Cardiac Pharmacology: Ideas For Advancing Your Clinical Practice The image cannot be displayed. Your computer may not have enough memory to open the image, or 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 RISK BENEFIT Cardiotonic Agents? Patient Outcome? 1
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-β 1 Adrenoceptor polymorphism Ach Pharmacol 375:303-309, 2007 2
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 3
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-proBNP 1-134 probnp 1-108 Active components Inactive components probnp 1-108 BNP 1-32 NT-proBNP BNP 3-32 BNP 7-32 BNP CLINICAL APPLICATIONS Diagnostic Modality (Bio marker) CHF (dyspnea) Noncardiac Surgery Cardiac Surgery Treatment Modality CHF Cardiac Surgery 4
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 5
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 6
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 7
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 8
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 9
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 10
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 11
ORAL AGENTS PDE-V INHIBITORS PDE V Inhibitors Clinical Applications Primary pulmonary hypertension Secondary pulmonary hypertension Valvular disease PIH CHF Congenital heart disease Half Life PDE V Inhibitors Sidenafil (4-5 hours) Tadalafil (17.5 hours) 12
COMBINATION THERAPY camp + cgmp ACh + Bradykinin A232877 + G q UK 14304 + G i Θ Phospholipase C Adenylate Cyclase Pertussis Toxin Ca 2+ L-Citrulline Pulmonary Endothelial Cell NO SNP TNG L-Arginine NO Synthase Guanylate Cyclase GTP Relaxation EDRF/NO cgmp Vascular Smooth Muscle Cell Treatment of Pulmonary Hypertension New Strategies Inhalational Agents New Oral Agents (PDE-V) Combination Therapy (camp + cgmp) 13
VASOPRESSIN Dx Vasodilatory Shock 14
Vasodilatory Shock Components MAP < 65 mmhg SVR < 650 dynes/sec/cm -5 CI > 2.5 l/min/m 2 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 15
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) 16
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, T 4 or Free T 4 ) Additional New Findings: Inotropic support with Milrinone (preop) Conferred protection against vasoplegia (Patarroyo et al: J Heart Lung Transplant, 2011) Thyroid Hormone (CPB) 17
Thyroid Hormone and Cardiac Surgery Impact of CPB on Thyroid Function Low T3 Syndrome Serum T 3 Normal T 4 and TSH rt 3 Total serum and free T 3 levels from 50-70% in post CPB period Decrease persists for 1-4 days Low T 3 Syndrome and CPB Proposed Mechanisms: Hypothermia Hemodilution Activation of inflammatory mediators Peripheral conversion of T 4 / T 3 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 18
T 3 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 T 3 states Administration of T 3 reverses hemodynamic derangements May donor pool (by vasopressor requirements) EMERGING DRUGS 19
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 K ATP Channels Levosimendan Hemodynamic Effects CO (+ myocardial 0 2 consumption) Peripheral vasodilation Coronary artery dilation + Lusotrophic effect LV filling pressures No effect on PVR Half Life 1 hour 20
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: Will it Result in Improved Outcomes? Anesth Analg 164:766-773, 2007 SUMMARY Natriuretic Peptide Pulmonary Vasodilators Vasopressin Thyroid Hormone 21
SUMMARY Emerging Drugs: Levosimendan? Clinical Application? 22
23