442 - Tolerance to furosemide diuresis in infants with bronchopulmonary dysplasia

Poster Number: 442
Publication Number: 442.430

Nicolas A. Bamat, Childrens Hospital of Philadelphia, Philadelphia, PA, United States; Matthew Huber, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Justine Shults, Perelman School of Medicine at the University of Pennsylvania, Ambler, PA, United States; Athena Zuppa, Childrens Hospital of Philadelphia, Medford, NJ, United States; Eric Eichenwald, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Matthew Laughon, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States; Sara B. DeMauro, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States; Kristin J. Mckenna, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Scott A. Lorch, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States; Benjamin L. Laskin, Childrens Hospital of Philadelphia, Philadelphia, PA, United States

Background: Infants with severe bronchopulmonary dyplasia (sBPD) exposed to repeated doses of furosemide have a median exposure duration of 7 days (d). Rapid tolerance to furosemide diuresis has been shown within 72 hours (h) in other populations, questioning the utility of prolonged exposures to this common, potentially harmful medication.

Objective: To test for furosemide diuretic tolerance over time in infants with sBPD and identify characteristics associated with tolerance, defined as a statistically significant increase in fluid balance (FB, intake minus output, ml/kg/24h) between initial and subsequent 24 h time intervals of sustained exposure.

Design/Methods: We performed a cohort study in infants with sBPD exposed to furosemide per clinical care. Inclusion required at least 72 h of furosemide exposure without change in route, dose & frequency, following no use in the preceding 7 d. Exposures were excluded if blood products or fluid boluses were given. We compared differences in FB at baseline and in each of three 24 h intervals after exposure with longitudinal modeling. Associations between cohort characteristics and the change in FB between the first and final post-exposure interval were evaluated with multivariable linear regression. Post-hoc, we modeled the associations between characteristics and the change in FB between baseline and the first interval (initial diuretic response) to assess if characteristics associated with greater tolerance also had a greater initial response.

Results: Cohort characteristics (n = 45) are shown in Table 1. A significant decrease in FB in the first 24 h interval was followed by a progressive increase in subsequent intervals (Fig. 1). Glucocorticoid co-administration, furosemide route of administration, dose and frequency were associated with tolerance in bivariable analyses and included in multivariable models. No characteristics held a statistically significant association with the extent of tolerance in adjusted models, but effect estimates suggested clinically relevant differences (Table 2). With the exception of glucocorticoid co-administration, characteristics associated with a trend towards greater tolerance were also associated with a trend towards greater initial response.Conclusion(s): Tolerance to furosemide diuresis develops rapidly in sBPD, discouraging chronic use. Characteristics associated with greater tolerance may be those that cause a greater initial response. Prospective trials comparing furosemide treatment duration are needed. Longer treatment may expose infants to adverse effects despite diminishing diuresis-mediated benefits.
Table 1. Cohort characteristicsa Includes both intravenous and enteral exposures, reported as intravenous equivalents using a 1:2 intravenous to enteral ratio to convert for presumed bioavailability
b n = 43, represents greatest degree of missingness
c Estimated with Schwartz formula modified for preterm infants = (length in centimeters * k) / serum creatinine; k = 0.34
Figure 1. Tolerance to furosemide diuresis during repeated-dose exposures in infants with bronchopulmonary dysplasia.For each time interval, box-and-whisker plots identify the median value (horizontal line within box), 25th and 75th percentile (lower and upper edges of box, respectively), lower and upper adjacent values (whiskers extending from box) and outlying values (individual dots).