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August 2017, VOLUME7 /ISSUE 8

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

  1. Joshua Davis, MDa,
  2. Amy D. Thompson, MDa,
  3. Jonathan M. Mansbach, MD, MPHb,
  4. Pedro A. Piedra, MDc,
  5. Kohei Hasegawa, MD, MPHd,
  6. Ashley F. Sullivan, MS, MPHd,
  7. Janice A. Espinola, MPHd and
  8. Carlos A. Camargo Jr, MD, DrPHd
  1. aDepartment of Emergency Medicine, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware;
  2. bDepartment of Medicine, Boston Children’s Hospital, and
  3. dDepartment of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and
  4. cDepartments of Molecular Virology and Microbiology, and Pediatrics, Baylor College of Medicine, Houston, Texas
  1. Address correspondence to Amy D. Thompson, MD, Emergency Department, Nemours/ Alfred I. duPont Hospital for Children, 1600 Rockland Rd, Wilmington, DE 19803. E-mail: amy.thompson{at}nemours.org
  1. Drs Davis and Thompson conceptualized and designed the current analysis, contributed to data collection, and drafted the manuscript; Drs Mansbach and Piedra contributed to the design of the original studies, contributed to data collection, and made critical revisions to the manuscript; Dr Hasegawa contributed to the design of the original studies and analysis of the results and made critical revisions to the manuscript; Ms Sullivan conceptualized and designed the original studies, supervised the data collection, and made critical revisions to the manuscript; Ms Espinola conceptualized and designed the current analysis, analyzed the results, and drafted the manuscript; Dr Camargo conceptualized and designed the original studies and current analysis, supervised both studies, and drafted the manuscript; and all authors approved the final manuscript for submission.

Abstract

OBJECTIVES: Among children hospitalized for bronchiolitis, we examined temporal trends in the use of hypertonic saline (HTS) and the characteristics associated with receiving this treatment.

METHODS: We conducted a secondary analysis of data from 2 large, multicenter prospective cohort studies that included young children hospitalized with bronchiolitis during 5 winter seasons (2008–2014). Our outcome was receipt of HTS any time during the preadmission visit or hospitalization. For comparison with the observed trends in HTS use, we conducted a PubMed literature review of studies evaluating HTS use for bronchiolitis. We classified publications according to their assessment of HTS efficacy (positive, negative, or neutral).

RESULTS: Among 2709 hospitalized children, 241 (8.9%) received HTS. There was marked variability in HTS use by site (0%–91%), with use more common among children admitted to the ICU than those treated on the ward (31% vs 15%). Over the study period, administration of HTS increased from 2% during the 2008–2009 season to 27% during the 2011–2012 season, but then it decreased to 11% during the 2013–2014 season. Before 2010, the number of PubMed HTS publications ranged from 0 to 3 articles per year, with all classified as either positive or neutral. The number of positive publications increased in 2010 (n = 5), whereas negative publications peaked in 2014 (n = 4).

CONCLUSIONS: Use of HTS in children hospitalized with bronchiolitis increased during the 2008 to 2012 winter seasons and then declined. These findings paralleled trends in the HTS literature, with positive articles encouraging HTS use in early years followed by a growing number of neutral and negative articles after 2012.

Bronchiolitis is the leading cause of hospitalization of young children in the United States.1,2 The mean cost of these hospitalizations is $8500, with a median length-of-stay (LOS) of 2 to 3 days.3,4 The annual direct cost of bronchiolitis hospitalizations nationwide is estimated at $543 million,4 with total charges in excess of $1.6 billion.3 Therefore, reducing LOS in bronchiolitis could greatly reduce health care expenditure.

Currently, the mainstay of treatment is supportive, including supplemental oxygen, nasopharyngeal suctioning, intravenous fluids, and pressure-support ventilation, when necessary.5 Pharmacological treatment in bronchiolitis is highly variable.68 Several approaches have been tried, including the use of inhaled bronchodilators, inhaled and systemic corticosteroids, and ribavirin. The American Academy of Pediatrics (AAP) recommends against all of these approaches in the routine management of bronchiolitis.9 A more recently introduced treatment of severe bronchiolitis is the use of inhaled 3% or 5% hypertonic saline (HTS).10,11 Although several early, small studies supported HTS use in infants with bronchiolitis, the studies differed in their inclusion criteria, concentration of HTS, and concomitant bronchodilator use.1214 In a 2013 Cochrane systematic review, HTS was shown to reduce inpatient LOS and clinical severity scores in both the inpatient and outpatient setting.10 However, this same review found no significant short-term change in bronchiolitis severity when HTS was given in the emergency department (ED).10 A recent randomized trial of hypertonic versus normal saline found no difference in LOS, severity scores, or need for supplemental oxygen among hospitalized infants with bronchiolitis.15 Although the most recent 2014 AAP guidelines recommend against HTS use in the ED, they state that HTS may be considered for infants hospitalized with bronchiolitis.9 The actual usage of HTS over the past decade is not known.

To address this knowledge gap, we analyzed multicenter, multiyear databases of children hospitalized with bronchiolitis to identify temporal trends in the usage of this new treatment approach for severe bronchiolitis. We also examined the demographic and clinical characteristics associated with HTS administration. Although all patients were enrolled before the release of the 2014 AAP guidelines,9 we hypothesized that the use of HTS over time would parallel the results of published studies that either did or did not support this novel treatment. Therefore, we conducted a literature review on HTS use for bronchiolitis to compare with the temporal trends observed in our cohort studies.

Methods

Study Design

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.1621

Literature Search

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.

Statistical Analyses

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.

Results

HTS Use Among Children Hospitalized for Bronchiolitis

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.

TABLE 1

Characteristics of Children Hospitalized for Bronchiolitis by Use of HTS from 2008 to 2014

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%).

FIGURE 1

Trends in HTS use for bronchiolitis compared with relevant literature. A, HTS use among children hospitalized for bronchiolitis from 2008 to 2014. B, Number of PubMed publications evaluating HTS use for bronchiolitis from 2002 to 2014.

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.

TABLE 2

Predictors of Receiving HTS among 2709 Infants Hospitalized for Bronchiolitis from 2008 to 2014

Literature Search

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.

Discussion

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 bronchiolitis68,2227; however, national guidelines appear to be decreasing unnecessary testing and the use of ineffective treatments.2528 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,3032 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.

Conclusions

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.

Appendix

Eugene Mowad, MDAkron Children’s Hospital, Akron, OH
Jonathan Mansbach, MD, MPHBoston Children’s Hospital, Boston, MA
John Cheng, MD and Carlos Delgado, MDChildren’s Healthcare of Atlanta at Egleston, Atlanta, GA
Lisa Zaoutis, MDChildren’s Hospital of Philadelphia, Philadelphia, PA
M. Jason Sanders, MDChildren’s Memorial Hermann Hospital, Houston, TX
Brian Pate, MDChildren’s Mercy Hospital & Clinics, Kansas City, MO
Stephen Teach, MD, MPHChildren’s National Medical Center, Washington, DC
Besh Barcega, MDLoma Linda University Children’s Hospital, Loma Linda, CA
Frank LoVecchio, DOMaricopa Medical Center, Phoenix, AZ
Paul Hain, MD and Mark Riederer, MDMonroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN
Dorothy Damore, MD and Nikhil Shah, MDNew York Presbyterian Hospital, New York, NY
Michelle Stevenson, MD, MSNorton Children’s Hospital, Louisville, KY
Erin Stucky Fisher, MDRady Children’s Hospital, San Diego, CA
Haitham Haddad, MDRainbow Babies & Children’s Hospital, Cleveland, OH
Alan Schroeder, MDSanta Clara Valley Medical Center, San Jose, CA
Charles Macias, MD, MPHTexas Children’s Hospital, Houston, TX
APPENDIX TABLE 1

Principal Investigators at the 16 Participating Sites in MARC-30

Appendix

Amy Thompson, MDAlfred I. duPont Hospital for Children, Wilmington, DE
Federico Laham, MD, MSArnold Palmer Hospital for Children, Orlando, FL
Jonathan Mansbach, MD, MPHBoston Children’s Hospital, Boston, MA
Vincent Wang, MD, MHAChildren’s Hospital of Los Angeles, Los Angeles, CA
Michelle Dunn, MDChildren’s Hospital of Philadelphia, Philadelphia, PA
Juan Celedon, MD, DrPHChildren’s Hospital of Pittsburgh, Pittsburgh, PA
Michael Gomez, MD, MSChildren’s Hospital at St. Francis, Tulsa, OK
Brian Pate, MD and Henry Puls, MDChildren’s Mercy Hospital & Clinics, Kansas City, MO
Stephen Teach, MD, MPHChildren’s National Medical Center, Washington, DC
Richard Strait, MDCincinnati Children’s Hospital and Medical Center, Cincinnati, OH
Ilana Wanik, MDConnecticut Children’s Medical Center, Hartford, CT
Sujit Iyer, MDDell Children’s Medical Center of Central Texas, Austin, TX
Ari R. Cohen, MD and Wayne Shreffler, MD, PhDMassachusetts General Hospital, Boston, MA
Michelle Stevenson, MD, MSNorton Children’s Hospital, Louisville, KY
Anne Beasley, MDPhoenix Children’s Hospital, Phoenix, AZ
Thida Ong, MDSeattle Children’s Hospital, Seattle, WA
Charles Macias, MD, MPHTexas Children’s Hospital, Houston, TX
APPENDIX TABLE 2

Principal Investigators at the 17 Participating Sites in MARC-35

Footnotes

  • FINANCIAL DISCLOSURE: Dr Camargo received the grants mentioned below; the other authors have indicated they have no financial relationships relevant to this article to disclose.

  • FUNDING: This study was supported by grants U01 AI-067693, U01 AI-087881, R01 AI-114552, and UG3 0D-023253 to Dr Camargo from the National Institutes of Health (Bethesda, MD). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Funded by the National Institutes of Health (NIH).

  • POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

References