CardioRenal Axis Disorders - To and Fro

i
Editors

Nephrology Section
Chief Editor
Ass. Prof. Dr Ahmed Fathy EL Koraie
Internal Medicine & Nephrology - Faculty of Medicine Alex Univ
Head of Nephrology Department Kidney & Urology Center
Alexandria EGY
Founder & Chairman of Junior Nephrology Club

Co-Editor & Reviewer
Dr Mohammed Abdel Gawad
Nephrology Specialist & Head of Medical Development Department
Kidney & Urology Center
Alexandria EGY
Founder & Chairman of NephroTube
Email: drgawad@gmail.com

g
Urology Section
Chief Editor
Prof. Dr Wael Sameh
Professor of Urology
Faculty of Medicine Alex Univ
Fellow of Moffitt Cancer Center
University of South Florida (USF) - USA
;

Journal Coordinators

Dr Mohammed Essam
Nephrology Specialist & Head of quality assurance department at KUC
Deputy Director of KUC
Alexandria EGY
Email: m_elrgal@hotmail.com

Dr Kareem EL Fass PharmD,BPharm
Head of Clinical Pharmacy Department
Alexandria EGY
Email: kareem.elfass@gmail.com

Journal Secretary: Dr Mohammed Abdel Gawad
ii

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Contents & Contributor
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Diseases CardioRenal Axis Nephrology Section

Topic Contributor Page
RENOCARDIAC VERSUS
CARDIORENAL SYNDROME
CHANGING PARADIGM

Ass. Prof. Dr Ahmed Fathy EL Koraie
Internal Medicine & Nephrology - Faculty of Medicine
Alex Univ
Head of Nephrology Department Kidney & Urology
Center - Alexandria EGY
Founder & Chairman of Junior Nephrology Club
2
REFRACTORY EDEMA WITH
CONGESTIVE HEART FAILURE
STEPWISE APPROACHES -
NEPHROLOGY PERSPECTIVES

Dr Mohammed Abdel Gawad
Nephrology Specialist & Head of Medical
Development Department
Kidney & Urology Center Alexandria EGY
Founder & Chairman of NephroTube

11
ULTRAFILTRATION VERSUS
DIURETICS IN ACUTE
DECOMPENSATED HEART FALIURE
(ADHF)

Dr Mohammed Essam
Head of quality assurance & Nephrology Specialist
Deputy Director of KUC department at KUC
Kidney & Urology Center Alexandria EGY
24
INOTROPES IN CARDIORENAL
SYNDROME (CRS),
IS THERE A ROOM?

Dr Alyaa El Ghitani
Clinical pharmacist Kidney & Urology Center
Head of internal medicine clinical pharmacy
department at main university hospital
Alexandria EGY

29

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Kidney Advances, Volume 5, June 2014 Cardio-Renal Axis Disorders

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RENOCARDIAC VERSUS CARDIORENAL SYNDROME
CHANGING PARADIGM

Ahmed F. EL Koraie

With the advance in our knowledge and
understanding of the physiological changes
that are responsible for the maintenance of
blood volume, vascular tone, and
hemodynamic stability and how much they
depend on a set of elegant interactions
between the heart and kidney, it is now widely
accepted that severe dysfunction in either of
these organs seldom occurs in isolation.
However, there is still huge debate not only to
the pathophysiologic mechanisms of the
cardiorenal syndrome but even to its true
definition.
The process itself remains enigmatic; our
understanding of the complex physiological,
biochemical, and hormonal derangements that
encompass the CRS is woefully deficient and
may lead to improper medical management of
patients.
The definition is now changing from the
simple notion of being a state in which therapy
to relieve heart failure symptoms is limited by
further worsening renal function, to a more
complicated process that address the complex
and bidirectional nature of pathophysiological
interactions between the failing heart and
kidneys. That is, each dysfunctional organ has
the ability to initiate and perpetuate disease in
the other organ through common
hemodynamic, neurohormonal, and
immunologic/biochemical feedback pathways.
(1)

Renocardiac versus Cardiorenal
syndrome: what is the
difference?
Epidemiological observations that correlates
cardiovascular morbidity and mortality and
decreased kidney function are now well
established. This relationship exists regardless
of whether the initial event is cardiac disease
or renal parenchymal disease. The
cardiovascular mortality of patients with
congestive heart failure whose serum
creatinine level is only moderately elevated
[0.3 mg/dl] has been shown to be increased.
(2)
Although the mechanisms underlying this
cardiorenal syndrome have not been clearly
elucidated, nevertheless, increased cardiac
preload and cardiac dilatation are known to be
associated with enhanced ventricular wall
stress, cardiac remodeling, increased left
ventricular mass index and higher mortality.
(3)
In this context, as the kidney is the primary
regulator of sodium and water excretion, even
a modest decrease in normal renal function in
patients with congestive heart failure could
contribute to increased cardiac preload,
cardiac dilatation, left ventricular hypertrophy
and increased mortality. This sequence of
events can, therefore, justifiably be termed
'cardiorenal syndrome'.
(4)

In contrast to cardiorenal syndrome, should
the enhancement of cardiovascular death
initiated by kidney disease be termed
'renocardiac syndrome'? Again renal
parenchymal disease is associated with an
increase in the risk of cardiovascular death.
Slight elevation of serum creatinine
concentration by as little as (0.3 mg/dl) can
increase this risk. In fact, 90% of patients with
chronic kidney disease will die of
cardiovascular complications before they
progress to end-stage renal disease. The
processes underlying the increase in
cardiovascular mortality initiated by primary
kidney disease are not well defined, but there
are several potential mechanisms. These
include, but are not limited to, uncontrolled
hypertension, phosphate retention, secondary
hyperparathyroidism, myocardial and vascular
calcification, inflammation and oxidant
injury.
(5)
Lastly, it should be acknowledged
that there is overlap between these two

syndromes; diabetes and hypertension can
initiate both cardiac and renal pathology.
Collectively some authors proposed
modification for the definition of CRS to
stress the bidirectional nature of the heart-
kidney interaction. Where they divide CRS
into five subtypes: type I, acute CRS; type II,
chronic CRS; type III, acute renocardiac
syndrome; type IV, chronic renocardiac
syndrome; and type V, secondary CRS,
meaning systemic diseases such as diabetes,
sepsis and amyloidosis causing simultaneous
cardiac and renal dysfunction.
(6)

Cardiorenal syndrome (3)

Renocardiac syndrome. (5)
Renocardiac versus Cardiorenal
syndrome: what marker to use?
The puzzle in understanding the
pathophysiology of CRS is far complicated. A
reduced cardiac output (CO) in CHF resulting
in decreased renal perfusion could be an easy
explanation for the worsening renal function.
Interestingly, worsening renal function has
been demonstrated in patients with ADHF
even though left ventricular EF is preserved.
(7)
This decline in renal function, despite a
presumed preservation of blood flow to the
kidneys, has led to the search for other
mechanisms of CRS, including the role of the
RAAS, various chemicals (nitric oxide [NO],
prostaglandins, natriuretic peptides,
endothelins, etc), oxidative stress and
sympathetic overactivity. Thus CO is not a
reliable indicator to assess the severity of
CRS. More often, CO will be normal in cases
of CRS. So that, the presence of low filling
pressures, a low cardiac index or even reduced
renal perfusion is not necessary to identify
CRS.
(8)
On the other hand, while making a diagnosis
of CRS, it should be kept in mind that there is
weak correlation between serum creatinine
and GFR. Relative to a decline in EF, a fall in
GFR is more important regarding the
prognosis in heart failure patients. In such a
setting measurements of serum creatinine
alone could also be misleading in terms of
prognosis. Approximately two-thirds of
patients admitted for acute exacerbations of
CHF have decreased GFR or creatinine
clearance, despite many of them having
relatively normal levels of serum creatinine.
Thus, estimation of GFR should be a part of
the initial evaluation because GFR provides a
general sense of prognosis. Moreover, GFR is
helpful in the evaluation for planning a
management strategy (use of ACE inhibitors,
ARBs and radiocontrasts for diagnostic tests,
etc).
(9)

Myocardial
Dysfunction
Left Ventricular
Hypertrophy
Vascular
and
Myocardial
Calcification
Phosphate
Retention
Renal Insufficiency
GFR < 60 ml/min/1.73
2
Sodium
Retention
Inflammation
Oxidativ
e Stress
Hypertension
INCREASED CARDIOVASCULAR
MORBIDITY AND MORTALITY
Atherosclerosi
s
INCREASED CARDIOVASCULAR
MORBIDITY AND MORTALITY
Anemia
Increased
Parathyroid
Hormone
Chronic Cardiac
Failure
Increased
Cardiac Filling
Pressure
Arterial
Underfilling
Sodium & Water
Retention
Sympathetic and
RAAS Activity
Resistance
to
Natriuretic
Peptides
Failure to
Escape from
Aldosterone
Proximal Tubule
Sodium and Water
Reabsorption
Decreased Distal Na
and Water Delivery
Cardiac
Dilatation

Renocardiac vs cardio renal
prognosis
Impact of Renal Disease on Clinical
Outcomes in Patients with HF
As mentioned earlier, renal dysfunction is one
of the most important independent risk factors
for poor outcomes and all-cause mortality in
patients with HF. Baseline glomerular
filtration rate (GFR) appears to be a stronger
predictor of mortality in patients with HF than
left ventricular ejection fraction or NYHA
functional class. Both elevated serum
creatinine on admission and worsening
creatinine during hospitalization predict
prolonged hospitalization, rehospitalization,
and death.
(10)
HF Outcomes in Patients with Renal
Disease
Patients with chronic renal insufficiency are at
strikingly higher risk for myocardial
infarction, HF with systolic dysfunction, HF
with preserved left ventricular ejection
fraction, and death resulting from cardiac
causes compared with individuals with normal
GFR.(11) In a meta-analysis individuals with
primary renal disease were more likely to die
of cardiovascular causes than renal failure
itself.(12) In a multicenter cohort study of 432
patients, 31% planning to initiate hemodialysis
had HF symptoms, and 33% of such patients
had estimated left ventricular ejection fraction
<40%.(13) Conversely, reversal of renal
dysfunction can improve cardiac function. In a
study of 103 hemodialysis patients with HF
and left ventricular ejection fraction <40%, the
mean ejection fraction increased from 32% to
52% after renal transplantation, and 70% had
normalization of cardiac function.(14) Studies
from two decades have shown
echocardiographic evidence of left ventricular
hypertrophy in 45% of individuals with
creatinine clearance <24 mL/min and in 70%
of those planning to initiate hemodialysis.
Even more those patients have accelerated
rates of coronary events compared to those
with normal left ventricular mass, and a high
proportion of these individuals develop
clinical HF.(15)
Renocardiac vs cardiorenal
pathophysiology
The Low-Flow-State Hypothesis
Traditionally progressive decline in GFR
observed in HF was thought to primarily
reflect inadequate renal perfusion secondary to
reduced cardiac output. Which in turn prompts
renin release by the juxtaglomerular cells of
the afferent arterioles through low-flow states
in the ascending limb of the loop of Henle and
pressure-sensing baroreceptors. Renin release
and RAAS activation confer extreme sodium
avidity, volume retention, decreased
glomerular perfusion (i.e., afferent arteriolar
constriction), and profibrotic neurohormone
increases, leading to ventricular remodeling.
Although this reasoning is not incorrect
because all of the above conditions are
observed in HF (neurohormonal stimulation,
decreased fractional excretion of sodium,
myocardial fibrosis), experience would also
suggest that, by augmenting contractility, heart
rate, and cardiac index, inotropes can lead to
short-term improvement in urine output,
mental status, and other clinical indicators of
organ perfusion. However, recent
investigations suggest that this viewpoint is
extremely limited and management of patients
with CRS based solely on the low-flow theory
does not lead to improved outcomes. In the
ESCAPE trial there was no correlation
between baseline renal function and cardiac
index. Furthermore, improvement in cardiac
index did not result in improved renal
function, prevention of death, or prevention of
rehospitalization.(16) This notion is supported
by the findings of multiple other investigations
in which improved cardiac index or decreased
pulmonary capillary wedge pressure during
pulmonary artery catheterguided therapy
failed to predict improvement in renal
function. (17-19) Collectively, these data do
not support poor forward flow and altered
hemodynamics as primary determinants of
progressive renal failure in the HF population.
Renin-Angiotensin-Aldosterone Axis and
Renal Dysfunction
It is well known that the extreme sodium
avidity and ventricular remodeling conferred

by RAAS elaboration in HF are a maladaptive
response to altered hemodynamics,
sympathetic signaling, and progressive renal
dysfunction. Thus the benefits of angiotensin-
converting enzyme (ACE) inhibition and
aldosterone antagonism through blockade of
the intracardiac RAAS, reduction in
adrenergic tone, improvement in endothelial
function, and prevention of myocardial
fibrosis are well described in cardiac failure;
RAAS inhibition has been a main focus of
therapy in HF for the last 2 decades and has
led to improved outcomes for many patients.
Unfortunately, little is known about the long-
term benefits or adverse effects of RAAS
inhibition on kidney function in HF.(4)
Although ACE inhibitors and angiotensin
receptor blockers have important
renoprotective effects in hypertensive patients
with nondiabetic renal disease and individuals
with diabetic nephropathy, it is not clearly
established,(20) whether there is a
renoprotective role of ACE inhibitors and
angiotensin receptor blockers in systolic HF
that is independent of direct preservation of
ventricular function has not been
established.(21) Furthermore ACE inhibitors
and angiotensin receptor blockers cause dose-
dependent increases in angiotensin II (AT-II).
Significantly, AT-II directly contributes to
kidney damage. AT-II upregulates the
cytokines transforming growth factor-, tumor
necrosis factor-, nuclear factor-B, and
interleukin-6 and stimulates fibroblasts,
resulting in cell growth, inflammation, and
fibrotic damage in the renal parenchyma.(22)

implication to treatment
Factors Influencing Medication Use
The commencement of renal impairment in
HF patients usually warrant unjustified
reduction or holding of the mainstay for
therapy of cardiac failure; diuretics and RAAS
blockade, under the notion of preventing
further deterioration in renal function. Such
patients are frequently discharged from the
hospital with inadequate resolution of
symptoms and thus have high short-term
rehospitalization rates. Recognition that
elevated serum creatinine portends worse
outcomes in HF prompts physicians to be
concerned about the renal effects of these
agents. However, mean serum creatinine
increased even though outcomes were better in
the Cooperative North Scandinavian Enalapril
Survival Study (CONSENSUS).(23) With
diuresis, serum creatinine is more likely to
increase in patients receiving ACE inhibition
and in those with the lowest blood
pressures.(24) These data suggest that some
increase in creatinine should be tolerated with
the use of ACE inhibition, and other
interventions (such as decreased diuresis)
might be needed to accomplish this. The
advantage of ACE inhibitors in delaying
progression and death in HF is undeniable,
and their use should be encouraged unless
detrimental effects are clearly proven.(4)
Fluid Removal and Renal Effects
Although diuretics are commonly used in HF
and appear necessary, their possible adverse
effects are just starting to be explored, and
better knowledge of how to use them is
essential. Worsening serum creatinine,
azotemia, and metabolic contraction alkalosis
often limit conventional diuresis in patients
with HF. Both clinical and experimental
studies highlighted their detrimental effects to
the heart as well as the kidney. (25,26)
Nevertheless, they will remain the mainstay of
treatment until other interventions are proven
to be safer and more effective.
On the other hand continuous venovenous
ultrafiltration is emerging as a possible
alternative to pharmacological diuresis in
these scenarios and may offer greater ease and
efficacy of volume and sodium reduction
without further compromising renal function
Although routine use of ultrafiltration has not
been shown to lead to better renal outcomes, if
the ultrafiltration rate does not exceed the
interstitium to intravascular refill rate (15
mL/min), it is possible that the more steady
fluid removal will prevent renal dysfunction.
(27,28)
Results of Nesiritide, ( a synthetic drug form
of human B-type natriuretic peptide) on both
fluid status and renal function in patients with

HF have been disappointing. Although
nesiritide does have natriuretic effects and
improves GFR in normal individuals, the
effects in patients with HF are more
questionable.(29) Indeed, a meta-analysis
suggested that it might worsen renal
function.(30) Therefore, the Acute Study of
Clinical Effectiveness in Decompensated
Heart Failure (ASCEND-HF) was designed as
a prospective, multicenter, double-blind,
randomized trial to examine the use of
nesiritide in this common, morbid, and often
lethal clinical condition. Two coprimary end
points, dyspnea and 30-day hospital
readmission or death, were chosen to examine
symptomatic response and objective
outcomes, respectively. Preliminary reports
from ASCEND-HF investigators suggest no
significant improvement in symptoms or
clinical outcomes, although no adverse effect
on mortality or renal function was noted. (31)
Inotropes
To date no inotrope has proven to be
successful in reversing the CRS, albeit
inotropic therapy will continue to be used in
patients with worsening renal function
presumed to be secondary to decreased cardiac
output. Considering the multiple causes of
CRS in patients with HF, it is not surprising
that the data for inotropes as treatment are
mixed. It is true that dobutamine and
milrinone have been shown to increase cardiac
index and renal blood flow in most studies,

(32) However, the clinical consequences are
not clear, with urine output and outcomes not
having shown improvement in many
studies.(33,34) The routine use of inotropes to
permit more effective diuresis and treatment in
patients with HF was rejected in the OPTIME
study.(35) Again inspite of multiple studies
with dopamine and fenoldopam, no clinical
benefit has been demonstrated.(36-38)

laboratory perspectives
Renal labs:
Blood Urea Nitrogen (BUN); As BUN
depends on both cardiac and kidney function,
since it takes into account cardiac output and
is a marker of neurohormonal activation. This
may be the explanation why BUN was found
to correlate with 60-d mortality more than
either serum creatinine or eGFR. In the
ADHERE registry, using admission BUN of
more than 43 mg/dl, this was found to be the
best identifier of in-hospital mortality in
patients with ADHF (39). Lower systolic BP
and higher serum creatinine were the second
and third best identifiers, respectively. The
same finding was observed in a retrospective
analysis of OPTIME-CHF. (35) In their
analysis, the highest BUN quartile was
associated with lowest BP, lowest plasma
sodium concentration, highest jugular venous
pressure (JVP) (41), and, therefore, worse
outcome. Trying to explain this finding, the
low cardiac output leads to significant
neurohumoral activation, including the
nonosmotic release of AVP that in turn results
in enhanced reabsorption of urea through urea
transporters in the collecting duct (42).
Moreover, in ADHF increased plasma AVP is
associated with activation of RAAS and SNS,
known predictors of mortality.

Hyponatremia; Hyponatremia is common in
patients with ADHF. Vasopressin stimulation
of the V1 and V2 receptors not only worsen
the signs, symptoms, and LV function of
patients with acute HF but also causes water
retention and hyponatremia, through
stimulation of the V2 receptors on the
collecting duct principal cells by vasopressin.
Blocking the V2 receptor vasopressin corrects
hyponatremia in HF and improves dyspnea.
However, there are no data that correction of
hyponatremia leads to better survival outcome
in patients with ADHF (43 46).
Lee et al. (47) demonstrated that hyponatremia
has associated with higher mortality in chronic
HF patients. Again the analysis of
OPTIMIZE- HF registry, showed that 19.7%
of patients were admitted with hyponatremia
(Na ` 135 mmol/L). Interestingly, lower
serum sodium concentration was associated
with higher mortality during hospitalization
and Post discharge and a higher risk of
readmission within 6 months.(48,49)


Cardiac labs:
B Type Natriuretic Peptide (BNP); There are
two major natriuretic peptides produced by the
heart: ANP in the atria and BNP in the
ventricles (50). In HF, congestion causes
cardiac chamber stretch and this leads to
release of these hormones. Patients with HF
who presented with BNP level of _480 pg/ml
had a 51% chance of death, hospital
readmission, or emergency room visit in 6 mo,
as opposed to 2.5% in HF patients who had a
BNP level of _230 pg/ml. (51)

Troponin; Cardiac-specific troponins I and T
are highly sensitive and specific markers of
myocardial injury. Approximately 40% of
patients who are admitted to the hospital with
ADHF have plasma elevations in troponin that
are not associated with any EKG changes or
findings of acute ischemia (52). In the
(EFFECT) study, (53) and an analysis of the
ADHERE (54) registry, there was a strong
association between elevated troponin, either
I or T subtypes, and mortality in patients with
no other evidence of acute ischemia on
presentation. Patients with positive troponin
had lower systolic BP on admission, a lower
ejection fraction, and higher in-hospital
mortality.

Anemia:
Anemia is a common finding in patients with
HF, regardless of the presence of kidney
parenchymal disease. Whereas the mechanism
of anemia in CHF is almost certainly
multifactorial. Congestion with renal sodium
and water retention will lead to hemodilution,
relative erythropoietin deficiency may ensue
with renal impairment. Inflammation and
increased cytokine production occur with HF
and can suppress erythrocytosis by the bone
marrow, Nutritional and vitamin deficiency is
also common in patients with HF and may
contribute to anemia. (55, 56) On the other
hand correction of anemia and the target Hb in
those patients revealed contradicting results.
One analysis of the database of the Study of
LV Dysfunction (SOLVD) by Al-Ahmad et al.
showed that for every decrease in Haematocrit
of 1% the mortality rate increases by 2.7%
(57). Moreover, a number of small studies in
chronic heart failure patients have shown
significant improvement in outcomes by
increasing hemoglobin level up to 12 to 13
g/dl (58). Whereas, the Correction of
Hemoglobin and Outcomes In Renal
Insufficiency (CHOIR) study (59) in CKD
patients with anemia receiving alfa poetic led
to increased hospital admission due to CHF
exacerbation, rate of death and cardiovascular
events.
Initiated in 2006,( RED-HF) trial had
randomized 2278 anemic patients with
symptomatic left ventricular systolic
dysfunction to either darbepoetin alfa or
placebo. The aim in the treatment group was a
target hemoglobin of at least 13.0 g/dL. The
primary end point was a composite of time to
death from any cause or first hospital
admission for worsening HF in subjects with
heart failure and anemia. The rates of the
primary end point were no different between
groups (hazard ratio 1.01, 95% CI 0.90
1.13). The trial's failure echoes that of
the Trial to Reduce Cardiovascular Events
With Aranesp Therapy(TREAT) in 2009,
reported by heartwire , which showed no
benefit of darbepoetin alfa on death, CV
events, CV death, or renal events in diabetic
patients with chronic kidney disease and
anemia.(60)

Collectively the to and fro relationship
between the heart and the kidney in all aspects
form pathophysiology down to the
management does implicate the concept of
renocardiac &/or cardiorenal syndrome

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1219March 28, 2013

11 www.kidney advances.com (For Personal Use Only)

REFRACTORY EDEMA WITH CONGESTIVE HEART FAILURE
STEPWISE APPROACHES - NEPHROLOGY PERSPECTIVES

Mohammed A. Gawad

INTRODUCTION
Generalized edema occurs secondary to many
clinical disorders, as heart failure, liver
cirrhosis, nephrotic syndrome, and renal
failure. The usual management of edema is the
using of diuretics with other lines of
precautions and steps of treatment specific for
each clinical disorder. In general, failure to
decrease the extracellular fluid volume despite
liberal use of diuretics often is termed diuretic
resistance. The scope of this article is to discuss
the cause of refractory edema to usual
management with diuretics in patients with
chronic congestive heart failure (CHF) and
how to deal with it.

MECHANISM OF DEVELOPMENT
OF REFRACTORY EDEMA
Many factors are involved in the development
of refractory edema, and the decreased
response to the usual diuretic regimen. First
factor is high salt intake which prevents net
fluid loss even with adequate therapeutic doses
of diuretics.(1)

Second factor that may contribute to refractory
edema is decreased loop diuretic secretion. An
important step in the mechanism of action of
loop diuretics is that they enter the tubular
lumen by secretion in the proximal tubule, not
by glomerular filtration. After that loop
diuretics inhibit the Na-K-2Cl carrier in the
luminal membrane of the thick ascending limb
of the loop of Henle, which will reduce NaCl
reabsorption Fig-1. Diuretic efficacy is directly
related to urinary excretion rates, rather than to
plasma drug concentrations.(2) In case of CHF,
renal perfusion and tubular blood supply is
decreased due to decreased cardiac output,
which decrease the delivery of diuretics to their
site of action causing insignificant effect. It is
also well known that

loop diuretics are highly (95 percent) protein
bound, which keeps the diuretic within the
intravascular space, which will ensure good
delivery of the diuretic to the kidney.
Hypoalbuminemia may occur in CHF if
albumin is filtered in the urine secondary to
high venous pressure. Secondary to this
hypoalbuminemia; the degree of diuretic -
protein binding is reduced, which will result in
a larger extravascular space of distribution of
the diuretic with a slower rate of delivery to the
kidney, and then reduced diuresis. In addition,
the filtered albumin in the urine secondary to
high venous pressure may bind loop diuretics
in the tubular lumen and interfere with its
action.(3)

Figure-1 Site of action of different diuretics

The third and one of the important causes of
diuretic resistance is the use of nonsteroidal
anti-inflammatory drugs, which reduce the
synthesis of prostaglandins, which will affect
diuretic responsiveness.(4)

The fourth factor is that some patients with
diuretic resistance have decreased natriuresis,
despite adequate urinary delivery of the
diuretic. This problem is often due to increased


tubular sodium reabsorption in nephron
segments other than the loop of Henle with the
chronic use of diuretics (the diuretic braking
phenomenon).(5,6) Increased tubular sodium
reabsorption associated with the diuretic
braking phenomenon may occur at different
segments of the nephron:
In the proximal tubule, secondary to the
activation of angiotensin II and
Norepinephrine. The neurohumoral activation
occurs secondary to the heart failure itself and
also may occur as a consequence of diuretic-
induced water and salt loss.(7)
In the distal tubule, a flow-dependent hypertrophy
can occur with chronic loop diuretic therapy, which
increases sodium reabsorption secondary to the
increased activity of the sodium chloride
cotransporter in the luminal membrane of the
distal tubule cells and its hypertrophy.(8,9)
In the collecting tubules, due to increased
mineralocorticoid activity that occurs also
secondary to neurohumoral activation as that
affect sodium reabsorption in PCT.(4)

The fifth factor causing refractory edema is
inadequate diuretic dose or frequency, and the
non compliance of the patient for his prescribed
doses.(3)

The final and one of the most important factors
is that in patients with CHF there may be
decreased intestinal perfusion, reduced
intestinal motility, and also intestinal mucosal
edema, which will reduce the diuretic
absorption, and hence diuretic delivery to the
kidney and diuretic excretion rate.(10)

All these factors must be excluded during the
stepwise approach of management of refractory
edema in patients with CHF.

STEPWISE APPROACHES FOR
MANAGEMENT OF REFRACTORY
EDEMA WITH CHF
Stepwise approaches for management of
refractory edema with CHF are summarized in
Fig-2, Fig-5 and Fig-6.
It is important to know that these approaches
are based on our clinical experience and cases
in Kidney and Urology Center (KUC) -
Alexandria - Egypt. No available enough data
about target fluid loss or monitoring of
overloaded resistant patients. Any physician
can change any of the steps in our approach
according the clinical situation and the need of
the patient. The following approach is just only
a skeleton that we will go around.

Pre-Diuresis Precautions (Fig-2)
It is important to ensure dietary sodium
restriction, as increased sodium intake will
cause refractory edema (refer to mechanism of
development of refractory edema above). To
estimate salt intake in CHF patients with
refractory edema, a 24-hour urine should be
collected. A value above 100 mEq per day
indicates that noncompliance with sodium
restriction.(6) The 2010 Heart Failure Society
of America (HFSA) guidelines on acute
decompensated HF (ADHF) recommend a
sodium intake of less than 2 g/day. They even
recommend greater sodium restriction in
patients with recurrent or refractory volume
overload. Water restriction may also be
important.(11)

Also stop all nonsteroidal anti-inflammatory
drugs the patient uses, as they are of the
important factors causing refractory edema
(refer to mechanism of development of
refractory edema above).(4)

An important precaution is to exclude
concomitant aminoglycosides use, as this may
increase the incidence of ototoxicity with the
high doses of loop diuretics use (12) (refer to
monitoring side effects and toxicity
ototoxicity below).

Pre-Diuresis Lab and Imaging (Fig-2)
Pre-Diuresis Lab: Serum Albumin,
urea/BUN, creatinine, Na, K, Ca, Mg, uric
acid, Hb, Ht%, and other lab investigations (as
indicated).
Pre-diuresis Imaging: chest X-ray, ultrasound
abdomen and pelvis, ECHO.


The idea behind the pre-diuresis investigations
is to have a baseline for all the parameters of
the patient assessment that will be needed later
to follow the response or to detect the side
effects of the diuretics.

Figure-2 Pre-diuresis precautions, Lab & imaging
investigations (refer to the paragraph for details)

Posture during Diuresis (Fig-5, 6)
Patients with CHF cannot increase cardiac
output in upright position; subsequently renal
perfusion and urinary diuretic delivery will
decrease. In addition, renal salt and water
reabsorption increase. The efficacy of
assuming a supine position was evaluated in a
randomized trial. The supine position was
associated with significantly higher mean
creatinine clearance and diuretic response. The
upright position was associated with significant
increases in plasma norepinephrine, renin, and
aldosterone; which is theoretically
reasonable.(13)

Furosemide-Albumin I nfusion (Fig-5, 6)
As mentioned some patients with
hypoalbuminemia may be resistant to the usual
diuretic therapy (refer to mechanism of
development of refractory edema above).
Theoretically, infusion of the furosemide-
albumin complex can increase diuretic delivery
to the kidney by keeping furosemide within the
vascular space.(14) However, subsequent
studies found that the use of mixture of loop
diuretic and albumin in hypoalbuminemic
patients (secondary to cirrhosis or nephrotic
syndrome), with mean plasma albumin
3.0 g/dL, produced only a modest increase in
sodium excretion compared with furosemide
alone without an increase in the rate of
furosemide excretion.(15,16) But the
significance of infusion of loop diuretic plus
albumin may appear in patients with refractory
edema and severe hypoalbuminemia (plasma
albumin less than 2.0 g/dL). However, the
evidence supporting this is weak as this has not
been studied yet.

I ntermittent I ntravenous (I V) Bolus
versus Continuous I V I nfusion
Diuretic Therapy
The efficacy of a continuous IV infusion
compared with intermittent IV bolus therapy
has been evaluated in randomized trials, and
they appear to have similar efficacy. But a
continuous intravenous infusion is safer, less
ototoxicity (tinnitus and hearing loss) than
bolus injections of loop diuretics (refer to
monitoring side effects and toxicity
ototoxicity below).(17-19)
Also continuous IV infusion is able to maintain
an effective stable rate of drug excretion and
therefore a maintained inhibition of sodium
chloride reabsorption in the loop of Henle
through the duration of therapy. In contrast,
intermittent IV bolus therapy will lead to
initially higher rate of diuretic excretion,
followed thereafter by lower rates; as a result,
sodium excretion is at maximal levels for the
first two hours but then gradually falls.(19)
(Fig-3)

Figure-3: Diuresis peak following IV bolus and IV
continuous infusion of loop diuretic
Pre-Diuresis Precautions:
- Ensure dietary sodium restriction
- Stop NSAIDs
- Exclude aminoglycosides
Pre-Diuresis Lab: Serum Albumin, Urea/BUN,
Creatinine, Na, K, Ca, Mg, Uric acid , Hb, Ht%
Other lab Ix (as indicated)

Pre-diuresis Imaging: CXR, USS Abdomen &
Pelvis, ECHO.


Single and Maximum Effective I V
Dose of Loop Diuretics
Before discussing the stepwise bolus and
continuous infusion approaches, we have to
know first the concepts of single and maximum
IV effective dose of loop diuretics.

Single IV Effective Dose of Loop Diuretics

Diuretics have a dose-response curve (Fig-4),
as there will be no natriuresis seen until a
threshold rate of drug excretion in urine is
attained. For example, if a patient does not
respond, i.e. no diuresis, to 40 mg
of furosemide, the dose may not have exceeded
the threshold of the single effective dose, so
this single dose (40 mg) should be increased to
60 or 80 mg, rather than giving it twice a day.
Once a single effective dose has been
determined, i.e. there is a response of diuresis,
it should be administered multiple times per
day, with a frequency which is individualized
according to the diuretic needs of the
patient.(19-21) So simply, single effective dose
is the least dose that will cause response i.e.
diuresis.

Figure-4: Dose response curve of furosemide

Maximum IV Effective Dose of Loop
Diuretics
The maximum IV effective dose is the dose at
which loop sodium chloride transport is
completely inhibited. So administering higher
doses will produce little or no further diuresis,
a plateau is reached (Fig-4), but it may increase
the risk of toxicity and side effects. Maximum
IV effective dose differs according the cause of
edema and renal function of the patient. In CHF
patients with normal or near normal estimated
glomerular filtration rate (eGFR), the maximum
effective IV dose is 40 to 80 mg of furosemide, 1 to
2 mg of bumetanide, and 20 to 40 mg
of torsemide.(3) In chronic kidney disease, the
maximum IV effective dose varies with the
severity of the kidney disease (eGFR). In
moderate chronic kidney disease; maximum IV
effective dose is 80 mg of furosemide, 2 to 3
mg of bumetanide, and 20 to 50 mg
of torsemide. In severe chronic kidney disease;
it is 200 mg of furosemide, 8 to 10 mg
of bumetanide, and 50 to 100 mg
of torsemide.(21) The 2013 American College
of Cardiology/American Heart Association
(ACC/AHA) guideline on heart failure
recommended maximum IV effective dose of
furosemide (160 to 200 mg), bumetanide (4 and 8
mg), and torsemide (100 to 200 mg) for
patients with severe heart failure and a
substantially reduced GFR. This recommendation
differs in the dose of bumetanide and torsemide
than other literature.(22)

The rate of IV bolus administration is
important to be slow to decrease the incidence
of side effects. A bolus dose of about 20 to 40
mg of furosemide is better to administered over
5 minutes, while a bolus dose of 60 to 120 mg
is better to administered over 20 minutes, and
finally a bolus dose of 160 to 200 mg
of furosemide is better to be given over 40 to
50 minutes.

I ntermittent I V Bolus Diuretic Therapy
Stepwise Regimen (Fig-5)
Start IV bolus loop diuretic targeting to reach
the single effective dose (mentioned above).
The usual initial intravenous bolus dose
of furosemide is 20 to 40 mg. Next action
depends on the response of the patient:
If good diuretic response, continue the same
dose with follow up (refer to monitoring response
and side effects of IV diuretic therapy below).
If little or no response to the initial bolus dose,
the dose should be doubled at two-hour intervals as
needed up to the maximum recommended doses
(discussed above).(19,20,23)


If partial diuretic response to once daily
single effective or maximum bolus dose,
different strategies can be done to increase the
response, for example the loop diuretic dose
can be repeated twice or even three times a day
(8), and also adding a thiazide diuretic can add
a lot of benefit (refer to when to add thiazides
below).

Continuous I V I nfusion Diuretic
Therapy Stepwise Regimen (Fig-6)
Loading Bolus Dose:
Use of a continuous IV infusion requires the
patient to be responsive to loop diuretics. Thus,
a continuous IV infusion should not be tried in
CHF patients who have not responded to
repeated bolus doses up to the maximum bolus
doses (discussed above). IV bolus therapy will
lead to initially higher rate of diuretic
excretion, which will lead to high initial rates
of urinary diuretic and sodium excretion.(24)
(Fig-3)

Continues IV Infusion Therapy:
If there is a good response to the initial loading
bolus dose, then it must be followed by the
continuous IV infusion, which dose is
dependent on the renal function of the patient.
A start of continues infusion dose of
approximately 5 mg/h is reasonable in patients
with normal or near normal renal function
(eGFR >75 mL/min) and of approximately
20 mg/h in patients with impaired kidney
function (estimated GFR < 30 mL/min).(25)

Maximum I nfusion Dose
Higher infusion rates of up to 240 mg/h (4
mg/min) are reported, but the risk of
ototoxicity and other side effects is high and
the use of this high infusion rate must be
weighed against alternative strategies such as
the addition of a thiazide diuretic or fluid
removal via ultrafiltration. This high infusion
rate is not recommended.(3,12) Acute and
Chronic kidney diseases also increase the risk of
ototoxicity. Permanent deafness has been reported
in patients with acute kidney injury receiving
furosemide continuous IV infusion dose of 80 to
160 mg/h.(26) (refer to monitoring side effects and
toxicity ototoxicity below).

Furosemide
IV
Torsemide
IV / PO
Bumetanide
IV / PO
20 mg 10 mg 1 mg
40 mg 20 mg 2 mg
Table 1 equivalent doses of other loop diuretics to
furosemide dose

I f I V Furosemide is I neffective, Can I
Switch to Equivalent I V Dose of
Bumetanide or Torsemide?
If the patient is resistant to IV furosemide, it is
not likely to respond to an equivalent
intravenous dose of any other loop diuretic as
bumetanide or torsemide.(3)

When to Add Thiazide Diuretic?(Tabel-2)
One mechanism for overcoming diuretic
resistance is by sequential nephron blockade.
Sequential nephron blockade means the
concurrent use of diuretics acting upon
different segments of the nephron; therefore
producing an additive or synergistic diuretic
response.(27) (Fig-1)
As mentioned above, long term administration of
a loop diuretic will increase the distal sodium
delivery, a flow-dependent hypertrophy in distal
convoluted tubule can, which increases sodium
reabsorption secondary to the increased activity
of the sodium chloride cotransporter in the
luminal membrane of the distal tubule cells and
its hypertrophy.(8,9) Therefore adding thiazide
diuretic (in patient with known long term use of
loop diuretics) will block the distal reabsorption of
sodium, leading to a better diuretic effect. Also
thiazides will add benefit if added to cases with
partial diuretic response to the single
effective/maximum bolus dose, or cases with partial
diuretic response to continuous IV infusion diuretic
therapy.(28) (Fig 5,6)
The timing of combination therapy depends
upon the route by which the diuretics are given.
Loop and thiazides diuretics can be
administered at the same time if given by the
same route i.e. intravenous or oral. If, however,
a thiazide diuretic is given orally, so the
thiazide diuretic should precede the loop
diuretic by 2-5 hours, since the peak effect of
the thiazide is 4-6 hours after ingestion.(29)



Pre-Diuresis Precautions,
Pre-Diuresis Lab and Pre-diuresis Imaging
(refer to Fig-2 and related paragraph, discussed before)

Albumin infusion
in case of hypoalbuminemia (<2 g/dl)
(refer to Furosemide - Albumin Infusion discussed above)
or Hypertonic Saline
(refer to IV High-Dose Furosemide and Hypertonic Saline Solutions)

Initial intravenous bolus dose of furosemide is 20 to 40 mg (or equivelant)
Good response
Continue the
same dose with
follow up
Little or no response
to intial bolus dose
Double the dose every 2 hrs
as needed up to the
maximum recommended
doses
Normal eGFR
Maximum IV
effective IV dose is
40 mg (over 5
minutes) to 80 mg
(over 20 minutes)
of furosemide,
1 to 2 mg
of bumetanide,
20 to 40 mg
of torsemide.
Moderate chronic kidney disease
Maximum IV
effective dose is
80 mg
of furosemide
(over 20
minutes),
2 to 3 mg
of bumetanide,
20 to 50 mg
of torsemide.
Severe chronic kidney disease
Maximum IV
effective dose is
200 mg (over 40
to 50 minutes)
of furosemide,
8 to 10 mg
of bumetanide
50 to 100 mg
of torsemide.
ACC/AHA
recommendations:
Maximum IV
effective dose is
160 to 200 mg (over
40 to 50 minutes) of
furosemide,
4 and 8 mg of
bumetanide
100 to 200 mg of
torsemide
Partial diuretic response to once daily
single effective or maximum bolus
dose
- Repeat loop diuretic dose can twice
or even three times a day,
- Add thiazide diuretic (refer to when
to add thiazides diuretic?)
Posture

When to start with Thiazide?
if the patient was chronically on
oral diuretics since long time
(refer to when to add thiazides
diuretic?)

When to add Spironolactone?
1- CHF (NYHA Class III and IV)
2- If hypokalemia is present at
first or with follow up.
3- Before the addition of a
thiazide diuretic
(refer to when to add
spironolactone?)

Figure-5: Intermittent IV Bolus Diuretic Therapy Stepwise Regimen



Pre-Diuresis Precautions,
Pre-Diuresis Lab and Pre-diuresis Imaging
(refer to Fig-2 and related paragraph, discussed before)

Albumin infusion
in case of hypoalbuminemia (<2 g/dl)
(refer to Furosemide - Albumin Infusion discussed above)
or Hypertonic Saline
(refer to IV High-Dose Furosemide and Hypertonic Saline Solutions)

IV loading dose of furosemide (or equivelant - Table 1)
refer to Fig-5
Normal or near normal renal function
(eGFR >75 mL/min)
Continuous Furosemide infusion, 5 mg/h (or
equivelant)
Follow Up UOP after 2 hrs:
Minimumal required UOP: 0.5-1 ml/kg/h, which can be
increased according clinical situation
Adequate UOP
Assess UOP every 2
hrs
Increase or
decrease infusion
rate according to
monitoring
parameters**
Convert to oral
therapy *****
Inadequate or No
UOP
a second bolus is given followed by
a higher infusion rate of 10 mg/h
+ Thiazide Initial dose
Minimal required UOP: 0.5-1 ml/kg/h, which can be
increased according to clinical situation
If inadequate or No UOP:
+ Thiazide maximum dose
No UOP
UF
Inadequate UOP
Impaired renal function
(eGFR <30 mL/min)
Continuous Furosemide infusion, 20 mg/h(or
equivelant)
Minimumal required UOP: 0.5-1 ml/kg/h, which can be
increased according clinical situation
Inadequate or NO
UOP
+ Thiazide Initial dose
If inadequate or No UOP:
+ Thiazide maximum dose
Inadequate UOP
Higher infusion rates of up to 240 mg/h
(4 mg/min) are reported, but the risk of
ototoxicity and other side effects is high
(refer to Maximum Infusion Dose)
No UOP
UF
Adequate UOP
Assess UOP every 2
hrs
Increase or
decrease infusion
rate according to
monitoring
parameters
Convert to oral
therapy
Figure-6: Continuous IV Infusion Diuretic Therapy Stepwise Regimen

Posture

When to start with Thiazide?
if the patient was chronically on
oral diuretics since long time (refer
to when to add thiazides diuretic?)

When to add Spironolactone?
1- CHF (NYHA Class III and IV)
2- If hypokalemia is present at first or
with follow up.
3- Before the addition of a thiazide
diuretic
(refer to when to add
spironolactone?)



Chlorothiazide Edema:
Oral, I.V.: 500-1000 mg once or twice daily; intermittent
treatment (eg, therapy on alternative days) may be appropriate
for some patients
CrCl <10 mL/minute:
Avoid use.
Ineffective with CrCl <30 mL/minute unless in combination with a
loop diuretic (Aronoff, 2007)
Note: ACC/AHA 2009 Heart Failure Guidelines suggest that
thiazides lose their efficacy when CrCl <40 mL/minute
Hydrochlorothiazide Edema:
Oral: 25-100 mg daily in 1-2 divided doses; may administer
intermittently on alternate days or on 3-5 days each week.
Alternate recommendations: Mild fluid retention in heart
failure: Oral: Initial: 25 mg once or twice daily; maximum dose:
200 mg daily (Yancy, 2013)
Renal Impairment:
No dosage adjustment provided in manufacturers labeling;
However, the following adjustments have been recommended
(Aronoff, 2007):
o CrCl 10 mL/minute: No dosage adjustment necessary.
o Usually ineffective with CrCl <30 mL/minute unless in
combination with a loop diuretic.
o CrCl <10 mL/minute: Use not recommended; use is
contraindicated with anuria.
Metolazone Edema:
Oral: Initial: 2.5-10 mg once daily; may increase as necessary to 20
mg once daily (ACC/AHA 2009 Heart Failure Guidelines);
Note: Dosing frequency may be adjusted based on patient-
specific diuretic needs (eg, administration every other day or
weekly) (Lindenfeld, 2010).
Renal Impairment:
Use caution in patients with severely impaired renal function, as
most of the drug is excreted by the renal route and accumulation
may occur.
Not dialyzable (0% to 5%) via hemo- or peritoneal dialysis;
supplemental dose is not necessary.
Hydrochlorothiazide
and Spironolactone

Edema:
Oral: Hydrochlorothiazide 25-200 mg daily and spironolactone 25-
200 mg daily in single or divided doses
Renal Impairment:
No dosage adjustment provided in manufacturers labeling.
Efficacy of hydrochlorothiazide is limited in patients with CrCl <30
mL/minute;
Contraindicated in patients with anuria, acute renal insufficiency,
or significant impairment of renal excretory function.
Table 2 - Thiazides Dosing


When to Add Spironolactone? (Table-3)
Utilization of spironolactone may be more
effective when circulating aldosterone
concentrations are increased (which is usually
the case in more advanced CHF, such as New
York Heart Association classes III and IV).(30)
The associated reduction in collecting tubule
sodium reabsorption and potassium secretion
enhanced by spironolactone (Fig-1) can both
increase the diuresis and minimize the degree of
potassium wasting. Therefore, it may be highly
suggested to start spironolactone in patients who
have developed low or low-normal serum
potassium with loop diuretic therapy alone. It is
also reasonable to start a spironolactone before the
addition of a thiazide diuretic, as combination
therapy of loop diuretics and thiazides can lead to a
marked diuresis and hypokalemia.(29)

Normal
GFR
Edema: Oral: 25-200 mg daily in 1-
2 divided doses
Hypokalemia: Oral: 25-100 mg
once daily
Abnormal
GFR
Heart failure (Yancy, 2013):
eGFR 50 mL/minute/1.73 m
2
:
o Initial dose: 12.5-25 mg once daily;
o Maintenance dose (after 4 weeks
of treatment with potassium 5
mEq/L): 25 mg once or twice daily
eGFR 30-49 mL/minute/1.73 m
2
:
o Initial dose: 12.5 mg once daily or
every other day;
o Maintenance dose (after 4 weeks
of treatment with potassium 5
mEq/L): 12.5-25 mg once daily
eGFR <30 mL/minute/1.73 m
2
: Not
recommended.
Note: Contraindicated in patients
with anuria, acute renal insufficiency,
or significant impairment of renal
excretory function

I V High-Dose Furosemide and
Hypertonic Saline Solutions (Fig-5, 6)
Excessive diuresis induces hypovolemia and
reduced cardiac output, which will diminish
GFR.(31) So, theoretically it is reasonable that
maintaining an adequate intravascular volume
during high dose diuretic therapy will maintain
good renal perfusion, which in turn will reduce
the incidence and frequency of side effects.
Different studies approved that this can be
achieved by combining high dose furosemide
with the administration of hypertonic saline
solution (HSS).
A study showed that the combination of high
dose furosemide intravenous infusion (250-
2,000 mg/d) with the administration of small
volume HSS (150 mL of 1.4%-4.6% NaCl)
twice a day for 6 to 12 days improves clinical
signs and symptoms of CHF; also it improves
the severity of the illness (NYHA class).(32)
Another study compared 30-minute
intravenous infusion of furosemide (500-1,000
mg) plus HSS (150 mL of 1.4%-4.6% NaCl)
twice daily in one group of patients, versus an
intravenous bolus infusion of furosemide alone
in another group. Symptoms improved in both
groups, but the severity of the illness (NYHA
class) was greatly improvement in patients
receiving HSS. Also urine output and sodium
excretion were significantly of a greater degree
in the group treated with HSS and furosemide
than in those received furosemide alone. Serum
creatinine level decreased in patients receiving
HSS and furosemide.(33)
Also it was proved that combined high
furosemide IV dose and HSS has long-term
benefits, regarding reducing mortality and
hospital readmission rates.(34)
A randomized double blind study was done to
detect the effect of the furosemide and HSS
infusion on brain natriuretic peptide (BNP)
plasma levels in patients with advanced CHF
(NYHA functional class IV) (35), as it is well
known that natriuretic peptides have a very
powerful prognostic markers.(36) The results
of the study showed that plasma levels of BNP
were significantly lower in the HSS group at 6
days and at 30 days after treatment.(35) Also
combined therapy reduces the plasma levels of
markers of neurohormonal and inflammatory
activation.(37)
To conclude, studies examined the use of
intravenous high dose furosemide in
combination with small volume HSS in
management of refractory edema with CHF;
suggest that this combination therapy may be
of high benefit as a step of management of
Table 3 - Spironolactone Dosing


these cases. In my own opinion, HSS may be of
high value if the treated patient is already
hyponatremic, or having a low border line
blood pressure which may exacerbate the
depletion of the intravascular effective
circulating volume with the used aggressive
diuresis.

Monitoring Response and Side Effects
of I V Diuretic Therapy (Table-4)
Lab: Na, K (daily)
Urea/BUN, Creatinine (daily)
Hb, Ht% (daily)
ABG (daily)
Ca, Mg
Uric Acid
Serum Albumin
Other lab Ix (as indicated)
Radiology
(as
needed):
CXR
USS Abdomen & Pelvis
ECHO
Clinical: Weight measurement: should be
performed at the same time each
day, usually in the morning, prior to
eating and after voiding.
Signs of hypovolemia (not less
than 4 times/day):
o Weakness
o Hypotension
o orthostatic hypotension
o cool extremities
o + elevated serum creatinine
o + rapidly elevated Ht%
Signs of ototoxicity(not less than
4 times/day):
o decreased hearing
o tinnitus
o deafness: transient (most lasting
30 minutes to 24 hours) or
permanent deafness
Table 4 Monitoring Response and Side Effects of IV
Diuretic Therapy

Effect on Renal Function
The blood urea nitrogen (BUN) and serum
creatinine often rise during diuretic treatment
of HF and careful monitoring is recommended.
Heart Failure Society of America 2010
Comprehensive Heart Failure Practice
Guidelines for management of patients with HF
with elevated or rising BUN and/or serum
creatinine include the following:
Other potential causes of kidney injury (eg,
use of nephrotoxic medications, urinary
obstruction) should be evaluated and
addressed.
Patients with severe symptoms or signs of
congestion, particularly pulmonary edema,
require continued fluid removal independent of
changes in GFR. In the presence of elevated
central venous pressure, renal function may
improve with diuresis.
If the BUN rises and the serum creatinine is
stable or increases minimally, and the patient is
still fluid overloaded, the diuresis can be
continued to achieve the goal of eliminating
clinical evidence of fluid retention with careful
monitoring of renal function.
If increases in serum creatinine appear to
reflect intravascular volume depletion, then
reduction in or temporary discontinuation of
diuretic and/or angiotensin converting enzyme
(ACE) inhibitor/angiotensin II receptor blocker
therapy should be considered. Adjunctive
inotropic therapy may be required.(11)
As stated in the American College
of Cardiology/American Heart Association HF
guideline, adverse effects must be monitored
closely:
Electrolyte imbalances (particularly
hypokalemia, hypomagnesemia, and metabolic
alkalosis) that develop during diuresis should
be promptly treated while the diuresis is
continued.
If hypotension or worsening renal function
develops before the goals of treatment are
achieved, the diuresis may be slowed. Diuresis
should be maintained until fluid retention is
eliminated even if this results in asymptomatic
mild to moderate decreases in blood pressure or
renal function. Excessive concern about
hypotension and azotemia can lead to
underutilization of diuretics and persistent
volume overload. Persistent volume overload
contributes to continued symptoms, may
reduce the efficacy of drug therapy for HF,
and, persistent volume overload may be
associated with increased mortality.(25)


Ototoxicity
Monitory the evidence of toxicity during the
therapy period is mandatory. Decreased
hearing , tinnitus, or deafness transient (most
lasting 30 minutes to 24 hours) or permanent
deafness.(38) As mentioned above the mechanism
of action of loop diuretics is mediated by a Na-K-
2Cl cotransporter inhibition at the ascending loop
of Henle. A secretory isoform of this cotransporter
is present in the inner ear and plays an important
role in the composition of endolymph. It was
approved that inactivation of this transporter in
mouse led to reduced endolymph secretion,
structural damage to the inner ear, and
deafness.(39)
The following are the factors which may
increase the risk of ototoxicity in CHF patients
receiving loop diuretics:
Patients who are treated with high IV dose
of bolus therapy are at high risk of developing
ototoxicity. Bolus IV furosemide doses of 160
to 200 mg (and the equivalent doses of
bumetanide and torsemide) can cause transient
tinnitus. This effect can be minimized by
giving the dose more slowly as mentioned
above in bolus IV therapy.(38)
Although the risk of ototoxicity may be
reduced by a continuous infusion rather than
bolus therapy.(24,38) But continuous diuretic
infusion can also cause ototoxicity especially
with rates above 4 mg/min.(3,12)
Risk of ototoxicity is increased if the
patient is already taking other ototoxins such as
aminoglycoside antibiotic.(12)
Acute and Chronic kidney diseases also
increase the risk of ototoxicity. Permanent
deafness has been reported in patients with
acute kidney injury receiving furosemide
continuous IV infusion dose of 80 to
160 mg/h.(26)

Switching from I V to Oral Loop
Diuretics (Table-5)
When to
start?
It depends on the clinical
decision of the treating
physician.
Dosage The oral dose
of Furosemide is approximately
twice the intravenous dose.
The oral dose of Torsemide &
Bumetanide is the same as the
intravenous dose.
Important
Considerations
In our mind it is important to
try at least one to two days on
oral therapy will the patient still
in hospital. This facilitates the
adjustment of the oral dose to
avoid over or under diuresis.
No special recommendations.
But mainly the dose of diuretic
should be adjusted once the
patients dry body weight is
attained to the minimum dose
required to maintain dry body
weight.
Table5 Switching from IV to Oral Loop Diuretics

The decision of replacing IV diuretic therapy
by the oral one depends on the clinical situation
and the clinician sense. No special
recommendations for when to switch from IV
to oral loop diuretics. When converting to oral
therapy, the dose should usually be doubled for
oral furosemide, a twofold higher dose than the
intravenous dose is a reasonable starting point
as its mean bioavailability is only about 50%,
with substantial interpatient and intrapatient
variability (range 10 to 100 percent). Further
dose adjustments may be needed according to
the patient response, the dose of diuretic should
be adjusted once the patients dry body weight
is attained to the minimum dose required to
maintain dry body weight. In contrast, the
intravenous and oral doses are similar in
patients treated with bumetanide or torsemide,
which have higher rates of oral bioavailability
(70 to 95 percent and 80 to 90 percent,
respectively), but also with further dose
adjustments may be needed according to the
patient response.(3,25,40)

Can We Use Dopamine to Enhance
Diuresis?
There is no strong evidence conformation
about the significant benefit and effect from
intravenous dopamine (natriuretic and renal
vasodilator activity), few data and reports are
available on this subject.(41)



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40. A comprehensive review of the loop diuretics:
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Ann Pharmacother. 2009;43(11):1836
41. Dopamine does not enhance furosemide-induced
natriuresis in patients with congestive heart failure.
Vargo DL, Brater DC, Rudy DW, Swan SK. J Am Soc
Nephrol. 1996;7(7):1032


ULTRAFILTRATION VERSUS DIURETICS IN ACUTE
DECOMPENSATED HEART FALIURE (ADHF)

Mohammed Essam

Introduction:
Heart Failure (HF) is a major public health
problem with increasing prevalence owing to
the substantial rise in population aged over 65
years of age. Fluid overload and congestion are
major characteristics of HF and among the most
important targets of treatment. Acute
Cardiorenal syndrome (type 1) is worsening of
renal function in acute decompensated heart
failure (ADHF). This article will discuss the
benefits and drawbacks of ultrafiltration (UF)
therapy versus diuretic based therapeutic
regimens in ADHF through currently available
studies in this field.

Reduced GFR and prognosis of HF:
A reduced glomerular filtration rate (GFR) is
generally associated with a worse prognosis in
patients with heart failure (HF), whether present
at baseline or developing during therapy for HF.
The prevalence of moderate to severe reductions
in glomerular filtration rate (GFR less than
60 mL/min per 1.73m
2
) in patients with HF has
ranged from 30 to 60 percent in large clinical
studies.
(1,2)
This observation is important
clinically because the baseline GFR is a
predictor of mortality in both acute and chronic
HF.
(13)
The relationship between change in
GFR and prognosis is more
complex. Worsening of GFR during hospital
stay is associated with increased mortality
risk.
(4)

These findings imply into 2 points:
Decreased efficacy of diuretics in
patients with renal impairment.
Effect of diuretics and UF on renal
functions during hospital stay.

Current Practice & its deficiencies:
Current Practice in management of ADHF is
based mainly on hospitalization for IV diuretics,
to relieve congestion and dyspnea, and
vasodilators. The use of UF is preserved for
patients with refractory edema (diuretic
resistance) or impaired kidney functions

Drawbacks of diuretic therapy include:
1. Efficacy: Conventional diuretic therapy
lack the adequate decongestion needed
to relieve patients symptoms. In the
ADHERE registry with over than
100000 patients enrolled, around half of
the patients admitted for ADHF were
discharged with symptoms of congestion
after receiving conventional diuretic
based therapy.
(5)

2. Diuretic resistance: common in Heart
failure (HF).
(6)

3. New onset AKI during hospital
admission or worsening of renal
function.
4. Uncertainties about optimal dose, mode
of administration and stepped approach
in resistant cases.
5. Electrolyte abnormalities: (hypokalemia,
etc.,,,)
6. Hypersensitivity and ototoxicity.

Theoretical advantages of
ultrafiltration:
Ultrafiltration was thought to have some
theoretical advantages over diuretic therapy
including:


1. Higher mass clearance of sodium for
similar volumes of fluid removal.
2. Rapid controlled fluid removal.
3. Decreased renal venous congestion.
4. Lack of neurohormonal activation.
5. No resistance to its action.
6. Low risk of electrolyte abnormalities.
7. Sustained clinical benefits.
8. Decreased hospital length of stay and
rehospitalization for HF.
9. Ability to restore diuretic sensitivity.

Ultrafiltration in heart failure
(Clinical trials):
The idea behind the use of ultrafiltration in HF
is decongestion; ultrafiltration can remove fluid
from the blood at the same rate that fluid can be
naturally recruited from the tissue. The transient
removal of blood elicits a compensatory
mechanism, called plasma or intravascular refill
(PR), aimed at minimizing this reduction.
(7)
The
plasma refill (PR) response is a compensatory
response by the circulation in response to
volume loss.

The rate of plasma refill is
important, for if the ultrafiltration rate is too
aggressive intravascular volume may decrease
because the rate of refill from the interstitial to
the intravascular space is exceeded. This in turn
may lead to hemodynamic instability and renal
dysfunction. There have been studies that
document an increase in creatinine and
hemodynamic instability when ultrafiltration
rates are too aggressive in a high-risk, advanced
HF subset of patients.
(7,8)

This led to the adventure of new ultrafiltration
devices with new technology that has the
advantage of:
1. Small sized portable devices.
2. Adjustable blood flow rates (10-40
ml/min).
3. Small polysulphone filters (0.12 m
2
).
4. Small extracorporeal blood volume of
less than 50 ml.
5. The ability to use peripheral veins.

In the RAPID-CHF trial, 40 patients with ADHF
and renal insufficiency (serum
creatinine1.5 mg/dL) and/or anticipated
diuretic resistance (high daily oral diuretic
doses) were randomly assigned to receive usual
care with or without ultrafiltration.
Ultrafiltration was associated with significant
increases in fluid removal after 24 hours (4650
versus 2838 mL without ultrafiltration) and
weight loss (2.5 versus 1.9 kg) without a
difference in serum creatinine.
(9)

The UNLOAD trial
(10)
, one of the largest trials in
this field, randomized 200 patients with ADHF
to receive either UF therapy or standard
intravenous (IV) diuretic therapy. UF was done
at a rate up to 500 cc / hour, while IV diuretics
were given at least 2 times the daily oral dose
for the first 48 hours as bolus or continuous
infusion.
Results of the UNLOAD trial:
1. Weight and fluid loss were greater in the
UF group without significant change in
blood pressure (BP) or serum creatinine.
2. The ultrafiltration group showed fewer
patient rehospitalizations for HF at 90
days.



Figure 1: Primary Efficacy and Safety End Points (A)
Mean weight loss in kilograms; (B) mean dyspnea
score (from 1 = markedly worse to 7 = markedly
better) at 48 h after randomization in the
ultrafiltration (blue circles) and standard-care (red
circles).

Figure 2: Freedom from Heart Failure
Rehospitalization Kaplan-Meier estimate of freedom
from rehospitalization for heart failure within 90 days
after discharge in the ultrafiltration (red line) and
standard care (blue line) groups.

Drawbacks of the UNLOAD trial:
1. Patients with hemodynamic instability
were excluded, systolic BP of > 90
mmHg or requiring IV vasopressors
were excluded. This might be in favor
for the UF group as UF theoretically has
more hemodynamic instability.
2. Suboptimal use of diuretics at 48 hours
made the fluid loss greater in the UF
group which had an UF rate up to 500 cc
/ hour.
3. Higher serum creatinine in UF group
although not significant.

The Cardiorenal Rescue Study in Acute
Decompensated Heart Failure (CARRESS-HF)
trial
(11)
, randomized 188 patients with ADHF,
worsened renal functions and persistent
congestion despite standard therapy to receive
stepped pharmacological therapy or UF.
Results of CARRESS-HF:
1. UF didnt show greater weight loss than
stepped medical therapy (5.7 kg for UF
versus 5.5 kg for medical therapy;
P=0.58).
2. Patients in UF group showed significant
increase in serum creatinine level (+0.23
mg/dl for UF group versus -0.04 mg/dl
for medical therapy group; P=0.003).
3. Higher rate of serious adverse events in
UF group was also noted.

Figure 3A: Changes in Serum Creatinine and Weight
at 96 Hours (Bivariate Response).


Figure 3B: Changes in Serum Creatinine and Weight
at different points (Bivariate Response).

Drawbacks of CARRESS-HF trial:
1. The addition of IV vasodilators or positive
inotropic agents was prohibited unless indicated
as a rescue therapy, while it was allowed in the
diuretic group for patients in whom the target
urine output (3-5 liters/day) could not be
attained.
2. Although the pharmacological approach was
stepped up to target urine output of 3-5
liters/day, UF was delivered in a constant rate of
200 ml/hour. As discussed above the UF rate
should be adjusted according to the plasma refill
rate, but delivering a constant rate of UF to
different patients may contribute to the greater
rise in serum creatinine in this group.
3. In the ultrafiltration group, most of the fluid
removal was achieved with ultrafiltration, which
implied that less fluid was eliminated by the
kidney through glomerular filtration. By
contrast, in the pharmacologic-therapy group,
the excess fluid was eliminated exclusively
through the kidney. Since, according to the
manufacturer, creatinine is not removed with the
Aquadex System 100 ultrafiltration procedure
used in the study, it could be anticipated that a
smaller amount of creatinine was excreted
through glomerular filtration and tubular
secretion. Hence, besides being clinically
irrelevant, the small increase in the serum
creatinine level in the ultrafiltration group, as
compared with the changes observed in the
pharmacologic-therapy group, was nothing
other than the expected result given the choice
of this primary end point.

The study of Heart Failure Hospitalizations after
Aquapheresis Therapy Compared to Intravenous
(IV) Diuretic Treatment (AVOID-HF) is an
ongoing trial to determine if patients have fewer
Heart Failure (HF) events after receiving
Aquapheresis (AQ) therapy compared to IV
diuretics up to 90 days of discharge from the
hospital. Heart Failure events are defined as
returning to the hospital, clinic or emergency
department (ED) for treatment of HF symptoms.
UF versus Diuretics, many
questions:
Thus, although ultrafiltration may be helpful for
fluid removal in acute decompensated HF in
patients unresponsive to diuretic therapy, the
available evidence does not establish
ultrafiltration as first line therapy for AHDF or
as an effective therapy for Cardiorenal
syndrome.
Drawbacks of UF:
1. Effect on renal functions: Data are
conflicting regarding the effect of UF on renal
functions. Studies have failed to show any
protective effects of UF.
2. Cost versus standard medical therapy is much
higher. Studies to impact that by proving the
decrease incidence of rehospitalization.
3. No data regarding long term outcome.
4. Problems with vascular access, although
peripheral veins may be used.
5. Uncertainties regarding patient choice, UF
rate and monitoring efficacy.


Current guidelines:
This made ultrafiltration to be reserved for
patients who do not achieve an adequate
response to an aggressive diuretic regimen. The
2009 AHA/ACC guidelines state that
ultrafiltration is reasonable for patients with
refractory congestion not responding to medical
therapy.
(12)
This recommendation is also
consistent with the 2013 ACCF/AHA HF
guidelines.
(13)

Conclusion:
UF should not replace diuretic therapy in the
initial management of patients with HF and
Cardiorenal syndrome, and should be reserved
to those cases with refractory edema.

References:
1. Smith GL, Lichtman JH, Bracken MB, Shlipak
MG, Phillips CO, DiCapua P, et al. Renal
impairment and outcomes in heart failure:
systematic review and meta-analysis. J. Am. Coll.
Cardiol. 2006;47(10):198796.
2. Heywood JT, Fonarow GC, Costanzo MR, Mathur
VS, Wigneswaran JR, Wynne J. 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(6):422
30.
3. Hillege HL, Nitsch D, Pfeffer MA, Swedberg K,
McMurray JJ V, Yusuf S, et al. Renal function as a
predictor of outcome in a broad spectrum of
patients with heart failure. Circulation.
2006;113(5):6718.
4. Damman K, Navis G, Voors AA, Asselbergs FW,
Smilde TDJ, Cleland JGF, et al. Worsening renal
function and prognosis in heart failure: systematic
review and meta-analysis. J. Card. Fail.
2007;13(8):599608.
5. Gheorghiade M. Reassessing treatment of acute
heart failure syndromes: the ADHERE Registry.
Eur. Hear. J. Suppl. 2005;7(Suppl B):B13B19.
6. Shchekochikhin D, Al Ammary F, Lindenfeld JA,
Schrier R. Role of diuretics and ultrafiltration in
congestive heart failure. Pharmaceuticals (Basel).
2013;6(7):85166.
7. Marenzi G, Lauri G, Grazi M, Assanelli E,
Campodonico J, Agostoni P. Circulatory response
to fluid overload removal by extracorporeal
ultrafiltration in refractory congestive heart failure.
J. Am. Coll. Cardiol. 2001;38(4):9638.
8. Liang K V, Hiniker AR, Williams AW, Karon BL,
Greene EL, Redfield MM. Use of a novel
ultrafiltration device as a treatment strategy for
diuretic resistant, refractory heart failure: initial
clinical experience in a single center. J. Card. Fail.
2006;12(9):70714.
9. Bart BA, Boyle A, Bank AJ, Anand I, Olivari MT,
Kraemer M, et al. Ultrafiltration versus usual care
for hospitalized patients with heart failure: the
Relief for Acutely Fluid-Overloaded Patients With
Decompensated Congestive Heart Failure
(RAPID-CHF) trial. J. Am. Coll. Cardiol.
2005;46(11):20436.
10. Costanzo MR, Guglin ME, Saltzberg MT, Jessup
ML, Bart BA, Teerlink JR, et al. Ultrafiltration
versus intravenous diuretics for patients
hospitalized for acute decompensated heart failure.
J. Am. Coll. Cardiol. 2007;49(6):67583.
11. Bart BA, Goldsmith SR, Lee KL, Givertz MM,
OConnor CM, Bull DA, et al. Ultrafiltration in
decompensated heart failure with cardiorenal
syndrome. N. Engl. J. Med. 2012;367(24):2296
304.
12. Hunt SA, Abraham WT, Chin MH, Feldman AM,
Francis GS, Ganiats TG, et al. 2009 focused
update incorporated into the ACC/AHA 2005
Guidelines for the Diagnosis and Management of
Heart Failure in Adults: a report of the American
College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines:
develope. Circulation. 2009;119(14):e391479.
13. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey
DE, Drazner MH, et al. 2013 ACCF/AHA
guideline for the management of heart failure: a
report of the American College of Cardiology
Foundation/American Heart Association Task
Force on practice guidelines. Circulation.
2013;128(16):e240327.



INOTROPES IN CARDIORENAL SYNDROME (CRS),
IS THERE A ROOM?

Alyaa EL-ghitany
What are inotropes?
An inotrope is an agent that alters the force or
energy of muscular contractions.
Our concern here is about positive cardiac
inotropes which increase myocardial
contractility, and cardiac output.
They include, Beta-receptor agonist (as
Dopamine, Dobutamine), Digoxin,
Phosphodiesterase inhibitors (as Milrinone),
Calcium sensitizers (as Levosimendan) and
others. See table 1.
Phosphodiesterase (PDE) inhibitors decrease
the rate of cyclic adenosine monophosphate
(AMP) degradation. The ensuing increase in
cyclic AMP concentration leads to enhanced
calcium influx into the cell, a rise in cell
calcium concentration, and increased
contractility. These drugs also cause systemic
arterial and venous dilation via inhibition of
peripheral PD [1].In many ways, their effects
are similar to those of dobutamine but with a
lower incidence of dysrhythmias.
Dobutamine (Dobutrex) is not a vasopressor
but rather is an inotrope that causes
vasodilation. Dobutamine's predominant beta-1
adrenergic receptor effect increases inotropy
and chronotropy and reduces left ventricular
filling pressure. However, minimal alpha- and
beta-2 adrenergic receptor effects result in
overall vasodilation, complemented by reflex
vasodilation to the increased CO. The net effect
is increased CO, with decreased SVR with or
without a small reduction in blood pressure [2].
Dopamine (Intropin) has a variety of effects
depending upon the dose range administered.
At doses of 1 to 2 mcg/kg per minute,
dopamine acts predominantly on dopamine-1
receptors in the renal, mesenteric, cerebral, and
coronary beds, resulting in selective
vasodilation. Some reports suggest that
dopamine increases urine output by augmenting
renal blood flow and glomerular filtration rate,
and natriuresis by inhibiting aldosterone and
renal tubular sodium transport [3]. These effects
may be blunted by haloperidol and other
butyrophenones [3]. However, the clinical
significance of these phenomena is unclear, and
some patients may develop hypotension at these
low doses [4].
At 5 to 10 mcg/kg per minute, dopamine also
stimulates beta-1 adrenergic receptors and
increases cardiac output, predominantly by
increasing stroke volume with variable effects
on heart rate [5]. Doses between 2 and
5 mcg/kg per minute have variable effects on
hemodynamics in individual patients:
vasodilation is often balanced by increased
stroke volume, producing little net effect upon
systemic blood pressure. Some mild alpha
adrenergic receptor activation increases SVR,
and the sum of these effects is an increase in
MAP.
Calcium sensitizing agents act through a
common pathway involving beta receptors,
cyclic adenosine monophosphate (AMP),
protein kinase A, and increased calcium influx
to the cardiomyocyte. However, increased
calcium influx leading to calcium loading may
increase arrhythmic risks and result in worse
outcomes. One concern regarding such
compounds is the possible impairment of
myocardial relaxation [6]. However, at least one
of these compounds, levosimendan, appears to


have a favorable effect on relaxation properties
in failing hearts [7]. Most calcium-sensitizing
agents have additional pharmacologic
properties, such as phosphodiesterase inhibition,
which may increase inotropy and vasodilation
and contribute significantly to their clinical
profile.

Why inotropes in CRS?
The Low-Flow-State Hypothesis [8]
Traditional reasoning held that the progressive
decline in GFR observed in HF primarily
reflects inadequate renal perfusion secondary to
reduced cardiac output. Many surmised that
inadequate renal blood flow or perfusion
pressure prompts renin release by the
juxtaglomerular cells of the afferent arterioles
through low-flow states in the ascending limb of
the loop of Henle and pressure-sensing
baroreceptors. Renin release and RAAS
activation confer extreme sodium avidity,
volume retention, decreased glomerular
perfusion (i.e., afferent arteriolar constriction),
and profibrotic neurohormone increases, leading
to ventricular remodeling. On one hand, this
reasoning is not incorrect because all of the
above conditions are observed in HF
(neurohormonal stimulation, decreased
fractional excretion of sodium, myocardial
fibrosis). Experience would also suggest that, by
augmenting contractility, heart rate, and cardiac
index, inotropes can lead to short-term
improvement in urine output, mental status, and
other clinical indicators of organ perfusion.
However, recent investigations suggest that this
viewpoint is extremely limited and management
of patients with CRS based solely on the low-
flow theory does not lead to improved
outcomes.

Inotropes in CRS, Yes or No and
When?
The role of inotropes in patients with CRS is
uncertain and the routine use of inotropes
cannot be recommended given their lack of
proven efficacy and their association with
adverse events when used outside of selected
patients with cardiogenic shock or acute
decompensated HF [9].
Although it has been proposed that inotropic
agents might improve renal function in patients
with severe HF by increasing renal blood flow
and possibly by reducing renal venous pressure,
data supporting such a potential benefit are
limited as illustrated by the following
observations regarding use of dopamine:
The clinical efficacy and safety of dopamine for
preservation of renal function in patients with
HF has not been established.
A report from the DAD-HF trial of 60 patients
with acute decompensated HF found that the
combination of dopamine 5 mcg/kg/min plus
low-dose furosemide (5mg/h continuous
infusion) produced similar urine output as high-
dose furosemide (20 mg/h) with reduced risk of
worsening renal function (defined as rise in
serum creatinine of >0.3 mg/dL from baseline to
24 hours; 7 versus 30 percent) [10].
The Renal Optimization Strategies Evaluation
(ROSE) trial also tested the hypothesis of
whether low-dose dopamine (2mcg/kg/min) (n
= 122) would improve urine output and renal
function compared to placebo (n = 119) among
patients hospitalized with HF and concomitant
renal disease [11]. Low-dose dopamine did not
enhance decongestion or improve renal function
when added to diuretic therapy.
Routine use of inotropes in patients hospitalized
for heart failure was found to be harmful in the
OPTIME-CHF trial [12]. In this trial, 949
patients admitted to the hospital with an acute
exacerbation of chronic HF were randomly
assigned to a 48 to 72 hour infusion
of milrinone or placebo. Milrinone therapy was
associated with significant increases in
hypotension requiring intervention and atrial
arrhythmias, and with nonsignificant increases
in mortality in-hospital (3.8 versus 2.3 percent)
and at 60 days (10.3 versus 8.9 percent). This


trial did not evaluate patients whose treating
physicians felt could not be randomized, but
demonstrates overall adverse effects in
noncritical patients despite improved symptoms.
Levosimendan, a phosphodiesterase inhibitor
with lusitropic activity (calcium sensitizer),
improves hemodynamics and renal perfusion
and in a small randomized trial was found to
improve eGFR at 72 hours by 45.5% versus
0.1% (P < 0.001) compared with
dobutamine. This result was not confirmed in
the larger SURVIVE (Survival of Patients With
Acute Heart Failure in Need of Intravenous
Inotropic Support) study, and although
levosimendan appears in the European Society
of Cardiology guidelines for management of
heart failure, the drug currently is not available
in North America and its precise role in the
treatment or avoidance of CRS is unclear [13].
A recent large trial of pulmonary artery
catheterguided management of 433 individuals
admitted with acute decompensated congestive
heart failure (Evaluation Study of Congestive
Heart Failure and Pulmonary Artery
Catheterization Effectiveness [ESCAPE]) found
no correlation between baseline renal function
and cardiac index. Furthermore, improvement in
cardiac index did not result in improved renal
function, prevention of death, or prevention of
rehospitalization. This notion is supported by
the findings of multiple other investigations in
which improved cardiac index or decreased
pulmonary capillary wedge pressure during
pulmonary artery catheterguided therapy failed
to predict improvement in renal
function. Collectively, these data do not support
poor forward flow and altered hemodynamics as
primary determinants of progressive renal
failure in the HF population [8].
There is concern that inotropic agents may
adversely impact outcomes in patients with
ADHF with congestion without a low output
state [12,14]. Inotropic agents may increase
heart rate and myocardial oxygen consumption
and thus provoke ischemia and potentially
damage hibernating but viable myocardium,
particularly in patients with ischemic heart
disease. In addition, inotropic agents can
increase atrial [12] and ventricular [15]
arrhythmias. Given these concerns, careful
patient selection is required for inotrope use.

Related guidelines
The 2013 American College of Cardiology
Foundation / American Heart Association
guideline on HF recommended short-term
continuous intravenous inotropic support to
maintain systemic perfusion and preserve end-
organ performance until definitive therapy (eg,
coronary revascularization, mechanical
circulatory support, or heart transplantation) is
instituted or resolution of the acute precipitating
problem has occurred. It was also felt
reasonable in patients for whom definitive
therapy was not planned [16].
Similarly, the 2010 HFSA guidelines for ADHF
include the following recommendations for use
of inotropes [17]:
Intravenous inotropes may be considered to
relieve symptoms and improve end-organ
function in patients with advanced HF
characterized by LV dilation, reduced LVEF,
and diminished peripheral perfusion or end-
organ dysfunction (low output syndrome),
particularly if these patients have marginal
systolic blood pressure (<90 mmHg), have
symptomatic hypotension despite adequate
filling pressure, or are unresponsive to, or
intolerant of, intravenous vasodilators.
Intravenous inotropes may be considered in
similar patients (i.e., patients with depressed
systolic function and marginal cardiac output)
with evidence of fluid overload if they respond


poorly to intravenous diuretics or manifest
diminished or worsening renal function.
When adjunctive therapy is needed in other
patients with ADHF (eg, patients with preserved
cardiac output), administration of vasodilators
should be considered instead of intravenous
inotropes.
Intravenous inotropes are not recommended
unless left heart filling pressures are known to
be elevated or cardiac index is severely
impaired based on direct measurement or clear
clinical signs.

Administration of intravenous inotropes in the
setting of ADHF should be accompanied by
continuous or frequent blood pressure
monitoring and continuous monitoring of
cardiac rhythm.
If symptomatic hypotension or worsening
tachyarrhythmias develop during administration
of these agents, discontinuation or dose
reduction should be considered.
Inotropes are not indicated for treatment of
ADHF in the setting of preserved systolic
function.

Table 1 Inotropes clinical effects and side effects [9,18]
+++: Very strong effect; ++: Moderate effect; +: Weak effect; 0: No effect.
CO: cardiac output, SVR: systemic vascular resistance, PVR: pulmonary vascular resistance, SV: stroke volume.
* Doses between 2. and 5. mcg/kg/min have variable effects.
Practical issues [9]:
Inotropes other than digoxin are given as
continuous Infusions because of their short
half-life. Further their effects on the
cardiovascular System are potent and dosing
must be carefully monitored and adjusted.
This is only possible with an infusion.
Inotropes should be administered through an
appropriately positioned central venous
catheter, if available. This facilitates more
rapid delivery of the agent to the heart for
systemic distribution and eliminates the risk
of peripheral extravasation. When a patient
does not have a central venous catheter,

Drug
Receptor activity/ Mechanism Predominant
clinical effects
Side effects
Alpha-1 Beta-1 Beta-2 dopaminergic
Dopamine (mcg/kg/min)*
0.5 to 2 0 + 0 ++
CO, dilate renal and
mesenteric artery
beds
Risk of tachyarrhythmia
5 to 10 + ++ 0 ++ CO, SVR
10 to 20 ++ ++ 0 ++ SVR
Dobutamine 0/+ +++ ++ 0 CO, SVR
Tachyarrhythmia,
myocardial oxygen
demand, risk of
hypotension
Milrinone PDE III Inhibitor
SVR,PVR, SV,
cardiac
contractility,
vasodilatation
Hypotension, arrhythmia
levosimendan Ca sensitizer, possible PDE III Inhibitor
cardiac
contractility
without myocardial
oxygen
consumption
Effect on mortality unclear



inotropic agents can be administered
through an appropriately positioned
peripheral intravenous catheter temporarily,
until a central venous catheter is inserted.
Inotropes should be titrated to ensure the
minimum amount of drug is used to
maintain adequate tissue perfusion without
causing adverse effects. The aim is not to
maintain a specific blood pressure but to
achieve satisfactory end organ perfusion,
which can be assessed clinically or with
measured markers of organ perfusion.
Choice of inotrope depends on clinical
findings. Dobutamine or milrinone
recommended for patients with systolic BP
85 to 100 mmHg. Dopamine is
recommended for patients with systolic BP
<85 mmHg [19].
Responsiveness to these drugs can decrease
over time due to tachyphylaxis. Doses must
be constantly titrated to adjust for this
phenomenon and for changes in the patient's
clinical condition.

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JD. The effects of dobutamine on cardiac
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3. Dasta JF, Kirby MG. Pharmacology and
therapeutic use of low-dose dopamine.
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4. Duke GJ, Briedis JH, Weaver RA. Renal support
in critically ill patients: low-dose dopamine or low-
dose dobutamine? Crit Care Med 1994; 22:1919.
5. Lllgen H, Drexler H. Use of inotropes in the
critical care setting. Crit Care Med 1990; 18:S56.
6. Hajjar RJ, Gwathmey JK. Calcium-sensitizing
inotropic agents in the treatment of heart failure: a
critical view. Cardiovasc Drugs Ther 1991; 5:961.
7. Givertz MM, Andreou C, Conrad CH, Colucci
WS. Direct myocardial effects of levosimendan in
humans with left ventricular dysfunction: alteration
of force-frequency and relaxation-frequency
relationships. Circulation 2007; 115:1218.
8. Jeremy S. Bock and Stephen S. Gottlieb.
Cardiorenal Syndrome: New Perspectives.
Circulation. 2010;121:2592-2600.
9. Uptodate 2014, Use of vasopressors and
inotropes, Cardiorenal syndrome: Prognosis and
treatment.
10. Giamouzis G, Butler J, Starling RC, et al. Impact
of dopamine infusion on renal function in
hospitalized heart failure patients: results of the
Dopamine in Acute Decompensated Heart Failure
(DAD-HF) Trial. J Card Fail 2010; 16:922.
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