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Three Part Question

In [children <2yrs with acute viral bronchiolitis] does [regular administration of nebulised hypertonic saline] lead to reduction in [mortality/morbidity rates or length of hospital stay]

Clinical Scenario

A 3 month old books in to the Emergency Department with a 4 day history of a coryzal illness followed by breathing difficulties and decreased oral intake. It is December. Inwardly you sigh heavily, berating the fact that bronchiolitis season is upon you and all you really have to offer is supplemental oxygen, nasogastric feeding and paediatric admission.
Just then, one of your colleagues mentions perusing the Cochrane Database recently and seeing something about the use of nebulised hypertonic saline in bronchiolitis. The paediatricians in the department are sceptical. A spark of hope alights in you that there may be an evidence-based treatment out there after all. You quickly decide to find out for yourself one way or the other.....

Search Strategy

Cochrane Database of Systematic Reviews - One completed review found, last assessed as up to date on 12/11/2007
Using NHS Library 2.0 as an interface:
MEDLINE 2007 - 7/1/2009
EMBASE 2007 - 7/1/2009
CINAHL 2007 - 7/1/2009
[exp Bronchiolitis OR Bronchiolit$ OR Bronchiolitis, viral OR exp Respiratory syncitial viruses/ OR Respiratory syncitial vir$ OR exp Paramyxoviridae infections OR exp Respirovirus infections/ OR exp Influenza, Human/ OR exp Adenoviridae] AND [exp saline solution, hypertonic/ OR hypertonic saline.mp. OR exp sodium chloride/ OR saline.mp OR 3% adj saline.mp OR 3% adj sodium chloride.mp] AND [exp "Nebuizers and Vaporizers"/ OR (nebulis$ or neuliz$).mp. OR exp administration, inhalation/ OR inhal$.mp OR exp aerosols/ OR aerosol$.mp.]
Limit to human and English Language.

Search Outcome

1 Cochrane review found directly relevant to the three part question.
50 articles found from the repeat literature search limited to 2007 - current. 2 directly relevant. 1 discarded as journal club article. 1 included in above Cochrane review.
The 2008 Cochrane review is summarised below:

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Zhang et al. 2008 Brazil	254 children <2 years of age with acute viral bronchiolitis (clinical diagnosis based on predefined criteria). Patients with previous wheezing episode excluded from all trials. RSV positive rates varied from 69-87%. Total 189 inpatients and 65 outpatients included in four seperate trials.	Systematic review (Level 1a) of 4 double blind parallel group RCTs. Randomisation, double blinding and allocation concealment methods were judged to be adequate in all 4 trials, with Jadad scores of 5 for each. 3% hypertonic saline was used as the intervention in each trial, with 3 trials using 4mls and 1 using 2mls per treatment. 0.9% saline acted as the control solution. Bronchodilators were added routinely to the randomised treatment solution in 3 trials (adrenaline or terbutaline). In one trial, while addition was not encouraged or required, 60% of trial patients were given bronchodilators by attending physicians (albuterol or adrenaline). Treatment with study solution was given at 8 hourly intervals in three trials and a decreasing regimen beginning 2 hourly, in the last trial. All three inpatient trials used length of stay as the primary outcome, with 2 of the trials using the Wang clinical severity score as a secondary outcome. The 1 outpatient trial looked at the rate of hospitalistion and clinical severity score as outcome measures. Side effects associated with therapy were reported in all 4 trials.	Length of hospital stay	Infants treated with nebulised 3% saline had a statistically significant shorter mean length of hospital stay compared to those treated with 0.9% saline. Mean difference was -0.94 days (95% CI -1.48 to -0.40, p=<0.001) which represents a 25.9% reduction in mean length of hospital stay.	Three of the four trials did not analyse on an intention to treat basis. Relatively small sample size of review. Underpowered to assess efficacy in preventing hospitalisation.
			Clinical severity scoring	Baseline clinical scores were comparable between the two groups. On day 1 the pooled results from 3 trials demonstrated a significantly lower post inhalation clinical score favouring treatment with nebulised 3% saline, with a mean difference of -0.75 (95% CI -1.38 to -0.12, p=0.02). This represents a 11.2% reduction from the mean severity score in the control group. On day 2, the pooled results demonstrate benefit of nebulised 3% saline in reducing the post inhalation clinical score on the second day of treatment, with a mean difference of -1.18 (95% CI -1.97 to -0.39, P=0.003). This represents a 20% reduction from the mean clinical score in the control group.
			Hospitalisation rates	Only one outpatient trial looked at hospitalisation rate as an outcome. This failed to achieve a statistically significant evidence of benefit, with relative risk in the 3% group of 0.67 (95% CI 0.12 to 3.75, P=0.65).
			Adverse events	No adverse events related to 3% saline inhalation were reported in any of the four trials. In one trial, 5 infants were withdrawn at their parent's request because of perceived adverse effects. Only 2 of these infants had received 3% saline.

Comment(s)

Bronchiolitis is one of the most common lower respiratory tract infections in infants and, with increasing hospitalisation rates, produces a significant burden of care. The principal pathological findings include peribronchial inflammatory infiltrate, submucosal oedema and excess mucus secretion. This combination leads to airway plugging, atelectasis and impaired gas exchange. The diagnosis is clinical. The previous evidence-base suggests only supportive therapy. Hypertonic saline is thought to work in this condition by lowering the viscosity of mucus secretions, inducing an dilutional osmotic flow into the mucus layer and stimulation of cilia. These factors all help to clear airway obstruction, reduce mucosal oedema and promote expectoration. Hypertonic saline has been shown to increase muco-ciliary clearance in normal subjects, and has been used in cystic fibrosis patients to clear mucus with no adverse effects. In all of the trials featured in the above review, nebulised hypertonic saline was tolerated without side effects and produced a significant decrease in length of stay. Several of the trials also suggest a continued improvement using clinical scoring systems. In all trials hypertonic saline was given in tandem with other bronchodilators (Terbutaline, albuterol, adrenaline) to avoid the risk of reflex bronchoconstriction. It would thus seem prudent to continue with this adjunct given the excellent safety profile seen. However, no evidence seems to exist as to the optimum regimen/combination.

Clinical Bottom Line

Nebulised 3% Hypertonic Saline Solution given at regular intervals decreases clinical severity scores and length of hospital stay in children under 18 months with viral bronchiolitis. The most frequent regimen used in the trial data was 4ml 3% hypertonic saline by nebuliser at least 8 hourly, in conjunction with a bronchodilator. From an Emergency Medicine perspective, there is limited evidence to suggest the efficacy of this treatment in decreasing hospitalisation rates. Further large RCTs in this interesting area are warranted, together with an assessment of the optimum delivery intervals and additional bronchodilators.

References

1. Zhang L et al. Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Cochrane Database of Systematic Reviews 10/2008; Issue 4; 1-21; Art. No.: CD006458