Reviews| Volume 106, ISSUE 1, P90-96, January 1999

Diuretic treatment and diuretic resistance in heart failure


      Diuretic therapy decreases capillary wedge pressure and improves New York Heart Association (NYHA) functional class both in acute and chronic heart failure. In advanced symptomatic heart failure, loop diuretics are generally necessary to improve symptoms of congestion. Diuretic resistance in the edematous patient has been defined as a clinical state in which diuretic response is diminished or lost before the therapeutic goal of relief from edema has been reached. The major causes of diuretic resistance are functional renal failure (prerenal azotemia), hyponatremia, altered diuretic pharmacokinetics, and sodium retention caused by counterregulatory mechanisms intended to reestablish the effective arterial blood volume. Therapeutic approaches to combat diuretic resistance include restriction of fluid and sodium intake, use of angiotensin-converting-enzyme (ACE) inhibitors, changes in route (oral, intravenous) and timing (single dose, multiple doses, continuous infusion) of diuretic therapy, and use of diuretic combinations.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Levy D
        • Larson M.G
        • Vasan R.S
        • et al.
        The progression from hypertension to congestion heart failure.
        J Am Med Assoc. 1996; 275: 1557-1562
        • Dahlöf B
        • Lindholm L.H
        • Hansson L
        • et al.
        Morbidity and mortality in the Swedish Trial in Old Patients with hypertension (STOP-Hypertension).
        Lancet. 1991; 338: 1281-1285
        • SHEP Cooperative Research Group
        Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Eldery Program (SHEP).
        J Am Med Assoc. 1991; 265: 3255-3264
        • Gottdiener J.S
        • Reda D.J
        • Massie B.M
        • et al.
        Effect of single-drug therapy on reduction of left ventricular mass in mild to moderate hypertension: comparison of six antihypertensive agents. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.
        Circulation. 1997; 95: 2007-2014
        • Dikshit K
        • Vyden J.K
        • Forrester J.S
        • et al.
        Renal and extrarenal effects of furosemide in congestive heart failure after acute myocardial infarction.
        NEJM. 1973; 288: 1087-1090
        • Silke B
        Haemodynamic impact of diuretic therapy in chronic heart failure.
        Cardiology. 1994; 84: 115-123
        • Johnston G.D
        • Hiatt W.R
        • Nies A.S
        • et al.
        Factors modifying the early nondiuretic vascular effects of furosemide in man. The possible role of renal prostaglandins.
        Circ Res. 1983; 53: 630-635
        • Hasenfuß G
        • Holubarsch C
        • Herzog C
        • et al.
        Influence of cardiac function on the diuretic and hemodynamic effects of the loop diuretic piretanide.
        Clin Cardiol. 1987; 10: 83-89
        • Wilson J.R
        • Reicheek N
        • Dunkman W.B
        • Goldberg S
        Effect of diuresis on the performance of the failing left ventricle in man.
        Am J Med. 1981; 70: 234-239
        • Düsing R
        • Piesche L
        Second line therapy of congestive heart failure with torsemide.
        Progr Pharmacol Clin Pharmacol. 1990; 8: 105-120
        • Stauch M
        • Stiehl L
        Controlled double-blind clinical trial of the efficacy and tolerance of torsemide in comparison with furosemide in patients with congestive heart failure.
        Progr Pharmacol Clin Pharmacol. 1990; 8: 121-126
        • Anand I.S
        • Kalra G.S
        • Harris P
        • et al.
        Diuretics as initial and sole treatment in chronic cardiac failure.
        Cardioscience. 1991; 2: 273-278
        • The Consensus Trial Study Group
        Effects of enalapril on mortality in severe congestive heart failure. Results of the cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).
        NEJM. 1987; 316: 1429-1435
        • Packer M, O’Connor CM, Ghali JK, et al, for the Prospective Randomized Amlodipine Survival Evaluation Study Group
        Effect of amlodipine on morbidity and mortality in severe chronic heart failure.
        NEJM. 1996; 335: 1107-1114
        • The RALES Investigators
        Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the randomized aldactone evaluation study [RALES]).
        Am J Cardiol. 1996; 78: 902-907
        • Packer M, Bristow MR, Cohn JN, et al, for the U.S. Carvedilol Heart Failure Study Group
        The effect of carvedilol on morbidity and mortality in patients with chronic heart failure.
        NEJM. 1996; 334: 1349-1355
        • The DIGITALIS Investigation Group
        The effect of digoxin on mortality and morbidity in patients with heart failure.
        NEJM. 1997; 336: 525-533
        • Waagstein F, Bristow MR, Swedberg K, et al, for the Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group
        Lancet. 1993; 342: 1441-1446
        • The SOLVD Investigators
        Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
        NEJM. 1991; 325: 293-302
        • Davies RF, Beanlands DS, Nadeau C, et al, for the Canadian Enalapril versus Digoxin Study Group
        J Am Coll Cardiol. 1991; 18: 1602-1609
        • The SOLVD Investigators
        Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions.
        NEJM. 1992; 327: 685-691
        • Sharpe N
        • Murphy J
        • Smith H
        • Hannan S
        Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction.
        Lancet. 1988; i: 255-259
        • The Task Force of the Working Group on Heart Failure of the European Society of Cardiology
        The treatment of heart failure.
        Eur Heart J. 1997; 18: 736-753
        • Cotter G
        • Metzkor E
        • Kaluski E
        • et al.
        Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema.
        Lancet. 1998; 351: 389-393
        • Dzau V.J
        • Colucci W.S
        • Williams G.H
        • et al.
        Sustained effectiveness of converting-enzyme inhibition in patients with severe congestive heart failure.
        NEJM. 1989; 302: 1373-1379
        • Anand I.S
        • Ferrari R
        • Kalra G.S
        • et al.
        Edema of cardiac origin.
        Circulation. 1989; 80: 299-305
        • Anand I.S
        • Veal N.B
        • Kalra G.S
        • et al.
        Treatment of heart failure with diuretics.
        Eur Heart J. 1989; 10: 445-450
        • Fliser D
        • Franek E
        • Joest M
        • et al.
        Renal function in the elderly.
        Kidney Int. 1997; 51: 1196-1204
        • Risler T
        • Krämer B
        • Müller G.A
        The efficacy of diuretics in acute and chronic renal failure.
        Drugs. 1991; 41: 69-79
        • Friedman E
        • Shadel M
        • Halkin H
        • Farfel Z
        Thiazide-induced hyponatremia. Reproducibility by single dose rechallenge and an analysis of pathogenesis.
        Ann Intern Med. 1989; 110: 24-30
        • Riegger G.A.J
        • Liebau G
        • Kochsiek K
        Antidiuretic hormone in congestive heart failure.
        Am J Med. 1982; 72: 49-52
        • Lee W.H
        • Packer M
        Prognostic importance of serum sodium concentration and its modification by commencing enzyme inhibition in patients with severe chronic heart failure.
        Circulation. 1986; 73: 257-267
        • Vasko M.R
        • Brown-Cartwright D
        • Knochel J.P
        • et al.
        Furosemide absorption altered in decompensated congestive heart failure.
        Ann Intern Med. 1985; 102: 314-318
        • Offerhaus L
        Drug interaction at excretory mechanisms.
        Pharmacol Ther. 1981; 15: 69-78
        • Eiskjaer H
        • Bagger J.P
        • Danielsen H
        • et al.
        Mechanisms of sodium retention in heart failure.
        Am J Physiol. 1991; 260: F883-F889
        • Laragh J.H
        Atrial natriuretic hormone, the renin–aldosterone axis, and blood pressure–electrolyte homeostasis.
        NEJM. 1985; 313: 1330-1340
        • Smith J.B
        • Lincoln T.M
        Angiotensin decreases cyclic GMP accumulation produced by atrial natriuretic factor.
        Am J Physiol. 1987; 253: C147-C150
        • Schiffrin E.L
        Decreased density of binding sites for atrial natriuretic peptide on platelets of patients with severe congestive heart failure.
        Clin Sci. 1988; 74: 213-218
        • Cavero P.G
        • Margulies K.B
        • Winaver J
        • et al.
        Cardiorenal actions of neutral endopeptidase inhibition in experimental congestive heart failure.
        Circulation. 1990; 82: 196-201
        • Eiskjaer H
        • Bagger J.P
        • Danielsen H
        • et al.
        Attenuated renal excretory response to atrial natriuretic peptide in congestive heart failure in man.
        Int J Cardiol. 1991; 33: 61-74
        • Volpe M
        • Magri P
        • Rao M.A.E
        • et al.
        Intrarenal determinants of sodium retention in mild heart failure. Effect of angiotensin-converting enzyme inhibition.
        Hypertension. 1997; 30: 168-176
        • Martin P.Y
        • Schrier R.W
        Sodium and water retention in heart failure.
        Kidney Int. 1997; 51: 57-61
        • Kaissling B
        • Stanton B.A
        Adaptation of distal tubule and collecting duct to increased sodium delivery. I. Ultrastructure.
        Am J Physiol. 1988; 255: F1256-F1268
        • Stanton B.A
        • Kaissling B
        Adaptation of distal tubule and collecting duct to increased sodium delivery. II. Na+ and K+ transport.
        Am J Physiol. 1988; 225: F1269-F1275
        • Brater D.C
        • Chennavasin P
        • Seiwell R
        Furosemide in patients with heart failure.
        Clin Pharmacol Ther. 1989; 28: 182-186
        • Wilcox C.S
        • Mitch W.E
        • Kelly R.A
        • et al.
        Response of the kidney to furosemide. I. Effects of salt intake and renal compensation.
        J Lab Clin Med. 1983; 102: 450-458
      1. Brater DC, Sundblad KJ, Becker PK, et al. Diuretic duration and prevention of sodium retention. (Abstr.) In: Heart Failure 1997. Second International Meeting of the Working Group on Heart Failure. Cologne, Germany May 24–27, 1997:82.

        • Dzau V.J
        • Hollenberg N.K
        Renal response to captopril in severe heart failure.
        Ann Intern Med. 1984; 100: 777-782
        • Motwani J.G
        • Fenwick M.K
        • Morton J.J
        • Struthers A.D
        Furosemide-induced natriuresis is augmented by ultra-low-dose captopril but not by standard doses of captopril in chronic heart failure.
        Circulation. 1992; 86: 439-445
        • Good J.M
        • Brady A.J.B
        • Noormohamed F.H
        • et al.
        Effect of intense angiotensin II suppression on the diuretic response to furosemide during chronic ACE inhibition.
        Circulation. 1994; 90: 220-224
        • Ellison D.H
        The physiologic basis of diuretic synergism.
        Ann Intern Med. 1991; 114: 886-894
        • 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: 482-488
        • Knauf H
        • Mutschler E
        Sequential nephron blockade breaks resistance to diuretics in edematous states.
        J Cardiovasc Pharmacol. 1997; 29: 367-372
        • Dormans T.P
        • Gerlag P.G
        Combination of high-dose furosemide and hydrochlorothiazide in the treatment of refractory congestive heart failure.
        Eur Heart J. 1996; 17: 1867-1874
        • Van Vliet A.A
        • Donker A.J.M
        • Nauta J.J.P
        • Verheugt F.W.A
        Spironolactone in congestive heart failure refractory to high-dose loop diuretic and low-dose angiotensin-converting enzyme inhibitor.
        Am J Cardiol. 1993; 71: 21A-28A
        • Struthers A.D
        Aldosterone escape during ACE inhibitor treatment in chronic heart failure.
        Eur Heart J. 1995; 16: 103-106
        • Rudy D.W
        • Voelker J.R
        • Greene P.K
        • et al.
        Loop diuretics for chronic renal insufficiency.
        Ann Intern Med. 1991; 115: 360-366
        • Van Meyel J.J.M
        • Smits P
        • Dormans T
        • et al.
        Continuous infusion of furosemide in the treatment of patients with congestive heart failure and diuretic resistance.
        J Intern Med. 1994; 235: 329-334
        • Kramer W.G
        • Smith W.B
        • Ferguson J
        • et al.
        Pharmacodynamics of torsemide administered as an intravenous injection and as a continuous infusion to patients with congestive heart failure.
        J Clin Pharmacol. 1996; 36: 265-270
        • Gerlag P
        • Van Meijel J.J
        High-dose furosemide in the treatment of refractory congestive heart failure.
        Arch Intern Med. 1988; 148: 286-291
        • Marangoni E
        • Oddone A
        • Surian M
        • et al.
        Effect of high-dose furosemide in refractory congestive heart failure.
        Angiology. 1990; 41: 862-868
        • Lahav M
        • Regev A
        • Rà anani P
        • Theodor E
        Intermittent administration of furosemide vs continuous infusion preceded by a loading dose for congestive heart failure.
        Chest. 1992; 102: 725-731
        • Herchuelz A
        • Derenne F
        • Deger F
        • et al.
        Interaction between nonsteroidal anti-inflammatory drugs and loop diuretics.
        J Pharmacol Exp Ther. 1989; 248: 1175-1181
        • Riegger G.A.J
        • Kahles H.W
        • Elsner D
        • et al.
        Effects of acetylsalicylic acid on renal function in patients with chronic heart failure.
        Am J Med. 1991; 90: 571-575
        • Thompson B.T
        • Cockrill B.A
        Renal-dose dopamine.
        Lancet. 1994; 344: 7-8
        • Denton M.D
        • Chertow G.M
        • Brady H.R
        “Renal dose” dopamine for the treatment of acute renal failure.
        Kidney Int. 1996; 49: 4-14
        • Vargo D.L
        • Brater D.C
        • Rudy D.W
        • Swan S.K
        Dopamine does not enhance furosemide-induced natriuresis in patients with congestive heart failure.
        J Am Soc Nephrol. 1996; 7: 1032-1037
        • Elsner D
        • Müntze A
        • Kromer E.P
        • Riegger G.A.J
        Effectiveness of endopeptidase inhibition (candoxatril) in congestive heart failure.
        Am J Cardiol. 1992; 82: 196-201
        • Good J.M
        • Peters M
        • Wilkins M
        • et al.
        Renal response to candoxatrilat in patients with heart failure.
        J Am Coll Cardiol. 1995; 25: 1273-1281
        • Nishikimi T
        • Kawano Y
        • Saito Y
        • Matsuoka H
        Effect of long-term treatment with selective vasopressin V1 and V2 receptor antagonist on the development of heart failure in rats.
        J Cardiovasc Pharmacol. 1996; 27: 275-282