Download Lecture Slides for Acute Decompensated Heart Failure

4/26/2016
Pharmacotherapy of the Critically Ill Patient
ACUTE DECOMPENSATED HEART FAILURE
Brent N. Reed, PharmD, BCPS-AQ Cardiology, FAHA
Assistant Professor, Department of Pharmacy Practice and Science
University of Maryland School of Pharmacy
@brentnreed
J Am Coll Cardiol 2013;62:e147-239.
DEFINITIONS
DEFINITIONS
• Acute decompensated heart failure
Emergence of new or worsening signs and/or
symptoms of heart failure
• Cardiogenic shock
Heart failure with systemic hypoperfusion
Heart Failure with
Reduced Ejection
Fraction (HFrEF)
Heart Failure with
Preserved Ejection
Fraction (HFpEF)
Impaired ejection of
blood, formerly known
as systolic dysfunction;
ejection fraction < 40%
Impaired filling of blood,
formerly known as
diastolic dysfunction;
ejection fraction > 40-50%
Muscle images from “Heart Failure”, Cleveland Clinic Center for Continuing Education. Heart image from Marieb
& Hoehn. Anatomy & Physiology, 9e. Pearson, 2013.v
DEFINITIONS
EPIDEMIOLOGY OF HEART FAILURE
• 5.7 million adults in the US have heart failure
• Expected to increase by over half by year 2030
• Over 1 million are hospitalized annually
• 1 in 4 are readmitted within 30 days
Left Heart Failure
Right Heart Failure
Biventricular failure
Circulation 2015;131(4):e29–322.
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DISEASE PROGRESSION
PATHOPHYSIOLOGY
Heart failure
decompensations
Venous Congestion
Signs and symptoms
of venous congestion,
congestive end-organ
dysfunction
Myocardial
Function
Volume Overload
Time
Low Cardiac Output
Both
Adapted from Am J Cardiol. 2005 Sep 19;96(6A):11G-17G.
PATHOPHYSIOLOGY
PATHOPHYSIOLOGY
Mean Arterial
Pressure (MAP)
Impaired organ
function, signs and
symptoms of
decreased perfusion
Volume Overload
Low Cardiac Output
Volume Overload
Both
Low Cardiac Output
Both
PRECIPITATING CAUSES
QUESTION #1
• Nonadherence to
medications or diet
• Pulmonary embolus
• Negative inotropes
• Endocrine
abnormalities
List five (5) precipitating causes of acute
decompensated heart failure (ADHF). What is the
most likely cause in this patient?
• Drugs that promote
salt retention
• Myocardial ischemia
• High blood pressure
• Arrhythmias
• Alcohol or illicit drugs
• Infections
• Other acute
cardiovascular
disorders
J Am Coll Cardiol. 2013 Oct 15;62(16):e147-239.
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THERAPEUTIC GOALS
QUESTION #2
• Relieve symptoms
What are the therapeutic goals for this patient’s
ADHF?
• Optimize volume status
• Restore hemodynamic stability
• Reduce inpatient mortality
• Address reason(s) for decompensation
• Minimize risk for rehospitalization
PATIENT PRESENTATION
Fluid Overload
Low Cardiac Output
• Dyspnea on exertion
• Orthopnea
• Paroxysmal nocturnal
dyspnea
• Crackles
• S3 gallop
• Early satiety
• Jugular venous distention
• Hepatojugular reflex
• Ascites
• Peripheral edema
•
•
•
•
•
•
•
Altered mental status
Fatigue
Cool extremities
Narrow pulse pressure
Hypotension
Hyponatremia
Evidence of impaired endorgan perfusion (renal, hepatic
function)
Chest x-ray showing significant
pulmonary edema
Same patient following diuresis
(2 days later)
University of Virginia Department of Radiology. Available from https://www.meded.virginia.edu/courses/rad/cxr/pathology2chest.html. Accessed 2015 Mar 05.
CARDIAC OUTPUT
HEMODYNAMIC MONITORING
• Preload (volume)
• Afterload (impedance)
• Contractility (strength)
Right Heart
Catheterization
(RHC)
A pulmonary artery
(PA) catheter (also
known as a SwanGanz catheter) is
advanced through
the right side of the
heart and into a
small branch of the
pulmonary artery
Can obtain a
pulmonary capillary
wedge pressure
(PCWP), which
approximates left
ventricular enddiastolic pressure
(LVEDP), i.e., preload
CO – cardiac output; HR – heart rate; SV – stroke volume
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PRELOAD
VOLUME STATUS
normal
Cardiac Index
(Stroke Volume)
Cardiac Index
(Stroke Volume)
“Dry”
“Wet”
Shortness of breath
Pulmonary
congestion
Peripheral edema
Jugular venous
distention (JVD)
heart failure
overload
8 – 12
Symptoms
18
18
PCWP or LVEDP
PCWP or LVEDP
mm Hg (Preload)
mm Hg (Preload)
AFTERLOAD
CONTRACTILITY
SVR
Intrinsic strength of myocardial contraction
dyne · s / cm5 (Afterload)
Beta Receptor
900 – 1400
normal
Cardiac Index
(Stroke Volume)
heart failure
Angiotensin II
Receptor
Image from Circulation Research. 2011; 109: 217-230 .
CONTRACTILITY
CARDIAC OUTPUT
SVR
Can be impaired as a result of
damage to myocardial cells.
dyne · s / cm5 (Afterload)
Remodeling
2.8 – 4.2
Chronic
pathological
changes to the
structure and
function of
myocardial tissue
(e.g., hypertension,
neuro-hormonal
mediators)
Treatment
Myocardial
infarction
Loss of coronary
perfusion resulting
in a localized zone of
myocardial tissue
damage
Severe impairment may require inotropic drugs,
mechanical circulatory support, or transplantation.
Cardiac Index
“Warm”
2.2
L/min/m2
“Cold”
Symptoms
Cold, clammy
extremities
Altered mental status
PCWP or LVEDP
(Preload)
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HEMODYNAMIC SUBSETS
QUESTION #3
SVR
(Afterload)
Optimize chronic
oral therapy
Cardiac Index
“Warm and Dry”
“Warm and Wet”
Diuretics +/adjunct therapies
“Cold and Dry”
“Cold and Wet”
Diuretics +/vasodilators
and/or inotropes
Classify this patient into a hemodynamic subset.
If a pulmonary artery catheter was inserted, what
values for pulmonary capillary wedge pressure
and cardiac index would you expect?
2.2
Vasodilators
and/or inotropes
18
PCWP or LVEDP
(Preload)
MANAGING HOME MEDICATIONS
IV LOOP DIURETICS
I
Medication
Criteria for Discontinuation
ACE inhibitor or ARB
• Acute kidney injury unrelated to ADHF
• Cardiogenic shock or hypotension
• Severe hyperkalemia
Beta blocker
• ADHF due to initiation or dose increase
• Cardiogenic shock or hypotension
• Symptomatic bradycardia
Aldosterone antagonist
• Acute kidney injury unrelated to ADHF
• Severe hyperkalemia
Isosorbide dinitrate /
hydralazine
• Cardiogenic shock or hypotension
Digoxin
• Symptomatic bradycardia
• Life-threatening arrhythmia
• Elevated serum digoxin concentrations or
signs/symptoms of toxicity
ACE – angiotensin converting enzyme; ADHF – acute decompensated heart failure; ARB –
angiotensin-receptor blocker
III
Fluid overload should be promptly treated with
IV loop diuretics
Advantages
Disadvantages
• Improvements in heart
failure signs and symptoms
• No improvements in longterm morbidity or mortality
• Improvements in
hemodynamics
• Neurohormonal activation
• Renal impairment
• Electrolyte abnormalities
QUESTION #4
Onset Duration IV Equivalence Bolus
(min)
IIb
J Am Coll Cardiol 2013;62:e147-239. Eur J Heart Fail 2007;9:1064–1069. Ann Intern Med 1985;103:1–6.
IV LOOP DIURETICS
Agent
IIa
B
Infusion
(h)
(mg)
(mg)
(mg/h)
Furosemide
2-5
6
20-40
20-200
2.5-40
Torsemide
< 10
6-12
20
10-100
2-10
Bumetanide
2-3
4-6
1
1-10
0.5 -2
Recommend an initial therapeutic regimen for
this patient’s ADHF, including drug, dose, route,
and frequency of administration. What are two
parameters you would use to monitor efficacy?
Safety?
Adapted from Vardeny O, Ng TMH. Pharmacotherapy Principles & Practice. 2013:79-108.
• For most patients: up to 2.5x outpatient dose (IVB or CI)
• Signs of hypoperfusion: 1x outpatient dose (IVB or CI)
• CI vs IVB: tenuous hemodynamics; diuretic resistance (?)
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Pharmacokinetic
Mechanisms
Pharmacodynamic
Mechanisms
Distal
convoluted
tubule
Decreased gut
absorption and/or
renal perfusion
OVERCOMING DIURETIC RESISTANCE
Compensatory
sodium
reabsorption
Glomerulus
Proximal
convoluted
tubule
Ultrafiltration or Vasopressin Antagonist
(select patients only)
Remodeling of
the nephron
Collecting
duct
Reninangiotensinaldosterone
system
Add Targeted Therapies
Enhance Blood Flow
Arginine
vasopressin
Loop of
Henle
Intravenous Vasodilator or Inotrope
(refractory patients or those with low cardiac output)
Neurohormonal
activation
Common
Mechanisms of
Diuretic
Resistance
Augment Diuresis
Change Diuretic Strategy or Add an Alternative Diuretic
(most patients exhibiting diuretic resistance)
Nephron diagram from: OpenStax College. Anatomy & Physiology [Connexions Web site]. January
3, 2014. Available at: http://cnx.org/content/col11496/1.6/.
CHANGING DIURETIC STRATEGY
I
Effective diuresis
Normal
Heart Failure
IIb
III
If initial diuresis is inadequate, regimen may
be intensified by adding a second diuretic
Dose
Route Initial
(mg)
Agent
Higher doses required for
diuretic effect
IIa
IIb
III
B
If initial diuresis is inadequate, regimen
may be intensified by increasing the dose
Convert to a continuous infusion?
Image adapted from Cardiology. 96;2001:132-143. J Am Coll Cardiol 2013;62:e147-239.
IV VASODILATORS
Venous
Vasodilation
• Mobilizes fluid
in periphery
• Decongests
kidneys
Nitroglycerin*
Sodium Nitroprusside
Nesiritide
I
IIa
B
Diminished maximal
diuretic response
Diuretic Concentration
I
DIURETIC SYNERGY
IIa
IIb
A
III
Max Dose*
Duration
6-12
(mg)
(h)
Chlorothiazide
IV
250 – 500
1000
Hydrochlorothiazide
PO
25 – 50
200
6-12
Metolazone
PO
2.5
20
12-24
* Doses
may be divided twice daily.
• Not required to administer 30 minutes prior to loop diuretic
• Enhanced diuresis may increase risk of adverse effects
J Am Coll Cardiol 2013;62:e147-239.
LOW-DOSE DOPAMINE
Arterial
Vasodilation
• Improved renal
blood flow due
to reduced
impedance
Sodium Nitroprusside
Nesiritide
Selective renal
vasodilation*
I
In absence of hypotension, IV vasodilators
may be used as an adjuvant to diuretics
*At high-doses (> 100 mcg/min), nitroglycerin exerts venous and arterial dilating effects.
J Am Coll Cardiol 2013;62:e147-239. Kidney image from Marieb & Hoehn. Anatomy & Physiology, 9e.
IIa
IIb
B
III
Low-dose dopamine may be considered
in addition to loop diuretic therapy
*Like centaurs, this too is a myth.
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QUESTION #5
VASOPRESSIN ANTAGONISTS
Although the patient responds initially, his
symptoms persist. He remains warm and wellperfused with a blood pressure of 118/82 mmHg.
What modifications would you make to his
regimen? If you add another drug, provide a dose,
route, and frequency of administration, as well as
two parameters each for safety and efficacy.
• Arterial under-filling
stimulates AVP release
Tolvaptan
• Hyponatremia linked to
poor outcomes in ADHF
• Vasopressin antagonists,
such as tolvaptan,
improve serum sodium
concentrations and
some ADHF symptoms
• No improvements in
long-term outcomes
Vasopressin antagonists bind to V2 receptors
to prevent aquaporin synthesis.
AVP – arginine vasopressin
Arch Intern Med 2007;167:1998-2005. Image from Circulation. 2008 Jul 22;118(4):410-21.
SALT-1*
140
Tolvaptan
135
130
Placebo
0
10
20
30
40
Day
I
IIa
IIb
III
B
Serum Sodium (mmol/L)
Serum Sodium (mmol/L)
VASOPRESSIN ANTAGONISTS
ULTRAFILTRATION VS. HEMODIALYSIS
SALT-2*
140
Tolvaptan
Ultrafiltration
135
High
Pressure
130
Low
Pressure
Hemodialysis
High
Concentration
Low
Concentration
Placebo
0
10
20
30
40
Day
Short-term vasopressin antagonist use may
be considered in patients with volume
overload and severe hyponatremia or those
at-risk for cognitive symptoms
*Vertical dotted lines indicate the end of the treatment period. Images adapted from N Engl J Med
2006;355:2099-112. J Am Coll Cardiol 2013;62:e147-239.
Fluid crosses semipermeable
membrane due to pressure
differences; No solute removal
Fluid and solutes cross
semipermeable membrane due
to concentration differences
Venous system image from Marieb & Hoehn. Anatomy & Physiology, 9e. Pearson, 2013.v
ULTRAFILTRATION
QUESTION #6
• Isotonic rather than hypotonic fluid removal
What is the role of ultrafiltration in patients with
ADHF? How is it similar to conventional
hemodialysis? How is it different? Should it be
considered at this time?
• Enhances volume removal and weight loss
• Worsens existing renal impairment and increases
adverse effects vs. pharmacologic therapy
• Should not be used to avoid vasoactive drugs
• Must balance with cost, need for venovenous access
I
IIa
IIb
B/C
III
Ultrafiltration may be considered for obvious
fluid overload (B), or refractory congestion
unresponsive to medical therapy (C)
J Am Coll Cardiol 2007;49:675-83. N Engl J Med 2012;367:2296-304. J Am Coll Cardiol 2013;62:e147-239.
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LOW CARDIAC OUTPUT
INTRAVENOUS VASODILATORS
Low CO
No
Agent
Dilation
Dosing
Nesiritide
Arterial,
Venous
2 mcg/kg bolus,
0.01 mcg/kg/min
Norepinephrine
Dopamine
Nitroglycerin
Venous >
Arterial
5–200 mcg/min
• High doses required for
arterial vasodilation
• Tachyphylaxis
IV Inotropes
Sodium
Nitroprusside
Arterial,
Venous
0.3–3 mcg/kg/min
• Accumulation of toxic
metabolites in hepatic,
renal impairment
Optimize chronic
medications
< 2.2 L/min/m2
Yes
Adequate MAP
Fluids, Inopressors
No
(> 50 mm Hg)
Yes
Adequate SBP
IV Vasodilators
Nesiritide
Nitroglycerin
Sodium Nitroprusside
Yes
(SBP > 90 mmHg,
absence of
symptomatic
hypotension, stable
renal function)
No
Dobutamine
Milrinone
Adapted from DiPiro JT, et al (eds). Pharmacotherapy: A pathophysiological approach, 9th edition.
New York: McGraw-Hill; 2014.
INTRAVENOUS INOTROPES
Agent
Dose
CO
HR
SVR
2.5–5



5–20



5–10



10–20



Milrinone
0.1–0.75


Norepinephrine
0.01–3*

/
Dobutamine
Dopamine
(mcg/kg/min)
• Favored over inotropes given fewer adverse outcomes
• Class disadvantages: hypotension, ± invasive monitoring
J Am Coll Cardiol 2013;62:e147-239. J Am Coll Cardiol. 2005; 46: 57–64.
INTRAVENOUS INOTROPES
t½
(min)
Considerations
2 – 10
Blood pressure
response varies
2 – 10
Lower doses not
renoprotective

60-120
Undergoes renal
clearance
/
1-2
Use only in low
blood pressure
I
IIa
IIb
III
Until definitive therapy or resolution of
the acute precipitating problem, patients
with cardiogenic shock should receive
intravenous inotropic support
IIa
IIb
III
Short-term inotropic support may be
reasonable in the setting of low blood
pressure and low cardiac output
III
Use of intravenous inotropes in the
absence of impaired perfusion and low
cardiac output is potentially harmful
C
I
B
I
IIa
IIb
B
• Consider only for those with evidence of low output
• Increased risk of tachyarrhythmia, mortality
Beta
Blocker
Pharmacologic
Effects
Chronic Changes to
Receptor Profile
Metoprolol
Inhibits β1 >> β2
receptors
Up-regulation of β
receptors; improved
G-protein coupling
Inhibits α1, β1, and
β2 receptors
Diminished effects at
α1; no change in β1, β2
expression
BETA BLOCKERS & INOTROPES
Parameter
Dobutamine
BETA BLOCKERS & INOTROPES
J Am Coll Cardiol 2013;62:e147-239.
Milrinone*
*Commonly dosed in mcg/min (1-20). J Am Coll Cardiol 2013;62:e147-239.
Carvedilol
Disadvantages
• 20-minute half-life
• High cost
Baseline
Metoprolol
Carvedilol
CI (L/min/m2)


/
PCWP (mmHg)



SVR (dyn s/cm5)
/


MAP (mmHg)



HR (bpm)


/

CI (L/min/m2)


PCWP (mmHg)



SVR (dyn s/cm5)



MAP (mmHg)



HR (bpm)



CI – cardiac index; HR – heart rate; MAP – mean arterial pressure; PCWP – pulmonary capillary
wedge pressure; SVR – systemic vascular resistance. *Original study used enoximone
J Am Coll Cardiol 2002;40:1248–58.
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QUESTION #7
REFRACTORY HEART FAILURE
The patient’s condition worsens. He endorses cold
extremities and weak distal pulses with a blood
pressure of 92/62 mmHg. His serum creatinine
has risen to 2.6 mg/dL and pulmonary artery
catheterization reveals a cardiac index of 1.6
L/min/m2. Provide a recommendation for drug
therapy, including drug, dose, route, and
frequency of administration. Why did you select
this agent? Name two monitoring parameters
each for efficacy and safety.
Despite your best efforts, the patient’s condition
continues to deteriorate. Your team consults an
interventionalist and cardiac surgeon to
determine the best course of action.
MECHANICAL CIRCULATORY SUPPORT
IIa
I
IIb
III
B
Percutaneous Mechanical Circulatory Support
Intra-aortic
balloon pump
Impella®
TandemHeart®
ECMO
Temporary MCS may be considered as a
bridge to recovery or decision in
carefully selected patients with acute,
profound hemodynamic compromise
• Cardiogenic shock (e.g., MI, ADHF, graft rejection)
• Cardiovascular intervention in high-risk patients
• Bridge to durable MCS or transplantation
• Right ventricular failure
ADHF – acute decompensated heart failure; MCS – mechanical circulatory support; MI – myocardial
infarction; J Am Coll Cardiol 2013;62:e147-239.
Surgical Mechanical Circulatory Support
CentriMag®
ECMO – extracorporeal membrane oxygenation; Adapted from Eur Heart J. 2014 Jan;35(3):156-67
INTRA-AORTIC BALLOON PUMP
Diastolic Phase
The balloon inflates during diastole, which
increases diastolic pressure thereby
enhancing coronary perfusion
Ao
PA
RA
LV
Can provide left ventricular,
right ventricular, or biventricular support (biventricular configuration
shown)
Ao – aorta; LV – left ventricle; PA – pulmonary artery; RA – right atrium
Intra-Aortic Balloon Pump Control
• Trigger for each cycle (pressure, ECG)
• Augmentation (balloon inflation)
• Frequency (1:1, 1:2, or 1:3 cardiac cycles)
• Various other parameters
To device console
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INTRA-AORTIC BALLOON PUMP
Systolic Phase
The balloon deflates during systole; resulting
vacuum-like effect reduces aortic pressure,
thereby reducing left ventricular afterload
Intra-Aortic Balloon Pump Control
• Trigger for each cycle (pressure, ECG)
• Augmentation (balloon inflation)
• Frequency (1:1, 1:2, or 1:3 cardiac cycles)
• Various other parameters
To device console
CLINICAL CONSIDERATIONS
Contraindications*
Complications
Neurologic devastation
Peripheral vascular disease
Sepsis/systemic infection
Bleeding diatheses
Ventricular septal defect
(TandemHeart®)
• Aortic disease (IABP, Impella®)
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Thrombosis
Bleeding
Infection
Arrhythmias
Malposition
Vascular/tissue damage
Neurologic complications
Perforation (TandemHeart®)
Hemolysis (Impella®)
Thrombocytopenia (IABP)
*Generally considered relative contraindications; differs by device
Crit Care Med. 2014 Jan;42(1):158-68
QUESTION #8
Describe how an intra-aortic balloon pump
provides hemodynamic support in patients with
cardiogenic shock.
Pharmacotherapy of the Critically Ill Patient
ACUTE DECOMPENSATED HEART FAILURE
Brent N. Reed, PharmD, BCPS-AQ Cardiology, FAHA
Assistant Professor, Department of Pharmacy Practice and Science
University of Maryland School of Pharmacy
@brentnreed
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