70
10. Flores-Gonzales J, Comino-Vazquez P, Rodriquez-Campoy P, Jiminez-Gomez G, Matamala-Morillo M, et al Does the nebulized 3% hypertonic saline solution reduce admissions to PICU in acute bronchiolitis? Archives of Disease in Childhood 2014; 99(A354)
11. Jacobs J, Foster M, Wan J, Pershad J 7% hypertonic saline in acute bronchiolitis: a randomised controlled trial Pediatrics 2014; 133(1):e8-13