Management of Acute Decompensated Heart Failure in ... · Cardiogenic shock Evidence of tissue hypo-perfusion induced by HF after correction of preload and major arrhythmias Rapid

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AbstrAct• Objective: Toreviewthecurrent in-hospitalmanage-

ment of patients with acute decompensated heartfailure(ADHF).

• Methods:Reviewoftheliterature.• Results: Heart failure is a leading cause of hospi-

talization in theelderly,andmorbidity,mortality,andhospital readmission rates for ADHF remain high.The patient’s hemodynamic status along with theuse of prognostic models for short-term mortalitymay facilitate patient triage and encourage the useof evidence-based therapy, especially in high-riskpatients. Initial treatment should target the relief ofcongestivesymptoms,andintravenousloopdiureticsarethemainstayoftherapy.ThepreferredIVvasoac-tivemedicationhasyet tobedetermined ina largeprospectiverandomizedtrial.Positiveinotropicagentsshouldbereservedforpatientswithsignsoflowcar-diac output and tissue hypoperfusion; however, therisk/benefitequationshouldbeevaluated judiciouslywith each treatment option before initiating therapy.For patients with refractory hemodynamic collapse,ventricularassistdevicescanallowstabilizationuntilrecoveryordecisionregardingtransplantationversusdestinationtherapy.

• Conclusion:PatientswithADHFareatincreasedriskforreadmissiontothehospitalaswellasatincreasedriskfordeath.Riskfactorsneedtobeidentifiedandreferral to a heart disease management programshouldbe considered for thosepatients deemed atincreasedriskforrehospitalization.

Heart 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 decompen-sated 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

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 bil-lion 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 STUDYInitial Presentation

A 64-year-old woman with a nonischemic di-lated 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 exami-nation is remarkable for distended neck vein, S3 gallop, end expiratory wheezing in the bases, and lower extrem-ity 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 manage-ment.

• WhatareaspectsofinitialmanagementintheED?

Most patients that present for evaluation and manage-ment of ADHF are first evaluated in the ED. Initial man-agement includes an assessment of oxygenation, hemody-

Management of Acute Decompensated Heart Failure in Hospitalized PatientsCarlos E. Sanchez, MD, and David R. Richards, DO

Case-based review

From Ohio Health, Riverside Methodist Hospital, Columbus, OH.

180 JCOM April 2015 Vol. 22, No. 4 www.jcomjournal.com

Acute DecompensAteD HeArt FAilure

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, aggres-sive 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].

• HowarepatientswithADHFclassified?

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 di-agnosis 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

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 hypoper-fusion 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]. Specifi-cally, 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 hyperten-sion in patients with signs and symptoms of heart fail-ure, shock, and acutely worsening right heart failure (Table 1) [5].

Low

per

fusi

ona

tres

t?

Congestionatrest?

No

Warmanddry

Yes

Warmandwet

Coldanddry Coldandwet

No

Yes

Figure. 2×2tableofhemodynamicprofilesinpatientswithheartfailure.ReprintedfromNohriaA,LewisE,StevensonLW.Medicalmanagementofadvancedheartfailure.JAMA2002;287:628–40.

Evidence for Congestion (Elevated Filling Pressure)

Orthopnea AscitesHighjugularvenouspressure Rales(uncommon)IncreasingS3 AbdominalrefluxLoudP2 ValsalvasquarewaveEdema

Evidence for Low Perfusion

NarrowpulsepressurePulsusalterationsCoolforearmsandlegsMaybesleepy,obtundedACEinhibitor-relatedsymptomatic

hypotensionDecliningserumsodiumlevelWorseningrenalfunction


• Whatriskassessmenttoolsareavailable?

B-type natriuretic peptide (BNP) and N-terminal frag-ment 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 di-agnostic uncertainty and associated mismanagement of patients presenting with nonspecific symptoms of dysp-nea [4,5,7]. Low or normal levels (BNP < 100 pg/ml or NT-proBNP < 500 pg/ml) have a high negative pre-dictive value for excluding heart failure.

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 hospi-tal 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 pre-discharge BNP levels (BNP > 350 ng/l; P < 0.001) in pa-tients with ADHF seem to identify those at increased risk of death or readmission after in-patient management [9].

Case-based review

Table 1. ClinicalClassificationofHospitalizedPatientswithAcuteHeartFailureBasedonACCF/AHAGuidelines[5]andClinicalPresentationwithManagementConsiderations

Clinical Classification

Characteristics

Congestion

Sign and Symptoms of ADHF

Management Considerations Based on Clinical Presentation

Acutecoronaryischemiaandheartfailure

ADHFwithclinical,laboratoryand/orECGevidenceofacutecoronarysyndrome

Variable:Nonetopulmonarycongestionoracutepulmonaryedema

15%ofpatientswithACShavesymptomsofheartfailure

ADHFfrequentlyassoci-atedorprecipitatedbybradycardia,atrialfibrillation,andven-triculartachycardia

Coronaryangiography

Revascularization:PCI/CABG

Mechanicalcirculatorysupport

Treatarrhythmias

Evaluatesystolicanddiastolicventricularfunction,valvularfunctionormechanicalcompli-cationswithechocardiography

Acceleratedhyper-tensionwithacuteheartfailure

SignsandsymptomsofHFaccompaniedbyacceleratedhyper-tension

RelativelypreservedLVsystolicfunction

Lowhospitalmortality

Frequentpulmonarycongestion/acutepulmonaryedemawithoutsystemiccongestion

Euvolemicormildhy-pervolemic

Tachycardia

Hypertensionduetoincreasedsympathetictone(vasoconstriction)

Vasodilators

Diuretics:withvolumeoverloadorpulmonaryedema

Cardiogenicshock Evidenceoftissuehypo-perfusioninducedbyHFaftercorrectionofpreloadandmajorarrhythmias

Rapiddevelopmentofpulmonarycon-gestion/edema

SBP<90mmHgordropofMAP>30mmHg

Oliguria

Evidenceoforganhypoperfusion

Arrhythmiasarecommon

Positiveinotropes

Norepinephrineordopamine:IftheinotropesfailtorestoreSBPandsignsoforganhypo-perfusionpersist

Mechanicalcirculatorysupport

Intubation

Acuteisolatedrightheartfailure

Lowoutputsyndromeintheabsenceofpulmo-narycongestion

Nopulmonarycongestion

Peripheraledema

IncreasedJVP

± Hepatomegaly

Lowleftventricularfillingpressures

Avoidmechanicalventilation

Inotropes:withsignsoforganhypoperfusion

±Diuresis

EvaluatePEandRVmyocardialinfarctionasthecause

ADHF=acutedecompensatedheart failure;ACS=acutecoronarysyndrome;BP=bloodpressure;CABG=coronaryarterybypassgraft;ECG=electrocardiogram;HF=heart failure;JVP= jugularvenouspressure;LV= leftventricle;MAP=meanarterialpressure;PCI=percutaneouscoronaryintervention;PE=pulmonaryembolism;RV=rightventricle;SBP=systolicbloodpressure.



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

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, Fon-arow 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].

Table 2. In-hospitalMortalityPredictorModelsinPatientsPresentingwithADHF

Predictor Model

Number of Patients

Best Predictors for Mortality

Mortality Risk

Comments

AHAGetWiththeGuidelines-HeartFailure[12]

39,783 Olderage

SBP

BUN

In-hospitalmortalityratesvariedbydecilesrang-ingfrom0.4%to9.7%withapredictiveriskvariationof>24-foldacrossdeciles

Theprobabilityofin-hospitalmortalityisestimatedbysummingpointsassignedtothevalueofeachpredic-torwithavalidatedtoolforriskstratification.

ADHERE[13] 65,275

Derivationandvalidationcohort

BUN>43mg/dL

AdmissionSBP<115mmHg

Creatinine>2.75mg/dL

In-hospital:4.2% AdmissionSBP≥115mmHghadlowermortalityrisk

OPTIME-CHF[14]

949 HighBUN

NYHAclassIV

Increasingage(per10-yearincrease)

LowSBP

Lowserumsodium

60-daymortality:9.6% IncreasedSBPandserumsodiumhadlowermortality

EFFECT[15] 4031 Olderage

Respiratoryrate

Hyponatremia<136mEq/L

IncreasedBUN

Comorbidconditions(eg,dementia)

In-hospital:8.9%

30-day:10.7%

1-year:32.9%

HigherSBP(per10-unitincrease)hadlowermortality

Optimize-HF[16]

48,612 Serumcreatinine

AdmissionSBP

Patientsage

In-hospital:3.8% In-hospitalmortalityin-creased18%forevery0.3mg/dLincreaseinSCrupto3.5mg/dL

Every10-yearincreaseinagewasassociatedwitha34%higherriskforin-hospitalmortality

HigheradmissionSBPwasassociatedwithalowerriskofin-hospitalmortality(upto160mmHg)

AHA=AmericanHeartAssociation;BUN=bloodureanitrogen;NYHA=NewYorkHeartAssociation;SBP=systolicbloodpressure;SCr=serumcreatinine.(Modifiedfromreference50.)


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 impor-tance 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.

CaseContinued

Upon further evaluation by a cardiologist, the patient is cool and clammy with elevated neck

veins and prominent S3 confirmed. She continues to re-port 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 in-hospital 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 per-fusion. Enoxoparin 40 mg subcutaneously once daily was initiated for venous thromboembolism prophylaxis.

• What are important aspects of therapy forADHF?

Several days to weeks prior to the appearance of signs and symptoms of volume overload, patients may develop he-modynamic congestion, defined as an elevation of ventric-ular filling pressure/pulmonary capillary wedge pressure independent of clinical evidence of fluid overload [17].

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 condi-tions (Table 3) and treating them appropriately in con-junction with volume overload [5]. Echocardiogram is a widespread and readily available diagnostic tool provid-ing important information on systolic and diastolic ven-tricular function as well as other structural heart disease abnormalities. Additionally, myocardial ischemia evalua-tion with noninvasive testing or cardiac catheterization should be performed if ischemia is a potential contributor to the patient’s heart failure symptoms. The most com-mon 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 iden-tify barriers to appropriate self-management.

Although use of vasoactive medications such as nitro-glycerin 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 pro-cedures, and prolonged hospitalizations when IV diuretics, vasodilators (nitroglycerin, nitroprusside, nesiritide,) and/or positive inotropes (milrinone, dobutamine) are initi-ated in the ED within 6 hours of an ADHF presentation [18,19]. However, whether prompt ED intervention im-pacts 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 pro-phylaxis 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.

• Whattreatmentsareusedtorelievecongestion?

Diuresis

In patients admitted to the hospital with ADHF, initial effective diuresis is vital to lowering cardiac filling pres-

Case-based review



sures and relieving symptoms of congestion. Intravenous loop diuretics represent the first line of treatment and have long been the mainstay of therapy for decompensat-ed heart failure with preserved or reduced ejection frac-tion, 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. Medica-tion dosage sufficient to produce a rate of diuresis that will optimize volume status and relieve signs and symp-toms of congestion without causing kidney injury or hy-potension is recommended [5]. Due to the relatively short half-life of loop diuretics and concerns about tubular so-dium reabsorption in the kidneys, continuous IV diuretic infusion has been suggested to enhance diuresis and

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 Evalu-ation (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 compos-ite 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 previ-ously 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 di-agnosis 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 maxi-mum 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 alternat-ing 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 infu-sion doses (1–3 mcg/min) directly activates dopaminergic receptors in the kidney promoting renal vasodilatation. This vasodilatory effect augments renal blood flow lead-ing to an increase in urine output. This theoretical ef-fect, however, has not translated into improved clinical outcomes in patients with ADHF. The recent Renal Optimization Strategies Evaluation in Acute Heart Failure

Table 3. PrecipitatingFactorsinAcuteDecompensatedHeartFailure

Dietarynoncompliance(excessivesodiumandwaterintake)

Medicationnoncompliance,includinglackofaccesstomedications

Iatrogenicvolumeoverload

Unwarrantedvolumereplacement

Majorsurgery

Progressivecardiacdysfunction

Worseningunderlyingdisease

Alcoholabuse,cocaine

Valvularheartdisease(stenosisorregurgitation)

Atrialfibrillationwithrapidventricularresponse

Ventriculartachyarrhythmias

Bradyarrhythmias

Uncontrolledhypertension

Acutecoronarysyndrome

Myocardialdysfunctionfromrightventricularpacing

Pulmonarydisease

Chronicobstructivepulmonarydisease

Obstructivesleepapnea

Pulmonaryembolism

Anemia

Hyper-orhypothyroidism

Medicationrelated

Pioglitazoneorrosiglitazone

Non-steroidalanti-inflamatorydrugs

Tricyclicantidepressants(increaseriskofventriculararrhythmia)

Theophylline

B-agonistbronchodilators(inducetachyarrhythmia)

Calciumchannelblockers

Bladderoutletobstruction

Adaptedfromreference5.


(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 unre-sponsive to diuretic therapy, peripheral ultrafiltration may be considered. Initial data demonstrated that early

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

Case-based review

Table 4. MedicationsUsedintheManagementofADHF

Drug Initial Dose Maximum Single Dose Intravenous Infusion

Loop Diuretics*Bumetanide 1.0mgIV 4to8mgIV 1mgIVloadthen0.5–2mg/hour

Furosemide 40mgIV 160to200mgIV 40mgIVloadthen10to40mg/hour

Torsemide 10mgIV 100to200mgIV 20mgIVloadthen5to20mg/hour

Thiazide Diuretics – Add to Loop Diuretic

Metolazone 2.5mgoralonceortwicedaily

5mgoralonceortwicedaily

Chlorthiazide 500mgIVonceortwicedaily

1000mgIVonceortwicedaily

Chlortalidone 12.5to25mgoncedaily

100mgoncedaily

Hydrochlorothiazide 25mgoralonceortwicedaily

100mgoralonceortwicedaily

Intravenous Vasodilators

Nitroglycerin 20–30mcg/minIV >100mcg/min 10to>100mcg/min

Closemonitoringwithhighdoses

Nitroprusside 10–20mcg/min 300mcg/min

Rarelyrequiredandincreasesriskoftoxicity

10to300mcg/min

Maybeincreasedby20mcg/min

Niseritide 0.01mcg/kg/min 0.03mcg/kg/min 0.01to0.03mcg/kg/min

Maybeincreasedby0.005mcg/kg/mintoachievedesiredhemodynamiceffects

Intravenous Inotropic Agents

Dopamine 1-3mcg/kg/min 20mcg/kgmin 1–3mcg/kg/minactivatesdopaminergicrecep-torscausingvasodilatation.

3–8mcg/kg/minexertspositivechronotropicandinotropiceffects.

5–20mcg/kg/minresultsinvasoconstriction.

Dobutamine 2mcg/kg/min 20mcg/kg/min 2to20mcg/kg/mintitratetodesiredresponseby1–2mcg/kg/min

Milrinone 0.25mcg/kg/min 0.75mcg/kg/min 0.25to0.75mcg/kg/min

IV=intravenous.

*Loopdiureticsequivalentdose:Oral–1mgbumetanide=20torsemide=80mgfurosemide;IV–1mgbumetanide=20torsemide=40mgfurosemide.



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 sur-vival benefit [29]. However, the more recent Cardiorenal Rescue Study in ADHF (CARRESS-HF) trial involv-ing 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, ultrafiltra-tion 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 op-tion if all diuretic strategies are unsuccessful in relieving congestion [5].

Vasopressin-ReceptorAntagonists

The vasopressin-receptor antagonists represent a relatively new class of medications that target the vasopressin recep-tors V1a and V2. Activation of the vasopressin V2 receptors by arginine vasopressin in heart failure causes inappropri-ate 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 hos-pitalization for heart failure [32,33]. However, hyponatre-mia, 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, vaso-pressin 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].

CaseContinued

After 24 hours of medical therapy in the CCU, the patient is no longer clammy and cool but con-

tinues to have shortness of breath, and peripheral edema

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 morn-ing 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 roleofvasoactivemedications intreatment?

Vasodilators

Nitroglycerin is a venodilating medication with preload reduction properties at low doses and an arterial dila-tor 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 prepa-rations 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 nitro-glycerin in up to 20% of patients, and hypotension, which may occur before significant preload reduction effect can be obtained [37]. When symptomatic hypo-tension becomes a problem, the highest hemodynami-cally 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 preload- and afterload-reducing effect [35]. Afterload reduc-tion through its arteriodilator effect has the benefit of increasing cardiac output and decreasing myocardial oxygen demand with improvement of pulmonary con-gestion [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 in-


fusions, especially in patients with reduced hepatic per-fusion 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 care-fully 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 increas-ing the bioavailability of nitric oxide through stimulation of cyclic guanosine monophosphate. Its primary mecha-nism 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 (Vasodila-tion in the Management of Acute Congestive Heart Fail-ure) 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 improve-ment 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, all-cause 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 admit-ted 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 va-sodilators such as nitroglycerin or nitroprusside may be preferred by many clinicians.

Overall, vasodilators represent a good treatment op-tion for patients presenting with ADHF characterized by

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].

InotropicTherapy

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 adreno-receptor 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, inotro-pic 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 inotro-pic 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 intracel-lular cyclic AMP to exert its positive inotropic effect on the myocardium. Milrinone also exerts systemic and pulmonary vasodilator effects in the circulation decreas-ing 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 ven-tricular 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 adr-enoreceptor agonist that works by increasing myo-cardial contractility leading to an increase in cardiac output as its primary cardiovascular effect. Currently, routine use of IV positive inotropic agents in the ab-sence of imminent cardiogenic shock or low output ADHF with systemic hypoperfusion is generally not recommended due to concerns of adverse effects [5]. The

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ACCF/AHA guidelines recommend the use of posi-tive 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 dys-function (such as hypotension, altered mentation, cool extremities, low urine output and serum markers indica-tive 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].

• Istherearoleformorphine?

For decades morphine has been considered an essential component in the armamentarium for the treatment of ADHF. Its preload-reducing effect, anti-anxiety proper-ties, 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 me-chanical ventilation, prolonged hospitalization, increased intensive care unit admissions, and higher mortality, bringing into question its safety profile [46]. Until a ran-domized trial is completed demonstrating safety and ben-efit, caution is advised regarding the use of morphine in ADHF.

CaseContinued

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 dis-continued, dobutamine was weaned off, and the patient was transitioned to guideline-directed medical therapy with an angiotensin-converting enzyme (ACE) inhibitor

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.

• WhenismechanicalcirculatorysupportindicatedinADHFpatients?

Mechanical circulatory support has emerged as a reason-able 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 car-diogenic 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 com-plications. Therefore, when patients present with severe acute cardiogenic shock refractory to medical therapy, mechanical circulatory support with either ventricular as-sist devices (VAD) or extracorporeal membrane oxygen-ation (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 sta-tus are still uncertain [48,49]. There are several options currently available for mechanical circulatory support, including surgically implanted VADs or the percutane-ously implanted VADs, such as the Impella 2.5, 3.5 and 5.0 (Abiomed, Danvers, MA) and the TandemHeart


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].

• Whatelementsofcaremayhelpoptimizethedischargeprocess?

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 in-patient 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 read-mission include patients with renal insufficiency, low output state, diabetes mellitus, chronic lung disease, persistent NYHA functional class III, IV symptoms, frequent hospitalizations, multiple comorbidities, his-tory 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 improv-ing 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 writ-ten 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].

CaseConclusion

The patient tolerated well the initiation of guideline-directed medical therapy and is con-

tinued on the ACE inhibitor and beta-blocker medica-tions. 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 rein-forced, 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 en-countered and often initially managed in the ED. Initial history and physical examination are important to esti-mate 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. Posi-tive 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 col-lapse, 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 identi-fied and referral to a heart disease management program should be considered for those patients deemed at in-creased risk for rehospitalization.

Corresponding author: Carlos E. Sanchez, MD, 3705 Olentanfy River Rd., Columbus, OH 43214, [email protected].

Financial disclosures: None.

Case-based review



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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