Multicenter Observational Study of the Use of Nebulized Hypertonic Saline to Treat Children Hospitalized for Bronchiolitis From 2008 to 2014

We analyzed data from 2 large, prospective, multicenter studies of children hospitalized for bronchiolitis: the 30th Multicenter Airway Research Collaboration (MARC-30) and the 35th Multicenter Airway Research Collaboration (MARC-35)^16,17  (Appendix Tables 1 and 2). A more detailed description has been published elsewhere.^16,17  Both studies were observational in nature and data collection was coordinated by the Emergency Medicine Network in Boston, Massachusetts. The number of participating sites varied over 6 bronchiolitis seasons (November 1–April 30): 13 from 2007 to 2008 (MARC-30), 16 from 2008 to 2009 (MARC-30), 14 from 2009 to 2010 (MARC-30), 9 from 2011 to 2012 (MARC-35), 17 from 2012 to 2013 (MARC-35), and 6 from 2013 to 2014 (MARC-35).

Patient management was at the discretion of the on-site health care provider. All patients were enrolled within 24 hours of admission. Inclusion criteria were an attending physician’s diagnosis of bronchiolitis, age <24 months (MARC-30) or <12 months (MARC-35), and parent or guardian informed consent. Exclusion criteria for both studies were previous enrollment, transfer to a participating hospital >48 hours after the original admission time, and declining the nasopharyngeal aspirate collection.^16,17  Both studies were approved by all local institutional review boards. The details of patient data collection and viral testing have been previously described.^16–21 

To compare the observed HTS usage to trends in the literature, we conducted a PubMed search in December 2014 using the keywords “bronchiolitis” and “hypertonic saline.” We included English language articles on HTS use in bronchiolitis in all clinical settings with no date limit. A single author (J.D.) then categorized the conclusions of each HTS article as positive, negative, neutral, or noninformative. A positive article was defined as one that showed clinical benefit (eg, decreased hospitalization rate, decreased LOS, improved clinical score, positive conclusion). Inversely, a negative article was defined as one reporting clinical harm or a negative conclusion. A neutral article was one in which HTS demonstrated neither clinical benefit nor harm. Lastly, noninformative articles were those that did not primarily discuss HTS use in hospitalized children with bronchiolitis.

The primary outcome was HTS receipt at any point during the preadmission period or inpatient stay for bronchiolitis. Data for inpatient HTS treatment was unavailable during the 2007–2008 season of MARC-30; thus, the primary analysis was restricted to the 2008–2014 study period (n = 2709). Of these, 2179 (80%) children had their “preadmission” visit in the enrolling hospital’s ED, whereas the remaining children were directly admitted from other locations (eg, another hospital, doctor’s office). All analyses were performed by using Stata 14.1 (StataCorp, College Station, TX). Data are presented as proportions and medians with interquartile ranges (IQRs).

We examined trends in the use of HTS treatment by study season and compared them with trends in the bronchiolitis literature. Unadjusted associations between receipt of HTS treatment and patient characteristics were analyzed by using χ², Fisher’s exact test, and Wilcoxon rank sum test, as appropriate. A multivariable logistic regression was conducted to evaluate independent predictors of HTS treatment. The final regression model accounts for potential clustering by site, with results reported as odds ratios with 95% confidence intervals . All P values were 2-tailed, with P < .05 considered statistically significant.

Overall, the median age of the 2709 children hospitalized for bronchiolitis was 3.7 months, and 60% were male (Table 1). In total, 241 (9%) children received HTS during their ED or inpatient stay. Of these 241 children, most (69%) received HTS during their inpatient stay only, 15% received it in the ED only, and 16% received HTS in both settings.

From the 2008–2009 season to the 2011–2012 season, administration of HTS increased from 2% of patients to 27% of patients. In the 2012–2013 season, it dropped to 15% of patients and continued to drop to 11% of patients in the 2013–2014 season (P < .001, Fig 1A). From 2011 to 2012, most HTS was contributed by 3 out of 9 (33%) sites. From 2012 to 2013, it was contributed by 6 out of 17 (35%) sites, with 1 site using HTS on 91% (10 out of 11) of its enrolled patients. For sites with data for both seasons (2008–2009 and 2009–2010) of MARC-30, 31% (5 out of 16) of sites increased their use of HTS between the 2 enrollment seasons. The decrease in HTS use from 2013 to 2014 was largely due to 1 site decreasing use from 58% to 29%. The 5 other sites with high use from 2012 to 2013 did not enroll patients in the 2013–2014 season. Although site participation varied by enrollment season, the type of sites selected for participation (eg, academic medical centers) remained relatively consistent. Among the 6 sites that participated in all 4 enrollment seasons, there was still a pronounced increase in the proportion of patients receiving HTS (2008–2009, 2%; 2009–2010, 6%; 2011–2012, 35%) and then a decline in use (2012–2013, 27%).

Of the 241 children receiving HTS, 31% were admitted to the ICU, compared with 15% of those who did not receive HTS (P < .001). Intubation was also more common among those receiving HTS compared with those who did not (8% vs 3%; P = .001). Of the patients who received HTS, 184 (77%) also received bronchodilator therapy: 75 (31%) only in the ED, 25 (10%) only in the inpatient setting, and 84 (35%) in both settings. The median LOS of patients who received HTS was 3 days (IQR, 2–5 days) vs a median of 2 days (IQR, 1–4 days, P < .0001) in other children.

In the multivariable model, children hospitalized during the 3 seasons from 2011 to 2014 were more likely to have received HTS compared with those enrolled in the 2008–2009 season (Table 2). Other factors associated with an increased likelihood of HTS use were ICU at birth, breathing problem started <1 day before arrival, parental rating of breathing problem as “severe,” previous use of inhaled bronchodilator before arrival, and respiratory syncytial virus (RSV) infection. Also, children ≥12 months (only included in MARC-30) were less likely to receive HTS than those <2 months of age.

Between 1998 and 2014, 69 total articles were published evaluating HTS effectiveness for bronchiolitis; 25 (36%) positive, 38 (55%) neutral, and 6 (9%) negative. Before 2010, 1 to 3 articles were published on the topic annually (Fig 1B). However, between years 2010 and 2011, a total of 22 relevant articles were published, of which 7 were positive, 13 were neutral, and 2 were negative. Between years 2012 and 2014, 36 additional articles were published, of which 12 were positive, 20 were neutral, and 4 were negative. All of the negative studies in this period came in 2014.

In our study, 9% of children hospitalized for bronchiolitis were treated with HTS. Among children who received HTS, indicators of severe disease (ie, ICU admission, longer hospital LOS, <1 day of symptoms, and a parental rating of breathing problem as “severe”) were more common compared with children who did not receive HTS. HTS use varied over season and enrolling sites, with an initial increase from 2008 to 2012 and then a decline during the 2012–2014 seasons. This variation in HTS use over time remained robust after adjustment for potential confounders in multivariable analyses.

Previous studies have noted wide practice variation in various treatments for bronchiolitis^{6–8,22–27} ; however, national guidelines appear to be decreasing unnecessary testing and the use of ineffective treatments.^25–28  Beyond supportive care, no treatment has been clearly established for children with bronchiolitis. This study, however, is the first to show a rapid adoption in HTS use for bronchiolitis in parallel with literature supporting its novel use but before official sanctioning in national guidelines. The initial increase may have been due to more research publications describing HTS use in bronchiolitis patients. As time progressed, further research showed equivocal and inconsistent results for the efficacy of HTS,^8,15,29  and its overall usage subsequently declined in parallel with our findings. The quick uptake is also likely related to its negligible side effect profile, especially when coadministered with bronchodilators,^30–32  and the lack of other effective treatments. In this context, it is not surprising that sicker patients were more likely to receive HTS because clinicians would be more willing to try novel treatments in patients not improving after more established treatments failed. This can lead to confounding by severity in observational studies of medication effectiveness.³³ 

More recently, a systematic review reported on all available trials of HTS up to May 2015 and concluded that nebulized HTS is associated with reduced LOS among admitted infants and reduced hospital admissions when used in the outpatient setting.³⁴  However, a reanalysis of 2 large meta-analyses questions these results and shows that the improvement in LOS disappears when a single outlier study is removed and the results are controlled for day of illness at presentation.³⁵  Although further research is needed to clarify the role of HTS in the management of bronchiolitis, it is also important to study the use and uptake of new treatments among clinicians.

This study had several potential limitations. First, the uptake and usage of HTS by clinicians could be affected by a variety of factors that we did not measure. However, our observations paralleled usage trends seen in the literature on the treatment of bronchiolitis. Our literature search strategy was limited to a single database (PubMed) and our categorization of articles relied on the assessment of 1 author. In addition, this was an observational study, which complicates the evaluation of the treatment effectiveness of HTS.³³  Also, our sample included only children hospitalized for bronchiolitis in academic medical centers and not all eligible children were enrolled, which may limit the generalizability of the results. Finally, not all study sites enrolled participants in all years; some findings might be due to site variability and not necessarily usage variability. The variability in site participation coincided with the largest changes observed in HTS use; therefore, these changes may be exaggerated. Despite these limitations, this study suggests that for severe bronchiolitis, providers are quick to trial novel therapies like HTS given the absence of other effective treatments.

The use of HTS in children hospitalized with bronchiolitis initially increased during the 2008–2012 seasons but then declined. The average usage over the course of our analysis was 9%, but it varied significantly across years and sites. Factors associated with HTS use included younger age, RSV infection, bronchodilator use before presentation, and need for NICU at birth; sicker patients also were more likely to receive HTS. We believe our findings are at least partially explained by the trends in HTS literature with a predominance of positive articles early on followed by an increase in negative and neutral articles after 2012. Although further research will likely clarify the role of HTS in the management of bronchiolitis, it is also important to study the use and uptake of new treatments by clinicians. By using new treatments before they are proven effective, especially when no clear alternatives are available, patients could be placed at unjustified risk for adverse events.