718717

review-article2017
TAK0010.1177/1753944717718717Therapeutic Advances in Cardiovascular DiseaseN Shah, R Madanieh

Therapeutic Advances in Cardiovascular Disease Review

A perspective on diuretic resistance in

Ther Adv Cardiovasc Dis

2017, Vol. 11(10) 271­–278

chronic congestive heart failure DOI: 10.1177/

https://doi.org/10.1177/1753944717718717
https://doi.org/10.1177/1753944717718717
1753944717718717

© The Author(s), 2017.

Reprints and permissions:
Niel Shah, Raef Madanieh, Mehmet Alkan, Muhammad U. Dogar, http://www.sagepub.co.uk/
journalsPermissions.nav
Constantine E. Kosmas and Timothy J. Vittorio

Abstract:  Chronic congestive heart failure (CHF) is a complex disorder characterized

by inability of the heart to keep up the demands on it, followed by the progressive pump
failure and fluid accumulation. Although the loop diuretics are widely used in heart failure
(HF) patients, both pharmacodynamic and pharmacokinetic alterations are thought to
be responsible for diuretic resistance in these patients. Strategies to overcome diuretic
resistance include sodium intake restriction, changes in diuretic dose and route of
administration and sequential nephron diuretic therapy. In this review, we discuss the
definition, prevalence, mechanism of development and management strategies of diuretic
resistance in HF patients.

Keywords:  cardiorenal syndrome, diuretics, diuretic resistance, heart failure, renal failure

Received: 22 February 2017; revised manuscript accepted: 2 June 2017

Introduction fractional excretion of sodium (FENa+) of <0.2% Correspondence to:

Timothy J. Vittorio
The loop diuretics are often used in many patients that represents the amount of sodium excreted St. Francis Hospital, The
with chronic congestive heart failure (CHF) due (mmol/time) as a percentage of the filtered Heart Center®, Center
for Advanced Cardiac
to their indisputable efficacy in relieving conges- sodium load.4 Therapeutics, 100 Port
tive symptoms. In simple terms, diuretic resist- Washington Boulevard,
Roslyn, NY 11576-1348,
ance in heart failure (HF) patients can be Epstein and colleagues conducted a study to USA
explained as a failure of diuretics to control salt delineate the efficacy of the metolazone-furosemide t_vittorio@hotmail.com
Niel Shah
and water retention even when used in appropri- regimen in patients with diuretic refractory Raef Madanieh
ate doses.1 It may occur due to decrease in renal edema.5 The investigators studied 24 patients Muhammad U. Dogar
St. Francis Hospital, The
function which leads to pharmacokinetic abnor- who were initially considered to be refractory to Heart Center ®, Center
malities such as reduction or delay in peak con- large doses of conventional loop diuretics during for Advanced Cardiac
Therapeutics, Roslyn,
centrations of loop diuretics in the renal tubular an 18-month period. Among those 24 patients, 8 NY, USA
fluid.1 However, it can also occur in the absence were presumed to have refractory edema and thus Mehmet Alkan
of such pharmacokinetic abnormalities. entered the study. In one of the study criteria, Brown University, College
of Arts and Sciences,
they mentioned diuretic resistance as a failure to Providence, RI, USA
excrete sodium (at least 90 mmol) within 72 h of Constantine E. Kosmas
Definition and prevalence of diuretic giving oral furosemide (160 mg) twice a day.5 Icahn School of Medicine,
Mount Sinai Hospital
resistance Only three out of those eight patients who entered Center, New York, NY, USA
The term ‘diuretic resistance’ remains inade- the study met the study criteria for diuretic refrac-
quately defined despite its increasing frequency. tory edema.
It can simply be defined as either a loss of response
or reduction in the response to loop diuretics.2 It Diuretic resistance is less commonly encountered
can develop in one out of every three HF patients.3 in patients with mild CHF and preserved renal
Generally, failure to reduce the volume of extra- function, compared with patients with moderate
cellular fluid despite using diuretics appropriately and severe CHF.6,7 Meanwhile, it is reported in
can be termed as ‘diuretic resistance’. More pre- another study that 38% of the patients with CHF
cisely, diuretic resistance can be expressed as a have renal impairment and thus they are at an

http://tac.sagepub.com 271
Therapeutic Advances in Cardiovascular Disease 11(10)
increased risk for the development of diuretic
resistance.8 Several trials have shown that HF is
commonly accompanied by a reduction in the
estimated glomerular filtration rate (eGFR) and
the prevalence of moderate to severe kidney
impairment is approximately 30–60% in patients
with HF.9–13 The Acute Decompensated Heart
Failure National Registry (ADHERE) database
reported data on over 100,000 patients with HF
requiring hospitalization and approximately 30%
of those patients had a diagnosis of chronic kidney
disease, while only 9% had a normal eGFR.10,11
Mechanisms of diuretic resistance in heart
failure
There are several theories that can explain the
mechanism of diuretic resistance development.
Several physiological changes in CHF can lead to
alterations in drug pharmacokinetics, such as
alterations in absorption, distribution, metabo-
lism and elimination of the loop diuretics.
However, diuretic resistance in CHF patients
cannot be fully explained by these pharmacoki-
netic changes alone because if only alterations in
pharmacokinetics were responsible, then diuretic
resistance should be overcome by increasing the
dose or changing the route of administration.3
Instead, the diuretic resistance may be better
explained by parallel changes in drug pharmaco-
dynamics and pharmacokinetics affecting the
time course of drug delivery.14 When compared
with healthy volunteers, CHF patients have a
reduced rate of drug absorption which leads to a
delay in the time to achieve a threshold dose, with
the consequent development of diuretic resist-
ance.15,16 However, bioavailability of diuretics
remains unchanged, therefore these changes can
be better explained by the presence of gastrointes-
tinal edema in patients with active HF.17
Usually, furosemide reaches the tubular fluid by
its secretion from the organic anion transporter
located in the proximal tubule.18 In patients with
CHF, renal insufficiency leads to diuretic resist-
ance due to insufficient intratubular concentra-
tions of diuretics, which can be explained by
decreased renal blood flow and impaired secre-
tion by the proximal convoluted tubule (PCT).17,19
The secretion of loop diuretics is reduced due to
the accumulation of endogenic organic anions
which compete with loop diuretics for binding at
the receptor site on organic anion transporter.20
This competitive inhibition can be overcome by
increasing the dose of loop diuretics and this
272 http://tac.sagepub.com
explains the need for higher loop diuretic doses to
achieve therapeutic urinary concentration in
CHF patients with renal impairment.
Another important theory behind diuretic resist-
ance is the drug–drug interactions, such as non-
steroidal anti-inflammatory agents (NSAIDs),
which may interfere with diuretics action by inhib-
iting prostaglandins and thus reducing renal per-
fusion.17,21–23 In severe HF, prostaglandins are
vital for maintaining renal perfusion and for pro-
moting sodium and water excretion. Therefore,
inhibition of prostaglandins with either aspirin or
any other NSAIDs can eventually attenuate diu-
retic efficacy by inhibiting sodium and water
excretion.23 It has been reported that after the dis-
continuation of 100 mg of aspirin in patients with
terminal, intravenous (IV) catecholamine-dependent
HF, there was a marked improvement, stabiliza-
tion and abatement of hyponatremia with an
impressive reduction in diuretic requirements.24
In an animal model, administration of prostaglan-
din E2 in indomethacin-treated rats was shown to
restore the natriuretic response to furosemide and
thus the model favors the fact that the use of
NSAIDs is one of the major causes of apparent
diuretic resistance.25
In general, acute administration of loop diuretics
in healthy patients can cause activation of the
renin-angiotensin-aldosterone system (RAAS)
reflexively, which further increases sodium and
water retention and thus curtails the diuretic
effect.26 This should not be prominent in severe
CHF, as such patients already have an activated
RAAS and thus loop diuretics cannot further acti-
vate RAAS or increase the release of neurohor-
mones.3 Additionally, most patients with CHF
are receiving RAAS inhibitors, so this should
counteract further activation of RAAS following
acute administration of diuretics.27 Haller and
colleagues reported a case of a 29-year old patient
having dilated cardiomyopathy refractory to high-
dose furosemide and concluded that the diuretic
resistance was due to the combination of heart
pump failure, dietary indiscretion and hyperaldo-
steronism.28 Thus, it is not unusual for a CHF
patient to have multiple mechanisms responsible
behind the development of diuretic resistance.
High sodium intake may mask the diuretic effects
and thus it can cause difficulty to the clinician in
determining diuretic resistance. Dietary non-
compliance is not an actual form of diuretic
resistance, but it may lead to diuretic failure. In

patients with dietary indiscretion, loop diuretics
lead to pronounced natriuresis initially but that
can be followed by post-diuresis avid sodium
reabsorption, thereby causing diuretic failure.29
CHF patients are usually placed on long-term
diuretic treatment which may be associated with
pharmacological alterations within the nephron,
thus resulting in an aggravated response to
sodium intake.3 Data from patients with hyper-
tension and experimental animal studies demon-
strated that the chronic inhibition of sodium
reabsorption in the loop of Henle due to chronic
administration of loop diuretics, led to the deliv-
ery of sodium in higher amounts to the early dis-
tal convoluted tubule (DCT) causing cellular
hypertrophy and thus augmented sodium reab-
sorption, which eventually led to a diminished
natriuresis with shifting of the dose–response
curve to down and right (See Figure 1). This
diminished natriuretic effect due to the chronic
administration of loop diuretics is known as the
‘braking phenomenon’.18,26,30–32
Critically ill patients admitted in intensive care
units (ICUs) may sometimes develop another
variant of diuretic resistance, which is termed as
‘occult diuretic resistance’. In this variant, such
ICU patients on loop diuretics excrete only free
water with no or very little sodium in their urine
which ultimately lead to dehydration and hyper-
natremia. It is a frustrating condition as such
patients initially seem to respond to the loop diu-
retics. This temporary diuretic failure develops
due to a combination of factors in ICU patients
such as: (i) the stress causes their kidneys to
retain more sodium and thus loop diuretics stim-
ulate the production of dilute urine with very low
sodium; (ii) they may have excess sodium intake
in the form of various medications and IV drips
formulated in normal saline and (iii) an inability
to drink water due to intubation which may lead
to dehydration and thus increased sodium and
water re-absorption from the kidneys. There may
be none or very little net fluid loss when these
patients are rehydrated. The ‘occult diuretic
resistance’ can be managed by a traditional
approach in which the lost free water is replaced
by enteral water or IV 5% dextrose while con-
tinuing diuresis. However, the ultimate amount
of the lost fluid will be very low. The better
approach to counteract this type of diuretic
resistance is by adding a thiazide diuretic to loop
diuretic therapy [Please refer ‘combination diu-
retic therapy (sequential nephron blockade)’
below].33
http://tac.sagepub.com 273
N Shah, R Madanieh et al.
Figure 1.  Dose–response curve in patients with CHF
on chronic loop diuretics.
Management of diuretic resistance
Noncompliance
The first step to be taken when diuretic resistance
is encountered is to exclude noncompliance with
either medication intake or sodium restriction
(sodium intake should be <100 mmol/day).1 As
discussed above, when sodium intake exceeds 100
mmol/day, sodium lost by diuresis can be com-
pletely compensated by postdiuretic avid sodium
retention.34 Sodium intake is usually assessed by
measuring 24 h urine sodium excretion in the
steady state.1 Dietary noncompliance is suspected
in subjects receiving diuretic therapy, when
sodium excretion is as high as >100 mmol/day
without any associated weight loss. Meanwhile,
medication (diuretic) compliance can be assessed
by measurement of the amount of diuretic excreted
in urine, although this assessment would prove
useful only in a very few cases.1
Dose adjustment
The pharmacodynamic and pharmacokinetic
changes of loop diuretics occurring in CHF
patients can be compensated by increasing the
dose of diuretics.1 Few researchers have studied
the usefulness of high-dose furosemide in the
management of refractory CHF.35,36 A study
reported the safety and efficacy of high-dose furo-
semide (250–4000 mg/day, oral or IV) in 35
patients with significantly compromised kidney
function and severe CHF unresponsive to con-
ventional diuretic treatment.36 All patients
showed improvement in symptoms and weight
reduction with no significant side effects.36 As
discussed before, patients with renal impairment
have diminished renal blood flow and compro-
mised organic anion transporter activity which
Therapeutic Advances in Cardiovascular Disease 11(10)
interferes with furosemide secretion and thus
leads to lower concentrations in the tubular fluid.1
Many patients with CHF have some impairment
in renal function that makes it necessary to
increase the diuretic dose to deliver the drug at its
site of action in appropriate amounts. When salt
intake is not adequately restricted, postdiuretic
sodium retention is an important mechanism
responsible for diuretic resistance as most loop
diuretics are short acting.1 This postdiuretic salt
retention can be overcome by more frequent
administration of the diuretic (3 times daily or
more) that results in reduction of the drug-free
interval.1
As shown in Figure 1, the urinary drug concen-
trations required to achieve adequate diuresis in
healthy subjects may not be able to achieve the
expected diuresis in CHF patients. It means that
it is often required to increase the loop diuretic
dose, even without any abnormalities in drug
pharmacokinetics. Bumetanide and torsemide
have better bioavailability than furosemide and
thus some physicians consider them more effec-
tive than furosemide in CHF patients.1 Generally,
the bioavailability of furosemide shows significant
intrapatient/interpatient variability and ranges
from 10–100%.37 In contrast, bumetanide and
torsemide have a bioavailability of 80% and 80–
100%, respectively.15 Both furosemide and
bumetanide were found equally efficacious when
equipotent doses were administered, even though
bumetanide is 40-times more potent than furo-
semide on a weight basis.38,39
IV bolus injection or continuous infusion of a
loop diuretic
As previously discussed, one mechanism of diu-
retic resistance in CHF patients is impaired
absorption of loop diuretics without an absolute
change in their bioavailability, compared with
normal subjects.40,41 This leads to the delayed
and decreased peak concentrations in the urine.
This problem may be obviated by moderately
increasing the dose or switching the route of drug
administration to IV.35 Within minutes after a
bolus injection of furosemide in patients having
congestive symptoms caused by acute ischemia or
valvular heart disease, pulmonary artery pressure
decreases and venous capacitance increases.42
This finding may help to explain why the patients
with pulmonary edema show quick symptom
relief even before achieving significant diuresis
after getting IV furosemide.1 The concern with
274 http://tac.sagepub.com
rapid IV injection of a loop diuretic in high doses
is the development of ototoxicity, especially in
patients simultaneously receiving other ototoxic
drugs, such as aminoglycosides.43 Therefore, it is
necessary to be cautious while considering a bolus
infusion of high-dose furosemide and to avoid
this complication, the maximum recommended
rate of furosemide infusion is 4 mg/min.43 It is
recommended to infuse furosemide slowly when
doses are higher than 80 mg to avoid an abrupt
increase in peak serum concentration.44
Continuous IV infusion of a loop diuretic may
prove effective when other strategies to manage
diuretic resistance have failed.1 It has been found
to be a safe and effective therapy in CHF patients
who are refractory to high-dose oral as well as IV
diuretic therapy, also it prevents postdiuretic salt
retention completely.1 Several studies have com-
pared the efficacy of continuous infusion with
intermittent IV bolus administration of a loop
diuretic in patients with advanced HF.45–47 The
dose of furosemide for continuous infusions
ranged from 3–200 mg/h, with most patients
receiving 10–20 mg/h while bumetanide was
administered as 0.5 mg bolus followed by a con-
tinuous infusion at 0.5 mg/h. It was reported that
the similar daily dose of loop diuretics when
administered as a continuous infusion caused
excretion of higher amounts of urine and electro-
lytes. Additionally, the risk of ototoxicity was low
as the maximal plasma concentration of furosem-
ide was significantly lower.45–48
Combination diuretic therapy (sequential
nephron blockade)
When the previously discussed strategies fail to
overcome diuretic resistance, combination diu-
retic therapy or sequential nephron inhibitors
should be considered. Diuretics that act on PCT,
such as carbonic anhydrase inhibitors should be
avoided in patients with HF as they can cause
metabolic acidosis. The efficacy of combination
therapy with loop and thiazide diuretics has been
studied well in CHF patients.49–51 One of those
studies showed that in 20 patients with severe HF
(NYHA functional class III or IV) and impaired
renal function having diuretic resistance to high-
dose (at least 250 mg) of oral or IV furosemide,
the addition of 25–100 mg of hydrochlorothiazide
or any other thiazide diuretic proved to be very
effective in the form of reduction in body weight
(6.7 ± 3.3 kg per patient) and an increase in
FENa+ (3.5 ± 3.2% to 11.5 ± 9.0%), as well as

mean daily urine volume (1899 ± 958 ml to 3065
± 925 ml).50 Side effects were hypokalemia,
hyponatremia, dehydration and worsening renal
dysfunction.50 Another study showed that addi-
tion of thiazide diuretics proved to be very effec-
tive in achieving diuresis in patients refractory to
high-dose loop diuretics. This study compared
the effects of bendrofluazide 10 mg and metola-
zone 10 mg in severe resistant HF (NYHA func-
tional class III or IV unresponsive to IV loop
diuretics for 48 h).51 Most patients reported sig-
nificant improvement in their CHF functional
class and also showed significant weight loss when
a thiazide or a thiazide-like diuretic was added.51
Median (range) maximal weight loss noted as
−5.05 (−11.3 to 1.6) kg after the addition of ben-
drofluazide, while −5.6 (−12.2 to 4.8) kg after the
addition of metolazone.51 The area under the
curves for body weight loss against time reflected
no significant difference between these two diu-
retics.51 However, currently, there is no valid
explanation available to consider metolazone as
superior to any other thiazide diuretic.
Loop diuretics and thiazide diuretics can block
the reabsorption of approximately 25% and
5–10% of filtered sodium, respectively.1
Additionally, thiazide diuretics are ineffective as
monotherapy in patients with advanced HF due
to their weak natriuretic effect.1 It has been dem-
onstrated in experimental animal studies that a
chronic increase in the sodium load in the DCT
can lead to an increase in its sodium transport
capacity.30,31 This increase in transport capacity
may be due to alterations in cellular ultrastruc-
ture of that segment. As previously discussed, in
patients with resistance to loop diuretics due to
chronic administration, a high amount of sodium
load reaches early in the DCT and gets reab-
sorbed by altered cells present at that site.52 The
thiazide diuretics usually act on the early DCT to
prevent the reabsorption of sodium at that site.
Therefore, combining loop diuretics with thiazide
diuretics in CHF patients with diuretic resistance
is an effective treatment option because it takes
this synergistic pathophysiological mechanism
into consideration. Metolazone, a thiazide-like
diuretic acts on the DCT similarly to thiazide
diuretics and thus also provides a synergistic
effect when combined with loop diuretics. While
considering this combination therapy, it is usually
recommended to administer DCT-acting diuret-
ics 30 min before administering loop diuretics to
maximize the efficacy of this approach.53,54 The
thiazide and thiazide-like diuretics have long
http://tac.sagepub.com 275
N Shah, R Madanieh et al.
half-lives and therefore take longer to show their
peak effects after oral administration. Hence, the
rationale behind the recommendation of predos-
ing these drugs with loop diuretics can be
explained by their synergistic diuretic effect with
loop diuretics and long half-lives.53,54
Many thiazide-like diuretics have been evaluated
for combination therapy with loop diuretics. All
combinations have shown similar results overall
and thus we can say that no thiazide-like diuretic
is superior to another. In patients with advanced
renal failure, metolazone has been considered
superior to other thiazide-like diuretics, but other
thiazide-like diuretics have also improved the
response to loop diuretics in the similar type of
patients. A recent small retrospective single-center
cohort study while comparing the two most com-
monly used thiazide-like diuretics, namely oral
metolazone and IV chlorothiazide as an add-on to
loop diuretics, did not find any statistically signifi-
cant differences in safety or efficacy.55
Spironolactone is a mineralocorticoid antagonist
and a potassium-sparing diuretic. It acts primarily by
competitive binding to the aldosterone-dependent
sodium-potassium exchange sites located in the
DCT and collecting duct. A small study reported
a successful response to the introduction of
spironolactone in 13 of 16 HF patients resistant to
a high-dose loop diuretic.56 However, one patient
developed reversible hyperkalemia and azotemia
due to dehydration but it is worth mentioning that
the dose of spironolactone used (100 mg/day) in
the study was much higher than the average dose
(25 mg/day) that produced a survival benefit in
RALES study.57 It is advisable to monitor hydra-
tion status and serum potassium levels when this
high dose is administered. This high dose should
be followed by a maintenance dose of 25 mg once
all the excessive fluid gets removed.1 The use of
spironolactone for the treatment of diuretic resist-
ance in CHF patients is generally not recom-
mended as the evidence in favor of spironolactone
is limited.1
Conclusion
Fluid overload resistant to conventional-dose diu-
retic therapy is a common problem encountered in
patients with CHF. From the above discussion, we
conclude that the high prevalence of renal impair-
ment in CHF patients is associated with a higher
risk of diuretic resistance. In addition to renal
impairment, poor diuretic absorption, drug–drug
Therapeutic Advances in Cardiovascular Disease 11(10)
interactions, chronic administration of diuretics
and high sodium intake are other potential factors
behind the development of diuretic resistance in
HF. Diuretic resistance can be overcome by man-
aging it in a step by step manner, such as to exclude
drug noncompliance, to increase the dose of diu-
retic, to change the route of administration from
oral to IV, and finally to use combination diuretic
therapy. This stepwise approach in treating diu-
retic resistance might lead to a more rapid allevia-
tion of symptoms and potentially to a decreased
length of stay in patients hospitalized for decom-
pensated HF. Once the diuretic resistance has
been treated successfully, the treatment of CHF
should be optimized in order to reduce further
morbidity and mortality.
Acknowledgements
Timothy J Vittorio conceived with an idea about
this work and approved the final manuscript;
Niel Shah was responsible for reviewing of the
literatures and studies, drafting the outline and
main manuscript as well as editing of the main
manuscript; Raef Madanieh, Mehmet Alkan,
Muhammad U. Dogar and Constantine E.
Kosmas were responsible for critically reviewing
the manuscript for intellectual content, review-
ing of the literatures and editing of the main
manuscript.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest statement
The authors declare that there is no conflict of
interest.
References
1. De Bruyne LKM. Mechanisms and management
of diuretic resistance in congestive heart failure.
Postgrad Med J 2003; 79: 268–271.
2. Ter Maaten JM, Rao VS, Hanberg JS, et al. Renal
tubular resistance is the primary driver for loop
diuretic resistance in acute heart failure. Eur J
Heart Fail. Epub ahead of print 19 January 2017.
DOI: 10.1002/ejhf.757.
3. Ravnan SL, Ravnan MC and Deedwania PC.
Pharmacotherapy in congestive heart failure:
diuretic resistance and strategies to overcome
resistance in patients with congestive heart
failure. Congest Heart Fail 2002; 8: 80–85.
276 http://tac.sagepub.com
4. Knauf H and Mutschler E. Sequential nephron
blockade breaks resistance to diuretics in
edematous states. J Cardiovasc Pharmacol 1997;
29: 367−372.
5. Epstein M, Lepp BA, Hoffman DS, et al.
Potentiation of furosemide by metolazone
in refractory edema. Curr Ther Res 1977; 21:
656−667.
6. Taylor SH. Diuretic therapy in congestive heart
failure. Cardiol Rev 2000; 8: 104–114.
7. Kramer BK, Schweda F and Riegger GA.
Diuretic treatment and diuretic resistance in heart
failure. Am J Med 1999; 106: 90−96.
8. McClellan WM, Flanders WD, Langston
RD, et al. Anemia and renal insufficiency are
independent risk factors for death among
patients with congestive heart failure admitted to
community hospitals: a population-based study. J
Am Soc Nephrol 2002; 13: 1928–1936.
9. Smith GL, Lichtman JH, Bracken MB, et al.
Renal impairment and outcomes in heart failure:
systematic review and meta-analysis. J Am Coll
Cardiol 2006; 47: 1987–1996.
10. Adams KF Jr, Fonarow GC, Emerman CL,
et al. Characteristics and outcomes of patients
hospitalized for heart failure in the United
States: rationale, design, and preliminary
observations from the first 100,000 cases in the
Acute Decompensated Heart Failure National
Registry (ADHERE). Am Heart J 2005;149:
209–216.
11. Heywood JT, Fonarow GC, Costanzo MR,
et al. High prevalence of renal dysfunction and
its impact on outcome in 118,465 patients
hospitalized with acute decompensated heart
failure: a report from the ADHERE database. J
Card Fail 2007; 13: 422–430.
12. Ezekowitz J, McAlister FA, Humphries KH,
et al. The association among renal insufficiency,
pharmacotherapy, and outcomes in 6,427
patients with heart failure and coronary artery
disease. J Am Coll Cardiol 2004; 44: 1587–1592.
13. Hillege HL, Girbes AR, de Kam PJ, et al. Renal
function, neurohormonal activation, and survival
in patients with chronic heart failure. Circulation
2000; 102: 203–210.
14. Gottlieb SS, Khatta M, Wentworth D, et al.
The effects of diuresis on the pharmacokinetics
of loop diuretic furosemide and torsemide in
patients with heart failure. Am J Med 1998; 104:
533−538.
15. Brater DC, Day B, Burdette A, et al. Bumetanide
and furosemide in heart failure. Kidney Int 1984;
26: 183−189.

16. Brater DC, Seiwell R, Anderson S, et al.
Absorption and disposition of furosemide in
congestive heart failure. Kidney Int 1982; 2:
171−176.
17. Brater DC. Resistance to loop diuretics. Why it
happens and what to do about it. Drugs 1985; 30:
427−443.
18. Aronson D. The complexity of diuretic resistance.
Eur J Heart Fail. Epub ahead of print 31 March
2017. DOI: 10.1002/ejhf.815.
19. Gerlag PG and van Meijel JJ. High-dose
furosemide in the treatment of refractory
congestive heart failure. Arch Intern Med 1988;
148: 286−291.
20. Wilcox CS. Diuretics. In: Brenner BM and
Rector FC (eds) The kidney. Philadelphia: WB
Saunders, 1996, pp.2299–2330.
21. Kimberly RP and Plotz PH. Aspirin-induced
depression of renal function. N Engl J Med 1977;
296: 418–424.
22. Muther RS, Potter DM and Bennett WM.
Aspirin-induced depression of glomerular
filtration rate in normal humans. role of
sodium balance. Ann Intern Med 1981; 94:
317–321.
23. Koopmans PP, Thien T and Gribnau FW.
Influence of non-steroidal anti-inflammatory
drugs on diuretic treatment of mild to moderate
essential hypertension. Br Med J Clin Res Ed
1984; 289: 1492–1494.
24. Hall D. Controversies in heart failure. Are
beneficial effects of angiotensin-converting
enzyme inhibitors attenuated by aspirin in
patients with heart failure? Cardiol Clin 2001; 19:
597−603.
25. Kirchner KA, Martin CJ and Bower JD.
Prostaglandin E2 but not I2 restores furosemide
response in indomethacin-treated rats. Am J
Physiol 1986; 250: F980–F985.
26. Loon NR, Wilcox CS and Unwin RJ. Mechanism
of impaired natriuretic response to furosemide
during prolonged therapy. Kidney Int 1989; 36:
682−689.
27. Aaser E, Gullestad L, Tollofsrud S, et al. Effect
of bolus injection versus continuous infusion
of furosemide on diuresis and neurohormonal
activation in patients with severe congestive
heart failure. Scand J Clin Lab Invest 1997; 57:
361−367.
28. Haller C, Salbach P, Katus H, et al. Refractory
oedema in congestive heart failure: a contributory
role of loop diuretics? J Intern Med 1995; 237:
211−214.
http://tac.sagepub.com 277
N Shah, R Madanieh et al.
29. Cody RJ, Kubo SH and Pickworth KK. Diuretic
treatment for the sodium retention of congestive
heart failure. Arch Intern Med 1994; 154:
1905−1914.
30. Kaissling B and Stanton BA. Adaptation of distal
tubule and collecting duct to increased sodium
delivery. I. Ultrastructure. Am J Physiol 1988;
255: F1256–F1268.
31. Stanton BA and Kaissling B. Adaptation of
distal tubule and collecting duct to increased Na
delivery. II. Na+ and K+ transport. Am J Physiol
1998; 255: F1269–F1275.
32. Brater DC, Chennavasin P and Seiwell R.
Furosemide in patients with heart failure: shift in
dose-response curves. Clin Pharmacol Ther 1980;
28: 182–186.
33. Farkas J. PulmCrit- Overcoming occult
diuretic resistance: achieving diuresis without
dehydration, https://emcrit.org/pulmcrit/occult-
diuretic-resistance (2016, accessed 3 May
2017).
34. Ellison DH. Diuretic resistance: physiology and
therapeutics. Semin Nephrol 1999: 19: 581–597.
35. Kuchar DL and O’Rourke MF. High-dose
furosemide in refractory cardiac failure. Eur Heart
J 1985; 6: 954–958.
36. Gerlag PGG and van Meijel JJM. High-dose
furosemide in the treatment of refractory
congestive heart failure. Arch Intern Med 1988;
148: 286–291.
37. Wargo KA and Banta WM. A comprehensive
review of the loop diuretics: should furosemide
be first line? Ann Pharmacother 2009; 43: 1836–
1847.
38. Abrams J. Intramuscular bumetanide and
furosemide in congestive heart failure. J Clin
Pharmacol 1981; 21: 673–679.
39. Sagar S, Sharma BK, Sharma PL, et al. A
comparative randomized double-blind clinical
trial of bumetanide and furosemide in congestive
cardiac failure and other edema states. Int J Clin
Pharmacol Ther Toxicol 1984; 22: 473–478.
40. Vargo DL, Kramer WG, Black PK, et al.
Bioavailability, pharmacokinetics, and
pharmacodynamics of torsemide and furosemide
in patients with congestive heart failure. Clin
Pharmacol Ther 1995; 57: 601–609.
41. Vasko MR, Brown-Cartwright D, Knochel
JP, et al. Furosemide absorption altered in
decompensated congestive heart failure. Ann
Intern Med 1985; 102: 314–318.
42. Raftery EB. Hemodynamic effects of diuretics in
heart failure. Br Heart J 1994; 72: S44–S47.
Therapeutic Advances in Cardiovascular Disease 11(10)
Visit SAGE journals online
journals.sagepub.com/
home/tac
SAGE journals
278 http://tac.sagepub.com
43. Ryback LP. Ototoxicity of loop diuretics.
Otolaryngol Clin North Am 1993; 26: 829–844.
44. Oh SW and Han SY. Loop diuretics in clinical
practice. Electrolyte Blood Press 2015; 13: 17–21.
45. Lahav M, Regev A, Ra’anani P, et al. Intermittent
administration of furosemide vs continuous
infusion preceded by a loading dose for congestive
heart failure. Chest 1992; 102: 725–731.
46. van Meijel JJ, 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.
47. Dormans TPJ, van Meijel JJM, Gerlag PGG,
et al. Diuretic efficacy of high-dose furosemide
in severe heart failure: bolus injection versus
continuous infusion. J Am Coll Cardiol 1996; 28:
376–382.
48. Ferguson JA, Sundblad KJ, Becker PK, et al.
Role of duration of diuretic effect in preventing
sodium retention. Clin Pharmacol Ther 1997; 62:
203–208.
49. Kiyingi A, Field MJ, Pawsey CC, et al. Metolazone
in treatment of severe refractory congestive cardiac
failure. Lancet 1990; 335: 29–31.
50. Dormans TPJ and Gerlag PGG. Combination of
high-dose furosemide and hydrochlorothiazide
in the treatment of refractory congestive heart
failure. Eur Heart J 1996; 17: 1867–1874.
51. Channer KS, McLean KA, Lawson-Matthew P,
et al. Combination diuretic treatment in severe
heart failure: a randomised controlled trial. Br
Heart J 1994; 71: 146–150.
52. Fliser D, Schröter M, Neubeck M, et al.
Coadministration of thiazides increases the
efficacy of loop diuretics even in patients with
advanced renal failure. Kidney Int 1994; 46:
482–488.
53. Lorenz RA and Elwell RJ. Pre-dosing metolazone
with loop diuretic combination regimens. Nephrol
Nurs J 2006; 33: 78–79.
54. Ellison DH. The physiologic basis of diuretic
synergism: its role in treating diuretic resistance.
Ann Intern Med 1991; 144: 886–894.
55. Moranville MP, Choi S, Hogg J, et al.
Comparison of metolazone versus chlorothiazide
in acute decompensated heart failure with
diuretic resistance. Cardiovasc Ther 2015; 33:
42–49.
56. van Vliet AA, Donker AJM, Nauta JJP, et al.
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.
57. Pitt B, Zannad F, Remme WJ, et al. The effect
of spironolactone on morbidity and mortality in
patients with severe heart failure. N Engl J Med
1999; 341: 709–717.