PHM 601 Heart Failure Lecture Slides

7/27/2019 PHM 601 Heart Failure Lecture Slides

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Heart Failure

Nicholas B. Norgard, PharmD, BCPSUniversity at Buffalo SoPPs


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Heart Failure...It is an Epidemic

Estimated that over 6 million Americans have heart failure

Estimated 500,000 new cases per year- Prevalence of HF has grown by 500% over the last 30 years

- 85% of new cases in patients over 65 years

Number one reason for hospital admissions in the US- Over 1 million hospitalizations per year with HF as primary diagnosis

High readmission rate:- 20% within one month

- 50% within six months

- 17% are readmitted two or more times

Significant cause of mortality:- Approximately 20% of HF patients die within one year of diagnosis

- 50% die within five years of diagnosis

1

Centers for Medicare and Medicaid Services. 2000 MedPAR data. DRG 127.2 Fonarow, GC. Rev Cardiovasc Med. 2002;3(suppl 4):S3.3 Krumholz HM et al. Readmission after Hospitalization for Congestive Heart Failure Among Medicare Beneficiaries. Archives of Internal Medicine, 1997 Jan 13; 157(1): 99-1-4.4 Heart Disease and Stroke Statistics 2004 Update. American Heart Association and American Stroke Association, 2004.


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Heart Failure...It is an Epidemic

Estimated that over 6 million Americans have heart failure

Estimated 500,000 new cases per year- Prevalence of HF has grown by 500% over the last 30 years

- 85% of new cases in patients over 65 years

Number one reason for hospital admissions in the US- Over 1 million hospitalizations per year with HF as primary diagnosis

High readmission rate:- 20% within one month

- 50% within six months

- 17% are readmitted two or more times

Significant cause of mortality:- Approximately 20% of HF patients die within one year of diagnosis

- 50% die within five years of diagnosis

1

Centers for Medicare and Medicaid Services. 2000 MedPAR data. DRG 127.2 Fonarow, GC. Rev Cardiovasc Med. 2002;3(suppl 4):S3.3 Krumholz HM et al. Readmission after Hospitalization for Congestive Heart Failure Among Medicare Beneficiaries. Archives of Internal Medicine, 1997 Jan 13; 157(1): 99-1-4.4 Heart Disease and Stroke Statistics 2004 Update. American Heart Association and American Stroke Association, 2004.


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Who will take care of

the heart failure patients? 2007 HF hospital discharges: 990,000

2007 HF office visits: 3,434,000 83% hospitalized once

43% hospitalized at least 4 times

2010 internists, and generalists: 50,070

2010 physicians and surgeons: 293,740

2010 cardiologists: 20,000


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Heart failure is a complex clinical syndromethat can result from any structural or

functional cardiac disorder that impairs theability of the ventricle to fill with or eject blood(i.e. heart failure is a disorder of impairedcardiac output)

Heart Failure:Definition


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HF is defined as a clinical syndrome that is characterized by specificsymptoms (dyspnea and fatigue) in the medical history and signs(edema, rales) on the physical examination.

There is no single diagnostic test for HF because it is largely a clinicaldiagnosis that is based on a careful history and physical examination.

Ways to define HF:

1. Based on ejection fraction

Heart failure with reduced ejection fraction (HFREF)

- HF symptoms and ejection fraction less than 40%

Heart failure with preserved ejection fraction (HFPEF)- HF symptoms and ejection fraction greater than 40%

2. Ischemic or nonischemic origin

CAD is most common cause of HF3. Based on HF etiology



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Ways to define HF:









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Ways to define HF:









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Each time the heart beats, a volume of blood is ejected. Thisstroke volume (SV), times the number of beats per minute (heartrate, HR), equals the cardiac output (CO).

- CO = SV HR Ventricular stroke volume is the difference between the

ventricular end-diastolic volume (EDV) and the end-systolicvolume (ESV).

- SV = EDV - ESV The EDV is the filled volume of the ventricle prior to

contraction

The ESV is the residual volume of blood remaining in theventricle after ejection

Heart Failure:Hemodynamics


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CO = (EDV - ESV) HR



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CO = (EDV - ESV) HR

Normal



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CO = (EDV - ESV) HR

Diastolic dysfunction -Impaired ventricular fillingPrimary abnormality inheart failure with preserved

ejection fraction (HFPEF)



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CO = (EDV - ESV) HR

Systolic dysfunction -Impaired ventricular emptyingAbnormality seen in heartfailure with reduced ejection

fraction (HFREF)



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Three determinants ofstroke volume:

1.Afterload2.Preload3.Contractility

CO = (EDV - ESV) HR


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Heart Failure Hemodynamics


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Contractility is difficult tomeasure but isreasonably reflected by

the ejection fraction (EF)

Ejection Fraction -percentage of end-diastolic volume ejected

with each contraction

- (stroke volumeend-diastolic volume)

Ejection Fraction cangenerally be adequatelyassessed noninvasively

with echocardiography.


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StrokeVolume

Afterload

Systemic Vascular resistance

Severe LVdysfunction

Mild LVdysfunction

Normal LVdysfunction

StrokeVolume

Afterload

Systemic Vascular resistance


Mild LVdysfunction

Normal LVdysfunction

Afterload - the forceresisting myocardial fibercontraction at the start ofsystole

It is determined bychamber pressure,volume, and wall thicknessat the time the aortic valveopens

Clinically, systolic BPrepresents peak systolicwall stress andapproximates afterload


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Preload

(End-diastolic volume)

StrokeV

olume Normal


Mild LVdysfunction

Preload


StrokeV

olume Normal


Mild LVdysfunction

Frank-Starling Mechanism -describes the relationshipbetween preload and cardiacperformance.

Strength of ventricular contractionis increased, the more theventricle is stretched prior to

contraction

If venous return is increased, theventricular end-diastolic pressureand volume of the ventricle areincreased, which stretches thesarcomeres (increases their

preload).

Increased preload increasesstroke volume (or decreasedpreload decreases stroke volume)which alters the force of cardiacmuscle contraction.


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Preload


StrokeV

olume Normal


Mild LVdysfunction

Preload


StrokeV

olume Normal


Mild LVdysfunction

Frank-Starling Mechanism -describes the relationshipbetween preload and cardiacperformance.

Strength of ventricular contractionis increased, the more theventricle is stretched prior to

contraction

If venous return is increased, theventricular end-diastolic pressureand volume of the ventricle areincreased, which stretches thesarcomeres (increases theirpreload

).

Increased preload increasesstroke volume (or decreasedpreload decreases stroke volume)which alters the force of cardiacmuscle contraction.

Congestion

*The heart needs a certain amount of preload (fluid from the venous system) to operate at peak efficiency. Too littlefluid and the heart fails, too much fluid and it gets backed up into the pulmonary systems (pulmonary edema).


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Heart Failure...It is a Progressive Disorder

Cardiac dysfunction precipitates

changes in vascular function, blood

volume, and neurohumoral status.

Compensatory mechanisms activate:

- Tachycardia and increasedcontractility

- Frank-Starling mechanism -increase in preload results in an

increase in stroke volume

- Vasoconstriction- Ventricular hypertrophy and

remodeling

These compensatory changes over

months and years can worsen

cardiac function

Sympathetic nervous system (SNS)Renin-Angiotensin-Aldosterone system (RAAS)


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Heart Failure...It is a Progressive Disorder


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AHA HF Classification

HF A d Cl ifi i


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Stage A

Patients with risk factors for thedevelopment of structural heartdisease or overt HF

Stage BPresence of structural heartdisease (e.g. MI, LV dysfunction, or

valvular disease) without HFsymptoms

Stage CPatients with structural heartdisease and current or prior HFsymptoms

Stage DHF refractory to conventionaltreatment requiring ventricularassist device, transplantation, orpalliative care

Class INo symptoms

Class IISymptoms with moderate exertion

Class IIISymptoms with minimal exertion

Class IVSymptoms at rest

AHA Prognostic Classification NYHA Symptomatic Classification

HF Assessment and Classification


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Diagnosis of Heart Failure

Major criteria:

Paroxysmal nocturnaldyspnea

Neck vein distention Rales

Radiographic cardiomegaly(increasing heart size onchest radiography)

Acute pulmonary edema S3 gallop Increased central venous

pressure Hepatojugular reflux Weight loss >4.5 kg in 5 days

in response to treatment

Minor criteria:

Bilateral ankle edema Nocturnal cough Dyspnea on exertion Hepatomegaly

Pleural effusion Decrease in vital capacity byone third from maximumrecorded

Tachycardia (HR>120 bpm)

Minor criteria are acceptable only ifthey can not be attributed toanother medical condition (such aspulmonary hypertension, chroniclung disease, cirrhosis, or ascites).

Diagnosis of HF requires the simultaneous presence of at least 2 major

criteria or 1 major criterion in conjunction with 2 minor criteria

McKee PA, et al. N Engl J Med. 1971;285(26):1441-6


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Brain Natriuretic Peptide (BNP)

Patient presenting with Dyspnea

Physical ExamECG

Chest X-Ray

BNP < 100 pg/mlNT-proBNP < 300 pg/ml

BNP 100-500 pg/mlNT-proBNP 300-1800 pg/ml

BNP > 500 pg/mlNT-proBNP > 1800 pg/ml

Unlikely Heart FailureRule Out:

Pulmonary embolism, renalfailure, or pulmonary HTN

Likely Heart Failure


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Time progression paradigm of

chronic heart failure

T Al i h f H F il i h


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Treatment Algorithm for Heart Failure with

Reduced Ejection Fraction

McMurray J. N Engl J Med 2010;362:228-238

Diuretic + ACE inhibitor (or ARB) + Beta-blocker

Persisting signs and symptoms?

Add aldosterone antagonist;In blacks, add hydralazine-isosorbide dinitrate

Persistingsymptoms?

Considerdigoxin, LVAD,

transplant

Consider implantablecardioverter-defibrillator

No furthertreatment required

QRS >120 msec?

Consider CardiacResynchronization

Therapy Defibrillator

Yes

Yes

Yes No

LVEF


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Pathophysiological Mechanism of Heart Failure

Reduced cardiac output


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Sympathetic nervoussystem activationRenin


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Sympathetic nervoussystem activation

Vasoconstriction

Renin

Angiotensin I

Angiotensin II

Aldosterone


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Vasoconstriction

Renin

Angiotensin I

Angiotensin II

Aldosterone

Elevated cardiac wall tension


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Vasoconstriction

Renin

Angiotensin I

Angiotensin II

Aldosterone


Sodium and water retention


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Vasoconstriction

Renin

Angiotensin I

Angiotensin II

Aldosterone

CardiacRemodeling




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Heart Failure



Vasoconstriction

Renin

Angiotensin I

Angiotensin II

Aldosterone

CardiacRemodeling




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Heart Failure



Vasoconstriction

Renin

Angiotensin I

Angiotensin II

Aldosterone

CardiacRemodeling



Beta-blockers

Beta-blockers

VasodilatingBeta-blockers


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Effects of sympathetic activation in chronic

heart failure


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Beta Blockers

Cornerstone of pharmacotherapy for patients withheart failure

Beta-blockade is recommended in all patients withsymptomatic HF and an EF 40%

Beta-blockade improves LV function, patient well-being, reduces hospital admission for worsening HF

and increases survival

In hospitalized patients, treatment should be initiatedbefore discharge


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Poole-Wilson PA, et al. Lancet. 2003;362:7-13.

Comparison of carvedilol and metoprolol on clinical outcomes in

patients with chronic heart failure in the Carvedilol Or MetoprololEuropean Trial (COMET)

Beta Blockers

HR 0.83 [95% CI 0.74-0.93],P

= 0.0017

0 1 2 3 4 50

10

20

30

40 Metoprolol TartrateCarvedilol

Time (Years)

Mortality(%

)


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Poole-Wilson PA, et al. Lancet. 2003;362:7-13.

Comparison of carvedilol and metoprolol on clinical outcomes in

patients with chronic heart failure in the Carvedilol Or MetoprololEuropean Trial (COMET)

Beta Blockers

HR 0.83 [95% CI 0.74-0.93],P

= 0.0017

0 1 2 3 4 50

10

20

30

40 Metoprolol TartrateCarvedilol

Time (Years)

Mortality(%

)

Beta-Blockers:


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Initiate as soon as clinically stable Begin with low doses and titrate slowly

- Increase dose by 50-100% every 2 4weeks Can be done more rapidly in hospital settings

- Prior to dose titration monitor heart rate,blood pressure, pulse, fluid status andcongestion

Beta-Blockers:Dose Titration

Drug Initiation Dose Target Dose

Carvedilol 3.125 mg bid 25 mg bid

Metoprolol XL 12.5 mg daily 200 mg daily

Bisoprolol 1.25 mg daily 10 mg daily

Beta-Blockers:


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Patients with mild congestion- Maintain current beta-blocker dose

Patients with moderate to severe congestion- Increase diuretic dose, or- Reduce beta-blocker dose by 50%

In the absence of symptoms continueincreasing to maximum dose

Instruct patients that they may initially feelworse, but this should improve over time




Metoprolol XL 12.5 mg daily 200 mg dailyBisoprolol 1.25 mg daily 10 mg daily


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Beta-Blockers:


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Patients with mild congestion- Maintain current beta-blocker dose

Patients with moderate to severe congestion- Increase diuretic dose, or- Reduce beta-blocker dose by 50%

In the absence of symptoms continueincreasing to maximum dose

Instruct patients that they may initially feelworse, but this should improve over time




Metoprolol XL 12.5 mg daily 200 mg dailyBisoprolol 1.25 mg daily 10 mg daily


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Heart Failure


Sympathetic nervous

system activation

Vasoconstriction

Renin

Angiotensin I

Angiotensin II

Aldosterone

CardiacRemodeling



Beta-blockers

ACE inhibitorsBeta-blockers

Vasodilating

Beta-blockers


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Renin-Angiotensin-Aldosterone System Blockade

AT1 receptor

Ang I

Biologicaleffects

ACE

Non ACE pathways

Reninenzyme

Aldosterone

Retention ofwater and

salt

Ang = Angiotensin.ACE = Angiotensin converting enzyme.

AT1 = Angiotensin II Type 1.

Adapted from: Mller & Luft. Clin J Am Soc Nephrol. 2006;1:2218.

Excretionof

potassium

Ang II

Angiotensinogen


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AT1 receptor

Ang I

Biologicaleffects

ACE

Non ACE pathways

Reninenzyme

Aldosterone


salt




Excretionof

potassium

Ang II

Angiotensinogen


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AT1 receptor

Ang I

Biologicaleffects

ACE

Non ACE pathways

Reninenzyme

Aldosterone


salt




Excretionof

potassium

Ang II

Angiotensinogen

ACE Inhibitor


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ACE Inhibitors


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ACE Inhibitors Cornerstone of pharmacotherapy for patients with heart failure

An ACE inhibitor is recommended in all patients with symptomatic HFand an EF 40%

Treatment with an ACE inhibitor improves LV function, patient well-being, reduces hospital admission for worsening HF and increases

survival

In hospitalized patients, treatment should be initiated beforedischarge

FIGURE 2. Angiotensin-converting enzyme inhibitor mortality trials:

CONSENUS (enalapril)31

SAVE (captopril)32

SOLVD (enalapril )33

AIRE (ramipril)34

11 0.25 0.5 0.75 1.25 1.5 1.75 2.0

31% P=.001

19% P=.19

16% P=.0014

27% P=.002

Relative risk reductions and 95% condence intervals


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Aim for dose shown to reduce mortality inclinical trials

Monitor SCr and K+ before and 1-2 weeksafter initiation and then every 3-6 months

Symptomatic hypotension and renaldysfunction typically seen in patients who arevolume depleted from diuretics

ACE Inhibitors

Drug Initiation Target Maximum

Enalapril 5 mg BID 10 mg BID 20 mg BID

Lisinopril 5 mg daily 20 mg daily 40 mg daily

Captopril 25 mg TID 50 mg TID 100 mg QID

Quinapril 10 mg BID 20 mg BID 40 mg BID

Benazepril 10 mg daily 40 mg daily 80 mg daily

Ramipril 5 mg daily 10 mg daily 20 mg daily


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Heart Failure


Sympathetic nervous

system activation

Vasoconstriction

Renin

Angiotensin I

Angiotensin II

Aldosterone

CardiacRemodeling



Beta-blockers

ACE inhibitors

ARBARB

Beta-blockers

VasodilatingBeta-blockers


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AT1 receptor

Ang I

Biologicaleffects

ACE

Non ACE pathways

Reninenzyme

Aldosterone


salt




Excretionof

potassium

Ang II

Angiotensinogen

ACE Inhibitor

Non ACE pathways can takeover Angiotensin IIproduction after ACE inhibitor is initiated

Some patients have Angiotensin II levels returnto normal ~ 6months after ACE inhibitor started


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AT1 receptor

Ang I

Biologicaleffects

ACE

Non ACE pathways

Reninenzyme

Aldosterone


salt




Excretionof

potassium

Ang II

Angiotensinogen

ACE Inhibitor

ARB

Non ACE pathways can takeover Angiotensin IIproduction after ACE inhibitor is initiated

Some patients have Angiotensin II levels returnto normal ~ 6months after ACE inhibitor started


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Generic/ BrandName

Initial Dose Target Dose

Losartan/

Cozaar

12.5 mg/day 50 100 mg/day

Valsartan/Diovan

80 mg/day 160 mg BID

Candasartan/Antacand

4 mg/day 32 mg/day

Angiotensin Receptor Blockers (ARBs)

An ARB is recommended in patients withHF and EF 40% who:- Are intolerant to ACE inhibitors

-Remain symptomatic despite optimal ACE inhibitortherapy (not a strong recommendation)


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Generic/ BrandName


Losartan/

Cozaar


Valsartan/Diovan



4 mg/day 32 mg/day





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Generic/ BrandName


Losartan/

Cozaar


Valsartan/Diovan



4 mg/day 32 mg/day





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Heart Failure


Sympathetic nervous

system activation

Vasoconstriction

Renin

Angiotensin I

Angiotensin II

Aldosterone

CardiacRemodeling



Beta-blockers

ACE inhibitors

ARBARB

Beta-blockers

VasodilatingBeta-blockers Diuretics


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Diuretics

Should be prescribed to all HF patients who haveevidence of fluid retention Used to restore and maintain normal volume status

(sodium and water balance)- Enhance urinary sodium excretion

- Few patients can maintain proper sodium balance without diuretics

Reduce End-Diastolic Volume (preload) Diuretics improve symptoms and exercise tolerance in

HF patients

- Produce symptomatic benefits more rapidly than any other drug for HF- Relieve pulmonary and peripheral edema within hours or days- Diuretics alone are unable to maintain the clinical stability of HF

patients for long periods of time


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Diuretics

Should be prescribed to all HF patients who haveevidence of fluid retention Used to restore and maintain normal volume status

(sodium and water balance)- Enhance urinary sodium excretion

- Few patients can maintain proper sodium balance without diuretics

Reduce End-Diastolic Volume (preload) Diuretics improve symptoms and exercise tolerance in

HF patients

- Produce symptomatic benefits more rapidly than any other drug for HF- Relieve pulmonary and peripheral edema within hours or days- Diuretics alone are unable to maintain the clinical stability of HF

patients for long periods of time


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Diuretics


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Diuretics


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Diuretics

Diuretics:


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Optimal use of diuretics is the cornerstone of a successful HF treatmentregimen

Loop diuretics > thiazides- If a patient does not response adequately to a loop, a thiazide can be added on

Initial use:- Start at low dose and titrate to effect- Once a diuretic effect is achieved with loop diuretic, increase frequency to 2-3 times a

day if necessary, rather than increasing a single dose.- Titrate dose and frequency until urine output increases and weight decreases

(generally by 0.5 to 1.0 kg daily)

- Keep output > input until patient reaches dry weight- Then back off dose and frequency to keep output = input- Have patients monitor their weight every day on the same scale

If weight goes up >2 pounds instruct patients to take an extra diuretic dose

Under diuresis can lead to fluid retention, which can increase symptomsand need for hospitalization

Over diuresis can lead to electrolyte abnormalies and volume contraction,

which can increase the risk of hypotension and renal insufficiency with

ACEIs and ARBs

Diuretics:More art than science

Diuretics:


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ACEIs and ARBs


Diuretics:


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ACEIs and ARBs


Diuretics:


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Furosemide Bumetanide Torsemide Ethacrynic Acid

Equivalent intravenous doses 2040 mg 1 mg 20 mg 50 mg

Initial daily dose 2040 mg/day ortwice daily

0.51 mg/day ortwice daily

10 20 mg/day 25 50 mg/day ortwice daily

Maximum daily dosage 600 mg 10 mg 200 mg 200 mg

Duration of action 46 hours 68 hours 1216 hours 6 hours

Half-life ~ 2 hours 11 hours 24 hours 14 hours

Bioavailability 40%70% 80%95% 80%90% 100%

Intravenous-to-oral conversion 1:2 1:1 1:1 1:1

Information from Lindenfeld J, Albert NM, Boehmer JP, et al. Heart Failure Society of America 2010 comprehensive heart failure practiceguidelines. J Card Fail 2010;16:e1-e194.


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Under Diuresis

J.B. is a 54-year-old African-American man with dilated cardiomyopathy (ejectionfraction of 25% on echocardiogram 1 year ago) being seen in the clinic today with a7-day history ofdyspnea on exertion and increased lower extremity andabdominal swelling. J.B. has no other complaints. His weight has increasedfrom baseline (185 pounds) to 197 pounds. On physical examination, J.B.,routinely New York Heart Association (NYHA) class II heart failure, reports

symptoms with minimal exertion over the past week.

Vital signs are as follows blood pressure 142/62 mm Hg and heart rate 85 beats/minute. He has an S3 gallop,jugular venous distention, ascites, and 3+ pittingedema bilaterally. An electrocardiogram showed normal sinus rhythm at 80 beats/minute and QRS is 110 msec. Laboratory values include sodium 142 mmol/L,potassium 5.0 mmol/L, blood urea nitrogen 26 mg/dL, and creatinine 0.9 mg/dL.

J.B.s medical history is significant for uncontrolled hypertension and osteoarthritis.His drugs include lisinopril 20 mg/day and carvedilol 6.25 mg twice daily. J.B.recently began taking naproxen 220 mg 3 times/day for arthritic pain.


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Over Diuresis

B.S. is a 48-year-old woman, with a history of idiopathic dilatedcardiomyopathy. While in the hospital for decompensated HF,she continued her chronic drugs (lisinopril 20 mg/day andcarvedilol 25 mg twice daily) and also received intravenousfurosemide and oral metolazone. She has lost 5.5 kg since her

hospital admission 3 days ago. You notice that herblood ureanitrogen concentration has increased to 61 mg/dL andserum creatinine concentration to 2.5 mg/dL (blood ureanitrogen 23 mg/dL, and creatinine 1.1 mg/dL on admission).B.S.s vital signs are BP 86/60 mm Hg and HR 90 beats/

minute while supine. She has orthostatic BP changes withstanding.



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Persistingsymptoms?


transplant



QRS >120 msec?



Yes

Yes

Yes No

LVEF


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Heart Failure


Sympathetic nervous

system activation

Vasoconstriction

Renin

Angiotensin I

Angiotensin II

Aldosterone

CardiacRemodeling



Beta-blockers

ACE inhibitors

Aldosterone Antagonists

ARB

ARB

Beta-blockers

VasodilatingBeta-blockers Diuretics


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AT1 receptor

Ang I

Biologicaleffects

ACE

Non ACE pathways

Reninenzyme

Aldosterone


salt




Excretionof

potassium

Ang II

Angiotensinogen

ACE Inhibitor

ARB


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AT1 receptor

Ang I

Biologicaleffects

ACE

Non ACE pathways

Reninenzyme

Aldosterone


salt




Excretionof

potassium

Ang II

Angiotensinogen

ACE Inhibitor

ARB


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AT1 receptor

Ang I

Biologicaleffects

ACE

Non ACE pathways

Reninenzyme

Aldosterone


salt




Excretionof

potassium

Ang II

Angiotensinogen

ACE Inhibitor

ARB

Aldosterone Antagonist

Aldosterone Antagonists:


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Aldosterone Antagonists:Spironolactone and Eplerenone

Add an aldosterone antagonist tobackground ACE inhibitor and beta-blocker therapy in patients withsymptomatic HF (NYHA class II-IV) andan EF 40%

Aldosterone antagonists arecontraindicated in patients with:

- Potassium >5.0 mEq/L- CrCl 2.5 mg/dL)

It is recommended that renal function

and potassium be measured atbaseline, then 1 week, 1 month, andevery 3 months

Zannad F, et al. N Engl J Med2011;364:1121.

Drug Initiation Target

Spironolactone 6.25 or 12.5 mg daily 25 mg daily

Eplerenone 12.5 or 25 mg daily 50 mg daily


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Heart Failure


Sympathetic nervous

system activation

Vasoconstriction

Renin

Angiotensin I

Angiotensin II

Aldosterone

CardiacRemodeling



Beta-blockers

ACE inhibitors

Aldosterone Antagonists

ARB

ARB

Beta-blockers

Hydralazine/IsosorbideVasodilating

Beta-blockers Diuretics


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Hydralazine/Isosorbide dinitrate

Isosorbide dinitrate- venodilation and reductions in preload- increase in nitric oxide bioavailability secondary to

nitric oxide donation

Hydralazine- arterial dilation to reduce afterload and increasestroke volume and cardiac output

- increase in nitric oxide bioavailability secondary toreduction in oxidative stress

Nitric oxide attenuates myocardial remodeling andmay play a protective role in heart failure.


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Cohn JN, et al. N Engl J Med. 1991;325(5):303310.

ACE inhibitors have a reduction in mortality Hydralazine/isosorbide dinitrate improvesexercise capacity

Hydralazine/isosorbide dinitrate vs ACE inhibitors in treatment of

HF with reduced EF

Hydralazine/Isosorbide dinitrate:


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Hydralazine/Isosorbide dinitrate:A Racist Drug?

White patients:- HF more likely secondary to CAD

and the activation ofneurohormonal mechanisms

Black patients:- HF more likely secondary to

hypertension related to avascular deficiency of nitric oxide


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Recommended for black HF patients whoremain symptomatic despite optimal medicaltherapy

-Not a substitute for ACE inhibitors or ARB

Appropriate as first-line therapy in all HFpatients unable to tolerate either an ACEinhibitor or ARB because of renal

insufficiency, hyperkalemia, or possiblyhypotension



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Persistingsymptoms?


transplant



QRS >120 msec?



Yes

Yes

Yes No

LVEF


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yModes of Death

MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trialin congestive heart failure (MERIT-HF). LANCET. 1999;353:2001-07.

12%

24%

64%

CHF

Other

SuddenDeath

n = 103

NYHA II

26%

15%

59%

CHF

Other

SuddenDeath

n = 103

NYHA III

56%

11%

33%

CHF

Other

SuddenDeath

n = 27

NYHA IV

85% of sudden death in HF from ventriculararrhythmias

Implantable Cardioverter-Defibrillator


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(ICD)

Implantable Cardioverter-Defibrillator


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(ICD)


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g






Persistingsymptoms?


transplant



QRS >120 msec?



Yes

Yes

Yes No

LVEF


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(CRT)

Cardiac remodeling can lead toconduction irregularities anddyssynchrony between the rightventricle and left ventricle

- Wide QRS (


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(CRT)

Cardiac remodeling can lead toconduction irregularities anddyssynchrony between the rightventricle and left ventricle

- Wide QRS (


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g






Persistingsymptoms?


transplant



QRS >120 msec?



Yes

Yes

Yes No

LVEF


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gSerum concentrations

Digoxin increases parasympathetic activity- Increases cardiac index and decreases preloadwith little effect on blood pressure

Improves symptoms, exercise tolerance, andquality of life in HF patients with reduced ejectionfraction

- No mortality benefit has been shown

Serum digoxin concentrations of 0.50.8 ng/mLare associated with the best outcomes

- Levels over 1.2 ng/mL have been associatedwith an increased morbidity/mortality risk

Digoxin:S t ti


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Serum concentrations

Digoxin increases parasympathetic activity- Increases cardiac index and decreases preloadwith little effect on blood pressure

Improves symptoms, exercise tolerance, andquality of life in HF patients with reduced ejectionfraction

- No mortality benefit has been shown

Serum digoxin concentrations of 0.50.8 ng/mLare associated with the best outcomes

- Levels over 1.2 ng/mL have been associatedwith an increased morbidity/mortality risk

Digoxin


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Digoxin

Bauman JL,et al. Arch Intern Med. 2006;166(22):2539-2545



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Persistingsymptoms?


transplant



QRS >120 msec?



Yes

Yes

Yes No

LVEF


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LV Assist Device


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LV Assist Device

LV Assist Device


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LV Assist Device

Heart Transplant


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Heart Transplant

Older age (usual limit 6065 y)

Active infection

Severe diabetes mellitus with other end-organ disease

Pulmonary function < 60%* predicted, or chronicbronchitis

Serum creatinine > 2 mg/dL or clearance < 40 mL/min*

Bilirubin > 2.5 mg/dL, transaminases 2 normal*

PAS > 60 mm Hg, TPG > 15 mm Hg*

High risk of life-threatening noncompliance

Specific contraindications tocardiac transplantation

Heart Transplant


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Heart Transplant


Active infection








Heart Transplant


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Heart Transplant


Active infection








Heart Transplant


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Heart Transplant


Active infection








Drugs to avoid in patients with HF withReduced Ejection Fraction


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Drugs known to adversely affect the clinical statusof patients with current or prior symptoms of HF andreduced LVEF should be avoided or withdrawnwhenever possible

- NSAIDs- Antiarrhythmics: Class Ia, Class Ic, dronedarone

- Non-dihydropyridine calcium channel blockers

- Thiazolidinediones

Treatment for Heart Failure with



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Hormonal therapies other than to repletedeficiencies are not recommended and may beharmful to patients with current or priorsymptoms of HF and reduced LVEF.

Use of nutritional supplements as treatment forHF is not indicated in patients with current or

prior symptoms of HF and reduced LVEF.

Heart Failure with Preserved

Ejection Fraction (HFPEF)


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20 to 50 percent of patients with HF have apreserved ejection fraction

Patients with HFPEF:- Typically older and more likely to be women- Higher prevalence of hypertension, obesity,

renal failure, anemia, and atrial fibrillation

No evidence- based treatment for patients withHFPEF





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Treat hypertension according to publishedguidelines

- Be wary of compelling indications such asdiabetes and left ventricular hypertrophy

Treat CAD according to publishedguidelines Control ventricular rate in patients with

HFPEF and atrial fibrillation Use diuretics to control pulmonary

congestion and peripheral edema

Acute heart failure syndromes (AHFS)


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New-onset, gradual, or rapidly worsening HF signs andsymptoms that require urgent therapy.



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Predictors of Mortality Based on


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Analysis of ADHERE DatabaseThree variables are the strongest predictors of mortality inhospitalized acute decompensated HF patients:

Patients with all three characteristics had an in-hospitalmortality of 21.9 percent compared to 2.1 percent inpatients with none.

BUN > 43 mg/dL

Systolic blood pressure < 115 mmHg

Serum creatinine > 2.75 mg/dL

Fonarow GC et al. JAMA 2005;293:572-80



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Medical management of AHFS is based on

precipitating factors and clinical presentationIdentification of potential precipitating factors for acuteHF is critical to guide therapy:

acute coronary syndromes/coronary ischemia severe hypertension atrial and ventricular arrhythmias infections

pulmonary emboli

renal failure medical or dietary noncompliance



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In patients experiencing a HF exacerbation requiring

hospitalization:

- Treatment with ACE inhibitors or ARBs should be continued inmost patients in the absence of hemodynamic instability

- Continuation of beta blocker therapy is recommended in mostpatients, unless they develop cardiogenic shock, refractoryvolume overload, or symptomatic bradycardia.

Temporary dose reduction may be considered Avoid abrupt discontinuation

Reinstate or gradually increase prior to discharge Titrate dose to previously tolerated dose as soon as possible

In hospitalized HF patients not treated with ACE inhibitors orARBs and beta-blocker therapy, initiation of these therapies isrecommended in stable patients prior to hospital discharge.



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Medical management of AHFS is based on precipitating

factors and clinical presentation

Warm & Dry Warm & Wet

Cold & WetCold & Dry

Congestion at Rest?

Low Perfusionat Rest?

I II

III IV

No

No Yes

Yes

CardiacIndex

2.2l/min/m2

PCWP

18 mmHg

Evidence of low perfusion:

Cool extremities

Narrow pulse pressure Low serum sodium Renal dysfunction Hypotension with ACE inhibitorAltered Mental Status

Signs/symptoms of congestion:

Orthopnea/PND JVDAscites Edema Rales

Congestion

Hypoperfusion

Hemodynamic Monitoring


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Hemodynamic Monitoring Swan-Ganz Catheter Used when congestion and perfusion cannot be

determined from clinical assessment or whensymptoms persist despite empiric adjustment ofstandard therapies

Allows measurement:- Right atrial pressure- Right ventricular pressure- Pulmonary artery capillary pressure ("wedge"

pressure)

- Cardiac index- Systemic vascular resistance

Acute Heart Failure Syndromes (AHFS)


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PCWP18 mmHg



I II

III IV

CardiacIndex

2.2l/min/m2

Normal

Mild to ModerateLV Dysfunction

SevereLV Dysfunction

Warm and Wet


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Warm and Wet

T.J. is a 65-year-old man who came into the hospital withincreasing dyspnea at rest. A physical examination revealsrales throughout his lung fields. His chest X-Ray showedpulmonary congestion. He was diagnosed with AHFS.Echocardiography revealed an LVEF of 45%. He has a

history of hypertension, hyperlipidemia, and coronary arterydisease with a three-vessel coronary artery bypass graft 2years ago. T.J.s vital signs are BP 182/81 mm Hg and HR 85beats/minute.

Warm and Wet


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Warm and Wet

T.J. is a 65-year-old man who came into the hospital withincreasing dyspnea at rest. A physical examination revealsrales throughout his lung fields. His chest X-Ray showedpulmonary congestion. He was diagnosed with AHFS.Echocardiography revealed an LVEF of 45%. He has a

history of hypertension, hyperlipidemia, and coronary arterydisease with a three-vessel coronary artery bypass graft 2years ago. T.J.s vital signs are BP 182/81 mm Hg and HR 85beats/minute.

A Swan-Ganz catheter reveals a cardiac index of 2.6 L/minute/m2 and pulmonary capillary wedge pressure (PCWP)of 25 mm Hg.

Acute Heart Failure Syndromes (AHFS)Warm & Wet


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PCWP

18 mmHg



I II

III IV

Cardiac

Index2.2

l/min/m2

Use drugs that reducepreload (PCWP)

Diuretics

Vasodilators

Warm & Wet

Warm & Wet



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Warm & Wet

Assess voluConsider ca

diuresis vsif hypovol

HF progress

Fluid overload:Orthopnea/PND JVD

RalesDOE/SOBS3 or S4HJR NT-proBNPWeight gainEdemaPulmonary edema

Assess signsand symptoms

Mild volume overload

IV diureticsIV furosemide: On oral furosemide as

outpatient: give 12 xpatient home dose as IVbolus (max = 180 mg)

No oral furosemide asoutpatient: give 20 40mg as IV bolus

Moderate to severevolume overload andSBP > 90 mm Hg

FatiguePre-renal azotemiaPoor response to IV

diuretic Oxygen requirementRequiring CPAP or BiPAP

If uncertain ofhemodynamic status,consider pulmonaryartery catheter

Assess response to initial diureticIf UOP < 250500 mL aer 2 hours:Double previous IV bolus dose

OR

Double previous IV bolus dosefollowed by continuous infusion

OR

Double previous IV bolus dose + POmetolazone or IV chlorothiazide

Reassess UOP as above, and ifineective, consider moderate tosevere volume overload or low CO

IV diuretics +IV vasodilators

IV diuretic: continue diuretic

regimen titrated to UOP goalsIV vasodilatorNitroglycerinNitroprussideNesiritideUltraltration is also an option

for uid removal

IV loop diuretics should begin in the emergencydepartment or outpatient clinic without delay

- Initial IV dose should equal or exceed chronicoral daily dose

Urine output, daily weight, and signs and symptomsof congestion should be serially assessed, and

diuretic dose should be titrated accordingly torelieve symptoms and to reduce fluid excess

When diuresis is inadequate to relieve congestionthe diuretic regimen should be intensified usingeither:

- higher and more frequent doses of loop diuretics;- addition of a second diuretic (metolazone or IV

chlorthiazide); or

- continuous infusion of a loop diuretic.



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Warm & Wet



HF progress













OR


OR






for uid removal

In patients with evidence ofseverely symptomatic fluidoverload in the absence ofsystemic hypotension, IV

vasodilators can be beneficialwhen added to diuretics and/orin those who do not respond todiuretics alone:

-Nitroglycerin

- Nitroprusside- Nesiritide?



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Warm & Wet



HF progress













OR


OR






for uid removal



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Warm & Wet



HF progress













OR


OR






for uid removal

In patients with evidence ofseverely symptomatic fluidoverload in the absence ofsystemic hypotension, IV

vasodilators can be beneficialwhen added to diuretics and/orin those who do not respond todiuretics alone:

-Nitroglycerin

- Nitroprusside- Nesiritide?

Acute Heart Failure Syndromes (AHFS)


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Effect of HF treatment should be monitored withcareful measurement of:- fluid intake and output- vital signs

-body weight, determined at the same time each day

- clinical signs (supine and standing) and symptoms of systemicperfusion and congestion

Daily serum electrolytes, blood urea nitrogen, andserum creatinine concentrations should be measured

during the use of IV diuretics or active titration of HFmedications.

Cold and Wet


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Cold and Wet

K.L., a 58-year-old man with a 3-year history of non-ischemiccardiomyopathy, is admitted to the hospital forsevereshortness of breath and altered mental status. He hasgained 11 kg over the past 2 weeks (now weighs 120 kg) andhas had decreased urine output despite increasing his

diuretic dose. A physical examination reveals ralesthroughout his lung fields. K.L.s blood pressure (BP) is 84/63mm Hg.

Cold and Wet


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Cold and Wet

K.L., a 58-year-old man with a 3-year history of non-ischemiccardiomyopathy, is admitted to the hospital forsevereshortness of breath and altered mental status. He hasgained 11 kg over the past 2 weeks (now weighs 120 kg) andhas had decreased urine output despite increasing his

diuretic dose. A physical examination reveals ralesthroughout his lung fields. K.L.s blood pressure (BP) is 84/63mm Hg.

A Swan-Ganz catheter reveals a cardiac index of 1.6 L/minute/m2 and pulmonary capillary wedge pressure (PCWP)of 25 mm Hg.

Acute Heart Failure Syndromes (AHFS)Cold & Wet


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PCWP

18 mmHg



I II

III IV

Cardiac

Index2.2

l/min/m2

Use combination of:

Inotropes (I) Diuretics (D)

Vasodilators (V)

I

D

V

I+V

D+V+I

Cold & Wet



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Intravenous inotropic drugs are reasonablefor patients presenting with (1) severesystolic dysfunction, (2) symptomatichypotension or (3) inability to maintain

systemic perfusion and preserve end-organperformance

- Dobutamine

-Milrinone

- Dopamine

Assess volume statusConsider careful IV

diuresis vs. uid bolusif hypovolemic

vs

HF progression to low CO

Assess blood pressure

NoYes

On -blocker chronically

nsms

SBP > 90 mm Hg SBP < 90 mm Hg

Low CO:Narrow pulse pressurePre-renal azotemia

Altered mental status

UOPPoor response to IVdiureticCool extremitiesPulsus alternans

DobutamineMilrinone

Continued signs/symptoms of low CO

c status,onary

r

Very low COConsider pulmonary artery catheterConsider vasodilators aer known

hemodynamic parametersConsider dopamine if severe

hypotension or cardiogenic shock

e diuretic

UOP goals

an option



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vs



NoYes


nsms





DobutamineMilrinone


c status,onary

r




e diuretic

UOP goals

an option

Drug Dose 1 1 2 DA

0.5 - 3 mcg/kg/min 0 0 0 +++++

Dopamine 4 - 10 mcg/kg/min ++ ++++ ++ +++++

> 10 mcg/kg/min ++++ ++++ ++ +++++

2.0 - 10 mcg/kg/min + +++++ +++ 0

10 - 20 mcg/kg/min ++ +++++ +++ 0

Milrinone0.375 to 0.75 mcg/kg/min

0 0 0 0

Milrinone is a selective phosphodiesterase-3 inhibitor (PDE3) thatincreases the level of cAMP by inhibiting its breakdown within the cell


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vs



NoYes


nsms





DobutamineMilrinone


c status,onary

r




e diuretic

UOP goals

an option

Dobutamine and milrinone are preferable over dopaminewhen blood pressure is adequate

-

Dobutamine reduces the systemic vascular resistanceand may not increase oxygen demands as much asdopamine, and is preferable when systolic bloodpressure >80 mmHg

-Milrinone is not dependent upon adrenergic receptoractivity and therefore, is preferable for patients on beta-blockers. Causes greatest reduction preload, thus may

be least likely to increase myocardial oxygen demand

Selection of an inotrope



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vs



NoYes


nsms





DobutamineMilrinone


c status,onary

r




e diuretic

UOP goals

an option

Dopamine should be initiated first for severehypotension

- Patients may not tolerate the vasodilating effects ofdobutamine or milrinone at low blood pressures

If dopamine at doses of 20 mcg/kg/min does not achievea MAP of 60-65 mm Hg, then norepinephrine can beadded

Selection of an inotrope

Hospital to Home


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p


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Questions?Contact me:

Nicholas B. Norgard, Pharm.D. BCPS

University at Buffalo School of Pharmacy &Pharmaceutical SciencesCenter of Excellence B3-322

Office: 716-645-4779

[email protected]

Documents

PHM 601 Heart Failure Lecture Slides