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Acute heart failure hospitalizations complicated by diuretic resistance are associated with worse outcomes. Yet, quantification of the frequency and accompanying risk from loop diuretic resistance is limited by the absence of a comprehensive definition with universal clinical application. Herein, we outline limitations of the current metrics used to identify and define diuretic resistance. We discuss the best available methods to identify and prognosticate outcomes in diuretic resistance. We propose a mechanism-based classification system of diuretic resistance by anatomical location as follows: pre-nephron resistance, pre-loop of Henle resistance, loop of Henle resistance, and post-loop of Henle resistance. Within this paradigm, we compare and contrast historical beliefs of resistance mechanisms with current literature specific to patients with heart failure. We recommend a treatment pathway to restore diuretic efficacy with a literature review of the various combination diuretic strategies and ongoing clinical trials that may impact current best practices.

Furosemide is the most commonly used diuretic in intensive care units (ICU). We aimed to evaluate the physiological effects of adjunctive acetazolamide with furosemide on diuresis and the prevention of potential furosemide-induced metabolic alkalosis. We performed a two-center, pilot, open-label, randomized trial. Where the treating physicians planned intravenous diuretic therapy, we randomized ICU patients to a bolus of furosemide (40 mg) plus acetazolamide (500 mg) (n = 15) or furosemide alone (40 mg) (n = 15). Urine output, additional furosemide use, acid-base parameters, and electrolytes were compared following a Bayesian framework. Adjunctive acetazolamide didn't increase urine output in the first six hours (mean difference: −112 ml, credible interval: [−742, 514]). However, compared with furosemide alone, it maintained a greater urine output response to furosemide over 24 h, with 100 % probability. Acetazolamide also acidified plasma (pH difference: −0.045, [−0.081, −0.008]) while alkalinizing urine (1.10, [0.04, 2.11]) at six hours, compared to furosemide alone with >95 % probability. Finally, we didn't observe severe acidosis or electrolyte disturbances over 24 h. Adjunctive acetazolamide may increase diuretic efficacy and counterbalance furosemide-induced metabolic alkalosis without safety concerns. Larger trials are warranted to verify these findings and assess their impacts on clinical outcomes. ACTRN12623000624684. A pilot trial of single versus dual diuretic therapy in the intensive care unit. •Pathophysiologic effects of adjunctive acetazolamide were assessed in this pilot RCT.•Acetazolamide may have preserved urine output response to furosemide.•Acetazolamide may have counterbalanced furosemide-induced metabolic alkalosis.•Adjunctive acetazolamide may not result in severe acidosis or electrolyte disturbance.•Larger trials to evaluate the effect of adjunctive acetazolamide appear justified.

Patients hospitalized with acute heart failure (HF) may experience diuretic resistance and require an add-on agent despite increasing loop diuretic dosage. While randomized controlled trials (RCTs) have compared add-on therapy to loop diuretics only, sparse literature exists on direct comparisons between various add-on therapies. We performed a systematic review and network meta-analysis of RCTs to assess the efficacy and safety of different diuretic add-on therapies in patients hospitalized with acute HF. Any RCT evaluating the effect of add-on diuretic therapy in patients hospitalized with acute HF was eligible for inclusion. A systematic search of EMBASE and PubMed was conducted until March 29, 2024. The primary outcome was the hospital length of stay. Data was pooled using a random-effects model for direct comparisons. A network meta-analysis using frequentist methods was performed under random-effects multiple treatment comparisons. We assessed ranking probability using the surface under the cumulative ranking curve (SUCRA) method. Of the 1,103 references, 29 RCTs enrolling 8,362 patients met the eligibility and were included. For the direct comparisons, there was no significant difference in hospital length of stay (MD -0.42, 95% CI= -0.87,0.02). Ranking probability based on SUCRA indicated that acetazolamide had the highest likelihood of being the best treatment for shorter hospital length of stay (SUCRA, 0.89), followed by SGLT2i (SUCRA, 0.70). The certainty of estimates for all outcomes ranged from moderate to very low. In conclusion, the efficacy of add-on therapy was associated with reduced hospital length of stay. Albeit uncertain, the results from NMA provide initial evidence suggesting there may be optimal treatment strategies to decongest patients with HF to achieve and maintain euvolemia. However, well-designed direct comparison RCTs are needed to increase the certainty of the estimates. Protocol registered in PROSPERO (CRD42023476669).

Diuretic resistance (DR) is common among patients admitted with acute heart failure (AHF) and can be estimated by BAN-ADHF scores. Among 317 consecutive patients hospitalized for AHF, BAN-ADHF scores were compared with metrics of DR and composite endpoint of all-cause mortality, HF hospitalization, LVAD, or heart transplantation. The BAN-ADHF score was incorporated into a diuretic dosing calculator and retroactively applied to a patient's diuretic dose to categorize them as adequately dosed or under-dosed (inadequate). The primary outcome studied was attaining >3 L of urine output within the first 24 hours of admission. The median BAN-ADHF score was 9 (IQR of 7-13). A higher BAN-ADHF score was associated with greater DR based on weight loss and urine output (all p <0.001). The highest quartile (Q4) had fewer patients achieve the admission urinary output goal (15% vs 32%, p = 0.004) and lower total urine output (2,009 mL vs 2,559 mL, p = 0.029) compared with the first 3 quartiles. In time-to-event analysis, Q4 of BAN-ADHF score was associated with increased risk of the primary composite endpoint (HR 2.07, 95% CI 1.41 to 3.04). Compared to those below the calculator's recommended dose, patients receiving loop diuretics at goal doses (37.7% of cohort) had greater 24-hour UOP (3,050 vs 2,050 mL), likelihood of UOP goal (45% vs 19%), and weight loss at discharge (8.95 kg vs 5.94 kg; all p <0.001). In conclusion, BAN-ADHF score correlated with diuretic resistance and prognosis, and may capture the risk of DR compared traditional measures like CKD or NT-proBNP.

Hospitalization for ADHF is linked to poor outcomes, with residual congestion at discharge significantly increasing the risk of HF readmissions and mortality. Diuretic resistance is a major contributor to inadequate decongestion during ADHF treatment. In this review, we discuss various decongestive strategies, emphasizing the management of diuretic resistance. Additionally, we examine the limitations of current decongestion trials and highlight key priorities for future research.

Abstract Diuretics, such as furosemide, are routinely administered to dogs with congestive heart failure (CHF). Traditionally, dose and determination of efficacy primarily are based on clinical signs rather than quantitative measures of drug action. Treatment of human CHF patients increasingly is guided by quantification of urine sodium concentration (uNa) and urine volume after diuretic administration. Use of these and other measures of diuretic responsiveness is associated with decreased duration of hospitalization, complication rates, future rehospitalization, and mortality. At their core, loop diuretics act through natriuresis, and attention to body sodium (Na) stores and handling offers insight into the pathophysiology of CHF and pharmacology of diuretics beyond what is achievable from clinical signs alone. Human patients with low diuretic responsiveness or diuretic resistance are at risk for difficult or incomplete decongestion that requires diuretic intensification or other remedial strategies. Identification of the specific etiology of resistance in a patient can help tailor personalized interventions. In this review, we advance the concept of loop diuretic responsiveness by highlighting Na and natriuresis. Specifically, we review body water homeostasis and congestion in light of the increasingly recognized role of interstitial Na, propose definitions for diuretic responsiveness and resistance in veterinary subjects, review relevant findings of recent studies, explain how the particular cause of resistance can guide treatment, and identify current knowledge gaps. We believe that a quantitative approach to loop diuretic usage primarily involving natriuresis will advance our understanding and care of dogs with CHF.

•Significant reductions in oral diuretic use were observed, with an average reduction of 65% at 24 months after metabolic surgery.•Decrease in body mass index and total body weight loss observed at 24 months are greater than reported in the general population.•Improvements in hemoglobin A1c levels were sustained ≥24 months postoperatively.•Trends toward less emergency department utilization for cardiac conditions and intravenous diuresis were observed.•Metabolic surgery indicates promising metabolic and cardiac benefits in patients with heart failure. The beneficial impacts of metabolic surgery (MS) on patients with heart failure (HF) are incompletely characterized. We aimed to describe the cardiac and metabolic effects of MS in patients with HF and hypothesized that patients with HF would experience both improved metabolic and HF profiles using glycemic control and diuretic dependency as surrogate markers. In this single-center, university-affiliated academic study in the United States, a review of 2,342 hospital records of patients who underwent MS (2017 to 2023) identified 63 patients with a medical history of HF. Preoperative characteristics, 30-day outcomes, and up to 2-year biometric and metabolic outcomes, medication usage, and emergency department utilization were collected. At 24 months, mean body mass index change was −16 kg/m2 (p <0.001) that corresponded to a mean percentage total body weight loss of 29% (p <0.001). Weight loss was accompanied by significant reductions in hemoglobin A1c (p <0.001) and a 65% decrease in diuretic use at 24 months after surgery (p <0.001). Similarly, emergency visits for cardiac conditions (p = 0.06) and intravenous diuresis (p = 0.07) trended favorably at 1 year after surgery compared with 1 year before surgery but were not statistically significant. In conclusion, in patients with HF who were carefully selected, MS appears to provide significant reduction in oral diuretic dependency, and metabolic improvements with trends toward lower rates of emergency department utilization.

Reduced efficacy of oral diuretics in the treatment of congestive heart failure (CHF) can be secondary to reduced enteral drug absorption. The aim of this study was to determine the efficacy of subcutaneous (SC) furosemide administration to control the signs of refractory CHF in dogs and cats and to assess the feasibility of this route of administration. The clinical records of 13 dogs and 17 cats with a history of refractory CHF treated with subcutaneous (SC) furosemide were reviewed retrospectively. Administration of SC furosemide was offered as an alternative therapy when animals experienced an unsatisfactory clinical response to oral diuretics despite multiple dose adjustments and when, for this reason, pet owners were considering euthanasia. The satisfactory control of the animal’s breathing rate and effort and overall pet owner’s satisfaction were observed in all cases. Following administration of SC furosemide, the median survival time was 106 (95% CI: 22–154) days in dogs and 89 (95% CI: 35 to 749) days in cats. This study showed that furosemide administered subcutaneously appears to be an efficacious and feasible therapeutic option for providing control of the signs of cardiac congestion in both dogs and cats with a previous unsatisfactory response to oral diuresis.

In cardiorenal Syndrome (CRS), diuretic resistance is frequent and congestion predominates in acute forms. In refractory cases, non-pharmacological ultrafiltration therapies have shown effectiveness on fluid removal, improved diuresis, and reduced rehospitalizations. However, the choice of modality remains individualized and resource-dependent. Both continuous renal replacement therapy (CRRT) and peritoneal dialysis (PD) offer hemodynamic advantages, but CRRT carries risks such as infection, bleeding, and high cost. PD has also demonstrated benefits in acute settings, providing effective sodium removal, and no need for anticoagulation, though it is not considered first-line therapy. There are few studies comparing different renal replacement therapies (RRT) in patients with acute CRS and there is no evidence on diuretic resistance. So, the question arises: could there be an advantage of a modality beyond fluid removal? The scarcity of comparative studies underscores the need for randomized trials that move beyond the cardiocentric perspective and include patients at risk of diuretic resistance.

Abstract Background: Diuretic resistance is among the most challenging problems that the cardio-nephrologist must address in daily clinical practice, with a considerable burden on hospital admissions and health care costs. Indeed, loop diuretics are the first-line therapy to overcome fluid overload in heart failure patients. The pathophysiological mechanisms of fluid and sodium retention are complex and depend on several neuro-hormonal signals mainly acting on sodium reabsorption along the renal tubule. Consequently, doses and administration modalities of diuretics must be carefully tailored to patients in order to overcome under- or overtreatment. The frequent and tricky development of diuretic resistance depends in part on post-diuretic sodium retention, reduced tubular secretion of the drug, and reduced sodium/chloride sensing. Sodium and chloride depletions have been recently shown to be major factors mediating these processes. Aquaretics and high-saline infusions have been recently suggested in cases of hyponatremic conditions. This review discusses the limitations and strengths of these approaches. Summary: Long-term diuretic use may lead to diuretic resistance in cardio-renal syndromes. To overcome this complication intravenous administration of loop diuretics and a combination of different diuretic classes have been proposed. In the presence of hyponatremia, high-saline solutions in addition to loop diuretics might be beneficial, whereas aquaretics require caution to avoid overcorrection. Key Messages: Diuretic resistance is a central theme for cardio-renal syndromes. Hyponatremia and hypochloremia may be part of the mechanisms for diuretic resistance. Aquaretics and high-saline solutions have been proposed as possible new therapeutic solutions.