{"paper_id":"45e8920f-78e5-4efa-b17b-474f2fc462d3","body_text":"Chlorothiazide is associated with a weaker diuretic response than furosemide in infants with bronchopulmonary dysplasia (BPD) | 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 Chlorothiazide is associated with a weaker diuretic response than furosemide in infants with bronchopulmonary dysplasia (BPD) Timothy Nelin, Matthew Huber, Heidi Morris, Erik Jensen, Kathleen Gibbs, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7068749/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To compare the diuretic effect of furosemide versus chlorothiazide in preterm infants with high-grade bronchopulmonary dysplasia (BPD). Study Design: We conducted a retrospective cohort study of infants with grade 2 or 3 BPD admitted to a level IV NICU between 36–60 weeks’ postmenstrual age. The primary outcome was within-subject change in net fluid balance (mL/kg) in the 24 hours before and after diuretic initiation. Multivariable linear regression adjusted for differences in diuretic and clinical variables. Results Among 136 furosemide and 215 chlorothiazide exposures in 300 infants, furosemide was most often dosed every 24 hours (73%), while chlorothiazide was most often dosed every 12 hours (90%). Median postmenstrual age at exposure was 44 weeks for furosemide and 42 weeks for chlorothiazide. Furosemide was associated with a significantly greater diuretic effect than chlorothiazide (-32.0 vs. -10.5 mL/kg; p < 0.001). Conclusions Furosemide resulted in a threefold greater diuretic effect than chlorothiazide in infants with high-grade BPD. Health sciences/Health care/Therapeutics Health sciences/Diseases/Respiratory tract diseases Figures Figure 1 INTRODUCTION As bronchopulmonary dysplasia (BPD) is the most common chronic morbidity of preterm birth, it is crucial to identify safe and effective therapeutic interventions. 1 Among infants with high-grade BPD (defined as grades 2 or 3), diuretics are the most prescribed class of medications, and furosemide and chlorothiazide are the most prescribed diuretics. 2 – 5 Despite their common use in infants with high-grade BPD, a paucity of data exist to guide clinical decision making regarding diuretic agent choices. A wide array of diuretic prescribing practices exist in neonatal intensive care units (NICU) in the United States. 2 , 4 , 6 Diuretic choice, most commonly between loop and thiazide diuretics, represents an important branch point in the management of preterm infants. 2 , 3 When considering which diuretic to use, clinicians must consider the mechanisms of action and measure the clinical benefit against adverse effects. Our previous work has challenged common assumptions about furosemide and chlorothiazide exposures in preterm infants as we found that compared to chlorothiazide, furosemide may not have a greater impact on sodium, potassium, or chloride wasting or exposure to electrolyte supplementation. 3 , 7 The comparative diuretic effect of furosemide vs chlorothiazide in infants with high-grade BPD is a significant knowledge gap. Therefore, we aimed to measure this clinical impact of these two diuretic choices by estimating the change in net fluid balance in the 24-hour intervals before and after the initiation of either diuretic. We hypothesized that furosemide would be associated with a greater effect on fluid balance than chlorothiazide due to its therapeutic action in the loop of Henle, a nephron segment with higher sodium reabsorption capacity, versus the distal convoluted tubule, where chlorothiazide acts. 8 , 9 METHODS Study Population We performed a retrospective cohort study in a convenience sample of infants born between 2010 and 2021, diagnosed with high-grade BPD, and admitted to the Children’s Hospital of Philadelphia NICU. We used the 2019 Neonatal Research Network (NRN) criteria to diagnose and stratify BPD at 36 weeks’ postmenstrual age (PMA) or at the time of transfer if after 36 weeks’ PMA. 10 Infants were excluded if they had a congenital anomaly that plausibly impacted renal function. Data collection was approved by the Institutional Review Board of the Children’s Hospital of Philadelphia (IRB #19-016420). Novel Diuretic Exposure Novel furosemide and chlorothiazide exposures occurred between 36- and 60-weeks’ PMA. We defined eligible exposures as at least 1 dose of furosemide or chlorothiazide, at every 8-, 12-, or 24-hour dosing interval in infants without exposure to the diuretic in the preceding 7 days. For example, infants with an eligible chlorothiazide exposure could not have been exposed to chlorothiazide in the prior week but may have been exposed to furosemide. Of note, there were no infants who were started on furosemide and chlorothiazide in the same 24-hour interval. We standardized enteral and intravenous diuretic exposures assuming an enteral bioavailability of 50% for furosemide and 20% for chlorothiazide. 11 Exposures were excluded if a fluid bolus or packed red blood cells were administered during the exposure period. Infants could contribute to both furosemide and chlorothiazide exposures at distinct periods of their admission, but we limited the analysis to use the first qualifying exposure for each diuretic type. Outcome: Diuretic Effect We quantified diuretic effect as the change in net fluid balance (mL/kg) between the 24-hour intervals before and after diuretic administration. Fluid balance was calculated as the net of all inputs minus all outputs for each 24-hour interval. Fluid inputs included medication volume, intravenous fluid, parenteral nutrition, and enteral feeding volumes. Fluid outputs included urine, stool, emesis, and drains if present. We chose the change in net fluid balance as a pragmatic measure of intended diuretic effect given its relevance to clinical practice and the availability of data in the electronic health record (EHR), and chose to model 24-hour intervals as diuretic medications are commonly prescribed and fluid balance is commonly assessed in 24-hour intervals. 12 Outlying values were identified and individually assessed in the EHR during data curation to reduce the influence of implausible or physiologically inconsistent measurements. Statistical Analysis We used standard descriptive characteristics to summarize cohort characteristics. We used multivariable linear regression to measure within-subject change in net fluid balance in the 24 hours before and after diuretic initiation, beginning after the time of first dose administration. We adjusted for potential confounding through a priori inclusion of diuretic dose, frequency, and route of administration as well as candidate covariates associated with change in net fluid balance at P < 0.10 in bivariable regression. These variables were: infant sex; gestational age (GA); PMA at diuretic exposure; BPD grade; concomitant diuretic administration (administration of furosemide within 72 hours of chlorothiazide exposure or administration of chlorothiazide within 72 hours of furosemide exposure); concomitant administration of hydrocortisone, dexamethasone, dopamine, sodium chloride (NaCl), or potassium chloride (KCl); serum albumin; serum blood urea nitrogen; serum sodium; serum chloride; serum creatinine; and estimated glomerular filtration rate (eGFR). We used clustered robust variance estimates to account for repeated observations within subjects. For clinical relevance, we estimated and reported change in net fluid balance using post-estimation margins. We utilized a two-sided p -value of < 0.05 to indicate statistical significance. We conducted two post-hoc analyses to investigate whether the sequence of diuretic exposure is associated with diuretic effect and whether diuretic dose is associated with diuretic response by drug type (furosemide vs chlorothiazide). We included an interaction term between diuretic category and concomitant diuretic administration in the final multivariable linear regression model to assess whether adding furosemide to an ongoing chlorothiazide regimen differed in impact from adding chlorothiazide to ongoing furosemide. We included an interaction term between diuretic category and dosing frequency to evaluate whether frequency of dosing had differential effects depending on whether furosemide or chlorothiazide was administered. A statistically significant interaction would suggest dose-response relationships differ by diuretic class. All statistical analyses were performed using Stata 18 (StataCorp, College Station, TX, USA). RESULTS We identified 136 furosemide and 215 chlorothiazide exposures in 300 eligible infants. Table 1 displays demographic and clinical characteristics of infants exposed to furosemide and chlorothiazide. Median exposure PMA was 44 weeks for furosemide and 42 weeks for chlorothiazide. Every 24 hours was the most common dosing frequency for furosemide (73%) while every 12-hour dosing was most common for chlorothiazide (90%). Furosemide was co-administered in 78% of evaluated chlorothiazide exposures, while chlorothiazide was present in 54% of evaluated furosemide exposures. Table 2 displays the change in net fluid balance associated with the evaluated clinical and diuretic exposure characteristics. Furosemide was associated with a significantly greater negative change in net fluid balance compared to chlorothiazide (13.3 mL/kg difference; -27.0 vs -13.7 mL/kg, p < 0.001). There was no significant association of any candidate covariate with change in net fluid balance in bivariable regression, however serum BUN met the threshold for inclusion in bivariable regression modeling ( p = 0.087). Figure 1 displays the results of multivariable linear regression modeling comparing change in net fluid balance between furosemide and chlorothiazide, adjusting for diuretic dose, diuretic dosing frequency, diuretic route of administration, and serum BUN. After covariate adjustment, furosemide exposure was associated with a -32.0 mL/kg change in net fluid balance compared with a -10.5 mL/kg change in net fluid balance observed for novel chlorothiazide exposure ( p < 0.001). Additionally, every 12-hour dosing for both furosemide and chlorothiazide was associated with greater diuretic effect than every 24-hour dosing (-22.4 mL/kg vs -11.3 mL/kg, p = 0.032). No other infant or diuretic characteristics were associated with a significant diuretic effect (Table 3). In post-hoc analyses, the additive effect of concomitant diuretic therapy on net fluid balance did not depend on the order in which diuretics were added nor did dosing frequency-response relationships significantly differ by diuretic class (Supplemental Table 1). DISCUSSION In this cohort of infants with high-grade BPD, furosemide was associated with a threefold greater diuretic effect than chlorothiazide when quantified by the change in 24-hour net fluid balance (-32.0 mL/kg vs -10.5 mL/kg). This finding agrees with our hypothesis that furosemide is associated with significantly greater diuresis and is plausible based on their differing pharmacotherapeutic mechanisms. In our study, 54% of eligible novel furosemide exposures occurred in infants concomitantly receiving chlorothiazide and 78% of novel chlorothiazide exposures occurred in infants concomitantly receiving furosemide. These patterns likely reflect an underlying clinical rationale grounded in the concept of diuretic synergy, or sequential nephron blockade—a strategy well described in the adult literature as a means to overcome diuretic resistance. 13 – 15 This approach is based on the understanding that during sustained diuretic therapy, downstream segments of the nephron adapt by increasing sodium and chloride reabsorption, which diminishes diuretic efficacy over time. 15 Therefore, adding another diuretic that targets a different part of the nephron may help overcome this resistance. Although evidence is limited in preterm infants, Segar et al. reported increased diuresis and natriuresis among infants on repeated-dose furosemide after adding metolazone, a thiazide-like diuretic, compared to continuing furosemide alone. 16 Despite common concomitant diuretic exposure for both furosemide and chlorothiazide, a significant difference in diuretic effect was still noted between furosemide and chlorothiazide. While our study was not designed to assess sequential nephron blockade, we speculate that the greater effect of furosemide reflects its action in the loop of Henle, where sodium reabsorption is highest. 8 These findings highlight the need for future studies to explore the potential for synergy in combination diuretic therapy in this population. We investigated the relationship of several clinical and diuretic characteristics with change in net fluid balance as clinical or dosing characteristics may impact differences in diuretic effect between furosemide and chlorothiazide. We identified that every 12-hour dosing was associated with a two-fold greater diuretic effect compared to every 24-hour dosing. This finding likely reflects the impact of more frequent furosemide dosing, as 90% of chlorothiazide was dosed at an every 12-hour interval with much less variation. While a wide variation exists in diuretic prescribing practices in NICUs in the United States, 1 mg/kg/day is the most common furosemide dose based on historical pharmacokinetic data. 2 , 6 A recent study using data from Pediatrix NICUs collected from 1997 to 2016 found that furosemide dosing practices were similar across PMA groups, despite previous studies reporting a shorter half-life and higher clearance among infants at an older PMA. 17 More frequent diuretic dosing is older infants with established BPD and the maturational capacity to rapidly clear furosemide likely results in a significantly greater amount of time in which a diuretic effect is present. These findings highlight the importance of future studies investigating dosing regimens as the efficacy and safety of more frequent dosing may differ in older infants with established BPD based on higher clearance with maturation in this population. No other infant or diuretic characteristic was significantly associated with diuretic effect in multivariable modeling. Notably, we found that prescribers consistently prescribed furosemide at a standardized IV-equivalent dose of 1 mg/kg, whereas chlorothiazide dosing was more variable. This variability may reflect a paucity of data on the pharmacokinetics of chlorothiazide in preterm infants. In the absence of robust pharmacokinetic data in preterm infants with BPD, we rely on presumptions about bioavailability, which may differ substantially depending on the clinical context, gestational age, and route of administration. 11 , 18 Mischaracterization of these parameters and the narrow dosing range observed in practice could obscure true associations of diuretic dose with diuretic effect. These findings underscore the need for future pharmacokinetic and pharmacodynamic studies to better characterize optimal dosing strategies and improve the precision of diuretic prescribing in this vulnerable population. It is important to contextualize our finding that furosemide has a threefold greater diuretic effect than chlorothiazide within the risk-benefit profiles of these diuretics, considering both therapeutic and adverse effects. In a retrospective study of 3252 infants in the Pediatric Health Information System Database, infants who had or were at risk of BPD and exposed to a prolonged thiazide course were more likely than infants exposed to a prolonged furosemide course to received NaCl and KCl supplementation. 3 In a more recent study among infants with high-grade BPD admitted to a single-center level IV NICU, changes in serum sodium, potassium, and chloride were similar between novel chlorothiazide and furosemide exposures, questioning the perception that chlorothiazide is a broadly “gentler” diuretic with respect to electrolyte loss. 7 Clinicians should weigh the significantly greater diuretic effect of furosemide compared to chlorothiazide (-32.0 vs. -10.5 mL/kg) with similar risks of sodium, potassium and chloride derangement. Our study has several strengths. First, it examined 136 furosemide and 215 chlorothiazide exposures among 300 infants with high-grade BPD, representing the largest study comparing furosemide and chlorothiazide in this population. Second, we employed multivariable linear regression with robust variance estimates to account for confounding and within-subject repeated measures. Our study has limitations. First, this was a retrospective study relying on electronic health record abstraction and susceptible to misclassification bias from inaccurate documentation. However, outlying values were removed in the data curation process, limiting the impact of extreme values due to incorrect documentation. Additionally, there is potential for unmeasured confounders to influence the observed differences in diuretic effect, however we anticipate the likelihood of this to be low given the inclusion criteria for the cohort generation. Third, this study focused on short-term rather than long-term differences in fluid balance due to complex issues related to quantifying total exposure and the impact of renal homeostasis on diuretic effect over time, therefore these findings should not be generalized to the comparative diuretic effects of furosemide and chlorothiazide during prolonged repeated-dose exposures. Fourth, there was a high rate of diuretic co-exposure: 54% of furosemide and 78% of chlorothiazide exposures occurred concomitantly with the other diuretic. This necessitates a more nuanced interpretation as our results may not reflect the effect of these diuretics on fluid balance during diuretic monotherapy. However, such co-exposures are common in clinical practice. 2 Lastly, our study incorporates data from a single center, with its own culture surrounding diuretic prescription. Our center does not utilize specific clinical practice guidelines for diuretic prescription among infants with high-grade BPD, therefore exposure patterns in this study reflect individual prescriber preferences, which may not generalize to clinical settings or infants with high-grade BPD. In this large cohort of infants with high-grade BPD, furosemide was associated with a threefold greater diuretic effect than chlorothiazide. Given the similar risk of electrolyte imbalance, clinicians should weigh the greater efficacy of furosemide when choosing diuretic therapy. 3 , 7 Although furosemide and chlorothiazide are the most prescribed diuretics among infants with high-grade BPD, there are limited prospective data available to guide clinical practice related to these medications. Our findings should inform prospective studies to better understand optimal diuretic dosing, the potential for loop and thiazide diuretic synergy, and their impact on long-term clinical outcomes in preterm infants with high-grade BPD. Declarations Conflict of Interest Disclosures: The authors have no financial interests to disclose. References Thébaud B, Goss KN, Laughon M, et al. Bronchopulmonary dysplasia. Nat Rev Dis Primers . 2019;5(1). doi: 10.1038/s41572-019-0127-7 Bamat NA, Kirpalani H, Feudtner C, et al. Medication use in infants with severe bronchopulmonary dysplasia admitted to United States children’s hospitals. Journal of Perinatology . Published online 2019. doi: 10.1038/s41372-019-0415-9 Nelin TD, Lorch S, Jensen EA, et al. The association between diuretic class exposures and enteral electrolyte use in infants developing grade 2 or 3 bronchopulmonary dysplasia in United States children’s hospitals. Journal of Perinatology . 2021;41(4). doi: 10.1038/s41372-021-00924-y Bamat NA, Nelin TD, Eichenwald EC, et al. Loop Diuretics in Severe Bronchopulmonary Dysplasia: Cumulative Use and Associations with Mortality and Age at Discharge. In: Journal of Pediatrics . Vol 231.; 2021. doi: 10.1016/j.jpeds.2020.10.073 Tan C, Sehgal K, Sehgal K, Krishnappa SB, Sehgal A. Diuretic use in infants with developing or established chronic lung disease: A practice looking for evidence. J Paediatr Child Health . Published online 2020. doi: 10.1111/jpc.14877 Slaughter JL, Stenger MR, Reagan PB. Variation in the Use of Diuretic Therapy for Infants With Bronchopulmonary Dysplasia. Pediatrics . Published online 2013. doi: 10.1542/peds.2012-1835 Nelin TD, Huber M, Jensen EA, et al. Association of furosemide versus chlorothiazide exposures with serum sodium, potassium, and chloride among infants with bronchopulmonary dysplasia. Journal of Perinatology . Published online November 5, 2024. doi: 10.1038/s41372-024-02159-z Segar JL. Neonatal Diuretic Therapy: Furosemide, Thiazides, and Spironolactone. Clin Perinatol . Published online 2012. doi: 10.1016/j.clp.2011.12.007 Thompson EJ, Benjamin DK, Greenberg RG, et al. Pharmacoepidemiology of Furosemide in the Neonatal Intensive Care Unit. Neonatology . 2021;117(6). doi: 10.1159/000510657 Jensen EA, Dysart K, Gantz MG, et al. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants An Evidence-based Approach. Am J Respir Crit Care Med . Published online 2019. doi: 10.1164/rccm.201812-2348OC Segar JL. Evidence-based approach to diuretic therapy in the neonate. In: Renal, Fluid and Electrolyte Disorders: Neonatology Questions and Controversies . Fourth. Elsevier; 2024:114–124. Bamat NA, Huber M, Shults J, et al. Diuretic Tolerance to Repeated-Dose Furosemide in Infants Born Very Preterm with Bronchopulmonary Dysplasia. J Pediatr . 2024;266:113813. doi: 10.1016/j.jpeds.2023.113813 Loon NR, Wilcox CS, Unwin RJ. Mechanism of impaired natriuretic response to furosemide during prolonged therapy. Kidney Int . 1989;36(4). doi: 10.1038/ki.1989.246 Ellison DH. The physiologic basis of diuretic synergism: Its role in treating diuretic resistance. Ann Intern Med . 1991;114(10). doi: 10.7326/0003-4819-114-10-886 Jentzer JC, Dewald TA, Hernandez AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. J Am Coll Cardiol . 2010;56(19). doi: 10.1016/j.jacc.2010.06.034 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(6). doi: 10.1016/S0022-3476(05)81972-9 Bamat NA, Thompson EJ, Greenberg RG, et al. Association between postmenstrual age and furosemide dosing practices in very preterm infants. Journal of Perinatology . 2022;42(4). doi: 10.1038/s41372-022-01320-w Osman MA, Patel RB, Irwin DS, Craig WA, Welling PG. Bioavailability of chlorothiazide from 50, 100, and 250 mg solution doses. Biopharm Drug Dispos . 1982;3(2). doi: 10.1002/bdd.2510030202 Tables Table 1 to 3 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 SupplementalTable1.docx Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-7068749\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":487116894,\"identity\":\"c16acc0f-2b19-49d2-aa02-1678c174e941\",\"order_by\":0,\"name\":\"Timothy 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21:10:28\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-7068749/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-7068749/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":87345533,\"identity\":\"96a2484d-ef9e-4db0-9b73-237e89af132c\",\"added_by\":\"auto\",\"created_at\":\"2025-07-23 02:14:59\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":47949,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eDecrease in fluid balance after multivariable modeling of furosemide versus chlorothiazide exposure adjusting for diuretic dose, dosing frequency, route of administration, and serum BUN.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7068749/v1/aaf63b9bc164ed4b19d3e224.png\"},{\"id\":88256587,\"identity\":\"9f87bdc5-4275-486c-bd6d-8718653c0a48\",\"added_by\":\"auto\",\"created_at\":\"2025-08-04 14:33:40\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":441725,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7068749/v1/b88a0d4d-c63c-4d61-88c5-d51c770315b7.pdf\"},{\"id\":87345540,\"identity\":\"d9a95e8b-c507-4170-bf1e-5311ff596695\",\"added_by\":\"auto\",\"created_at\":\"2025-07-23 02:14:59\",\"extension\":\"docx\",\"order_by\":2,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":19954,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Table1.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7068749/v1/103a69b642cd5670751ffa2c.docx\"},{\"id\":87345537,\"identity\":\"8962d397-5dd5-4719-bcc4-9bb511630740\",\"added_by\":\"auto\",\"created_at\":\"2025-07-23 02:14:59\",\"extension\":\"docx\",\"order_by\":3,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":20081,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Table2.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7068749/v1/a3884b4a5412efec033d0450.docx\"},{\"id\":87345534,\"identity\":\"509ffd6b-cae9-47f1-b60f-cf26d0006fc3\",\"added_by\":\"auto\",\"created_at\":\"2025-07-23 02:14:59\",\"extension\":\"docx\",\"order_by\":4,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":15179,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Table3.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7068749/v1/82fed2cb9edabcea0f2b0e4d.docx\"},{\"id\":87345538,\"identity\":\"9ba586fd-9b8f-4cd1-885e-3b2733007f6e\",\"added_by\":\"auto\",\"created_at\":\"2025-07-23 02:14:59\",\"extension\":\"docx\",\"order_by\":6,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":14942,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"SupplementalTable1.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7068749/v1/44b5f09727633fec0726c2d4.docx\"}],\"financialInterests\":\"There is \\u003cb\\u003eNO\\u003c/b\\u003e conflict of interest to disclose.\",\"formattedTitle\":\"Chlorothiazide is associated with a weaker diuretic response than furosemide in infants with bronchopulmonary dysplasia (BPD)\",\"fulltext\":[{\"header\":\"INTRODUCTION\",\"content\":\"\\u003cp\\u003eAs bronchopulmonary dysplasia (BPD) is the most common chronic morbidity of preterm birth, it is crucial to identify safe and effective therapeutic interventions.\\u003csup\\u003e\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u003c/sup\\u003e Among infants with high-grade BPD (defined as grades 2 or 3), diuretics are the most prescribed class of medications, and furosemide and chlorothiazide are the most prescribed diuretics.\\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR3 CR4\\\" citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e–\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u003c/sup\\u003e Despite their common use in infants with high-grade BPD, a paucity of data exist to guide clinical decision making regarding diuretic agent choices.\\u003c/p\\u003e\\u003cp\\u003eA wide array of diuretic prescribing practices exist in neonatal intensive care units (NICU) in the United States.\\u003csup\\u003e\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e\\u003c/sup\\u003e Diuretic choice, most commonly between loop and thiazide diuretics, represents an important branch point in the management of preterm infants.\\u003csup\\u003e\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e\\u003c/sup\\u003e When considering which diuretic to use, clinicians must consider the mechanisms of action and measure the clinical benefit against adverse effects.\\u003c/p\\u003e\\u003cp\\u003eOur previous work has challenged common assumptions about furosemide and chlorothiazide exposures in preterm infants as we found that compared to chlorothiazide, furosemide may not have a greater impact on sodium, potassium, or chloride wasting or exposure to electrolyte supplementation.\\u003csup\\u003e\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e\\u003c/sup\\u003e The comparative diuretic effect of furosemide vs chlorothiazide in infants with high-grade BPD is a significant knowledge gap. Therefore, we aimed to measure this clinical impact of these two diuretic choices by estimating the change in net fluid balance in the 24-hour intervals before and after the initiation of either diuretic. We hypothesized that furosemide would be associated with a greater effect on fluid balance than chlorothiazide due to its therapeutic action in the loop of Henle, a nephron segment with higher sodium reabsorption capacity, versus the distal convoluted tubule, where chlorothiazide acts.\\u003csup\\u003e\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e\"},{\"header\":\"METHODS\",\"content\":\"\\u003cp\\u003e\\u003cem\\u003eStudy Population\\u003c/em\\u003e\\u003c/p\\u003e\\u003cp\\u003eWe performed a retrospective cohort study in a convenience sample of infants born between 2010 and 2021, diagnosed with high-grade BPD, and admitted to the Children’s Hospital of Philadelphia NICU. We used the 2019 Neonatal Research Network (NRN) criteria to diagnose and stratify BPD at 36 weeks’ postmenstrual age (PMA) or at the time of transfer if after 36 weeks’ PMA.\\u003csup\\u003e\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e\\u003c/sup\\u003e Infants were excluded if they had a congenital anomaly that plausibly impacted renal function. Data collection was approved by the Institutional Review Board of the Children’s Hospital of Philadelphia (IRB #19-016420).\\u003c/p\\u003e\\u003cp\\u003e\\u003cem\\u003eNovel Diuretic Exposure\\u003c/em\\u003e\\u003c/p\\u003e\\u003cp\\u003eNovel furosemide and chlorothiazide exposures occurred between 36- and 60-weeks’ PMA. We defined eligible exposures as at least 1 dose of furosemide or chlorothiazide, at every 8-, 12-, or 24-hour dosing interval in infants without exposure to the diuretic in the preceding 7 days. For example, infants with an eligible chlorothiazide exposure could not have been exposed to chlorothiazide in the prior week but may have been exposed to furosemide. Of note, there were no infants who were started on furosemide and chlorothiazide in the same 24-hour interval. We standardized enteral and intravenous diuretic exposures assuming an enteral bioavailability of 50% for furosemide and 20% for chlorothiazide.\\u003csup\\u003e\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e\\u003c/sup\\u003e Exposures were excluded if a fluid bolus or packed red blood cells were administered during the exposure period. Infants could contribute to both furosemide and chlorothiazide exposures at distinct periods of their admission, but we limited the analysis to use the first qualifying exposure for each diuretic type.\\u003c/p\\u003e\\u003cp\\u003e\\u003cem\\u003eOutcome: Diuretic Effect\\u003c/em\\u003e\\u003c/p\\u003e\\u003cp\\u003eWe quantified diuretic effect as the change in net fluid balance (mL/kg) between the 24-hour intervals before and after diuretic administration. Fluid balance was calculated as the net of all inputs minus all outputs for each 24-hour interval. Fluid inputs included medication volume, intravenous fluid, parenteral nutrition, and enteral feeding volumes. Fluid outputs included urine, stool, emesis, and drains if present. We chose the change in net fluid balance as a pragmatic measure of intended diuretic effect given its relevance to clinical practice and the availability of data in the electronic health record (EHR), and chose to model 24-hour intervals as diuretic medications are commonly prescribed and fluid balance is commonly assessed in 24-hour intervals.\\u003csup\\u003e\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e\\u003c/sup\\u003e Outlying values were identified and individually assessed in the EHR during data curation to reduce the influence of implausible or physiologically inconsistent measurements.\\u003c/p\\u003e\\u003ch2\\u003eStatistical Analysis\\u003c/h2\\u003e\\u003cp\\u003eWe used standard descriptive characteristics to summarize cohort characteristics. We used multivariable linear regression to measure within-subject change in net fluid balance in the 24 hours before and after diuretic initiation, beginning after the time of first dose administration. We adjusted for potential confounding through \\u003cem\\u003ea priori\\u003c/em\\u003e inclusion of diuretic dose, frequency, and route of administration as well as candidate covariates associated with change in net fluid balance at \\u003cem\\u003eP\\u003c/em\\u003e \\u0026lt; 0.10 in bivariable regression. These variables were: infant sex; gestational age (GA); PMA at diuretic exposure; BPD grade; concomitant diuretic administration (administration of furosemide within 72 hours of chlorothiazide exposure or administration of chlorothiazide within 72 hours of furosemide exposure); concomitant administration of hydrocortisone, dexamethasone, dopamine, sodium chloride (NaCl), or potassium chloride (KCl); serum albumin; serum blood urea nitrogen; serum sodium; serum chloride; serum creatinine; and estimated glomerular filtration rate (eGFR). We used clustered robust variance estimates to account for repeated observations within subjects. For clinical relevance, we estimated and reported change in net fluid balance using post-estimation margins. We utilized a two-sided \\u003cem\\u003ep\\u003c/em\\u003e-value of \\u0026lt; 0.05 to indicate statistical significance.\\u003c/p\\u003e\\u003cp\\u003eWe conducted two post-hoc analyses to investigate whether the sequence of diuretic exposure is associated with diuretic effect and whether diuretic dose is associated with diuretic response by drug type (furosemide vs chlorothiazide). We included an interaction term between diuretic category and concomitant diuretic administration in the final multivariable linear regression model to assess whether adding furosemide to an ongoing chlorothiazide regimen differed in impact from adding chlorothiazide to ongoing furosemide. We included an interaction term between diuretic category and dosing frequency to evaluate whether frequency of dosing had differential effects depending on whether furosemide or chlorothiazide was administered. A statistically significant interaction would suggest dose-response relationships differ by diuretic class. All statistical analyses were performed using Stata 18 (StataCorp, College Station, TX, USA).\\u003c/p\\u003e\"},{\"header\":\"RESULTS\",\"content\":\"\\u003cp\\u003eWe identified 136 furosemide and 215 chlorothiazide exposures in 300 eligible infants. Table 1 displays demographic and clinical characteristics of infants exposed to furosemide and chlorothiazide. Median exposure PMA was 44 weeks for furosemide and 42 weeks for chlorothiazide. Every 24 hours was the most common dosing frequency for furosemide (73%) while every 12-hour dosing was most common for chlorothiazide (90%). Furosemide was co-administered in 78% of evaluated chlorothiazide exposures, while chlorothiazide was present in 54% of evaluated furosemide exposures.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eTable 2 displays the change in net fluid balance associated with the evaluated clinical and diuretic exposure characteristics. Furosemide was associated with a significantly greater negative change in net fluid balance compared to chlorothiazide (13.3 mL/kg difference; -27.0 vs -13.7 mL/kg, \\u003cem\\u003ep\\u0026nbsp;\\u003c/em\\u003e\\u0026lt; 0.001). There was no significant association of any candidate covariate with change in net fluid balance in bivariable regression, however serum BUN met the threshold for inclusion in bivariable regression modeling (\\u003cem\\u003ep\\u0026nbsp;\\u003c/em\\u003e= 0.087).\\u003c/p\\u003e\\n\\u003cp\\u003eFigure 1 displays the results of multivariable linear regression modeling comparing change in net fluid balance between furosemide and chlorothiazide, adjusting for diuretic dose, diuretic dosing frequency, diuretic route of administration, and serum BUN. After covariate adjustment, furosemide exposure was associated with a -32.0 mL/kg change in net fluid balance compared with a -10.5 mL/kg change in net fluid balance observed for novel chlorothiazide exposure (\\u003cem\\u003ep\\u0026nbsp;\\u003c/em\\u003e\\u0026lt; 0.001). Additionally, every 12-hour dosing for both furosemide and chlorothiazide was associated with greater diuretic effect than every 24-hour dosing (-22.4 mL/kg vs -11.3 mL/kg, \\u003cem\\u003ep\\u0026nbsp;\\u003c/em\\u003e= 0.032). No other infant or diuretic characteristics were associated with a significant diuretic effect (Table 3). In post-hoc analyses, the additive effect of concomitant diuretic therapy on net fluid balance did not depend on the order in which diuretics were added nor did dosing frequency-response relationships significantly differ by diuretic class (Supplemental Table 1).\\u003c/p\\u003e\"},{\"header\":\"DISCUSSION\",\"content\":\"\\u003cp\\u003eIn this cohort of infants with high-grade BPD, furosemide was associated with a threefold greater diuretic effect than chlorothiazide when quantified by the change in 24-hour net fluid balance (-32.0 mL/kg vs -10.5 mL/kg). This finding agrees with our hypothesis that furosemide is associated with significantly greater diuresis and is plausible based on their differing pharmacotherapeutic mechanisms.\\u003c/p\\u003e\\u003cp\\u003eIn our study, 54% of eligible novel furosemide exposures occurred in infants concomitantly receiving chlorothiazide and 78% of novel chlorothiazide exposures occurred in infants concomitantly receiving furosemide. These patterns likely reflect an underlying clinical rationale grounded in the concept of diuretic synergy, or sequential nephron blockade\\u0026mdash;a strategy well described in the adult literature as a means to overcome diuretic resistance.\\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR14\\\" citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e\\u003c/sup\\u003e This approach is based on the understanding that during sustained diuretic therapy, downstream segments of the nephron adapt by increasing sodium and chloride reabsorption, which diminishes diuretic efficacy over time.\\u003csup\\u003e\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e\\u003c/sup\\u003e Therefore, adding another diuretic that targets a different part of the nephron may help overcome this resistance. Although evidence is limited in preterm infants, Segar et al. reported increased diuresis and natriuresis among infants on repeated-dose furosemide after adding metolazone, a thiazide-like diuretic, compared to continuing furosemide alone.\\u003csup\\u003e\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e\\u003c/sup\\u003e Despite common concomitant diuretic exposure for both furosemide and chlorothiazide, a significant difference in diuretic effect was still noted between furosemide and chlorothiazide. While our study was not designed to assess sequential nephron blockade, we speculate that the greater effect of furosemide reflects its action in the loop of Henle, where sodium reabsorption is highest.\\u003csup\\u003e\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u003c/sup\\u003e These findings highlight the need for future studies to explore the potential for synergy in combination diuretic therapy in this population.\\u003c/p\\u003e\\u003cp\\u003eWe investigated the relationship of several clinical and diuretic characteristics with change in net fluid balance as clinical or dosing characteristics may impact differences in diuretic effect between furosemide and chlorothiazide. We identified that every 12-hour dosing was associated with a two-fold greater diuretic effect compared to every 24-hour dosing. This finding likely reflects the impact of more frequent furosemide dosing, as 90% of chlorothiazide was dosed at an every 12-hour interval with much less variation. While a wide variation exists in diuretic prescribing practices in NICUs in the United States, 1 mg/kg/day is the most common furosemide dose based on historical pharmacokinetic data.\\u003csup\\u003e\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e\\u003c/sup\\u003e A recent study using data from Pediatrix NICUs collected from 1997 to 2016 found that furosemide dosing practices were similar across PMA groups, despite previous studies reporting a shorter half-life and higher clearance among infants at an older PMA.\\u003csup\\u003e\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e\\u003c/sup\\u003e More frequent diuretic dosing is older infants with established BPD and the maturational capacity to rapidly clear furosemide likely results in a significantly greater amount of time in which a diuretic effect is present. These findings highlight the importance of future studies investigating dosing regimens as the efficacy and safety of more frequent dosing may differ in older infants with established BPD based on higher clearance with maturation in this population.\\u003c/p\\u003e\\u003cp\\u003eNo other infant or diuretic characteristic was significantly associated with diuretic effect in multivariable modeling. Notably, we found that prescribers consistently prescribed furosemide at a standardized IV-equivalent dose of 1 mg/kg, whereas chlorothiazide dosing was more variable. This variability may reflect a paucity of data on the pharmacokinetics of chlorothiazide in preterm infants. In the absence of robust pharmacokinetic data in preterm infants with BPD, we rely on presumptions about bioavailability, which may differ substantially depending on the clinical context, gestational age, and route of administration.\\u003csup\\u003e\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e\\u003c/sup\\u003e Mischaracterization of these parameters and the narrow dosing range observed in practice could obscure true associations of diuretic dose with diuretic effect. These findings underscore the need for future pharmacokinetic and pharmacodynamic studies to better characterize optimal dosing strategies and improve the precision of diuretic prescribing in this vulnerable population.\\u003c/p\\u003e\\u003cp\\u003eIt is important to contextualize our finding that furosemide has a threefold greater diuretic effect than chlorothiazide within the risk-benefit profiles of these diuretics, considering both therapeutic and adverse effects. In a retrospective study of 3252 infants in the Pediatric Health Information System Database, infants who had or were at risk of BPD and exposed to a prolonged thiazide course were more likely than infants exposed to a prolonged furosemide course to received NaCl and KCl supplementation.\\u003csup\\u003e\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e\\u003c/sup\\u003e In a more recent study among infants with high-grade BPD admitted to a single-center level IV NICU, changes in serum sodium, potassium, and chloride were similar between novel chlorothiazide and furosemide exposures, questioning the perception that chlorothiazide is a broadly \\u0026ldquo;gentler\\u0026rdquo; diuretic with respect to electrolyte loss.\\u003csup\\u003e\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e\\u003c/sup\\u003e Clinicians should weigh the significantly greater diuretic effect of furosemide compared to chlorothiazide (-32.0 vs. -10.5 mL/kg) with similar risks of sodium, potassium and chloride derangement.\\u003c/p\\u003e\\u003cp\\u003eOur study has several strengths. First, it examined 136 furosemide and 215 chlorothiazide exposures among 300 infants with high-grade BPD, representing the largest study comparing furosemide and chlorothiazide in this population. Second, we employed multivariable linear regression with robust variance estimates to account for confounding and within-subject repeated measures. Our study has limitations. First, this was a retrospective study relying on electronic health record abstraction and susceptible to misclassification bias from inaccurate documentation. However, outlying values were removed in the data curation process, limiting the impact of extreme values due to incorrect documentation. Additionally, there is potential for unmeasured confounders to influence the observed differences in diuretic effect, however we anticipate the likelihood of this to be low given the inclusion criteria for the cohort generation. Third, this study focused on short-term rather than long-term differences in fluid balance due to complex issues related to quantifying total exposure and the impact of renal homeostasis on diuretic effect over time, therefore these findings should not be generalized to the comparative diuretic effects of furosemide and chlorothiazide during prolonged repeated-dose exposures. Fourth, there was a high rate of diuretic co-exposure: 54% of furosemide and 78% of chlorothiazide exposures occurred concomitantly with the other diuretic. This necessitates a more nuanced interpretation as our results may not reflect the effect of these diuretics on fluid balance during diuretic monotherapy. However, such co-exposures are common in clinical practice.\\u003csup\\u003e\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e\\u003c/sup\\u003e Lastly, our study incorporates data from a single center, with its own culture surrounding diuretic prescription. Our center does not utilize specific clinical practice guidelines for diuretic prescription among infants with high-grade BPD, therefore exposure patterns in this study reflect individual prescriber preferences, which may not generalize to clinical settings or infants with high-grade BPD.\\u003c/p\\u003e\\u003cp\\u003eIn this large cohort of infants with high-grade BPD, furosemide was associated with a threefold greater diuretic effect than chlorothiazide. Given the similar risk of electrolyte imbalance, clinicians should weigh the greater efficacy of furosemide when choosing diuretic therapy.\\u003csup\\u003e\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e\\u003c/sup\\u003e Although furosemide and chlorothiazide are the most prescribed diuretics among infants with high-grade BPD, there are limited prospective data available to guide clinical practice related to these medications. Our findings should inform prospective studies to better understand optimal diuretic dosing, the potential for loop and thiazide diuretic synergy, and their impact on long-term clinical outcomes in preterm infants with high-grade BPD.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003ch2\\u003eConflict of Interest Disclosures:\\u003c/h2\\u003e\\u003cp\\u003eThe authors have no financial interests to disclose.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eTh\\u0026eacute;baud B, Goss KN, Laughon M, et al. Bronchopulmonary dysplasia. \\u003cem\\u003eNat Rev Dis Primers\\u003c/em\\u003e. 2019;5(1). doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1038/s41572-019-0127-7\\u003c/span\\u003e\\u003cspan address=\\\"10.1038/s41572-019-0127-7\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eBamat NA, Kirpalani H, Feudtner C, et al. Medication use in infants with severe bronchopulmonary dysplasia admitted to United States children\\u0026rsquo;s hospitals. \\u003cem\\u003eJournal of Perinatology\\u003c/em\\u003e. Published online 2019. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1038/s41372-019-0415-9\\u003c/span\\u003e\\u003cspan address=\\\"10.1038/s41372-019-0415-9\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eNelin TD, Lorch S, Jensen EA, et al. The association between diuretic class exposures and enteral electrolyte use in infants developing grade 2 or 3 bronchopulmonary dysplasia in United States children\\u0026rsquo;s hospitals. \\u003cem\\u003eJournal of Perinatology\\u003c/em\\u003e. 2021;41(4). doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1038/s41372-021-00924-y\\u003c/span\\u003e\\u003cspan address=\\\"10.1038/s41372-021-00924-y\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eBamat NA, Nelin TD, Eichenwald EC, et al. Loop Diuretics in Severe Bronchopulmonary Dysplasia: Cumulative Use and Associations with Mortality and Age at Discharge. In: \\u003cem\\u003eJournal of Pediatrics\\u003c/em\\u003e. Vol 231.; 2021. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1016/j.jpeds.2020.10.073\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/j.jpeds.2020.10.073\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eTan C, Sehgal K, Sehgal K, Krishnappa SB, Sehgal A. Diuretic use in infants with developing or established chronic lung disease: A practice looking for evidence. \\u003cem\\u003eJ Paediatr Child Health\\u003c/em\\u003e. Published online 2020. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1111/jpc.14877\\u003c/span\\u003e\\u003cspan address=\\\"10.1111/jpc.14877\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSlaughter JL, Stenger MR, Reagan PB. Variation in the Use of Diuretic Therapy for Infants With Bronchopulmonary Dysplasia. \\u003cem\\u003ePediatrics\\u003c/em\\u003e. Published online 2013. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1542/peds.2012-1835\\u003c/span\\u003e\\u003cspan address=\\\"10.1542/peds.2012-1835\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eNelin TD, Huber M, Jensen EA, et al. Association of furosemide versus chlorothiazide exposures with serum sodium, potassium, and chloride among infants with bronchopulmonary dysplasia. \\u003cem\\u003eJournal of Perinatology\\u003c/em\\u003e. Published online November 5, 2024. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1038/s41372-024-02159-z\\u003c/span\\u003e\\u003cspan address=\\\"10.1038/s41372-024-02159-z\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSegar JL. Neonatal Diuretic Therapy: Furosemide, Thiazides, and Spironolactone. \\u003cem\\u003eClin Perinatol\\u003c/em\\u003e. Published online 2012. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1016/j.clp.2011.12.007\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/j.clp.2011.12.007\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eThompson EJ, Benjamin DK, Greenberg RG, et al. Pharmacoepidemiology of Furosemide in the Neonatal Intensive Care Unit. \\u003cem\\u003eNeonatology\\u003c/em\\u003e. 2021;117(6). doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1159/000510657\\u003c/span\\u003e\\u003cspan address=\\\"10.1159/000510657\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eJensen EA, Dysart K, Gantz MG, et al. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants An Evidence-based Approach. \\u003cem\\u003eAm J Respir Crit Care Med\\u003c/em\\u003e. Published online 2019. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1164/rccm.201812-2348OC\\u003c/span\\u003e\\u003cspan address=\\\"10.1164/rccm.201812-2348OC\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSegar JL. Evidence-based approach to diuretic therapy in the neonate. In: \\u003cem\\u003eRenal, Fluid and Electrolyte Disorders: Neonatology Questions and Controversies\\u003c/em\\u003e. Fourth. Elsevier; 2024:114\\u0026ndash;124.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eBamat NA, Huber M, Shults J, et al. Diuretic Tolerance to Repeated-Dose Furosemide in Infants Born Very Preterm with Bronchopulmonary Dysplasia. \\u003cem\\u003eJ Pediatr\\u003c/em\\u003e. 2024;266:113813. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1016/j.jpeds.2023.113813\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/j.jpeds.2023.113813\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eLoon NR, Wilcox CS, Unwin RJ. Mechanism of impaired natriuretic response to furosemide during prolonged therapy. \\u003cem\\u003eKidney Int\\u003c/em\\u003e. 1989;36(4). doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1038/ki.1989.246\\u003c/span\\u003e\\u003cspan address=\\\"10.1038/ki.1989.246\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eEllison DH. The physiologic basis of diuretic synergism: Its role in treating diuretic resistance. \\u003cem\\u003eAnn Intern Med\\u003c/em\\u003e. 1991;114(10). doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.7326/0003-4819-114-10-886\\u003c/span\\u003e\\u003cspan address=\\\"10.7326/0003-4819-114-10-886\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eJentzer JC, Dewald TA, Hernandez AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. \\u003cem\\u003eJ Am Coll Cardiol\\u003c/em\\u003e. 2010;56(19). doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1016/j.jacc.2010.06.034\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/j.jacc.2010.06.034\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSegar JL, Robillard JE, Johnson KJ, Bell EF, Chemtob S. Addition of metolazone to overcome tolerance to furosemide in infants with bronchopulmonary dysplasia. \\u003cem\\u003eJ Pediatr\\u003c/em\\u003e. 1992;120(6). doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1016/S0022-3476(05)81972-9\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/S0022-3476(05)81972-9\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eBamat NA, Thompson EJ, Greenberg RG, et al. Association between postmenstrual age and furosemide dosing practices in very preterm infants. \\u003cem\\u003eJournal of Perinatology\\u003c/em\\u003e. 2022;42(4). doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1038/s41372-022-01320-w\\u003c/span\\u003e\\u003cspan address=\\\"10.1038/s41372-022-01320-w\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eOsman MA, Patel RB, Irwin DS, Craig WA, Welling PG. Bioavailability of chlorothiazide from 50, 100, and 250 mg solution doses. \\u003cem\\u003eBiopharm Drug Dispos\\u003c/em\\u003e. 1982;3(2). doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1002/bdd.2510030202\\u003c/span\\u003e\\u003cspan address=\\\"10.1002/bdd.2510030202\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"},{\"header\":\"Tables\",\"content\":\"\\u003cp\\u003eTable 1 to 3 are available in the Supplementary Files section.\\u003c/p\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7068749/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7068749/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eObjective\\u003c/h2\\u003e\\u003cp\\u003eTo compare the diuretic effect of furosemide versus chlorothiazide in preterm infants with high-grade bronchopulmonary dysplasia (BPD).\\u003c/p\\u003e\\u003ch2\\u003eStudy Design:\\u003c/h2\\u003e\\u003cp\\u003eWe conducted a retrospective cohort study of infants with grade 2 or 3 BPD admitted to a level IV NICU between 36\\u0026ndash;60 weeks\\u0026rsquo; postmenstrual age. The primary outcome was within-subject change in net fluid balance (mL/kg) in the 24 hours before and after diuretic initiation. Multivariable linear regression adjusted for differences in diuretic and clinical variables.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e\\u003cp\\u003eAmong 136 furosemide and 215 chlorothiazide exposures in 300 infants, furosemide was most often dosed every 24 hours (73%), while chlorothiazide was most often dosed every 12 hours (90%). Median postmenstrual age at exposure was 44 weeks for furosemide and 42 weeks for chlorothiazide. Furosemide was associated with a significantly greater diuretic effect than chlorothiazide (-32.0 vs. -10.5 mL/kg; \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001).\\u003c/p\\u003e\\u003ch2\\u003eConclusions\\u003c/h2\\u003e\\u003cp\\u003eFurosemide resulted in a threefold greater diuretic effect than chlorothiazide in infants with high-grade BPD.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Chlorothiazide is associated with a weaker diuretic response than furosemide in infants with bronchopulmonary dysplasia (BPD)\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-07-23 02:14:54\",\"doi\":\"10.21203/rs.3.rs-7068749/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"bd4978fe-7843-4525-9e0d-ad23ee614f97\",\"owner\":[],\"postedDate\":\"July 23rd, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[{\"id\":51717344,\"name\":\"Health sciences/Health care/Therapeutics\"},{\"id\":51717345,\"name\":\"Health sciences/Diseases/Respiratory tract diseases\"}],\"tags\":[],\"updatedAt\":\"2025-08-04T14:25:34+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-07-23 02:14:54\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7068749\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7068749\",\"identity\":\"rs-7068749\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}