Journal of Perinatology (2015) 35, 61–66 © 2015 Nature America, Inc. All rights reserved 0743-8346/15 www.nature.com/jp ORIGINAL ARTICLE Inhaled bronchodilator use for infants with bronchopulmonary dysplasia JL Slaughter1,2, MR Stenger1, PB Reagan2,3,4 and SR Jadcherla1,2,5 OBJECTIVE: To identify factors associated with bronchodilator administration to infants with bronchopulmonary dysplasia (BPD) and evaluate inter-institutional prescribing patterns. STUDY DESIGN: A retrospective cohort study of o29-week-gestation infants with evolving BPD defined at age 28 days within the Pediatric Health Information System database. Controlling for observed confounding with random-effects logistic regression, we determined demographic and clinical variables associated with bronchodilator use and evaluated between-hospital variation. RESULT: During the study period, 33% (N = 469) of 1429 infants with BPD received bronchodilators. Lengthening mechanical ventilation duration increased the odds of receiving a bronchodilator (odds ratio 19.6 (11 to 34.8) at ⩾ 54 days). There was profound between-hospital variation in use, ranging from 0 to 81%. CONCLUSION: Bronchodilators are frequently administered to infants with BPD at US children’s hospitals with increasing use during the first hospital month. Increasing positive pressure exposure best predicts bronchodilator use. Frequency and treatment duration vary markedly by institution even after adjustment for confounding variables. Journal of Perinatology (2015) 35, 61–66; doi:10.1038/jp.2014.141; published online 7 August 2014 INTRODUCTION Association Pediatric Health Information System (PHIS) database (Shawnee Mission, KS, USA). We chose our gestational age (o29 weeks) and birth Neonates with severe bronchopulmonary dysplasia (BPD) are o 4 2 predisposed to airway smooth muscle hyperreactivity.1,2 Inhaled weight ( 1500 g) cutoffs to include 97% of infants with BPD. We excluded infants admitted after 7 days-of-age to minimize exposure to bronchodilators, including both beta-agonists and muscarinic unmeasured inhaled bronchodilator treatment at outside hospitals and antagonists, have been administered to infants with BPD for over only included those who lived ⩾ 28 days, the earliest age at which BPD 30 years to reduce airway reactivity and subsequently improve may be assigned.1 We chose to define BPD at its 28 day onset, prior to 3 respiratory outcomes. Short-term benefits, including decreased severity staging at 36 weeks corrected age, since an infant’s respiratory airway resistance and improved gas exchange, are noted condition at BPD onset was more likely to influence a clinician’s decision following administration. Bronchodilators have not been shown regarding inhaled bronchodilator usage throughout the remainder of their to prevent BPD, treat BPD or diminish the severity of BPD.4,5 hospitalization than the 36 week outcome measurement. For reference, Although inhaled bronchodilator use is presumed widespread we also determined the frequency of mild, moderate and severe BPD at 6,7 36 weeks according to the National Institutes of Health (NIH) Consensus in preterm infants with BPD, factors associated with broncho- 1 9 dilator administration to these patients have not, to our know- Definition, as modified by Ehrenkranz et al. Surviving infants with ledge, been fully reported. Therefore, the current study was evolving BPD at age 28 days were assigned mild BPD if they were off undertaken to: (1) determine demographic and clinical variables oxygen at 36 weeks or discharged alive prior to 36 weeks, moderate BPD if on oxygen only at 36 weeks and severe BPD if they required CPAP or associated with bronchodilator administration and (2) to identify mechanical ventilation at 36 weeks gestation. variability between hospitals in frequency and duration of inhaled bronchodilator usage for infants with BPD. Data source The PHIS database contains administrative, billing and record-review data METHODS including patient demographics, diagnoses, procedures and medications We conducted a retrospective cohort study to evaluate inhaled labeled by route of administration from members of the US Children’s bronchodilator use for infants with BPD. Infants were considered to have Hospitals, which account for 85% of all national freestanding children’s evolving BPD if they survived until at least 28 days-of-age and received hospitals (Children’s Hospital Association, Shawnee Mission, KS, USA). respiratory support for the first 28 consecutive days of life via mechanical The study sample for patient-level analyses consisted of 1429 admis- ventilation, continuous-positive airway pressure (CPAP) and/or supple- sions from 35 hospitals with cases of evolving BPD at 28 days, as defined mental oxygen.8 The cohort, as described previously by Slaughter et al, 8 above. To prevent bias from the overweighting of institutions with smaller included infants with evolving BPD born prior to 29 weeks of gestation BPD sample sizes, between-hospital comparisons based on the mean with a birth weight o1500 g and admitted to neonatal intensive care units proportion of bronchodilator usage at each hospital were confined to the (NICUs) in children’s hospitals at o8 days-of-age with discharge dates 15 hospitals with at least 25 BPD cases representing 86% (N = 1226) of the from January 2007 to June 2011, as recorded in the Children’s Hospital study sample. 1The Department of Pediatrics, The Ohio State University College of Medicine and Nationwide Children’s Hospital, Columbus, OH, USA; 2The Center for Perinatal Research, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA; 3The Department of Economics, The Ohio State University, Columbus, OH, USA; 4Center for Human Resource Research, The Ohio State University, Columbus, OH, USA and 5The Neonatal and Infant Feeding Disorders Research Program, Nationwide Children’s Hospital, Columbus, OH, USA. Correspondence: Dr JL Slaughter, Center for Perinatal Research, The Research institute at Nationwide Children's Hospital, The Research Building 3, 700 Children’s Drive, Columbus, OH 43205, USA. E-mail: [email protected] Received 13 January 2014; revised 3 June 2014; accepted 16 June 2014; published online 7 August 2014 Bronchodilator therapy for bronchopulmonary dysplasia JL Slaughter et al 62 Study variables RESULTS Daily drug-specific inhaled bronchodilator administration, mechanical A total of 1429 infants met the criteria for BPD at 28 days, of which ventilation, CPAP, oxygen use, as well as length of stay and demographic 469 (33%) were treated with at least one inhaled bronchodilator variables were determined from each hospital’s daily charge records as dose. Among those treated with nebulized bronchodilators in the ’ included in PHIS. Each hospital s daily charge codes are translated into a first 100 days post admission, the percentage treated per hospital common classification system, the Clinical Transaction Classification codes, day is demonstrated in Figure 1. Usage steadily increased during to ensure comparability of charge-level data between institutions. Clinical fi Transaction Classification codes evaluated included: inhaled albuterol the rst month of hospitalization until day 37 when 9.7% received (181211.42), inhaled levalbuterol (181231.42), inhaled albuterol/ipratro- nebulized albuterol treatment. The proportion of bronchodilator- pium combination (181315.42), inhaled ipratropium bromide (181311.42), treated infants increased further during the third month of hospi- inhaled pirbuterol (181251.42), inhaled formoterol (181221.42) inhaled talization, ultimately peaking at 10.3% on day 99. In unadjusted salmeterol (181241.42), mechanical ventilation (521166), CPAP (521162), analysis, decreasing birth weight, decreasing gestational age and and oxygen delivery by cannula, tent or mask (521171). We evaluated the male gender, increasing exposure to CPAP or mechanical ventila- use of all inhaled bronchodilators included in the PHIS database within our tion, IVH and NEC were all associated with significantly increased o cohort population and excluded those with 1% frequency of use odds of bronchodilator treatment. When all variables were (pirbuterol, formoterol and salmeterol) from further analysis. We queried included in a multivariable logistic regression model with a the specific dosage form for each drug administration to determine random intercept to adjust for confounding and within-hospital whether delivery was by metered dose inhaler (MDI) or nebulizer. International Statistical Classification of Diseases, Ninth Revision (ICD-9) clustering (Table 1), the odds of an infant with BPD ever receiving Codes were used to determine the diagnoses of patent ductus arteriosus inhaled bronchodilators were significantly associated with birth (PDA; 747.0), intraventricular hemorrhage (IVH; 772.1) and necrotizing enterocolitis (NEC; 777.5). Table 1. Multivariable adjusted odds of receiving bronchodilators Statistical analysis All analyses were conducted using Stata 12.1 (StataCorp, College Station, Variable Ever received bronchodilators TX, USA). Unadjusted odds ratios (ORs) for bivariate associations between (n = 469, 33%) bronchodilator use and neonatal demographic/clinical risk factors were determined with simple logistic regression for binary outcome variables n (%) Adjusted odds ratio, and simple ordinary least squares regression for continuous outcomes. 95% CI Multivariable mixed logistic regression modeling with a random intercept for hospitals was used to adjust ORs for