Download Management of Acute Decompensated Heart Failure

Case-based review
Management of Acute Decompensated Heart
Failure in Hospitalized Patients
Carlos E. Sanchez, MD, and David R. Richards, DO
Abstract
• Objective: To review the current in-hospital management of patients with acute decompensated heart
failure (ADHF).
• Methods: Review of the literature.
• Results: Heart failure is a leading cause of hospitalization in the elderly, and morbidity, mortality, and
hospital readmission rates for ADHF remain high.
The patient’s hemodynamic status along with the
use of prognostic models for short-term mortality
may facilitate patient triage and encourage the use
of evidence-based therapy, especially in high-risk
patients. Initial treatment should target the relief of
congestive symptoms, and intravenous loop diuretics
are the mainstay of therapy. The preferred IV vasoactive medication has yet to be determined in a large
prospective randomized trial. Positive inotropic agents
should be reserved for patients with signs of low cardiac output and tissue hypoperfusion; however, the
risk/benefit equation should be evaluated judiciously
with each treatment option before initiating therapy.
For patients with refractory hemodynamic collapse,
ventricular assist devices can allow stabilization until
recovery or decision regarding transplantation versus
destination therapy.
• Conclusion: Patients with ADHF are at increased risk
for readmission to the hospital as well as at increased
risk for death. Risk factors need to be identified and
referral to a heart disease management program
should be considered for those patients deemed at
increased risk for rehospitalization.
H
eart failure is a major public health problem
in the United States and the leading cause of
hospitalization in patients 65 years of age and
older [1]. Patients hospitalized with acute decompensated heart failure (ADHF) have a readmission rate as
high as 50% within 6 months and 25% within 30 days
[2]. It is estimated that $32 billion is spent on heart
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failure care each year, the majority of which is directly
related to inpatient care. Projections show that by 2030
the total cost of heart failure will increase to $70 billion per year [1]. Despite the growing burden, advances
in treatment have been limited [2,3] and management
continues to be a challenge. In this article, we review
the current in-hospital management of patients with
ADHF.
CASE STUDY
Initial Presentation
A 64-year-old woman with a nonischemic dilated cardiomyopathy presents to the emergency
department (ED) with a 4-day history of progressive
dyspnea on exertion. She can not ambulate more than 50
feet without having to stop due to dyspnea and reports
increased lower extremity edema. She is found to have a
heart rate of 105 bpm, a respiratory rate of 30 breaths/min,
and a blood pressure of 90/51 mm Hg. Physical examination is remarkable for distended neck vein, S3 gallop,
end expiratory wheezing in the bases, and lower extremity edema. Blood tests, including a B-type natriuretic
peptide level, are pending. Electrocardiogram and chest
radiograph are ordered. The physician suspects that the
patient has ADHF and admits her for further management.
• What are aspects of initial management in the
ED?
Most patients that present for evaluation and management of ADHF are first evaluated in the ED. Initial management includes an assessment of oxygenation, hemody-
From Ohio Health, Riverside Methodist Hospital, Columbus,
OH.
Vol. 22, No. 4 April 2015 JCOM 179
Acute Decompensated Heart Failure
Evidence for Congestion (Elevated Filling Pressure)
Orthopnea
High jugular venous pressure
Increasing S3
Loud P2
Edema
Ascites
Rales (uncommon)
Abdominal reflux
Valsalva square wave
Evidence for Low Perfusion
Narrow pulse pressure
Pulsus alterations
Cool forearms and legs
May be sleepy, obtunded
ACE inhibitor-related symptomatic
hypotension
Declining serum sodium level
Worsening renal function
Low perfusion at rest?
Congestion at rest?
No
Yes
No
Warm and dry
Warm and wet
Yes
Cold and dry
Cold and wet
Figure. 2 × 2 table of hemodynamic profiles in patients with heart failure. Reprinted from Nohria A, Lewis E, Stevenson LW.
Medical management of advanced heart failure. JAMA 2002; 287:628–40.
namic status, and adequacy of tissue perfusion, as well as
for possibility of an acute coronary syndrome. A complete
history, physical examination, chest radiography, 12-lead
electrocardiogram, cardiac troponin T or I, electrolytes,
and complete blood count should be obtained to allow
rapid diagnosis and triage followed by prompt, aggressive treatment in the ED or observation unit. This should
allev-iate the patient’s symptoms sooner, and it is intuitive
that this would lessen morbidity and length of hospital
stay [4].
• How are patients with ADHF classified?
ADHF denotes the development of progressive signs
and symptoms of distress that require hospitalization in
patients with a previous diagnosis of heart failure. The
American College of Cardiology Foundation/American
Heart Association (ACCF/AHA) guideline for the diagnosis and management of heart failure in adults notes
that the hospitalized patient with heart failure can be
classified according to adequacy of systemic perfusion
and volume status [5]. Most patients can be classified
180 JCOM April 2015 Vol. 22, No. 4
during bedside assessment according to the diagram
shown in the Figure. Patients with fluid overload who
present with adequate peripheral perfusion and signs and
symptoms of congestion and are classified as “warm and
wet.” Patients without congestion but with low output
with evidence of tissue hypoperfusion due to heart failure
are “cold and dry,” and display a continuum of severity
manifested by hypotension, renal insufficiency and/or
shock. Patients with fluid overload and tissue hypoperfusion or shock are “cold and wet” [5]. Although these
clinical profiles differ in their prognostic significance,
clinicians should recognize the need for urgent therapy
based upon clinical signs and symptoms [6]. Specifically, cold and wet patients may need observation in
the cardiac care unit setting, and treatment should be
directed at improving tissue perfusion and relieving
congestion. The ACCF/AHA guideline also classifies
hospitalized patients with ADHF into subgroups with
distinct clinical and hemodynamic characteristics that
require special attention. These include patients with
acute coronary ischemia, accelerated arterial hypertension in patients with signs and symptoms of heart failure, shock, and acutely worsening right heart failure
(Table 1) [5].
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Case-based review
Table 1. Clinical Classification of Hospitalized Patients with Acute Heart Failure Based on ACCF/AHA Guidelines [5]
and Clinical Presentation with Management Considerations
Clinical
Classification
Sign and Symptoms
of ADHF
Management Considerations
Based on Clinical Presentation
Variable: None to pulmonary congestion or
acute pulmonary
edema
15% of patients with
ACS have symptoms
of heart failure
ADHF frequently associated or precipitated
by bradycardia, atrial
fibrillation, and ventricular tachycardia
Coronary angiography
Revascularization: PCI/CABG
Signs and symptoms
of HF accompanied
by accelerated hypertension
Relatively preserved LV systolic function
Low hospital mortality
Frequent pulmonary
congestion/acute
pulmonary edema
without systemic
congestion
Euvolemic or mild hypervolemic
Tachycardia
Hypertension due to
increased sympathetic
tone (vasoconstriction)
Vasodilators
Diuretics: with volume overload
or pulmonary edema
Evidence of tissue hypoperfusion induced by
HF after correction of
preload and major arrhythmias
Rapid development
of pulmonary congestion/edema
SBP < 90 mm Hg or drop
of MAP > 30 mm Hg
Oliguria
Evidence of organ hypoperfusion
Arrhythmias are common
Positive inotropes
Norepinephrine or dopamine: If the inotropes fail to restore
SBP and signs of organ hypoperfusion persist
Mechanical circulatory support
Peripheral edema
Increased JVP
± Hepatomegaly
Low left ventricular filling
pressures
Avoid mechanical ventilation
Inotropes: with signs of organ
hypoperfusion
± Diuresis
Evaluate PE and RV myocardial
infarction as the cause
Characteristics
Congestion
Acute coronary
ischemia and
heart failure
ADHF with clinical,
laboratory and/or ECG
evidence of acute
coronary syndrome
Accelerated hypertension with
acute heart
failure
Cardiogenic shock
Acute isolated right
heart failure
Low output syndrome in
the absence of pulmonary congestion
No pulmonary congestion
Mechanical circulatory support
Treat arrhythmias
Evaluate systolic and diastolic
ventricular function, valvular
function or mechanical complications with echocardiography
Intubation
ADHF = acute decompensated heart failure; ACS = acute coronary syndrome; BP = blood pressure; CABG = coronary artery bypass
graft; ECG = electrocardiogram; HF = heart failure; JVP = jugular venous pressure; LV = left ventricle; MAP = mean arterial pressure;
PCI = percutaneous coronary intervention; PE = pulmonary embolism; RV = right ventricle; SBP = systolic blood pressure.
• What risk assessment tools are available?
B-type natriuretic peptide (BNP) and N-terminal fragment proBNP (NT-proBNP) were recently validated as
diagnostic aids for the differentiation of etiologies of
dypnea in patients in the ED with possible symptoms
of ADHF. Use of these biomarkers can help reduce diagnostic uncertainty and associated mismanagement of
patients presenting with nonspecific symptoms of dyspnea [4,5,7]. Low or normal levels (BNP < 100 pg/ml
or NT-proBNP < 500 pg/ml) have a high negative predictive value for excluding heart failure.
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Elevated BNP or NT-proBNP levels may also yield
prognostic information, identifying patients at increased
risk of mortality or rehospitalization when value does not
fall after aggressive heart failure management [8,9]. In a
recent study by Fonarow et al, the levels of BNP on hospital admission correlated directly with the risk of in-hospital
mortality in patients admitted with ADHF independent of
left ventricular ejection fraction. When the levels of BNP
were below 430 pg/ml, the in-hospital mortality was 1.9%,
and when the levels were above 1730 pg/ml, the mortality
went up to 6% (P < 0.001) [8]. Additionally, elevated predischarge BNP levels (BNP > 350 ng/l; P < 0.001) in patients with ADHF seem to identify those at increased risk
of death or readmission after in-patient management [9].
Vol. 22, No. 4 April 2015 JCOM 181
Acute Decompensated Heart Failure
Table 2. In-hospital Mortality Predictor Models in Patients Presenting with ADHF
Predictor Model
Number of Patients
AHA Get With
the GuidelinesHeart Failure
[12]
39,783
ADHERE [13]
65,275
Derivation and validation cohort
OPTIME-CHF [14]
949
EFFECT [15]
4031
Optimize-HF [16]
48,612
Best Predictors
for Mortality
Mortality Risk
Comments
Older age
SBP
BUN
In-hospital mortality rates
varied by deciles ranging from 0.4% to 9.7%
with a predictive risk
variation of >24-fold
across deciles
The probability of in-hospital
mortality is estimated by
summing points assigned
to the value of each predictor with a validated tool for
risk stratification.
BUN > 43 mg/dL
Admission SBP < 115 mm Hg
Creatinine > 2.75 mg/dL
In-hospital: 4.2%
Admission SBP ≥ 115 mm Hg
had lower mortality risk
High BUN
60-day mortality: 9.6%
Increased SBP and serum sodium had lower mortality
Older age
Respiratory rate
Hyponatremia < 136mEq/L
Increased BUN
Comorbid conditions (eg, dementia)
In-hospital: 8.9%
30-day: 10.7%
1-year: 32.9%
Higher SBP (per 10-unit increase) had lower mortality
Serum creatinine
Admission SBP
Patients age
In-hospital: 3.8%
In-hospital mortality increased 18% for every 0.3 mg/dL increase in SCr up to 3.5 mg/dL
Every 10-year increase in
age was associated with
a 34% higher risk for inhospital mortality
Higher admission SBP was
associated with a lower risk
of in-hospital mortality (up
to 160 mm Hg)
NYHA class IV
Increasing age (per 10-year increase)
Low SBP
Low serum sodium
AHA = American Heart Association; BUN = blood urea nitrogen; NYHA = New York Heart Association; SBP = systolic blood pressure;
SCr = serum creatinine. (Modified from reference 50.)
Elevated cardiac troponin T or I in hospitalized patients
with ADHF also are associated with increased mortality,
including in those without acute coronary syndrome or
underlying coronary artery disease [10,11].
The American Heart Association Get With The
Guidelines–Heart Failure (GWTG-HF) developed a
validated risk score to predict in-hospital mortality in
182 JCOM April 2015 Vol. 22, No. 4
patients hospitalized for heart failure that uses commonly
available clinical variables. The admission variables that
were most predictive of in-hospital mortality were BUN,
systolic blood pressure, and age [12]. In addition, Fonarow et al published a detailed in-hospital mortality risk
stratification tool for ADHF derived from more than
65,000 patients in the ADHERE registry database [13].
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Case-based review
Of 39 variables, high admission BUN level (≥ 43) was
the best single predictor for mortality, followed by an
admission systolic blood pressure less than 115 mm Hg
and a serum creatinine level above 2.75 mg/dL. These
variables underscore the importance of renal function
as a predictor of cardiac outcomes among hospitalized
patients with ADHF. Other risk stratification models
and predictors of mortality in hospitalized patients
with ADHF have recently been published (Table 2)
[12–16]. These predictor models emphasize the importance of early identification of high-risk patients, which
may allow for focusing intensity of care where it is most
needed. Prospective studies will be needed to determine
to what degree risk stratification may improve outcomes.
Case Continued
Upon further evaluation by a cardiologist, the
patient is cool and clammy with elevated neck
veins and prominent S3 confirmed. She continues to report severe shortness of breath after 1 dose of intravenous
(IV) furosemide in the ED. Repeat vital signs shows a
blood pressure of 83/49 mm Hg and respiratory rate of
33. Her electrocardiogram shows sinus tachycardia. The
cardiologist determines that the patient’s clinical profile
is “cold and wet” and admits the patient to the cardiac
care unit (CCU) with a diagnosis of ADHF.
Initial blood tests show a BNP level of 1830 pg/ml,
troponin I is 0.63 and stable after 2 measurements, serum
creatinine is 1.6 mg/dL, BUN is 44 mg/dL, and serum
sodium is 132 mg/dL. The GWTG-HF risk score for inhospital mortality was calculated based on admission data
and the probability of death was estimated at > 5% to 10%
[12]. Prompt aggressive medical therapy was instituted
in the CCU consisting of furosemide infusion to reduce
congestion and IV dobutamine to improve systemic perfusion. Enoxoparin 40 mg subcutaneously once daily was
initiated for venous thromboembolism prophylaxis.
• What are important aspects of therapy for
ADHF?
Elevated filling pressure is the culprit in the development
of most of the signs and symptoms of ADHF and is the
target for treatment.
An important aspect in the management of ADHF is
identifying precipitating factors and/or comorbid conditions (Table 3) and treating them appropriately in conjunction with volume overload [5]. Echocardiogram is a
widespread and readily available diagnostic tool providing important information on systolic and diastolic ventricular function as well as other structural heart disease
abnormalities. Additionally, myocardial ischemia evaluation with noninvasive testing or cardiac catheterization
should be performed if ischemia is a potential contributor
to the patient’s heart failure symptoms. The most common cause of heart failure readmission is noncompliance
with medications or dietary restrictions. Hospitalization
provides an opportunity to educate the patient about
their condition and rationale for therapy as well as identify barriers to appropriate self-management.
Although use of vasoactive medications such as nitroglycerin or nitroprusside are not routinely recommended
for use in all ADHF patients admitted to the hospital,
retrospective analysis of the ADHERE database suggests
that there is a significant reduction of mortality, hospital
length of stay, admission to intensive care unit, invasive procedures, and prolonged hospitalizations when IV diuretics,
vasodilators (nitroglycerin, nitroprusside, nesiritide,) and/
or positive inotropes (milrinone, dobutamine) are initiated in the ED within 6 hours of an ADHF presentation
[18,19]. However, whether prompt ED intervention impacts intermediate- to long-term outcomes is unknown [4].
Hospitalized patients with ADHF are at increased
risk of venous thromboembolism mainly due to reduced
cardiac output, increased systemic venous pressure, and
reduced activity levels. Therefore, it is recommended that
during the hospitalization ADHF patients receive prophylaxis against venous thromboembolism with low-dose
unfractionated heparin or low-molecular-weight heparin
if there is no contraindication [5]. Individual therapeutic
choices for ADHF are reviewed in detail below.
• What treatments are used to relieve congestion?
Several days to weeks prior to the appearance of signs and
symptoms of volume overload, patients may develop hemodynamic congestion, defined as an elevation of ventricular filling pressure/pulmonary capillary wedge pressure
independent of clinical evidence of fluid overload [17].
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Diuresis
In patients admitted to the hospital with ADHF, initial
effective diuresis is vital to lowering cardiac filling pres-
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Acute Decompensated Heart Failure
Table 3. Precipitating Factors in Acute Decompensated
Heart Failure
Dietary noncompliance (excessive sodium and water intake)
Medication noncompliance, including lack of access to medications
Iatrogenic volume overload
Unwarranted volume replacement
Major surgery
Progressive cardiac dysfunction
Worsening underlying disease
Alcohol abuse, cocaine
Valvular heart disease (stenosis or regurgitation)
Atrial fibrillation with rapid ventricular response
Ventricular tachyarrhythmias
Bradyarrhythmias
Uncontrolled hypertension
Acute coronary syndrome
Myocardial dysfunction from right ventricular pacing
Pulmonary disease
Chronic obstructive pulmonary disease
Obstructive sleep apnea
Pulmonary embolism
Anemia
Hyper- or hypothyroidism
Medication related
Pioglitazone or rosiglitazone
Non-steroidal anti-inflamatory drugs
Tricyclic antidepressants (increase risk of ventricular arrhythmia)
Theophylline
B-agonist bronchodilators (induce tachyarrhythmia)
Calcium channel blockers
Bladder outlet obstruction
Adapted from reference 5.
sures and relieving symptoms of congestion. Intravenous
loop diuretics represent the first line of treatment and
have long been the mainstay of therapy for decompensated heart failure with preserved or reduced ejection fraction, reducing fluid overload, and relieving symptoms.
Despite its long track record, the dose administration
of IV diuretics is more of an art than a science. Medication dosage sufficient to produce a rate of diuresis that
will optimize volume status and relieve signs and symptoms of congestion without causing kidney injury or hypotension is recommended [5]. Due to the relatively short
half-life of loop diuretics and concerns about tubular sodium reabsorption in the kidneys, continuous IV diuretic
infusion has been suggested to enhance diuresis and
184 JCOM April 2015 Vol. 22, No. 4
avoid sodium and fluid rebound [5,20,21]. However,
continuous loop diuretic infusion has not proven superior
to intermittent IV bolus dosing in clinical studies. Recent
data from the Diuretic Optimization Strategies Evaluation (DOSE) trial comparing bolus versus continuous
infusion diuretic strategy in patients with ADHF showed
no difference in global symptom relief, diuresis, or any
of the clinical secondary endpoints including composite of death, re-hospitalization, or ED visits with either
IV bolus versus continuous infusion or low versus high
doses of furosemide [22]. Concern has also been previously raised about adverse outcomes utilizing high doses
of loop diuretics in the treatment of ADHF [20,23,24].
However, the DOSE trial also evaluated the safety of 2
strategies for furosemide dosing in patients with ADHF.
The study randomized ADHF patients with a prior diagnosis of chronic heart failure to 4 different treatment
groups, either a high dose (2.5x their daily chronic oral
furosemide dose) or low dose (1x their daily chronic oral
furosemide dose), which was given either twice daily via
IV bolus or via continuous infusion. The study showed no
difference in change in renal function from baseline to 72
hours with either IV bolus versus continuous infusion or
low versus high doses of furosemide [22].
One protocol which seems reasonable is to first give
an IV dose of a loop diuretic twice that of the home oral
dose and reassess in 1 to 2 hours for response; if there is
no response to the initial dose, the loop diuretic should
be increased until adequate diuresis occurs or the maximum recommended dose is reached. In patients who fail
to respond to large doses of loop diuretics, the addition
of a non-loop diuretic (ie, thiazide or potassium-sparing
diuretic) may be effective in enhancing the response to
the loop diuretic. If the desired clinical response is not
achieved, professional guidelines also recommend alternating either a bolus or continuous infusion therapy different
from the initial strategy, or other loop diuretic may be
considered (Table 4) [5]. Finally, previous studies have
suggested that the addition of low-dose dopamine to
diuretic therapy may enhance decongestion and preserve
renal function in ADHF [25–27]. Dopamine at low infusion doses (1–3 mcg/min) directly activates dopaminergic
receptors in the kidney promoting renal vasodilatation.
This vasodilatory effect augments renal blood flow leading to an increase in urine output. This theoretical effect, however, has not translated into improved clinical
outcomes in patients with ADHF. The recent Renal
Optimization Strategies Evaluation in Acute Heart Failure
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Case-based review
Table 4. Medications Used in the Management of ADHF
Drug
Initial Dose
Maximum Single Dose
Intravenous Infusion
Bumetanide
1.0 mg IV
4 to 8 mg IV
1 mg IV load then 0.5–2 mg/hour
Furosemide
40 mg IV
160 to 200 mg IV
40 mg IV load then 10 to 40 mg/hour
Torsemide
10 mg IV
100 to 200 mg IV
20 mg IV load then 5 to 20 mg/hour
Loop Diuretics*
Thiazide Diuretics – Add to Loop Diuretic
Metolazone
2.5 mg oral once or
twice daily
5 mg oral once or twice daily
Chlorthiazide
500 mg IV once or
twice daily
1000 mg IV once or twice daily
Chlortalidone
12.5 to 25 mg once
daily
100 mg once daily
Hydrochlorothiazide
25 mg oral once or
twice daily
100 mg oral once or twice daily
Nitroglycerin
20–30 mcg/min IV
>100 mcg/min
10 to > 100 mcg/min
Close monitoring with high doses
Nitroprusside
10–20 mcg/min
300 mcg/min
Rarely required and increases
risk of toxicity
10 to 300 mcg/min
May be increased by 20 mcg/min
Niseritide
0.01 mcg/kg/min
0.03 mcg/kg/min
0.01 to 0.03 mcg/kg/min
May be increased by 0.005 mcg/kg/min to
achieve desired hemodynamic effects
Intravenous Vasodilators
Intravenous Inotropic Agents
Dopamine
1-3 mcg/kg/min
20 mcg/kg min
1–3 mcg/kg/min activates dopaminergic receptors causing vasodilatation.
3–8 mcg/kg/min exerts positive chronotropic and
inotropic effects.
5–20 mcg/kg/min results in vasoconstriction.
Dobutamine
2 mcg/kg/min
20 mcg/kg/min
2 to 20 mcg/kg/min titrate to desired response
by 1–2 mcg/kg/min
Milrinone
0.25 mcg/kg/min
0.75 mcg/kg/min
0.25 to 0.75 mcg/kg/min
IV = intravenous.
*Loop diuretics equivalent dose: Oral – 1 mg bumetanide = 20 torsemide = 80 mg furosemide; IV – 1 mg bumetanide = 20 torsemide =
40 mg furosemide.
(ROSE-AHF) study randomized patients with ADHF
and renal dysfunction to low-dose dopamine (2 mcg/
kg/min) or placebo in addition to diuretic therapy. The
study failed to demonstrate significant differences in urine
output at 72 hours or improved renal function in patients
randomized to dopamine compared to placebo [27].
Ultrafiltration
For patients with marked fluid overload who are unresponsive to diuretic therapy, peripheral ultrafiltration
may be considered. Initial data demonstrated that early
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ultrafiltration effectively and safely reduced congestion
in patients with ADHF with diuretic resistance and renal
insufficiency. Length of stay was reduced, with 60% of
discharges in 3 days or less and 1 readmission at 30 days.
Neurohormonal activation, indicated by reduction in
BNP level, was reduced without worsening glomerular
filtration rate, hypotension or electrolyte abnormalities
[28]. The UNLOAD trial confirmed these results and
extended their findings to show that patients undergoing
peripheral ultrafiltration had greater weight and net fluid
loss at 48 hours and reduced rate of rehospitalization at
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Acute Decompensated Heart Failure
90 days when compared with IV diuretic therapy alone
in ADHF patients. Interestingly, there was no difference
in the dyspnea score at 48 hours and there was a trend
toward worsening of renal function in the ultrafiltration
group. The study was not powered to document a survival benefit [29]. However, the more recent Cardiorenal
Rescue Study in ADHF (CARRESS-HF) trial involving patients with ADHF and worsening renal function
showed that there was no difference in weight loss between
patients randomized to ultrafiltration or a strategy of
stepped pharmacologic therapy. Additionally, ultrafiltration was associated with a significant increase in creatinine
at 96 hours and a higher rate of adverse events related to
the procedure, driven by complications from intravenous
catheter insertion. There was no difference between the
2 groups in death or rehospitalization for heart failure
[30]. At present, ultrafiltration may be a reasonable option if all diuretic strategies are unsuccessful in relieving
congestion [5].
Vasopressin-Receptor Antagonists
The vasopressin-receptor antagonists represent a relatively
new class of medications that target the vasopressin receptors V1a and V2. Activation of the vasopressin V2 receptors
by arginine vasopressin in heart failure causes inappropriate free water retention contributing to the symptoms of
congestion and hyponatremia [31]. Currently, the only 2
vasopressin-receptor antagonists available for clinical use
are conivaptan (V1a /V2 receptor antagonist) and tolvaptan
(V2 receptor antagonist). The effectiveness of tolvaptan
was tested in a randomized study (EVEREST) in patients
hospitalized with ADHF [32,33]. At 1 year there was
no difference seen in the primary endpoints of all-cause
mortality, death from cardiovascular causes, or first hospitalization for heart failure [32,33]. However, hyponatremia, when present, was improved in the tolvaptan group.
Conivaptan has a similar hemodynamic profile compared
to tolvaptan, but without improving signs and symptoms
in hospitalized patients with ADHF [34]. Currently, vasopressin antagonists are recommended in the management
of ADHF by professional guidelines as only a class IIb
indication in hospitalized patients with volume overload
and severe hyponatremia [5].
Case Continued
After 24 hours of medical therapy in the CCU,
the patient is no longer clammy and cool but continues to have shortness of breath, and peripheral edema
186 JCOM April 2015 Vol. 22, No. 4
is not improving. She continues to have elevated JVP and
S3. Her blood pressure is now 120/79 mm Hg and her
heart rate is 110. A Swan-Ganz catheter placed this morning showed a cardiac index of 1.8 L/minute/m2 (reference
range, 2.5–4.0 L/min/m2); pulmonary capillary wedge
pressure is 28 mm Hg (reference range, 6–12 mm Hg)
and systemic vascular resistance is 1932 dyne/second/
cm5 (reference range, 800–1200 dynes/sec/cm5).
The physician decides to add nitroprusside to lower her
filling pressure and systemic vascular resistance.
• What is the role of vasoactive medications in
treatment?
Vasodilators
Nitroglycerin is a venodilating medication with preload
reduction properties at low doses and an arterial dilator at high doses [35]. Preload reduction improves left
ventricular filling pressures and pulmonary congestion
without increasing the oxygen demand in the heart in
patients with ADHF. This leads to an improvement of
symptoms, including dyspnea, in as early as 5 minutes
[36]. For a highly symptomatic patient, nitroglycerin
given sublingually can be useful in an acute situation
because it is typically immediately available while preparations are made for administration of IV medications.
Limitations of nitroglycerin include rapid tachyphylaxis
within several hours of continuous exposure at high
doses, resistance to the hemodynamic effects of nitroglycerin in up to 20% of patients, and hypotension,
which may occur before significant preload reduction
effect can be obtained [37]. When symptomatic hypotension becomes a problem, the highest hemodynamically tolerable dose should be given. Another agent with
a potent vasodilator effect used in the treatment of heart
failure is sodium nitroprusside (SNP). As opposed to
nitroglycerin, this drug has an equally potent preloadand afterload-reducing effect [35]. Afterload reduction through its arteriodilator effect has the benefit of
increasing cardiac output and decreasing myocardial
oxygen demand with improvement of pulmonary congestion [36]. SNP is used in less than 1% of patients
hospitalized with heart failure [38], probably due to the
potential for causing marked hypotension, its need for
invasive hemodynamic monitoring, and the rare risk for
thiocyanate toxicity with high doses and/or longer inwww.jcomjournal.com
Case-based review
fusions, especially in patients with reduced hepatic perfusion and renal function, as in the case of low-output
heart failure [35]. However, data demonstrating safety
and efficacy of SNP infusion in patients with ADHF are
limited [39]. A single-center, retrospective case-control
study suggested that the administration of SNP in carefully selected patients with advanced low-output ADHF
was safe and may be associated with favorable long-term
clinical outcomes [39]. SNP can be attractive in severely
congested patients with hypertension or severe mitral
regurgitation complicating left ventricular failure, but
prospective trials are needed to clarify the safety and
efficacy in this patient population.
Nesiritide is a human recombinant form of BNP that
has a direct effect on the vascular endothelium by increasing the bioavailability of nitric oxide through stimulation
of cyclic guanosine monophosphate. Its primary mechanism of action is to reduce left ventricular filling pressures
by a systemic and pulmonary vasodilator effect. It also
promotes diuresis and natriuresis [40]. The initial efficacy
of nesiritide was demonstrated in the VMAC (Vasodilation in the Management of Acute Congestive Heart Failure) study, a randomized trial of IV nesiritide versus IV
nitroglycerin or placebo in decompensated heart failure
patients. A significant reduction in pulmonary capillary
wedge pressure was demonstrated within 15 minutes in
the nesiritide group and maintained at 3 hours compared
to either nitroglycerin or placebo, with a similar improvement in dyspnea extending out to 24 hours [41].
The large ASCEND-HF (Acute Study of Clinical
Effectiveness of Nesiritide in Decompensated Heart
Failure) randomized ADHF patients to nesiritide or
placebo and tested the hypothesis that nesiritide would
be superior to placebo in improving acute dyspnea, allcause mortality, and heart failure readmission in patients
presenting with ADHF [42]. Nesiritide-treated patients
showed only a modest early improvement in self-assessed
dyspnea and no difference in the composite endpoint of
death or rehospitalization at 30 days in patients admitted with ADHF. Reassuringly, there was no increase in
renal failure compared to placebo; however, the incidence
of symptomatic hypotension was higher with nesiritide
[42]. Although nesiritide remains in the armentarium
of vasoactive medications for ADHF, less expensive vasodilators such as nitroglycerin or nitroprusside may be
preferred by many clinicians.
Overall, vasodilators represent a good treatment option for patients presenting with ADHF characterized by
www.jcomjournal.com
low cardiac output, high filling pressures, and elevated
systemic vascular resistance. There is no clear evidence,
however, to suggest that IV vasodilators improve survival
in hospitalized patients with ADHF; thus, its use should
be restricted to the relief of dyspnea in patients with
stable blood pressure [5].
Inotropic Therapy
The most commonly used positive inotropic agents in
the management of patients with ADHF in the United
States are dobutamine (beta-1, beta-2, and alpha adrenoreceptor agonist) and milrinone (phosphodiesterase-III
inhibitor) [38]. Inotropes increase cardiac output by
increasing myocardial contractility, reduce left and right
ventricular filling pressures, and improve hemodynamic
parameters. Despite these hemodynamic effects, inotropic agents have not demonstrated a survival benefit in
patients with ADHF. A major limitation regarding these
agents is that they increase the risk of cardiac arrhythmias
by increasing intracellular calcium in cardiac myocytes.
In fact, retrospective analyses suggest that most inotropic agents are associated with an increased risk of death
[38,43].
Milrinone inhibits type III isoform of the enzyme
phosphodiasterase leading to an increase in intracellular cyclic AMP to exert its positive inotropic effect
on the myocardium. Milrinone also exerts systemic and
pulmonary vasodilator effects in the circulation decreasing right atrial, pulmonary capillary wedge, and mean
arterial pressure. In the OPTIME-CHF trial, patients
with chronic heart failure admitted to the hospital with
ADHF were randomized to short term infusion of
milrinone vs. placebo plus standard therapy. Milrinone
resulted in more hypotension, atrial fibrillation and ventricular arrhythmias without any benefit on mortality or
re-hospitalization [44]. A retrospective analysis from the
ADHERE registry showed that in-hospital mortality was
twofold higher with the use of dobutamine or milrinone
in patients with ADHF when compared to treatment
with vasodilators [38].
Dobutamine is a beta-1, beta-2, and alpha adrenoreceptor agonist that works by increasing myocardial contractility leading to an increase in cardiac
output as its primary cardiovascular effect. Currently,
routine use of IV positive inotropic agents in the absence of imminent cardiogenic shock or low output
ADHF with systemic hypoperfusion is generally not
recommended due to concerns of adverse effects [5]. The
Vol. 22, No. 4 April 2015 JCOM 187
Acute Decompensated Heart Failure
ACCF/AHA guidelines recommend the use of positive inotropic agents to relieve symptoms, improve
systemic perfusion and preserve end-organ function in
patients with severe left ventricular systolic failure and
low output syndrome with evidence of end-organ dysfunction (such as hypotension, altered mentation, cool
extremities, low urine output and serum markers indicative of renal and/or hepatic dysfunction) with or without
congestion [5].
Continuous outpatient therapy with inotropes may
be a viable option in patients with stage D (end stage)
heart failure who are deemed unlikely to survive hospital
discharge [45]. This is also supported by the ACCF/
AHA practice guidelines where IV inotropic support
may be considered for the previous reasons only after all
alternative therapies to achieve stability have failed (Class
IIB indication) [5].
• Is there a role for morphine?
For decades morphine has been considered an essential
component in the armamentarium for the treatment of
ADHF. Its preload-reducing effect, anti-anxiety properties, and breathlessness suppression has made morphine
a popular medication in the treatment of ADHF. Despite
its common use, there is a lack of prospective randomized
trials demonstrating the safety and benefit of this drug.
In a retrospective analysis from the ADHERE database,
IV morphine used for ADHF was associated with higher
rates of adverse events, including increase use of mechanical ventilation, prolonged hospitalization, increased
intensive care unit admissions, and higher mortality,
bringing into question its safety profile [46]. Until a randomized trial is completed demonstrating safety and benefit, caution is advised regarding the use of morphine in
ADHF.
Case Continued
Over the next 72 hours the patient’s symptoms
improved. She no longer has dyspnea at rest, she
has had a proper urine-output response to therapy, her
serum creatinine has returned to normal, and her vital
signs have remained stable. The IV vasodilator was discontinued, dobutamine was weaned off, and the patient
was transitioned to guideline-directed medical therapy
with an angiotensin-converting enzyme (ACE) inhibitor
188 JCOM April 2015 Vol. 22, No. 4
while continuing IV furosemide. Hospitalized patients
who are hemodynamically stable should be transitioned
to guideline-directed medical therapy with an oral
ACE inhibitor unless the patient has a contraindication,
such as marked azotemia or hyperkalemia. Low-dose
carvedilol was initiated after optimization of volume
status was confirmed. In the absence of shock and after
optimization of volume status, every effort should be
made to initiate low-dose beta blockers prior to hospital
discharge.
• When is mechanical circulatory support indicated
in ADHF patients?
Mechanical circulatory support has emerged as a reasonable option in selected patients with acute and reversible
cardiogenic shock (ie, acute coronary syndrome or an
acute mechanical problem such as a torn papillary muscle
or ventricular septal defect) [5]. Recently, the utility of
intraaortic balloon pump (IABP) in the setting of cardiogenic shock resulting from acute coronary syndrome
was called into question with the negative results from
the Intraaortic Balloon Pump in Cardiogenic Shock
II (IABP-SHOCK II) trial [47]. The study compared
IABP with best available medical therapy alone among
patients with acute myocardial infarction complicated
by cardiogenic shock for who early revascularization was
planned. Use of IABP did not reduce 30-day mortality
compared with medical therapy in this patient population
[47]. Whether IABP has a significant role in mechanical
complications, such as acute ventricular septal rupture or
papillary muscle rupture, is unknown due to the paucity
of data in the management of patients with such complications. Therefore, when patients present with severe
acute cardiogenic shock refractory to medical therapy,
mechanical circulatory support with either ventricular assist devices (VAD) or extracorporeal membrane oxygenation (ECMO) is the preferred means to reverse terminal
circulatory collapse. VADs are effective in the short-term
as a “bridge-to-recovery” or as a “bridge-to-decision”
when recovery, transplant candidacy, or neurologic status are still uncertain [48,49]. There are several options
currently available for mechanical circulatory support,
including surgically implanted VADs or the percutaneously implanted VADs, such as the Impella 2.5, 3.5 and
5.0 (Abiomed, Danvers, MA) and the TandemHeart
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Case-based review
pump (Cardiac Assist, Pittsburgh, PA). The ideal device
and optimal duration of temporary support are yet to
be defined. A detailed description of the function and
clinical effects of mechanical support devices is beyond
the scope of this article, although thorough reviews are
available [48,49].
• What elements of care may help optimize the
discharge process?
Transition of care in hospitalized patients with ADHF
to outpatient care is a critical and vulnerable period for
patients given the complexity of the discharge planning
for heart failure. A multidisciplinary heart failure disease
management program is recommended in both the inpatient and outpatient setting to address the barriers to
successful transition of care [5]. Physicians and physician
extenders, nurses, pharmacists, and social workers can
work together to identify risk factors for readmission
and bridge the gap between the inpatient and outpatient
setting.
Patients at high risk for hospital readmission should
be referred to a heart failure disease management
program [5,37]. Patients at high risk for hospital readmission include patients with renal insufficiency, low
output state, diabetes mellitus, chronic lung disease,
persistent NYHA functional class III, IV symptoms,
frequent hospitalizations, multiple comorbidities, history of depression, cognitive impairment, or recurrent
problems with noncompliance. There is strong evidence
that a heart failure disease management program will
reduce rehospitalization rates and costs while improving functional status and quality of life of the patient
[37]. In addition, a heart failure disease management
clinic often can see the patient shortly after discharge,
which may allow earlier discharge of the patient and
shorter length of stay. Proven therapies such as ACE
inhibitors, angiotensin-receptor blockers, beta blockers,
and aldosterone antagonists can be titrated frequently in
this setting.
It is strongly recommended that comprehensive written discharge instructions be provided at the end of
hospitalization with special emphasis on diet, discharge
medications, activity level, follow-up appointment, daily
weight monitoring, and instructions for recurrence of
symptoms [5].
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Case Conclusion
The patient tolerated well the initiation of
guideline-directed medical therapy and is continued on the ACE inhibitor and beta-blocker medications. After 4 days IV furosemide is discontinued and
transitioned to oral furosemide. Precipitant causes of
heart failure were addressed throughout hospitalization.
It was determined that the patient had been taking high
doses of nonsteroidal anti-inflammatory drugs due to
knee pain. She was educated on this and other potential
precipitant factors. Heart failure education was reinforced, including self-care, emergency plans, and need
for medication and diet adherence. She is scheduled an
early follow-up visit within 2 weeks of hospital discharge
in the multidisciplinary heart failure disease management
clinic.
Summary
ADHF is a major public health problem commonly encountered and often initially managed in the ED. Initial
history and physical examination are important to estimate the degree of congestion and peripheral perfusion.
The patient’s hemodynamic status along with the use
prognostic models for short-term mortality may facilitate
patient triage and encourage the use of evidence-based
therapy, especially in high-risk patients. Initial treatment
should target the relief of congestive symptoms and
intravenous loop diuretics are the mainstay of therapy.
The preferred IV vasoactive medication has yet to be
determined in a large prospective randomized trial. Positive inotropic agents should be reserved for patients with
signs of low cardiac output and tissue hypoperfusion,
however, the risk/benefit equation should be evaluated
judiciously with each treatment option before initiating
therapy. For patients with refractory hemodynamic collapse, ventricular assist devices can allow stabilization
until recovery or decision regarding transplantation
versus destination therapy. Patients with ADHF are at
increased risk for readmission to the hospital as well as
increased risk for death. Risk factors need to be identified and referral to a heart disease management program
should be considered for those patients deemed at increased risk for rehospitalization.
Corresponding author: Carlos E. Sanchez, MD, 3705
Olentanfy River Rd., Columbus, OH 43214, [email protected].
Financial disclosures: None.
Vol. 22, No. 4 April 2015 JCOM 189
Acute Decompensated Heart Failure
Author contributions: conception and design, CES; analysis
and interpretation of data, CES; drafting of article, CES;
critical revision of the article, CES, DRR; collection and
assembly of data, CES.
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