Early Use of Bronchodilators and Outcomes in Bronchiolitis

This was a multicenter, retrospective, cross-sectional study of infants presenting to the ED with bronchiolitis. Data for this study were obtained from the Pediatric Health Information System (PHIS), an administrative database that contains inpatient, ED, ambulatory surgery and observation encounter-level data from >49 not-for-profit, tertiary care pediatric hospitals in the United States. These hospitals are affiliated with the Children’s Hospital Association (Lenexa, KS). Data quality and reliability are assured through a joint effort between the Children’s Hospital Association and participating hospitals. Portions of the data submission and data quality processes for the PHIS database are managed by Truven Health Analytics (Ann Arbor, MI). For the purposes of external benchmarking, participating hospitals provide discharge and encounter data, including demographics, diagnoses, and procedures. Nearly all of these hospitals also submit resource use data, including pharmaceuticals, imaging, and laboratory, into PHIS. Data are deidentified at the time of submission and subjected to a number of reliability and validity checks before being included in the database. The Committee on Clinical Investigation at Boston Children’s Hospital approved this study with a waiver of informed consent.

Infants <12 months of age who were diagnosed with bronchiolitis in the ED were included. In the analysis of trends, infants presenting between January 1, 2010, and December 31, 2018, were included. The analysis of outcomes was limited to infants presenting between January 1, 2015, and December 31, 2018. This time period was selected to reflect current hospital-level practice patterns, which may be distinct from clinical practices before the publication of the newest AAP guidelines in 2014.^3,5  Infants with bronchiolitis were identified by using the International Classification of Diseases, Ninth Revision, Clinical Modification, (ICD-9-CM) code of 466.1 or International Classification of Diseases, 10th Revision, Clinical Modification, (ICD-10-CM) code of J21 as the primary discharge diagnosis. Infants with complex chronic conditions were identified according to the pediatric complex chronic conditions classification and excluded.^10,11 

Patient demographics (sex, age, race, ethnicity, primary insurance, and disposition) as well as hospital characteristics (ED to inpatient admission rate and ED patient volume) were measured. Primary insurance was classified as public payer, private payer, or other. Diagnoses and procedures were identified by using ICD-9-CM, ICD-10-CM, Current Procedural Terminology, and PHIS-specific clinical transaction codes. Illness severity was measured by using All Patient Refined Diagnosis Related Group (APR-DRG) severity scores, a marker of the severity of illness and risk of death in hospitalized children.¹² 

The primary outcomes were the rates of bronchodilator use, hospitalization, admission to an ICU, ED return visit within 3 days of initial ED discharge, noninvasive ventilation, and invasive ventilation among the study sample.

Hospital-level rates of “early” (as defined by administration on the date of presentation) bronchodilator use among the study sample were calculated. Hospitals in the lowest and highest quartiles of bronchodilator use were classified as low and high users, respectively. Early bronchodilator use was defined as the administration of a nebulized bronchodilator on the calendar day of presentation.

Bronchodilator use and invasive and noninvasive ventilation were identified by using ICD-9-CM, ICD-10-CM, Current Procedural Terminology, and PHIS clinical transaction codes. Bronchodilators included nebulized albuterol, racemic epinephrine, ipratropium, and levalbuterol. Noninvasive ventilation was defined by using codes for continuous positive airway pressure, bilevel positive airway pressure, noninvasive positive pressure ventilation, and noninvasive ventilation. Invasive ventilation was defined by using the mechanical ventilation flag created by PHIS, which includes codes for continuous invasive mechanical ventilation, respiratory ventilation, and mechanical ventilation.

Descriptive statistics were used to characterize the demographic features of the patients, by using frequencies with proportions and medians with interquartile ranges for categorical and continuous variables, respectively. To compare patient demographics between hospitalizations with and without bronchodilator therapy, χ² and Wilcoxon rank tests were used for categorical and continuous variables, respectively. Patient demographics included race and ethnicity as a means of describing the population of infants with bronchiolitis in the study.

Logistic regression models were used to assess linear trends over time in the rates of any bronchodilator use, hospital admission, admission to an ICU, ED return visit within 3 days of initial ED discharge, noninvasive ventilation, and invasive ventilation. The independent variable for these models was calendar year.

Descriptive statistics were used to characterize the use of bronchodilators as well as patient-level and hospital-level factors at hospitals with high and low early bronchodilator use. χ² and Kruskal-Wallis rank sum tests were used to compare patient and hospital factors between hospitals with high and low early bronchodilator use for categorical and continuous variables, respectively.

Multivariable logistic regression was used to test the association of hospital-level early bronchodilator use (high versus low users) with patient-level hospitalization, admission to an ICU, noninvasive and invasive ventilation on the initial hospital day, and ED return visit after initial ED discharge. The model was adjusted for patient-level age and median APR-DRG severity scores for all infants with bronchiolitis in the study at each hospital. Age has been previously identified as the strongest predictor of disease severity in children with bronchiolitis.¹³  The medians of APR-DRG severity scores for all infants with bronchiolitis in the study at each hospital were used as a marker of severity of illness of the patients with bronchiolitis seen at each center.¹⁴  The model used robust SEs clustered on hospital to account for intrahospital correlation among patients.

Odds ratios (ORs) for the outcomes and 95% confidence intervals (CIs) were calculated. All tests were 2-tailed, and α was set at .05. Statistical analyses were conducted by using Stata SE, version 15 (Stata Corp, College Station, TX).

A total of 466 696 emergency visits of infants with bronchiolitis from 49 hospitals were included in the analysis. The median age was 5 months (interquartile range: 2–8). More infants were male (59.9%), white (49.9%), non-Hispanic (65.3%), and publicly insured (71.5%). Overall, 142 873 (32.0%) were treated with bronchodilators. Infants who received bronchodilators were more likely to be male, an older age, Black, non-Hispanic, and publicly insured than those who did not (Table 1; all P < .001).

Bronchodilator use decreased from 51.5% to 22.8% between 2010 and 2018 (linear trend by year [OR: 0.83; 95% CI 0.83–0.83]; Fig 1). Hospital admissions decreased from 34.4% to 33.1% (OR: 0.98; 95% CI 0.98–0.99), and ICU admissions increased from 2.4% to 4.3% (OR: 1.06; 95% CI 1.05–1.06; Fig 1). ED visits within 3 days after initial ED discharge declined from 5.9% to 5.2% (OR: 0.98; 95% CI 0.98–0.99) over the study period. Noninvasive ventilation increased from 1.0% to 2.9% (OR: 1.15; 95% CI 1.14–1.16), and invasive ventilation increased from 0.7% to 1.5% (OR: 1.06; 95% CI 1.04–1.07).

The study included 111 310 infants in the hospital-level analysis, with 56 852 and 54 458 infants at hospitals with high and low early use of bronchodilators, respectively. Rates of early bronchodilator therapy for infants with bronchiolitis ranged from 13.6% to 53.7% and 3.3% to 12.8% at hospitals categorized as having high and low early use of bronchodilators, respectively.

Infants admitted to hospitals with high early use of bronchodilators for bronchiolitis were older than those admitted to hospitals with low early use of bronchodilators (P < .001). Hospitals with high early use of bronchodilators had lower overall ED admission rates, higher annual ED volumes, and higher median APR-DRG severity scores than hospitals with low early use of bronchodilators (all P < .001; Supplemental Table 3).

There were no significant differences in any outcomes in patients at hospitals with high versus low early use of bronchodilators (Table 2). Hospital admissions (OR: 0.93; 95% CI 0.7–1.3), ICU admissions (OR: 1.5; 95% CI 0.7–3.1), ED return visits after initial ED discharge (OR: 1.2; 95% CI 0.99–1.4), noninvasive ventilation (OR: 3.5; 95% CI 0.7–19.1), and invasive ventilation (OR: 8.2; 95% CI 0.99–67.5) did not differ significantly between hospitals with high and low early bronchodilator use.

In the multivariable models, the odds of all outcomes decreased significantly with increasing age in months, including hospital admissions (OR: 0.91; 95% CI 0.89–0.93), ICU admissions (OR: 0.93; 95% CI 0.89–0.96), invasive ventilation (OR: 0.92; 95% CI 0.89–0.95), noninvasive ventilation (OR: 0.94; 95% CI 0.91–0.98), and ED return visits after initial ED discharge (OR: 0.91; 95% CI 0.90–0.93).

In a large study of infants at pediatric centers, bronchodilator use in the ED for bronchiolitis declined significantly from 2010 to 2018. Despite this decline, there was a statistically significant but small and clinically unremarkable decrease in hospital admissions. However, ICU admissions and invasive and noninvasive ventilation have risen during this time period. In adjusted analyses, hospital-level early bronchodilator use is not associated with reduction in hospital admission, ICU admission, return visits to the ED after initial ED discharge, invasive ventilation, or noninvasive ventilation.

Between 2010 and 2018, infants treated with bronchodilators for bronchiolitis decreased by two-thirds. These trends in bronchodilator use were likely driven by the growing literature suggesting that bronchodilators are not an effective therapy in bronchiolitis as well as the clinical practice guideline on the management of bronchiolitis from the AAP recommending against their use published in 2014.^5–8 

Despite this extensive reduction in bronchodilator use, admissions and ED return visits after initial ED discharge during the study period slightly declined. These contemporaneous trends do not show any adverse associations with the reductions in bronchodilator use for stable patients. However, critical care admissions, invasive ventilation, and noninvasive ventilation have risen. These trends are similar to published increases in noninvasive and invasive ventilation for bronchiolitis from 2000 to 2016.³  The rising use of noninvasive ventilation for bronchiolitis may have driven this rise in critical care admissions, which may represent a lower threshold to initiate noninvasive ventilation or increasing illness severity among infants with bronchiolitis over the study period. The increasing use of high-flow nasal cannula may also contribute to rising rates of critical care admissions because of some institutional policies requiring critical care admission for its administration.^15,16  This study provides further support that the use of bronchodilators does not improve measurable outcomes when used in the management of bronchiolitis in stable patients who are likely to be discharged from the ED or admitted to the inpatient ward. The simultaneous rising rates of invasive ventilation as bronchodilator use has decreased raises the question of whether these trends are associated.

This study suggests that early use of bronchodilators is not associated with reductions in hospital admissions in infants with bronchiolitis, which is consistent with previous literature.^5–8  The study adds to the existing literature as a large, hospital-level analysis aimed to characterize association with ED discharge. Anecdotally, some physicians may sense that there is a subgroup of infants with bronchiolitis who show response to bronchodilators. This large study was performed because it had adequate power to identify small changes, which may have been the first step to identifying that population. Yet, no difference in any outcomes, including admission rates, between hospitals with high and low early use of bronchodilators was identified. Therefore, this study provides further evidence that bronchodilators are not an effective therapy for bronchiolitis.

The strengths of this study include the large sample size and assessment of hospital-level practice patterns in early bronchodilator use as a predictor to mitigate the problem of confounding by indication, which occurs when using patient-level treatment as a predictor. The limitations of this study include the challenges associated with the administrative nature of these data sources, including insufficient patient-level data to quantify illness severity, and preclude conclusions of causality in associations. In addition, administrative data are at risk for recording errors. The PHIS database includes data from tertiary care children’s hospitals only, limiting generalizability to patients in other settings. Further investigation is needed to potentially characterize a subgroup of infants with bronchiolitis who may benefit from bronchodilators.

In a large, national study of infants admitted to children’s hospitals for bronchiolitis, early bronchodilator therapy for bronchiolitis declined markedly from 2010 to 2018, whereas admissions and ED return visits declined slightly. Hospital-level bronchodilator use was not associated with a meaningful difference in hospital admissions for bronchiolitis. This large, multicenter study presents further evidence that bronchodilators are not an effective therapy in bronchiolitis. Future study may define a subgroup of infants with bronchiolitis who respond to bronchodilators.

AAP

American Academy of Pediatrics

APR-DRG

All Patient Refined Diagnosis Related Group

CI

confidence interval

ED

emergency department

ICD-9-CM

International Classification of Diseases, Ninth Revision, Clinical Modification

ICD-10-CM

International Classification of Diseases, 10th Revision, Clinical Modification

OR

odds ratio

PHIS

Pediatric Health Information System