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PERIOPERATIVE VENTRICULAR DYSFUNCTION: CURRENT STRATEGIES FOR MANAGING SERIES 2000 copyright Sanofi-Synthelabo, and Ventiv Healthcare CURRENT CONCEPTS IN CARDIAC SURGERY Changing demographics and increasing use of angioplasty, stenting, and platelet inhibitors Older patients with greater myocardial dysfunction and increased comorbidities Estafanous FG, et al. Ann Thorac Surg. 1998;65:383-389. Fontana GP. Chest Surg Clin N Am. 1998;8:871-890. Verrier ED. J Am Coll Surg. 1999;188:104-110. CURRENT CONCEPTS IN CARDIAC SURGERY (CONTD) Expanding use of beating heart and minimally invasive cardiac surgical techniques Alternative surgical therapies for treating congestive heart failure (CHF) Estafanous FG, et al. Ann Thorac Surg. 1998;65:383-389. Fontana GP. Chest Surg Clin N Am. 1998;8:871-890. Verrier ED. J Am Coll Surg. 1999;188:104-110. NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL CLASSIFICATION Class I No symptoms or limitations on ordinary activity Class II Slight limitation of physical activity. Ordinary activity results in fatigue, dyspnea, or angina Goldman L, et al. Circulation. 1981;64:1227-1234. NYHA FUNCTIONAL CLASSIFICATION (CONTD) Class III Marked limitation of physical activity. Patients are asymptomatic at rest and can carry out only very limited physical activity Class IV Inability to perform any physical activity without developing symptoms. Some symptoms are present even at rest Goldman L, et al. Circulation. 1981;64:1227-1234. MEDICAL THERAPY OF HEART FAILURE Diuretics Angiotensin-converting enzyme inhibitors b-Adrenergic–receptor blockers (mild to moderate heart failure) Digoxin Vasodilators—oral/intravenous (IV) IV inotropic/inodilator agents (acute decompensation) b1- AND b2-ADRENERGIC RECEPTOR Receptor density (fmol/mg) SUBPOPULATIONS IN HUMAN VENTRICULAR MYOCARDIUM 100 75 b1- and b2-receptor densities in ventricular myocardial membranes prepared from nonfailing (n = 27) and failing (n = 28) human hearts *P<.05 50 25 0 Total Bristow MR, et al. Circ Res. 1986;59:297-309. b1 b2 ANALYSIS OF b-ADRENERGIC RECEPTOR LEVELS IN HUMAN VENTRICULAR BIOPSY SPECIMENS Progressive reduction of b1-adrenergic receptors in heart failure NYHA Class II 7% NYHA Class III 26% NYHA Class IV >50% Reduction in b1 Receptor Levels (%) Engelhardt S, et al. J Am Coll Cardiol. 1996;27:146-154. DIRECT EVIDENCE OF ACUTE CARDIAC b-RECEPTOR DESENSITIZATION DURING CARDIOPULMONARY BYPASS (CPB) IN HUMANS Acute b1-receptor desensitization—20% Proposed etiology Uncoupling of G-protein from b1-receptor complex Impaired adenylate cyclase activity b2-receptor density unchanged Abraham WT, et al. In: Poole-Wilson PA, et al, eds. Heart Failure. 1997:127-141. Booth JV, et al. Anesthesiology. 1998;89:602-611. Landolfo K, et al. Anesth Analg. 1997;84:SCA 6. Abstract. Schwinn DA, et al. Circulation. 1991;84:2559-2567. Smiley R, et al. Anesth Analg. 1992;74:212-218. SYMPATHETIC DOWN-REGULATION IN HEART FAILURE* Normal NE E b1 b1 AC +++ +++ cAMP Down-regulated +++ Contractility NE NE NE E b1 *NE indicates norepinephrine; E, epinephrine; AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate. Braunwald E. Heart Disease: A Textbook of Cardiovascular Medicine. 1992:393-443. AC + cAMP + +Contractility b-BLOCKADE IN CHRONIC HEART FAILURE Previous thinking: contraindicated Short-term adverse effects Current thinking: indicated in stable mild to moderate heart failure Australia/New Zealand Heart Failure Research Collaborative Group. Lancet. 1997;349:375-380. Colucci WS, et al. Circulation. 1996;94:2800-2806. Packer M, et al. Circulation. 1996;94:2793-2799. Packer M, et al. N Engl J Med. 1996;334:1349-1355. EFFECTS OF b-BLOCKADE IN CHRONIC HEART FAILURE Improves cardiac function ejection fraction (EF) left ventricular (LV) end-diastolic volume LV end-systolic volume Australia/New Zealand Heart Failure Research Collaborative Group. Lancet. 1997;349:375-380. CIBIS-II Investigators and Committees. Lancet. 1999;353:9-13. Colucci WS, et al. Circulation. 1996;94:2800-2806. Merit HF Study Group. Lancet. 1999;353:2001-2007. Packer M, et al. Circulation. 1996;94:2793-2799. Packer M, et al. N Engl J Med. 1996;334:1349-1355. EFFECTS OF b-BLOCKADE IN CHRONIC HEART FAILURE (CONTD) Reduces symptoms and improves functional class Slows disease progression Reduces risk of hospitalization Improves survival Australia/New Zealand Heart Failure Research Collaborative Group. Lancet. 1997;349:375-380. CIBIS-II Investigators and Committees. Lancet. 1999;353:9-13. Colucci WS, et al. Circulation. 1996;94:2800-2806. Merit HF Study Group. Lancet. 1999;353:2001-2007. Packer M, et al. Circulation. 1996;94:2793-2799. Packer M, et al. N Engl J Med. 1996;334:1349-1355. CARDIAC SURGERY IN PATIENTS WITH DIABETES Diffuse multivessel coronary artery disease Increased preoperative and perioperative myocardial infarction rate Less distensible ventricle due to interstitial glycoprotein Potential for autonomic dysfunction Factor SM, et al. N Engl J Med. 1980;302:384-388. Hiramatsu K, et al. Am J Cardiol. 1992;70:1185-1189. CARDIAC SURGERY IN PATIENTS WITH DIABETES (CONTD) Catecholamines worsen hyperglycemia Increased renal insufficiency, sternotomy complications, and sepsis Increased peripheral vascular disease and intra-aortic balloon pump complications Increased hospital stay and costs Factor SM, et al. N Engl J Med. 1980;302:384-388. Hiramatsu K, et al. Am J Cardiol. 1992;70:1185-1189. IMPLICATIONS OF BEATING-HEART SURGERY Beating heart with controlled myocardial ischemia Hemodynamic instability produced by mechanical stabilizers and manipulation Vasoactive and inotropic support may be required during acute periods of surgical revascularization ACUTE MYOCARDIAL DYSFUNCTION AND RECOVERY AFTER CORONARY SURGERY 60 Percentage 50 40 LVEF = left ventricular ejection fraction 30 RVEF = right ventricular ejection fraction 20 Preop Immed postop Nadir (~4 h) Recovery (6-7 h) 10 0 RVEF Breisblatt WM, et al. J Am Coll Cardiol. 1990;15:1261-1269. LVEF RISK FACTORS FOR LOW CARDIAC OUTPUT AFTER CPB Preoperative LV dysfunction Long aortic cross-clamp time and total CPB time Incomplete cardiac surgical revascularization Emergency surgery Persistent ischemia Reperfusion injury and inflammatory changes Hardy JF, et al. J Cardiothorac Vasc Anesth. 1993;7:33-39. RISK FACTORS FOR LOW CARDIAC OUTPUT AFTER CPB (CONTD) Dysrhythmias Pulmonary hypertension and right ventricular (RV) failure Hardy JF, et al. J Cardiothorac Vasc Anesth. 1993;7:33-39. PREOPERATIVE AND INTRAOPERATIVE PREDICTORS OF INOTROPIC SUPPORT AND LONGTERM OUTCOME IN PATIENTS HAVING CABG Lower preoperative EF Older age Cardiac enlargement on chest x-ray Female sex Higher baseline and postcontrast LV end-diastolic pressure Prolonged bypass or ischemic time Royster RL, et al. Anesth Analg. 1991;72:729-736. FACTORS THAT PREDICT THE NEED FOR INOTROPIC DRUG SUPPORT DURING CARDIAC VALVE SURGERY Increased age History of CHF Increased length of CPB Decreased LVEF Pulmonary hypertension Concurrent coronary artery bypass graft (CABG) Butterworth JF, et al. Anesth Analg. 1998;86:461-467. CONSEQUENCES OF “FAILED WEAN” FROM CPB Ventricular distention ischemia contractility Added pump time Increased risk of coagulopathy, pulmonary dysfunction, and neurological injury Greater risk of atrial and ventricular dysrhythmias Lewis KP. J Cardiothorac Vasc Anesth. 1993;7:40-45. Parr GVS, et al. Circulation. 1975;51:867-874. CONSEQUENCES OF “FAILED WEAN” FROM CPB (CONTD) Systemic hypotension and organ injury Subsequent need for mechanical support Additional operating room time and costs Lewis KP. J Cardiothorac Vasc Anesth. 1993;7:40-45. Parr GVS, et al. Circulation. 1975;51:867-874. POTENTIAL ROLE OF EARLY INOTROPIC THERAPY FOR WEANING FROM CPB Reduced incidence of Ventricular distention Need for mechanical assist devices Multiorgan dysfunction Decreased time on CPB Decreased cost Doolan LA, et al. J Cardiothorac Vasc Anesth. 1997;11:37-41. ADVANTAGES OF INTRAOPERATIVE ECHOCARDIOGRAPHY Systolic and diastolic function LV volume Regional wall motion Direct valve assessment Assessment of the aorta PERIOPERATIVE ECHOCARDIOGRAPHY: DIAGNOSTIC INDICATIONS Hemodynamic instability of uncertain etiology Valve anatomy and function Aortic assessment Valve repair or replacement Congenital heart surgery Aortic dissection or aneurysm High-risk myocardial revascularization PERIOPERATIVE ECHOCARDIOGRAPHY: DIAGNOSTIC INDICATIONS (CONTD) Ventricular assist devices Endocarditis Intracardiac air or mass Assessment of myocardial infarction complications Assessment during beating-heart and minimally invasive cardiac surgery ADVANTAGES OF INTRAOPERATIVE ECHOCARDIOGRAPHY Transesophageal echocardiography (TEE) can measure cardiac output and indicate why it is low Global LV and RV dysfunction Regional LV dysfunction (ischemia) LV volume Valvular dysfunction INTRAOPERATIVE ECHOCARDIOGRAPHIC ASSESSMENT OF AORTA TEE Dissection Type I, II, or III, AR, hemopericardium Aneurysm Location, size, thrombus Epiaortic echo Identifies atherosclerosis of the ascending aorta Risk factor for perioperative CNS injury Wareing TH, et al. Ann Thorac Surg. 1993;55:1400-1407. INTRAOPERATIVE ECHOCARDIOGRAPHY: HIGH-RISK CORONARY BYPASS Major management alteration Surgical (33%) Pharmacologic therapy (51%) Reduced morbidity and mortality (retrospective) Myocardial infarction (1.2% vs 3.8%) In-hospital CNS morbidity (1.2% vs 3.3%) Hospital mortality (1.2% vs 3.8%) Savage RM, et al. Ann Thorac Surg. 1997;64:368-373. SYSTOLIC AND DIASTOLIC FAILURE Normal CHF (systolic failure) Compliance (diastolic failure) Normal USE OF IV POSITIVE INOTROPIC DRUGS IN CARDIAC SURGERY Incidence of drug usage varies widely Administered in response to ventricular dysfunction during weaning from bypass Therapy usually continued to the ICU Additional therapy may be required in ICU; however, consider other reversible causes Clinical Process Improvement Program. Clinical Process Improvement: Coronary Artery Bypass Graft (CABG) Clinical Benchmarking Database. Report #2, 1996. Royster RL. J Cardiothorac Vasc Anesth. 1993;7:19-25. COMPLICATIONS OF SYMPATHOMIMETIC THERAPY Dysrhythmias Altered systemic and pulmonary vascular resistance Myocardial ischemia Electrolyte disturbances Hyperglycemia USE OF INOTROPIC AGENTS AND DYSRHYTHMIAS Any inotropic agent may exert proarrhythmic effects by increasing intracellular cAMP Patients with LV dysfunction may be more prone to nonsustained ventricular tachycardia with any inotropic therapy The incidence of dysrhythmias attributable to all inotropic agents is similar and relatively low Naccarelli GV, et al. Am J Cardiol. 1989;63:35A-40A. GOALS OF THERAPY Maintain organ perfusion pressure Maintain myocardial O2 supply Optimize O2 delivery Optimize ventricular loading conditions Optimize pulmonary and systemic arterial afterload conditions PHARMACOLOGIC APPROACHES FOR PERIOPERATIVE BIVENTRICULAR DYSFUNCTION Vasodilator therapy Inotropic agents Catecholamines Phosphodiesterase inhibitors Digoxin, calcium, T3 New agents Not within product labeling currently approved by the USFDA. currently approved by the FDA for use in the United States. Pulmonary vasodilators Phosphodiesterase inhibitors Inhaled nitric oxide Prostaglandins Not Bailey JM, et al. Adult Cardiac Surgery. 1997:225-254. Bennett-Guerrero E, et al, for the Duke T3 Study Group. JAMA.1996;275:687-692. Levy JH. J Cardiothorac Vasc Anesth. 1993;7(suppl):46-51. Royster RL, et al. Cardiovasc Anesth. 1992;74:3-13. VASODILATOR THERAPY Arterial vasodilation decreases ventricular wall stress Venodilation decreases venous return and preload Multiple mechanisms for improving systolic and diastolic dysfunction Nitrate tolerance (chronic use) Therapy may be limited by hypotension Kikura M, et al. Curr Opin Anesth. 1994;7:42-52. Levy JH, et al. Calcium Antagonists in Clinical Medicine. 1997. Levy JH. J Cardiothorac Vasc Anesth. 1993;7(suppl):46-51. Munzel T, et al. Am J Cardiol. 1996;77:24C-30C. Munzel T, et al. J Am Coll Cardiol. 1996;27:297-303. CATECHOLAMINES: SELECTIVITY OF SYMPATHOMIMETIC DRUGS Alpha Phenylephrine Norepinephrine Epinephrine Dopamine Dobutamine Dopexamine Isoproterenol Beta Not currently approved by the FDA for use in the United States. Bailey JM, et al. Adult Cardiac Surgery. 1997:225-254. Levy JH. J Cardiothorac Vasc Anesth. 1993;7(suppl):46-51. PARENTERAL PHOSPHODIESTERASE INHIBITORS Methylxanthines (aminophylline) Bipyridines (milrinone and amrinone) Imidazolones (enoximone) Benzylisoquinolines (papaverine) Not currently approved by the FDA for use in the United States. Bailey JM, et al. Adult Cardiac Surgery. 1997:225-254. Levy JH. J Cardiothorac Anesth. 1993;7(suppl):46-51. INOTROPIC EFFECTS OF PHOSPHODIESTERASE INHIBITORS* b-adrenergic agonists Calcium channel Ca++ Ca++ Extracellular Cell membrane Adenylyl cyclase ATP Phosphodiesterase cAMP Mg++ Phosphorylated active kinase 5' AMP PDE inhibitors Inactive protein kinase Ca++ Ca++ Increased contractility Colucci WS, et al. N Engl J Med. 1986;314:290-299. Intracellular *ATP indicates adenosine triphosphate; AMP, adenosine monophosphate; PDE, phosphodiesterase. PERIOPERATIVE DOSING AND ADMINISTRATION OF MILRINONE Loading dose of 50 mcg/kg over 10 min followed by an infusion of 0.5 mcg/kg/min Titrate (0.25-0.75 mcg/kg/min) depending on effect Weaning protocols vary Half-life may increase with renal and prolonged administration BENEFITS OF EARLY PHOSPHODIESTERASE INHIBITOR ADMINISTRATION Increased inotropy (LV and RV) Pulmonary vasodilation Possible avoidance of mechanical pumps Dilation of internal mammary artery (IMA) Possible prevention of a “failed wean” Doolan LA, et al. J Cardiothorac Vasc Anesth. 1997;11:37-41. Doyle AR, et al. Ann Thorac Surg. 1995;59:S3-S11. Hardy JF, et al. J Cardiothorac Vasc Anesth. 1993;7:33-39. Lobato EB, et al. Br J Anaesth. 1998;81:782-784. MILRINONE EFFECTS ON LV END-DIASTOLIC PRESSURE AND DP/DT ECG dP/dt mm Hg 100 LV 50 0 Baseline Baim DS, et al. N Engl J Med. 1983;309:748-756. Milrinone MILRINONE CONCENTRATION AND CARDIAC INDEX (CI) IN CARDIAC SURGICAL PATIENTS 120 % Change in CI 100 80 60 40 20 0 0 100 200 300 400 Milrinone Concentration (ng/mL) Bailey JM, et al. Anesthesiology. 1994;81:616-622. 500 THE EFFECT OF MILRINONE ON CI AFTER EMERGENCE FROM CPB Changes in CI (mean ± SD) *† 5.0 CI (L/min/m2) * 4.0 * *† *† * 3.0 2.0 1.0 0 3 5 Time (min) Not *† *† *† within product labeling currently approved by the USFDA. Kikura M, et al. Anesth Analg. 1997;85:16-22. 10 MIL 50 MIL 50 + 0.5 MIL 75 + 0.75 Control THE EFFECT OF MILRINONE ON LV FUNCTION AFTER EMERGENCE FROM CPB Changes in velocity of circumferential fiber shortening corrected for heart rate (Vcfc) (mean ± SD) Vcfc (circ/sec) 2.0 *† 1.6 *† *† 1.2 *† *† *† 0.8 0.4 0.0 0 3 5 Time (min) Not within product labeling currently approved by the USFDA. Kikura M, et al. Anesth Analg. 1997;85:16-22. 10 MIL 50 MIL 50 + 0.5 MIL 75 + 0.75 Control THE EFFECT OF MILRINONE ON CI AND VCFC AFTER EMERGENCE FROM CPB CI and Vcfc significantly increased from baseline at 5 and 10 min in all milrinone groups CI and Vcfc were significantly higher at 5 and 10 min than in control group No significant changes in CI and Vcfc were observed in control group Kikura M, et al. Anesth Analg. 1997;85:16-22. CAVEATS OF MILRINONE THERAPY Milrinone is a potent venodilator, therefore give cautiously in the hypovolemic patient If patient has LV outflow tract obstruction and mitral regurgitation due to systolic anterior motion of the mitral valve, milrinone should not be administered Hypotension can be attenuated with slower administration, volume administration, and/or concomitant catecholamines A COMPARISON OF MILRINONE LOADING DOSES IN PATIENTS UNDERGOING CARDIAC SURGERY 4.5 CI (L/min/m2) 4.0 3.5 3.0 2.5 25 mcg/kg 50 mcg/kg 75 mcg/kg 2.0 1.5 B1 B2 2.5 5 7.5 10 20 Elapsed Time (min) Not within product labeling currently approved by the USFDA. Butterworth J, et al. Anesth Analg. 1995;81:783-792. 30 45 60 IN VITRO EFFECTS OF PHOSPHODIESTERASE INHIBITORS ON HUMAN IMA RELAXATION 0 % Relaxation 20 40 60 A = amrinone E = enoximone M = milrinone P = papaverine 80 E A M 100 0.1 1 10 Concentration (mcmol) Not currently approved by the FDA for use in the United States. Salmenpera M, Levy, JH. Anesth Analg. 1996;82:954-957. 100 P 1000 IMA FLOW AFTER MILRINONE AND EPINEPHRINE IMA Flow (mL/min) 60 *P<.05 compared with pretreatment Values are mean ± SD M = milrinone 50 mcg/kg E = epinephrine 0.03 mcg/kg/min * 50 40 30 20 10 0 Before M After M Lobato EB, et al. J Cardiothorac Vasc Anesth. In press. Before E After E MILRINONE IN THE CARDIAC TRANSPLANT SETTING Use to test reversibility of elevated pulmonary vascular resistance Continuation depends on predrug and postdrug hemodynamics List as status Ia or lb and continue agent(s) until transplant Minimal problems with thrombocytopenia Not within product labeling currently approved by the USFDA. Givertz MM, et al. J Am Coll Cardiol. 1996;28:1775-1780. Skoyles JR, et al. J Cardiothorac Vasc Anesth. 1993;6:222-225. MILRINONE IN THE CARDIAC TRANSPLANT SETTING (CONTD) Continue agent(s) as a “tune-up” for days to weeks Optimize oral agents and send home as status II Intraoperative and postoperative use to prevent or treat RV failure Givertz MM, et al. J Am Coll Cardiol. 1996;28:1775-1780. Skoyles JR, et al. J Cardiothorac Vasc Anesth. 1993;6:222-225. PERIOPERATIVE VENTRICULAR DYSFUNCTION IN PEDIATRIC PATIENTS Incomplete repair Prolonged CPB and ischemic time Immature myocardium (very calcium-dependent) Afterload sensitivity Pulmonary hypertension HEMODYNAMIC EFFECTS OF MILRINONE IN NEONATES Increased cardiac output (47%) Decreased systemic vascular resistance (36%) Decreased pulmonary vascular resistance (30%) Decreased right and left atrial pressure Not within product labeling currently approved by the USFDA. Chang AC, et al. Crit Care Med. 1995;23:1907-1914. HEMODYNAMIC EFFECTS OF A LOADING DOSE (50 MCG/KG) OF MILRINONE IN INFANTS AND CHILDREN Increased cardiac output (18%) Decreased blood pressure (12%) Decreased systemic vascular resistance (25%) Not within product labeling currently approved by the USFDA. Bailey JM, et al. Anesthesiology. 1999;90:1012-1018. PHARMACOKINETICS AND DOSING OF MILRINONE IN PEDIATRIC PATIENTS Larger volume of distribution and clearance than adults Clearance is lower in infants than children A 50 mcg/kg loading dose is therapeutic— an additional loading dose may be needed to maintain therapeutic levels Not within product labeling currently approved by the USFDA. Bailey JM, et al. Anesthesiology. 1999;90:1012-1018. Ramamoorthy C, et al. Anesth Analg. 1998;86:283-289. PHARMACOKINETICS AND DOSING OF MILRINONE IN PEDIATRIC PATIENTS (CONTD) A 0.5 mcg • kg-1 • min-1 infusion will maintain therapeutic levels Not within product labeling currently approved by the USFDA. Bailey JM, et al. Anesthesiology. 1999;90:1012-1018. Ramamoorthy C, et al. Anesth Analg. 1998;86:283-289. COMPARISON OF MILRINONE VERSUS AMRINONE Shorter context-sensitive half-life More titratable Less adverse effects on platelets Similar pharmacodynamic profiles Bailey JM, et al. Anesthesiology. 1994;81:616-622. Kikura M, et al. Int Anesthesiol Clin. 1995;33:21-37. Kikura M, et al. Anesth Analg. 1995;81:44-48. Rathmell JP, et al. Anesth Analg. 1998;86:683-690. Salmenpera M, et al. Anesth Analg. 1996;82:954-957. SURGICAL APPROACHES TO HEART FAILURE High-risk myocardial revascularization Mitral valve reconstruction Orthotopic heart transplantation (OHT) Ventricular assist devices (as a bridge to OHT, in lieu of OHT) Partial left ventriculectomy Cardiomyoplasty Not currently approved by the FDA for use in the United States. SURGICAL APPROACHES TO HEART FAILURE: MITRAL VALVE RECONSTRUCTION Preservation of annular-chordal-papillary muscle continuity Maintenance of ellipsoidal chamber geometry Maintenance of LV systolic function Lower LV volume Less end-systolic wall stress Bolling SF, et al. J Thorac Cardiovasc Surg. 1998;115:381-386. PARTIAL LEFT VENTRICULECTOMY WITH MITRAL VALVE REPAIR Not currently approved by the FDA for use in the United States. MECHANICAL CIRCULATORY SUPPORT Intra-aortic balloon pump Abiomed BVS 5000 Bio-Medicus Thoratec Farrar DJ, et al. Ann Thorac Surg. 1996;61:276-282. Frazier OH, et al. Ann Surg. 1995;222:327-338. Jett GK. Ann Thorac Surg. 1996;61:301-304. McCarthy PM, et al. Sem Thorac Cardiovasc Surg. 1994;6:174-180. TCI HeartMate left ventricular assist device (LVAD) Novacor LVAD Axial flow pumps Noon GP, et al. Ann Thorac Surg. 1996;61:291-295. Torchiana DF, et al. J Thorac Cardiovasc Surg. 1997;113:758-769