The Relationship between Acute Pressure  Derangements  Comprehensive  Vascular Protection in the Setting of  CT Surgery

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CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School 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 studie24

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The Relationship between Acute Pressure Derangements Comprehensive Vascular Protection in the Setting of CT Surgery

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1. The Relationship between Acute Pressure Derangements & Comprehensive Vascular Protection in the Setting of CT Surgery Solomon Aronson, MD Program Co-Chairman FACC, FCCP, FAHA, FASE Professor and Executive Vice Chairman Dept of Anesthesiology Duke University Health System

2. CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School 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

3. Program Educational Objectives

6. The Relationship between Acute Pressure Derangements & Comprehensive Vascular Protection in the Setting of CT Surgery Solomon Aronson, MD Program Co-Chairman FACC,FCCP,FAHA,FASE Professor and Executive Vice Chairman Dept of Anesthesiology Duke University Health System

7. “A man is as old as his arteries”

11. Physiology Perioperative Hypertension Hyperadrenergic response to surgery Increase SVR, decrease preload Rapid intravascular volume shifts Renin angiotensin activation Adrenergic stimulation (cardiac & neural) Serotonergic overproduction Baroreceptor denervation Altered cardiac reflexes Inadequate anesthesia Cross clamp

12. Perioperative Antihypertension Therapy During Cardiac Surgery Vuylsteke et al conducted a survey of anesthetic practice in US and European institutions. A total of 191 anesthesiologists provide data on 1930 patients who underwent cardiac surgery. In general, patients with a preoperative history of hypertension were more likely to experience an acute perioperative hypertensive episode. Vuylsteke et al conducted a survey of anesthetic practice in US and European institutions. A total of 191 anesthesiologists provide data on 1930 patients who underwent cardiac surgery. In general, patients with a preoperative history of hypertension were more likely to experience an acute perioperative hypertensive episode.

13. Blood Pressure “Phenotypes” Steady Component (MAP,SBP,DBP) Dynamic Component (Pulse Pres.)

14. Remodeling

15. Pathogenic Role of Mechanical Forces

16. The Endothelium Modulates Vascular Tone The endothelium is a source of vasodilatory molecules such as nitric oxide (NO) and prostacyclin. A rise in BP triggers release of these vasoactive molecules to maintain homeostasis. The endothelium is a source of vasodilatory molecules such as nitric oxide (NO) and prostacyclin. A rise in BP triggers release of these vasoactive molecules to maintain homeostasis.

17. Proposed Vascular Pathophysiology of Hypertensive Urgency Hypertensive urgencies/emergencies are thought to be triggered by catecholamine release or by release of endothelial-derived vasoconstrictors such as angiotensin II and vasopressin. The result is an abrupt rise in systemic vascular resistance. Eventually, vasodilatory responses are overwhelmed. Among possible mechanisms for this loss of endothelial function are proinflammatory responses induced by mechanical force and upregulation of endothelial adhesion molecules. Hypertensive urgencies/emergencies are thought to be triggered by catecholamine release or by release of endothelial-derived vasoconstrictors such as angiotensin II and vasopressin. The result is an abrupt rise in systemic vascular resistance. Eventually, vasodilatory responses are overwhelmed. Among possible mechanisms for this loss of endothelial function are proinflammatory responses induced by mechanical force and upregulation of endothelial adhesion molecules.

18. Proposed Vascular Pathophysiology of Hypertensive Emergency A hypertensive emergency is characterized by increased endothelial permeability with perivascular edema, arteriolar fibrinoid necrosis, platelet activation, and activation of the coagulation cascade. A hypertensive emergency is characterized by increased endothelial permeability with perivascular edema, arteriolar fibrinoid necrosis, platelet activation, and activation of the coagulation cascade.

20. SBP HTN and Adverse Events

24. Pathophysiology of Acute Hypertensive Syndromes Acute hypertension is characterized by a complex series of events triggered by mechanical stress and release of neurohormonal mediators.Acute hypertension is characterized by a complex series of events triggered by mechanical stress and release of neurohormonal mediators.

25. "Zoned Out“ Blood Pressure Control in CT Surgery What Do RCT & Registries Tell Us About Acute Pressure Management and Outcomes Solomon Aronson, MD Program Co-Chairman FACC, FCCP, FAHA, FASE Professor and Executive Vice Chairman Dept of Anesthesiology Duke University Health System

26. Acute Hypertension Patients with a hypertensive emergency should be admitted to an intensive care unit for continuous monitoring. Because a hypertensive urgency is not accompanied by progressive end-organ damage, it is generally treated in the emergency department. Perioperative hypertension occurs immediately prior to, during, or following surgical procedures, and is seen in the setting of the operating room or the postanesthesia care unit. Patients with a hypertensive emergency should be admitted to an intensive care unit for continuous monitoring. Because a hypertensive urgency is not accompanied by progressive end-organ damage, it is generally treated in the emergency department. Perioperative hypertension occurs immediately prior to, during, or following surgical procedures, and is seen in the setting of the operating room or the postanesthesia care unit. The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) defines a hypertensive emergency as BP greater than 180/120 mm Hg accompanied by evidence of impending or progressive target organ damage. A hypertensive urgency is an acute severe elevation in BP without target organ damage. Patients in this subgroup are considered to be at lower risk of adverse consequences.(1) Chobanian AV et al. Hypertension. 2003;42:1206-52. End-organ Damage CHF ACS/AMI Renal failure Stroke and ICH Encephalopathy Aortic dissection Pre-eclampsia Other? Urgencies Typical presenting symptoms include arrhythmia, epistaxis, headache, and psychomotor agitation Usual primary emergency department (ED) diagnosis is HTN Hypertensive urgency can generally be managed with oral medications and requires BP lowering over several days Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneys IV antihypertensives may be considered when oral therapy is not feasible Chobanian AV et al. Hypertension. 2003;42:1206-52. Zampaglione et al, Hypertension 1996;27:144. Patients with a hypertensive emergency should be admitted to an intensive care unit for continuous monitoring. Because a hypertensive urgency is not accompanied by progressive end-organ damage, it is generally treated in the emergency department. Perioperative hypertension occurs immediately prior to, during, or following surgical procedures, and is seen in the setting of the operating room or the postanesthesia care unit. Patients with a hypertensive emergency should be admitted to an intensive care unit for continuous monitoring. Because a hypertensive urgency is not accompanied by progressive end-organ damage, it is generally treated in the emergency department. Perioperative hypertension occurs immediately prior to, during, or following surgical procedures, and is seen in the setting of the operating room or the postanesthesia care unit. The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) defines a hypertensive emergency as BP greater than 180/120 mm Hg accompanied by evidence of impending or progressive target organ damage. A hypertensive urgency is an acute severe elevation in BP without target organ damage. Patients in this subgroup are considered to be at lower risk of adverse consequences.(1) Chobanian AV et al. Hypertension. 2003;42:1206-52. End-organ Damage CHF ACS/AMI Renal failure Stroke and ICH Encephalopathy Aortic dissection Pre-eclampsia Other? Urgencies Typical presenting symptoms include arrhythmia, epistaxis, headache, and psychomotor agitation Usual primary emergency department (ED) diagnosis is HTN Hypertensive urgency can generally be managed with oral medications and requires BP lowering over several days Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneys IV antihypertensives may be considered when oral therapy is not feasible Chobanian AV et al. Hypertension. 2003;42:1206-52.Zampaglione et al, Hypertension 1996;27:144.

27. ECLIPSE: Trial Design 3 prospective, randomized, open-label, parallel comparisons of clevidipine to NTG or SNP periop, or NIC postop in pts undergoing cardiac surgery - 61 medical centers Primary endpoint: Safety of clevidipine (death, myocardial infarction, stroke, renal) Secondary endpoints: Other AEs, BP control Key Message: ECLIPSE (Evaluation of Clevidipine in the Perioperative Treatment of Hypertension Assessing Safety Events program is addressing gaps in the evidence base regarding perioperative BP control. Conducted in 1512 cardiac surgery patients, ECLIPSE has two objectives: Assess the relationship of BP to postoperative outcomes Compare different pharmacologic strategies for perioperative BP control Clevidipine Initiated at 2 mg/h either pre-op, intra-op, post-op Titrated every 90 seconds in doubling increments until lowering of BP achieved or maximum dose of 16 mg/h 40 mg/h maximum Comparators (NTG, SNP, NIC) as per institutional practice Treatment duration until ICU discharge Concomitant antihypertensive administered per investigator choice, but discouraged Statistical methods Assumptions Sample size 1500 patients recommended by FDA for safety profile assessment Descriptive analytical methods Prespecified safety analysis by treatment received Pooled data for clevidipine and all comparator arms Prespecified analyses of clevidipine versus each comparator Data pooled for 1512 patients A multiple logistic regression analysis was performed to determine the association of BP control with 30-day mortality BP control was expressed as the cumulative area under the curve (AUC) outside specified SBP ranges AUC was analyzed as a continuous variable Aronson S et al. Abstract 1020-169. American College of Cardiology Annual Meeting; March 24-27 2007; New Orleans, LA. Key Message: ECLIPSE (Evaluation of Clevidipine in the Perioperative Treatment of Hypertension Assessing Safety Events program is addressing gaps in the evidence base regarding perioperative BP control. Conducted in 1512 cardiac surgery patients, ECLIPSE has two objectives: Assess the relationship of BP to postoperative outcomes Compare different pharmacologic strategies for perioperative BP control Clevidipine Initiated at 2 mg/h either pre-op, intra-op, post-op Titrated every 90 seconds in doubling increments until lowering of BP achieved or maximum dose of 16 mg/h 40 mg/h maximum Comparators (NTG, SNP, NIC) as per institutional practice Treatment duration until ICU discharge Concomitant antihypertensive administered per investigator choice, but discouraged Statistical methods Assumptions Sample size 1500 patients recommended by FDA for safety profile assessment Descriptive analytical methods Prespecified safety analysis by treatment received Pooled data for clevidipine and all comparator arms Prespecified analyses of clevidipine versus each comparator Data pooled for 1512 patients A multiple logistic regression analysis was performed to determine the association of BP control with 30-day mortality BP control was expressed as the cumulative area under the curve (AUC) outside specified SBP ranges AUC was analyzed as a continuous variable Aronson S et al. Abstract 1020-169. American College of Cardiology Annual Meeting; March 24-27 2007;New Orleans, LA.

28. ECLIPSE Baseline Characteristics Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.

29. Incidence of Death, MI, Stroke, Renal Dysfunction Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.

30. BP Control Assessed via AUC Analysis ECLIPSE investigators measured BP excursions above or below prespecified SBP limits. BP control was expressed as the cumulative area-under-the-curve (AUC) for these excursions. ECLIPSE investigators measured BP excursions above or below prespecified SBP limits. BP control was expressed as the cumulative area-under-the-curve (AUC) for these excursions.

31. AUC Targeted BP Range by Treatment The results of this AUC evaluation showed that nitroglycerin was less likely than either clevidipine or nicardipine to reduce BP to target levels, while sodium nitroprusside proved more volatile and difficult to titrate appropriately Reference Data on file. The Medicines Company. The results of this AUC evaluation showed that nitroglycerin was less likely than either clevidipine or nicardipine to reduce BP to target levels, while sodium nitroprusside proved more volatile and difficult to titrate appropriately Reference Data on file. The Medicines Company.

33. AUC Predictive of Mortality at 30 Days

34. Excursions in Perioperative BP Control Related to Increased 30-day Mortality Multiple logistic regression analysis was used to estimate the risk for different degrees of BP control. A 1 mm Hg excursion, if sustained for 60 minutes, was associated with a 20% increase in risk of death. Risk rose rapidly with each additional 1 mm Hg outside of the prespecified SBP range. Multiple logistic regression analysis was used to estimate the risk for different degrees of BP control. A 1 mm Hg excursion, if sustained for 60 minutes, was associated with a 20% increase in risk of death. Risk rose rapidly with each additional 1 mm Hg outside of the prespecified SBP range.

35. Systolic BP Control Over 24 Hours

36. AUC Narrowed BP Range by Treatment The results of this AUC evaluation showed that nitroglycerin was less likely than either clevidipine or nicardipine to reduce BP to target levels, while sodium nitroprusside proved more volatile and difficult to titrate appropriately Reference Data on file. The Medicines Company. The results of this AUC evaluation showed that nitroglycerin was less likely than either clevidipine or nicardipine to reduce BP to target levels, while sodium nitroprusside proved more volatile and difficult to titrate appropriately Reference Data on file. The Medicines Company.

37. Perioperative BP Lability Predicts Mortality in Patients Undergoing Cardiac Surgery Analysis of DUKE Heart Center database in pts undergoing CT surgery N =5238 3.1M BP evaluations AUC (95-135mmHg) predictive of 30-day mortality : We tested the relationship between 30-day mortality and perioperative BP instability from the Duke Heart Center and Perioperative Database of cardiac surgical patients. : We tested the relationship between 30-day mortality and perioperative BP instability from the Duke Heart Center and Perioperative Database of cardiac surgical patients.

38. Mean Duration of Excursions

40. Predictors of Postoperative Renal Dysfunction Further analysis of the ECLIPSE data showed that BP control was an independent risk factor for 30-day renal dysfunction (defined as a creatinine level of 2.0 mg/dL or greater, with a minimum increase of 0.7 mg/dL). Compared with a cumulative AUC in the first quartile, an AUC in the 4th quartile was associated with a 72.5% increase in risk. Further analysis of the ECLIPSE data showed that BP control was an independent risk factor for 30-day renal dysfunction (defined as a creatinine level of 2.0 mg/dL or greater, with a minimum increase of 0.7 mg/dL). Compared with a cumulative AUC in the first quartile, an AUC in the 4th quartile was associated with a 72.5% increase in risk.

43. 1500 pts, 21 hospitals, 79% therapy in ED Median age 58, Women 49%, AA 58% Initial BP 201/110 90% HTN, 33% kidney history , 17% drug abuse

44. Systolic BP Control Over 24 Hours by First IV Antihypertensive

45. Systolic BP Control Over 24 Hours by First IV Antihypertensive

51. "Under Pressure"—Vascular Dysfunction and Acute Pressure Syndromes in the Setting of Cardiovascular Surgery Challenges, Innovations, and Landmark Trials (ECLIPSE)—From Threat to Therapy Jerrold H Levy, MD, FAHA Professor of Anesthesiology Emory University School of Medicine Deputy Chairman for Research Director, Cardiothoracic Anesthesiology Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia

52. Evolution of Perioperative Care Changing demographics and increasing use of stenting and platelet inhibitors Older patients with comorbidities presenting for surgery and to ICUs with vascular and endothelial dysfunction due to multiple causes Endothelial and vascular dysfunction common across this cardiac, neurological, and critically ill patient populations—acute and chronic disease

54. Endothelial and Vascular Dysfunction are the Hallmarks of our Patients

55. Perioperative Hypertension The Cardiothoracic Surgery Setting Patients with preoperative hypertension are at increased risk for perioperative complications1 Approximately 30% to 56% of patients undergoing routine cardiac surgery experience acute rises in blood pressure that require administration of a parenteral antihypertensive agent2 Antihypertensive therapy is often needed to manage life-threatening arterial bleeding, myocardial ischemia, or cardiac failure3 Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.

56. Considerations for Perioperative BP Control During Cardiac Surgery Acute, Severe Elevations in Blood Pressure are Triggered by Multiple Perioperative Events Intraoperative Events Induction Cannulation Protamine and hemostasis (aortotomy/suture lines) Chest closure Transport Postoperative Events Temperature management (warming and shivering) Emergence Weaning and extubation Volume status

57. Goals for an Ideal Antihypertensive Agent in Setting of Cardiac Surgery Rapid onset of action Predictable dose response Titratable to desired BP Highly vascular selective Maintain stroke volume and cardiac output Rapidly reversible Low risk of overshoot hypotension Low risk of adverse reactions Treatment choice should be based on each patient’s presentation and specific to underlying conditions and the organ at risk. Ideally, the agent should have: A rapid onset High vascular selectivity Rapid reversibility Minimal safety risk of excessive BP lowering (ie, overshooting target BP zone) Too great a reduction may lead to hypoperfusion, resulting in ischemia and infarction References Aggarwal M, Khan IA. Hypertensive crisis: hypertensive emergencies and urgencies. Cardiol Clin. 2006;24:135-146. Cheung AT. Exploring an optimum intra/postoperative management strategy for acute hypertension in the cardiac surgery patient. J Card Surg. 2006;21:S8-S14. Varon J, Marik PE. Clinical review: the management of hypertensive crises. Crit Care. 2003;7:374-384. Varon J, Marik PE. The diagnosis and management of hypertensive crises. CHEST. 2000;118:214-227.Treatment choice should be based on each patient’s presentation and specific to underlying conditions and the organ at risk. Ideally, the agent should have: A rapid onset High vascular selectivity Rapid reversibility Minimal safety risk of excessive BP lowering (ie, overshooting target BP zone) Too great a reduction may lead to hypoperfusion, resulting in ischemia and infarction References Aggarwal M, Khan IA. Hypertensive crisis: hypertensive emergencies and urgencies. Cardiol Clin. 2006;24:135-146. Cheung AT. Exploring an optimum intra/postoperative management strategy for acute hypertension in the cardiac surgery patient. J Card Surg. 2006;21:S8-S14. Varon J, Marik PE. Clinical review: the management of hypertensive crises. Crit Care. 2003;7:374-384. Varon J, Marik PE. The diagnosis and management of hypertensive crises. CHEST. 2000;118:214-227.

58. Therapeutic Approaches to Arterial Vasodilation: Armamentarium ACE inhibition Alpha-1 adrenergic blockade Calcium channel blockade Dopamine-1 stimulation Ganglionic blockade Cyclic nucleotide stimulation PDE inhibition Potassium channel modulation

59. Hypertension in Surgical Patients (1) Patients who are normotensive may become hypertensive Most blood pressure changes develop acutely and require rapid intervention with IV agents Characterized by systemic vasoconstriction with intravascular hypovolemia Patients may have preoperative biventricular dysfunction

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

61. Nitropusside: Issues and Concerns Metabolized to CN, then thiocyanate Problematic Aspects Pregnancy Coronary steal Dose dependent ? in CBF Caution with high ICP Hypoxemia (? V/Q mismatch) Requires special delivery system Usually requires direct arterial pressure monitoring

62. Nitrovasodilators Nitroprusside is a commonly used, potent agent that acts primarily as an arterial and venous dilator. Given IV it provides smooth, immediate BP reduction. Its use is limited by the potential for severe toxicity from cyanide poisoning, especially in patients with liver or renal disease. Co-administration of hydroxycobalamine may decrease the risk of cyanide poisoning. Since it is such a potent vasodilator, nitroprusside may also cause coronary steal syndrome and increase intracranial pressure due to dilation of the large intracerebral arteries. If used, limited infusion rates and times are recommended. Newer, less toxic agents are usually preferred. Nitroprusside is a commonly used, potent agent that acts primarily as an arterial and venous dilator. Given IV it provides smooth, immediate BP reduction. Its use is limited by the potential for severe toxicity from cyanide poisoning, especially in patients with liver or renal disease. Co-administration of hydroxycobalamine may decrease the risk of cyanide poisoning. Since it is such a potent vasodilator, nitroprusside may also cause coronary steal syndrome and increase intracranial pressure due to dilation of the large intracerebral arteries. If used, limited infusion rates and times are recommended. Newer, less toxic agents are usually preferred.

63. Nitroprusside Therapy Potent venodilator/arterial vasodilator Cardiac output is often affected due to venodilation Volume replacement is often required for venodilation

64. IV DHP Calcium Channel Blockers 1st Generation: Nifedipine 2nd Generation: Nicardipine, isradipine 3rd Generation: Clevidipine

65. Selectivity of Calcium Channel Antagonists

66. Properties of Dihydropyridines Arterial vasodilator1 Decreases SVR2-6 More selective for vascular smooth muscle than cardiac muscle1 No significant increase in ICP7 No direct inotropic or dromotropic effects2-6 In patients treated for postoperative hypertension, the mean time to therapeutic response, defined as a >15% reduction in DBP or SBP, was 11.5 ± 0.8 minutes. The average maintenance dose was 3.0 mg. Following infusion, nicardipine plasma concentrations decline tri-exponentially, with a rapid early distribution phase (alpha half-life of 2.7 minutes), an intermediate phase (beta half-life of 44.8 minutes), and a slow terminal phase (gamma half-life of 14.4 hours) that can be seen only after long-term infusions. The apparent volume of distibution using a noncompartment model is 8.3 L/kg. The pharmacokinetics of nicardipine are linear over the dose range of 0.5 mg/h to 40.0 mg/h. Upon termination of the infusion, nicardipine concentrations decrease rapidly, with at least a 50% decrease during the first 2 hours postinfusion. Nicardipine is highly protein bound (>95%).1 Nicardipine is rapidly and extensively metabolized by the liver. Approximately 49% was recovered in the urine and 43% in the feces. None of the dose was recovered as unchanged nicardipine. Nicardipine does not induce or inhibit its own metabolism and does not induce or inhibit hepatic microsomal enzymes. Caution is advised when titrating nicardipine in patients with congestive heart failure or impaired hepatic or renal function. Strong coronary artery dilation increases coronary blood flow. Weak cerebral artery dilation minimizes increased ICP.1 Cardene IV [package insert]. ESP Pharma, Inc; 2002.In patients treated for postoperative hypertension, the mean time to therapeutic response, defined as a >15% reduction in DBP or SBP, was 11.5 ± 0.8 minutes. The average maintenance dose was 3.0 mg. Following infusion, nicardipine plasma concentrations decline tri-exponentially, with a rapid early distribution phase (alpha half-life of 2.7 minutes), an intermediate phase (beta half-life of 44.8 minutes), and a slow terminal phase (gamma half-life of 14.4 hours) that can be seen only after long-term infusions. The apparent volume of distibution using a noncompartment model is 8.3 L/kg. The pharmacokinetics of nicardipine are linear over the dose range of 0.5 mg/h to 40.0 mg/h. Upon termination of the infusion, nicardipine concentrations decrease rapidly, with at least a 50% decrease during the first 2 hours postinfusion. Nicardipine is highly protein bound (>95%).1 Nicardipine is rapidly and extensively metabolized by the liver. Approximately 49% was recovered in the urine and 43% in the feces. None of the dose was recovered as unchanged nicardipine. Nicardipine does not induce or inhibit its own metabolism and does not induce or inhibit hepatic microsomal enzymes. Caution is advised when titrating nicardipine in patients with congestive heart failure or impaired hepatic or renal function. Strong coronary artery dilation increases coronary blood flow. Weak cerebral artery dilation minimizes increased ICP.1 Cardene IV [package insert]. ESP Pharma, Inc; 2002.

67. Hemodynamic Effects of Nicardipine

68. Arterial Spasm

69. Vasospasm/Vascular Dysfunction Studies 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: 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. 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. Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)-induced vasoconstriction in human IMA. Br J Anaesth 2004;93:257-262.

70. Studies on Arteriolar Vasodilators Nitroglycerin is the most potent; but nitrate tolerance occur Milrinone, dihydropyridines, PGE1, were also effective at therapeutically used doses

71. Vasodilator Effects of Clevidipine on Human IMA Clevidipine was effective anti-vasospasm agent at therapeutically used doses

72. Simulated Drug Level Curves

73. The Clevidipine Molecule The goal of the clevidipine development program was to fill a gap in the acute hypertension marketplace by overcoming the limitations of current dihydropyridines The strategy behind this program was to rationally design an agent, based on the dihydropyridine model, that was: Ultrashort acting Arterial specific Titratable Vascular based; not dependent on the kidney or liver Able to lower systemic vascular resistance with no direct affect on the heart To design this agent, a cross-functional team was assembled and included a variety of participants, from marketing experts to biochemists experienced specifically with dihydropyridine calcium channel blockersThe goal of the clevidipine development program was to fill a gap in the acute hypertension marketplace by overcoming the limitations of current dihydropyridines The strategy behind this program was to rationally design an agent, based on the dihydropyridine model, that was: Ultrashort acting Arterial specific Titratable Vascular based; not dependent on the kidney or liver Able to lower systemic vascular resistance with no direct affect on the heart To design this agent, a cross-functional team was assembled and included a variety of participants, from marketing experts to biochemists experienced specifically with dihydropyridine calcium channel blockers

74. Clevidipine — Metabolized by Plasma and Tissue Esterases Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive carboxylic acid metabolite The resulting molecule, clevidipine, is rapidly metabolized by esterases in the blood and extravascular tissue to an inactive carboxylic acid H 152/81 metabolite References Ericsson H, Fakt C, Hoglund L, et al. Pharmacokinetics and pharmacodynamics of clevidipine in healthy volunteers after intravenous infusion. Eur J Clin Pharmacol. 1999;55:61-67. Ericsson H, Tholander B, Regardh CG. In vitro hydrolysis rate and protein binding of clevidipine, a new ultrashort-acting calcium antagonist metabolised by esterases, in different animal species and man. Eur J Pharm Sci. 1999;8:29-37. The resulting molecule, clevidipine, is rapidly metabolized by esterases in the blood and extravascular tissue to an inactive carboxylic acid H 152/81 metabolite References Ericsson H, Fakt C, Hoglund L, et al. Pharmacokinetics and pharmacodynamics of clevidipine in healthy volunteers after intravenous infusion. Eur J Clin Pharmacol. 1999;55:61-67. Ericsson H, Tholander B, Regardh CG. In vitro hydrolysis rate and protein binding of clevidipine, a new ultrashort-acting calcium antagonist metabolised by esterases, in different animal species and man.Eur J Pharm Sci. 1999;8:29-37.

75. Clevidipine — Rapid Onset of Action BP-lowering effects are seen within 2–3 minutes of clevidipine infusion In clinical trials of perioperative cardiac surgery patients, clevidipine also had a rapid onset of action BP-lowering effects were seen within 1–2 minutes of start of infusion Median time to target BP reduction of 15% was 6 minutes Reference Levy JH, Mancao MY Jr, Gitter R, Grigore AM, Newman MF, and the GPRO ESCAPE-1 Investigators. Clevidipine effectively and rapidly controls elevated blood pressure preoperatively in cardiac surgery patients [abstract]. Anesthesiology. 2005;103:A354.In clinical trials of perioperative cardiac surgery patients, clevidipine also had a rapid onset of action BP-lowering effects were seen within 1–2 minutes of start of infusion Median time to target BP reduction of 15% was 6 minutes Reference Levy JH, Mancao MY Jr, Gitter R, Grigore AM, Newman MF, and the GPRO ESCAPE-1 Investigators. Clevidipine effectively and rapidly controls elevated blood pressure preoperatively in cardiac surgery patients [abstract]. Anesthesiology. 2005;103:A354.

76. Clevidipine — Linear Pharmacokinetics 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 At steady state, there is a linear relationship between the dose rate of clevidipine and the arterial blood concentrations in healthy volunteers A linear relationship is maintained throughout the full dosing spectrum (doses as high as 21.9 mcg/kg/min) References Ericsson H, Bredberg U, Eriksson U, Jolin-Mellgard A, Nordlander M, Regardh CG. Pharmacokinetics and arteriovenous differences in clevidipine concentration following a short- and a long-term intravenous infusion in healthy volunteers. Anesthesiology. 2000;92:993-1001. Ericsson H, Fakt C, Jolin-Mellgard A, et al. Clinical and pharmacokinetic results with a new ultrashort- acting calcium antagonist, clevidipine, following gradually increasing intravenous doses to healthy volunteers. Br J Clin Pharmacol. 1999;47:531-538. At steady state, there is a linear relationship between the dose rate of clevidipine and the arterial blood concentrations in healthy volunteers A linear relationship is maintained throughout the full dosing spectrum (doses as high as 21.9 mcg/kg/min) References Ericsson H, Bredberg U, Eriksson U, Jolin-Mellgard A, Nordlander M, Regardh CG. Pharmacokinetics and arteriovenous differences in clevidipine concentration following a short- and a long-term intravenous infusion in healthy volunteers. Anesthesiology. 2000;92:993-1001. Ericsson H, Fakt C, Jolin-Mellgard A, et al. Clinical and pharmacokinetic results with a new ultrashort-acting calcium antagonist, clevidipine, following gradually increasing intravenous doses to healthy volunteers. Br J Clin Pharmacol. 1999;47:531-538.

77. Clevidipine — Rapid Offset After discontinuation of clevidipine infusion, there was rapid clearance BP returned to baseline in <10 minutes in healthy volunteers This graph shows MAP and heart rate (HR) following clevidipine infusion in healthy volunteers The first part of the graph shows the steady state (baseline) MAP and HR. Clevidipine was infused for 20 minutes (as shown by the shaded area on the figure). Immediately upon administration there was a rapid onset of effect: a decline in MAP. When clevidipine infusion was stopped, there was a rapid return to the baseline MAP Clevidipine has a rapid offset After discontinuation of clevidipine infusion, there was a rapid rise in BP In healthy volunteers, BP returned to baseline in <10 minutes Reference Ericsson H, Bredberg U, Eriksson U, Jolin-Mellgard A, Nordlander M, Regardh CG. Pharmacokinetics and arteriovenous differences in clevidipine concentration following a short- and a long-term intravenous infusion in healthy volunteers. Anesthesiology. 2000;92:993-1001.This graph shows MAP and heart rate (HR) following clevidipine infusion in healthy volunteers The first part of the graph shows the steady state (baseline) MAP and HR. Clevidipine was infused for 20 minutes (as shown by the shaded area on the figure). Immediately upon administration there was a rapid onset of effect: a decline in MAP. When clevidipine infusion was stopped, there was a rapid return to the baseline MAP Clevidipine has a rapid offset After discontinuation of clevidipine infusion, there was a rapid rise in BP In healthy volunteers, BP returned to baseline in <10 minutes Reference Ericsson H, Bredberg U, Eriksson U, Jolin-Mellgard A, Nordlander M, Regardh CG. Pharmacokinetics and arteriovenous differences in clevidipine concentration following a short- and a long-term intravenous infusion in healthy volunteers. Anesthesiology. 2000;92:993-1001.

78. Clevidipine — Ultrashort Half-Life Clinically relevant half-life: Approximately 1 minute Clevidipine is considered to be an ultrashort-acting agent Its triphasic elimination profile has an initial phase of 48 seconds, an intermediate phase of 2.3 minutes, and a terminal phase of 21.7 minutes 85%–90% of the dose is eliminated in the first, or alpha, phase of elimination Reference Ericsson H, Bredberg U, Eriksson U, Jolin-Mellgard A, Nordlander M, Regardh CG. Pharmacokinetics and arteriovenous differences in clevidipine concentration following a short- and a long-term intravenous infusion in healthy volunteers. Anesthesiology. 2000;92:993-1001.Clevidipine is considered to be an ultrashort-acting agent Its triphasic elimination profile has an initial phase of 48 seconds, an intermediate phase of 2.3 minutes, and a terminal phase of 21.7 minutes 85%–90% of the dose is eliminated in the first, or alpha, phase of elimination Reference Ericsson H, Bredberg U, Eriksson U, Jolin-Mellgard A, Nordlander M, Regardh CG. Pharmacokinetics and arteriovenous differences in clevidipine concentration following a short- and a long-term intravenous infusion in healthy volunteers. Anesthesiology. 2000;92:993-1001.

79. Clevidipine and Arterial Selectivity A study examining the hemodynamic effects of clevidipine for the treatment of hypertension in patients following coronary artery surgery shows the dose-dependent decrease in systemic vascular resistance (SVR), which corresponds with the dose-dependent decrease in MAP. This provides evidence that clevidipine is a potent systemic vasodilator In the figures on the left, C1 and C2 refer to two control/baseline periods Central venous pressure, a major determinant of filling pressure, was not altered during clevidipine infusion. This shows that clevidipine has no effect on venous capacitance vessels in a clinical setting and that it is arterial selective Reference Kieler-Jensen N, Jolin-Mellgard A, Nordlander M, Ricksten SE. Coronary and systemic hemodynamic effects of clevidipine, an ultrashort-acting calcium antagonist, for treatment of hypertension after coronary artery surgery. Acta Anaesthesiol Scand. 2000;44:186-193. A study examining the hemodynamic effects of clevidipine for the treatment of hypertension in patients following coronary artery surgery shows the dose-dependent decrease in systemic vascular resistance (SVR), which corresponds with the dose-dependent decrease in MAP. This provides evidence that clevidipine is a potent systemic vasodilator In the figures on the left, C1 and C2 refer to two control/baseline periods Central venous pressure, a major determinant of filling pressure, was not altered during clevidipine infusion. This shows that clevidipine has no effect on venous capacitance vessels in a clinical setting and that it is arterial selective Reference Kieler-Jensen N, Jolin-Mellgard A, Nordlander M, Ricksten SE. Coronary and systemic hemodynamic effects of clevidipine, an ultrashort-acting calcium antagonist, for treatment of hypertension after coronary artery surgery. Acta Anaesthesiol Scand. 2000;44:186-193.

80. Clevidipine: Minimal Effect on Heart Rate In a study of clevidipine in preoperative hypertension among non-anesthetized patients who received the drug prior to surgery: HR increased as expected relative to baseline during clevidipine administration In a study of clevidipine in postoperative hypertension among anesthetized patients who received the drug within 4 hours after surgery: HR did not increase relative to baseline during clevidipine administration References Levy JH, Mancao MY Jr, Gitter R, Grigore AM, Newman MF, and the GPRO ESCAPE-1 Investigators. Clevidipine effectively and rapidly controls elevated blood pressure preoperatively in cardiac surgery patients [abstract]. Anesthesiology. 2005;103:A354. Singla N, Warltier DC, Lumb PD, Sladen RN; the GPRO ESCAPE-2 Investigators. Clevidipine is effective in rapidly controlling elevated blood pressure postoperatively in cardiac surgery patients [abstract]. Anesthesiology. 2005;103:A292.In a study of clevidipine in preoperative hypertension among non-anesthetized patients who received the drug prior to surgery: HR increased as expected relative to baseline during clevidipine administration In a study of clevidipine in postoperative hypertension among anesthetized patients who received the drug within 4 hours after surgery: HR did not increase relative to baseline during clevidipine administration References Levy JH, Mancao MY Jr, Gitter R, Grigore AM, Newman MF, and the GPRO ESCAPE-1 Investigators. Clevidipine effectively and rapidly controls elevated blood pressure preoperatively in cardiac surgery patients [abstract]. Anesthesiology. 2005;103:A354. Singla N, Warltier DC, Lumb PD, Sladen RN; the GPRO ESCAPE-2 Investigators. Clevidipine is effective in rapidly controlling elevated blood pressure postoperatively in cardiac surgery patients [abstract]. Anesthesiology. 2005;103:A292.

81. Clevidipine Clinical Development Clevidipine has now been studied in more randomized clinical trials and in more patients than any other IV antihypertensive agent Reference Data on file. The Medicines Company.Clevidipine has now been studied in more randomized clinical trials and in more patients than any other IV antihypertensive agent Reference Data on file. The Medicines Company.

82. Acknowledgements — ECLIPSE Trial Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.

83. ECLIPSE — Rationale Clevidipine is an IV dihydropyridine calcium channel blocker with an ultrashort half-life (~1 min) Phase I and II studies (300 pts) demonstrated: Dose: 2–16 mg/hr effective1 Phase III safety program required for FDA registration Evaluation: Death, MI, Stroke, Renal Dysfunction Comparators: Nitroglycerin (NTG), Sodium nitroprusside (SNP), Nicardipine (NIC) Rapid onset: BP control in 5 min2 Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.

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

85. ECLIPSE: Trial Design

86. Treatment Protocol Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.

87. Outcome Endpoints Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.

88. Patient Disposition Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.

89. Baseline Characteristics Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.

90. Procedural Characteristics

91. ECLIPSE NTG — Drug Administration

92. ECLIPSE SNP: Drug Administration

93. ECLIPSE NIC: Drug Administration

94. RESULTS — Primary Endpoint Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.

95. Primary End Points by Treatment Comparison

96. Serious Adverse Events Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.Clevidipine is the first third-generation IV dihydropyridine calcium channel blocker under study for the treatment of hypertension when oral therapy is not feasible or not desirable Other dihydropyridine calcium channel blockers include the first- and second-generation oral antihypertensives nifedipine (first generation), nicardipine, amlodipine, isradipine, felodipine, nimodipine, and nisoldipine (all second generation) The only second-generation IV antihypertensives are nicardipine and nimodipine (Europe) Reference Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology. 1990;41:987-991.

97. ECLIPSE: Atrial Fibrillation

98. ECLIPSE Secondary Endpoint Systolic Blood Pressure Control Over 24 Hours

99. Logistic Regression Results Predictors of Mortality

101. SUMMARY (1) Multiple pharmacologic agents produce vasodilation via different mechanisms. Arterial vasoconstriction is characteristic of perioperative hypertension with intravascular hypovolemia. Nitrovasodilators decrease both preload and resistance vessels DHP CCBs produce arterial selective vasodilation that controls BP without producing venodilation or negative inotropic and conduction effects, and reverses vasospasm in the IMA and other vascular beds.

102. SUMMARY (2) ECLIPSE is the largest safety program ever performed with an intravenous antihypertensive (n=1,512) agents that examine management of acute, severe hypertension in the perioperative setting AUC data suggests better overall BP control with clevidipine compared with SNP and NTG Clevidipine represents a safe alternative to commonly used antihypertensive agents in the cardiovascular surgery setting, and demonstrated superior blood pressure control as assessed by integral analysis of excursions outside specified ranges over time Data supports importance of precise blood pressure control in a critically ill patient population Clevidipine represents the first potential nitroprusside replacement for clinicians

104. Comprehensive Neurovascular Protection in Patients Undergoing Cardiac Surgery

105. We all know changing demograhics.We all know changing demograhics.

106. Vascular Stiffness and Cardiovascular Outcomes Reflected pulse wave returns early in systole Rising systolic blood but declining diastolic B/P (rising pulse pressure) Increases strain on myocardium Exposes micro-circulation of brain and kidney to chronically high pressures and resultant pathophysiologic changes Go over the importance of reflected waves for morphology of arterial waveform. When occurs later augments coronary perfusionGo over the importance of reflected waves for morphology of arterial waveform. When occurs later augments coronary perfusion

107. Pulsatile Pressure Changes in the Vascular Tree

108. Vascular stiffness in general population is an independent predictor of death, MI, stroke and other adverse cv outcomes.Vascular stiffness in general population is an independent predictor of death, MI, stroke and other adverse cv outcomes.

109. DWI and PWI in Acute Stroke DWI identifies densely ischemic tissue/infarct PWI identifies area surrounding the core infarct getting enough blood to survive, not enough to function PWI-DWI (diffusion-perfusion mismatch) ~ “ischemic penumbra”

110. Ischemic penumbra. Area at riskIschemic penumbra. Area at risk

111. SPECT Imaging Before CABG HOW FREQUENT IS THIS PROBLEM? TWO CAUSES OF BRAIN INJURY: EMBOLISM AND HYPOPERFUSION Top Left: normal Right 1-2 regional perfusion defects; lower left 3-4 perfusion defects; ight lorwe > 4 regional perfusion defects. 75% of 82 patients had regional perfusion defects before surgery WE are not curing this problem.HOW FREQUENT IS THIS PROBLEM? TWO CAUSES OF BRAIN INJURY: EMBOLISM AND HYPOPERFUSION Top Left: normal Right 1-2 regional perfusion defects; lower left 3-4 perfusion defects; ight lorwe > 4 regional perfusion defects. 75% of 82 patients had regional perfusion defects before surgery WE are not curing this problem.

112. Watershed Strokes Detected with DWI After Cardiac Surgery Watershed infarcts present in 68% of 98 strokes MAP ? = 10 mm Hg during CPB ? risk 4 fold for bilateral watershed infarct c/w other infarct patterns TO FURTHER ILLUSTRATE THE IMPORTANCE OF HYPOPERFUSIONTO FURTHER ILLUSTRATE THE IMPORTANCE OF HYPOPERFUSION

113. Blood Pressure Management During CPB CBF-BP autoregulation believed intact (?-stat) Lower limit MAP of 50 mmHg? Higher CBF might be deleterious Increase cerebral embolic load “Wash-out” cardioplegia via non-coronary collaterals The optimal and safe MAP during CPB is one of the most controversial and contentious issues in the practice of cardiac anesthesia for the past half-century.The optimal and safe MAP during CPB is one of the most controversial and contentious issues in the practice of cardiac anesthesia for the past half-century.

115. Autoregulation Monitoring using ICM+

116. Cerebral Autoregulation Cerebral Autoregulation Is Central to the Treatment of Hypertensive Crises Autoregulation refers to the inherent regulation of arterial diameter to allow maintenance of a relatively constant amount of blood flow in different vascular beds and is most frequently discussed in terms of cerebral tissue.1 Autoregulation is lost in ischemic tissue. In patients with chronic hypertension, the structure of the arterioles thickens and the entire autoregulatory curve is shifted to the right. When BP is increased beyond the upper limits of autoregulation, “breakthrough” hyperperfusion occurs. In previously normotensive patients, whose vessels have not been altered by prior exposure to high pressures, breakthrough typically occurs at a MAP of about 120 mm Hg. In chronic hypertensive patients, the breakthrough may occur at 160 mm Hg.2 As such, a normotensive patient would be expected to develop end-organ damage at a lower BP than a chronic hypertensive. Lowering BP into the normal range in a poorly controlled, chronic hypertensive patient may actually accelerate end-organ damage.2 This difference in autoregulatory set points has important implications for the management of hypertensive urgency and emergency. The majority of the complications seen in the management of hypertensive emergency are actually from overly aggressive BP reductions. Care should be exercised in patients with chronic hypertension, or patients whose previous BP status is unknown, so that their MAP is not lowered to the point where they suffer from ischemia (“fall off the left side of the curve”).2 1. Berne RM, Levy MN. Cardiovascular Physiology. 8th ed. Philadelphia, Pa: Mosby; 2001. 2. Strandgaard S. Autoregulation of cerebral blood flow in hypertensive patients: the modifying influence of prolonged antihypertensive treatment on the tolerance to acute, drug-induced hypotension. Circulation. 1976;53:720-727.Cerebral Autoregulation Is Central to the Treatment of Hypertensive Crises Autoregulation refers to the inherent regulation of arterial diameter to allow maintenance of a relatively constant amount of blood flow in different vascular beds and is most frequently discussed in terms of cerebral tissue.1 Autoregulation is lost in ischemic tissue. In patients with chronic hypertension, the structure of the arterioles thickens and the entire autoregulatory curve is shifted to the right. When BP is increased beyond the upper limits of autoregulation, “breakthrough” hyperperfusion occurs. In previously normotensive patients, whose vessels have not been altered by prior exposure to high pressures, breakthrough typically occurs at a MAP of about 120 mm Hg. In chronic hypertensive patients, the breakthrough may occur at 160 mm Hg.2 As such, a normotensive patient would be expected to develop end-organ damage at a lower BP than a chronic hypertensive. Lowering BP into the normal range in a poorly controlled, chronic hypertensive patient may actually accelerate end-organ damage.2 This difference in autoregulatory set points has important implications for the management of hypertensive urgency and emergency. The majority of the complications seen in the management of hypertensive emergency are actually from overly aggressive BP reductions. Care should be exercised in patients with chronic hypertension, or patients whose previous BP status is unknown, so that their MAP is not lowered to the point where they suffer from ischemia (“fall off the left side of the curve”).2 1. Berne RM, Levy MN. Cardiovascular Physiology. 8th ed. Philadelphia, Pa: Mosby; 2001. 2. Strandgaard S. Autoregulation of cerebral blood flow in hypertensive patients: the modifying influence of prolonged antihypertensive treatment on the tolerance to acute, drug-induced hypotension. Circulation. 1976;53:720-727.

117. Autoregulatory Threshold: COx vs Doppler

118. Note upward autoregulatory level. That is, short plateauNote upward autoregulatory level. That is, short plateau

119. 75 mm Hg75 mm Hg

120. Approach to High Risk Patient We don’t know where to keep MAP MAP > 70 mmHg (???) NIRS monitoring

121. Make the point about postop bp lability and diastolic dysfunction leading to bp lability.Make the point about postop bp lability and diastolic dysfunction leading to bp lability.

122. Conclusions Cerebral vascular disease is prevalent in contemporary cardiac surgery practice Blood pressures during CPB deemed “safe” in the past may expose patients to cerebral hypoperfusion and brain injury Blood pressure within a “tight” range may be preferable Individualized blood pressure management based on NIRS?

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