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Management of Heart Failure: Acute vs' Chronic

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Title: Management of Heart Failure: Acute vs' Chronic


1
Management of Heart Failure Acute vs. Chronic
  • John Butterworth, MD
  • Professor Head
  • Section on Cardiothoracic Anesthesia
  • Wake Forest University School of Medicine
  • Winston-Salem, North Carolina

2
Management of Heart Failure Acute vs. Chronic
  • Chronic heart failure
  • Perioperative acute heart failure
  • Summary

3
CHF Statistics
  • Epidemic in western democracies
  • USA data
  • 550,000 new cases annually (2004)
  • 5 million (2.2 of population) total patients
    affected (2001)
  • Hospital discharges 995,000 (2001)
  • Mortality 19,805 (2001)
  • 28.8 billion in annual health care costs (2004)

USA Center for Disease Control, National Center
for Health Statistics
4
Many elderly female patients with CHF
of all males or of all females
Source USA Center for Disease Control, National
Center for Health Statistics
Age (yrs)
5
Many etiologies of CHF
  • Coronary artery disease
  • Hypertension
  • Valvular heart disease
  • Congenital heart disease
  • Toxins
  • Peripartum cardiomyopathy
  • Many others

McMurray, Pfeffer. JACC 2004442398-405 Pinski.
JAMA 2003289754-6 Schmitt. Science
20032991410-3
6
CHF Systole vs. Diastole
  • Diastolic HF (HF-PSV)
  • Dyspnea
  • Congestion (edema)
  • ?BNP
  • Normal LVEF
  • ?LV mass
  • Normal LVEDV
  • Abnormal mitral inflow
  • Abnormal mitral annular velocity
  • Systolic HF
  • Dyspnea
  • Congestion (edema)
  • ?BNP
  • ?LVEF
  • ?LV mass
  • ?LVEDV
  • Usually also have diastolic abnormalities

Aurigemma, Gassch. NEJM 20043511097-1105 Brucks.
Am J Cardiol 200595603-6
7
Heart failure with preserved systolic function
8
Heart failure with preserved systolic function
  • Get new videos of systolic and diastolic
    dysfunction

Peak early diastolic mitral annular velocity lt8
cm/s
9
CHF Systole vs. Diastole
  • Diastolic filling dysfunction on echo is common
  • NOT the same as myocardial diastolic dysfunction!
  • NOT HF with preserved systolic function (HF-PSV)!
  • Most 75 year olds have at least mild diastolic
    filling abnormalities on echo (abnormal filling
    common without HF)
  • HF-PSV more common in women
  • Diastolic dysfunction more common in men!

Maurer, JACC 2004441543-9 McMurray, Pfeffer.
JACC 2004442398-405 Pinski. JAMA
2003289754-6 Schmitt. Science 20032991410-3
10
CHF Systole vs. Diastole
  • Diastolic HF (HF-PSV)
  • Dyspnea
  • Congestion (edema)
  • ?BNP
  • Normal LVEF
  • ?LV mass
  • Normal LVEDV
  • Abnormal mitral inflow
  • Abnormal mitral annular velocity
  • Systolic HF
  • Dyspnea
  • Congestion (edema)
  • ?BNP
  • ?LVEF
  • ?LV mass
  • ?LVEDV
  • Usually also have diastolic abnormalities

Aurigemma, Gassch. NEJM 20043511097-1105 Brucks.
Am J Cardiol 200595603-6
11
Chronic Systolic Dysfunction
  • Get new videos of systolic and diastolic
    dysfunction

12
Pathophysiologic changes in CHF
  • ?Renal blood flow activates renin-angiotensin-aldo
    sterone
  • Compensatory changes
  • ?blood volume
  • ?total body water
  • ?total body Na
  • ?TNFa, ?ANP, ?BNP
  • BNP lt15 pmol/L excludes HF etiology of dyspnea

(pg/mL)
Doust. Arch Int Med 20041641978-84 Rodeheffer.
JACC 200444740-9 Feldman JACC
200035537-44 Torre-Amione JACC 1996271201-6
13
CHF activates sympathetic nervous system
  • Fewer ?1-receptors (?1-ARs)
  • ?1-ARs uncouple from
  • adenylyl cyclase
  • ? ?-AR,nucleoside kinase
  • ? G?i
  • Preserved number of ?2-ARs (activate both Gs and
    Gi)
  • Upregulation of ?3-ARs (neg. inotropy)
  • End result ?cAMP generation ?inotropy

?-AR G Adenylyl Protein
Cyclase
Cheng. Circ Res 200189599-606 Kilts. Circ Res
200087705-9 Movsesian. JACC 199934318-24
Ungerer. Circulation 199387454-63
14
Chronic therapy and outcomes in HF
  • Drugs that decrease mortality
  • ?-AR blockers
  • ACE inhibitors
  • Angio receptor blockers
  • Aldosterone antagonists
  • Isosorbide and hydralazine in blacks
  • Drugs that may improve symptoms without worsening
    outcome
  • Cardiac glycosides
  • Loop diuretics
  • Drugs that increase mortality
  • Dobutamine
  • Xamoterol
  • Pimobendam
  • Flosequinan
  • Vesnarinone
  • Ibopamine
  • Inamrinone
  • Milrinone
  • Enoximone

15
Chronic therapy and outcomes in HF
  • Drugs that decrease mortality
  • ?-AR blockers
  • ACE inhibitors
  • Aldosterone antagonists
  • Angio receptor blockers
  • Isosorbide and hydralazine in blacks
  • Drugs that may improve symptoms without worsening
    outcome
  • Cardiac glycosides
  • Loop diuretics
  • Drugs that increase mortality
  • Dobutamine
  • Xamoterol
  • Pimobendam
  • Flosequinan
  • Vesnarinone
  • Ibopamine
  • Inamrinone
  • Milrinone
  • Enoximone

16
Chronic therapy and outcomes in HF
  • Drugs that decrease mortality
  • ?-AR blockers
  • ACE inhibitors
  • Angio receptor blockers
  • Aldosterone antagonists
  • Isosorbide and hydralazine in blacks
  • Drugs that may improve symptoms without worsening
    outcome
  • Cardiac glycosides
  • Loop diuretics
  • Drugs that increase mortality
  • Dobutamine
  • Xamoterol
  • Pimobendam
  • Flosequinan
  • Vesnarinone
  • Ibopamine
  • Inamrinone
  • Milrinone
  • Enoximone

17
Ineffective therapies in CHF
  • Anti-adrenergic
  • Moxonidine (MOXCON)
  • Prazosin (V-HeFT 1)
  • Anti-cytokine
  • Anti-TNF (ATTACH)
  • Etanercept (RENEWAL)

18
Cardiac glycosides
  • William Withering used
  • foxglove to treat edema in 1785
  • An Account of the Foxglove,
  • and Some of Its Medical Uses
  • Inhibits Na-K ATPase, ?intracellular
  • Na, ?Ca through Na-Ca exchange
  • Recent studies show digoxin
  • Sensitizes cardiac baroreceptors
  • Decreases sympathetic nervous outflow
  • Decreases renin secretion
  • Neurohormonal modulator

NEJM 19933291-7 NEJM 20023471403-11 Ann Int
Med 2005142132-45
19
Effect of Digoxin on Mortality and Morbidity
Digoxin Investigation Group
  • 6800 patients with LV EF lt.45 digoxin or placebo
  • Mean 37 mo follow up
  • Similar mortality (35)
  • Digoxin fewer hospitalizations
  • Use it when symptoms persist despite ß-blocker
    ACE inhibitor

Hospitalized for Worsening HF

NEJM 1997336525-33 Ann Int Med 2005142132-45
plt.001
20
ACE-Is Should Generally be Used before ARBs in HF
  • Incontrovertible evidence of ACE-I efficacy
    (SOLVD-T)
  • ACE-Is inhibit bradykinin metabolism
  • ACE-I intolerance
  • ACE-I and/or ARB?
  • Angio-II catalyzed by enzymes other than ACE
  • VALIANT shows ARB as effective as ACE-I,
    combination leads to more AEs
  • ELITE 2 shows ACE-I superior to ARB in HF
  • CHARM-Added shows benefit to adding ARB to
    standard Rx

Ann Int Med 2005142132-45
21
McMurray Circulation 20041103281-8
22
ACE-Is Should Generally be Used before ARBs in HF
  • Incontrovertible evidence of ACE-I efficacy
    (SOLVD-T)
  • Angio-II catalyzed by enzymes other than ACE
  • ACE-Is inhibit bradykinin metabolism
  • ACE-I intolerance
  • ACE-I and/or ARB?
  • VALIANT shows ARB as effective as ACE-I, but
    combination leads to more adverse events
  • ELITE 2 shows ACE-I superior to ARB in HF
  • CHARM-Added shows benefit to adding ARB to
    standard Rx

Ann Int Med 2005142132-45
23
Key role of aldosterone in CHF
  • Compound identified by Simpson and Tait (1951)
  • Initial studies in renovascular hypertension
  • Adverse LV remodelling with aldo (Brilla 1990)
  • RALES and EPHESUS trials show benefit to aldo
    antagonists in CHF (Pitt 1999, 2003)

Sylvia Simpson and James Tait From Tan. Int J
Cardiol 2004 96321-333
24
Spironolactone reduces mortality in patients with
severe CHF
  • 1663 NYHA III IV patients with LVEF 35
    treated with ACE, loop diuretic, digoxin
  • 25 mg spiro vs placebo 24 mo follow up
  • 30 reduced mortality 35 reduction in
    hospitalization for worsening CHF, both plt.001

mortality
Pitt et al NEJM 1999341709-17
25
Epleronone reduces mortality in patients with LV
dysfunction after MI
  • Patients assigned to epleronone 25-50 mg qd
    (n3313) or placebo (n3319)
  • gt75 receiving ACE-I (or angio blocker), ?Bs,
    aspirin
  • 90 have symptoms of CHF
  • Epl reduced deaths (RR .85), CV deaths (RR .87),
    sudden CV deaths (RR .79)
  • 10,400-21,900 per life-year gained

Number of Deaths
All All Sudden CV CV
NEJM 20033481309-21 Circulation 2005Feb 21 Epub
26
?-ARBs and chronic heart failure
  • Long thought contraindicated for CHF
  • Antiarrhythmic, antioxidant, antiischemic,
    sympatholytic effects
  • Inhibit ß3 actions?
  • ?symptoms, ?functional capacity, ?LVF
  • Use drugs shown to ?mortality in clinical trials
    (carvedilol, bisoprolol, and metoprolol)
  • Outcome benefit to using target drug doses from
    clinical trials outcome unrelated to HR reduction

JACC 200545252-9 Ann Int Med 2005142132-45
27
Multicenter ?-ARB mortality trials
Gheorghiade. Circulation 20031071570-5
28
Carvedilol or Metoprolol European Trial (COMET)
  • 1511 patients receive carvedilol (25 mg BID)
    1518 receive metoprolol (50 mg BID)
  • NYHA II-IV EFlt.35 ACE-I diuretic (if
    tolerated)
  • Mean 58 months in trial
  • Carvedilol reduced all-cause (HR .83) and CV
    (.80) mortality relative to meto


Deaths Deaths
Poole-Wilson. Lancet 20033627-13
29
Combination of isosorbide and hydralazine in
blacks with HF
  • V-HeFT I suggests that black patients more likely
    to benefit
  • 1050 blacks randomized to fixed dose iso/hydra or
    placebo standard therapy
  • NYHA III IV
  • Improved survival and QOL

Iso Hydra
Overall survival ()
Placebo
Days since baseline visit
Taylor. NEJM 20043512049-2057
30
Is there a role for positive inotropes for any
patients with CHF?1
  • Cardiogenic shock
  • Congestion, hypoperfusion no shock?
  • Support until resolution of other conditions2
  • Hospitalization for HF, no need3
  • Intermittent outpatient therapy?
  • Bridging until transplant?
  • Destination end of life care?

1Stevenson. Circulation 2003108367-72 2Hayes.
NEJM 19943301717-22 3Cuffe. JAMA 20022871541-7
31
Levosimendam vs dobutamine for severe low-output
HF (LIDO study)
  • 203 patients
  • Levo 24 mg/kg 10 min 0.1 mg/kg/min vs dob 5
    µg/kg/min
  • 1o outcome CO to ? 30 PCWP ?25
  • 28 Levo patients, 15 dob patients achieved
    primary outcome
  • Fewer deaths with levo (HR 0.57)

Levo
Dob
Percent surviving
Time (days)
Follath. Lancet 2002360196-202
32
Nesiritide (B-type natriuretic peptide) for acute
exacerbations of HF
  • Nesiritide better than nitroglycerine or placebo
    added to standard therapy for decompensated CHF
    (hemodynamics, symptoms)
  • Nesiritide better than dobutamine for
    decompensated CHF (premature beats, tachycardia)

Am Heart J 20021441102-8 JAMA
20022871531-40 J Cardiothorac Vasc Anesth
200418780-7
33
Management of Heart Failure Acute vs. Chronic
  • Chronic heart failure (CHF)
  • Perioperative acute heart failure
  • Summary

34
Reduced cardiac output syndrome in cardiac surgery
  • GA surgery neuroendocrine response
  • CPB
  • Hemodilution
  • Hypothermia
  • ?Ca, ?Mg
  • ?1-AR downregulation
  • Systemic inflammatory response
  • Ischemia reperfusion stunning with aortic
    clamping or OPCAB
  • Preexisting congenital, coronary, or valvular
    heart disease all ? CHF
  • Occasional vasoparesis syndrome

35
Routine myocardial dysfunction and recovery after
CABG

4 hr 8-16 hr
Breisblatt JACC 1990151261-9
36
Potential mechanisms of reversible heart failure
after heart surgery
  • Stunning
  • Follows ischemia and reperfusion
  • Normal CBF and MVO2
  • Treatable with positive inotropes
  • Reverses over time
  • Hibernation
  • Ischemia

Bolli. Circulation 1992861671-91
37
Potential mechanisms of reversible heart failure
after heart surgery
  • Stunning
  • Hibernation
  • Associated with chronic ischemia
  • ?CBF
  • Recruitable by dobutamine stress echo
  • Viable by PET study
  • Potentially reversible with revascularization
  • Ischemia

Bolli. Circulation 1992861671-91
38
Potential mechanisms of reversible heart failure
after heart surgery
  • Stunning
  • Hibernation
  • Ischemia
  • ?CBF
  • Reversible with drugs or revascularization

Bolli. Circulation 1992861671-91
39
Factors associated with inotropic drug support in
elective coronary surgery
  • Older age
  • Female sex
  • Cardiac enlargement on chest radiograph
  • Reduced LVEF
  • Greater LV end-diastolic pressure
  • Prolonged CPB and Aortic X-clamp times

Royster. Anesth Analg 1991 72729-36
40
Factors associated with use of positive inotropes
in valve surgery
  • Control group from neuroprotection RCT
  • Logistic regression
  • Multivariate associations age gt60, CHF, LVEF
    -5, anesthesiologist
  • Unlike CABG, no association with female sex, CPB
    time

Odds ratios in multivariate logistic model
Butterworth. Anesth Analg 199886461-7
41
Positive inotropic drugs
  • cAMP independent agents
  • Cardiac glycosides
  • Calcium salts
  • Liothyronine (T3)
  • ?-AR agonists
  • Calcium sensitizers
  • cAMP dependent agents
  • ß-adrenergic agonists
  • Epinephrine
  • Dobutamine
  • Dopaminergic agonists
  • Dopamine
  • Dopexamine
  • Phosphodiesterase inhibitors
  • Milrinone
  • Inamrinone
  • Olprinone

42
CaCl2 does not increase CI after CABG
  • N12 patients
  • Studied on 1st postoperative day cross-over RCT
  • CaCl2 10 mg/kg bolus 2 mg/kg/hr
  • CaCl2 ?Cai ?MAP, but no ?CI

,
L/min/m2
plt.05 vs BL plt.05 vs Ca
Zaloga. Circulation 199081196-200
43
Ca sensitizing agents levosimendam
Cardiac output (L/min)
  • Binds to troponin C Cai dependently
  • Does not impair diastolic relaxation
  • Hemodynamic effects continue 24 hours after drug
    stopped in CHF patients active metabolite?
  • Small trials in cardiac surgery patients using
    8-36 µg/kg loading doses 0.2-0.3 µg/kg/min
    infusion (?CO, ?SVR and ?PVR)
  • Not available in USA

µg/kg
µg/kg
Elapsed time (min)
Kivikko. Circulation 200310781-86 Follath.
Lancet 2002360196-202 Nijhawan. J CV Pharmacol
199934219-28 Lilleberg. Eur Heart J
199819660-8
44
Positive inotropic drugs
  • cAMP independent agents
  • Cardiac glycosides
  • Calcium salts
  • Liothyronine (T3)
  • ?-AR agonists
  • Calcium sensitizers
  • cAMP dependent agents
  • ß-adrenergic agonists
  • Epinephrine
  • Dobutamine
  • Dopaminergic agonists
  • Dopamine
  • Dopexamine
  • Phosphodiesterase inhibitors
  • Milrinone
  • Inamrinone
  • Olprinone

45
Stevenson. Circulation 2003108492-7
46
Dobutamine increases HR more than epinephrine
after CABG
change
  • 52 patients recovering from CABG awake and
    extubated in the ICU
  • Dob 2.5 5 ?g/kg/min Epi 10 30 ng/kg/min
  • After high dose, stroke volume index similar
    Dob ?HR more than Epi

Butterworth. J Cardiothorac Vasc Anes
19926535-41
47
Fullerton left vs right atrial administration of
epi
Greater ?cardiac output, less ?PA pressure with
left atrial than right atrial epinephrine
infusion (70 ng/kg/min)
48
Renal dose dopamine does not always produce
renal concentrations
DA in ?g/L
  • 9 healthy male volunteers received DA 3 10
    ?g/kg/min
  • HPLC measurement of arterial DA
  • Great variation in DA concentrations
  • t1/2 ?, ? 0.5, 12.3 min

DA infusion rate (?g/kg/min)
MacGregor. Anesthesiology 200092338-46
49
Milrinone, an effective first-line inotrope to
wean sick patients from CPB
  • 30 patients LVEF 35 or mean PAP 20 mmHg
  • Recd milrinone 50 µg/kg 0.5 µg/kg/min or
    saline prior to end of CPB
  • Successful separation in 15/15 milrinone patients
    but only 5/15 saline
  • Failures separated from CPB when given milrinone

N
Doolan. J Cardiothorac Vasc Anesth 19971137-41
50
Milrinone prevents low cardiac output syndrome
after correction of congenital heart disease
  • 238 patients
  • 3 groups
  • Placebo
  • 25 µg/kg 0.25 µg/kg/min
  • 75 µg/kg 0.75 µg/kg/min
  • 64 reduced incidence of LCOS by 75 µg/kg dose

Hoffman et al. Circulation 2003107996-1002
51
Drug Interactions
  • Drugs can interact additively, synergistically,
    or antagonistically
  • Interaction between ?-AR agonists and PDE
    inhibitors is at least additive, possibly
    synergistic
  • Interaction between Ca salts and ?-AR agonists is
    antagonistic
  • Interaction between dobutamine (partial agonist)
    and epinephrine (full agonist) can be antagonistic

52
Calcium inhibits dobutamine
Calcium inhibits cardiac stimulation by
dobutamine (5 µg/kg/min) after CABG
Cardiac output
Stroke volume
Increase
Plt.05
After Ca Ca 1.61 mM
Before Ca Ca 1.13 mM
Butterworth. Chest 1992101174-80
53
Dobutamine antagonizes epinephrine CI and cAMP
production
cAMP production pmol/106 cells/10 min
  • DB or Epi ?CI dose dependently in patients
  • DB Epi less CI response than epi alone
  • DB or Epi ?cAMP production in lymphs
  • DB Epi 10-6M response no greater than DB
    (partial agonist)

log DB (mol/L)
Prielipp. Anesthesiology 19988949-57
54
Amrinone epi Royster
Inamrinone (1.5 mg/kg) adds to epi (30 ng/kg/min)
after CPB Royster et al. Anesth Analg
199377662-72
Plac Plac
Plac Epi
Inam Plac
Inam Epi
Minutes
55
Management of Heart Failure Acute vs. Chronic
  • Chronic heart failure
  • Perioperative acute heart failure
  • Summary

56
Management of Heart Failure Acute vs. Chronic
Summary
  • Chronic Heart Failure
  • Neurohormones (R-A-A)
  • Remodeling
  • HF with preserved LVF
  • BNP
  • Treatment
  • ACE-Is
  • ß-ARBs
  • Aldo antagonists
  • ARBs if ACE-I intolerant
  • Digoxin, loop diuretics
  • Levosimendan
  • Nesiritide
  • New perioperative LV dysfunction (NOT CHF)
  • ischemia
  • stunning
  • hibernation
  • cAMP independent agents not useful (except
    levosimedan?)
  • PDE inhibitors effective likely synergize ?-AR
    agonists
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