Association between route of furosemide administration and diuretic response in very preterm infants with bronchopulmonary dysplasia

Association between route of furosemide administration and diuretic response in very preterm infants with bronchopulmonary dysplasia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Association between route of furosemide administration and diuretic response in very preterm infants with bronchopulmonary dysplasia Nicolas Bamat, Matthew Huber, Heidi Morris, Timothy Nelin, Kevin Downes, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8197255/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Apr, 2026 Read the published version in Journal of Perinatology → Version 1 posted 9 You are reading this latest preprint version Abstract Objective: Furosemide is commonly prescribed in hospitalized infants with grade 2-3 bronchopulmonary dysplasia (BPD). Intravenous (IV), gastric, and duodenal administrations are common, with a 1:2 IV-to-enteral conversion often used despite uncertain bioavailability. Our objective was to compare diuretic responses between routes in infants with BPD. Study Design: Single-center observational cohort of very preterm infants with grade 2-3 BPD prescribed furosemide. The association between route (exposure) and diuretic response (change in net fluid balance after administration, outcome) was evaluated using multivariable regression adjusting for dosing and infant characteristics. Results : Among 153 infants (median postmenstrual age of 43.3 weeks at exposure), furosemide reduced fluid balance by -25.6 (29.8) ml/kg/d. Adjusted mean changes were similar across routes: IV, -25.3 (-35.8, -14.7), gastric, -25.8 (-32.2, -19.4), and duodenal, -25.8 (-34.2, -17.4). Conclusions : Our data suggest a 1:2 IV-to-enteralconversion leads to comparable diuretic effects in infants with established BPD, supporting this common clinical practice. Health sciences/Medical research/Outcomes research Biological sciences/Physiology/Kidney Health sciences/Diseases/Respiratory tract diseases Health sciences/Health care/Therapeutics/Drug therapy/Drug delivery Health sciences/Health care/Paediatrics Figures Figure 1 Introduction Furosemide is the most frequently prescribed pharmacotherapy in infants with established bronchopulmonary dysplasia (BPD) admitted to neonatal intensive care units (NICU) in United States children’s hospitals. 1 In a report of medication prescriptions among 3252 infants with BPD between 36 weeks postmenstrual age (PMA) and discharge, furosemide was prescribed at least once in 74% of infants and present in one-third of all patient-days across the study cohort. 1 Despite its common use, clinical research evidence supporting furosemide use in BPD is lacking, and key knowledge gaps in its neonatal pharmacology remain. For example, furosemide’s enteral bioavailability – the proportion of drug reaching the circulation in active form - remains uncertain, with limited data from 4 preterm infants in the 1980s reporting a wide range (20–106%). 2,3 Adult studies report typical bioavailability values between 60–70% and similarly note high variability. 4 , 5 A recently published neonatal trial applied a 1:2 intravenous-to-enteral conversion consistent with 50% bioavailability, yet a Food and Drug Administration label update based on unpublished pharmacokinetic (PK) data from the same trial describes a bioavailability estimate of 79%. 6,7 Data from the Pediatrix NICU network identify 1 mg/kg is the predominant intravenous (IV) dose prescribed in very preterm infants and while 2 mg/kg is the most common enteral dose, 1 mg/kg is also used often, highlighting uncertainty and practice variation. 8 In infants with BPD, uncertainty surrounding enteral furosemide dosing is further complicated by the common use of duodenal feedings as a lung protection strategy. 9 , 10 At our center, single-lumen oro- or nasoduodenal tubes are often used concurrently for feedings and medications, despite the possibility for differential absorption when drugs are administered to the duodenum. In a small cross-over PK study in adult volunteers, duodenal administration increased furosemide bioavailability by 30%, yet gastric furosemide led to a 12% greater diuretic effect over 8 hours. 11 One explanation for this discordance is that gastric administration leads to more gradual absorption, maintaining furosemide concentrations within an optimal therapeutic window for a longer duration, and enhancing diuretic “efficiency”, as described by prior investigators. 11 , 12 The objective of the current study was to compare the diuretic response to furosemide delivered by differing routes of administration in very preterm infants with BPD. Given the possibility that enteral bioavailability may often exceed 50% and that gastric dosing may enhance diuretic efficiency, we hypothesized that gastric administration would produce a greater diuretic response than either IV or duodenal administrations. Methods Study Design, Data Source and Population We performed a single-center observational study using the clinical data warehouse at Children’s Hospital of Philadelphia (CHOP). This resource contains data extracted from the electronic health record (EHR), inclusive of time-stamped medication administration records and detailed, longitudinal flowsheet data input by bedside providers. Identification of the study population is shown in Fig. 1. We included very preterm infants (< 32 weeks birth gestational age) admitted to the CHOP NICU between 2010 and 2021 and classified with grade 2 or 3 BPD per the 2019 Neonatal Research Network/Jensen definition. 13 BPD grade was based on the highest respiratory support used at 36 weeks PMA or at admission (when occurring after 36 weeks PMA). Furosemide prescriptions qualifying for study occurred between 36- and 60-weeks PMA, reflecting the age range of infants with established BPD routinely managed in our NICU. To avoid the influence of homeostatic tolerance on diuretic response, we excluded prescriptions that lacked at least 7 preceding days without furosemide exposure. 14 , 15 Qualifying furosemide prescriptions were ordered as a one-time dose, or as repeated dosing with consistent route of administration and a milligram per kilogram (mg/kg) dose of 1 mg/kg IV or 1 or 2 mg/kg enteral every 12 or 24 hours. Single doses and repeated doses scheduled every 24-hours were grouped together as our primary outcome was based on diuretic response over the first 24 hours, a time-period over which these exposures are analogous. We excluded furosemide prescriptions with concomitant red blood cell or fluid bolus administrations to decrease excess variance in fluid balance measures. Lastly, we excluded infants with congenital anomalies that we deemed could plausibly impact diuretic responsiveness, identifying these by reviewing International Classification of Diseases diagnostic codes. The data used in this study were approved for collection under the CHOP Neonatal and Infant Chronic Lung Disease Program clinical data registry by the CHOP Institutional Review Board, #19-016420. Study Variables The objective of our study was to determine the association between route of furosemide administration and diuretic response. The primary predictor variable was route of administration ascertained from the medication administration record and modeled as a nominal variable with 3 categories: IV, gastric, and duodenal. The primary outcome variable was diuretic response, defined as the within-subject change in total net fluid balance in the 24-hours before and after initiation of furosemide. Fluid balance was calculated as the net of all fluids administered minus all recorded outputs for each time interval. Input was inclusive of medication volumes, intravenous fluids, parenteral nutrition, and enteral feeding volumes, while output was inclusive of urine, stool, emesis and drains, when present. To adjust for inexact total time between repeated-dosage prescriptions, fluid balance was standardized as milliliters per kilogram per (24 hours) day (ml/kg/d), accounting for incomplete hours and days in the denominator. To adjust for potential confounders between route of administration and diuretic response, we considered furosemide dosage and infant characteristics plausibly associated with diuretic response as covariates. Drug covariates were IV-equivalent dose and dose frequency, considered as separate variables. We reported all prescriptions as IV-equivalent doses, assuming a bioavailability of 50% for enteral formulations, such that a 2 mg/kg enteral dose was reported as 1 mg/kg IV-equivalent. These dosing characteristics reflect our typical institutional practice patterns. Under this approach, a similar diuretic response across route of administration would support our typical 1:2 IV to enteral conversion assumptions. Infant covariates were: birth gestational age group, in completed weeks; sex; BPD grade; PMA at furosemide exposure; plasma albumin, blood urea nitrogen (BUN), sodium and chloride levels, abstracted from the EHR at the time point nearest to furosemide exposure – prior to administration when available, or following exposure if not; estimated glomerular filtration rate using the Schwartz formula modified for preterm infants 16 ; and co-administration of thiazides diuretics, hydrocortisone, dexamethasone, or dopamine, all categorized as absent or present on the day of exposure. Statistical Analyses Cohort characteristics were summarized with descriptive statistics. The association between route of administration and diuretic response was modeled with linear regression, applying robust variance estimates. The unadjusted associations between route of administration and all candidate covariates were first examined in bivariable analyses. All characteristics associated with diuretic response at p < 0.10 were included with furosemide dose and frequency (selected a priori ) as covariates in the multivariable model. In a post-hoc sensitivity analyses, the model was modified to include total daily furosemide dose (considering both administration dose and dose frequency; e.g 1 mg/kg/dose every 12 hours results in 2 mg/kg/day) rather than administration dose. P -values < 0.05 were considered statistically significant. Analyses were performed using STATA 17 (College Park, TX). Results We identified 153 very preterm infants who met eligibility criteria (Figure 1). Characteristics of the full study cohort, and stratified by prescribed route of furosemide administration, are displayed in Table 1. Among eligible infants, 56% were born between 22 and 25 completed weeks GA and 67% had grade 3 BPD. The median (interquartile) PMA at furosemide exposure was 43.3 (39.6 - 47.9) weeks. Gastric was the most common route of furosemide administration (42%), followed by IV (32%), then duodenal (26%). The most common dose frequency was once or every 24 hours (69%). An IV-equivalent dose of 1 mg/kg was prescribed in 84% of infants, with the remaining 16% exposed to 0.5 mg/kg (equivalent to 1 mg/kg enteral furosemide). Among medication co-administrations, only thiazide diuretics were common (46%). The median laboratory values were largely within normal limits. All were obtained prior to furosemide exposure except 8 (6%) albumin values. The mean (standard deviation) net fluid balances in the 24 hours before and after furosemide administration were +51.5 (23.2) and +25.8 (27.6) ml/kg/d, with a mean (standard deviation) diuretic response (within-subject change) of -25.6 (29.8) ml/kg/d across the full cohort. Table 2 displays the unadjusted bivariable association between evaluated characteristics and diuretic response. Diuretic response was similar across all routes of administration. Only dose frequency (greater diuretic response with every 12 vs every 24-hour dosing) and BUN (lower diuretic response with greater values) were statistically significant. Birth gestational age also met criteria for inclusion in the multivariable analysis. Diuretic responses were similar across route of administration in adjusted multivariable modeling (Table 3), with estimated mean (95% confidence interval) values of -25.8 (-32.2, -19.4), -25.3 (-35.8, -14.7), and -25.8 (-34.2, -17.4) ml/kg for gastric, IV, and duodenal administrations, respectively. The effect estimates trended towards a greater diuretic response with more frequent and higher dosing but these associations lacked statistical significance. Greater BUN values were observed to have a statistically significant association with diuretic response, with higher values resulting in a smaller (less negative) diuretic response. The sensitivity analysis considering total daily furosemide dose rather than administration dose had consistent findings (Table 4). Discussion The objective of our study was to compare the diuretic response to furosemide delivered by differing routes of administration in very preterm infants with BPD. We hypothesized that a gastric furosemide administration route would be associated with a greater diuretic effect than either an IV or duodenal administration when standardized to a 1:2 IV-to-enteral dose conversion. This hypothesis was based on the rationale that the enteral bioavailability of furosemide may exceed 50% on average and on prior research suggesting that gastric furosemide administration may be most “efficient” by sustaining therapeutic concentrations over a longer period. 12 Our findings did not support our hypothesis. In the first 24 hours following administration, changes in net fluid balance were similar among the three routes. This pattern was consistent in both unadjusted bivariable analyses and adjusted models. Opportunities to compare our findings with prior relevant research are limited. We are unaware of other neonatal studies evaluating how route of furosemide administration impacts diuretic response. Consistent with our findings, a pharmacokinetic study of 7 adult patients with congestive heart failure reported comparable urine output over 24 hours with IV vs oral furosemide. 5 In turn, data from 4 healthy adult volunteers receiving gastric vs duodenal furosemide via endoscopy found 12% greater diuretic effect over 8 hours with gastric furosemide. 11 While inconsistent with our findings, the relevance of these data is limited by the small sample size and differences in study population. Our findings are relevant to the contemporary care of infants with BPD, in whom furosemide is the most frequently prescribed pharmacotherapy. 1 Our data suggest that a 1:2 IV-to-enteral dose conversion leads to a comparable diuretic effect in infants with established BPD, lending support to this common, though variable, clinical practice. 6 , 8 Furthermore, our findings provide reassurance that duodenal administration produces a comparable diuretic response in infants with BPD. Notably, no prior data exist on the effects of duodenal furosemide in preterm infants, despite its routine use in clinical practice. Our models identified a statistically significant association between greater BUN levels and a lower diuretic response. This association is biologically plausible, as elevated BUN may reflect renal dysfunction – particularly reduced renal perfusion (i.e. pre-renal azotemia) – and may trigger neurohormonal pathways that limit urine output. 17 Consistent with our finding, multiple clinical studies in adults with heart failure have reported an independent association between elevated BUN and a decreased diuretic response. 18 , 19 However, our observation was post hoc , and replication in dedicated studies is needed to establish whether BUN could serve as a useful predictor of diuretic responsiveness in preterm infants. Our study has several limitations. We used changes in net fluid balance as a surrogate measure of diuresis, relying on real-world clinical data. Although urine output and natriuresis are more direct measures of furosemide renal responsiveness, fluid balance is routinely assessed in clinical care and offers a pragmatic alternative, as intake strongly influences output and urine volumes cannot be reliably discriminated from stool in routine neonatal practice. Prior studies have similarly used net fluid balance as a marker of diuresis. 14 , 20 – 22 Our finding of a 50% reduction in net fluid balance after furosemide administration reflects expected patterns, and supports the construct validity of this measure, which has also been demonstrated in prior studies. 14 , 20 – 22 Our data are susceptible to information bias, such as erroneous route of administration assignment in the medication administration record, inaccurate measurements or calculations of fluid intake and output, or transcription errors into the electronic health record. Carefully conducted prospective studies may reduce these. Despite including 153 infants, our study lacked sufficient power to detect clinically meaningful associations. We expected both dose and dosing frequency would influence diuretic response and included them a priori in our models. Although effect estimates suggested a 52% greater response with every 12 vs 24-hour dosing and a 36% greater response with a 1 vs 0.5 mg/kg IV-equivalent dose, these sizeable differences did not reach statistical significance. Multicenter studies with larger sample sizes may allow greater statistical precision. Lastly, the generalizability of our findings is limited by our single-center design and by our focus on infants with established grade 2–3 BPD who received furosemide at a median PMA of 43 weeks. Prior studies suggests that furosemide pharmacokinetics, particularly renal clearance, change rapidly with maturation in preterm infants. 2 Thus, our results may not extend to younger preterm infants. In summary, our findings suggest that IV, gastric, and duodenal furosemide, when dosed using a 1:2 IV-to-enteral conversion, produce a similar initial diuretic response in preterm infants with established BPD, supporting the appropriateness of these dosing practices. Our findings do not necessarily imply a typical 50% bioavailability for gastric and duodenal furosemide, as bioavailability reflects drug exposure rather than clinical response. Characterization of the dose-exposure-response relationship requires further study, such as comparative bioavailability trials measuring circulating furosemide concentrations alongside diuretic effect. Finally, although furosemide is widely used in this population, its broader safety and effectiveness in improving meaningful outcomes in infants with BPD remain uncertain. Our findings will help inform the careful design of future phase III trials, which remain greatly needed. Abbreviations BPD, bronchopulmonary dysplasia NICU, neonatal intensive care unit PMA, postmenstrual age PK, pharmacokinetic IV, intravenous CHOP, Children’s Hospital of Philadelphia EHR, electronic health record mg/kg, milligram per kilogram ml/kg/d, milliliters per kilogram per day BUN, blood urea nitrogen Declarations Conflict of Interest Disclosures : This work was supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development grant K23HD10165 and the Perelman School of Medicine at the University of Pennsylvania Thomas B. McCabe and Jeannette E. Laws McCabe Fund to NAB. The funding sources had no role in the study design; the collection, analysis, and interpretation of the data; the writing of the report or the decision to submit for publication. NAB wrote the first draft of the manuscript. No compensation honorarium, grant, or other form of payment was given to produce the manuscript. KJD receives research support to his institution from Merck, Inc., Veloxis Pharmaceuticals, Inc., and Paratek Pharmaceutical unrelated to the current work. References Bamat NA, Kirpalani H, Feudtner C, Jensen EA, Laughon MM, Zhang H et al. Medication use in infants with severe bronchopulmonary dysplasia admitted to United States children’s hospitals. Journal of Perinatology 2019; 39: 1291–1299. Mirochnick MH, Miceli JJ, Kramer PA, Chapron DJ, Raye JR. Furosemide pharmacokinetics in very low birth weight infants. J Pediatr 1988; 112: 653–7. Peterson RG, Simmons MA, Rumack BH, Levine RL, Brooks JG. Pharmacology of furosemide in the premature newborn infant. J Pediatr 1980; 97: 139–43. Vargo DL, Kramer WG, Black PK, Smith WB, Serpas T, Brater DC. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide and furosemide in patients with congestive heart failure. Clin Pharmacol Ther 1995; 57: 601–609. Greither A, Goldman S, Edelen JS, Benet LZ, Cohn K. Pharmacokinetics of furosemide in patients with congestive heart failure. Pharmacology 1979; 19: 121–131. Greenberg RG, Lang J, Smith PB, Shekhawat P, Courtney SE, Hudak ML et al. Furosemide Safety in Preterm Infants at Risk for Bronchopulmonary Dysplasia: A Randomized Clinical Trial. J Pediatr 2025; 283: 114629. U.S. Food and Drug Administration. Furosemide injection. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/018267s029lbl.pdf. 2024. Bamat NA, Thompson EJ, Greenberg RG, Lorch SA, Zuppa AF, Eichenwald EC et al. Association between postmenstrual age and furosemide dosing practices in very preterm infants. Journal of Perinatology 2022; 42: 461–467. Levin JC, Kielt MJ, Hayden LP, Conroy S, Truog WE, Guaman MC et al. Transpyloric feeding is associated with adverse in-hospital outcomes in infants with severe bronchopulmonary dysplasia. Journal of Perinatology 2024; 44: 307–313. Jensen EA, Zhang H, Feng R, Dysart K, Nilan K, Munson DA et al. Individualising care in severe bronchopulmonary dysplasia: A series of N-of-1 trials comparing transpyloric and gastric feeding. Arch Dis Child Fetal Neonatal Ed 2020; e-pub ahead of print November 4 2019; doi:10.1136/archdischild-2019-317148. Lee WI, Yoon WH, Shin WG, Song IS, Lee MG. Pharmacokinetics and pharmacodynamics of furosemide after direct administration into the stomach or duodenum. Biopharm Drug Dispos 1996; 18: 753-67. Kaojarern S, Day B, Brater DC. The time course of delivery of furosemide into urine: an independent determinant of overall response. Kidney Int 1982; 22: 69–74. Jensen EA, Dysart K, Gantz MG, McDonald S, Bamat NA, Keszler M et al. The diagnosis of bronchopulmonary dysplasia in very preterm infants: an evidence-based approach. Am J Respir Crit Care Med 2019; 200: 751–759. Bamat NA, Huber M, Shults J, Li Y, Zong Z, Zuppa A et al. Diuretic Tolerance to Repeated-Dose Furosemide in Infants Born Very Preterm with Bronchopulmonary Dysplasia. Journal of Pediatrics 2024; 266: 113813. Segar JL, Robillard JE, Johnson KJ, Bell EF, Chemtob S. Addition of metolazone to overcome tolerance to furosemide in infants with bronchopulmonary dysplasia. J Pediatr 1992; 120: 966–73. Brion LP, Fleischman AR, McCarton C, Schwartz GJ. A simple estimate of glomerular filtration rate in low birth weight infants during the first year of life: Noninvasive assessment of body composition and growth. J Pediatr 1986; 109: 698–707. Kazory A. Emergence of blood urea nitrogen as a biomarker of neurohormonal activation in heart failure. American Journal of Cardiology. 2010; 106: 694-700. ter Maaten JM, Valente MAE, Metra M, Bruno N, O’Connor CM, Ponikowski P et al. A combined clinical and biomarker approach to predict diuretic response in acute heart failure. Clinical Research in Cardiology 2016; 105: 145–153. Valente MA, Voors AA, Damman K, Van Veldhuisen DJ, Massie BM, O’Connor CM et al. Diuretic response in acute heart failure: clinical characteristics and prognostic significance. Eur Heart J 2014; 35: 1284-93. Kim GJ, Capparelli E, Romanowski G, Proudfoot JA, Tremoulet AH. Development of Tolerance to Chronic Intermittent Furosemide Therapy in Pediatric Patients. J Pediatr Pharmacol Ther 2017; 22: 394–398. Price JF, Younan S, Cabrera AG, Denfield SW, Tunuguntla HARI, Choudhry S et al. Diuretic Responsiveness and Its Prognostic Significance in Children With Heart Failure. J Card Fail 2019; 25: 941-947. McCallister KM, Chhim RF, Briceno-Medina M, Shelton CM, Figueroa M, Rayburn M. Bumetanide continuous infusions in critically ill pediatric patients. Pediatric Critical Care Medicine 2015; 16: e19-22. Tables Tables 1 to 4 are available in the Supplementary Files section Additional Declarations There is NO conflict of interest to disclose. Supplementary Files Table1.docx Table2.docx Table3.docx Table4.docx Cite Share Download PDF Status: Published Journal Publication published 16 Apr, 2026 Read the published version in Journal of Perinatology → Version 1 posted Editorial decision: revise 26 Jan, 2026 Review # 2 received at journal 22 Jan, 2026 Reviewer # 2 agreed at journal 15 Jan, 2026 Review # 1 received at journal 23 Dec, 2025 Reviewer # 1 agreed at journal 03 Dec, 2025 Reviewers invited by journal 25 Nov, 2025 Submission checks completed at journal 25 Nov, 2025 Editor assigned by journal 24 Nov, 2025 First submitted to journal 24 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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10:39:12","extension":"html","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97656,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8197255/v1/5a8054eae26f638422d07185.html"},{"id":97151886,"identity":"ed2e934d-f326-427d-a6b9-dcd5e82659b6","added_by":"auto","created_at":"2025-12-01 10:39:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":540580,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the study population\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8197255/v1/96210e9b6d440a2d51fef350.png"},{"id":107130535,"identity":"82b42eec-f5cd-4056-add2-680d372f29da","added_by":"auto","created_at":"2026-04-17 07:05:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":564794,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8197255/v1/04fae0a4-888b-4ff8-aed6-1301d04a769c.pdf"},{"id":97151862,"identity":"90bf7f51-9a7d-49e4-933e-f46fb6475676","added_by":"auto","created_at":"2025-12-01 10:39:10","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":23926,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8197255/v1/7ac020f02d7080c0ba52bd71.docx"},{"id":97151869,"identity":"fd94d260-6f5c-43ac-b289-8eae6d71bf2d","added_by":"auto","created_at":"2025-12-01 10:39:10","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":21686,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8197255/v1/12e7221f1ba3a0c2f42f60f1.docx"},{"id":97151881,"identity":"8d25be4d-1d87-46e6-ae0d-58591161b299","added_by":"auto","created_at":"2025-12-01 10:39:11","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":18904,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-8197255/v1/9687ed72f993228ff6bb2ea7.docx"},{"id":97151879,"identity":"ea0a6959-2389-467d-bf66-a441d10c5979","added_by":"auto","created_at":"2025-12-01 10:39:11","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":19600,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-8197255/v1/6ba8c556f33af9b0c0170159.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Association between route of furosemide administration and diuretic response in very preterm infants with bronchopulmonary dysplasia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFurosemide is the most frequently prescribed pharmacotherapy in infants with established bronchopulmonary dysplasia (BPD) admitted to neonatal intensive care units (NICU) in United States children\u0026rsquo;s hospitals.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e In a report of medication prescriptions among 3252 infants with BPD between 36 weeks postmenstrual age (PMA) and discharge, furosemide was prescribed at least once in 74% of infants and present in one-third of all patient-days across the study cohort.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eDespite its common use, clinical research evidence supporting furosemide use in BPD is lacking, and key knowledge gaps in its neonatal pharmacology remain. For example, furosemide\u0026rsquo;s enteral bioavailability \u0026ndash; the proportion of drug reaching the circulation in active form - remains uncertain, with limited data from 4 preterm infants in the 1980s reporting a wide range (20\u0026ndash;106%).\u003csup\u003e2,3\u003c/sup\u003e Adult studies report typical bioavailability values between 60\u0026ndash;70% and similarly note high variability.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e A recently published neonatal trial applied a 1:2 intravenous-to-enteral conversion consistent with 50% bioavailability, yet a Food and Drug Administration label update based on unpublished pharmacokinetic (PK) data from the same trial describes a bioavailability estimate of 79%.\u003csup\u003e6,7\u003c/sup\u003e Data from the Pediatrix NICU network identify 1 mg/kg is the predominant intravenous (IV) dose prescribed in very preterm infants and while 2 mg/kg is the most common enteral dose, 1 mg/kg is also used often, highlighting uncertainty and practice variation.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eIn infants with BPD, uncertainty surrounding enteral furosemide dosing is further complicated by the common use of duodenal feedings as a lung protection strategy.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e At our center, single-lumen oro- or nasoduodenal tubes are often used concurrently for feedings and medications, despite the possibility for differential absorption when drugs are administered to the duodenum. In a small cross-over PK study in adult volunteers, duodenal administration increased furosemide bioavailability by 30%, yet gastric furosemide led to a 12% greater diuretic effect over 8 hours.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e One explanation for this discordance is that gastric administration leads to more gradual absorption, maintaining furosemide concentrations within an optimal therapeutic window for a longer duration, and enhancing diuretic \u0026ldquo;efficiency\u0026rdquo;, as described by prior investigators.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe objective of the current study was to compare the diuretic response to furosemide delivered by differing routes of administration in very preterm infants with BPD. Given the possibility that enteral bioavailability may often exceed 50% and that gastric dosing may enhance diuretic efficiency, we hypothesized that gastric administration would produce a greater diuretic response than either IV or duodenal administrations.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Design, Data Source and Population\u003c/h2\u003e\u003cp\u003eWe performed a single-center observational study using the clinical data warehouse at Children\u0026rsquo;s Hospital of Philadelphia (CHOP). This resource contains data extracted from the electronic health record (EHR), inclusive of time-stamped medication administration records and detailed, longitudinal flowsheet data input by bedside providers. Identification of the study population is shown in Fig.\u0026nbsp;1. We included very preterm infants (\u0026lt;\u0026thinsp;32 weeks birth gestational age) admitted to the CHOP NICU between 2010 and 2021 and classified with grade 2 or 3 BPD per the 2019 Neonatal Research Network/Jensen definition.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e BPD grade was based on the highest respiratory support used at 36 weeks PMA or at admission (when occurring after 36 weeks PMA). Furosemide prescriptions qualifying for study occurred between 36- and 60-weeks PMA, reflecting the age range of infants with established BPD routinely managed in our NICU. To avoid the influence of homeostatic tolerance on diuretic response, we excluded prescriptions that lacked at least 7 preceding days without furosemide exposure.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Qualifying furosemide prescriptions were ordered as a one-time dose, or as repeated dosing with consistent route of administration and a milligram per kilogram (mg/kg) dose of 1 mg/kg IV or 1 or 2 mg/kg enteral every 12 or 24 hours. Single doses and repeated doses scheduled every 24-hours were grouped together as our primary outcome was based on diuretic response over the first 24 hours, a time-period over which these exposures are analogous. We excluded furosemide prescriptions with concomitant red blood cell or fluid bolus administrations to decrease excess variance in fluid balance measures. Lastly, we excluded infants with congenital anomalies that we deemed could plausibly impact diuretic responsiveness, identifying these by reviewing International Classification of Diseases diagnostic codes. The data used in this study were approved for collection under the CHOP Neonatal and Infant Chronic Lung Disease Program clinical data registry by the CHOP Institutional Review Board, #19-016420.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy Variables\u003c/h3\u003e\n\u003cp\u003eThe objective of our study was to determine the association between route of furosemide administration and diuretic response. The primary predictor variable was route of administration ascertained from the medication administration record and modeled as a nominal variable with 3 categories: IV, gastric, and duodenal. The primary outcome variable was diuretic response, defined as the within-subject change in total net fluid balance in the 24-hours before and after initiation of furosemide. Fluid balance was calculated as the net of all fluids administered minus all recorded outputs for each time interval. Input was inclusive of medication volumes, intravenous fluids, parenteral nutrition, and enteral feeding volumes, while output was inclusive of urine, stool, emesis and drains, when present. To adjust for inexact total time between repeated-dosage prescriptions, fluid balance was standardized as milliliters per kilogram per (24 hours) day (ml/kg/d), accounting for incomplete hours and days in the denominator.\u003c/p\u003e\u003cp\u003eTo adjust for potential confounders between route of administration and diuretic response, we considered furosemide dosage and infant characteristics plausibly associated with diuretic response as covariates. Drug covariates were IV-equivalent dose and dose frequency, considered as separate variables. We reported all prescriptions as IV-equivalent doses, assuming a bioavailability of 50% for enteral formulations, such that a 2 mg/kg enteral dose was reported as 1 mg/kg IV-equivalent. These dosing characteristics reflect our typical institutional practice patterns. Under this approach, a similar diuretic response across route of administration would support our typical 1:2 IV to enteral conversion assumptions. Infant covariates were: birth gestational age group, in completed weeks; sex; BPD grade; PMA at furosemide exposure; plasma albumin, blood urea nitrogen (BUN), sodium and chloride levels, abstracted from the EHR at the time point nearest to furosemide exposure \u0026ndash; prior to administration when available, or following exposure if not; estimated glomerular filtration rate using the Schwartz formula modified for preterm infants\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e; and co-administration of thiazides diuretics, hydrocortisone, dexamethasone, or dopamine, all categorized as absent or present on the day of exposure.\u003c/p\u003e\n\u003ch3\u003eStatistical Analyses\u003c/h3\u003e\n\u003cp\u003eCohort characteristics were summarized with descriptive statistics. The association between route of administration and diuretic response was modeled with linear regression, applying robust variance estimates. The unadjusted associations between route of administration and all candidate covariates were first examined in bivariable analyses. All characteristics associated with diuretic response at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.10 were included with furosemide dose and frequency (selected \u003cem\u003ea priori\u003c/em\u003e) as covariates in the multivariable model. In a \u003cem\u003epost-hoc\u003c/em\u003e sensitivity analyses, the model was modified to include total daily furosemide dose (considering both administration dose and dose frequency; e.g 1 mg/kg/dose every 12 hours results in 2 mg/kg/day) rather than administration dose. \u003cem\u003eP\u003c/em\u003e-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant. Analyses were performed using STATA 17 (College Park, TX).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe identified 153 very preterm infants who met eligibility criteria (Figure 1). Characteristics of the full study cohort, and stratified by prescribed route of furosemide administration, are displayed in Table 1. Among eligible infants, 56% were born between 22 and 25 completed weeks GA and 67% had grade 3 BPD. The median (interquartile) PMA at furosemide exposure was 43.3 (39.6 - 47.9) weeks. Gastric was the most common route of furosemide administration (42%), followed by IV (32%), then duodenal (26%). The most common dose frequency was once or every 24 hours (69%). An IV-equivalent dose of 1 mg/kg was prescribed in 84% of infants, with the remaining 16% exposed to 0.5 mg/kg (equivalent to 1 mg/kg enteral furosemide). Among medication co-administrations, only thiazide diuretics were common (46%). The median laboratory values were largely within normal limits. All were obtained prior to furosemide exposure except 8 (6%) albumin values.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe mean (standard deviation) net fluid balances in the 24 hours before and after furosemide administration were +51.5 (23.2) and +25.8 (27.6) ml/kg/d, with a mean (standard deviation) diuretic response (within-subject change) of -25.6 (29.8) ml/kg/d across the full cohort. Table 2 displays the unadjusted bivariable association between evaluated characteristics and diuretic response. Diuretic response was similar across all routes of administration. Only dose frequency (greater diuretic response with every 12 vs every 24-hour dosing) and BUN (lower diuretic response with greater values) were statistically significant. Birth gestational age also met criteria for inclusion in the multivariable analysis.\u003c/p\u003e\n\u003cp\u003eDiuretic responses were similar across route of administration in adjusted multivariable modeling (Table 3), with estimated mean (95% confidence interval) values of -25.8 (-32.2, -19.4), -25.3 (-35.8, -14.7), and -25.8 (-34.2, -17.4) ml/kg for gastric, IV, and duodenal administrations, respectively. The effect estimates trended towards a greater diuretic response with more frequent and higher dosing but these associations lacked statistical significance. Greater BUN values were observed to have a statistically significant association with diuretic response, with higher values resulting in a smaller (less negative) diuretic response. The sensitivity analysis considering total daily furosemide dose rather than administration dose had consistent findings (Table 4).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe objective of our study was to compare the diuretic response to furosemide delivered by differing routes of administration in very preterm infants with BPD. We hypothesized that a gastric furosemide administration route would be associated with a greater diuretic effect than either an IV or duodenal administration when standardized to a 1:2 IV-to-enteral dose conversion. This hypothesis was based on the rationale that the enteral bioavailability of furosemide may exceed 50% on average and on prior research suggesting that gastric furosemide administration may be most \u0026ldquo;efficient\u0026rdquo; by sustaining therapeutic concentrations over a longer period.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Our findings did not support our hypothesis. In the first 24 hours following administration, changes in net fluid balance were similar among the three routes. This pattern was consistent in both unadjusted bivariable analyses and adjusted models.\u003c/p\u003e\n\u003cp\u003eOpportunities to compare our findings with prior relevant research are limited. We are unaware of other neonatal studies evaluating how route of furosemide administration impacts diuretic response. Consistent with our findings, a pharmacokinetic study of 7 adult patients with congestive heart failure reported comparable urine output over 24 hours with IV vs oral furosemide.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e In turn, data from 4 healthy adult volunteers receiving gastric vs duodenal furosemide via endoscopy found 12% greater diuretic effect over 8 hours with gastric furosemide.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e While inconsistent with our findings, the relevance of these data is limited by the small sample size and differences in study population.\u003c/p\u003e\n\u003cp\u003eOur findings are relevant to the contemporary care of infants with BPD, in whom furosemide is the most frequently prescribed pharmacotherapy.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Our data suggest that a 1:2 IV-to-enteral dose conversion leads to a comparable diuretic effect in infants with established BPD, lending support to this common, though variable, clinical practice.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Furthermore, our findings provide reassurance that duodenal administration produces a comparable diuretic response in infants with BPD. Notably, no prior data exist on the effects of duodenal furosemide in preterm infants, despite its routine use in clinical practice.\u003c/p\u003e\n\u003cp\u003eOur models identified a statistically significant association between greater BUN levels and a lower diuretic response. This association is biologically plausible, as elevated BUN may reflect renal dysfunction \u0026ndash; particularly reduced renal perfusion (i.e. pre-renal azotemia) \u0026ndash; and may trigger neurohormonal pathways that limit urine output.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Consistent with our finding, multiple clinical studies in adults with heart failure have reported an independent association between elevated BUN and a decreased diuretic response.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e However, our observation was \u003cem\u003epost hoc\u003c/em\u003e, and replication in dedicated studies is needed to establish whether BUN could serve as a useful predictor of diuretic responsiveness in preterm infants.\u003c/p\u003e\n\u003cp\u003eOur study has several limitations. We used changes in net fluid balance as a surrogate measure of diuresis, relying on real-world clinical data. Although urine output and natriuresis are more direct measures of furosemide renal responsiveness, fluid balance is routinely assessed in clinical care and offers a pragmatic alternative, as intake strongly influences output and urine volumes cannot be reliably discriminated from stool in routine neonatal practice. Prior studies have similarly used net fluid balance as a marker of diuresis.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Our finding of a 50% reduction in net fluid balance after furosemide administration reflects expected patterns, and supports the construct validity of this measure, which has also been demonstrated in prior studies.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Our data are susceptible to information bias, such as erroneous route of administration assignment in the medication administration record, inaccurate measurements or calculations of fluid intake and output, or transcription errors into the electronic health record. Carefully conducted prospective studies may reduce these. Despite including 153 infants, our study lacked sufficient power to detect clinically meaningful associations. We expected both dose and dosing frequency would influence diuretic response and included them \u003cem\u003ea priori\u003c/em\u003e in our models. Although effect estimates suggested a 52% greater response with every 12 vs 24-hour dosing and a 36% greater response with a 1 vs 0.5 mg/kg IV-equivalent dose, these sizeable differences did not reach statistical significance. Multicenter studies with larger sample sizes may allow greater statistical precision. Lastly, the generalizability of our findings is limited by our single-center design and by our focus on infants with established grade 2\u0026ndash;3 BPD who received furosemide at a median PMA of 43 weeks. Prior studies suggests that furosemide pharmacokinetics, particularly renal clearance, change rapidly with maturation in preterm infants.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Thus, our results may not extend to younger preterm infants.\u003c/p\u003e\n\u003cp\u003eIn summary, our findings suggest that IV, gastric, and duodenal furosemide, when dosed using a 1:2 IV-to-enteral conversion, produce a similar initial diuretic response in preterm infants with established BPD, supporting the appropriateness of these dosing practices. Our findings do not necessarily imply a typical 50% bioavailability for gastric and duodenal furosemide, as bioavailability reflects drug exposure rather than clinical response. Characterization of the dose-exposure-response relationship requires further study, such as comparative bioavailability trials measuring circulating furosemide concentrations alongside diuretic effect. Finally, although furosemide is widely used in this population, its broader safety and effectiveness in improving meaningful outcomes in infants with BPD remain uncertain. Our findings will help inform the careful design of future phase III trials, which remain greatly needed.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBPD, bronchopulmonary dysplasia\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNICU, neonatal intensive care unit\u003c/p\u003e\n\u003cp\u003ePMA, postmenstrual age\u003c/p\u003e\n\u003cp\u003ePK, pharmacokinetic\u003c/p\u003e\n\u003cp\u003eIV, intravenous\u003c/p\u003e\n\u003cp\u003eCHOP, Children’s Hospital of Philadelphia\u003c/p\u003e\n\u003cp\u003eEHR, electronic health record\u003c/p\u003e\n\u003cp\u003emg/kg, milligram per kilogram\u003c/p\u003e\n\u003cp\u003eml/kg/d, milliliters per kilogram per day\u003c/p\u003e\n\u003cp\u003eBUN, blood urea nitrogen\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest Disclosures\u003c/strong\u003e: This work was supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development grant K23HD10165 and the Perelman School of Medicine at the University of Pennsylvania Thomas B. McCabe and Jeannette E. Laws McCabe Fund to NAB. The funding sources had no role in the study design; the collection, analysis, and interpretation of the data; the writing of the report or the decision to submit for publication. NAB wrote the first draft of the manuscript. No compensation honorarium, grant, or other form of payment was given to produce the manuscript. KJD receives research support to his institution from Merck, Inc., Veloxis Pharmaceuticals, Inc., and Paratek Pharmaceutical unrelated to the current work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eBamat NA, Kirpalani H, Feudtner C, Jensen EA, Laughon MM, Zhang H et al. Medication use in infants with severe bronchopulmonary dysplasia admitted to United States children\u0026rsquo;s hospitals. Journal of Perinatology 2019; 39: 1291\u0026ndash;1299.\u003c/li\u003e\n \u003cli\u003eMirochnick MH, Miceli JJ, Kramer PA, Chapron DJ, Raye JR. Furosemide pharmacokinetics in very low birth weight infants. J Pediatr 1988; 112: 653\u0026ndash;7.\u003c/li\u003e\n \u003cli\u003ePeterson RG, Simmons MA, Rumack BH, Levine RL, Brooks JG. Pharmacology of furosemide in the premature newborn infant. J Pediatr 1980; 97: 139\u0026ndash;43.\u003c/li\u003e\n \u003cli\u003eVargo DL, Kramer WG, Black PK, Smith WB, Serpas T, Brater DC. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide and furosemide in patients with congestive heart failure. Clin Pharmacol Ther 1995; 57: 601\u0026ndash;609.\u003c/li\u003e\n \u003cli\u003eGreither A, Goldman S, Edelen JS, Benet LZ, Cohn K. Pharmacokinetics of furosemide in patients with congestive heart failure. Pharmacology 1979; 19: 121\u0026ndash;131.\u003c/li\u003e\n \u003cli\u003eGreenberg RG, Lang J, Smith PB, Shekhawat P, Courtney SE, Hudak ML et al. Furosemide Safety in Preterm Infants at Risk for Bronchopulmonary Dysplasia: A Randomized Clinical Trial. J Pediatr 2025; 283: 114629.\u003c/li\u003e\n \u003cli\u003eU.S. Food and Drug Administration. Furosemide injection. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/018267s029lbl.pdf. 2024.\u003c/li\u003e\n \u003cli\u003eBamat NA, Thompson EJ, Greenberg RG, Lorch SA, Zuppa AF, Eichenwald EC et al. Association between postmenstrual age and furosemide dosing practices in very preterm infants. Journal of Perinatology 2022; 42: 461\u0026ndash;467.\u003c/li\u003e\n \u003cli\u003eLevin JC, Kielt MJ, Hayden LP, Conroy S, Truog WE, Guaman MC et al. Transpyloric feeding is associated with adverse in-hospital outcomes in infants with severe bronchopulmonary dysplasia. Journal of Perinatology 2024; 44: 307\u0026ndash;313.\u003c/li\u003e\n \u003cli\u003eJensen EA, Zhang H, Feng R, Dysart K, Nilan K, Munson DA et al. Individualising care in severe bronchopulmonary dysplasia: A series of N-of-1 trials comparing transpyloric and gastric feeding. Arch Dis Child Fetal Neonatal Ed 2020; e-pub ahead of print November 4 2019; doi:10.1136/archdischild-2019-317148.\u003c/li\u003e\n \u003cli\u003eLee WI, Yoon WH, Shin WG, Song IS, Lee MG. Pharmacokinetics and pharmacodynamics of furosemide after direct administration into the stomach or duodenum. Biopharm Drug Dispos 1996; 18: 753-67.\u003c/li\u003e\n \u003cli\u003eKaojarern S, Day B, Brater DC. The time course of delivery of furosemide into urine: an independent determinant of overall response. Kidney Int 1982; 22: 69\u0026ndash;74.\u003c/li\u003e\n \u003cli\u003eJensen EA, Dysart K, Gantz MG, McDonald S, Bamat NA, Keszler M et al. The diagnosis of bronchopulmonary dysplasia in very preterm infants: an evidence-based approach. Am J Respir Crit Care Med 2019; 200: 751\u0026ndash;759.\u003c/li\u003e\n \u003cli\u003eBamat NA, Huber M, Shults J, Li Y, Zong Z, Zuppa A et al. Diuretic Tolerance to Repeated-Dose Furosemide in Infants Born Very Preterm with Bronchopulmonary Dysplasia. Journal of Pediatrics 2024; 266: 113813.\u003c/li\u003e\n \u003cli\u003eSegar JL, Robillard JE, Johnson KJ, Bell EF, Chemtob S. Addition of metolazone to overcome tolerance to furosemide in infants with bronchopulmonary dysplasia. J Pediatr 1992; 120: 966\u0026ndash;73.\u003c/li\u003e\n \u003cli\u003eBrion LP, Fleischman AR, McCarton C, Schwartz GJ. A simple estimate of glomerular filtration rate in low birth weight infants during the first year of life: Noninvasive assessment of body composition and growth. J Pediatr 1986; 109: 698\u0026ndash;707.\u003c/li\u003e\n \u003cli\u003eKazory A. Emergence of blood urea nitrogen as a biomarker of neurohormonal activation in heart failure. American Journal of Cardiology. 2010; 106: 694-700.\u003c/li\u003e\n \u003cli\u003eter Maaten JM, Valente MAE, Metra M, Bruno N, O\u0026rsquo;Connor CM, Ponikowski P et al. A combined clinical and biomarker approach to predict diuretic response in acute heart failure. Clinical Research in Cardiology 2016; 105: 145\u0026ndash;153.\u003c/li\u003e\n \u003cli\u003eValente MA, Voors AA, Damman K, Van Veldhuisen DJ, Massie BM, O\u0026rsquo;Connor CM et al. Diuretic response in acute heart failure: clinical characteristics and prognostic significance. Eur Heart J 2014; 35: 1284-93.\u003c/li\u003e\n \u003cli\u003eKim GJ, Capparelli E, Romanowski G, Proudfoot JA, Tremoulet AH. Development of Tolerance to Chronic Intermittent Furosemide Therapy in Pediatric Patients. J Pediatr Pharmacol Ther 2017; 22: 394\u0026ndash;398.\u003c/li\u003e\n \u003cli\u003ePrice JF, Younan S, Cabrera AG, Denfield SW, Tunuguntla HARI, Choudhry S et al. Diuretic Responsiveness and Its Prognostic Significance in Children With Heart Failure. J Card Fail 2019; 25: 941-947.\u003c/li\u003e\n \u003cli\u003eMcCallister KM, Chhim RF, Briceno-Medina M, Shelton CM, Figueroa M, Rayburn M. Bumetanide continuous infusions in critically ill pediatric patients. Pediatric Critical Care Medicine 2015; 16: e19-22.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8197255/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8197255/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eFurosemide is commonly prescribed in hospitalized infants with grade 2-3 bronchopulmonary dysplasia (BPD). Intravenous (IV), gastric, and duodenal administrations are common, with a 1:2 IV-to-enteral conversion often used despite uncertain bioavailability. Our objective was to compare diuretic responses between routes in infants with BPD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design:\u003c/strong\u003e Single-center observational cohort of very preterm infants with grade 2-3 BPD prescribed furosemide. The association between route (exposure) and diuretic response (change in net fluid balance after administration, outcome) was evaluated using multivariable regression adjusting for dosing and infant characteristics.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Among 153 infants (median postmenstrual age of 43.3 weeks at exposure), furosemide reduced fluid balance by -25.6 (29.8) ml/kg/d. Adjusted mean changes were similar across routes: IV, -25.3 (-35.8, -14.7), gastric, -25.8 (-32.2, -19.4), and duodenal, -25.8 (-34.2, -17.4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: Our data suggest a 1:2 IV-to-enteralconversion leads to comparable diuretic effects in infants with established BPD, supporting this common clinical practice.\u003c/p\u003e","manuscriptTitle":"Association between route of furosemide administration and diuretic response in very preterm infants with bronchopulmonary dysplasia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 10:39:02","doi":"10.21203/rs.3.rs-8197255/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2026-01-26T13:35:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-01-22T13:36:41+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-01-15T22:55:55+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-12-23T15:35:52+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-12-03T15:46:20+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-11-26T01:12:03+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-25T15:46:48+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-24T23:04:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Perinatology","date":"2025-11-24T23:04:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"90165423-182d-4efd-ba0b-51fd905d63ac","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":58612601,"name":"Health sciences/Medical research/Outcomes research"},{"id":58612602,"name":"Biological sciences/Physiology/Kidney"},{"id":58612603,"name":"Health sciences/Diseases/Respiratory tract diseases"},{"id":58612604,"name":"Health sciences/Health care/Therapeutics/Drug therapy/Drug delivery"},{"id":58612605,"name":"Health sciences/Health care/Paediatrics"}],"tags":[],"updatedAt":"2026-04-17T07:05:38+00:00","versionOfRecord":{"articleIdentity":"rs-8197255","link":"https://doi.org/10.1038/s41372-026-02662-5","journal":{"identity":"journal-of-perinatology","isVorOnly":false,"title":"Journal of Perinatology"},"publishedOn":"2026-04-16 04:00:00","publishedOnDateReadable":"April 16th, 2026"},"versionCreatedAt":"2025-12-01 10:39:02","video":"","vorDoi":"10.1038/s41372-026-02662-5","vorDoiUrl":"https://doi.org/10.1038/s41372-026-02662-5","workflowStages":[]},"version":"v1","identity":"rs-8197255","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8197255","identity":"rs-8197255","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}