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ABC Heart Fail Cardiomyop. 2022; 2(2):173-181 173
Review Article
Abstract
Worsening congestion is the main reason for
hospitalization of most acute heart failure (AHF) patients.
However, most patients are discharged with residual
congestion, resulting in early readmissions that portend
poor outcomes. Diuretics remain the mainstay of therapy.
Nevertheless, these drugs stimulate the renin-angiotensin–
aldosterone (RAA) axis and the sympathetic system and
elicit adaptive responses in the nephron that may be
counterproductive and lead to diuretic resistance. Renal
failure and AHF are common and coexist in up to 40%
of cases. Diuretic strategies that rely on combinations
of diuretics are emphasized as a method to prevent
resistance. If diuretic resistance does develop, higher-dose
combination regimens, hypertonic saline solution, and
mechanical ultrafiltration can be used to overcome diuretic
adaptations and restore diuretic efficacy.
Introduction
Acute heart failure (AHF) accounts for 22.8% of admissions
for cardiovascular causes in Brazil, according to the Ministry of
Health hospital information system maintained by the Unified
Health System (SUS - Sistema Único de Saúde). Despite the
high cost of episodes of heart failure decompensation, rates
of hospital readmission and death remain high. Intrahospital
mortality from AHF in Brazil was 12.6%, according to data
from the BREATHE study, which is much higher than rates in
developed countries.1
Hypervolemia is one of the pathophysiologic pillars
of AHF, whether because of fluid retention or because of
volume redistribution. Congestion was observed in 90 and
93% of patients in the BREATHE and ADHERE (The Acute
Decompensated HEart Failure National REgistry)2 registers
respectively.
Despite the near universal use of diuretics in hospitalized
patients with AHF, many patients leave hospital without
adequate decongestion. In the ADHERE registry, it was found
that 33% of patients had lost a maximum of 2.5 kg at hospital
discharge, while 20% had gained up to 5 kg while in hospital.
This is even a common occurrence in clinical trials, which are
Mailing Address Germana Porto Linhares •
Rua Frei Cirilo, 3480. Postal Code 60840-285. Messejana, Fortaleza, CE - Brazil
E-mail: Germanalinharesbackup@gmail.com
Manuscript received April 11, 2022, revised manuscript April 18, 2022,
accepted May 03, 2022
Keywords
Heart Failure; Diuretics; Ultrafiltration.
DOI: https://doi.org/10.36660/abchf.20220043
situations that are far from representative of the “real world” of
clinical practice. For example, 48% of participants in the classic
studies DOSE-AHF (Diuretic Optimal Strategy Evaluation in
Acute Heart Failure)3 and CARRESS-HF (Cardiorenal Rescue
Study in Acute Decompensated Heart Failure),4 which will
be covered in detail below, still had residual congestion
at hospital discharge.5 Concerns with worsening renal
function associated with restoration of normovolemia are
not justified, since it has been demonstrated that presence of
congestion is a better predictor of mortality than creatinine
elevation in patients discharged from hospital after AHF
decompensation6 (Figure 1). On the other hand, elevated
creatinine in conjunction with persistent signs of congestion
indicates poor prognosis, because it is often associated with
diuretic resistance.
Diuretic resistance is defined as incapacity to achieve
decongestion despite using diuretics at appropriate doses.7
The lack of a consensus on specific criteria to define diuretic
resistance means that its true prevalence is unknown.
However, it is known to be an ominous complication of AHF
that is predictive of mortality.8
The pathophysiology of resistance to diuretics is complex
and has not yet been fully understood.9 It involves a myriad
of factors (Figure 2) that act in synergy to create and
perpetuate the insufficient response to diuretics. Reabsortion
of sodium in the distal tubules has emerged as one of its main
determinants10,11 and it is known that hypertrophy of distal
tubule cells is present after even a few days of treatment with
loop diuretics, which results in increased sodium resorption.12
The “braking phenomenon” is already well known. This is
a term used to designate the reduction in response after
repeated doses of diuretics.9 It is a homeostatic mechanism
that strives to prevent excessive volume depletion during
continual exposure to diuretics, but which is exacerbated in
patients with AHF and contributes to diuretic resistance.13
The principal predictor of renal failure in patients with AHF
is central venous pressure. The increased venous pressure is
transmitted retrogradely to the renal vein, reducing glomerular
filtration pressure and natriuresis capacity and setting up a
vicious cycle that perpetuates congestion.15 It is essential to
identify patients with diuretic resistance early, so they can be
given the appropriate treatment.
Treatment of congestion
Loop diuretics
Loop diuretics (furosemide, torsemide, and bumetanide)
are essential medications in the management of hypervolemic
patients, because they have greater natriuretic potential.
The AHF treatment guidelines emphatically recommend
use of diuretics to relieve the signs and symptoms of fluid
overload.16-18
Treatment Strategies for Refractory Congestion
Germana Porto Linhares1 and João Davi Souza-Neto1
Hospital Carlos Alberto Studart Gomes,1 Messejana, Fortaleza, CE – Brazil
ABC Heart Fail Cardiomyop. 2022; 2(2):173-181
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Treatment of Refractory Congestion
Adequate management of these medications requires
knowledge of their pharmacokinetic and pharmacodynamic
properties. In contrast with the other members of this drug
class, the bioavailability of furosemide is variable (10 to
90%) and is even more erratic in the presence of AHF,19
which generally involves loop edema. Next, furosemide is
transported in the convoluted proximal tubule by the organic
acids transport system and reaches Henle’s loop, where it
inhibits NKCC2 cotransporter in the thick ascending limb.
It also inhibits the same symport in the apical membrane
of macula densa cells, blocking chloride reabsortion and
stimulating renin secretion. This neurohumoral activation
can contribute to perpetuation of harmful effects in patients
with AHF.7
Loop diuretic dose is chosen empirically and should be
guided by urinary output and clinical status. Excessive use
of diuretics activates reflex neuro-hormonal mechanisms
and was linked with worse outcomes in the ESCAPE
study (Evaluation Study of Congestive Heart Failure and
Pulmonary Artery Catheterization Effectiveness).20 It should
be remembered that patients who are chronic diuretic
users will probably need higher doses. Diuretics have an
S-shaped dose-response curve (Figure 3), and both AHF
and renal failure shift the curve to the right, since higher
doses are needed to achieve the maximum natriuretic
response. In renal failure, furosemide and organic acids that
accumulate in uremia compete for tubular secretion, in a
situation analogous to what happens with administration of
nonsteroidal anti-inflamatory drugs.21
Furosemide doses and administration strategies were
compared in the DOSE multicenter study (Diuretic Optimization
Strategies Evaluation), which is the largest clinical trial that has
been conducted to date addressing this issue. The study enrolled
308 patients with AHF and used a factorial 2x2 design to assign
them to intravenous administration of furosemide at a dose 2.5
times greater than their daily dose (high dose groups) or at the
same dose as their oral dose (low dose groups) and to either
receive intermittent doses (twice a day) or by continuous infusion
for 72 hours. The patients were given an average of 260 mg or
120 mg of furosemide (high and low dose groups, respectively).
There were no differences between groups in terms of overall
symptoms assessment (primary outcome). However, the high
dose group had greater relief of dyspnea, greater weight loss,
and greater liquid loss (secondary outcomes). Worsening renal
function by 72 hours (the other primary outcome) tended to
occur more frequently in the high dose group. The authors also
failed to detect any difference between the continuous infusion
and intermittent dose diuretic administration strategies, which
was possibly related to absence of a loading dose at the start
of continuous infusion.
A post hoc analysis of the DOSE study data showed that
an increase in creatinine concomitant with diuretic treatment
was paradoxically associated with better outcomes.22 This
association was also observed by other authors6,23 and probably
reflects changes in glomerular hemodynamics, and not tubular
injury.24 To the extent that withdrawal, or even a decrease
of the diuretic dose is not warranted in the event of renal
dysfunction, if signs of hypervolemia are still present.
Figure 1 – Survival curve according to presence of congestion and worsening renal function in acute heart failure patients discharged from hospital. Cong:
congestion; WRF: worsening renal function. Adapted from Metra et al.6
Survival
Days
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
30 60 90 120 150 180 210 240 270 300 330 3903600
Without congestion + without WRF
With congestion + with WRF
WRF/Cong
Without WRF/Cong
44 35 27 22 20 18 18 17 16 15 14 13 12
265 244 219 205 192 177 168 158 149 144 140 134 133
253 227 208 183 163 158 143 131 120 113 107 103 98
31 28 23 20 18 18 16 15 13 11 11 11 11
WRF/Without Cong
Without WRF/without Cong
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Treatment of Refractory Congestion
Figure 2 – Mechanisms of diuretic resistance and proposed treatments. NSAIDs: non-steroidal anti-inflamatory drugs; ARB: angiotensin receptor
blockers; ACEi: angiotensin-converting enzyme inhibitors; ARNI: angiotensin receptor and neprilysin inhibitors; GFR: glomerular filtration rate.
Adapted from Jentzer et al.14
Figure 3 – Relationship between natriuresis and loop diuretic concentration logarithmic scale. Adapted from Ellison DH7
Reduced GFR:
Proximal tubule
hyperfunction:
Distal tubular hypertrophy:
Distal nephron
hyperfunction:
Henle’s loop
hyperfunction:
Barriers Possible solution
Glomerular
hemodynamic
changes
Withdrawal
NSAIDS,
consider
withdrawing
ACEi, ARB, and
ARNI
Low cardiac
output Hemodynamic
support
Chronic kidney
disease or
functional
renal
hypoperfusion
Increase loop
diuretic dose
Barriers Possible solution
Neuro-
hormonal
activation
ACEi, ARB, or
NARI
Sodium
hyperavidity Increase loop
diuretic doses,
acetazolamide
Post-diuretic
effect Multiple
daily doses,
continuous
infusion of loop
diuretics
Excessive daily
sodium intake Sodium
restriction
Barriers Possible solution
Excessive
aldosterone-
mediated
sodium
retention
Aldosterone
antagonist,
potassium-
sparing diuretic
Excessive
vasopressin-
mediated
water
retention
Vasopressin
antagonist, free
water restriction
Barriers Possible solution
Rebound
sodium
retention
Sequential
nephron blockade
(combined
diuretic
treatment)
Barriers Possible solution
“Braking”
effect Higher loop
diuretic doses
Proximal
convoluted
tubule
(65-70%)
Distal convoluted
tubule (5%)
Thiazides
Glomerulus
Carbonic
anhydrase
inhibitor
Loop diuretics
Potassium-sparing diuretic /
aldosterone antagonist
Thick
descending
limb
Thick
ascending
limb
Henle’s loop
(25%) Urine
Cortex
Medulla
Aldosterone
Na+
Na+
Na+/K+
2Cl–
Collecting
duct
(1-2%)
K+
Na+
NaHCO3
Cl–
Na+
Excretion
Normal
D
log [Diuretic]p
R
ADHF
‘ceiling’
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Treatment of Refractory Congestion
Thiazide diuretics
Thiazide diuretics (hydrochlorothiazide, chlorothiazide,
and others) and “thiazide-like” diuretics (metolazone,
chlorthalidone) block the sodium and potassium cotransporter
in the distal convoluted tubule and can, at least partially,
counterbalance the increased sodium resorption that is
associated with chronic use of loop diuretics.7 When used
as monotherapy, they have a natriuretic effect equivalent to
30 to 40% of the effect of loop diuretics. Different members
of the class basically differ in terms of their pharmacokinetic
characteristics. In Brazil, only hydrochlorothiazide and
chlorthalidone are available.
Combinations of thiazide and loop diuretics are often
used to overcome diuretic resistance, although the evidence
for doing so is not robust.13 While there are more than 50
publications on the subject, just 300 patients with AHF were
enrolled on small studies, many without control groups, and
with primary focus on physiological variables, rather than
clinical outcomes. There are two ongoing clinical trials that
will provide more information about the magnitude of the
effect of this combination (ClinicalTrials NCT0164793229
and ReBEC RBR-5qkn8h30).
Certain concepts that are used in clinical practice, but
which have not been confirmed in clinical trials merit
discussion. The first is that metolazone could be more
effective for combined treatment with loop diuretics, possibly
because of its inhibitory effect on the proximal tubule,25
but there was no evidence of superiority in comparative
studies.26,27 The second concept is that thiazide should be
administered 30 minutes before the loop diuretic, but this has
not been assessed in studies of combination use of diuretics.28
Hydroelectrolytic disorders are more common with
thiazide than with loop diuretics. The potential for caliuresis
is greater because two to three potassium ions are lost for
each sodium ion excreted. The combination of these two
drug classes, in particular, greatly increases the predisposition
to hypokalemia, which was present in almost two thirds of
the patients in one clinical trial.26 The North-American AHF
guidelines recommend that the combination with thiazide
should be reserved for cases that do not respond well to
moderate to high doses of loop diuretics.
Mineralocorticoid receptor antagonists (MRA)
Sprinolactone is the only mineralocorticoid receptor
antagonist (MRA) available in Brazil. It has been used as
part of treatment to modify the disease in heart failure with
reduced ejection fraction (HFrEF) because of its pleiotropic
effects.29 When used at high doses, it has diuretic properties.
Use of sprinolactone may be useful to counterbalance
secondary hyperaldosteronism provoked by loop diuretics
(30). High aldosterone levels have a harmful effect on the
myocardium, contribute directly to diuretic resistance,31
and have been associated with increased rates of mortality
and readmission for AHF.32
These data were the basis for the ATHENA-HF study
(Aldosterone Targeted Neurohormonal Combined with
Natriuresis Therapy in Heart Failure),33 a double-blind
clinical trial that compared addition of sprinolactone in
high doses (100 mg) or usual doses (25 mg) to the standard
treatment of 360 patients with AHF. The sample comprised
patients with AHF, but without the criteria for diuretic
resistance. Although this treatment was well-tolerated,
administration of high doses of MRA did not result in any
differences in the primary outcomes (plasma levels of
N-terminal fragment of B-type natriuretic peptide [NT-
proBNP]) or secondary outcomes (relief from congestive
symptoms, dyspnea grade, urinary output, or weight loss).
The short protocol duration (96 hours) is insufficient for the
active metabolite of potassium canrenoate to accumulate
and probably contributed to the null results, as did the fact
that the study did not include patients with a very high
severity profile.
Despite the results of ATHENA-HF, use of sprinolactone
in high doses is one option for avoiding hypokalemia
in patients taking large quantities of potassium wasting
diuretics.
Carbonic anhydrase inhibitor
From a pathophysiologic point of view, strategies that
target the proximal tubule could offer some benefil could
offer some benefit for treatment of congestion. This segment
is where the greatest quantity of sodium is reabsorbed,
particularly in conditions such as AHF.
Acetazolamide blocks reabsortion of sodium bicarbonate
in the proximal convoluted tubule by inhibiting the
carbonic anhydrase enzyme. A greater quantity of sodium
is therefore available for exchange at the level of Henle’s
loop, increasing the effect of loop diuretics, particularly in
renal malperfusion states. Furthermore, the greater quantity
of chloride available in the macula densa can inhibit renin
secretion (reducing neurohumoral activation). When
administered as monotherapy, acetazolamide has very poor
natriuretic activity and so its use is restricted to combined
therapy. It can be useful for treatment of metabolic alkalosis
induced by loop diuretics.
Some small observational studies demonstrated that
acetazolamide had a positive impact on natriuresis.34,35
One of them showed that acetazolamide increased diuretic
efficiency in patients with AHF, with additional excretion
of 100 mmol of sodium for each 40 mg of furosemide
equivalent administered. The second observed an increased
diuretic response to addition of 250 mg of acetazolamide,
similar to the response achieved by doubling the furosemide
dose.
The ADVOR study (Acetazolamide in Decompensated
Heart Failure With Volume OveRload)36 (NCT03505788) is
a double-blind randomized clinical trial that is ongoing in
Belgium, with completion predicted for 2022. This study
enrolled around 500 patients to test the effect of adding
500 mg of intravenous acetazolamide or placebo to a high
dose loop diuretic regimen.
Tolvaptan
Arginine vasopressin antagonists (or vaptans) were
developed to selectively block the V2 receptor (tolvaptan)
in the collecting duct. The V2 receptors increase aquaporin-
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Treatment of Refractory Congestion
mediated water reabsorption. Blocking it therefore
increases excretion of electrolyte-free water, with no effect
on excretion of electrolytes.37 These drugs are therefore
considered aquaretics.
Tolvaptan was tested in the ACTIV in CHF (Acute and
Chronic Therapeutic Impact of a Vasopressin Antagonist in
Congestive Heart Failure)38 and EVEREST studies (Efficacy
of Vasopressin Antagonism in Heart Failure Outcome Study
With Tolvaptan).39 In both studies, there were benefits
for weight loss, dyspnea, and edema, and improvements
in hyponatremia, without impact on mortality or rate of
readmission for AHF.
Despite the neutral results for mortality and hospital
admissions, tolvaptan demonstrated some favorable
effects in patients with diuretic resistance in the EVEREST
trial, such as greater weight loss, less dyspnea, and
less edema. Notwithstanding this result, there is scant
evidence to recommend tolvaptan for treatment of diuretic
resistance. It is not currently approved by the Food and
Drug Administration (FDA) for treatment of AHF, but it is
approved for treatment of associated hyponatremia.
Ultrafiltration
Ultrafiltration (UF) is an alternative to diuretics for
treatment of hypervolemia.40 It consists of passing blood
through hollow fibers surrounded by semipermeable
membranes, subjected to a pressure gradient. The result
is mechanical removal of fluid, termed the ultrafiltrate.
Ultrafiltration removes sodium more effectively because
whereas the ultrafiltrate is isonatremic in relation to
plasma,41 diuretics produce hypotonic urine, with around
60 to 80 mmol of sodium per liter. Moreover, it does not
trigger neuro-hormonal responses or stimulate the macula
densa. In other words, the process of decongestion is
physiologically different.
To date, seven clinical trials have been published
comparing UF with pharmacological treatment in patients
with AHF, five of which examined clinical outcomes. The
largest of these enrolled 224 patients, highlighting the
difficulty of recruiting participants for studies evaluating
invasive methods of treatment.
The first clinical trial was the RAPID-CHF (Relief for
Acutely Fluid-Overloaded Patients With Decompensated
Congestive Heart Failure),42 with just 40 patients randomized
to UF or pharmacological therapy. The study observed that
UF improved symptoms and provoked greater loss of liquid,
but with no differences in weight.
The first large study was published in 2007, randomizing
188 patients for a single UF session or standard treatment with
diuretics within 24 hours of admission for AHF: the UNLOAD
study (Ultrafiltration Versus Intravenous Diuretics for Patients
Hospitalized for Acute Decompensated Heart Failure).43 The
results were positive, since there was a 52% reduction in
unplanned visits after hospital discharge, a 44% reduction
in hospital admissions for AHF, and a 63% reduction in days
in hospital after readmission. Some limitations of UNLOAD
should be noted, such as that it was sponsored by industry
and did not have an independent events committee.
The CARRESS-HF study was published next, enrolling
188 patients on a randomized clinical trial, funded by
the National Heart, Lung, and Blood Institute. This study
compared the effects of UF at a fixed velocity of 200 mL/h
with goal-scaled drug treatment (loop diuretics, thiazide,
vasodilators, and inotropics). No significant differences were
observed in outcomes including weight loss (5.7 ± 3.9 vs.
5.5 ± 5.1 kg, respectively, p = 0.58), degree of dyspnea,
and wellbeing rating, rated on a visual analog scale. There
were no differences in mortality, emergency visits, or
readmissions for heart failure by 60 days. However, the UF
group had a higher rate of complications (7.2% vs. 5.7%,
p = 0.03), represented by bleeding and dialysis catheter
infection. Strangely, while the group on pharmacological
treatment had a reduction in creatinine levels, the UF group
had creatinine elevation of 0.23 mg/dL.
Certain details of the CARRESS-HF study merit mention
because they could have contributed to the null result.
First, the group on pharmacological treatment were given
medication at doses titrated to maintain daily urinary output
at 3 to 5 liters, whereas the UF group were given a fixed
rate of 200 mL/hour of UF, which was not individualized.
Second, the mean duration of intervention was much
longer in the drug treatment group (92 hours) than in the
UF group (40 hours). Another important limitation of this
study was the high rate of cross-over, because 30% of the
patients in the UF group were given diuretics after the end
of the protocol and 10% of the patients allocated to UF did
not receive it for a range of reasons. These results should
therefore be treated with caution.
It should also be noted that the CARRESS-HF study
cannot be considered a counterpoint to the UNLOAD study,
since there were significant differences in the inclusion
criteria and study protocols (Table 1).
The CUORE study (Continuous Ultrafiltration for
Congestive Heart Failure)44 was a smaller study that
assessed UF and pharmacological treatment in 56 patients
at two centers. As in the UNLOAD study, patients were
also randomized within 24 h of admission to flexible UF
strategies (rate and duration) or conventional unguided
pharmacological therapy. In contrast with other trials, the UF
group was also given pharmacological treatment. There was
no difference in weight at hospital discharge between the two
groups, but the UF group had a lower rate of readmission
and mortality (combined) at 1 year.
The AVOID-HF study (Aquapheresis Versus. Intravenous
Diuretics and Hospitalization for Heart Failure)45 was designed
to compare guided UF strategies and pharmacological
treatment. It was designed to enroll 810 patients with AHF,
but was unfortunately terminated early by the study sponsor,
because of budget problems and slow recruitment. Although
it did not achieve sufficient statistical power, analysis of the
outcomes of the 224 patients recruited was favorable to UF,
with a lower rate of occurrence of a first AHF-related event by
90 days (25% in the UF group vs. 35% in the pharmacological
treatment group). The primary study outcome, time to
first event, was longer in the UF group (62 days) than in
the pharmacological treatment group (34 days), although
without statistical significance (p = 0.106). At 30 days after
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hospital discharge, fewer patients in the UF group had been
readmitted for AHF (p = 0.034).
Due to the inconsistent results, the majority of centers
reserve UF as a salvage strategy for patients whose hypervolemia
cannot be resolved with pharmacological treatment. Figure 4
depicts a proposed algorithm for refractory congestion. Use of
both methods (UF and pharmacological treatment) in synergy
can also be considered..
The AHF treatment guidelines recommend UF in cases
of refractory hypervolemia, but diverge on the degree of
recommendation and level of evidence. According to the
Brazilian guidelines, this indication is class I with level of
evidence B, whereas the European guidelines give it a class
IIb recommendation and level of evidence C. The recently-
published American guidelines do not contain any specific
recommendations on UF in patients with AHF.
Hypertonic saline solution
In the elegant work by Issa et al.,46 the infusion of 7,5%
HSS twice daily for three days prevented renal dysfunction
in patients with decompensated heart failure. During the
study protocol, the increase in serum creatinine (0,3mg/dl or
above) occurred in 2 (10%) of the HSS arm and 6 (50%) of
the placebo arm. (relative risk 0,3; confidence interval 0,09
a 0,98; p=0,01). Relative to baseline, serum creatinine and
cystatin C levels were lower in HSS as compared to placebo.
Administration of hypertonic saline solution (HSS) has been
used as a treatment option in cases of resistance to diuretics
and refractory hypervolemia for more than two decades. Much
of what is known about use of HSS comes from experimental
models of hemorrhagic and septic shock.47-49 Infusion of
hypertonic NaCl solution results in a sudden increase in plasma
osmolarity, immediately displacing fluid from the interstitium
to the vascular space as a consequence of the increased
tonicity, expanding plasma volume, and increasing renal flow.
After infusion of HSS, a loop diuretic is administered in bolus.
Over 20 years of experience, infusion of HSS has proven to
be a safe and well-tolerated treatment.50
One of the first studies with HSS was observational, in
a sample of 30 patients who were given 150 mL of NaCl
solution (at 1.4 to 4.6%) administered twice a day, followed
by furosemide (250-2,000 mg) over 6 to 12 days.51 There
were improvements in dyspnea, edema, and disease severity,
according to functional class.
Later, the same authors conducted a single-blind
randomized study that recruited 60 patients to compare
furosemide (500-1,000 mg) combined with HSS (1.4 to
4.6% NaCl, depending on natremia) or placebo.52 This study
observed that the HSS group had greater urinary output and
greater natriuresis and improvements in creatinine and New
York Heart Association functional class.
Finally, a larger clinical trial with 107 patients tested the
effect of HSS on rates of hospital readmission and mortality.53
The same protocol as above was applied and resulted in
a lower rate of hospital readmission in the HSS group (25
patients out of a total of 53) than in the placebo group (43
patients out of a total of 54) over the 31 ± 14 months of
follow-up. Additionally, mortality was significantly lower in
the HSS group (24 patients vs. 47, p < 0.001) than in the
placebo group. Another large clinical trial (NCT05298098),
with a double-blind and randomized design, is ongoing and
will recruit 600 patients to test the effect of an even more
concentrated solution (NaCl 10%), with results predicted
for 2023.
The Brazilian guidelines recommend HSS in patients with
refractory congestion (class IIa, level of evidence B). While
the European guidelines do mention HSS, they do not make
any specific recommendations.
Albumin
Loop diuretics are organic acids that circulate firmly bonded
to albumin. Albumin increases secretion of furosemide in the
proximal tubule and therefore hypoalbuminemia may reduce
bioavailability of furosemide in Henle’s loop. However, there
are no studies of use of albumin in AHF and its role in the
genesis of diuretic resistance may be irrelevant. There is a
little evidence suggesting that infusion of albumin increases
the natriuretic response, as long as serum albumin is above
2 mg/dL.54 There is scant evidence on the role of albumin in
AHF, limited to case reports and the experience of centers
specialized in AHF.
Conclusions
Adequate management of congestion in patients with
advanced AHF remains a challenge. Over the last two
decades, several clinical trials in AHF patients have been
published, but unfortunately without yielding significant
advances in treatment for these patients. Better understanding
Table 1 – Comparison of the principal clinical trials assessing ultrafiltration in patients with acute heart failure
UNLOAD CARRESS-HF
Study design and protocol Early UF, within 24 h of admission of patients
with AHF
UF as salvage therapy in patients with AHF with
worsening renal function
Prescription of UF Flexible duration and rate of UF, to a maximum
of 500 mL/h UF duration and rate set at 200 mL/h
Drug treatment No predefined algorithm According to an algorithm for scaled diuretic
doses
CARRESS-HF: Cardiorenal Rescue Study in Acute Decompensated Heart Failure; AHF: acute heart failure; UF: ultrafiltration; UNLOAD: Ultrafiltration
Versus. Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure.
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Figure 4 – Therapeutic flow diagram illustrating treatment of congestion in acute hear t failure. UO: urinary output; SGLT2i: sodium-glucose cotransporter
2 inhibitors. Adapted from Mullens et al.36
Persistent congestion
Assess 24h urinary output
Ultraltration
Double dose of loop diuretic
up to maximum dose
Continue at current dose until
decongestion
Assess decongestion prior to
hospital discharge
Repeat up to
maximum loop
diuretic dose
Combined diuretic therapy:
First line: thiazide
Second line: acetazolamide or
amiloride
Third line: consider SGLT2i
UO < 3-4 L
Assess for
6 hours
< 100 mL diuresis per hour
No
Diuretic at
maximum
dose?
Persistent congestion
Consider reducing loop diuretic dose until UO > 5 L per day
Yes
UO > 3-4 L
ABC Heart Fail Cardiomyop. 2022; 2(2):173-181
180
Review Article
Linhares & Souza-Neto
Treatment of Refractory Congestion
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References
of the mechanisms of diuretic resistance can contribute to
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Author Contributions
Writing of the manuscript and Critical revision of the
manuscript for intellectual content: Linhares GP, Souza-Neto JD.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation
work.
Ethics approval and consent to participate
This article does not contain any studies with human
participants or animals performed by any of the authors.
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