Chlorothiazide is Associated with a Weaker Diuretic Response than Furosemide in Infants with Bronchopulmonary Dysplasia

Abstract

Objective

This study aimed to compare the acute 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 and 60 weeks postmenstrual age. Novel diuretic exposures were defined as administration of furosemide or chlorothiazide without prior exposure to the same agent in the preceding 7 days. The primary outcome was the within-subject change in net fluid balance (mL/kg) in the 24 hours before and after diuretic initiation. Multivariable linear regression was performed adjusted for diuretic dosing, route, frequency, and clinical covariates.

Results

Among 300 infants contributing 136 furosemide and 215 chlorothiazide exposures, furosemide was most often dosed every 24 hours (73%) and chlorothiazide every 12 hours (90%). After covariate adjustment, furosemide was associated with a threefold greater reduction in net fluid balance compared to chlorothiazide (−32.0 vs. −10.5 mL/kg; p < 0.001). More frequent dosing (every 12 hours) was associated with greater diuretic effect than every 24-hour dosing for both agents (−22.4 vs. −11.3 mL/kg; p = 0.032). Concomitant use of both agents was common, yet the order of administration did not significantly influence fluid balance. No other clinical or biochemical characteristics were significantly associated with diuretic response.

Conclusion

Furosemide has a significantly greater acute diuretic effect than chlorothiazide in infants with high-grade BPD. These findings may inform short-term fluid management strategies and support further investigation into optimal diuretic selection and dosing in this population.

Key Points

• Furosemide has a greater acute diuretic effect than chlorothiazide in infants with grade 2/3 BPD.

• More frequent dosing was associated with greater diuretic effect than daily dosing for both agents.

• Concomitant use of both agents was common; the order of administration did not impact fluid balance.

Keywords

bronchopulmonary dysplasia - furosemide - chlorothiazide - diuretic

Data Availability Statement

The datasets generated/or analyzed during the current study and the code used to analyze and manage the data are available from the corresponding author on reasonable request.

Publication History

Received: 11 August 2025

Accepted: 30 September 2025

Accepted Manuscript online:
03 October 2025

Article published online:
16 October 2025

• References

• 1 Thébaud B, Goss KN, Laughon M. et al. Bronchopulmonary dysplasia. Nat Rev Dis Primers 2019; 5 (01) 78
• 2 Bamat NA, Kirpalani H, Feudtner C. et al. Medication use in infants with severe bronchopulmonary dysplasia admitted to United States children's hospitals. J Perinatol 2019; 39 (09) 1291-1299
• 3 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. J Perinatol 2021; 41 (04) 779-785
• 4 Bamat NA, Nelin TD, Eichenwald EC. et al. Loop diuretics in severe bronchopulmonary dysplasia: cumulative use and associations with mortality and age at discharge. J Pediatr 2021; 231: 43-49.e3
• 5 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 2020; 56 (08) 1189-1193
• 6 Slaughter JL, Stenger MR, Reagan PB. Variation in the use of diuretic therapy for infants with bronchopulmonary dysplasia. Pediatrics 2013; 131 (04) 716-723
• 7 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. J Perinatol 2025; 45 (03) 312-318
• 8 Segar JL. Neonatal diuretic therapy: furosemide, thiazides, and spironolactone. Clin Perinatol 2012; 39 (01) 209-220
• 9 Thompson EJ, Benjamin DK, Greenberg RG. et al. Pharmacoepidemiology of furosemide in the neonatal intensive care unit. Neonatology 2020; 117 (06) 780-784
• 10 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 2019; 200 (06) 751-759
• 11 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
• 12 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
• 13 Loon NR, Wilcox CS, Unwin RJ. Mechanism of impaired natriuretic response to furosemide during prolonged therapy. Kidney Int 1989; 36 (04) 682-689
• 14 Ellison DH. The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med 1991; 114 (10) 886-894
• 15 Jentzer JC, DeWald TA, Hernandez AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. J Am Coll Cardiol 2010; 56 (19) 1527-1534
• 16 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 (06) 966-973
• 17 Bamat NA, Thompson EJ, Greenberg RG. et al. Association between postmenstrual age and furosemide dosing practices in very preterm infants. J Perinatol 2022; 42 (04) 461-467
• 18 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 (02) 89-94
• 19 Orth LE, O'Mara KL. Impact of early versus late diuretic exposure on metabolic bone disease and growth in premature neonates. J Pediatr Pharmacol Ther 2018; 23 (01) 26-33
• 20 Campfield T, Braden G, Flynn-Valone P, Powell S. Effect of diuretics on urinary oxalate, calcium, and sodium excretion in very low birth weight infants. Pediatrics 1997; 99 (06) 814-818
• 21 Patel H, Yeh TF, Jain R, Pildes R. Pulmonary and renal responses to furosemide in infants with stage III-IV bronchopulmonary dysplasia. Am J Dis Child 1985; 139 (09) 917-919
• 22 Engelhardt B, Elliott S, Hazinski TA. Short- and long-term effects of furosemide on lung function in infants with bronchopulmonary dysplasia. J Pediatr 1986; 109 (06) 1034-1039
• 23 Bar A, Srugo I, Amirav I, Tzverling C, Naftali G, Kugelman A. Inhaled furosemide in hospitalized infants with viral bronchiolitis: a randomized, double-blind, placebo-controlled pilot study. Pediatr Pulmonol 2008; 43 (03) 261-267