Heart Fail Rev (2007) 12:125130

DOI 10.1007/s10741-007-9015-4

Diuretics for the treatment of acute decompensated heart failure

Srinivas Iyengar William T. Abraham

Published online: 20 April 2007

Springer Science+Business Media, LLC 2007

Abstract Diuretics have been a mainstay for the treatment of acute decompensated heart failure (ADHF) for the
past four decades, though their short-term gains have been
questioned recently given their potential long-term deleterious systemic effects. The methods of diuretic administration as well as the optimal dosing regimen of these
agents are both areas that have been increasingly coming
under scrutiny. The lack of rigorous clinical trials examining diuretic use in ADHF, however, has led to a general
adoption of non-evidence based treatment algorithms for
this patient population. Though the use of intravenous
vasodilators for the treatment of decompensated heart
failure has grown tremendously over the last few years, the
fact remains that diuretics are still indispensable for alleviating congestive symptoms. Given this reality and until
further information is available about the most ideal utilization of these medications, diuretics will continue to
represent a double-edged sword for physicians treating this
disease process.

tors, angiotensin-receptor blockers (ARBs), beta-blockers,

and aldosterone antagonists, as well as device therapies
such as cardiac resynchronization therapy (CRT), the
mortality curve for patients with chronic heart failure has
been attenuated somewhat [26]. For patients with acute
decompensated heart failure (ADHF) however, no silver
bullet(s) yet exists as clinical trials in this area have been
lacking in the past.
The use of diuretics in the treatment of ADHF has been
a standard for the last four decades. Though the use of
these agents is considered standard of care in the acute
heart failure treatment algorithm, the consequences of
utilizing these medications has been linked to adverse effects on other organ systems. Additionally, the dosing and
method of diuretics administration has also been recently
scrutinized. Given the issue that large-scale randomized
trials do not exist for this class of medications, it is not
surprising that our present methods of treatment are being
re-examined as possibly having detrimental long-term
outcomes [7].

Keywords Acute heart failure
Diuretics
Renal

insufficiency
Background
Introduction

Heart failure and renal interactions

Heart failure is a disease process that has been growing at

an exponential rate across the United States over the last
twenty years [1]. Given the increased use of ACE inhibi-

Heart failure (HF) is directly related to the underlying

function of the renal system. The theory of the neurohormonal cascade is pivotal in this process, and involves
a detrimental decrease of cardiac output leading to hypoperfusion of the kidneys and subsequent systemic hormonal activation spiraling into a vicious cycle [8]. The
activation of the renin-angiotensin-aldosterone system
(RAAS) results in sympathetic activation and systemic
vasoconstriction. Sympathetic induced sodium reabsorp-

S. Iyengar (&)
W. T. Abraham

Division of Cardiovascular Medicine, The Ohio State University,
473 West 12th Avenue, Rm. 110P DHLRI, Columbus, Ohio
43210-1252, USA
e-mail: srinivas.iyengar@osumc.edu

123

126

tion is seen in the proximal tubule, and angiotensin II

activation stimulates vasoconstriction of the renal arterioles. Additionally, increased levels of aldosterone and
antidiuretic hormone (ADH) result in increased sodium and
water reabsorption.
Diuretic mechanisms
In the acute setting, use of loop diuretics can stimulate the
RAAS [9]. Loop diuretics, namely intravenous (IV) furosemide, are the most frequently utilized diuretics for patients presenting with ADHF. Loop diuretics act by
primarily inhibiting the Na-K-Cl transporter in the thick
ascending loop of Henle [10]. The plasma half-life of
furosemide is approximately 1.5 h with duration of action
of up to 6 h.
Thiazide diuretics inhibit sodium and chloride reabsorption primarily at the distal convoluted tubules. Thiazides typically produce a diuresis within two hours and their
effect can last for up to 12 h. The main IV formulation
utilized is chlorothiazide, and is generally only employed
as an adjunctive agent to furosemide. Thiazide diuretics are
generally less potent than loop diuretics, can lead to
worsening electrolyte depletion, and their use in renal
insufficiency has been debated [11]. Potassium-sparing
diuretics, like the thiazides, are also not as potent as the
loop diuretics and are rarely used in the acute setting for
heart failure.
Diuretic and cardio-renal interactions
As previously mentioned, IV furosemide can stimulate the
RAAS as well as acutely increasing levels of norepinephrine, arginine vasopressin, and heart rate [9] (Table 1).
Though it would appear that these actions would appear to
contribute to the worsening of acute HF, once a diuresis
ensues cardiac hemodynamics generally improve. This
initial effect of diuretic administration however, may
actually be contributing to the long-term worsening of
renal function in these patients.

Heart Fail Rev (2007) 12:125130

Increased Morbidity
And Mortality

Diuretic Therapy
Ne uro ho rm o n al
Activation

Development
Of Diuretic
R e s is t a nc e
Impaired renal
f un c t i o n

D i m i ni s he d
blood flow
Decreased renal
perfusion

Fig. 1 The latrogenic cardio-renal syndrome of heart failure

Patients presenting to the emergency room in acute HF

are often individuals with a history of chronic HF. Given
their underlying cardiac pathology, these patients are prone
to developing chronic renal insufficiency as well (the
cardio-renal syndrome) thus necessitating higher and
higher doses of intravenous diuretics to achieve an adequate response [12, 13]. This diuretic-resistant state usually
results from a progression of the patients heart failure
leading to chronic renal hypoperfusion with a subsequent
decrease in glomerular filtration rate (GFR) and reduction
in drug delivery (Fig. 1). The GFR itself can be independently detrimentally affected by IV diuretic use [14]. The
chronic use of loop diuretics can also lead to a braking
phenomenon, which creates alterations in the distal renal
tubule resulting in hypertrophy and an increased resorptive
ability of these structures and an overall decreased natriuresis [15].
Additionally, the use of non-steroidal anti-inflammatory
drugs (NSAIDS) can also be linked to diuretic resistance in
this population. Inhibition of cyclooxygenase by NSAIDS
can result in decreased renal prostaglandin synthesis that
are vital in balancing the systemic increase of vasoconstrictors induced by a chronic HF state and by also
increasing natriuresis [16]. Thus NSAID use can directly
affect diuretic efficacy and also potentially contribute to
worsening renal insufficiency.

Methods of administration in ADHF

Table 1 Systemic effects associated with acute high-dose diuretic

administration

Oral vs. IV formulations

RAAS stimulation

In patients presenting with ADHF, IV diuretics, specifically

IV furosemide, is the most widely used agent (Fig. 2).
Patients with ADHF generally have signs and symptoms of
systemic volume overload and pulmonary congestion.
Patients who present with signs of peripheral edema can
also have fluid deposition in internal organs as well,
including the GI tract. Gut edema can often prevent the
proper absorption of orally administered diuretic agents,
thus necessitating IV formulations.

AVP levels
HR
Norepinephrine levels
GFR
SVR
RAAS-renin-angiotensin-aldostrerone-system; AVP-arginine vasopressin; HR-heart rate; GFR-glomerular filtration rate; SVR-systemic
vascular resistance

123

Heart Fail Rev (2007) 12:125130

127

Al l E n r o l l e d D i s ch a r g e s ( n = 1 0 5 , 3 8 8 )
October 2001-January 2004
100

88%

90

Patients (%)

80
70
60
50
40
30
20

6%

1 0%

6%

10 %

3%

10

1%

0
IV Diuretic Dobutamine Dopamine

M i lr i n o n e

Nesiritide Nitroglycerin Nitroprusside

IV Vasoactive Meds

Fig. 2 Most commonly used IV medications. All enrolled discharges

(n = 105,388) October 2001-January 2004

Data from the Acute Decompensated Heart Failure

National Registry (ADHERE) has shed a significant
amount of light on the treatment patterns of patients
admitted with ADHF [17]. Information from this registry
has supported the notion that reduction of congestive
symptoms is paramount in the initial presentation and is
accomplished most often with the aid of IV diuretics. This
data however, also revealed that patients treated with IV
diuretics had longer lengths of stay and higher in-hospital
mortality rates when compared to non-IV diuretic treated
patients, even after adjustment of outside factors were
taken into account [18]. The ADHERE registry also
brought another surprising point to the surface: nearly 22%
of patients who were admitted with ADHF were discharged
with no weight loss or a gain in weight from their admission status (Fig. 3).
Worsening renal function induced by high-dose diuretic
regimens in the face of ADHF has also been examined.
Butler et al. performed a case-controlled study where data
was collected on 382 subjects who were hospitalized with
HF (191 patients with worsening renal function, defined as
a rise in serum creatinine level > 0.3 mg/dL, and 191
control subjects) [19]. They analyzed a number of factors,

Patients Discharged (%)

35%
30%

Men
- 3.5 kg
Women -2.5 kg

N=26,757

30%

24%

25%
20%

15%

15%
10%

13%

7%

6%

5%

3%

2%

0%
<-20

-20 to -15 -15 to -10 -10 to -5

-5 to 0

0 to 5

5 to 10

Change in Body Weight During Hospitalization (lbs)

Fig. 3 Diuresis during ADHF hospitalization

>10

but most notably the medical regimens the patients were on

prior to admission. The use of calcium channel blockers
(CCBs) and a higher dose of loop diuretics, but not ACE
inhibitors, were associated with a higher risk of worsening
renal function. Although assessment of in-house diuresis
was limited, the authors could not conclude that the deteriorating renal function could be explained by greater fluid
loss in these patients. Given the recent evidence linking
worsening renal function in patients with HF to increased
mortality and hospitalization highlights the concern of
what constitutes a safe and routine therapy for this
specific population [20, 21].
Combination therapy
Dosing regimens of IV diuretics have also been studied
when combined with other medications. Cotter et al.
studied twenty consecutive patients with ADHF who were
randomized to receive IV low-dose (4 mcg/kg/min) dopamine combined with low-dose (80 mg/day) oral furosemide (group A; n = 7), IV low-dose dopamine with
medium-dose furosemide (5 mg/kg/day through continuous IV administration; group B; n = 7), or high-dose
furosemide (10 mg/kg/day through continuous IV administration; group C; n = 6) [22]. Their results revealed that
renal function deteriorated significantly in groups B and C.
Creatinine clearance decreased by 41 23% and
42 23% in B and C but increased by 14 35% in group
A (P = 0.0074). Mean arterial pressure (MAP) decrease
was positively correlated with the decrease in creatinine
clearance (r = 0.7; P = 0.0007). The authors concluded
that combined low-dose IV dopamine and oral furosemide
had similar efficacy but induced less renal impairment than
higher doses of IV furosemide taken either alone or with
low-dose dopamine. The authors felt that the renal dysfunction induced by the IV diuretic regimens was most
likely due to hypotension induced by these medications,
though the concern of renal dysfunction induced by
diuretic use irrespective of hypotensive effects has become
a recognized issue (as mentioned earlier).
Cotter et al. also studied the use of IV diuretics in
combination with a commonly employed vasodilator, isosorbide dinitrate [23]. Patients presenting to the ER with
ADHF were treated with oxygen, IV furosemide 40 mg,
and morphine 3 mg bolus initially. 110 patients were then
randomly assigned (six had to be eventually removed)
either to group A, who received isosorbide dinitrate (3 mg
bolus administered IV every 5 min; n = 56) or to group B,
who received furosemide (80 mg bolus administered IV
every 15 min, as well as isosorbide dinitrate 1 mg/h,
increased every 10 min by 1 mg/h; n = 54). The treatment
arms were continued until oxygen saturation was above
96% or MAP had decreased by 30% or to below

123

128

90 mm Hg. The main endpoints were death, use of

mechanical ventilation, and myocardial infarction and the
analyses were by intention to treat. The authors found that
mechanical ventilation was required in seven (13%) of 52
group-A patients and 21 (40%) of 52 group-B patients
(P = 0.0041). Myocardial infarction occurred in nine
(17%) and 19 (37%) patients, respectively (P = 0.047) and
one patient in group A and three in group B died
(P = 0.61). The authors concluded that high-dose isosorbide dinitrate was safer and more effective in controlling
severe congestive symptoms and preventing mechanical
ventilation when compared to the high-dose furosemide/
low-dose isosorbide dinitrate treatment regimen. Though
the results of these two trials bring up notable points, their
relatively small sample size limits any concrete conclusions about the appropriate dosing of IV diuretics for
patients in ADHF.
Bolus versus continuous diuretic therapy
Dormans et al. examined the efficacy of a continuous
infusion of high dose furosemide (mean daily dosage
690 mg, range 2502,000 mg) versus a single bolus
injection of an equal dose in 20 patients with severe heart
failure (NYHA class III-IV) who were on chronic highdose oral diuretic therapy [24]. Roughly half of the study
population was in ADHF at the start of the study (an acute
decompensated state was not a requirement of the study).
The patients received an equal dosage of diuretic, either as
a single IV bolus injection or as an eight hour continuous
infusion preceded by a loading dose (20% of total dosage).
The results revealed that mean (SEM) daily urinary volume (infusion 2,860 240 ml, bolus 2,260 150 ml,
P = 0.0005)
and
sodium
excretion
(infusion
210 40 mmol, bolus 150 20 mmol, P = 0.0045) were
significantly higher after treatment with continuous infusion than with bolus injection, despite significantly lower
urinary furosemide excretion (infusion 310 60 mg every
24 h, bolus 330 60 mg every 24 h, P = 0.0195). The
maximal plasma furosemide concentration was significantly higher after bolus injection than during continuous
infusion (P < 0.0001). Five patients who had received the
bolus dose had reversible, short-term hearing loss. The
authors concluded that a continuous infusion of furosemide
was more efficacious and had fewer side effects than a
bolus injection regimen in this chronic HF patient sample.
Licata and colleagues performed a randomized, singleblind study to evaluate the effects of the combination of
high-dose furosemide and small-volume hypertonic saline
solution (HSS) infusion in patients with refractory NYHA
class IV HF [25]. They enrolled 107 patients (39 women
and 68 men, age range 6590 years) who were in NYHA
class IV of different etiologies, who were unresponsive to

123

Heart Fail Rev (2007) 12:125130

high oral doses of furosemide. Inclusion criteria included

an ejection fraction (EF) <35%, serum creatinine level
<2 mg/dL, blood urea nitrogen level <r = 60 mg/dL, and
low urine output. The patients were randomized into two
groups: Patients in group 1 (20 women and 33 men)
received an IV infusion of furosemide (5001,000 mg)
plus HSS (150 mL of 1.44.6% NaCl) twice a day in
30 min; Patients in group 2 (19 women and 35 men)
received an IV bolus of furosemide (5001000 mg) twice a
day, without HSS, during a period lasting 6 to 12 days.
During the treatment and after discharge, daily dietary and
fluid intake was monitored. Daily assessments of body
weight and 24 h urinary volume and laboratory parameters
were performed until patients reached a clinically euvolemic, or compensated state, where then the patients were
switched to an oral diuretic regimen. After discharge from
the hospital, patients were observed as outpatients weekly
for the first 3 months and then once a month. The authors
found that a significant increase in daily diuresis and
natriuresis was observed in both groups, but it was more
significant in the group receiving HSS (P < .05). The serum sodium level increased in group 1 and decreased in
group 2 (P < .05). The serum potassium level was decreased in both groups (P < .05). Body weight was reduced
in both groups (P < .05). Group 2 had an increase in serum
creatinine level and serum uric acid levels increased in
both groups. In the follow-up period (approximately
3 years), 25 patients from group 1 were readmitted to the
hospital for heart failure. In group 2, 43 patients were readmitted to the hospital at a higher class than at discharge.
Twenty-four patients in group 1 died during follow-up,
versus 47 patients in group 2 (55 versus 13% survival rate).
It should be noted, however, that like in the previously
discussed study, individuals in this trial were chronic HF
patients, not patients in ADHF, thus tempering the enthusiasm about altering treatment strategies for all patients
with HF.
A recently performed Cochrane database review by
Salvador et al. found that based on the data from the limited studies available, that an increased diuretic effect and a
better safety profile was observed with a continuous infusion of loop diuretics when compared to bolus dosing for
patients in NYHA III-IV HF [26]. The authors, however,
concluded that the currently available existing data still
does not allow definitive recommendations for clinical
practice and larger studies are needed before a conclusive
answer about therapy is made.

Conclusions
The use of diuretics for the treatment of patients with
ADHF represents an area of medicine with a paucity of

Heart Fail Rev (2007) 12:125130

rigorous clinical trials. The acceptance of diuretics into the

HF treatment paradigm is largely based on clinical and
anecdotal experience over the last forty years without the
benefit of large, multi-center randomized trials. It should be
noted however, that diuretics are ubiquitous in the initial
treatment strategies of most, if not all, clinicians treating
patients presenting with ADHF, given their track record of
successfully ameliorating congestive symptoms [27].
Additionally, diuretics have also been established as an
accepted part of HF therapy for patients with chronic disease and evidence of fluid retention and/or pulmonary
congestion [28].
The main obstacles in order to fully embrace diuretic
therapy for this patient population revolve around questions
such as optimal dosing, methods of administration, and potential systemic side-effects. It would appear with the limited
information available that low-dose IV diuretic therapy
delivered in a continuous fashion an IV vasodilator would
be the optimal method of treating this group. This statement
mandates verification on an investigational level and each
physician is obviously instructed to follow his or her best
clinical judgment in these instances. Though useful in
relieving symptoms, the increasing evidence for adverse
effects with diuretic use in decompensated HF has made the
medical community increasingly aware that until further
large-scale clinical trials are performed, diuretics can truly
be looked on as a double-edged sword of HF therapy.
References
1. American Heart Association (2005) 2005 Heart and stroke statistical update. American Heart Association, Dallas
2. The CONSENSUS Study Group (1987) Effects of enalapril on
survival on mortality in severe congestive heart failure: results of
the Cooperative North Scandinavian Enalapril Survival Study. N
Engl J Med 316:14291435
3. Cohn JN, Tognoni G (2001) A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl
J Med 345:16671675
4. Packer M, Bristow MR, Cohn JN et al (1996) The effect of
carvedilol on morbidity and mortality in patients with chronic
heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl
J Med 334:13491355
5. Pitt B, Zannad F, Remme WJ et al (1999) The effect of spironolactone on morbidity and mortality in patients with severe heart
failure. N Engl J Med 341:709717
6. Abraham WT, Fisher WG, Smith AL et al (2002) for the MIRACLE study group. Cardiac resynchronization in chronic heart
failure. N Engl J Med 346:18451853
7. Cody RJ (1993) Clinical trials of diuretic therapy in heart failure:
research directions and clinical considerations. J Am Coll Cardiol
22(Suppl A):165A171A
8. Schrier RW, Abraham WT (1999) Hormones and hemodynamics
in heart failure. N Engl J Med 341:577585
9. Francis GS, Siegel RM, Goldsmith SR et al (1985) Acute vasoconstrictor response to intravenous furosemide in patients with
chronic congestive heart failure. Activation of the neurohormonal
axis. Ann Intern Med 103:16

129
10. Opie LH (2001) Diuretics. In: Opie LH, Kaplan NM, Pool-Wilson P (eds) Drugs for the heart, 5th edn. W.B. Saunders, Philadelphia, PA pp. 84106
11. Brater DC (1998) Diuretic Therapy. N Engl J Med 339:387395
12. Heywood JT (2004) The cardiorenal syndrome: lessons from the
ADHERE database and treatment options. Heart Fail Rev 9:195
201
13. Kramer BK, Schweda F, Riegger GA (1999) Diuretic treatment
and diuretic resistance in heart failure. Am J Med 106:9096
14. Gottlieb SS, Brater DC, Thomas I et al (2002) BG9719 (CVT124), an A1 adenosine receptor antagonist, protects against the
decline in renal function observed with diuretic therapy. Circulation 105:13481353
15. Loon NR, Wilcox CS, Unwin RJ (1989) Mechanism of impaired
natriuretic response to furosemide during prolonged therapy.
Kidney Int 36:682689
16. Dzau VJ, Packer M, Lilly LS et al (1984) Prostaglandins in severe
congestive heart failure. Relation to activation of the reninangiotensin system and hyponatremia. N Engl J Med 310:347
352
17. ADHERETM (Acute Decompensated Heart Failure National
Registry). Third quarter 2004 National Benchmark Report,
Available at: www.ahereregistry.com.
18. Emerman CL, Marco TD, Costanzo MR, Peacock WF (2004)
Impact of intravenous diuretics on the outcomes of patients
hospitalized with acute decompensated heart failure: insights
from the ADHERE registry. J Card Fail 10:S116
19. Butler J, Forman DE, Abraham WT et al (2004) Relationship
between heart failure treatment and development of worsening
renal function among hospitalized patients. Am Heart J 147:331
338
20. Smith GL, Lichtman JH, Bracken MB et al (2006) renal
impairment and outcomes in heart failure: systematic review and
meta-analysis. J Am Coll Cardiol 47:19871996
21. Hillege HL, Nitsch D, Pfeffer MA et al (2006) Renal function as
a predictor of outcome in a broad spectrum of patients with heart
failure. Circulation 113:671678
22. Cotter G, Weissgarten J, Metzkor E et al (1997) Increased toxicity of high-dose furosemide versus low-dose dopamine in the
treatment of refractory congestive heart failure. Clin Pharmacol
Ther 62:187193
23. Cotter G, Metzkor E, Kaluski E et al (1998) Randomized trial of
high-dose isosorbide dinitrate plus low-dose furosemide versus
high-dose furosemide plus low-dose isosorbide dinitrate in severe
pulmonary edema. Lancet 351:389393
24. Dormans TP, van Meyel JJ, Gerlag PG et al (1996) Diuretic
efficacy of high dose furosemide in severe heart failure: bolus
injection versus continuous infusion. J Am Coll Cardiol 28:376
382
25. Licata G, DiPasquale P, Parrinello G et al (2003) Effects of highdose furosemide and small-volume hypertonic saline solution
infusion in comparison with a high-dose of furosemide as bolus in
refractory congestive heart failure: long-term effects. Am Heart J
145:459466
26. Salvador D, Rey N, Ramos G et al (2004) Continuous infusion
versus bolus injection of loop diuretics in congestive heart failure.
Cochrane Database Syst Rev 1:CD003178
27. Nieminen MS, Bohm M, Cowie MR, Drexler H, Filippatos GS,
Jondeau G, Hasin Y, Lopez-Sendon J, Mebazaa A, Metra M,
Rhodes A, Swedberg K, Priori SG, Garcia MA, Blanc JJ, Budaj
A, Cowie MR, Dean V, Deckers J, Burgos EF, Lekakis J, Lindahl
B, Mazzotta G, Morais J, Oto A, Smiseth OA, Garcia MA,
Dickstein K, Albuquerque A, Conthe P, Crespo-Leiro M, Ferrari
R, Follath F, Gavazzi A, Janssens U, Komajda M, Morais J,
Moreno R, Singer M, Singh S, Tendera M, Thygesen K, ESC
Committe for Practice Guideline (CPG) (2005) Executive sum-

123

130
mary of the guidelines on the diagnosis and treatment of acute
heart failure: the Task Force on Acute Heart Failure of the
European Society of Cardiology. Eur Heart J 26:384416
28. Hunt SA, Abraham WT, Chin MH et al (2005) ACC/AHA 2005
guideline update for the diagnosis and management of chronic

123

Heart Fail Rev (2007) 12:125130

heart failure in the adult: a report of the American college of
cardiology/American heart association task force on practice
guidelines (Writing committee to update the 2001 guidelines for
the evaluation and management of heart failure). Circulation
112:18251852