Treatment of refractory edema in adults
- D Craig Brater, MD
D Craig Brater, MD
- Emeritus Dean, Indiana University School of Medicine
- Vice President for Programs, Regenstrief Foundation
- Section Editors
- Richard H Sterns, MD
Richard H Sterns, MD
- Editor-in-Chief — Nephrology
- Section Editor — Fluid and Electrolytes
- Professor of Medicine
- University of Rochester School of Medicine and Dentistry
- Michael Emmett, MD
Michael Emmett, MD
- Editor-in-Chief — Nephrology
- Section Editor — Fluid and Electrolytes
- Chief of Internal Medicine
- Baylor University Medical Center
Generalized edema can occur in a variety of disorders, including heart failure, cirrhosis (where ascites is usually most prominent), the nephrotic syndrome, and renal failure; when massive, the excess fluid accumulation is called anasarca. Edematous patients generally respond to the combination of dietary sodium restriction and diuretic therapy, usually with a loop diuretic. Some patients, however, are resistant to this regimen.
A variety of factors can account for persistent fluid retention, including inadequate diuretic dose or frequency, excess sodium intake, delayed intestinal absorption of oral diuretics, decreased diuretic excretion into the urine, and increased sodium reabsorption at sites in the nephron other than those inhibited by the diuretic [1-4]. Nonsteroidal anti-inflammatory drugs, which reduce the synthesis of vasodilator and natriuretic prostaglandins, can impair diuretic responsiveness. Thus, these agents should be discontinued, if possible, in edematous patients [4,5].
The treatment of refractory edema in adults will be reviewed here. The initial therapy of edema, treatment of the different major edematous states, the clinical manifestations and diagnosis of edema in adults, and the evaluation and management of edema in children are discussed separately. (See "General principles of the treatment of edema in adults" and "Use of diuretics in patients with heart failure" and "Ascites in adults with cirrhosis: Initial therapy" and "Ascites in adults with cirrhosis: Diuretic-resistant ascites" and "Pathophysiology and treatment of edema in patients with the nephrotic syndrome" and "Clinical manifestations and diagnosis of edema in adults" and "Evaluation and management of edema in children".)
CHOICE OF DIURETIC
Edematous patients are typically treated with one of the sulfonamide-based loop diuretics – furosemide, bumetanide, and torsemide. Ethacrynic acid, which is not a sulfonamide, is rarely used because it may be more ototoxic than the sulfonamide diuretics in high doses and its relative insolubility makes it complicated to administer intravenously.
The primary indication for the use of ethacrynic acid is in patients who are allergic to sulfonamide-based diuretics, including thiazide diuretics. There is minimal evidence of allergic cross-reactivity between sulfonamide antimicrobials and non-antimicrobials. Thus, patients with a history of allergy to sulfonamide antimicrobial drugs would be expected to tolerate non-antimicrobial sulfonamides such as loop diuretics. Allergic reactions that do occur appear to be related to a predisposition to allergic reactions rather than sulfonamide cross-reactivity . (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Between sulfonamide antimicrobials and nonantimicrobials'.)
- Brater DC. Diuretic therapy. N Engl J Med 1998; 339:387.
- Rose BD. Diuretics. Kidney Int 1991; 39:336.
- Brater DC, Voelker JR. Use of diuretics in patients with renal disease. In: Pharmacotherapy of Renal Disease and Hypertension (Contemporary Issues in Nephrology), Bennett WM, McCarron DA (Eds), Churchill Livingstone, New York 1987. Vol 17.
- Ellison DH. Diuretic drugs and the treatment of edema: from clinic to bench and back again. Am J Kidney Dis 1994; 23:623.
- Brater DC. Analysis of the effect of indomethacin on the response to furosemide in man: effect of dose of furosemide. J Pharmacol Exp Ther 1979; 210:386.
- Strom BL, Schinnar R, Apter AJ, et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med 2003; 349:1628.
- Brater DC, Day B, Burdette A, Anderson S. Bumetanide and furosemide in heart failure. Kidney Int 1984; 26:183.
- Krämer BK, Schweda F, Riegger GA. Diuretic treatment and diuretic resistance in heart failure. Am J Med 1999; 106:90.
- Fredrick MJ, Pound DC, Hall SD, Brater DC. Furosemide absorption in patients with cirrhosis. Clin Pharmacol Ther 1991; 49:241.
- Murray MD, Deer MM, Ferguson JA, et al. Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. Am J Med 2001; 111:513.
- Gallagher KL, Jones JK. Furosemide-induced ototoxicity. Ann Intern Med 1979; 91:744.
- Dormans TP, van Meyel JJ, Gerlag PG, et al. Diuretic efficacy of high dose furosemide in severe heart failure: bolus injection versus continuous infusion. J Am Coll Cardiol 1996; 28:376.
- Salvador DR, Rey NR, Ramos GC, Punzalan FE. Continuous infusion versus bolus injection of loop diuretics in congestive heart failure. Cochrane Database Syst Rev 2004; :CD003178.
- Brown CB, Ogg CS, Cameron JS. High dose frusemide in acute renal failure: a controlled trial. Clin Nephrol 1981; 15:90.
- Delpire E, Lu J, England R, et al. Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter. Nat Genet 1999; 22:192.
- Flagella M, Clarke LL, Miller ML, et al. Mice lacking the basolateral Na-K-2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf. J Biol Chem 1999; 274:26946.
- Ellison DH. The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med 1991; 114:886.
- Wilcox CS, Mitch WE, Kelly RA, et al. Response of the kidney to furosemide. I. Effects of salt intake and renal compensation. J Lab Clin Med 1983; 102:450.
- Voelker JR, Cartwright-Brown D, Anderson S, et al. Comparison of loop diuretics in patients with chronic renal insufficiency. Kidney Int 1987; 32:572.
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62:e147.
- Salvador DR, Rey NR, Ramos GC, Punzalan FE. Continuous infusion versus bolus injection of loop diuretics in congestive heart failure. Cochrane Database Syst Rev 2005; :CD003178.
- Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011; 364:797.
- Rudy DW, Voelker JR, Greene PK, et al. Loop diuretics for chronic renal insufficiency: a continuous infusion is more efficacious than bolus therapy. Ann Intern Med 1991; 115:360.
- Ring-Larsen H, Henriksen JH, Wilken C, et al. Diuretic treatment in decompensated cirrhosis and congestive heart failure: effect of posture. Br Med J (Clin Res Ed) 1986; 292:1351.
- Inoue M, Okajima K, Itoh K, et al. Mechanism of furosemide resistance in analbuminemic rats and hypoalbuminemic patients. Kidney Int 1987; 32:198.
- Fliser D, Zurbrüggen I, Mutschler E, et al. Coadministration of albumin and furosemide in patients with the nephrotic syndrome. Kidney Int 1999; 55:629.
- Chalasani N, Gorski JC, Horlander JC Sr, et al. Effects of albumin/furosemide mixtures on responses to furosemide in hypoalbuminemic patients. J Am Soc Nephrol 2001; 12:1010.
- Loon NR, Wilcox CS, Unwin RJ. Mechanism of impaired natriuretic response to furosemide during prolonged therapy. Kidney Int 1989; 36:682.
- Wald H, Scherzer P, Popovtzer MM. Na,K-ATPase in isolated nephron segments in rats with experimental heart failure. Circ Res 1991; 68:1051.
- Almeshari K, Ahlstrom NG, Capraro FE, Wilcox CS. A volume-independent component to postdiuretic sodium retention in humans. J Am Soc Nephrol 1993; 3:1878.
- Abdallah JG, Schrier RW, Edelstein C, et al. Loop diuretic infusion increases thiazide-sensitive Na(+)/Cl(-)-cotransporter abundance: role of aldosterone. J Am Soc Nephrol 2001; 12:1335.
- Wollam GL, Tarazi RC, Bravo EL, Dustan HP. Diuretic potency of combined hydrochlorothiazide and furosemide therapy in patients with azotemia. Am J Med 1982; 72:929.
- Fliser D, Schröter M, Neubeck M, Ritz E. Coadministration of thiazides increases the efficacy of loop diuretics even in patients with advanced renal failure. Kidney Int 1994; 46:482.
- Dargie HJ, Allison ME, Kennedy AC, Gray MJ. High dosage metolazone in chronic renal failure. Br Med J 1972; 4:196.
- Oster JR, Epstein M, Smoller S. Combined therapy with thiazide-type and loop diuretic agents for resistant sodium retention. Ann Intern Med 1983; 99:405.
- Vargo DL, Brater DC, Rudy DW, Swan SK. Dopamine does not enhance furosemide-induced natriuresis in patients with congestive heart failure. J Am Soc Nephrol 1996; 7:1032.
- CHOICE OF DIURETIC
- BASIC PRINCIPLES OF DIURETIC DOSING
- Determine the effective dose
- Oral versus intravenous therapy
- RISK OF OTOTOXICITY
- Importance of dose and rate of administration
- PATHOGENESIS AND MANAGEMENT OF REFRACTORY EDEMA
- Exclude high salt intake
- Decreased loop diuretic secretion
- - Maximum effective dose of loop diuretics
- - Application to refractory edema
- - Continuous infusion
- - Posture
- - Infusion with albumin
- Enhanced tubular sodium reabsorption
- - Thiazide plus loop diuretics
- - Use of dopamine
- APPROACH TO REFRACTORY EDEMA
- Oral therapy
- Intravenous therapy
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS