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Diuretic Resistance in Heart Failure
Article in Cardiology in Review · March 2020

DOI: 10.1097/CRD.0000000000000310
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The Cardiology in Review Journal Publish Ahead of Print
DOI: 10.1097/CRD.0000000000000310
Diuretic Resistance in Heart Failure
Rubayat Rahman MD1, Pablo Paz MD1, Mohamed Elmassry MD1, Barbara Mantilla MD1,
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Logan Dobbe MD2, Scott Shurmur MD1, Kenneth Nugent MD1
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1
Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock,
Texas; 2Department of Graduate Medical Education, Madigan Army Medical Center, Tacoma,
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Washington
Running Head: Diuretic Resistance in Heart Failure
Corresponding author: Kenneth Nugent MD, 3601 4th Street, Lubbock, Texas 79430
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Kenneth.Nugent@ttuhsc.edu,
Conflicts of interest: none
Financial support: none

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Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
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Abstract
Decompensated heart failure accounts for approximately one million hospitalizations in
the United States annually, and this number is expected to increase significantly in the near
future. Diuretics provide the initial management in most patients with fluid overload. However,
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the development of diuretic resistance remains a significant challenge in the treatment of heart
failure. Due to the lack of a standard definition, the prevalence of this phenomenon remains
difficult to determine, with some estimates suggesting that 25% to 30% of patients with heart
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failure have diuretic resistance. Certain characteristics, including low systolic blood pressures,
renal impairment, and atherosclerotic disease, help predict the development of diuretic
resistance. The underlying pathophysiology is likely multifactorial, with pharmacokinetic

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alterations, hormonal dysregulation, and the cardiorenal syndrome having significant roles. The
therapeutic approach to this common problem typically involves increases in the diuretic dose
and/or frequency, sequential nephron blockade, and mechanical fluid movement removal with
ultrafiltration or peritoneal dialysis. Paracentesis is potentially useful in patients with intra-

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abdominal hypertension.
Key words: heart failure, diuretics, diuretic resistance, renal dysfunction

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Congestive heart failure (CHF) is a leading cause of hospitalization in the United States.1
Loop diuretics remain the cornerstone in the management of patients with acute decompensated
heart failure and are used in up to 90% of hospitalized patients, despite the lack of evidence of
improved survival in these patients.1,2 Consequently, diuretic resistance has become an important
concern since it is associated with deteriorating renal function and more frequent readmissions.3
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Diuretic resistance seems to develop as a compensatory response to chronic diuretic treatment.
These responses include increases in plasma renin activity, stimulation of the sympathetic
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nervous system, and adaptive changes in nephron structure and function resulting from diuretic-
induced increases in the distal sodium load.4
DEFINITION OF DIURETIC RESISTANCE

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Despite its prevalence, the term diuretic resistance does not have a standard well-
accepted definition. Definitions include failure to eliminate extracellular fluid despite an
adequate trial of diuretics,5 or a decreased response to diuretics leading to persistent congestion,

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or a fractional sodium excretion of <0.2% while on diuretics.8 Doering et al tried to define
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diuretic resistance in patients with heart failure presenting to an emergency department. These
investigators compared three different urine parameters as markers of a poor diuretic response,
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namely a fractional excretion of sodium of less than 0.2%, a spot urinary sodium less than 50
meq/L, and a urine sodium/potassium ratio less than 1.0. The patient populations identified by
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each of the three parameters differed significantly and had very little overlap; however, the study
did find significantly higher rates of readmission in patients with spot urinary sodium less than
50 meq/L.9
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PATIENT CHARACTERISTICS
Valente et al studied diuretic responses in 1,745 hospitalized patients with acute heart
failure and found that low systolic blood pressures, low serum potassium, high blood urea
nitrogen, diabetes, and atherosclerotic disease predicted a poor diuretic response.10 McClellan et
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al reported that 38% of patients with CHF have impaired renal function, placing them at
increased risk of developing diuretic resistance.11 Prerenal azotemia is present to some degree in
almost all patients with severe CHF.6 This condition involves diminished renal blood flow which
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reduces tubular delivery of loop diuretics and increases competition from accumulating anions
for the organic anion transporter.12
EPIDEMIOLOGY
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An acute heart failure registry reported that there are an estimated 1 million
hospitalizations with a primary diagnosis of CHF annually, and this number is expected to
increase over the next 2 decades.1 Ninety percent of patients admitted with decompensated heart
failure receive intravenous diuretics and have an average hospitalization lasting for 4.3 days.
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However, 50% of admitted patients lose less than five pounds, 20% actually gain weight during
hospitalization, and 42% of patients leave the hospital with persistent symptoms. Inadequate
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diuresis contributes to readmissions.1
Due to the lack of a standard definition, it is difficult to determine the exact frequency of
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diuretic resistance, with some estimates placing the number at 25% to 30% of patients.4 Most
hospitalizations for heart failure are due to fluid retention in patients refractory to oral diuretics.
Neuberg et al found that almost 35% of patients had diuretic resistance, defined as requirement
of furosemide > 80 mg daily or bumetanide > 2 mg daily for treatment.13
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PATHOPHYSIOLOGY
Pharmacokinetic Factors
Brater et al demonstrated that the time for diuretics to reach a steady state following oral
administration is increased in patients with CHF compared to healthy controls.14 This is most
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likely explained by mucosal edema in the gastrointestinal tract of patients with severe heart
failure.15 More than 95% of furosemide that enters the bloodstream binds to albumin, and it has
been suggested that exogenous albumin could increase diuretic delivery to the kidneys. However,
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a recent meta-analysis did not reveal any significant clinical benefit with the co-administration of
furosemide and albumin in hypoalbuminemic patients.16
Furosemide is secreted into the convoluted tubules by the organic anion transporter and
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then blocks the Na-K-2Cl transporter on the luminal surface of the ascending limb of the loop of
Henle.17 In patients with CHF, renal impairment leads to the accumulation of endogenous
organic anions which compete with loop diuretics for secretion by binding to the organic anion
transporter.18 This can reduce intratubular concentrations of diuretics, potentially contributing to

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diuretic resistance.15
Diuretic resistance may also be caused by interactions with medications, such as

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nonsteroidal anti-inflammatory agents (NSAIDs). In severe CHF, prostaglandins help maintain
renal perfusion and promote salt and water excretion.19 Nonsteroidal anti-inflammatory agents
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interfere with this process by inhibiting prostaglandin synthesis, thus reducing renal perfusion
and diuresis. Several studies have reported smaller reductions in mortality with conventional
heart failure treatment in patients taking aspirin.20-22
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Hyponatremia and Post-Diuretic Salt Retention
Hyponatremia has been frequently associated with reduced diuretic efficacy due to
diminished distal tubular sodium delivery and secondary hyperaldosteronism. Low sodium levels
are a marker for advanced heart failure and are associated with decreased survival.23
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Hyponatremia can be caused by diuretic treatment but is more often secondary to severe heart
failure’s stimulating thirst and the vasopressin axis that ultimately reduces excretion of free
water.24,25 This is particularly important in patients who are not adherent to fluid and salt intake
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restrictions. Wilcox et al reported that in healthy subjects eating a high-sodium diet there is a
marked increase in sodium absorption 6 to 24 hours after administration of furosemide. This
phenomenon is referred to as post-diuretic salt retention and can prevent the negative sodium
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balance expected with diuresis. In contrast, with a low-sodium diet, this compensatory increase
in sodium reabsorption did not occur, because sodium reabsorption had been near maximal at
baseline, thus furosemide given once daily led to negative sodium balance.26 Dietary
noncompliance should be suspected in patients on diuretics, when sodium excretion is greater

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than 100 mmol in 24 hours without any associated weight loss.27
Renal Blood Flow

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Increased proximal convoluted tubule sodium reabsorption as a consequence of diuretic-
induced volume depletion and decreased renal blood flow is a possible explanation of diuretic
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resistance. Diuretic administration can reduce the glomerular filtration rate (GFR) and increase
proximal fluid reabsorption at least over short study periods.28 However, this theory has been
questioned by the work of Loon et al.29 Following the work of Earley and Martino,30 Loon
assumed that a combination of loop diuretics and thiazides would block the major distal sites of
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sodium reabsorption, and any residual sodium reabsorption could then be attributed to the
proximal convoluted tubule. They treated patients on loop diuretics and thiazides with different
test combinations of intravenous furosemide, thiazides, and spironolactone and found no
significant difference in sodium excretion compared to placebo, indicating that proximal
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reabsorption was not greatly affected by diuretic therapy in chronically treated patients.
Greenwood et al actually found that infusions of loop diuretics reduced proximal fluid
reabsorption and attributed this effect to non-specific actions of loop diuretics, including
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inhibition of carbonic anhydrase.31
Hormonal Dysregulation
Volume depletion secondary to diuretics stimulates the renin-angiotensin-aldosterone

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system (RAAS), and this may contribute to the development of diuretic resistance. As the heart
fails, renal blood flow is initially maintained by autoregulation in the kidneys. Activation of the
RAAS and the sympathetic nervous system (SNS) preserves GFR. This is achieved by an
increase in efferent arteriolar resistance with subsequent augmentation of glomerular hydrostatic

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pressure and filtration fraction.32 In advanced heart failure, when renal perfusion falls below the
threshold of renal autoregulation, GFR becomes dependent on afferent and efferent arteriolar
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resistance controlled by norepinephrine and angiotensin II.33 Upregulation of RAAS becomes a
maladaptive process since both systemic and renal vasoconstriction further reduce renal blood
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flow, increase tubular sodium reabsorption, and increase congestion. However, this may not be
a major factor in diuretic resistance at least in patients with CHF since RAAS activity is already
elevated at baseline. Moreover, the convoluted tubules are the major sites of reabsorption in the
nephron, making it unlikely that aldosterone-induced reabsorption in the collecting tubules can
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overcome the natriuresis induced by loop diuretics or thiazides. Loon et al demonstrated that
addition of an aldosterone antagonist did not restore urinary sodium excretion in patients treated
with furosemide to that seen in patients on placebo.29
The SNS and RAAS increase sodium and water reabsorption in the proximal tubule,
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which leads to passive reabsorption of urea and a decrease in urine flow rate. Furthermore, as
GFR declines, vasopressin upregulates urea transporters in the collecting duct leading to an
additional increase in urea reabsorption. These mechanisms can help explain why the level of
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blood urea nitrogen (BUN) correlates with the degree of neuro-hormonal activation and is
associated with worsening heart failure.34 Therefore, the BUN can function as an indicator of
neuro-hormonal activation, reflects changes in GFR, and has a prognostic value in patients with
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heart failure.35,36
Testani et al analyzed 2,456 patients with compensated heart failure in the BEST trial
(Beta-blocker evaluation of Survival Trial) to determine if BUN could be used as a marker of
adverse effects of loop diuretics.37 The study classified patients into subgroups based on a
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baseline BUN level above or below the median (21 mg/dL) to study the relationship between
high dose loop diuretics (HDLD) and mortality. HDLD treatment (defined as total daily dose of
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≥160 mg of furosemide equivalents) was associated with higher mortality rates in patients with a
BUN above 21 mg/dL (hazard ratio [HR] 1.30; 95% confidence interval [CI]: 1.07 to 1.5;
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p=0.009) but improved survival in patients with a BUN below 21 mg/dL (HR: 0.71; 95% CI:
0.49 to 0.96, p =0.0042) after controlling for confounding variables.37 Patients taking HDLDs
had higher plasma norepinephrine levels with a baseline BUN above the median compared to
patients below the median. These findings suggest a link between the BUN level and renal
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neuro-hormonal activation that can help identify patients who will have adverse effects with loop
diuretics.37
Nuñez et al also studied the association between mortality and HDLD based on BUN and
carbohydrate antigen 125 (CA 125) levels following hospitalization in acute heart failure.38 The
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CA 125 is used as a marker of systemic congestion, and in patients with normal CA 125 levels,
HDLDs (defined by ≥120 mg/day in furosemide equivalents) were associated with higher
mortality rates in patients with BUNs above the median but not with BUNs below the median.
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These findings support the results reported by Testani et al37 in patients with stable chronic heart
failure. However, in patients with significant volume overload (i.e., CA 125 > 35 U/mL),
HDLDs improved survival in patients with high BUNs and decreased survival in patients with
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low BUNs.38 These results suggest that the degree of fluid overload also has an important role in
the relationship between BUN and adverse diuretic effects.
Structural Changes in the Renal Parenchyma
Diuretic treatment causes structural changes in the nephron itself. Continuous infusions
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of furosemide for 6 days in rats stimulate the proliferation of the distal convoluted tubules with
expansion of mitochondrial volume and basolateral membrane area. This suggests that the
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transcellular transport capacity of the distal convoluted tubules increases in response to
diuretics.39 Na and coworkers used immunoblotting to demonstrate proliferation of sodium

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channels in the ascending loop of Henle, the distal convoluted tubule, and collecting tubules
following continuous treatment with either loop and thiazide diuretics.40 Pendrin, a Cl-/HCO3-
cotransporter in the distal convoluted tubule, is upregulated in response to diuretic therapy in
mice; urine output increases 60% when this transporter is blocked.41 The carbonic anhydrase
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inhibitor acetazolamide downregulates pendrin and can potentiate the diuretic effect of other
diuretics.42 However, carbonic anhydrase inhibitors should be used cautiously, if at all, in
patients with heart failure since these drugs act on the proximal convoluted tubule and can cause
metabolic acidosis.18
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Renal Vein Hypertension and the Cardiorenal Syndrome
Patients with cardiorenal syndrome (CRS) have worsening renal function and diuretic
resistance. The syndrome can be divided into categories based on the organ affected first (kidney
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or heart) and on the acuity and nature of the insult.43 The pathophysiology is multifactorial and
is explained by the interaction of altered hemodynamics, hormonal dysregulation, and oxidative
stress. Both reduced renal blood flow and increased renal vein pressure contribute to the
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development of CRS.44 Central venous pressure (CVP) is an independent predictor of renal
function in CHF.45,46 In combination with pump failure, elevated CVP directly impairs renal
blood flow and renal perfusion pressure. As renal blood flow drops below the threshold of renal
autoregulation, renal perfusion pressure becomes directly pressure dependent, and any further
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increase in CVP leads to progressive fluid extravasation from the renal microcirculation.
Increased interstitial pressure causes renal parenchymal hypoxia and tubular dysfunction with
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activation of the renin-angiotensin-aldosterone system.47 This high degree of neurohormonal
activation causes pre-glomerular vasoconstriction and reduces GFR which reduces the kidneys’
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response to diuretics. The use of diuretics to reduce fluid overload could further compromise
renal blood flow and GFR.
Mullens et al studied 145 patients with severe heart failure managed in an intensive care
unit with right heart catheterization.48 They found that patients with worsening renal function
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defined by an increase in Cr of 0.3 mg/dL had higher CVPs on admission (18 ± 7 mm Hg vs. 12
± 6 mm Hg, p < 0.001) and after intensive medical therapy (11 ± 8 mm Hg vs. 8 ± 5 mm Hg, p =
0.04) than patients who did not have a deterioration in renal function. These results suggest that
venous congestion defined by an increase in CVP has an important role in the development of
CRS.48 A retrospective review of 2,557 patients who underwent right heart catheterization
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showed a strong association between CVP and eGFR (r = −0.108, p < 0.0001) in patients with
both reduced and preserved cardiac function. In particular, the magnitude of the relationship
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between CVP and eGFR was greater in patients with relatively normal cardiac indices. This
study showed that all-cause mortality increases with increasing CVP, particularly with pressures
above 6 mm Hg.45 Elevated CVP was an independent predictor of death (hazard ratio: 1.03 per
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mm Hg increase, 95% confidence interval: 1.01 to 1.05, p = 0.0032).45 The Evaluation Study of
Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial
with 433 patients admitted with acute decompensated heart failure demonstrated that baseline
serum creatinine correlated with baseline right atrial pressures and not the cardiac index.49
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Furthermore, there was no improvement in renal function with improvement in cardiac systolic
function.33,50 These results suggest that elevated CVPs have an important role in the development
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of CRS and suggest that treatment targeted to reduce venous congestion might improve renal
function, diuretic response, and survival.

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Abdominal Compartment Syndrome
Abdominal congestion occurs in a significant percentage of patients with severe heart
failure. Intra-abdominal pressure (IAP) is increased in 60% of patients admitted with advanced
CHF.44 Splanchnic capacitance veins contain 25% of the total blood volume and are able to
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buffer changes in volume status to maintain an adequate preload.44 Systemic congestion and
increased arteriolar vasoconstriction cause blood to shift from the effective circulatory volume to
splanchnic capacitance veins.50 At the same time sympathetic stimulation causes
venoconstriction reducing splanchnic capacitance.44 Splanchnic venous and interstitial
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congestion are present when both venous capacitance and lymph flow cannot compensate for
excess fluid causing increased IAP. Abdominal congestion in turn causes increased renal vein
pressure and reduced perfusion, leading to worsening renal function.44,51 Elevated IAP is
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transmitted trans-diaphragmatically and may cause elevated intrathoracic pressures independent
of venous return.52,53
Mullens et al studied forty patients with severe heart failure receiving intensive medical
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therapy and reported a strong association between elevated IAP and worsening renal impairment
(p=0.009).48 Furthermore, in patients with elevated IAPs at baseline, reducing IAP correlated
with improvement in renal function (r = 0.77, p < 0.001). This correlation was independent of
changes in hemodynamic measurements, such as right and left-sided filling pressures and cardiac
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index. The authors suggested that a persistently elevated IAP is a possible explanation for the
worsening of renal function that is sometimes observed despite improved hemodynamics with
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aggressive therapy of decompensated heart failure.54 In these patients, considered refractory to
aggressive therapy, mechanical fluid removal can improve renal function. A prospective study of
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9 patients with advanced heart failure refractory to diuretics found that fluid removal by either
paracentesis or ultrafiltration reduced IAP (from 13 ± 4 mm Hg to 7 ± 2 mm Hg, p=0.001) and
improved renal function (serum creatinine from 3.4 ± 1.4 mg/dL to 2.4 ± 1.1 mg/dL, p=0.01),
likely by reducing abdominal congestion.55
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The pathogenesis of diuretic resistance involves multiple potential factors and likely
differs in individual patients (Table 1).14,15,18,19,26,28,29,40,47,48
Management Strategies
Medication
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The medical management of diuretic resistance requires a careful review of relevant
clinical and pharmacological factors and sequential, often additive, changes in drug therapy.56
Rule-Out Noncompliance
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The first step in managing diuretic resistance is to ascertain whether or not dietary salt
intake is being restricted. In the absence of sodium restriction (<100 mmol/day), post-diuretic
salt and water retention can completely abolish the negative balance produced by diuresis.
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Measurement of 24-hour urinary sodium excretion can help assess sodium intake. Poor
adherence to medical treatment should be suspected when the daily salt excretion is greater than
100 mmol without associated weight loss.27
NSAIDs are an important cause of diuretic resistance, as discussed above. These

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medications have been associated with increased risk of hospital readmissions in patients with
pre-existing heart failure.57 Patients with persistent congestion despite adequate diuretic dosage
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and adherence to salt and fluid restriction should be asked about the use of NSAIDs.
Changes in Dosage and Route of Administration

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Increased diuretic dosage and frequency can help overcome diuretic resistance to some
degree. Gerlag et al showed that high-dose furosemide (250–4000 mg/day, oral or IV) improved
symptoms, weight loss, and renal function in severe CHF unresponsive to conventional diuretic
treatment.58 Increased frequency of administration (3 times daily or more) reduces diuretic-free
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intervals and can overcome post-diuretic salt retention.27 Switching to the intravenous route
ensures maximum bioavailability and circumvents the possibility of poor gastrointestinal
absorption. In patients who fail high dose intravenous diuretic therapy, continuous infusions of
diuretics has been found to be a safe and effective option in several studies.59-61 An often
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overlooked concern with high dose infusions of loop diuretics is the development of ototoxicity,
particularly in patients receiving other ototoxic agents (e.g., aminoglycosides).62
Diuretic Choice: Torsemide vs Furosemide
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Torsemide has more consistent bioavailability than furosemide regardless of the presence
of gastrointestinal mucosal edema.63 Studies have shown that torsemide can reduce cardiac
sympathetic tone and ameliorate myocardial fibrosis and ventricular remodeling.64,65 Miles et al
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did a meta-analysis of 8,127 patients with heart failure from 14 studies and found that torsemide
reduced readmission rates and improved New York Heart Association (NYHA) functional class
at 12 months. However, there was no significant difference in mortality between the two
diuretics.66 In separate analyses with 12,725 patients with CHF (4,580 from the Duke
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Echocardiography Lab Database, 7,141 from the Acute Study of Clinical Effectiveness of
Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial, 1004 from the Placebo-
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controlled Randomized study of the selective A1 adenosine receptor antagonist rolofylline for
patients hospitalized with acute heart failure and volume Overload to assess Treatment Effect on
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Congestion and renal funcTion (PROTECT) trial. Mentz et al found no difference in 30-day
mortality rates in patients treated with torsemide or furosemide after adjustment for baseline
disease severity and comorbidities.67-69
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Sequential Nephron Blockade
Combination therapy with loop and thiazide diuretics has been well-studied in CHF
patients. 70-72 Thiazides counteract the compensatory increase in transcellular sodium transport in
the distal convoluted tubule in response to loop diuretics. This approach, termed sequential
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nephron blockade, can increase urine output, salt excretion, and weight loss and improve
symptoms in patients refractory to loop diuretics alone. There is no difference in efficacy among
the commonly used thiazides in combination with loop diuretics to achieve sequential nephron
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blockade.18
Vasopressin Receptor Blockade
Vasopressin levels are increased in patients with heart failure and can increase fluid
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retention.73 Selective antagonists of vasopressin at the V2 receptors located in the kidney, such as
tolvaptan, increase urine output and reduce body weight in patients with heart failure.74 The
Kanagawa Aquaresis Investigators Trial of Tolvaptan on Heart Failure Patients with Renal
Impairment (K-STAR) study demonstrated that in patients with heart failure and persistent
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congestion and renal dysfunction refractory to standard therapy, the addition of tolvaptan was
superior to increased doses of furosemide and increased urine output without more renal
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dysfunction.75 However, there were no significant differences in the decrease in body weight or
in the improvement in signs and symptoms of congestion.75 Udelson et al demonstrated that by

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increasing water excretion tolvaptan reduced pulmonary capillary wedge pressures, right atrial
pressures, and pulmonary artery pressures, which should be associated with symptom
improvement.76 Wang et al published a systematic review and meta-analysis on the use of
tolvaptan in patients with acute heart failure.77 This study included 6 randomized control trials
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with 746 patients. Tolvaptan did not improve all-cause mortality, did not decrease the incidence
of clinical events or worsening renal function, and did not decrease the length of hospital stays in
patients. In patients with diuretic resistance, tolvaptan does not seem to be significantly better
than adding a different class of diuretics; its use might be preferred in patients with diuretic
resistance associated with hyponatremia and/or kidney dysfunction.78
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Aldosterone Antagonists
Spironolactone has a mild natriuretic effect and reduces potassium excretion by loop
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diuretics.79,80 Aldosterone antagonists decrease mortality and heart failure hospitalization in
patients with heart failure and reduced ejection fractions.56 Therefore, there is good evidence to
support the use of aldosterone antagonists when the GFR is stable and serum potassium levels
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are less than 5.5 mEq/l.56,79 In a trial of 100 patients with acute heart failure, adding
spironolactone was associated with rapid symptomatic relief and improved renal function.81 A
smaller study with 21 patients showed that the addition of spironolactone was associated with
marked diuresis and quicker symptom relief in patients refractory to loop diuretics.82 However,
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in the Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure
(ATHENA-HF) trial, adding high dose spironolactone to the usual care for patients with acute
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heart failure did not improve outcomes.83 Larger trials are needed to study the potential benefit of
aldosterone antagonists in patients with diuretic resistance.

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Dopamine
Low dose dopamine (<3 µg/kg/minute) works selectively on renal dopaminergic
receptors causing vasodilation of the renal vasculature and increased renal blood flow. The
Dopamine in Acute Decompensated Heart Failure II (DAD-HF II) trial and the Renal
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Optimization Strategies Evaluation (ROSE) trial showed that adding low-dose dopamine to low-
dose furosemide infusions was equally effective as high dose furosemide infusions.84,85 In
general, dopamine has no role in patients with acute heart failure and normal blood pressures
according to the available data.56,86,87 While dopamine has no proven benefit in diuretic
resistance, it may be used as a last resort in these patients given its theoretical benefits.56
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Nesiritide
Nesiritide is a recombinant B-type natriuretic peptide that has favorable effects on
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hemodynamics and dyspnea in small clinical trials and is Food and Drug Administration
approved for symptomatic relief. However, larger clinical trials, such as the ROSE trial and the
ASCEND HF trial, reported no clear benefit of nesiritide in the management of diuretic

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resistance.85,88 The ASCEND-HF trial randomized 7,141 heart failure patients to receive
nesiritide or placebo with standard treatment with loop diuretics. This study reported mild
improvement of dyspnea in the nesiritide group but no significant change in urine output when
compared to placebo.89,90
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The Low Dose Dopamine or Low Dose Nesiritide in Acute Heart Failure with Renal
Dysfunction (ROSE acute heart failure) trial compared both regimens to placebo but showed no
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increase in urine output or improvement in renal function when added to diuretic therapy in
patients with acute heart failure and renal dysfunction.91 However, it is worth mentioning that
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heart failure trials with nesiritide and dopamine were not focused on patients with diuretic
resistance.56
Hypertonic Saline
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Intravenous hypertonic saline can augment loop diuretic efficacy in refractory patients.
Hypertonic saline osmotically “pulls” free water from interstitial fluid into the renal vasculature
increasing renal blood flow, as well as improving sodium delivery to the loop of Henle, thus
restoring some of the loop diuretics’ effect.92
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Several studies showed that adding hypertonic saline to loop diuretic therapy improves
diuresis, improves renal function, and shortens hospitalizations.93,94 The Sodium Management in
Acute and Chronic Heart Failure trial compared the short- and long-term effects of intravenous
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furosemide plus hypertonic saline with intravenous furosemide alone in 1,771 decompensated
NYHA functional class III patients. The addition of hypertonic saline infusions improved
diuresis and reduced hospital stays compared to furosemide alone. Moreover, after a follow-up
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of 57 months, the furosemide plus hypertonic saline patients had fewer hospital readmissions
(18.5% vs 34.2%; P < 0.0001) and a lower mortality rate (12.9% vs 23.8%; P < 0.0001)
compared with the group that received furosemide alone.95
Management Strategies: Medical Devices

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Ultrafiltration
The 2013 American College of Cardiology Foundation/American Heart Association

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(ACCF/AHA) Task Force Guidelines recommend ultrafiltration as a possible treatment option
for patients with refractory congestion who are not responding to medical therapy.96 Standard
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ultrafiltration is a cumbersome process, requiring placement of a dual lumen central venous line,
and has several complications, including infection, hemorrhage, electrolyte disorders, anemia,
and thrombocytopenia.97 With technological advances, newer ultrafiltration devices have become
available that are smaller and more portable and require only peripheral venous access.98
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The data which support the efficacy of ultrafiltration in comparison to standard diuresis
are inconsistent. Two randomized controlled trials with 240 patients in total, the UNLOAD
(Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated
Congestive Heart Failure) trial and the RAPID-CHF (Relief for Acutely Fluid-Overloaded
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Patients with Decompensated Congestive Heart Failure) trial, reported greater weight loss and
fluid loss with ultrafiltration than with intravenous diuretics.99,100 Neither trial specifically tested
the efficacy of ultrafiltration in patients resistant to diuretics. The ULTRAfiltration vs. DIureticS
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on clinical, biohumoral and haemodynamic variables in patients with deCOmpensated heart
failure (ULTRADISCO) study recruited 30 patients with decompensated heart failure and found
significant improvement in symptoms, plasma aldosterone levels, and hemodynamics with

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ultrafiltration compared to diuretic therapy.101 The Cardiorenal Rescue Study in Acute
Decompensated Heart Failure (CARRESS-HF) trial studied 188 patients with severe heart failure
and cardiorenal syndrome and found ultrafiltration inferior to step diuretic therapy based on two
end points: changes in serum creatinine and body weight at 96 hours.97 In addition, the
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ultrafiltration arm had a higher risk of serious adverse events (72 % vs. 57 %). This trial was
unblinded and limited the ultrafiltration rate to 200 mL/hr; other studies allowed ultrafiltration
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rates of up to 500 mL/hr. Teo et al retrospectively reviewed 44 patients with decompensated
heart failure and diuretic resistance and found greater fluid loss (3,815 mL vs. 1,355 mL, p =
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0.0003) and greater weight loss (5.0 kg vs. 1.0 kg, p < 0.0001) at 48 hours with ultrafiltration
compared to standard care.102 The ultrafiltration group also had shorter hospitalizations (5.0 days
vs. 9.5 days, p = 0.0010) and fewer emergency department visits during a 90 day follow-up
period after discharge.
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Peritoneal Dialysis
Extracorporeal ultrafiltration can reduce fluid overload in hospitalized patients with acute
decompensated heart failure; however, its complexity and expense make it a poor option for
most patients with chronic heart failure during outpatient management. Peritoneal dialysis for the
treatment of resistant heart failure was first described in 1949 by Schneierson et al.103 Multiple
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cohort studies since then have demonstrated the effectiveness of peritoneal dialysis in advanced
heart failure and cardiorenal syndrome. A 10-year retrospective study involving 21 patients
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found significantly reduced rate of all-cause hospitalizations in peritoneal dialysis patients
compared to baseline.104 Koch et al followed 118 patients with NYHA class III or IV heart
failure and chronic kidney disease and reported peritoneal dialysis was well tolerated with
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significant reductions in body weight after 6 months (78.7 to 74.7 kg).105 Another prospective
single center study followed seventeen patients with CHF undergoing peritoneal dialysis and
found a dramatic reduction in hospitalization rates (62 ± 16 to 11 ± 5 days/patient/year, P =
0.003) together with significant improvement in NYHA functional status and pulmonary artery
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systolic pressure (44 ± 12 versus 27 ± 9 mmHg, P = 0.007) without changes in LVEF.106
Courivaud reported the outcomes in 126 patients treated with peritoneal dialysis for chronic
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refractory heart failure. These patients had a mean age of 72 ± 11 and a mean estimated GFR of
33.5 ±15.1 mL/min/1.73 m². The mean time on peritoneal dialysis was 16 ±16 months.107
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Patients with low ejection fractions had increases in ejection fraction during the first year of
peritoneal dialysis. The number of hospital days for acute decompensated heart failure was
reduced after the initiation of peritoneal dialysis. The number of days preceding dialysis was 3.3
± 2.6 days per patient-month compared to 0.3 ± 0.5 days after dialysis was started. The overall
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1-year mortality was 42%. Peritoneal dialysis appears to decrease the rate of hospitalization for
decompensated heart failure and may allow beneficial adjustments in chronic medications used
in these patients.
Lu et al reported a systematic review of 21 studies on patients with refractory congestive
heart failure who underwent peritoneal dialysis for fluid management.108 This review included
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673 patients with a mean age of 67.4 years and a mean follow-up time of 33.2 months. There
was a significant reduction in the number of hospital days from 6.3 to 1.2 days/year following
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induction of peritoneal dialysis. The left ventricular ejection fraction increased by approximately
4.1%, and the NYHA classification improved from 3.53 to 2.17 post dialysis. There was no
significant change in renal function in patients who did not have extremely low estimated GFRs
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at the onset of peritoneal dialysis. The mean incidence of peritonitis was 14.5 %/year; the
number of noninfectious complications was relatively low.
Patients with refractory fluid overload frequently require ultrafiltration to reduce fluid
accumulation. This typically requires hospitalization. The use of peritoneal dialysis at home can
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provide the same benefit with less cost and less inconvenience. These patients typically undergo
nocturnal peritoneal dialysis 2-3 times per week. However, peritoneal dialysis has definite
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limitations which include line migration and obstruction from infectious complications, such as
peritonitis and tunnel site infection, long-term metabolic derangements, and peritoneal sclerosis.
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The ultrafiltration goal can be programmed specifically, but the ultrafiltration capacity of
peritoneal dialysis patients varies widely and requires close follow-up and frequent adjustments
over time.109 There is a need for large randomized controlled trials to assess the effectiveness and
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utility of peritoneal dialysis compared to both conventional medical therapy and extracorporeal
ultrafiltration.
Peritoneal Catheters
Aisenberg reported the use of a peritoneal catheter for the removal of massive cardiac
ascites in one patient.110 This patient had a French pigtail catheter inserted in the peritoneal
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cavity and had a daily drainage of 5 L ascites for 14 days. This patient then was discharged and
remained stable for at least 4 months. Bevan et al reported the use of a permanent peritoneal
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catheter for palliation of diuretic resistant cardiac ascites in one patient.111 This patient had
frequent hospitalizations for fluid accumulation and had required paracentesis once. This patient
performed home drainage of between 2 to 4 L of ascitic fluid per week. His peripheral edema
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resolved, his GFR increased, his pro BNP decreased, and he had no heart failure related
hospitalizations.
The accumulation of large volumes of ascitic fluid in some patients with chronic heart
failure likely has important consequences. The fluid volume can decrease mobility and quality
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of life. In addition, the fluid likely increases intra-abdominal pressure and may compromise both
gastrointestinal function and renal function. Consequently, removal of this fluid using
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paracentesis may have short term benefits. However frequent paracenteses present practical
difficulties. The use of long-term peritoneal catheters can allow this to take place at home at
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lower costs. Many healthcare organizations use pleural catheters to manage malignant pleural
effusions. These organizations would have the experience and the staff needed to manage
outpatient peritoneal catheters.
Cardiac Resynchronization
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Some patients with advanced heart failure have both decreased left ventricular function
and cardiac dyssynchrony. Cleland and colleagues enrolled 813 patients in NYHA class III or
IV heart failure who had reduced left ventricular function and cardiac dyssynchrony into a
randomized control trial of medical therapy alone or medical therapy with cardiac
resynchronization.112 Patients in the cardiac resynchronization arm had better outcomes with a
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decreased death from any cause and decreased unplanned hospitalization for cardiac events.
These patients also had reduced intraventricular mechanical delay, reduced end-systolic volume,
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and a reduced area of mitral regurgitant jet; they had increased left ventricular ejection fractions
(difference between means-6.9% at 18 months) and improved quality of life (NYHA class 2.1 vs.
27 at 90 days). This study demonstrates that patients who have significant cardiac dyssynchrony
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can benefit from cardiac resynchronization when added onto standard medical therapy.
Medical devices can improve outcomes in patients with diuretic resistance and refractory
fluid overload (Table 2).55,99-101,108,110-112
Management Strategies in Patients with Hypotension and or Hyponatremia

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Management of Patients with Hypotension
Treatment for patients with acute heart failure and hypotension differs in patients with
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heart failure with reduced ejection fractions (HFrEF) and in patients with heart failure with
preserved ejection fractions (HFpEF).

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For patients with HFrEF associated with hypotension or clinical signs of shock and
evidence of an adequate preload, the addition of inotropic drugs (milrinone, dobutamine or
dopamine) is recommended.113 If worsening hypotension or new-onset tachyarrhythmia occur,
the dose of inotropes should be reduced or discontinued. If shock persists after adequate inotrope
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use and optimization of filling pressures, vasopressors (norepinephrine and high-dose dopamine)
might increase perfusion to vital organs. But these drugs will increase left ventricular afterload.
In patients with significant decreases in left ventricular function and severe hemodynamic
compromise despite adequate pharmacologic therapy, mechanical cardiac support
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(extracorporeal ventricular assist device, intra-aortic balloon pump or extracorporeal circulatory
membrane oxygenator) can be used.96,113
In patients with HFpEF, inotropes are contraindicated since dynamic left ventricular
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outflow tract obstruction, if present, can increase with the use of inotropes. These patients are
treated with beta blockers, and if there is no evidence of pulmonary congestion, cautious fluid
resuscitation. Vasopressors (phenylephrine and norepinephrine) can be added if hypotension

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persists after adequate hydration.114
Management of Patients with Hyponatremia
The presence of hyponatremia in patients with heart failure usually predicts a poor
prognosis; there is no evidence that correction of hyponatremia improves clinical outcomes.115

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Thus, correction of hyponatremia is reserved for patients with a sodium level < 120 mEq/L,
presence of symptoms associated with hyponatremia, or asymptomatic hyponatremia that could

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predispose patient to falls. The main therapy for hyponatremia in patients with heart failure is
water restriction.115 Angiotensin-converting enzyme inhibitors (ACE), angiotensin II receptor

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blockers (ARB), and loop diuretics, typically used in patients with heart failure, can also increase
sodium levels. ACE inhibitors decrease water reabsorption by antagonizing the effect of
antidiuretic hormone (ADH) in the collecting tubules.116 The increased cardiac output with the
24
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use of ACE inhibitors or ARB decreases the release of ADH.117 Loop diuretics reduce water
reabsorption by decreasing the concentration gradient in the renal medulla.118
Vasopressin receptor antagonists (tolvaptan and conivaptan) are approved for the
treatment of hyponatremia in patients with heart failure. These drugs improve sodium levels by
producing selective water diuresis.119 The Efficacy of Vasopressin Antagonism in Heart Failure
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Outcome Study with Tolvaptan [EVEREST] study and the Study of Ascending Levels of
Tolvaptan in Hyponatremia 1 and 2 [SALT-1 and SALT-2] have demonstrated the efficacy of
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tolvaptan to increase sodium level in patients with heart failure. In the EVEREST outcome trial,
tolvaptan significantly increased sodium levels in the first week of treatment (5.5 vs. 1.9 mEq/L
with placebo).120 The SALT-1 and SALT-2 trials included patients with hyponatremia and either
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heart failure, syndrome of inappropriate antidiuretic hormone, or cirrhosis; tolvaptan increased
the sodium levels by 7.0 vs. 2.5 mEq/L when compared to placebo.121 The use of tolvaptan is
potentially limited by hepatic toxicity with increases liver enzymes by more than 2.5-fold in
some patients.122 Based on the previous finding, the Food and Drug Administration recommends
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to not use tolvaptan for more than 30 days and to not use tolvaptan in patients with liver disease.
CONCLUSION
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Despite its limitations, stepped pharmacologic therapy remains the mainstay of treatment
for diuretic resistance. This best approach begins with excluding medication nonadherence,
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increasing the dose of diuretic or switching to continuous infusion, and eventually using
combination diuretic therapy. Measuring intra-abdominal pressure may help risk stratify patients,
and mechanical fluid removal with paracentesis, peritoneal dialysis, or ultrafiltration can
improve diuresis in patients with intra-abdominal hypertension. Ultrafiltration should be
25
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considered in patients who fail treatment with high intensity sequential nephron blockade.
Resynchronization can improve outcomes in patients with reduced left ventricular function and
cardiac dyssynchrony. There remains a paucity of clinical trial evidence to help guide therapy in
these patients, and in particular, clinicians need simple laboratory tests to identify patients who
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are unlikely to respond to diuretics. High BUN levels in combination with clinical assessment of
volume status can help identify patients at risk for adverse effects associated with diuretic
management.
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TE
EP
C
C
A
41
`
Table 1 Pathogenesis of diuretic resistance
Alterations in Consequences
CHF
Pharmacokinetic Delayed drug Reduced Drug
factors absorption14,15 tubular secretion18 interactions, eg,
D
with NSAIDS19
Increased Post diuretic
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dietary salt Na absorption26
Reduced renal Reduced
blood flow GFR28
Activation of Renal Increased Na
RAAS/SNS29 vasoconstriction reabsorption
EP
Structural Increased Na
changes in the reabsorption
nephron40
Renal vein Reduced Increased Tubular
hypertension47 renal blood flow interstitial edema compression
C
Increased intra- Increased Decreased Decreased

abdominal pressure48 renal vein pressure perfusion pressure GFR
C
Na- sodium; GFR- glomerular filtration rate; RAAS- renin- angiotensin- aldosterone
system; SNS- sympathetic nervous system
A
42
`
Table 2 Device therapy in heart failure
Technique Use
Paracentesis55 Periodic use in patients with ascites and intra-
abdominal hypertension
D
Indwelling Either short-term or long-term use in patients with
peritoneal catheters110,111 ascites and intra-abdominal hypertension
TE
Peritoneal dialysis108 Long-term use in patients with fluid overload and
diuretic resistance
Ultrafiltration99,100,101 Hospital based use in patients with symptomatic fluid
overload and diuretic resistance
Resynchronization112 Long-term use in patients with reduced left ventricular
EP
ejection fraction and cardiac dyssynchrony
C
C
A
43
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Diuretic Resistance in Heart Failure

Article in Cardiology in Review · March 2020

M Rubayat Rahman Pablo Paz

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Mohamed Elmassry Barbara Mantilla

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Diuretic Resistance in Heart Failure

Logan Dobbe MD2, Scott Shurmur MD1, Kenneth Nugent MD1

Running Head: Diuretic Resistance in Heart Failure

Conflicts of interest: none

Financial support: none

Decompensated heart failure accounts for approximately one million hospitalizations in

resistance. The underlying pathophysiology is likely multifactorial, with pharmacokinetic

ultrafiltration or peritoneal dialysis. Paracentesis is potentially useful in patients with intra-

Key words: heart failure, diuretics, diuretic resistance, renal dysfunction

induced increases in the distal sodium load.4

DEFINITION OF DIURETIC RESISTANCE

accepted definition. Definitions include failure to eliminate extracellular fluid despite an

adequate trial of diuretics,5 or a decreased response to diuretics leading to persistent congestion,

for the organic anion transporter.12

diuresis contributes to readmissions.1

of furosemide > 80 mg daily or bumetanide > 2 mg daily for treatment.13

furosemide and albumin in hypoalbuminemic patients.16

transporter.18 This can reduce intratubular concentrations of diuretics, potentially contributing to

Diuretic resistance may also be caused by interactions with medications, such as

nonsteroidal anti-inflammatory agents (NSAIDs). In severe CHF, prostaglandins help maintain

heart failure treatment in patients taking aspirin.20-22

Hyponatremia and Post-Diuretic Salt Retention

marked increase in sodium absorption 6 to 24 hours after administration of furosemide. This

noncompliance should be suspected in patients on diuretics, when sodium excretion is greater

than 100 mmol in 24 hours without any associated weight loss.27

Renal Blood Flow

Increased proximal convoluted tubule sodium reabsorption as a consequence of diuretic-

test combinations of intravenous furosemide, thiazides, and spironolactone and found no

significant difference in sodium excretion compared to placebo, indicating that proximal

Volume depletion secondary to diuretics stimulates the renin-angiotensin-aldosterone

increase in efferent arteriolar resistance with subsequent augmentation of glomerular hydrostatic

resistance controlled by norepinephrine and angiotensin II.33 Upregulation of RAAS becomes a

with furosemide to that seen in patients on placebo.29

(Beta-blocker evaluation of Survival Trial) to determine if BUN could be used as a marker of

the relationship between BUN and adverse diuretic effects.

Structural Changes in the Renal Parenchyma

transcellular transport capacity of the distal convoluted tubules increases in response to

diuretics.39 Na and coworkers used immunoblotting to demonstrate proliferation of sodium

cotransporter in the distal convoluted tubule, is upregulated in response to diuretic therapy in

diuretics.42 However, carbonic anhydrase inhibitors should be used cautiously, if at all, in

is explained by the interaction of altered hemodynamics, hormonal dysregulation, and oxidative

activation of the renin-angiotensin-aldosterone system.47 This high degree of neurohormonal

renal blood flow and GFR.

function, diuretic response, and survival.

Abdominal Compartment Syndrome

Abdominal congestion occurs in a significant percentage of patients with severe heart

splanchnic capacitance veins.50 At the same time sympathetic stimulation causes

venoconstriction reducing splanchnic capacitance.44 Splanchnic venous and interstitial

aggressive therapy of decompensated heart failure.54 In these patients, considered refractory to

paracentesis or ultrafiltration reduced IAP (from 13 ± 4 mm Hg to 7 ± 2 mm Hg, p=0.001) and

likely by reducing abdominal congestion.55

differs in individual patients (Table 1).14,15,18,19,26,28,29,40,47,48