What are the mechanisms and management strategies for diuretic resistance in heart failure (HF)?

From the Guidelines

Diuretic resistance in heart failure should be managed by optimizing the loop diuretic regimen, potentially adding a thiazide diuretic, and addressing underlying heart failure with guideline-directed medical therapy, as recommended by the most recent guidelines 1, 2. To manage diuretic resistance, the following steps can be taken:

• Optimize the loop diuretic regimen by switching to continuous intravenous infusion of furosemide, starting at 5-10 mg/hour after a loading dose, rather than bolus dosing, as this method has been shown to be effective in overcoming diuretic resistance 3, 2.
• If this is insufficient, add a thiazide diuretic such as metolazone (2.5-10 mg once daily) or chlorothiazide (500-1000 mg intravenously) to block distal tubule sodium reabsorption, creating sequential nephron blockade, as recommended by the 2022 AHA/ACC/HFSA guideline for the management of heart failure 1, 2.
• For patients with preserved renal function, acetazolamide (250-500 mg daily) can be added as a third agent, but its use should be carefully considered due to potential side effects.
• Ensure adequate blood pressure before initiating these combinations to avoid hypotension, and monitor electrolytes daily, particularly potassium, sodium, and magnesium, as aggressive diuresis can cause dangerous electrolyte abnormalities 3, 1.
• Temporary ultrafiltration through dialysis may be necessary in severe cases of diuretic resistance, as recommended by the guidelines 1, 2. The development of diuretic resistance is a complex process, involving decreased renal perfusion in heart failure, activation of the renin-angiotensin-aldosterone system causing sodium retention, distal tubule hypertrophy from chronic loop diuretic use, and reduced drug delivery to the kidney due to low cardiac output and hypoalbuminemia 3, 1. Addressing the underlying heart failure with guideline-directed medical therapy, including ACE inhibitors, beta-blockers, and mineralocorticoid receptor antagonists, may also help improve diuretic responsiveness over time, as these therapies have been shown to reduce morbidity and mortality in patients with heart failure 1, 2.

From the Research

Definition and Prevalence of Diuretic Resistance

• Diuretic resistance is defined as the failure to increase fluid and sodium output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of a loop diuretic to a ceiling level 4.
• The prevalence of diuretic resistance in heart failure is difficult to determine due to the lack of a standard definition, but estimates suggest that 25-30% of patients with heart failure have diuretic resistance 5.
• Up to 50% of patients hospitalized for acute heart failure show resistance to diuretics, contributing to a prolonged hospital length of stay and a higher risk of death 6.

Pathophysiology and Mechanisms

• Pharmacokinetic mechanisms of diuretic resistance include the low and variable bioavailability of furosemide and the short duration of all loop diuretics 4.
• Pathophysiological mechanisms include an inappropriately high daily salt intake, hyponatremia or hypokalemic, hypochloremic metabolic alkalosis, and reflex activation of the renal nerves 4.
• Nephron mechanisms include tubular tolerance, enhanced reabsorption in the proximal tubule, and adaptive increase in reabsorption in the downstream distal tubule and collecting ducts 4.

Diagnostic and Prognostic Value

• Diuretic resistance is a major cause of recurrent hospitalizations in patients with chronic heart failure and predicts death 4.
• The prognostic value of diuretic efficiency and predictors of natriuretic response in acute heart failure are important areas of research 7.
• Urine sodium concentration may serve as a functional, physiological, and direct measure for diuretic responsiveness to a given loop diuretic dose 7.

Treatment Strategies

• The therapeutic approach to diuretic resistance typically involves increases in the diuretic dose and/or frequency, sequential nephron blockade, and mechanical fluid movement removal with ultrafiltration or peritoneal dialysis 5.
• Combination diuretic regimens, such as the addition of metolazone, IV chlorothiazide, or tolvaptan to loop diuretics, may be effective in overcoming diuretic resistance 8.
• However, a systematic review and network meta-analysis found no significant differences in efficacy between different diuretic strategies in patients with diuretic-resistant acute heart failure 6.