Continuous Infusion and Sequential Nephron Blockade Versus Bolus Furosemide in Acute Heart Failure: A Systematic Review

Acute heart failure (AHF) is a leading cause of hospitalization worldwide, with congestion as its central pathophysiologic feature. Loop diuretics, particularly furosemide, remain the cornerstone of decongestive therapy, yet the optimal administration strategy, continuous infusion versus bolus dosing, remains debated. Furthermore, sequential nephron blockade through the addition of distal tubule-acting diuretics or sodium-glucose cotransporter-2 (SGLT2) inhibitors has emerged as a strategy to overcome diuretic resistance. This systematic review had two primary objectives: first, to compare continuous infusion versus bolus dosing of furosemide; second, to evaluate the efficacy and safety of adjunctive sequential nephron blockade (SGLT2 inhibitors, thiazides, and acetazolamide) added to loop diuretics within the context of the ongoing debate over optimal decongestion in AHF. A systematic literature search was conducted in PubMed, Scopus, Web of Science, the Cochrane Library, and ClinicalTrials.gov for studies published between 2021 and 2025. Eligible studies included randomized controlled trials (RCTs) and prospective observational studies evaluating either continuous furosemide infusion versus bolus furosemide or adjunctive sequential nephron blockade (added to loop diuretics) versus placebo, usual care, or, in one case, an active diuretic comparator. The Cochrane Risk of Bias 2 (RoB 2) tool was used for RCTs, and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool was used for the nonrandomized study. A narrative synthesis was performed because of substantial clinical and methodological heterogeneity. Ten studies (nine RCTs and one prospective observational study) comprising 2,972 patients were included. Continuous furosemide infusion consistently improved surrogate measures of decongestion (urine output and weight loss) compared with bolus dosing. However, these benefits did not reliably translate into improved symptoms or shorter hospital stays, and one large study reported increased renal injury and adverse events, highlighting a potential efficacy-safety trade-off. Sequential nephron blockade with SGLT2 inhibitors enhanced diuresis with favorable renal and electrolyte safety profiles and a nonsignificant trend toward lower mortality (the studies were not powered for mortality). Thiazide-based strategies achieved potent diuresis but significantly increased the risks of acute kidney injury and electrolyte disturbances without a mortality benefit. Acetazolamide improved decongestion safely but did not reduce mortality or readmissions. No single decongestive strategy is universally superior. However, direct comparisons across strategies are limited by substantial heterogeneity in study design, patient populations (e.g., renal function and congestion severity), and outcome definitions. Continuous furosemide infusion offers enhanced diuresis but inconsistent clinical benefits and potential renal harm. Based largely on surrogate outcomes from heterogeneous studies not designed to detect differences in mortality or readmissions, definitive clinical recommendations remain limited. SGLT2 inhibitors represent a promising but not yet proven adjunct in AHF, pending larger, adequately powered trials. Thiazide-based sequential blockade should be reserved for refractory cases with close monitoring. Treatment should be individualized based on baseline renal function, congestion severity, and electrolyte status.