Hypertonic saline in viral wheezing

In a recent issue of the journal, Kanjanapradap et al presented their interesting findings on nebulized hypertonic saline (HS) in acute viral wheezing in 6 months to 5 years old Thai children who attended a double-blind, randomized controlled trial (RCT). Patients were randomized to receive inhalations of 2.5 mg albuterol dissolved in 3%HS in 22 cases and in 0.9% normal saline (NS) in 25 cases. Length of stay (LOS) in hospital was shorter in the HS than NS group (medians 2 vs 3 days, P = 0.021), as was the duration of oxygen therapy (medians 1.5 vs 3 days, P = 0.026). Clinical severity scores, respiratory rates, and oxygen saturations improved more in the HS than in the NS group during the first 12 h of treatment. The results are given as medians, evidently because of skewed distributions, but despite of this the distributions are given as 95% confidence intervals (95%CI), which is a little bit unusual. The interpretation of the clinical meaning of the results is challenging. The patients were treated in hospital, and the age on admission varied from 6 months to 5 years, which means that, in addition to viral wheezing (called wheezy bronchitis in most European countries), children with bronchiolitis (those aged 6 to 12 months) and children with asthma (those age more than 24 or 36 months) were included. In subgroup analyses, the difference was significant in the age group of 6 to 15 months but not in the age group of 15 months to 5 years. However, randomization is not anymore valid in ad hoc subgroup analyses, if randomization has not happened as stratified. This age limit of 15 months is arbitrary, though dividing the patients into two equally large groups in the present study. The median in LOS was exactly the same (2 days) for HS patients in both age groups as well as for older NS patients. The results can also be interpreted that HS inhalations were not useful, but the NS inhalations were harmful for the patients younger than 15 months old. There is increasing evidence–based on new RCT studies and most recent meta-analyses–that HS inhalations are not useful in bronchiolitis in infants. The multicenter SABRE study form UK compared 141 infants hospitalized for bronchiolitis at less than 12 months of age and treated with HS inhalations 6-h, with 159 control infants treated with “minimal handling” standard care without any inhalations. There was no significant difference between the two treatment arms in time of being declared “fit for discharge” nor in time of actual discharge. The multicenter GUERANDE study from France compared 385 infants admitted for bronchiolitis to the emergency room at less than 12 months of age and treated with HS inhalations two times 20min apart, with 387 control infants treated with two NS inhalations. By 24 h, 48.1% of infants in the HS group and 52.2% in the NS group were hospitalized; this risk difference was not statistically significant. The most recent cumulative meta-analysis on HS inhalations in infants with bronchiolitis included 18 RCT studies. The heterogeneity was high in children hospitalized at more than 12 months of age and low in those children hospitalized at less than 12 months of age, and the mean difference (MD) in LOS favoring HS therapy was reduced in more recently published papers. Nine studies with the upper age limit of 12 months were analyzed separately, and the cumulative MD in LOS was 0.4 days (95%CI 0.1-0.7). This difference of 0.4 days is less than 10 h. When only the four studies with a low risk of bias were included, the MD was close to 0. As HS inhalations are not beneficial in 0-12-month old infants with bronchiolitis, the finding of Kanjanapradap et al that HS inhalations were beneficial in 6 to 15 months old infants with viral wheezing, but not in older wheezing children, is difficult to explain. Only one previous RCT study was published on HS inhalations in preschool children with viral wheezing. Forty-one Israeli children were admitted for viral wheezing to the emergency room, and further to hospital if needed, and young, less than 12 months old patients with bronchiolitis were excluded. The LOS was shorter in the HS than the NS group (medians 2 vs 3 days, P < 0.03), and the hospitalization rate was 62% vs 92% (P < 0.05). The upper age limit was 6 years, which means that no doubt also asthmatics were included. The authors did not present any analyses stratified for age. The time of small pilot studies on the use of HS inhalations in young wheezing children is over. The studies should be large enough allowing stratified analyses based on age and disease severity to reduce the aged-based heterogeneity. Although overlapping happens, most infants who wheeze first time at less than 12 months of age have bronchiolitis, and those who wheeze at more than 2 or 3 years of age have asthma. In these studies, as in clinical studies in general, the benefits must be clinically significant, not only statistically significant.