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CardioNerds (Amit Goyal and Daniel Ambinder), join Dr. Anjali Wagle (Internal medicine resident, Johns Hopkins Hospital) and Dr. Nick Smith (Cardiology fellow, Johns Hopkins Hospital) for an important discussion involving a patient with non-ischemic dilated cardiomyopathy and biventricular heart failure who had developed diuretic resistance. They discuss the role for invasive hemodynamic assessment of volume overload, initial strategies in managing a patient with volume overload, the role of guideline directed therapy in the management of patients with recurrent volume overload, and advanced strategies for diuretic resistance. Dr. Nisha Gilotra (Director of the Cardiac Sarcoidosis Program and assistant professor of medicine, Johns Hopkins Hospital) provides the E-CPR for this episode. Audio editing and Approach to Diuretic Resistance infographic by Dr. Gurleen Kaur (Director of the CardioNerds Internship).
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Patient Summary – Diuretic Resistance
A young woman in her 20s with non-ischemic dilated cardiomyopathy and NYHA class IV ACC stage D biventricular heart failure with an LV ejection fraction of 30-35% on palliative inotropic therapy complicated by cardiogenic cirrhosis and stage IIIb chronic kidney disease presented with acute decompensated heart failure with volume overload. During her hospitalization she exhibited profound signs of diuretic resistance with minimal improvement after increasing inotropes, increasing IV loop diuretics, adding IV thiazides, and trialing continuous IV furosemide. She was given high dose mineralocorticoids, IV acetazolamide, and hypertonic saline paired with IV furosemide and had a durable treatment response.
Episode Teaching – Diuretic Resistance
Pearls – Diuretic Resistance
- Diuretic resistance is a complex clinical problem defined as inadequate natriuresis despite an adequate diuretic regimen. However, the practitioner cannot overlook low output heart failure and/or insufficient renal perfusion as the causes for inadequate diuretic response. In cases of inadequate urine output due to low cardiac output, increased inotropic or mechanical support would be the first objective.
- Confirming adequate cardiac output to support renal perfusion and/or confirming high filling pressures may require invasive hemodynamic assessment.
- Sodium avidity is most effectively blunted by treating the patient with maximally tolerated guideline directed therapy. This includes but is not limited to a backbone of ARNI (or ACE or ARB), mineralocorticoid receptor antagonists, beta-blockers, and SGLT-2 inhibitors.
- In cases of advanced diuretic resistance, hypertonic saline paired with high dose IV furosemide can be an effective strategy.
- In cases of diuretic resistance combined with cirrhosis and heart failure there is a synergistic hyperaldosteronism that can be targeted with higher doses of mineralocorticoid receptors as is seen in the treatment of cirrhosis with ascites.
Notes – Diuretic Resistance
1. What is the role for invasive hemodynamic assessment in acute decompensated heart failure?
- Cases where intracardiac filling pressures are in question: right heart catheterization (RHC) can give insight into the presence and degree of right versus left sided filling pressures. We discussed the concepts of “RV equalizer” vs “RV compensated” groups in Episode 142 with Dr. Mark Drazner.
- Cases where cardiac output is in question, especially to guide vasoactive infusions during low flow states: RHC can assess cardiac output and cardiac power output.
- Cases with rising creatinine during diuresis despite a clinical exam suggesting volume overload.
- Cases where body habitus prevents optimal evaluation.
2. What are the initial strategies in managing a patient with volume overload?
- Initial furosemide dosing: The patient’s home dose, renal function, and reason for decompensation all help decide the initial IV diuretic dosing. However, in general if a patient has an outpatient furosemide regimen, the initial diuretic dose should 2.5 times the oral dosing for intermittent IV doses. For example, if a patient is taking 40 mg PO daily as an outpatient, a starting dose of 100 mg IV as a starting dose is appropriate.
- Furosemide escalation
- IV dosing: constantly assess the appropriateness of each furosemide dose by monitoring hourly urine output and daily standing weight changes. Post-dose urine sodium is another option. If the patient has not made 300 cc/hr after their last furosemide dose, you may need to escalate the dose. Due to the furosemide threshold effect, the patient may need to double the prior dose for every uptitration. Additionally, even though furosemide lasts for 6 hours, if the diuretic effect is minimal, immediately prescribe double the last dose of furosemide.
- Continuous infusion vs bolus: The DOSE trial, or Diuretic Optimization Strategies Evaluation, randomized 308 patients to either IV furosemide q12 or an equivalent dose as a continuous infusion and found no difference in secondary endpoints of change in weight or net fluid loses. There may be a role for continuous infusion furosemide in patients who are sensitive to large fluid shifts, such as patients with right heart failure.
- Adjunctive diuretics
- Thiazide diuretics: when high dose IV furosemide is failing, thiazide diuretics are commonly the first adjunct use. When given in combination with loop diuretics, they allow blockade of both the sodium-potassium-chloride channels in the loop as well as the sodium chloride channels distally to allow increased blockade of the ability to reabsorb sodium and potassium.
- Potassium sparing diuretics: the addition of potassium-sparing diuretics (i.e., mineralocorticoid receptor antagonists or ENaC inhibitors like amiloride or triamterene) may be especially helpful for hypokalemia caused by loop +/- thiazide diuretics.
- Acetazolamide: is a carbonic anhydrase inhibitor and acts in the proximal convoluted tubule. It aids in the excretion of sodium and bicarbonate. It is commonly, but not always, used in situations where serum bicarbonates become elevated.
3. What is the role of guideline directed therapy in the management of patients with recurrent volume overload?
- In short, maximally tolerated guideline directed therapy blunts sodium retention through multiple mechanisms, but none more so than blockers of the renin-angiotensin-aldosterone-system. By blocking aspects of this pathway, the kidneys’ propensity to reabsorb sodium is blunted upstream of the nephron, preventing some of the need for high dose diuretics. Individual GDMT therapies and some of their effects on diuretic dosing are explained below.
- ARNI (angiotensin receptor neprilysin inhibitor): post-hoc analysis of the PARADIGM trial demonstrated that patients were more likely to decrease diuretic dosing on ARNI compared to placebo. Other single center studies have demonstrated similar effects, finding that loop diuretic dosing decrease was achieved in 1/3 of patients with a mean reduction of 10±38 mg furosemide equivalent across the entire population. Conversely, be cautious of diuretic dosing when initiating a patient on an ARNI agent. Enjoy Episode 148 with Dr. Milton Packer discussing the history of ARNI!
- MRA: Post-hoc analysis of EPHESUS demonstrated that the mineralocorticoid receptor antagonist Eplerenone led to a mean furosemide equivalent dose reduction of −2.2 mg/day (−2.9 to −1.6) throughout the follow-up
- MADIT-CRT: A post-hoc analysis of the MADIT-CRT trial showed that CRT implant led to diuretic cessation in 9.7% of patients. In a subsequent retrospective study of 352 subjects on baseline diuretics, 36% of patients tolerated a down-titration of loop diuretic dose following CRT-implant. These effects appeared sustained and were associated with both an improved hemodynamic performance and decreased probability of HF or death.
- SGLT-2 inhibitors: SGLT-2 inhibitors have a modest diuretic effect through glycosuria. Post-hoc analysis of the DAPA-HF trial did not show reduction in diuretic requirements over the 18-month trial, however SGLT-2 inhibitors have been shown to lead to reduction in diuretic requirements when used in combination when used in combination with MRA, BB, and ARNI therapy as part of a GDMT regimen.
4. What are some advanced strategies for diuretic resistance?
- Dopamine: The ROPA-DOP trial was a small single center trial performed in hospitalized patients with acute decompensated heart failure with preserved ejection fraction. It showed that continuous low dose dopamine infusion had no significant impact on renal function or decongestion.
- High Dose Spironolactone: Post-hoc analyses of trials involving spironolactone have not demonstrated reductions in diuretic dosing. However, in patients with a combination of cirrhosis and heart failure the hyperaldosteronism that results can be profound. For these patients, natriuretic doses of aldosterone antagonists (spironolactone >50 mg/day) may be a potential option and have been studied in small proof-of-principle studies. The competitive natriuretic response of aldosterone antagonists is related to activity of the renin-angiotensin-aldosterone system: the higher the renin-angiotensin-aldosterone system activity, the higher the dose of aldosterone antagonist required to produce natriuresis.
- Hypertonic saline: Hypertonic saline combined with high-dose loop diuretics has been studied and shown to produce greater natriuresis than diuretics alone, particularly in patients with diuretic resistance. The proposed mechanism of hypertonic saline’s diuretic effect has been the instantaneous mobilization of extravascular fluid into the intravascular space through the osmotic action of hypertonic saline.
1) Felker GM, Institute DCR, Ellison DH, et al. Diuretic Therapy for Patients With Heart Failure: JACC 2020 Mar, 75 (10) 1178-195
2) DOSE Trial: Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364(9):797-805
3) Athena-HF: Butler J, Anstrom KJ, Felker GM, et al. Efficacy and Safety of Spironolactone in Acute Heart Failure. JAMA Cardiol. 2017;2(9):950–958
4) Wan S-H, Stevens SR, et al. Differential Response to Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Reduced or Preserved Ejection Fraction. Circulation: Heart Failure. 2016;9:e002593
5) Bansal S, Lindenfeld J, Schrier RW. Sodium retention in heart failure and cirrhosis: potential role of natriuretic doses of mineralocorticoid antagonist?. Circ Heart Fail. 2009;2(4):370-376.
6) ROPA-DOP Trial: Sharma K, Vaishnav J, Kalathiya R, et al. Randomized Evaluation of Heart Failure With Preserved Ejection Fraction Patients With Acute Heart Failure and Dopamine. JACC Heart Fail. 2018;6(10):859-870.
7) RALES trial: Pitt B, et al. “The effect of spironolactone on morbidity and mortality in patients with severe heart failure”. New England Journal of Medicine. 1999. 341(10):709-717.
8) PARADIGM Trial: McMurray JJV, et al. “Angiotensin-neprilysin inhibition versus enalapril in heart failure”. The New England Journal of Medicine. 2014. 371(11):993-1004.
9) Vardeny O, Claggett B, Kachadourian J, et al. Reduced loop diuretic use in patients taking sacubitril/ valsartan compared with enalapril: the PARADIGM-HF trial. Eur J Heart Fail 2019;21:337-41.
10) Kerr B, Mcdonald K, Angiotensin Receptor Neprilysin Inhibitors in HFrEF: Is This the First Disease Modifying Therapy Drug Class Leading to a Substantial Reduction in Diuretic Need? Int J Heart Fail. 2021 Apr;3(2):106-116