Viral bronchiolitis is a common reason for hospitalizations in infants and contributes to huge economic burden [1, 2].　Bronchiolitis is generally seasonal and hospitalization peaks between 3 and 6 months of life [2]. The standard treatment remains supportive care and includes ensuring adequate oxygen exchange, fluid intake and feeding of the infant [3, 4].　Meta analyses of data on the most-used therapies for acute bronchiolitis namely, nebulized bronchodilators, epinephrine, glucocorticoids and chest physiotherapy have failed to prove any effect on relevant clinical outcomes, in comparison with placebo except some benefits of epinephrine compared to placebo for short-term outcomes for outpatients, particularly in the first 24 hours of care [5-8].　Current clinical practice guidelines do not recommend the routine use of any medication but despite the evidence, use of ineffective therapies for bronchiolitis remains high [9].

Recently, several investigators have reported the use of hypertonic saline solution for infants with bronchiolitis with substantial benefits of therapy reported by many of them [10-19].　It has been reported to alter mucociliary clearance favorably in both normal and diseased lungs in multiple clinical settings including bronchiolitis [20-24]. This modality has enormous potential for cost-saving, both in developing and developed countries, more so if it could actually reduce length of hospitalization　as suggested by　a recent Cochrane review [13].　Thus, based on the available literature, we hypothesized that 3 % hypertonic saline would shorten length of hospital stay as compared to 0.9% saline in patients with bronchiolitis. We conducted this study to evaluate the efficacy of nebulized 3 % hypertonic saline in children diagnosed with clinical bronchiolitis.

Statistical analysis:　Primary objective of interest was to compare the length of hospital stay (time taken to reach clinical severity score　<3) and secondary objective was to compare the improvement in clinical severity scores in hospitalized children with acute bronchiolitis nebulized with 3% hypertonic saline and normal saline. Reduction in length of hospital stay of 1 day was previously proposed as being clinically significant. It was anticipated that this would require a sample size of 113 patients in each arm. This number was based on a pre study mean length of hospital stay of 3.5 ± 2.9 days [17]. Each variable was scanned for normalcy of distribution. Categorical variable were compared using the Chi-square test. All continuous variables were compared using the paired or unpaired t-test as appropriate. A P value <0.05 was considered statistically significant. To examine the clinical severity scores at 12-hourly intervals Mann-Whitney non-parametric U test was carried out in each treatment group separately. For this analysis, P value 0.005 was considered significant due to multiple comparisons.

Study was conducted during September 2009 to December 2010 and 277 potentially eligible candidates patients with a clinical diagnosis of bronchiolitis were admitted of which 248 successfully completed the protocol (Fig. 1). The two study groups were similar in baseline characteristics (Table I) including age, sex and clinical severity score.

Fig.1 Participant flow diagram.

TABLE I Baseline Characteristics Of Study Subjects

Clinical severity scores　monitored 12 hourly till discharge (132 hours) did not show statistically significant differences between the two groups (Fig. 2).　However, it is to be noted that the median clinical severity score　at time 0 would be based on 125 subjects whereas the data at 132 hours would be based on only 2 patients. There was no difference in mean length of hospital stay in 0.9% saline (63.93 ± 22.43 hours) & 3% hypertonic saline (63.51 ± 21.27) groups (P=0.878). Percentage of patients remaining in each group at 24 hourly intervals is depicted in　Fig. 3. No adverse events related to nebulized therapy were reported by the parents, caregivers or treating medical attendants in both groups.

Fig. 2 Median clinical severity score of two groups at 12-hourly intervals.

Fig.3 Patients remaining in each group at 24-h intervals.

Discussion

Ours is the one of the largest studies comparing 3% hypertonic saline and 0.9% (normal) saline nebulization in hospitalized children with acute bronchiolitis. Both the groups were comparable in baseline characteristics however; we did not find any advantage of hypertonic (3%) saline over normal (0.9%) saline in terms of length of hospital stay and clinical severity scores monitored from admission till discharge.

Shorter length of hospital stay and lower admission rates have been reported to be objective and clinically meaningful measure of cost effectiveness [26, 27].　In the Cochrane meta analysis (four studies) 24.1% shorter (mean 1.16 days, 95% CI -1.55 to - 0.77 days) length of hospital stay was reported with hypertonic saline [13]. However, one of these studies reporting the maximum reduction (-1.4 days) with hypertonic saline had longer length of stay (almost double that of other 3 studies) in both the groups leading to heterogeneity of data [17]. Khalid, et al. [18] have recently reported shorter length of stay with hypertonic saline but if we look at the actual length of hospital stay among the different groups, there is difference of few hours only which may not be significant clinically. Revisit rate 7 days after discharge was also similar in all the groups in their study reflecting the non superiority of hypertonic saline. Mean length of hospital stay was similar with 3% and normal saline in our study but it was shorter in both the groups as compared to all other investigators [18].

Most of the studies conducted in emergency care or outpatient settings did not show any significant advantage of hypertonic saline over normal saline in terms of improvement in clinical severity scores or hospitalization rates [11,12,14]. However, studies conducted in hospitalized patients with bronchiolitis have reported better improvement in clinical severity scores with hypertonic saline but the magnitude of improvement differed on different treatment days varying from 15.7 % on day 1 to 29.4 % on day 3 in hypertonic saline group [10,13,15-17]. Concentration dependent improvement (normal saline <3% saline <5% saline) in clinical severity scores reported by Khalid, et al. [18] were measured immediate post nebulization but transient improvement may not have effect on length of hospitalization [18]. We did not find any significant difference in CS score at enrollment and thereafter at 12 hourly intervals till discharge in both the groups.

Sood, et al. [28] have demonstrated that increasing the volume of airway surface liquid is associated with increased rates of mucociliary clearance in normal subjects. They found that the change in depth of airway surface liquid after normal saline or hypertonic saline inhalations is a function of the mass of NaCl added to the airway surface by the aerosols of different concentrations of NaCl. Ceiling effect of higher inhaled NaCl could be the possible reason for inability to document any difference with hypertonic saline and normal saline in our study.

We did not have a placebo group due to ethical considerations as the only placebo for nebulization therapy could be NS which itself is a treatment modality. We did not attempt virological diagnosis as we did not have the facility. Though this is the actual clinical scenario for management of bronchiolitis in developing countries yet, considering the age limit we might have enrolled a few children with diagnosis other than bronchiolitis.

To conclude, nebulized 3 % hypertonic saline is not superior to 0.9% saline in infants and children with clinically diagnosed acute bronchiolitis (without RSV confirmation). Further large-scale trials are required to prove its clinical benefits before recommending its routine use in patients with acute viral bronchiolitis.

Contributors:　BS, MG and SPR conceptualized the study and performed data analysis while BS and SPR　were involved　in data collection.　MKG　drafted the manuscript and BS and MG critically reviewed it.

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