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Cardiac Pharmacology: Ideas For Advancing Your Clinical Practice
Roberta L. Hines, M.D. Nicholas M. Greene Professor
Chair, Department of Anesthesiology Yale University School of Medicine
New Haven, CT
WHY ADMINISTER
CARDIOTONIC AGENTS ?
KEY QUESTION
? Patient Outcome ?
RISK BENEFIT Cardiotonic
Agents
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CAN WE IDENTIFY PATIENTS WHO
MAY BENEFIT FROM CARDIOTONIC
AGENTS?
In Patients Chronically Treated
with Metoprol, the Demand of Inotropic Catecholamine Support After CABG is Determined by the
Arg 389 Alg-β1 Adrenoceptor polymorphism
Ach Pharmacol 375:303-309, 2007
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LECTURE OBJECTIVES
Natriuretic Peptides Biology/Actions Prognostic/Diagnostic Valve Clinical Applications
Pulmonary Vasodilators
Physiological Advantage (Inhaled) PDE-V Inhibitors
Vasopressin
Hemodynamic Effects Clinical Applications
LECTURE OBJECTIVES
Vasoplegic Syndrome Thyroid Hormone Emerging Drugs: Levosimendan Pharmacology Clinical Indications
NATRIURETIC PEPTIDE
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Natriuretic Peptides Site of Synthesis
Heart ANP – atria in response to stretch BNP (Brain/B-type) – ventricle
Clinical effects modulated via specific receptors cGMP is second messenger
Pre-proBNP1-134
proBNP1-108
Inactive components
Active components
proBNP1-108
BNP1-32
BNP3-32
BNP7-32
NT-proBNP
BNP CLINICAL APPLICATIONS
Diagnostic Modality (Bio marker) Treatment Modality
CHF (dyspnea) Noncardiac Surgery Cardiac Surgery CHF Cardiac Surgery
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BNP and Pro-B-Type Natriuretic
Peptide
Diagnostic Applications
BNP, Age and Heart failure
90%, young healthy, BNP ≤ 25pg/ml
NT-proBNP ≤ 75pg/ml
Daniels LB, Maisel AS: J Am Coll Cardiol: 2007;50:2357
Clinical Caveat
The Introduction of Beta Blockade Increase
Plasma BNP and NT-pro BNP Levels
J Cardiovasc Pharmacol Therap 12(2):85-89, 2007
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BNP Congestive Heart Failure
Diagnostic Estimate filling pressures
Prognosticate adverse outcomes (dyspnea)
Confirm diagnosis (BNP > 100 pg/ml)
Circulation 105: 2392-2397, 2002 N Engl J Med 345: 1014-1021, 2001
Does BNP Have a Role in Perioperative Risk Assessment?
Heart 2006;92;1645
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Prognostic Value of Brain Natriuretic Peptide in Noncardiac Surgery
(A Meta-Analysis)
Anesthesiology 111:311-9, 2009
Meta-Analysis Results
(n = 15 publications)
Preoperative ↑ BNP → ↑ MACE ↑ All Cause Mortality ↑ Cardiac Death Results revealed ↑ risk for both
short term (< 43 days) and long term (> 6 mos) complications
Anesthesiology 111:311-9, 2009
BNP and Postoperative Outcomes Possible Etiologies
↑ BNP identifies patient with impaired CV function
↑ BNP identifies patients with ↑ ischemic
burden Preoperative BNP level strongly
associated with short-term (major adverse cardiac events) MACE
Anesthesiology 111:311-9, 2009
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Nt-Pro BNP in Cardiac Surgery Patients
Is It Helpful?
Levels Associated Need for inotropic Agents IABP Insertion Renal Failure ICU Stay
Anaesth Scand 52:182-187, 2008
BNP Treatment
Applications
Brain Natriuretic Peptides
HEMODYNAMIC EFFECTS
Vasodilation (preferentially acts on the venous system)
↓ CVP ↓ PCWP ↓ SVR ↓ PVR
No direct inotropic effect
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Nesiritide Administration in Patients with Left
Ventricular Dysfunction Undergoing CABG
J Am Coll Cardiol 2007; 45:727-728
NAPA : Objectives
To explore the effects of perioperative administration of nesiritide on clinical outcomes
and safety in heart failure patients undergoing cardiac
surgery
NAPA Trial Design
• Multi-center (54 centers) • Randomized • Double-blind • Placebo-controlled
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NAPA Trial Design
• LV dysfunction (EF < 40%) • NYHA Class II – IV • Undergoing CABG + MVS • Using cardiopulmonary
bypass
NAPA Findings
• Improved survival at 180 days • Improved Postop Renal Function
Greater improvement in patients with renal dysfunction at baseline
• Decreased LOS
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PULMONARY VASODILATORS
Selective Pulmonary Vasodilators
Inhaled Agents Nitric Oxide Nitroglycerin Prostacyclin/Prostaglandins PDE-III / PDE-V Inhibitors Oral Agents (PDE-V Inhibitors) Sildenafil Tadalafil
PULMONARY VASODILATORS CLINICAL INDICATIONS
(Inhaled)
Management of pulmonary hypertension (acute and chronic)
Rx of right ventricle dysfunction Challenges
Selectivity Matching ventilation / perfusion
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ORAL AGENTS
PDE-V INHIBITORS
PDE – V Inhibitors
Clinical Applications Primary pulmonary hypertension Secondary pulmonary hypertension Valvular disease PIH CHF Congenital heart disease
PDE – V Inhibitors
Half – Life
Sidenafil (4-5 hours)
Tadalafil (17.5 hours)
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COMBINATION THERAPY
cAMP + cGMP
Pulmonary Endothelial Cell
Guanylate Cyclase cGMP GTP
Relaxation
Vascular Smooth Muscle Cell
NO¯ SNP TNG
ACh A232877
Gq
Ca2+
Phospholipase C
Gi Adenylate Cyclase
Pertussis Toxin Θ
L-Arginine
L-Citrulline
EDRF/NO NO Synthase
UK 14304
+
+
+Bradykinin
Treatment of Pulmonary Hypertension
New Strategies
Inhalational Agents New Oral Agents (PDE-V) Combination Therapy (cAMP + cGMP)
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VASOPRESSIN
Dx
“Vasodilatory Shock”
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Vasodilatory Shock Components
MAP < 65 mmHg
SVR < 650 dynes/sec/cm-5 CI > 2.5 l/min/m2 Catecholamine resistance
Vasodilatory Shock Etiology
Levels of Endogenous AVP
AVP : Hemodynamic Effects
↑ BP ↑ SVR ↓ Catecholamine requirements + ↑ Urinary output Caveat Should not be used for Rx of ↓ BP/CO unless : ↓ SVR ↑ CI
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VASOPLEGIC SYNDROME
Preoperative Risk Factors and Clinical Outcomes Associated
with Vasoplegia in Recipients of Orthotopic Heart Transplantation
in the Contemporary Era
Patarroyo M, Simbaqueba C, Shrestha K, Starling RC, et al
J Heart Lung Transplant (2011)
Vasoplegic Syndrome
SVR (<800 dynes) Despite : > 2 pressors
Epinephrine > 4mcg/min Norepi > 4 mcg/min Dopamine > 5mcg/kg/min Vasopressin > 1 U/hr
Preserved CI > 2.5 L/min Time of onset 6-48 hrs after surgery Rx : Methylene Blue (Patarroyo et al: J Heart Lung Transplant, 2011)
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Results (n = 348 OHT’s)
11% developed vasoplegia Risk Factors (demonstrated in previous studies)
Unos Status 1A BSA, BMI Preop ASA Previous cardiac surgery Mechanical Support
(Patarroyo et al: J Heart Lung Transplant, 2011)
Newly Identified Risk Factors
Hypothyroidism ( TSH, T4 or Free T4 ) Additional New Findings:
Inotropic support with Milrinone (preop) Conferred protection against vasoplegia
(Patarroyo et al: J Heart Lung Transplant, 2011)
Thyroid Hormone
(CPB)
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Thyroid Hormone and Cardiac Surgery
Impact of CPB on Thyroid Function
“Low T3 Syndrome” Serum T3 Normal T4 and TSH rT3
• Total serum and free T3 levels from 50-70% in post CPB period • Decrease persists for 1-4 days
Low T3 Syndrome and CPB
Proposed Mechanisms:
Hypothermia Hemodilution Activation of inflammatory
mediators Peripheral conversion
of T4/ T3
Clinical Studies In High Risk Patients
Demonstrate : CO SVR
Incidence of atrial fibrillation
need for inotropic agents in post ischemic hearts
J Thorac Cardiovasc Surg 98:972-975, 1998 Engl J Med 333:1522-1527, 1995
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T3 Adult Cardiac Surgery
CABG : (conflicting evidence) May reduce need for inotropes in patients EF<40 May have a role as part of multi modal therapy for pts with EF
Anesth Analg 85:30-36, 1997; JAMA 275:687-692, 1996 J Thorac Cardio Vasc Surg 98:972-977, 1989
Role of Thyroid Hormone Administration in Potential
Organ Donors
Following BSD: Low T3 states Administration of T3 reverses hemo-dynamic derangements May donor pool (by vasopressor requirements)
Arch Surg 136:1377-1380, 2001
EMERGING DRUGS
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Emerging Drugs
Levosimendan
Levosimendan
Mechanisms of Action Inotrope/vasodilator (inodilator) Calcium sensitizing properties Increases sensitivity of contractile proteins to Ca
Binds calcium-dependently to cardiac troponin-C
No change in cytosolic Ca Opens KATP Channels
Levosimendan Hemodynamic Effects
CO (+ myocardial 02 consumption) Peripheral vasodilation Coronary artery dilation + Lusotrophic effect LV filling pressures No effect on PVR
Half Life – 1 hour
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Levosimendan
Early Clinical Applications Decompensated CHF Combination Therapy Worsening or refractory CHF Cardiac Surgery (EF<30%)
Eur Heart J 22:1527-1560, 2001
Anesth Analg 90:5-11, 2000 Lancet 360:196-202, 2002
Levosimendan in Cardiac Surgery: A Unique Drug for the Treatment of Perioperative Left Ventricular Dysfunction or Just Another Inodilator Searching for
a Clinical Application
Question:
Anesth Analg 164:766-773, 2007
Will it Result in Improved Outcomes?
SUMMARY Natriuretic Peptide
Pulmonary Vasodilators
Vasopressin
Thyroid Hormone
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SUMMARY Emerging Drugs:
Levosimendan
? Clinical Application ?
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