1. Critical Challenges in Cardiovascular Anesthesiology A Year 2007 Evidence-Based Update Applying Landmark Trials, Emerging Data, & Expert Analysis to Management of Severe or Life-Threatening Blood Pressure Elevations in the Perioperative Setting Critical Challenges in Cardiovascular Anesthesiology A Year 2007 Evidence-Based Update Applying Landmark Trials, Emerging Data, & Expert Analysis to Management of Severe or Life-Threatening Blood Pressure Elevations in the Perioperative Setting Program Co-Chairman Jerrold H. Levy, MD Professor and Deputy Chair for Research Emory University School of Medicine Director of Cardiothoracic Anesthesiology Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia Program Co-Chairman Jerrold H. Levy, MD Professor and Deputy Chair for Research Emory University School of Medicine Director of Cardiothoracic Anesthesiology Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia

2. CME-accredited symposium jointly sponsored by University of Massachusetts Medical Center, office of CME and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from The Medicines Company Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Welcome and Program Overview

3. Program Educational Objectives As a result of this session, cardiovascular anesthesiologists, cardiothoracic surgeons, cardiovascular critical care specialists and related specialists will be able to: As a result of this session, cardiovascular anesthesiologists, cardiothoracic surgeons, cardiovascular critical care specialists and related specialists will be able to: Identify criteria and management strategies for multiple disease states and clinical presentations associated with perioperative hypertension, manifesting as serious and/or life-threatening elevations in systolic and/or diastolic blood pressure. Identify criteria and management strategies for multiple disease states and clinical presentations associated with perioperative hypertension, manifesting as serious and/or life-threatening elevations in systolic and/or diastolic blood pressure. Learn to manage the hemodynamic derangements and complications of serious and/or life-threatening elevations in systolic and/or diastolic blood pressure in the perioperative setting. Learn to manage the hemodynamic derangements and complications of serious and/or life-threatening elevations in systolic and/or diastolic blood pressure in the perioperative setting. Learn evidence-based approaches to prompt and safe lowering of serious elevations in BP in the perioperative setting, using agents that are effective and that have an acceptable safety profile. Learn evidence-based approaches to prompt and safe lowering of serious elevations in BP in the perioperative setting, using agents that are effective and that have an acceptable safety profile. As a result of this session, cardiovascular anesthesiologists, cardiothoracic surgeons, cardiovascular critical care specialists and related specialists will be able to: As a result of this session, cardiovascular anesthesiologists, cardiothoracic surgeons, cardiovascular critical care specialists and related specialists will be able to: Identify criteria and management strategies for multiple disease states and clinical presentations associated with perioperative hypertension, manifesting as serious and/or life-threatening elevations in systolic and/or diastolic blood pressure. Identify criteria and management strategies for multiple disease states and clinical presentations associated with perioperative hypertension, manifesting as serious and/or life-threatening elevations in systolic and/or diastolic blood pressure. Learn to manage the hemodynamic derangements and complications of serious and/or life-threatening elevations in systolic and/or diastolic blood pressure in the perioperative setting. Learn to manage the hemodynamic derangements and complications of serious and/or life-threatening elevations in systolic and/or diastolic blood pressure in the perioperative setting. Learn evidence-based approaches to prompt and safe lowering of serious elevations in BP in the perioperative setting, using agents that are effective and that have an acceptable safety profile. Learn evidence-based approaches to prompt and safe lowering of serious elevations in BP in the perioperative setting, using agents that are effective and that have an acceptable safety profile.

4. Educational Objectives Learn how to select among intravenous pharmacologic agents, including Learn how to select among intravenous pharmacologic agents, including calcium channel blockers (dihydropyridines) that offer unique benefits for calcium channel blockers (dihydropyridines) that offer unique benefits for blood pressure control in the setting of cardiothoracic surgery blood pressure control in the setting of cardiothoracic surgery Learn how landmark trials and analyses focusing on BP reduction Learn how landmark trials and analyses focusing on BP reduction may have an impact on current and future strategies for management of BP may have an impact on current and future strategies for management of BP elevations in the setting of cardiovascular surgery. elevations in the setting of cardiovascular surgery. Be able to assess the need for and implement optimal BP-lowering Be able to assess the need for and implement optimal BP-lowering strategies for patients with serious and/or life-threatening elevations in strategies for patients with serious and/or life-threatening elevations in systolic and/or diastolic BP in the setting of cardiothoracic surgery. systolic and/or diastolic BP in the setting of cardiothoracic surgery. Understand the efficacy and safety profiles of specific pharmacologic Understand the efficacy and safety profiles of specific pharmacologic agents used for anesthesiology-based control of systemic blood pressure. agents used for anesthesiology-based control of systemic blood pressure. Be able to discuss the potential impact that new trials are likely to Be able to discuss the potential impact that new trials are likely to have on future management of patients with BP elevation in the have on future management of patients with BP elevation in the perioperative setting. perioperative setting. Learn how to select among intravenous pharmacologic agents, including Learn how to select among intravenous pharmacologic agents, including calcium channel blockers (dihydropyridines) that offer unique benefits for calcium channel blockers (dihydropyridines) that offer unique benefits for blood pressure control in the setting of cardiothoracic surgery blood pressure control in the setting of cardiothoracic surgery Learn how landmark trials and analyses focusing on BP reduction Learn how landmark trials and analyses focusing on BP reduction may have an impact on current and future strategies for management of BP may have an impact on current and future strategies for management of BP elevations in the setting of cardiovascular surgery. elevations in the setting of cardiovascular surgery. Be able to assess the need for and implement optimal BP-lowering Be able to assess the need for and implement optimal BP-lowering strategies for patients with serious and/or life-threatening elevations in strategies for patients with serious and/or life-threatening elevations in systolic and/or diastolic BP in the setting of cardiothoracic surgery. systolic and/or diastolic BP in the setting of cardiothoracic surgery. Understand the efficacy and safety profiles of specific pharmacologic Understand the efficacy and safety profiles of specific pharmacologic agents used for anesthesiology-based control of systemic blood pressure. agents used for anesthesiology-based control of systemic blood pressure. Be able to discuss the potential impact that new trials are likely to Be able to discuss the potential impact that new trials are likely to have on future management of patients with BP elevation in the have on future management of patients with BP elevation in the perioperative setting. perioperative setting.

5. Program Faculty Solomon Aronson, MD, FACC. FCCP, FAHA, FASE Program Co-Chairman Professor Duke University Medical Center Executive Vice Chair Department of Anesthesiology Durham, NC Jerrold H. Levy, MD Program Co-Chairman Professor and Deputy Chair for Research Emory University School of Medicine Director of Cardiothoracic Anesthesiology Cardiothoracic Anesthesiology and Critical Care and Critical Care Emory Healthcare Atlanta, Georgia Solomon Aronson, MD, FACC. FCCP, FAHA, FASE Program Co-Chairman Professor Duke University Medical Center Executive Vice Chair Department of Anesthesiology Durham, NC Jerrold H. Levy, MD Program Co-Chairman Professor and Deputy Chair for Research Emory University School of Medicine Director of Cardiothoracic Anesthesiology Cardiothoracic Anesthesiology and Critical Care and Critical Care Emory Healthcare Atlanta, Georgia Kevin A. Stierer Sr., MD Chief Cardiac Anesthesia Associate Director Cardiac Surgery ICU Surgery ICU The Heart Institute St. Joseph Medical Center Towson, MD Kevin A. Stierer Sr., MD Chief Cardiac Anesthesia Associate Director Cardiac Surgery ICU Surgery ICU The Heart Institute St. Joseph Medical Center Towson, MD

6. Faculty COI Financial Disclosures Solomon Aronson, MD Grant/Research Support: Abbott Consultant: The Medicines Company Speakers Bureau: Baxter Major Shareholder: Medwave Jerrold H. Levy, MD Grant/Research Support: Alexion Consultant: Bayer HealthCare, Dyax, Novo Nordisk, and Organon Kevin A. Stierer Sr., MD Nothing to report Solomon Aronson, MD Grant/Research Support: Abbott Consultant: The Medicines Company Speakers Bureau: Baxter Major Shareholder: Medwave Jerrold H. Levy, MD Grant/Research Support: Alexion Consultant: Bayer HealthCare, Dyax, Novo Nordisk, and Organon Kevin A. Stierer Sr., MD Nothing to report

7. NOTE There will be off-label discussionsboth indications and dosingduring this CME symposium, and speakers will note such off-label information. This information does not imply or constitute endorsement of such strategies, which must be evaluated on the basis of evidence and expert analysis. There will be off-label discussionsboth indications and dosingduring this CME symposium, and speakers will note such off-label information. This information does not imply or constitute endorsement of such strategies, which must be evaluated on the basis of evidence and expert analysis. Off-Label Discussion and Information

8. Management of Perioperative Hypertension in the Cardiac Surgery Patient A New Look at an Old Problem Solomon Aronson, M.D. FACC, FCCP, FAHA, FASE Professor and Executive Vice Chairman Department of Anesthesiology Duke University Health System

9. A man is as old as his arteries Sir William Osler

10. The Aging Population Population (in millions) 30 35 40 45 50 55 60 70 65 75 Age (Years) 0 2 4 6 8 10 Percent 1976-1980 1988-1991 CHF mortality National Health & Nutrition Examination Survey II 1976-1980 and 1988-1991

11. Risk > 115/75 90% pts > 55 years of age 90% pts > 55 years of age Pre-HTN > 115/75 < 140/90 Average in Europe: 136/83; USA & Canada: 127/77 # 1 cause of HD death, #3 cause of stroke death $63.5 B direct & indirect costs 50 M (25% population) 30 M high normal, 20-35% (white coat) Joint National Committee (JNC-6 & 7) On Prevention, Detection, Evaluation, & Treatment of Hypertension: Arch Int Med 157; 2413-46,1997 JAMA 289; 2560-72,2003 Hypertension: Costs and Consequences

12. Pre-Hypertension (>120/80 120/80 <140/90) Pre-Hypertension is common: 40% Associated with increased risk: OR CI CV death 1.58 1.12-2.21 MI 1.76 1.40-2.22 Stroke 1.931.49-2.50 CHF 1.36 1.05-1.77 Circulation 115;855-60, 2007

13. JACC 40;119-25,2002 Muscle sympathetic nerve activity Baroreceptor sensitivity White Coat Hypertension

14. EssentialSecondary Endocrine, Renal, ICP, coarctation, contraceptives, pregnancy, etc. NE release (stress) Thickened arterial wall Altered vasomotor DBP, SBP, MAP, PP Orthostatic BP changes Hypertension: Types and Mechanism

15. Category Systolic mmHg Diastolic mmHg Optimal < 120 and < 75 Normal < 130 and < 85 Mild HTN 140-159 or 90-99 Moderate160-179 or 100-109 Severe> 180 or > 110 Isolated SBP HTN > 140 and 140 and < 90 Pulse Pressure > 65mmHg Orthostatic changes Hyper response > 20 mmHg Hypo response < 20 mmHG Hypo response < 20 mmHG Classification

16. Physiology: Perioperative HTN Increase SVR, increase preload Increase SVR, increase preload Rapid intravascular volume shifts Rapid intravascular volume shifts Renin angiotensin activation Renin angiotensin activation Adrenergic stimulation (cardiac & neural) Adrenergic stimulation (cardiac & neural) Serotonergic overproduction Serotonergic overproduction Baroreceptor denervation Baroreceptor denervation Altered cardiac reflexes Altered cardiac reflexes Depth anesthesia inadeq Depth anesthesia inadeq Cross clamp Cross clamp

17. Historically, the most important factor Historically, the most important factor Benchmark measure for trials Benchmark measure for trials Index of Microcirculation Index of Microcirculation Perioperative risk defined by this index Perioperative risk defined by this index Diastolic Blood Pressure

18. Historical Perspective Decade Study Comment 1970 Prys Roberts Preop severe(>115mmHg) – risk 1980 Goldman Preop mod (< 110 mmHg) – no risk Intraoperative control BP important Intraoperative control BP important 1990 Charlson Defined intraoperative BP patterns associated with postoperative risk

19. Adverse events are higher with isolated systolic blood pressure HTN, than with diastolic blood pressure HTN Kannel, Framingham Heart Study Systolic Blood Pressure

20. Systolic BP: HTN Risk Factor 1962 Insurance industry Mortality = SBP > DBP 1965 London business menSBP predicts events in CAD 1969 Framingham Heart Study Challenged DBP as 1 0 risk 1974 Old Age AssistanceSBP > DBP 1978 Royal Canadian Air Force SBP > DBP 1982 Italian Rural populationSBP > DBP 1983 Hawaiian – JapaneseSBP > DBP 1985 British Male Civil ServiceSBP > DBP 1987 Oslo, Norwegian Country No difference of CV Risk 2002 McSpi Perioperative SBP HTN predicts adverse outcome during CABG

21. Negative outcome* O.R. 2.1 p=0.01 Anesth Analg 94;1079- 84,2002 Anesth Analg 95;273-7,2002 *LOS > 10 days, or death SBP > 160 mmHg Renal O.R. 1.3 (1.0-1.9) Stroke 1.7 (1.2-2.3) LV dysfunction 1.3 (1.0-1.6) Combined 1.4 (1.1-1.7) Intraoperative Preoperative Systolic BP: Hypertension

22. 0 10 20 30 2030 405060 7080 90 Age Prevalence % Women Men Prevalence of Isolated Systolic Hypertension Circulation 2006;114:2780-7

23. Determinants of Systolic BP Stroke Volume* Rate of Systolic Ejection Arterial Distensibility SBP (wave reflections)** * < 50 yrs ** >70 yrs

24. Risk of CV Events by Type of HTN Age Adjusted Risk Ratio* Age Adjusted Risk Ratio* 35-64 yrs 65-94 yrs 35-64 yrs 65-94 yrs Men Women Men Women Men Women Men Women Isolated diastolic1.8 1.2 1.2 1.6 Isolated systolic2.4 1.9 1.9 1.4 Combined2.7 2.2 2.2 1.6 * Reference groups consist of normotensive persons 36 Year Follow-Up (Framingham Study According to Age & Sex) Am Jour of Card; 85, 2000

25. SBP-DBP = Pulse Pressure SBP-DBP = Pulse Pressure Traditionally, not in risk assessment Traditionally, not in risk assessment Wide PP = high risk Wide PP = high risk Treatment not understood Treatment not understood Pulse Pressure

26. FLOW PRESSURE HR x SV = CO *BP/ CO = SVR CO x MAP = work MAP = 1/3 PP + DBP All in the absence of pulsations (*BP = MAP -RAP) Pressure/Flow Relationships

27. Rate /1,000 Rate /1,000 35-64 yrs 65-94yrs 35-64 yrs 65-94yrs Pulse Pressure (mm Hg) Women Men Women Men 2-39 9 4 2 17 40-49 13 6 16 19 50-59 16 7 32 22 60-69 22 10 39 25 70-182 33 16 58 32 Regression 0.024 0.025 0.024 0.014 Risk factor 0.018 0.019 0.021 0.010 Framingham Study (30 Year Follow-Up) The American Journal of Cardiology Vol 85, January 15, 2000 Pulse Pressure and Cardiac Risk

28. Dependent on; Ventricular Ejection Viscoelastic properties: Large arteries Wave Reflection Pulse Pressure Pulse Pressure

29. Wave Propagation Proximal Aorta: Compliant (accepts SV with low SBP) Femoral Femoral Brach. stiffer Brach. stiffer Radial Radial Pulse picks up speed as it moves distally; then wave reflected back at peak PVR Energy distending arterial tree in systole returned in diastole returned in diastole due to proximal aorta elasticity Energy distending arterial tree in systole returned in diastole returned in diastole due to proximal aorta elasticity

30. 5450 pts 67% current or past history HTN Mean Preoperative Pressure SBP - mildly elevated (133 + 18) DBP - minimally reduced (75 + 10) ISH - 5% IDH - 3% Presenting Pulse Pressure 50% between 40-60 mmHg 33% between 60-80 mmHg 8% > 80 mmHg CT Surgery Renal Risk Influence of PPH Circulation 115,733-42,2007

31. Cerebral (5.5 % vs. 2.8 %; P = 0.004) Cerebral (5.5 % vs. 2.8 %; P = 0.004) Renal (8.6 % vs. 4.5 %; P = 0.0003) Renal (8.6 % vs. 4.5 %; P = 0.0003) CHF (12.8 % vs. 7.8 %; P = 0.003) CHF (12.8 % vs. 7.8 %; P = 0.003) Cardiac death (4.7 % vs. 2.4 %; P = 0.0001 Cardiac death (4.7 % vs. 2.4 %; P = 0.0001 Overall mortality (5.8 % vs. 2.8 %; P = Overall mortality (5.8 % vs. 2.8 %; P = 0.0018) 0.0018) Each Pulse Pressure (PP) Increment of 10 mm Hg Increases Risk PP > 80 mm Hg Associated with 2X Ischemic Events _____________________________

32. Each 20 mmHg increase > 40mmHg Each 20 mmHg increase > 40mmHg Additive risk [OR 1.49; CI, 1.17-1.89 (P = 0.001)] Additive risk [OR 1.49; CI, 1.17-1.89 (P = 0.001)] PPH > 80 mmHg assoc 3X renal-related PPH > 80 mmHg assoc 3X renal-related death death [3.7% vs. 1.1%] [3.7% vs. 1.1%] Renal injury doubled if PP > 80mmHg Renal injury doubled if PP > 80mmHg [8.6 % vs. 4.5 %; P = 0.0003] [8.6 % vs. 4.5 %; P = 0.0003] Renal dysfunction [5 % vs. 3 %; P = 0.0004] Renal dysfunction [5 % vs. 3 %; P = 0.0004] Renal failure [5.5 % vs. 2.5 %; P = 0.001] Renal failure [5.5 % vs. 2.5 %; P = 0.001] Renal RISK INDEX and PULSE PRESSURE Circulation 115,733-42,2007

33. Brain (96% increase in composite cerebral events) Heart (61% increase in CHF) Kidneys (91% increase in composite renal injury) PPH & Ischemic Complications PPH accelerates ischemic processes causing fatal & nonfatal complications over hours to days rather than years

34. Increased Pulse Pressure Is Associated With Decreased Long-term Survival After CABG Surgery SCA Montréal 2007

35. Mean Arterial Pressure (MAP) Determinants Ventricular Ejection Ventricular Ejection Peripheral Vascular Resistance (PVR) Peripheral Vascular Resistance (PVR)

36. Blood Pressure Components Steady Component (MAP) Steady Component (MAP) Pulsatile Component (Pulse Pressure) Pulsatile Component (Pulse Pressure)

37. Hypertension and Perioperative Risk End organ involvement Type of surgery Type of HTN Treatment effectiveness Pulsatile flow Endothelial cell dysfunction Smooth Muscle cell hypertrophy HTN VASC DISEASE

38. Baseline DBP Category 76849198 105 mmHg 1 2 3 45 0.25 1.00 0.50 2.00 4.00 Relative Risk CHD, Stroke Approximate Mean Usual DBP Approximate Mean Usual DBP Coronary Heart Disease and Diastolic Blood Pressure x x x x x Lancet. 1990;335,765-74

39. Hypertension,1999;34:375-80 Each 10 mm Hg increase in PP: Each 10 mm Hg increase in PP: 11% increase in stroke 11% increase in stroke MAP, SBP and PP Independent Predictors of Risk Independent Predictors of Risk Each 10 mm Hg rise in MAP: Each 10 mm Hg rise in MAP: 20% increase in stroke 20% increase in stroke Each 10 mm Hg increase in PP: 16% increase Each 10 mm Hg increase in PP: 16% increase in death and 12% increase in recurrent MI in death and 12% increase in recurrent MI Cardiac mass associated with SPB Work to drive blood = SBP despite MAP & SVR Work to drive blood = SBP despite MAP & SVR Increase PP associated with decreased coronary BF

40. J – Curve Hypothesis Lowering DBP (too much) increases risk for coronary events esp in patients CAD & wide pulse pressures (> 60 mmHg) Farnett et al. JAMA, 265:489-95, 1991 Farnett et al. JAMA, 265:489-95, 1991

41. J – Curve Hypothesis Gray Rj. Am J Cardiol 1985;56:49F-56F *P < 0.05 vs baseline +P < 0.05 vs. esmolol *P < 0.05 vs baseline +P < 0.05 vs. esmolol PercentChangePercentChange HRSBPDBPPaO 2

42. ECLIPSE Secondary Endpoint Systolic Blood Pressure Control Over 24 Hours Time (hours) SBP Lower Upper 06122418 Lower ECLIPSE Trial; Presented at ACC, March 27, 2007

43. Logistic Regression Results: Predictors of Mortality P-Value Odds Ratio 95% CI [Lower Limit, Upper Limit] Surgery Duration (hour) <0.00011.517 [1.240, 1.856] Age (year) 0.00031.070 [1.031, 1.110] Pre-op Creatinine 1.2 mg/dL 0.00312.670 [1.392, 5.122] AUC (area outside the range) 0.00691.003 [1.001, 1.004] Additional surgical procedures 0.00892.409 [1.246, 4.655] Pre-op Hgb (g/dL) 0.01350.824 [0.707, 0.961] Pre-op SBP >160 or DBP > 105 0.02282.386 [1.147, 4.963] History of COPD 0.02282.326 [1.125, 4.812] History of recent MI (<6 months prior) 0.03122.197 [1.073, 4.497]

44. I mmHg x 60 min 2 mmHg x 60 min 3 mmHg x 60 min 4 mmHg x 60 min 5 mmHg x 60 min 30 Day Mortality by Magnitude of AUC Odds Ratio 95% CI [Lower Limit, Upper Limit]1.20 [1.06, 1.27] 1.43 [1.13, 1.61] 1.71 [1.20, 2.05] 2.05 [1.27, 2.61] 2.46 [1.35, 3.31]

45. Adverse Events & BP Control AUC Quartile All agents* n/N (%) Death1st 7/380 (1.8) 4th 16/378 (4.2) MI1st 6/380 (1.6) 4th 11/378 (2.9) Stroke1st 4/380 (1.1) 4th 6/378 (1.6) Renal1st 24/380 (6.3) 4th 39/378 (10.3) *ECLIPSE clinical trials, N=1512 SBP range of 75 – 145 (pre & post-op), 65-135 (intra-op)

46. Cumulative AUC at Targeted BP Ranges n=751 n=756 p=0.0004 p<0.0001 p=0.0002 mm Hg x min/h 65 75 85 95 105 75 85 Intra-op SBP (mmHg) Pre/post SBP (mmHg)

47. BP Control : Clevidipine vs SNP n=295 n=284 P=0.0027 P=0.0009 P=0.0003 P=0.0068 mm Hg x min/h specified+10+20+30

48. BP Control : Clevidipine vs NTG n=269 n=278 P=0.0006 P=0.0002 P=0.0016 P=0.0556 mm Hg x min/h specified+10+20+30

49. BP Control : Clevidipine vs NIC n=187 n=194 P=0.8508 P=0.8949 P=0.3086 P=0.0231 mm Hg x min/h specified +10+20 +30

50. RISK AND AGE Relationship to Blood Pressure Index Age (years) Pressure Index ________________________________ < 50 DBP 50-59 SBP, DBP, MAP > 60 PP

51. Baseline preoperative value & class Baseline preoperative value & class important important 20% tolerance treatment threshold 20% tolerance treatment threshold In chronic HTN* higher BP needed In chronic HTN* higher BP needed (e.g.sweet spot) (e.g.sweet spot) * shift in autoregulatory curve, non compliant vasculature, etc. Conclusions and Caveats

52. Advancing Management of Acute and Serious Elevations in Blood Pressure – A Critical, Comparative, and Clinical Examination of the Available Pharmacologic Armamentarium for Cardiothoracic Surgery Jerrold H Levy, MD Professor of Anesthesiology Emory University School of Medicine Deputy Chairman for Research Director, Cardiothoracic Anesthesiology Emory Healthcare Atlanta, Georgia

53. Doctors pour drugs of which they know little for disorders of which they know less into patients of which they know nothing. Voltaire Wisdom for Thought

54. VASOACTIVE THERAPY Vasoconstrictors BP = SVR X CO BP = SVR X CO Vasodilators (SV x HR) Inotropes Beta Blockers Other agents Other agents

55. Beta Adrenergic Blockers Beta blockers represent first line agents for hypertension and tachycardia; especially in patients with ischemic heart disease. Beta blockers represent first line agents for hypertension and tachycardia; especially in patients with ischemic heart disease. Beta blockers produce negative inotropic effects and conduction defects, and should be used cautiously in patients with reactive airways disease and ventricular dysfunction. Beta blockers produce negative inotropic effects and conduction defects, and should be used cautiously in patients with reactive airways disease and ventricular dysfunction. Beta blockers have ceiling effects as antihypertensive agents, and effects are limited by heart rate. Beta blockers have ceiling effects as antihypertensive agents, and effects are limited by heart rate.

56. Vascular Regulation Landry NEJM 2001; 345: 588.

57. Vasodilators (1) ACE inhibitors ACE inhibitors Adenosine Adenosine A-II antagonists A-II antagonists Alpha-1-adrenergic antagonists Alpha-1-adrenergic antagonists Alpha-2-adrenergic agonists Alpha-2-adrenergic agonists ANP (nesiritide) ANP (nesiritide) Beta-2-adrenergic agonists Beta-2-adrenergic agonists

58. Vasodilators (2) Calcium channel blockers Calcium channel blockers Dopamine-1-agonists Dopamine-1-agonists Hydralazine Hydralazine Nitrovasodilators Nitrovasodilators Phosphodiesterase inhibitors Phosphodiesterase inhibitors Prostaglandins Prostaglandins

59. Therapeutic Approaches To Vasodilation ACE inhibition ACE inhibition Alpha-1 adrenergic blockade Alpha-1 adrenergic blockade Calcium channel blockade Calcium channel blockade Dopamine-1 stimulation Dopamine-1 stimulation Ganglionic blockade Ganglionic blockade Cyclic nucleotide stimulation Cyclic nucleotide stimulation PDE inhibition PDE inhibition Potassium channel modulation Potassium channel modulation Novel agents Novel agents Levy JH: The ideal agent for perioperative hypertension. Acta Anaesth Scand 1993; 37(S):20-25.

60. Vascular Smooth Muscle C - O - N H H H H H = O Nonenzymatic cysteine dithiothreitol N-acetylcysteine mercaptosuccinic acid thiosallcylic acid methylthiolsalicylic acid others (large concentrations) C - O - N H H H H H = O C - O - N H H H H H = O Enzymatic Unknown pathway. Likely requires glutathione. Less active in coronary microvessels <100 µm (Possibly secondary to decreased availability of glutathione) N = 0 Guanylate Cyclase NO 2 + Enzymatic Glutathione S-Transfers: Product is nitrate. Activity increased by excess GSH

61. Mechanisms of Nitrate Tolerance Decreased bioconversion to NO 1 Decreased bioconversion to NO 1 Depletion of sulfhydryl groups 2,3 Depletion of sulfhydryl groups 2,3 Neurohumoral adaptations 4 Neurohumoral adaptations 4 Superoxide anion production 5 Superoxide anion production 5 Upregulation of endothelin 1 6 Upregulation of endothelin 1 6 1.Münzel T. Am J Cardiol. 1996;77:24C-30C. 2.Parker JD, Parker JO. N Engl J Med. 1998;338:520-531. 3.Needleman P, Johnson EMJ. J Pharmacol Exp Ther. 1973;184:709-715. 4.Münzel T, et al. J Am Coll Cardiol. 1996;27:297-303. 5.Münzel T, et al. J Clin Invest. 1995;95:187-194. 6.Münzel T, et al. Proc Natl Acad Sci. 1995;92:5244-5248.

62. Hemodynamic effects of Inhaled NO in Patients with Heart Failure (n=19) Room Air NOP HR, bpm 90 ± 3 93 ± 3 NS MAP, mmHg 79 ± 3 81 ± 3 NS SVR, dyne –s-cm -5 1102 ± 104 1041 ± 97 NS PA, mmHg 35 ± 4 37 ± 4 NS PAWP, mmHg 25 ± 3 31 ± 4 <.001 LVEDP, mmHg: n=10 28 ± 4 34 ± 5.02 PVR, dyne – s cm -5 226 ± 30 119 ± 13 <.001 PA-PAWP, mmHG 11 ± 1 6 ± 0.5 <.001 SVI, mL/m 2 226 ± 30 24 ± ±2.03 CI, L-min-1 m -2 2.3 ± 0.2 2.1 ± 0.2.03 Loh E. Cardiovascular effects of iNO in patients with LV dysfunction. Circulation. 1994;90:2780.

63. Hypertension In Cardiac Surgical Patients (1) Patients normotensive may become hypertensive. Patients normotensive may become hypertensive. Most BP changes develop acutely and require rapid intervention. Most BP changes develop acutely and require rapid intervention. Characterized by systemic vasoconstriction with intravascular hypovolemia. Characterized by systemic vasoconstriction with intravascular hypovolemia. Patients may have preop biventricular dysfunction. Patients may have preop biventricular dysfunction.

64. Hypertension In Cardiac Surgical Patients (2) BP may be maintained at lower levels to avoid graft/suture line disruption. BP may be maintained at lower levels to avoid graft/suture line disruption. Patients are being Fast Tracked. Patients are being Fast Tracked. Mechanical manipulation, suturing with potential risk for coronary/IMA spasm. Mechanical manipulation, suturing with potential risk for coronary/IMA spasm. Ventricular dysfunction is common in patients with normal preop function due to stunning/reperfusion injury. Ventricular dysfunction is common in patients with normal preop function due to stunning/reperfusion injury.

65. Nitrovasodilators Sodium Nitroprusside Na + CN NO + CN Fe ++ CN Na +

66. Venodilation Occurs with Nitroprusside Therapy Nitroprusside is potent venous and arterial vasodilator Nitroprusside is potent venous and arterial vasodilator Venodilation: Venodilation: l Affects cardiac output l Often requires compensatory volume replacement Kerins DM, et al. In: Hardman JG, Limbird LE, eds. Goodman and Gilmans Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:843-870.

67. IV Dihydropyridines Calcium Channel Blockers Calcium Channel Blockers 1st Generation CCB: Nifedipine 1st Generation CCB: Nifedipine 2nd Generation CCB: Nicardipine, isradipine 2nd Generation CCB: Nicardipine, isradipine 3rd Generation CCB: Clevidipine 3rd Generation CCB: Clevidipine

68. Nicardipine Only IV dihydropyridine CCB available in the United States Only IV dihydropyridine CCB available in the United States Arterial vasodilator 1 Arterial vasodilator 1 Decreases SVR 2-6 Decreases SVR 2-6 More selective for vascular smooth muscle than cardiac muscle 1 More selective for vascular smooth muscle than cardiac muscle 1 No significant increase in ICP 7 No significant increase in ICP 7 1.Clarke B, et al. Br J Pharmacol. 1983;79:333P. 2.Lambert CR, et al. Am J Cardiol. 1987;60:471-476. 3.Silke B, et al. Br J Clin Pharmacol. 1985;20:169S-176S. 4.Lambert CR, et al Am J Cardiol. 1985;55:652-656. 5.Visser CA, et al. Postgrad Med J. 1984;60:17-20. 6.Silke B, et al. Br J Clin Pharmacol. 1985;20:169S-176S. 7.Nishiyama MT, et al. Can J Anaesth. 2000;47:1196-1201.

69. Hemodynamic Effects Of Nicardipine Control Nicardipine Control Nicardipine HR71 ± 1370 ± 14 MAP107 ± 1480 ± 9 PAOP9 ± 48 ± 3 MPAP15 ± 316 ± 4 RAP8 ± 38 ± 2 CI2.2 ± 0.32.8 ± 0.4 LV dP/dT 1509 ± 3761680 ± 485 LVEF%57 ± 968 ± 7 Lambert CR: Am J Cardiol 1993;71:420.

70. Hemodynamic Effects Of Isradipine VariableBaseline 30 Minutes SBP 150 ± 20 -30 ± 30 DBP 75 ± 9 -18 ± 8.0 MAP 101 ± 10 -23 ± 11.0 HR 89 ± 12 4 ± 12* CI 2.7 ± 0.6 0.4 ± 0.6 SVR 1470 ± 417 -478 ± 281 SVI 0.0310 ± 0.006 0.004 ± 0.006 PADP 13.4 ± 3.9 0.2 ± 3.2 PCW 11.7 ± 4.3 -0.0 ± 3.0 PVR 1.25 ± 0.9 -0.05 ± 0.47 Leslie: Circulation. 1994 Nov;90(5 Pt 2):II256.

71. Nicardipine Pharmacokinetics and Metabolism Redistribution phase after IV bolus Redistribution phase after IV bolus l Half-life=2.7 minutes Intermediate phase Intermediate phase l Half-life=44 minutes Terminal half-life after long-term infusion Terminal half-life after long-term infusion l Half-life=14.4 hours Cardene IV [package insert].

72. Nicardipine: Pharmacokinetics of IV Bolus Administration Adapted from Cheung AT, et al. Anesth Analg. 1999;89:1116. 0 50 100 150 00.51.01.52.02.53.03.5 Time after drug administration (h) -50 -40 -30 -20 -10 0 10 020406080100 Change in MAP (mm Hg) Nicardipine concentration (ng/mL) 120 140 Plasma nicardipine concentration (ng/mL) Group 1: 0.25 mg Group 2: 0.5 mg Group 3: 1.0 mg Group 4: 2.0 mg

73. Clevidipine In CABG A Dose-finding Study Clevidipine decreased MAP and SVR, without changes in heart rate, CVP, PAOP, or CI at increasing doses. Clevidipine decreased MAP and SVR, without changes in heart rate, CVP, PAOP, or CI at increasing doses. The early phase of drug disposition had a half- life of 0.6 min. The context-sensitive half-time <2 min for up to 12 hours of administration. The early phase of drug disposition had a half- life of 0.6 min. The context-sensitive half-time <2 min for up to 12 hours of administration. CONCLUSION: Clevidipine is a CCB that lowers BP without changing heart rate, CI, or cardiac filling pressures. CONCLUSION: Clevidipine is a CCB that lowers BP without changing heart rate, CI, or cardiac filling pressures. Bailey JM et al:Anesthesiology 2002;96:1086.

74. Clevidipine Effectively and Rapidly Controls Blood Pressure Preoperatively in Cardiac Surgery Results of the Randomized, Placebo- Controlled E fficacy S tudy of C levidipine A ssessing its P reoperative antihypertensive E ffect in Cardiac Surgery-(ESCAPE-1) Trial Levy JH: Anesth Analg, In Press.

75. Arterial Spasm Loss of endothelial function via vascular injury and platelet activation is potential mechanism, but other mechanisms include NO scavenging by hemoglobin. Thromboxane, a potent constrictor, has been implicated. Only certain drugs will completely reverse arterial spasm.

76. Vasospasm: Body of Literature Salmenperra MT: Effects of PDE inhibitors on the human IMA. Anesth Analg 1996; 82: 954-957. Salmenperra MT: Effects of PDE inhibitors on the human IMA. Anesth Analg 1996; 82: 954-957. Huraux C: Vasodilator effects of clevidipine on human IMA. Anesth Analg 1997; 85: 1000-1004. Huraux C: Vasodilator effects of clevidipine on human IMA. Anesth Analg 1997; 85: 1000-1004. Huraux C: A comparative eval of multiple vasodilators on human IMA. Anesthesiology 1998;88:1654-1659. Huraux C: A comparative eval of multiple vasodilators on human IMA. Anesthesiology 1998;88:1654-1659. Huraux C: Superoxide production, risk factors, and EDRF relaxations in human IMAs. Circulation 1999;99:53-59. Huraux C: Superoxide production, risk factors, and EDRF relaxations in human IMAs. Circulation 1999;99:53-59. Tsuda A: Reversal of histamine-induced vasodilation in the human IMA. Anesth Analg 2001;93:1453-1459. Tsuda A: Reversal of histamine-induced vasodilation in the human IMA. Anesth Analg 2001;93:1453-1459. Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin and fenoldopam in the human umbilical artery. Anesth Analg 2003;96:539-544. Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin and fenoldopam in the human umbilical artery. Anesth Analg 2003;96:539-544. Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)-induced vasoconstriction in human IMA. Br J Anaesth 2004;93:257-262. Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)-induced vasoconstriction in human IMA. Br J Anaesth 2004;93:257-262.

77. In Vitro Effects Of Phosphodiesterase Inhibitors On Human IMA Relaxation Salmenpera M, Levy, JH. Anesth Analg. 1996;82:954-957. % Relaxation Concentration (microM) 0 20 40 60 80 100 10001101000.1 M P A E A=amrinone E =enoximone M=milrinone P=papaverine

78. A Comparative Evaluation of the Effects of Multiple Vasodilators on Human IMA Nitroglycerin was most potent for thromboxane Nitroglycerin was most potent for thromboxane A2 inhibitor A2 inhibitor Milrinone,dihydropyridines, PGE1, and papaverine were also effective at therapeutically used doses Milrinone,dihydropyridines, PGE1, and papaverine were also effective at therapeutically used doses Huraux C et al. Anesthesiology. 1998;88:1654-1659.

79. Vasodilator Effects of Clevidipine on Human IMA Clevidipine was effective anti-vasospasm agent at therapeutically used doses Clevidipine was effective anti-vasospasm agent at therapeutically used doses Huraux C, Makita T, Szlam F, Nordlander M, Levy JH: Anesth Analg 1997; 85: 1000-1004.

80. Comparative Study of Calcium Antagonists On Human Radial Artery He GW: JTCVS 2000;119:94

81. Simulated Drug Level Curves Full loading dose = [Cp] x Vdss Smaller loading dose = [Cp] x Vc No loading dose Time (Half-life) 0 10 20 30 40 50 60 0123456 Therapeutic Concentration Range Plasma Drug Level

82. Fenoldopam (Corlopam) Selective vascular DA1 agonist Selective vascular DA1 agonist Produces arterial vasodilation, increases renal perfusion, and naturesis Produces arterial vasodilation, increases renal perfusion, and naturesis Short duration of action/half life Short duration of action/half life Approved in June 1997 Approved in June 1997 Expense, potency, reflex tachycardia are major issues Expense, potency, reflex tachycardia are major issues

83. Summary (1) Multiple pharmacologic agents produce vasodilation via different mechanisms. Multiple pharmacologic agents produce vasodilation via different mechanisms. Beta-blockers are important in hypertension and tachycardia, but effects are limited by heart rate. Beta-blockers are important in hypertension and tachycardia, but effects are limited by heart rate. Arterial vasoconstriction is characteristic of perioperative hypertension with intravascular hypovolemia. Arterial vasoconstriction is characteristic of perioperative hypertension with intravascular hypovolemia. Nitrate tolerance is important to consider in critically ill patients. Nitrate tolerance is important to consider in critically ill patients.

84. Summary (2) Nitrovasodilators decrease both preload and resistance vessels. Nitrovasodilators decrease both preload and resistance vessels. DHP CCBs produce arterial selective vasodilation, controlling BP without producing venodilation or negative inotropic and conduction effects, and reverses vasospasm in the IMA and other vascular beds. DHP CCBs produce arterial selective vasodilation, controlling BP without producing venodilation or negative inotropic and conduction effects, and reverses vasospasm in the IMA and other vascular beds. Large clinical trials regarding DHP CCBs will contribute to our understanding of their perioperative and other indications. Large clinical trials regarding DHP CCBs will contribute to our understanding of their perioperative and other indications.

85. VasoactiveTherapy.com

86. Emerging Agents for Blood Pressure Control in Cardiac Surgery Results of the ECLIPSE Trials Comparing Clevidipine with Available Agents in Perioperative Hypertension Kevin A. Stierer Sr., M.D. Chief Division of Cardiac and Thoracic Anesthesia Associate Director Cardiac Surgery ICU The Heart Institute at St. Joseph Medical Center Towson, Maryland

87. Acknowledgements Cornelius Dyke, MD Dean Kereiakes, MD Jerrold H. Levy, MD Philip Lumb, MD Albert Cheung, MD Howard Corwin, MD Solomon Aronson, MD* Mark Newman, MD *Acknowledgement and thanks to Dr. Solomon Aronson, who first presented much of this material as a Late Breaker at ACC 2007 Scientific Assembly on March 27, 2007.

88. Perioperative Hypertension Patients with preoperative hypertension are at an increased risk for perioperative complications 1 Patients with preoperative hypertension are at an increased risk for perioperative complications 1 Approximately 30% to 56% of patients undergoing routine cardiac surgery experience acute rises in blood pressure that require administration of a parenteral antihypertensive agent 2 Approximately 30% to 56% of patients undergoing routine cardiac surgery experience acute rises in blood pressure that require administration of a parenteral antihypertensive agent 2 Antihypertensive therapy is often needed to manage life-threatening arterial bleeding, myocardial ischemia, or cardiac failure 3 Antihypertensive therapy is often needed to manage life-threatening arterial bleeding, myocardial ischemia, or cardiac failure 3 1. Sladen, IARS Rev Course Lectures, 2002, p100; DeQuattro, J Cardiovasc Pharmacol Ther, 1997. 2. Cheung, J Card Surg, 2006, S8; Estafanous, Am J Cardiol, 1980, p685; Landymore, Can J Surg, 1980. 3. Cheung, J Card Surg, 2006, S8.

89. Considerations for Perioperative BP Control During Cardiac Surgery INTRAOPERATIVE INTRAOPERATIVE l Induction l Cannulation l Protamine and hemostasis (aortotomy/suture lines) l Chest closure l Transport POSTOPERATIVE POSTOPERATIVE l Temperature management (warming and shivering) l Emergence l Weaning and extubation l Volume status

90. Goals for an Ideal Antihypertensive Agent in Setting of Cardiac Surgery Rapid onset of action Rapid onset of action Predictable dose response Predictable dose response Titratable to desired BP Titratable to desired BP Highly vascular selective Highly vascular selective Maintain stroke volume and cardiac output Maintain stroke volume and cardiac output Rapidly reversible Rapidly reversible Low risk of overshoot hypotension Low risk of overshoot hypotension Low risk of adverse reactions Low risk of adverse reactions Levy JH. Anesthesiol Clin North Am. 1988;17:587-678. Oparil S et al. Am J Hypertens. 1999;12:653-664.

91. Clevidipine: The First Third- Generation Calcium Channel Blocker Generic Name Brand Name First Generation Nifedipine Procardia ®, Adalat ® Second Generation Nicardipine/ (I.V.) AmlodipineIsradipineFelodipine Nimodipine/ (I.V.) Nisoldipine Cardene ® /Cardene I.V. Norvasc ® DynaCirc ® Plendil ® Nimotop ® /Nimotop I.V. Sular ® Third Generation ClevidipineTBD Whiting RL, et al. Angiology. 1990;41:987-991.

92. Cl H CH 3 OOC H3CH3C COOCH 2 OOCC 3 H 7 CH 3 N H The Clevidipine Molecule Clevidipine is the first ultrashort acting dihydropyridine intravenous calcium channel blocker

93. Clevidipine: Metabolized by Plasma and Tissue Esterases Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive carboxylic acid metabolite Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive carboxylic acid metabolite + OH O H H O Clevidipine Cl O O O O N H O O * Esterases + O O N H Cl O O H Primary metabolite *The chiral center of clevidipine. Reproduced from Ericsson H, et al. Eur J Clin Pharmacol. 1999;55:61-67. Bailey JM, et al. Anesthesiology. 2002;96:1086-1094. Ericsson H, et al. Drug Metab Dispos. 1999;27:558-564. Ericsson H et al. Eur J Clin Pharmacol. 1999;55:61-67. Ericsson H, et al. Eur J Pharm Sci. 1999;8:29-37.

94. SBP changes for patients receiving clevidipine during a 30-minute treatment period. 10 5 0 –5 –10 –15 –20 –25 –30 051015202530 % Change From Baseline Time (min) SBP SBP Changes SBP Changes Clevidipine: Rapid Onset BP-lowering effects are seen within 2–3 minutes of clevidipine infusion BP-lowering effects are seen within 2–3 minutes of clevidipine infusion Levy JH, et al. Anesthesiology. 2005;103:A354.

95. Responders = treatment success : >10% decrease in MAP or >20% decrease in MAP at each measured concentration. Clevidipine: Linear Dose Response Linear dose response in postoperative cardiac surgery patients Linear dose response in postoperative cardiac surgery patients Effective in 95% of patients at 3.2 mcg/kg/min Effective in 95% of patients at 3.2 mcg/kg/min n=19 Infusion Rate (mcg/kg/min) 0 10 20 30 40 50 60 70 80 90 100 00.050.180.321.373.19 Responders (%) n=0 n=1 n=4 n=6 n=9 Bailey JM, et al. Anesthesiology. 2002;96:1086-1094.

96. *Css = concentration at steady state; median blood concentration of clevidipine obtained during the last 10 minutes of infusion. Clevidipine: Linear Pharmacokinetics At steady state, there is a linear relationship between dosage and arterial blood concentrations At steady state, there is a linear relationship between dosage and arterial blood concentrations Linear relationship maintained for dosages as high as 21.9 mcg/kg/min Linear relationship maintained for dosages as high as 21.9 mcg/kg/min 120 100 80 60 40 20 0 0510152035 Clevidipine Concentration at Css (nmol/L)* Dose Rate (nmol/kg/min) 2530 Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001. Ericsson H, et al. Anesthesiology. 2000;92:993-1001. Ericsson H, et al. Br J Clin Pharmacol. 1999;47:531-538.

97. Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001. Clevidipine: Ultrashort Half-Life Clinically relevant half-life: approximately 1 minute Clinically relevant half-life: approximately 1 minute Arterial and venous clevidipine blood samples

98. Clevidipine: Metabolized by Plasma and Tissue Esterases Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive carboxylic acid metabolite Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive carboxylic acid metabolite + OH O H H O Clevidipine Cl O O O O N H O O * Esterases + O O N H Cl O O H Primary metabolite *The chiral center of clevidipine. Reproduced from Ericsson H, et al. Eur J Clin Pharmacol. 1999;55:61-67. Bailey JM, et al. Anesthesiology. 2002;96:1086-1094. Ericsson H, et al. Drug Metab Dispos. 1999;27:558-564. Ericsson H et al. Eur J Clin Pharmacol. 1999;55:61-67. Ericsson H, et al. Eur J Pharm Sci. 1999;8:29-37.

99. Clevidipine: Rapid Offset After discontinuation of clevidipine infusion, there was a rapid clearance After discontinuation of clevidipine infusion, there was a rapid clearance BP returned to baseline in <10 minutes in healthy volunteers BP returned to baseline in <10 minutes in healthy volunteers Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001. 100 90 80 70 60 50 40 –50510152035 MAP (mm Hg) and HR (beats/min) Time (min) 2530 Clevidipine Infusion MAP

100. *P<0.05, P<0.001, P<0.01, control vs 0.375, 0.75, 1.5, and 3.0 mcg/kg / min –1 and post-drug control. Values are mean ± SEM. 12 mm Hg 8 4 0 00.3750.751.530 10 6 2 mcg/kg/min Pressure Central Venous Clevidipine: Arterial Selectivity 1400 Units 1200 1000 0 C10.3750.751.53 C2 Systemic Vascular Resistance mcg/kg/min C2 Mean Arterial Pressure 90 80 70 * C10.3750.751.53 mcg/kg/min mm Hg Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193.

101. SVR = systemic vascular resistance; RVEDV = right ventricular end-diastolic volume. Clevidipine: Hemodynamic Effects In postoperative patients In postoperative patients l Increased stroke volume, cardiac output l No reflex increase in HR or changes in cardiac preload l Lower SVR, higher cardiac filling pressures and RVEDV vs SNP Data from Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193. C2 75 mL/beat 70 65 0 C10.3750.751.53 Stroke Volume * L min –1 Cardiac Output 0 1 2 3 4 5 6 C10.3750.751.53C2 Infusion Rate (µg kg –1 min –1 ) *P<0.05 P<0.001

102. 10 5 0 –5 051015202530 % Change From Baseline Time (min) HR 5 0 –5 051015202530 % Change From Baseline Time (min) HR Preoperative HR Changes in Non-Anesthetized Patients Postoperative HR Changes in Anesthetized Patients HR changes for patients during the 30-minute treatment period Clevidipine Minimal Effect on Heart Rate Levy JH, et al. Anesthesiology. 2005;103:A354. Singla N, et al. Anesthesiology. 2005;103:A292.

103. Clevidipine Clinical Development Tolerability, Safety, PK Dose Response ESCAPE: Efficacy Clevidipine vs Placebo VELOCITY: Severe Hypertension PK, Metabolism, Rates and Routes of Excretion PK/BP ESCAPE: Efficacy Clevidipine vs Placebo PK PK/PD: Clevidipine vs Placebo ECLIPSE: Safety vs NTG QTc Study ECLIPSE: Safety vs SNP ECLIPSE: Safety vs NIC Dose Response: Clevidipine vs Placebo Hemodynamics: Clevidipine vs SNP BP, HR: Clevidipine vs SNP BP, Dose/PK BP: Clevidipine vs Placebo Phase I N=89 Phase II N=300 Healthy Volunteers Patients: Mild to Moderate Hypertension N=86 Phase III N=1821 Perioperative Hypertension N=1721 Severe Hypertension N=100 Patients: Perioperative N=214 Data on file. The Medicines Company.

104. ECLIPSE: Rationale Clevidipine is an IV dihydropyridine calcium channel blocker with an ultrashort half-life (~1 min) Clevidipine is an IV dihydropyridine calcium channel blocker with an ultrashort half-life (~1 min) Phase I & II studies (300 pts) demonstrated: Phase I & II studies (300 pts) demonstrated: l Dose: 2–16 mg/hr effective 1 Phase III safety program required for FDA registration Phase III safety program required for FDA registration l Evaluation: Death, MI, Stroke, Renal Dysfunction l Comparators: Nitroglycerin (NTG), Sodium nitroprusside (SNP), Nicardipine (NIC) l Rapid onset: BP control in 5 min 2 1 Bailey J. Anesthesiology 2002;96:1086-94. 2 Levy J. Anesth Analg 2006 (in press).

105. Blood Pressure Control with Clevidipine Compared with Nitroglycerin, Sodium Nitroprusside, or Nicardipine in the Treatment of Peri-operative Hypertension: Eclipse - NTG Eclipse - SNP Eclipse - NIC ECLIPSE 1, 2, and 3

106. Objectives of ECLIPSE Trial Primary Investigate the safety of clevidipine in perioperative HTN Investigate the safety of clevidipine in perioperative HTN Secondary Evaluate adverse events Evaluate adverse events Examine blood pressure control Examine blood pressure control

107. ECLIPSE: Protocols Randomized (1:1), open-label, parallel group with active comparators: nitroglycerin (NTG), sodium nitroprusside (SNP), or nicardipine (NIC) Randomized (1:1), open-label, parallel group with active comparators: nitroglycerin (NTG), sodium nitroprusside (SNP), or nicardipine (NIC) l NTG and SNP studies are perioperative and NIC is postoperative Patients undergoing cardiac surgery; CABG, OPCAB, Valve, MIDCAB Patients undergoing cardiac surgery; CABG, OPCAB, Valve, MIDCAB Treatment with study drug allowed until discharge from ICU Treatment with study drug allowed until discharge from ICU Data on file. The Medicines Company.

108. ECLIPSE: Trial Design Clevidipine vs nitroglycerin Clevidipine vs sodium nitroprusside Clevidipine vs nicardipine Perioperative Postoperative Clevidipine N=268 Nitroglycerin N=278 Clevidipine N=296 Sodium nitroprusside N=283 Clevidipine N=188 Nicardipine N=193 1:1 Data on file. The Medicines Company.

109. Inclusion Criteria Pre-randomization 18 years of age 18 years of age Written informed consent Written informed consent Planned CABG, OPCAB, MIDCAB surgery and/or valve repair/replacement surgery Planned CABG, OPCAB, MIDCAB surgery and/or valve repair/replacement surgeryPost-randomization Require treatment for perioperative HTN Require treatment for perioperative HTN

110. Exclusion Criteria Women of child bearing potential Women of child bearing potential CVA 3 months of randomization CVA 3 months of randomization Intolerance to calcium channel blockers Intolerance to calcium channel blockers Hypersensitivity to NTG, SNP or NIC Hypersensitivity to NTG, SNP or NIC Allergy to the lipid vehicle Allergy to the lipid vehicle Permanent ventricular pacing Permanent ventricular pacing Any disease/condition that would put the patient at risk Any disease/condition that would put the patient at risk Participation in another trial within 30 days Participation in another trial within 30 days

111. Treatment Clevidipine Clevidipine l Initiated 2 mg/hr l Titrated doubling increments Q 90s to 16 mg/hr l 40 mg/hr maximum Comparators (NTG, SNP, NIC) admin per institutional practice Comparators (NTG, SNP, NIC) admin per institutional practice Treatment duration up to discharge from the ICU Treatment duration up to discharge from the ICU Concomitant anti-hypertensives discouraged Concomitant anti-hypertensives discouraged

112. Outcome Endpoints Primary* (Cumulative rate of clinical outcomes at 30 days): Death Death MI: Symptomatic presentation, enzyme release, and/or new ECG changes MI: Symptomatic presentation, enzyme release, and/or new ECG changes Stroke: Hemorrhagic or ischemic Stroke: Hemorrhagic or ischemic Renal Dysfunction: Cr >2.0 with min absolute change of 0.7 Renal Dysfunction: Cr >2.0 with min absolute change of 0.7Secondary SAEs through day 7 SAEs through day 7 BP control during the first 24 h BP control during the first 24 h * Blinded CEC adjudication of all primary measures

113. Statistical Methods Assumptions Assumptions l Sample size (1500 pts) recommended by FDA for safety profile assessment Descriptive analytical methods Descriptive analytical methods l Pre-specified safety analysis population (pts according to actual treatment received) l Data pooled to provide an overall event rate for Clevidipine & comparator arms l Pre-specified analysis of each randomized comparison

114. Patient Disposition ClevidipineComparators Randomized patients 971993 Met post-randomization criteria 755757 Safety population 752754 Completed study 715719 Did not complete study Withdrew consent Withdrew consent Physician decision Physician decision Lost to follow up Lost to follow up Adverse experience Adverse experience Patient death Patient death Other Other3701150201351060280

115. Baseline Characteristics Clevidipine n=752 Comparators n=754 Age, median (range) 65 (24-87) 66 (19-89) Male72%74% Caucasian82%83% Hx HTN 88%85% CHF19%18% Insulin dependent diabetes 11%11% COPD14%15% Recent MI (< 6 mos) 17%18% Prior CABG 3%6%

116. Procedural Characteristics Clevidipine n=752 Comparators n=754 Surgery duration, median hrs 3.323.23 Procedure CABG CABG Valve replacement/repair Valve replacement/repair CABG & Valve replacement/repair CABG & Valve replacement/repair Other Other77%14%9%0.3%77%12%11%0.1%

117. ECLIPSE NTG: Drug Administration Clevidipine N=268 Nitroglycerin N=278 Initiated Pre-Op 92 (34.3) 119 (42.8) Initiated Intra-Op 145 (54.1) 132 (47.5) Initiated Post-Op 31 (11.6) 27 (9.7) Overall Infusion Duration (median) 3.35 hr 8.13 hr Data on file. The Medicines Company.

118. ECLIPSE SNP: Drug Administration Clevidipine N=296 Nitroprusside N=283 Initiated Pre-Op 52 (17.6) 34 (12.0) Initiated Intra-Op 161 (54.4) 158 (55.8) Initiated Post-Op 83 (28.0) 90 (31.8) Overall Infusion Duration (median) 4.03 hr 3.25 hr Data on file. The Medicines Company.

119. ECLIPSE NIC: Drug Administration Clevidipine N=188 Nicardipine N=193 Dosed During Post-Op 188 (100) 193 (100) Overall Infusion Duration (median) 5.55 hr 5.12 hr Data on file. The Medicines Company.

120. Primary Endpoint Death 30-Day Events (%) n=729n=700n=707n=700n=705n=712n=710n=719 MIStrokeRenal Dysfunction

121. Primary Endpoint by Treatment Comparison ClevidipineNTGClevidipineSNPClevidipineNIC Death2.8%3.4%1.7%4.7%*4.4%3.2% MI3.3%3.5%1.4%2.3%2.3%1.1% Stroke1.6%2.3%1.1%1.5%0.6%1.1% Renal Dysfunction 6.9%8.1%8.5%9.1%8.3%5.9% * p = 0.045

122. Serious Adverse Events Clevidipinen=752Comparatorsn=754 Total17.7%20.0% AFIB2.4%2.4% Respiratory failure 1.1%2.5% ARF2.3%1.7% Ventricular fibrillation 0.9%1.5% Cardiac arrest 0.5%1.1% CVA0.5%1.1% Post-procedural hemorrhage 0.5%1.1%

123. ECLIPSE: Atrial Fibrillation CLV n/N (%) NTG SNP NIC Afib (total) 275/752 (36.6) 91/278 (32.7) 95/283 (33.6) 71/193 (36.8) Afib (before March 25, 2005) 108/296 (36.5) 91/278 (32.7) 25/111 (22.5) 16/50 (32.0) Afib (after March 25, 2005) 67/188 (35.6) N/A 70/172 (40.7) 55/143 (38.5) ECLIPSE was put on hold due to higher AF rates in clevidipine in March 2004 and restarted in December 2005 No statistically significant differences in any of the arms or in overall comparison Data on file. The Medicines Company.

124. ECLIPSE Secondary Endpoint: SBP Control Within Predefined Range Over 24 Hours SBP Time (24hrs) Prespecified SBP ranges of 75 – 145 (pre and post-op), 65-135 (intra-op) Lower Upper

125. ECLIPSE: Summary Largest safety program to ever be performed with an intravenous antihypertensive (n=1,512) Largest safety program to ever be performed with an intravenous antihypertensive (n=1,512) Balanced demographics and baseline characteristics Balanced demographics and baseline characteristics Met primary endpoints with adverse event rates comparable across groups Met primary endpoints with adverse event rates comparable across groups Atrial fibrillation rates are equivalent Atrial fibrillation rates are equivalent AUC data suggests better overall BP control compared with SNP and NTG AUC data suggests better overall BP control compared with SNP and NTG Data on file. The Medicines Company.

126. Conclusions Clevidipine is a safe alternative to therapy with commonly used antihypertensive agents Clevidipine is a safe alternative to therapy with commonly used antihypertensive agents Clevidipine demonstrated superior blood pressure control as assessed by integral analysis of excursions outside specified ranges over time Clevidipine demonstrated superior blood pressure control as assessed by integral analysis of excursions outside specified ranges over time