Beating Diuretic Resistance

Educational Objectives

The goal of this program is to improve management of diuretic resistance. After hearing and assimilating this program, the clinician will be better able to:

1. Compare use of drip therapy using diuretics with bolus therapy.
2. Administer oral metolazone and intravenous furosemide in patients with diuretic resistance.
3. Differentiate among loop diuretics for potency.

Summary

Diuretic resistance (DR): occurs when counter-regulatory mechanisms neutralize the effects of diuretics before achieving therapeutic goals; this battle between disease and diuresis must be won to restore homeostasis; volume overload conditions (eg, congestive heart failure, cirrhosis with portal hypertension and ascites, nephrotic syndrome) contribute to salt and water retention; chronic kidney disease and low glomerular filtration rate (GFR) further exacerbates fluid overload; when multiple conditions overlap, diuresis becomes even more challenging

Case example: a man, 64 yr of age, was admitted with worsening shortness of breath >2 wk; history of 3 myocardial infarctions, a low ejection fraction of 15%, and pulmonary edema is present; despite doubling furosemide (Lasix) dose from 40 to 80 mg, he gained 22 lb of weight because of salt and water retention; he experienced difficulty breathing, had been sleeping in a chair (indicating possible paroxysmal nocturnal dyspnea), and suffered from painful leg edema, leading him to take ibuprofen; kidney function was impaired, with a baseline creatinine of 2 mg/dL; examination revealed bibasilar crackles, biventricular heaves, and pitting edema to the mid-thighs; he was caught in a cycle because ineffective arterial volume triggered hormonal responses that worsened fluid retention

Pharmacology of furosemide: it has variable bioavailability (40%-70%) and it is delivered to the kidneys via albumin; it is secreted through the proximal tubule to reach the loop of Henle, where it inhibits sodium-potassium-chloride transport; DR occurs when renal blood flow is reduced, albumin is low, or competing substances block furosemide’s action; nonsteroidal anti-inflammatory drugs (NSAIDs; eg, ibuprofen) directly counteract diuretic effects

Diuretic braking: DR can also develop through “diuretic braking,” where the nephron compensates by increasing sodium reabsorption proximally and distally; overcoming DR requires increasing the diuretic dose, using intravenous (IV) mode, using continuous infusion, adding synergistic diuretics, or addressing contributing factors (eg, low albumin, NSAID use)

Dosage of furosemide: a key question for patients is whether they urinate after taking a diuretic; if not, they need a higher dose; instead of multiple ineffective smaller doses (eg, 60 mg 3 times daily), a single high-dose administration (eg, 180 mg once) is more effective; the peak drug level directly influences sodium excretion; waiting too long to adjust dosing is another common mistake; oral furosemide takes effect in 20 to 30 min and lasts 4 to 6 hr; IV furosemide acts within minutes but lasts only 1 to 2 hr; IV furosemide has higher bioavailability; if an IV dose does not act <1 to 2 hr, the dose should be increased the same day

Mode of administration: compared with bolus therapy, drips allowed for easy dose adjustments, but scientific evidence supporting their superiority is limited; a 2023 study in the Quarterly Journal of Medicine analyzed 40 patients (mostly men) and found that while continuous infusion resulted in greater diuresis and lower body weight by day 3, there was no difference in clinical course, patient outcome, hemodynamics, renal function, mortality, or length of stay; additionally, electrolyte disturbances were more common; Karedath et al (2023) retrospectively examined 9 heart failure studies with 713 patients, balanced in gender representation; it showed lower body weight with continuous infusion but no significant differences in mortality, total urine output, hypokalemia, or brain natriuretic peptide reduction; the diuretic effect of continuous infusion was comparable to bolus therapy, making drips a convenience rather than a necessity

Diuretic selection: largely depends on a patient’s GFR; loop diuretics (eg, furosemide, bumetanide, torsemide, ethacrynic acid) are effective even at low GFRs (≥10 mL/min); ethacrynic acid, though rarely used, is valuable for patients allergic to sulfonamide drugs; thiazides, the most common diuretics, are ineffective at low GFRs, particularly hydrochlorothiazide <30 to 35 mL/min; however, metolazone (eg, Metoz, Zaroxolyn, Zytanix) remains effective because of its long half-life (24-30 hr), making it useful in combination therapy; another alternative is IV chlorothiazide, which is effective but expensive ($500)

Diuretic combination: combining loop and thiazide diuretics can enhance diuresis; a study by Risal et al (2022) published in Nepalese Heart Journal found that adding metolazone to IV furosemide significantly improved fluid removal without increasing hypotension, electrolyte abnormalities, or acute kidney injury; oral metolazone should be given 1 hr before IV furosemide to ensure optimal effect; in resistant heart failure cases, adding metolazone can be beneficial, with most patients responding <24 to 48 hr; failure to respond suggests a poor prognosis

Comparison of loop diuretics: furosemide, torsemide, and bumetanide (Busex) differ in potency, bioavailability, and cost; 40 mg of furosemide equals 20 mg torsemide; 1 mg of bumetanide equals 40 mg furosemide; has better oral bioavailability; bumetanide is the most potent and most expensive; furosemide is the most cost-effective and doubling its dose is effective option

Use of albumin: in nephrotic patients excreting >3 g of albumin/day, salt-poor albumin enhances diuresis when combined with furosemide; a study by Fliser et al (1999) showed that this combination produced the greatest urine output and sodium excretion, though it also increased albuminuria; despite this, the improved delivery of furosemide made it more effective than either agent alone; this approach is sometimes used in patients with cirrhosis and DR

Complications of diuretics: include potassium and magnesium depletion, hyponatremia, ototoxicity, pre-renal azotemia, acute kidney injury, and metabolic alkalosis; this alkalosis presents as rising bicarbonate because of increased natriuresis; to manage this, it is essential to recognize hypokalemic hypochloremic metabolic alkalosis; chloride depletion primarily drives the alkalosis, so potassium chloride is given not for potassium but for chloride replenishment; magnesium should also be checked and repleted since hypomagnesemia leads to potassium loss; without magnesium correction, potassium supplementation is ineffective; a rough guide for potassium repletion is 10 to 20 mEq for each 0.1 mEq/L reduction <4 mEq/L of potassium, preferably administered orally; if alkalosis worsens or potassium levels limit correction, acetazolamide (Diamox) can be used to promote bicarbonate excretion; for refractory cases, nephrology consultation is needed, as severe alkalosis can cause hypoxemia, confusion, nausea, and hinder extubation because of suppressed respiratory drive

Salt-poor albumin: can enhance natriuresis by 20% but has a short duration of 12 to 24 hr; it is best reserved for diuretic-resistant, intubated, or pre-dialysis patients; albumin binds to loop diuretics (eg, furosemide) enhancing their renal delivery; in nephrotic patients, decreasing proteinuria through angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or non-dihydropyridine calcium channel blockers improves diuretic efficacy

Other options: short-term dopamine or dobutamine may be considered, but these can induce myocardial cell death, worsening long-term outcomes; if diuresis fails, renal replacement therapy or a heart transplant is necessary, though low blood pressure can limit dialysis options; for heart failure patients, maintaining a systolic blood pressure >90 mm Hg is advised

Weight monitoring: preventing hospitalizations involves proactive weight monitoring; the “D5 rule” encourages patients to report weight changes of ≥5 pounds instead of waiting until a significant gain worsens their condition; a smart scale that alerts providers could prevent admissions; a personalized diuretic sliding scale, based on the patient’s ideal weight, adjusts diuretics and potassium supplementation while guiding when to seek medical advice; this method successfully prevented hospitalizations in a real-world case, proving its effectiveness

Readings

Alexander RT, Dimke H. Effect of diuretics on renal tubular transport of calcium and magnesium. Am J Physiol Renal Physiol. 2017;312(6):F998-F1015. doi:10.1152/ajprenal.00032.2017; Cuthbert JJ, Clark AL. Diuretic treatment in patients with heart failure: Current evidence and future directions - Part I: Loop diuretics. Curr Heart Fail Rep. 2024;21(2):101-114. doi:10.1007/s11897-024-00643-3; Dahiya G, Bensimhon D, Goodwin MM, et al. From oral to subcutaneous furosemide: The road to novel opportunities to manage congestion. Struct Heart. 2022;6(4):100076. doi:10.1016/j.shj.2022.100076; Fliser D, Zurbrüggen I, Mutschler E, et al. Coadministration of albumin and furosemide in patients with the nephrotic syndrome. Kidney Int. 1999;55(2):629-634. doi:10.1046/j.1523-1755.1999.00298.x; Karedath J, Asif A, Tentu N, et al. Continuous infusion versus bolus injection of loop diuretics for patients with congestive heart failure: A meta-analysis. Cureus. 2023;15(2):e34758. doi:10.7759/cureus.34758; Malha L, Mann SJ. Loop diuretics in the treatment of hypertension. Curr Hypertens Rep. 2016;18(4):27. doi:10.1007/s11906-016-0636-7; Nguyen BD, Roarke MC, Young JR, et al. Diuretic renal scintigraphy in patients with sulfonamide allergies: Possible alternative use of ethacrynic acid. J Nucl Med Technol. 2015;43(4):239-241. doi:10.2967/jnmt.115.161331; Risal UP, Karki P, Shah P. Treatment of acute decompensated chronic heart failure: Furosemide vs furosemide and metolazone: A cross-sectional comparative study. Nepalese Heart Journal. 2022;19(2):19–22. doi.org/10.3126/njh.v20i2.48870.

Disclosures

For this program, members of the faculty and the planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Borkan was recorded at the 2024 Controversies in Internal Medicine Conference, held May 6-10, 2024, on Kiawah Island, SC, and presented by Boston University School of Medicine. For information about upcoming CME activities from this presenter, please visit https://cme.bu.edu. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.25 CE contact hours.

Lecture ID:

IM721701

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.