Objectives: The goal of this study was to determine physician management choices for hospitalized premature infants with bronchiolitis compared with term infants and to evaluate predictors of steroid use in premature infants.
Methods: A chart review was conducted of premature and nonpremature infants admitted to 2 children’s hospitals with bronchiolitis. Reviewers selected charts based on International Classification of Diseases, Ninth Revision diagnosis codes and collected demographic and historical information, as well as evaluation, treatment, treatment effectiveness, length of stay, hospital readmission rates, and adverse outcomes. Reviewers compared documented rates of utilization and effectiveness of inhaled racemic epinephrine and albuterol between patients with and without a history of prematurity. Patients with a history of prematurity underwent subgroup analysis of factors relating to steroid use.
Results: A total of 1223 patients met the study criteria for inclusion. Premature infants represented 19% of all children hospitalized with bronchiolitis. These infants had a longer length of stay (3.8 vs 2.6 days; P < .001) and a more severe hospital course. Rates of inhaled therapy and steroid utilization did not differ between premature and term infants. There was no difference in rates of documented positive response to albuterol, but premature infants were more likely to have a positive response to epinephrine. Steroid use in premature infants was associated with older age, history of wheeze, and albuterol use; documentation of albuterol efficacy did not correlate with steroid use, however.
Conclusions: Management decisions among term and premature infants with bronchiolitis were similar. Premature infants who received albuterol were more likely to receive steroids; however, the decision regarding steroid use was not associated with documentation of efficacy of albuterol.
- care standardization
- diagnostic decision-making
- infectious diseases
- outcomes measurement
Bronchiolitis is a leading cause of hospitalization of infants, resulting in more than $500 million in health care expenditures annually in the United States.1 It has been estimated that >20% of infants aged <1 year will have bronchiolitis-associated wheezing.2 In the United States, >12% of infants are born before 37 weeks’ gestational age, and this rate is higher now than at any known historical level.3 Prematurity and chronic lung disease of prematurity are known risk factors for hospitalization in bronchiolitis, and chronic lung disease is disproportionately present among infants hospitalized with bronchiolitis.4 Up to 14% of all premature infants will be hospitalized with bronchiolitis early in life, and they will typically have a more severe course and a longer length of stay (LOS) than full term infants.5–7 More than one-half of premature infants <29 weeks’ gestational age may be admitted during infancy for respiratory distress,8 and up to 1 in 4 patients <28 weeks’ gestational age will exhibit moderate to severe respiratory dysfunction even at 2 years of age.9 Furthermore, diminished lung function in premature infants has been associated with increased likelihood of severe illness.10
Despite the known increase in hospitalization rates for premature infants with bronchiolitis, little is understood about how or whether their management should differ from that of nonpremature infants. Understanding management differences in premature infants with bronchiolitis is critical because of increasing rates of prematurity. Premature infants with chronic lung disease have substantial differences in anatomic structure and functional capacity compared with the lungs of term infants.11 These differences suggest that efficacy of typical therapeutic interventions for bronchiolitis may differ for premature infants; however, this concept has received little attention. In particular, because of their predilection for childhood asthma, there is reason to believe that premature infants may respond to therapy differently than term infants.12,13
The 2006 American Academy of Pediatrics’ guideline on management of bronchiolitis specifically excluded infants with chronic lung disease from many of the recommendations, including the use of bronchodilators, racemic epinephrine, and steroids.14 None of the studies in the 2010 Cochrane review assessing the effect of albuterol specifically evaluated infants with a history of prematurity, although 2 small studies included infants as young as 34 weeks of gestational age.15–17 Infants with chronic lung disease were likewise excluded from consideration in the Cochrane review and the 2 largest trials on inhaled racemic epinephrine in bronchiolitis.18–20 Furthermore, major studies on use of steroids in infants with bronchiolitis have excluded infants with known pulmonary disease.19,21,22
Given the paucity of evidence to guide management for this important subset of infants, the primary goal of the current study was to assess whether pediatricians manage preterm infants admitted with bronchiolitis differently. We hypothesized that physicians would tailor bronchiolitis therapy in preterm infants toward asthma management, favoring bronchodilators and systemic corticosteroids as opposed to the supportive care recommended in the American Academy of Pediatrics’ guideline. Furthermore, we chose to examine whether differences in therapy and outcome existed between premature infants who did and did not receive oral glucocorticoids.
This was a retrospective cohort study of physician management choices in preterm versus term infants hospitalized for bronchiolitis at 2 geographically diverse, freestanding children’s hospitals. Hasbro Children’s Hospital is the only children’s hospital in Rhode Island and admits ∼450 patients for bronchiolitis annually. University of Missouri Children’s Hospital admits ∼130 patients for bronchiolitis annually and is the primary pediatric inpatient facility in central Missouri. Both sites have full-time pediatric hospitalist services as well as specialist and community pediatricians that admit children for general inpatient pediatric illnesses. This study was approved by the institutional review boards at both study sites.
We reviewed the charts of all infants aged <24 months admitted to both study sites with a diagnosis of bronchiolitis from 2004 to 2008, by using an interrupted time series design. We used an existing database initially created to evaluate the impact of the American Academy of Pediatrics’ bronchiolitis guideline (unpublished data). There were no official systemic changes in practice (such as local pathways or guidelines) instituted at either institution over the time period of this study. Preguideline charts were from calendar years 2005 for site 1 and from 2004 to 2005 for site 2, and postguideline cases were from calendar years 2008 for site 1 and 2007 to 2008 for site 2. All charts with International Classification of Diseases, Ninth Edition codes of 466.19 (non–respiratory syncytial virus [RSV] bronchiolitis), 466.11 (RSV bronchiolitis), 786.03 (apnea), 465.9 (acute upper respiratory infection), 493.9 (asthma, unspecified), and V73.99 (unspecified viral illness) were screened for inclusion by reviewers. Charts were excluded if a primary or secondary discharge diagnosis of bronchiolitis (codes 466.11 or 466.19) was not present or if symptoms and clinical findings resulting in admission were not consistent with bronchiolitis upon detailed review of the chart. We excluded infants who were aged >24 months, were hospitalized for >21 days, and for whom we had an unknown gestational age.
Data were extracted from the charts by manual review by Drs McCulloh, Smitherman, and Koehn and their research teams. All reviewers were unblinded to the nature of the study and were supervised directly by the primary researcher at each study site. A random sampling of charts was reviewed by the supervisor at each site (Drs McCulloh and Koehn) for verification of accuracy of data. We collected patient demographic characteristics as well as pertinent historical data, including secondhand smoke exposure, day care exposure, and history of wheeze. Prematurity was defined as a gestational age <37 weeks. Data collected in relation to clinical management during the hospitalization included type of attending physician, types and frequencies of all inhaled therapies, use of systemic steroids, use of intravenous fluids, antibiotic administration, oxygen administration and duration of oxygen requirement, and radiologic procedures and laboratory tests performed. LOS, ICU admission, and rehospitalization within 4 weeks to the same facility were also noted. Other specific clinical outcomes recorded were clinical responsiveness to inhaled bronchodilators (albuterol and epinephrine) and presence of serious bacterial infection (including bacteremia, urinary tract infection, meningitis, and pneumonia). Documentation of response to inhaled therapies was accepted both through a scoring system (any decrease in score) and through written notes from any provider (physician, nurse, or respiratory therapist).
Continuous variables (LOS and age) were analyzed by using the Wilcoxon rank-sum test, and categorical variables were assessed by using χ2 analysis. Risk factors for responsiveness to bronchodilator therapy were assessed by using multiple logistic regression, with tests for interaction between variables found to be independently associated; factors contributing to LOS were assessed by using multiple regression. Risk factors were considered significant if a 2-sided P value was <.05. Because this was a retrospective cohort study, a power calculation of the primary outcome was not performed, and all eligible and available charts were reviewed. Statistical analysis was performed by using Stata for Windows version 11.2 (Stata Corp, College Station, TX).
There were 1231 patients who met selection criteria; 8 were excluded (3 for hospitalization >21 days and 5 for unknown gestational age), which resulted in a study group of 1223 patients (994 term infants and 229 premature infants) hospitalized for bronchiolitis. No patient in our cohort died, and there were no differences in the rates of prematurity according to hospital site. Table 1 presents our primary data extraction, including demographic characteristics and clinical outcomes according to premature and term infants in our cohort. Premature infants, on average, were older than nonpremature infants (6.6 vs 5.4 months; P = .0001). Premature infants were slightly less likely to attend day care (15.3% vs 23.9%; P = .019), but there were no differences between the 2 groups regarding a history of wheeze or secondhand smoke exposure. Premature infants were less likely to be febrile, had a longer hospital LOS, and were more likely to be admitted to the ICU.
Physician management decisions among premature infants are summarized in Table 2. Despite an increase in use of radiography, there was no difference in rate of diagnosis of pneumonia among premature infants. In the entire study cohort, there were also no cases of true bacteremia or meningitis, and there were only 4 urinary tract infections, all in nonpremature infants (P = .3). Premature infants were not significantly more likely to be tested for RSV or influenza. However, premature infants in this cohort were less likely to be RSV positive (49.8% vs 67.1%; P < .0001). There were no differences noted in rates of influenza.
Premature infants were not more likely to receive inhaled therapies. Approximately 75% of all patients received albuterol during hospitalization and 15% received epinephrine. Premature infants were significantly more likely to have a documented positive response to epinephrine than nonpremature infants (54.3% vs 28.1%; P = .003), but there was no difference noted in rates of positive response with albuterol. A response to inhaled epinephrine, either positive or negative, was documented in all charts when the drug was used, although this documentation was not true for albuterol. In multiple logistic regression analysis, prematurity was found to be independently associated with documented epinephrine response, with an odds ratio of 1.9 (P = .041). In testing for interaction between the independently associated variables, prematurity remained associated with documentation of epinephrine responsiveness independent of steroid administration and albuterol responsiveness. Both oxygen and epinephrine were associated with increased LOS; however, among patients who did not receive oxygen, patients who did and did not receive epinephrine had the same LOS (1.8 vs 1.9 days; P = .33).
Premature infants were not more likely to receive systemic corticosteriods. However, there were some differences between premature infants with bronchiolitis who did and did not receive steroids (Table 3). Premature infants receiving steroids were significantly older (10.8 vs 4.7 months; P < .0001) and were much more likely to have a history of wheeze. They were nearly universally receiving concomitant albuterol therapy (98.6% vs 66.5%; P < .0001). A nonresponse to albuterol was not reliably documented because albuterol was often simply discontinued without documentation of a reason. No difference in documented positive response to albuterol among premature infants receiving steroids was noted (52.9% vs 37.1%; P = .058). For premature infants with bronchiolitis receiving steroids, there was no significant difference in LOS noted (3.5 vs 3.9 days; P = .84). When only considering premature infants who were documented responders to albuterol, there was still no detectable association between steroid use and LOS. Rehospitalization rates were not associated with steroid administration. Forty-seven premature patients continued steroids after initial dosing. A subset analysis of these patients still showed no difference in LOS.
In a logistic regression analysis of possible factors associated with use of steroids in premature infants, only age and history of wheeze demonstrated a significant association (Table 4). It should be clearly stated that while albuterol use was strongly and independently associated with steroid use (and as such was dropped from the model for collinearity), documented efficacy of albuterol did not correlate with steroid use in premature infants.
Premature infants hospitalized at 2 separate academic centers comprised 19% of all patients diagnosed with bronchiolitis, a rate comparable to the national average of 12.7% of all infants.3 Infants in our study with a history of prematurity were older at the time of admission for bronchiolitis. In addition, these infants, when compared with their nonpremature counterparts, had some evidence of higher severity of illness, including longer LOS and more frequent ICU stays, although they were less likely to be febrile. These differences fit with our understanding of the increased risk for severe illness in premature infants. An older premature infant with mild viral infection may still have a more severe course and with attenuated fever as a result of a diminished immune response and airway remodeling.11,23,24
Despite the expected increased illness severity among premature infants in our cohort, the management choices by physicians were remarkably similar in the 2 groups. Premature infants were more likely to have arterial blood gas and chest radiography, which significantly correlated with increased ICU admission (data not shown). There were no other differences in testing between premature and nonpremature infants. There were no differences in rates of utilization of albuterol, steroids, or racemic epinephrine among premature infants. We expected premature infants to receive therapies typically considered in children with chronic lung disease or asthma, but we found that such therapies were used at equivalent rates in our cohort. The notable exception was that premature infants were more likely to receive oxygen; however, oxygen use was also associated with admission to the ICU. Because we evaluated oxygen use, and not documented hypoxia, a potential limitation of our study is that we employed oxygen use as a proxy for hypoxia in this cohort. We cannot distinguish whether premature infants were simply given oxygen without demonstrated hypoxia or whether premature infants were more likely to be hypoxic. Individual management preferences for different levels of hypoxia have been noted in the literature.25
An unexpected finding was that premature infants had twice the rate of documented positive clinical response to inhaled racemic epinephrine but no difference in rates of documented positive response to albuterol. This result may be due to the perceived need to pay closer attention to patients receiving epinephrine, which is often used on an as-needed basis, as opposed to albuterol, which is often scheduled. Our regression analysis demonstrated that prematurity, as opposed to other indicators of illness severity, was an independent predictor of documented racemic epinephrine responsiveness in our patient population (data not shown). Our study is a retrospective investigation of physician behavior, and we cannot comment on the therapeutic benefit of racemic epinephrine specifically in premature infants. To the best of our knowledge, there are no studies which indicate that there should be differences in the medical management of premature and nonpremature infants. However, our data suggest that there may be a preferential benefit for this therapy in premature infants. Further prospective study is needed to adequately assess this question.
It is important to note that although albuterol use was associated with steroid administration among premature infants in our cohort, the effectiveness documented in the patients’ charts did not correlate with this association. This finding implies that a clinical impression of reactive airways disease or asthma without assessing albuterol effectiveness may drive steroid use more than longitudinal clinical assessment. It is possible that in a prospective blinded study, differences in responsiveness to inhaled albuterol would be found among premature and nonpremature infants, but we did not detect that phenomenon. The use of steroids in patients with bronchiolitis is controversial, and in our study population it was not uncommon. Several studies have demonstrated a lack of benefit of steroids in bronchiolitis, and 1 study was novel in that the authors identified a subcohort of patients at risk for eventually developing asthma by using a modified Castro-Rodriguez score.22
Although we cannot draw any conclusions regarding causality in a retrospective study, it was notable that rates of steroid and inhaled albuterol use were not different between term and premature infants. Furthermore, there was no difference in LOS among premature infants who did and did not receive steroids, even when analyzing those who were documented as responding to albuterol. Premature infants are more likely to develop asthma later on in childhood.12,13 However, our study did not detect a difference in LOS in premature infants who did and did not receive steroids, even among the subgroup of infants documented as responding to albuterol. Clearly, a prospective and randomized study of premature infants might allow us to understand further if there should be any baseline differences in our approach to this population. To date, there are no available prospective data demonstrating that premature infants and term infants with viral wheezing should respond differently to albuterol or steroids.
There are several potential concerns with our study. Given its retrospective nature, our study was incapable of fully evaluating potential sources of bias. The utilization of a rigorous scoring system was intermittent and varied in use based on both geography and date. Even though there are several published scoring systems for young children with respiratory distress, such as the preschool respiratory assessment measure or the respiratory distress assessment index,26 the determination of these scores in a retrospective nonblinded study is clearly prone to bias. This made the determination of effectiveness of inhaled medications somewhat challenging. However, by broadly defining as much as possible “improvement” to include both scores and written notes, we sought to replicate the real-life determination of responsiveness to inhaled medications for the practicing pediatrician. Clear documentation of the practitioner’s opinion about the effectiveness of inhaled epinephrine was present in all the charts whereas this was not the case for albuterol.
Physicians managed premature infants hospitalized with bronchiolitis similarly to those who were term. Testing differences mostly focused around areas of concern for point of care, rather than diagnosis. Steroid use was common among both premature and nonpremature infants; among premature infants, steroid use was associated with albuterol use but not documentation of albuterol efficacy.
The authors thank Solomon Adelsky, Morgan Congdon, Jamie Librizzi, MD, and Jason Machan, PhD, for their help with data collection and analysis.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: All research was funded by independent departmental grants.
- length of stay
- respiratory syncytial virus
- Pelletier AJ,
- Mansbach JM,
- Camargo CA Jr.
- Greenough A,
- Cox S,
- Alexander J,
- et al
- Wang EE,
- Law BJ,
- Stephens D
- Kamper J,
- Feilberg Jørgensen N,
- Jonsbo F,
- Pedersen-Bjergaard L,
- Pryds O
- Drysdale SB,
- Wilson T,
- Alcazar M,
- et al
- Vogt H,
- Lindström K,
- Bråbäck L,
- Hjern A
- 14.↵American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics. 2006;118(4):1774–1793.
- Gadomski AM,
- Brower M
- Hartling L,
- Bialy LM,
- Vandermeer B,
- et al
- Corneli HM,
- Zorc JJ,
- Mahajan P,
- et al
- Mallory MD,
- Shay DK,
- Garrett J,
- Bordley WC
- Lowell DI,
- Lister G,
- Von Koss H,
- McCarthy P
- Copyright © 2013 by the American Academy of Pediatrics