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Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Program Chairman Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine.

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Presentation on theme: "Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Program Chairman Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine."— Presentation transcript:

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2 Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Program Chairman Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Acute Pressure Syndromes Evidence-Based Management of Acute Blood Pressure Elevation Across Multiple Disease States Optimizing Therapy for Life-Threatening Vascular Dysfunction SyndromesConnecting the Dots From Threat to Therapy A Year 2007 EM Update

3 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 Welcome and Program Overview

4 Program Educational Objectives As a result of this session, physicians wil: As a result of this session, physicians wil: Learn to identify underlying chronic and acute precipitants of acute elevations in systemic blood pressure and how these syndromes presents in the ED across multiple disease states and patient populations. Learn to identify underlying chronic and acute precipitants of acute elevations in systemic blood pressure and how these syndromes presents in the ED across multiple disease states and patient populations. Learn to assess and implement optimal pharmacologic interventions in the ED for patients presenting with manifestations of acute pressure syndromes, including elevated systolic or diastolic blood pressure, end organ dysfunction, and other cardiovascular, renovascular, and/or neurovascular derangements. Learn to assess and implement optimal pharmacologic interventions in the ED for patients presenting with manifestations of acute pressure syndromes, including elevated systolic or diastolic blood pressure, end organ dysfunction, and other cardiovascular, renovascular, and/or neurovascular derangements. Learn to characterize, identify, and evaluate myriad, acute disease states producing serious and/or life-threatening elevations in systemic blood pressure, among them: hypertensive urgency, hypertensive crisis, ischemic stroke, drug-induced acute pressure syndromes, subarachnoid hemorrhage, intracerebral hemorrhage, pulmonary edema, and related conditions. Learn to characterize, identify, and evaluate myriad, acute disease states producing serious and/or life-threatening elevations in systemic blood pressure, among them: hypertensive urgency, hypertensive crisis, ischemic stroke, drug-induced acute pressure syndromes, subarachnoid hemorrhage, intracerebral hemorrhage, pulmonary edema, and related conditions. As a result of this session, physicians wil: As a result of this session, physicians wil: Learn to identify underlying chronic and acute precipitants of acute elevations in systemic blood pressure and how these syndromes presents in the ED across multiple disease states and patient populations. Learn to identify underlying chronic and acute precipitants of acute elevations in systemic blood pressure and how these syndromes presents in the ED across multiple disease states and patient populations. Learn to assess and implement optimal pharmacologic interventions in the ED for patients presenting with manifestations of acute pressure syndromes, including elevated systolic or diastolic blood pressure, end organ dysfunction, and other cardiovascular, renovascular, and/or neurovascular derangements. Learn to assess and implement optimal pharmacologic interventions in the ED for patients presenting with manifestations of acute pressure syndromes, including elevated systolic or diastolic blood pressure, end organ dysfunction, and other cardiovascular, renovascular, and/or neurovascular derangements. Learn to characterize, identify, and evaluate myriad, acute disease states producing serious and/or life-threatening elevations in systemic blood pressure, among them: hypertensive urgency, hypertensive crisis, ischemic stroke, drug-induced acute pressure syndromes, subarachnoid hemorrhage, intracerebral hemorrhage, pulmonary edema, and related conditions. Learn to characterize, identify, and evaluate myriad, acute disease states producing serious and/or life-threatening elevations in systemic blood pressure, among them: hypertensive urgency, hypertensive crisis, ischemic stroke, drug-induced acute pressure syndromes, subarachnoid hemorrhage, intracerebral hemorrhage, pulmonary edema, and related conditions.

5 Program Educational Objectives Learn to understand the specific advantages and potential disadvantages of currently available intravenously administered pharmacologic agents used in the ED to reduce acute, serious, and/or life-threatening elevations in systemic blood pressure. Learn to understand the specific advantages and potential disadvantages of currently available intravenously administered pharmacologic agents used in the ED to reduce acute, serious, and/or life-threatening elevations in systemic blood pressure. Learn to identify the ideal properties of intravenous agents used in the ED to provide emergency- and critical care-based lowering of potentially serious and/or life-threatening elevations in systemic blood pressure. Learn to identify the ideal properties of intravenous agents used in the ED to provide emergency- and critical care-based lowering of potentially serious and/or life-threatening elevations in systemic blood pressure. Learn to discuss and assess the impact that new trials and novel agents are likely to have on future management of patients with acute pressure syndromes. Learn to discuss and assess the impact that new trials and novel agents are likely to have on future management of patients with acute pressure syndromes. Learn to apply national guidelines and expert, consensus-based recommendations in the ED in order to optimize emergency-based therapy of patients with serious, systemic elevations in blood pressure. Learn to apply national guidelines and expert, consensus-based recommendations in the ED in order to optimize emergency-based therapy of patients with serious, systemic elevations in blood pressure. Learn to understand the specific advantages and potential disadvantages of currently available intravenously administered pharmacologic agents used in the ED to reduce acute, serious, and/or life-threatening elevations in systemic blood pressure. Learn to understand the specific advantages and potential disadvantages of currently available intravenously administered pharmacologic agents used in the ED to reduce acute, serious, and/or life-threatening elevations in systemic blood pressure. Learn to identify the ideal properties of intravenous agents used in the ED to provide emergency- and critical care-based lowering of potentially serious and/or life-threatening elevations in systemic blood pressure. Learn to identify the ideal properties of intravenous agents used in the ED to provide emergency- and critical care-based lowering of potentially serious and/or life-threatening elevations in systemic blood pressure. Learn to discuss and assess the impact that new trials and novel agents are likely to have on future management of patients with acute pressure syndromes. Learn to discuss and assess the impact that new trials and novel agents are likely to have on future management of patients with acute pressure syndromes. Learn to apply national guidelines and expert, consensus-based recommendations in the ED in order to optimize emergency-based therapy of patients with serious, systemic elevations in blood pressure. Learn to apply national guidelines and expert, consensus-based recommendations in the ED in order to optimize emergency-based therapy of patients with serious, systemic elevations in blood pressure.

6 Program Faculty Program Chairman Program Chairman Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Chairman, Department of Emergency Medicine Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine of Medicine Philadelphia, Pennsylvania Distinguished Presenters James Ferguson III, MD, FACC Associate Director, Cardiology Research Texas Heart Institute at St. Lukes Episcopal Hospital Episcopal Hospital Associate Professor Baylor College of Medicine Clinical Assistant Professor University of Texas Health Science Center at Houston at Houston Houston, Texas Frank Peacock, MD, FACEP Professor of Emergency Medicine Department of Emergency Medicine Cleveland Clinic Hospitals and Clinics Cleveland, Ohio

7 Faculty Disclosures Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Grant/Research Support: GlaxoSmithKline Consultant: The Medicines Co., Schering-Plough, Sanofi-Aventis, BMS, Genentech Speakers Bureau: Schering-Plough, Sanofi-Aventis, BMS, Genentech James Ferguson III, MD, FACC Grant/Research Support: Eisai, The Medicines Company, Viatron/Medtronic Consultant: BMS, Eisai, Prism, Sanofi-Aventis, Schering Plough, Takeda, The Medicines Co., Therox Speakers Bureau: BMS, Sanofi-Aventis, Schering Plough Frank Peacock, MD, FACEP Grant/Research Support: Abbott, Accumetrics, Biosite, CHF Solutions, Inovise, Inverness, Scios, The Medicines Co., Vital Sensors Consultant: Abbott, Beckman-Coulter, Biosite, Inovise, Inverness, Ortho Clinical Diagnostics, PDL, Scios, The Medicines Co., Vital Sensors Speakers Bureau: Abbott, Scios, PDL, Biosite Major Shareholder: Vital Sensors

8 ACUTE PRESSURE SYNDROMES Hypertensive Urgencies and Emergencies Current Challenges for the Emergency Physician Charles V. Pollack, Jr., M.A., M.D., FACEP Program Chairman Chairman, Emergency Medicine, Pennsylvania Hospital Professor of Emergency Medicine, University of Pennsylvania, Philadelphia Introduction and Chairmans Overview

9 Hypertension An Epidemic Affects at least 65 million Americans Affects at least 65 million Americans Affects at least 1 BILLION individuals worldwide Affects at least 1 BILLION individuals worldwide Most current (2003) evidence basis for chronic managementThe Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Hypertension (JNC 7)lacks guidance for acute management of patients presenting to an ED with hypertension, especially severe acute elevations of BP Most current (2003) evidence basis for chronic managementThe Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Hypertension (JNC 7)lacks guidance for acute management of patients presenting to an ED with hypertension, especially severe acute elevations of BP Affects at least 65 million Americans Affects at least 65 million Americans Affects at least 1 BILLION individuals worldwide Affects at least 1 BILLION individuals worldwide Most current (2003) evidence basis for chronic managementThe Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Hypertension (JNC 7)lacks guidance for acute management of patients presenting to an ED with hypertension, especially severe acute elevations of BP Most current (2003) evidence basis for chronic managementThe Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Hypertension (JNC 7)lacks guidance for acute management of patients presenting to an ED with hypertension, especially severe acute elevations of BP JNC 7, JAMA 2003; 289:

10 Hypertensive Urgencies and Emergencies Epidemiologic data are largely lacking Epidemiologic data are largely lacking It is thought that ~ 1% of patients with hypertension will eventually present to the ED in hypertensive crisis It is thought that ~ 1% of patients with hypertension will eventually present to the ED in hypertensive crisis In a single-center Italian study, HU or HE accounted for 3% of all medicine admissions and 27.5% of all medical emergencies In a single-center Italian study, HU or HE accounted for 3% of all medicine admissions and 27.5% of all medical emergencies l HU:HE ratio of 3:1 in that study l Patients with HU much more likely to be unaware of their hypertension diagnosis than those with HE Zampaglione et al, Hypertension 1996;27:144.

11 Presenting Symptoms Hypertensive Urgencies Hypertensive Urgencies l Arrhythmia l Epistaxis l Headache l Psychomotor agitation Usual Primary ED Diagnosis Usual Primary ED Diagnosis l Hypertension Hypertensive Urgencies Hypertensive Urgencies l Arrhythmia l Epistaxis l Headache l Psychomotor agitation Usual Primary ED Diagnosis Usual Primary ED Diagnosis l Hypertension Hypertensive Emergencies Hypertensive Emergencies l Chest pain l Dyspnea l Neurologic deficits Usual Primary ED Diagnosis Usual Primary ED Diagnosis l CVA l Acute pulmonary edema l Hypertensive encephalopathy l Acute heart failure Hypertensive Emergencies Hypertensive Emergencies l Chest pain l Dyspnea l Neurologic deficits Usual Primary ED Diagnosis Usual Primary ED Diagnosis l CVA l Acute pulmonary edema l Hypertensive encephalopathy l Acute heart failure Zampaglione et al, Hypertension 1996;27:144.

12 JNC 7 Nomenclature Normal BP: Systolic < 120, Diastolic < 80 Normal BP: Systolic < 120, Diastolic < 80 Prehypertension: S = , D = Prehypertension: S = , D = Stage 1 hypertension: S = , D = Stage 1 hypertension: S = , D = Stage 2 hypertension: S > 160, D > 100 Stage 2 hypertension: S > 160, D > 100 Stage 3 hypertension (JNC 6): Stage 3 hypertension (JNC 6): l Systolic > 180, Diastolic > 110 l Functionally, this is hypertensive urgency What about crisis, emergency, and urgency? What about crisis, emergency, and urgency? Normal BP: Systolic < 120, Diastolic < 80 Normal BP: Systolic < 120, Diastolic < 80 Prehypertension: S = , D = Prehypertension: S = , D = Stage 1 hypertension: S = , D = Stage 1 hypertension: S = , D = Stage 2 hypertension: S > 160, D > 100 Stage 2 hypertension: S > 160, D > 100 Stage 3 hypertension (JNC 6): Stage 3 hypertension (JNC 6): l Systolic > 180, Diastolic > 110 l Functionally, this is hypertensive urgency What about crisis, emergency, and urgency? What about crisis, emergency, and urgency? JNC 7, JAMA 2003; 289:

13 JNC 7 Nomenclature Using JNC 7 nomenclature, hypertensive crisis is an acute, severe, stage 2 or 3 elevation in blood pressure Using JNC 7 nomenclature, hypertensive crisis is an acute, severe, stage 2 or 3 elevation in blood pressure Crisis is then differentiated into hypertensive emergencies (involving some end-organ damage) and urgencies (no end-organ damage) Crisis is then differentiated into hypertensive emergencies (involving some end-organ damage) and urgencies (no end-organ damage) Using JNC 7 nomenclature, hypertensive crisis is an acute, severe, stage 2 or 3 elevation in blood pressure Using JNC 7 nomenclature, hypertensive crisis is an acute, severe, stage 2 or 3 elevation in blood pressure Crisis is then differentiated into hypertensive emergencies (involving some end-organ damage) and urgencies (no end-organ damage) Crisis is then differentiated into hypertensive emergencies (involving some end-organ damage) and urgencies (no end-organ damage) JNC 7, JAMA 2003; 289:

14 End-Organ Damage Cardiopulmonary Cardiopulmonary l Acute heart failure l Acute coronary syndrome l Acute pulmonary edema with respiratory failure l Dissecting aorta CNS CNS l Hypertensive encephalopathy l CVA Ocular Ocular l Exudates l Papilledema l Retinal hemorrhages Renal Renal l Acute renal failure Cardiopulmonary Cardiopulmonary l Acute heart failure l Acute coronary syndrome l Acute pulmonary edema with respiratory failure l Dissecting aorta CNS CNS l Hypertensive encephalopathy l CVA Ocular Ocular l Exudates l Papilledema l Retinal hemorrhages Renal Renal l Acute renal failure JNC 7, JAMA 2003; 289:

15 Causes of Hypertensive Crises Essential hypertension Essential hypertension l Medication noncompliance Secondary hypertension Secondary hypertension l Aortic coarctation l Cushings syndrome l Elevated ICP l Renal dysfunction l Pregnancy l Hyperparathyroidism l Hyperthyroidism l Pheochromocytoma l Primary aldosteronism Essential hypertension Essential hypertension l Medication noncompliance Secondary hypertension Secondary hypertension l Aortic coarctation l Cushings syndrome l Elevated ICP l Renal dysfunction l Pregnancy l Hyperparathyroidism l Hyperthyroidism l Pheochromocytoma l Primary aldosteronism JNC 7, JAMA 2003; 289:

16 Goals of ED Therapy of Hypertensive Crises HU can generally be managed with oral medications and requires BP lowering over hours HU can generally be managed with oral medications and requires BP lowering over hours l Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneys Goal in hypertensive urgency is to reduce MAP by 10-15% and/or to a DBP of within one hour Goal in hypertensive urgency is to reduce MAP by 10-15% and/or to a DBP of within one hour l Aortic dissection requires even more rapid lowering l Once initial reduction achieved, transition to oral agents l Dug of choice for initial therapy often depends on which end- organ system is affected and on comorbidities HU can generally be managed with oral medications and requires BP lowering over hours HU can generally be managed with oral medications and requires BP lowering over hours l Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneys Goal in hypertensive urgency is to reduce MAP by 10-15% and/or to a DBP of within one hour Goal in hypertensive urgency is to reduce MAP by 10-15% and/or to a DBP of within one hour l Aortic dissection requires even more rapid lowering l Once initial reduction achieved, transition to oral agents l Dug of choice for initial therapy often depends on which end- organ system is affected and on comorbidities JNC 7, JAMA 2003; 289:

17 Why Are We Here Today? Severe hypertension is increasingly prevalent as population ages and obesity and diabetes become more common Severe hypertension is increasingly prevalent as population ages and obesity and diabetes become more common Currently available agents for the management of acute severe BP elevation leave much to be desired advancements are possible Currently available agents for the management of acute severe BP elevation leave much to be desired advancements are possible There is a new agent on the horizon that has been tested specifically in the ED There is a new agent on the horizon that has been tested specifically in the ED Severe hypertension is increasingly prevalent as population ages and obesity and diabetes become more common Severe hypertension is increasingly prevalent as population ages and obesity and diabetes become more common Currently available agents for the management of acute severe BP elevation leave much to be desired advancements are possible Currently available agents for the management of acute severe BP elevation leave much to be desired advancements are possible There is a new agent on the horizon that has been tested specifically in the ED There is a new agent on the horizon that has been tested specifically in the ED

18 Welcome to This Program! We will review the scope, pathophysiology, and epidemiology of hypertension as well as hypertensive urgencies and emergencies as they present in the ED We will review the scope, pathophysiology, and epidemiology of hypertension as well as hypertensive urgencies and emergencies as they present in the ED We will review and assess current therapy and goals of BP management in the ED We will review and assess current therapy and goals of BP management in the ED We will look to the near future of management of acute severe hypertension We will look to the near future of management of acute severe hypertension We will review the scope, pathophysiology, and epidemiology of hypertension as well as hypertensive urgencies and emergencies as they present in the ED We will review the scope, pathophysiology, and epidemiology of hypertension as well as hypertensive urgencies and emergencies as they present in the ED We will review and assess current therapy and goals of BP management in the ED We will review and assess current therapy and goals of BP management in the ED We will look to the near future of management of acute severe hypertension We will look to the near future of management of acute severe hypertension

19 The Emergency Department Armamentarium for Hypertension Therapy The Good and Bad News About Current Treatment Options Frank Peacock, MD, FACEP Professor of Emergency Medicine Department of Emergency Medicine Cleveland Clinic Hospitals and Clinics Cleveland, Ohio Frank Peacock, MD, FACEP Professor of Emergency Medicine Department of Emergency Medicine Cleveland Clinic Hospitals and Clinics Cleveland, Ohio From Hypertension Threat to Therapy A Year 2007 EM Update From Hypertension Threat to Therapy A Year 2007 EM Update

20 Established the modern method of measuring BP In 1855 Karl Vierdordt ( )

21 ED Hypertensive Emergencies Hypertensive emergencies and urgencies Hypertensive emergencies and urgencies l Account for 3% of all ED visits 1 An Internal Medicine ED An Internal Medicine ED l N=14,209 l 1634 had a medical urgency or emergency % of these were hypertensive crises27.4% of these were hypertensive crises Clinical treatment practices vary widely 3 Clinical treatment practices vary widely 3 Hypertensive emergencies and urgencies Hypertensive emergencies and urgencies l Account for 3% of all ED visits 1 An Internal Medicine ED An Internal Medicine ED l N=14,209 l 1634 had a medical urgency or emergency % of these were hypertensive crises27.4% of these were hypertensive crises Clinical treatment practices vary widely 3 Clinical treatment practices vary widely 3 1.Kitiyakara C, Guzman N. J Am Soc Nephrol. 1998;9: Zampaglione B, et al. Hypertension. 1996;27: Cherney D, Strauss S. J Gen Intern Med. 2002;17:

22 Hypertension in the ED Four Categories of Presentation Emergencies Emergencies Urgencies Urgencies Mild, uncomplicated Mild, uncomplicated Transient Transient Four Categories of Presentation Emergencies Emergencies Urgencies Urgencies Mild, uncomplicated Mild, uncomplicated Transient Transient

23 Hypertension Frequency CategoryFrequency Emergencies 1 cerebral and 1 cardiac/shift) Emergencies 1 cerebral and 1 cardiac/shift) Urgencies ?????? Urgencies ?????? Mild, uncomplicated 1/shift Mild, uncomplicated 1/shift TransientWho cares? TransientWho cares? CategoryFrequency Emergencies 1 cerebral and 1 cardiac/shift) Emergencies 1 cerebral and 1 cardiac/shift) Urgencies ?????? Urgencies ?????? Mild, uncomplicated 1/shift Mild, uncomplicated 1/shift TransientWho cares? TransientWho cares?

24 History and Physical US Obesity Epidemic US Obesity Epidemic l < 50% exercise more than occasionally l Colorado the thinnest state, only 13% obese l Too small a cuff falsely elevates BP US Obesity Epidemic US Obesity Epidemic l < 50% exercise more than occasionally l Colorado the thinnest state, only 13% obese l Too small a cuff falsely elevates BP

25 Definitions of Hypertension Mild, Uncomplicated HTN Mild, Uncomplicated HTN l Diastolic BP <115 mmHg without end organ symptoms l Educate, do not treat, arrange follow up Transient HTN Transient HTN l A reaction to some condition Pain, fright, epistaxis, drug ODPain, fright, epistaxis, drug OD l Treat the condition Mild, Uncomplicated HTN Mild, Uncomplicated HTN l Diastolic BP <115 mmHg without end organ symptoms l Educate, do not treat, arrange follow up Transient HTN Transient HTN l A reaction to some condition Pain, fright, epistaxis, drug ODPain, fright, epistaxis, drug OD l Treat the condition

26 Hypertensive Urgency Hypertensive Urgency l BP at a level that may be potentially harmful, but without focal findings l Usually sustained diastolic > 115 mmHg (120mmHg) Commonly due to non-complianceCommonly due to non-compliance l Ignore systolic BP: MAP= ( 2 Diastolic + systolic) / 3 l Lower BP over hours (give them a Rx) Avoid rapid BP reductionsAvoid rapid BP reductions l History, physical, and time may be all that is needed Hypertensive Urgency Hypertensive Urgency l BP at a level that may be potentially harmful, but without focal findings l Usually sustained diastolic > 115 mmHg (120mmHg) Commonly due to non-complianceCommonly due to non-compliance l Ignore systolic BP: MAP= ( 2 Diastolic + systolic) / 3 l Lower BP over hours (give them a Rx) Avoid rapid BP reductionsAvoid rapid BP reductions l History, physical, and time may be all that is needed Definition of Hypertension

27 Hypertension Treatment and Symptoms List of all the studies demonstrating acutely lowering the BP in a patient without symptoms has ANY benefit: List of all the studies demonstrating acutely lowering the BP in a patient without symptoms has ANY benefit: Isolated headache is not a manifestation of end organ damage

28 1) Gardner JW, Mountain GE, Hines EA. The relationship of migraine to hypertension and to hypertension headaches. Am J Med Sci 1940;200:50-3 2) Badran THA, Weir RJ, McGuiness JB. Hypertension and headache. Scott Med J 1970; 5: ) Bulpitt CJ, Dollery CT, Carne S. Change in symptoms of hypertensive patients after referral to a hospital clinic. Br Heart J 1976;38: ) Jaillard AS, Mazetti P, Kala E. Prevalence of migraine and headache in a high-altitude town of Peru: a population-based study. Headache 1997;37: ) Marcoux S, Berube S, Brisson J, et al. History of migraine and risk of pregnancy-induced hypertension. Epidemiol 1992;3: ) Markush RE, Herbert RK, Heyman A, et al. Epidemiologic study of migraine symptoms in young women. Neurology 1975;25: ) Cirillo M, Stellato D, Lombardi C, et al. Headache and cardiovascular risk factors: positive association with hypertension. Headache 1999;39: ) Featherstone HJ. Medical diagnosis and problems in individuals with recurrent idiopathic headaches. Headache 1985;25: ) Ziegler DK, Hassanein RS, Couch JR. Characteristics of life headache histories in a non-clinic population. Neurology 1977;27: ) Atkins JB. Migraine as a sequel to infect by L icterohaemorrhagiae. BMJ 1955;1: ) Francesschi M, Colombo B, Rossi P, et al. Headache in a population-based elderly cohort. An ancillary study to the Italian longitudinal study of aging (ILSA). Headache 1997;37: ) Gardner JW, Mountain GE, Hines EA. The relationship of migraine to hypertension and to hypertension headaches. Am J Med Sci 1940;200:50-3 2) Badran THA, Weir RJ, McGuiness JB. Hypertension and headache. Scott Med J 1970; 5: ) Bulpitt CJ, Dollery CT, Carne S. Change in symptoms of hypertensive patients after referral to a hospital clinic. Br Heart J 1976;38: ) Jaillard AS, Mazetti P, Kala E. Prevalence of migraine and headache in a high-altitude town of Peru: a population-based study. Headache 1997;37: ) Marcoux S, Berube S, Brisson J, et al. History of migraine and risk of pregnancy-induced hypertension. Epidemiol 1992;3: ) Markush RE, Herbert RK, Heyman A, et al. Epidemiologic study of migraine symptoms in young women. Neurology 1975;25: ) Cirillo M, Stellato D, Lombardi C, et al. Headache and cardiovascular risk factors: positive association with hypertension. Headache 1999;39: ) Featherstone HJ. Medical diagnosis and problems in individuals with recurrent idiopathic headaches. Headache 1985;25: ) Ziegler DK, Hassanein RS, Couch JR. Characteristics of life headache histories in a non-clinic population. Neurology 1977;27: ) Atkins JB. Migraine as a sequel to infect by L icterohaemorrhagiae. BMJ 1955;1: ) Francesschi M, Colombo B, Rossi P, et al. Headache in a population-based elderly cohort. An ancillary study to the Italian longitudinal study of aging (ILSA). Headache 1997;37: Studies Showing No Relation Between BP and Headache

29 1) Waters WE. Headache and blood pressure in the community. BMJ 1971;1: ) Weiss NS. Relation of high blood pressure to headache, epistaxis, and selected other symptoms. N Engl J Med 1972;287: ) Schele R, Ahlborg B, Ekbom K. Physical characteristics and allergic history in young men with migraine and other headaches. Headache 1978;18: ) Kottke TE, Tuomilehto J, Puska P, et al. The relationship of symptoms and blood pressure in a population sample. Int J Epidemiol 1979;8: ) Abramson JH, Hopp C, Epstein LM. Migraine and non-migrainous headaches: a community survey in Jerusalem. J Epidemiol Community Health 1980;34: ) Paulin JM, Waal-Manning J, Simpson FO, et al. The prevalence of headache in a small New Zealand town. Headache 1985;25: ) Chen TC, Leviton A, Edelstein S, et al. Migraine and other diseases in women of reproductive age. The influence of smoking on observed associations. Arch Neurol 1987;44: ) Hale WE, et al. Headache in the elderly: an evaluation of risk factors. Headache 1987;27: ) D'Alessandro, Benassi G, Lenzi PL, et al. Epidemiology of headache in the republic of San Marino. J Neurol Neurosurg Psychiatry 1988;51: ) Couch JR. Headache as risk factor in atherosclerosis-related diseases. Headache 1989;29: ) Rasmussen BK, Olesen J. Symptomatic and non-symptomatic headaches in a general population. Neurology 1992;42: ) Wang SJ, Fuh JL, Liu CY, et al. Chronic daily headache in Chinese elderly: prevalence, risk factors, and biannual follow up. Neurology 2000;54: ) Ho KH, Ong BK. Perceived headache associations in Singapore. Results of a randomized national survey. Headache 2001;41: ) Waters WE. Headache and blood pressure in the community. BMJ 1971;1: ) Weiss NS. Relation of high blood pressure to headache, epistaxis, and selected other symptoms. N Engl J Med 1972;287: ) Schele R, Ahlborg B, Ekbom K. Physical characteristics and allergic history in young men with migraine and other headaches. Headache 1978;18: ) Kottke TE, Tuomilehto J, Puska P, et al. The relationship of symptoms and blood pressure in a population sample. Int J Epidemiol 1979;8: ) Abramson JH, Hopp C, Epstein LM. Migraine and non-migrainous headaches: a community survey in Jerusalem. J Epidemiol Community Health 1980;34: ) Paulin JM, Waal-Manning J, Simpson FO, et al. The prevalence of headache in a small New Zealand town. Headache 1985;25: ) Chen TC, Leviton A, Edelstein S, et al. Migraine and other diseases in women of reproductive age. The influence of smoking on observed associations. Arch Neurol 1987;44: ) Hale WE, et al. Headache in the elderly: an evaluation of risk factors. Headache 1987;27: ) D'Alessandro, Benassi G, Lenzi PL, et al. Epidemiology of headache in the republic of San Marino. J Neurol Neurosurg Psychiatry 1988;51: ) Couch JR. Headache as risk factor in atherosclerosis-related diseases. Headache 1989;29: ) Rasmussen BK, Olesen J. Symptomatic and non-symptomatic headaches in a general population. Neurology 1992;42: ) Wang SJ, Fuh JL, Liu CY, et al. Chronic daily headache in Chinese elderly: prevalence, risk factors, and biannual follow up. Neurology 2000;54: ) Ho KH, Ong BK. Perceived headache associations in Singapore. Results of a randomized national survey. Headache 2001;41: Studies Showing an Association Between BP and Headache

30 Isolated Systolic Hypertension RCT: Double blind placebo vs active treatment for isolated systolic HTN in pts > 60 yrs old RCT: Double blind placebo vs active treatment for isolated systolic HTN in pts > 60 yrs old 4695 pts, SBP > , DBP , DBP < 95 mmHg l Excluded HTN emergency and secondary causes of HTN 2 year follow up 2 year follow up Treatment: Nitrendipine Treatment: Nitrendipine RCT: Double blind placebo vs active treatment for isolated systolic HTN in pts > 60 yrs old RCT: Double blind placebo vs active treatment for isolated systolic HTN in pts > 60 yrs old 4695 pts, SBP > , DBP , DBP < 95 mmHg l Excluded HTN emergency and secondary causes of HTN 2 year follow up 2 year follow up Treatment: Nitrendipine Treatment: Nitrendipine Staessen JA. Lancet, 1997;350:

31 Isolated Systolic Hypertension (Reported in 1000 patient years) Cardiovascular (HF, MI) Cardiovascular (HF, MI) l 20.5 placebo, 15.1 Tx (p=0.03) CVA CVA l 18 placebo, vs 11.8 Tx (p=0.006) Total Mortality Total Mortality l 24 placebo vs 20.5 Tx (p=0.08) l Difference = 3.5/1000 pt yrs Cardiovascular (HF, MI) Cardiovascular (HF, MI) l 20.5 placebo, 15.1 Tx (p=0.03) CVA CVA l 18 placebo, vs 11.8 Tx (p=0.006) Total Mortality Total Mortality l 24 placebo vs 20.5 Tx (p=0.08) l Difference = 3.5/1000 pt yrs Morbidity Staessen JA. Lancet, 1997;350:

32 Definition of Hypertensive Emergency Hypertensive Emergency Hypertensive Emergency l Increased BP WITH end organ damage At risk: Brain, heart, kidneysAt risk: Brain, heart, kidneys l No specific BP criteria Hypertensive Emergency Hypertensive Emergency l Increased BP WITH end organ damage At risk: Brain, heart, kidneysAt risk: Brain, heart, kidneys l No specific BP criteria

33 Acute BP Management Considerations What is the magnitude of: What is the magnitude of: l Disease risk? l Treatment benefit? l Treatment risk? How persistent is the benefit? How persistent is the benefit? What improved outcome is there for the patient? What improved outcome is there for the patient? What is the magnitude of: What is the magnitude of: l Disease risk? l Treatment benefit? l Treatment risk? How persistent is the benefit? How persistent is the benefit? What improved outcome is there for the patient? What improved outcome is there for the patient?

34 47-Year-Old Stock Broker Complains Of Chest Pain MVO 2 MAP x HR BP 162/110

35 Hemodynamics and Myocardial Ischemia Adapted from Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 6 th ed. W.B. Saunders Co.; Afterload or SVR Work O2 consumption Myocardial Blood Flow O2 delivery Left Ventricular (LV) Wall Tension Afterload or SVR Myocardial Ischemia Increased Afterload Increases O 2 Consumption and Decreases O 2 Delivery to the Heart Increased Afterload Increases O 2 Consumption and Decreases O 2 Delivery to the Heart

36 Acute Myocardial Infarction NTG NTG l Relieves only chest pain l No mortality difference in 77,000 patients -blockers -blockers Antiplatelets: ASA, clopidogrel Antiplatelets: ASA, clopidogrel Anticoagulants: LMWH, UFH Anticoagulants: LMWH, UFH GP IIb/IIIa antagonist or DTI w/clopidogrel GP IIb/IIIa antagonist or DTI w/clopidogrel NTG NTG l Relieves only chest pain l No mortality difference in 77,000 patients -blockers -blockers Antiplatelets: ASA, clopidogrel Antiplatelets: ASA, clopidogrel Anticoagulants: LMWH, UFH Anticoagulants: LMWH, UFH GP IIb/IIIa antagonist or DTI w/clopidogrel GP IIb/IIIa antagonist or DTI w/clopidogrel 2007 AHA/ACC Guidelines

37 NitroglycerinNitroglycerin Arterial and coronary venodilator Arterial and coronary venodilator l Mechanism: cGMP Onset, 2-5 minutes, t ½ 4 minutes Onset, 2-5 minutes, t ½ 4 minutes l Duration, 5-10 minutes Dose: Start at g/min Dose: Start at g/min l Titrate by 10 g/min q 3-5 minutes May cause headache, HR, vomiting, methemoglobinemia May cause headache, HR, vomiting, methemoglobinemia Special considerations Special considerations l Tachyphylaxis within hours l Coronary ischemia IV form requires special delivery system IV form requires special delivery system Arterial and coronary venodilator Arterial and coronary venodilator l Mechanism: cGMP Onset, 2-5 minutes, t ½ 4 minutes Onset, 2-5 minutes, t ½ 4 minutes l Duration, 5-10 minutes Dose: Start at g/min Dose: Start at g/min l Titrate by 10 g/min q 3-5 minutes May cause headache, HR, vomiting, methemoglobinemia May cause headache, HR, vomiting, methemoglobinemia Special considerations Special considerations l Tachyphylaxis within hours l Coronary ischemia IV form requires special delivery system IV form requires special delivery system The 7th Report of the JNC. JAMA 2003;289:

38 Nitroglycerin & PCWP versus Time n=9 ( 3 hr); n=12 (>3 hr) Added to standard therapy n=9 ( 3 hr); n=12 (>3 hr) Added to standard therapy Time (hr) Nitroglycerin Dose (mcg/min) Change in PCWP (mm Hg) NTG dose Change in PCWP * * * * * * * P<0.05 vs baseline Elkayam U et al. Am J Cardiol 2004;93:

39 Organic Nitrates: Tolerance Theories Decreased bioconversion to nitric oxide 1 Decreased bioconversion to nitric oxide 1 Cellular depletion of sulfhydryl groups 2,3 Cellular depletion of sulfhydryl groups 2,3 Neurohumoral adaptations 4 Neurohumoral adaptations 4 Superoxide anion production 5 Superoxide anion production 5 Upregulation of endothelin 6 Upregulation of endothelin 6 Decreased bioconversion to nitric oxide 1 Decreased bioconversion to nitric oxide 1 Cellular depletion of sulfhydryl groups 2,3 Cellular depletion of sulfhydryl groups 2,3 Neurohumoral adaptations 4 Neurohumoral adaptations 4 Superoxide anion production 5 Superoxide anion production 5 Upregulation of endothelin 6 Upregulation of endothelin 6 1.Münzel T. Am J Cardiol. 1996;77:24C-30C. 2.Parker JD, Parker JO. N Engl J Med. 1998;338: Needleman P, Johnson EMJ. J Pharmacol Exp Ther. 1973;184: Münzel T, et al. J Am Coll Cardiol. 1996;27: Münzel T, et al. J Clin Invest. 1995;95: Münzel T, et al. Proc Natl Acad Sci. 1995;92:

40 Nitroprusside Mechanism Spontaneously releases nitric oxide (NO) Spontaneously releases nitric oxide (NO) NO activates guanylyl cyclase, increasing cGMP NO activates guanylyl cyclase, increasing cGMP cGMP activates myosin light chain phosphatase (MLCP) cGMP activates myosin light chain phosphatase (MLCP) MLCP dephosphorylates myosin light chains MLCP dephosphorylates myosin light chains Leads to relaxation Leads to relaxation Spontaneously releases nitric oxide (NO) Spontaneously releases nitric oxide (NO) NO activates guanylyl cyclase, increasing cGMP NO activates guanylyl cyclase, increasing cGMP cGMP activates myosin light chain phosphatase (MLCP) cGMP activates myosin light chain phosphatase (MLCP) MLCP dephosphorylates myosin light chains MLCP dephosphorylates myosin light chains Leads to relaxation Leads to relaxation

41 Nitroprusside Arterial and venodilator Arterial and venodilator l Decreases preload and afterload l No chronotropic effect, but HR (baroreceptors) Onset 1-2 minutes, t ½ 3-4 minutes Onset 1-2 minutes, t ½ 3-4 minutes l 0.5 g/kg/min, then titrate l Average effective dose is 3 g/kg/min ( g/kg/min) Arterial and venodilator Arterial and venodilator l Decreases preload and afterload l No chronotropic effect, but HR (baroreceptors) Onset 1-2 minutes, t ½ 3-4 minutes Onset 1-2 minutes, t ½ 3-4 minutes l 0.5 g/kg/min, then titrate l Average effective dose is 3 g/kg/min ( g/kg/min) The 7th Report of the JNC. JAMA 2003;289:

42 Nitropusside: Issues and Concerns BP BP May cause N/V, twitching, sweating May cause N/V, twitching, sweating Metabolized to CN, then thiocyanate Metabolized to CN, then thiocyanate l RF issue BADNESS BADNESS PregnancyPregnancy Coronary steal?Coronary steal? Dose dependent in CBFDose dependent in CBF –Caution with high ICP Hypoxia ( Va/Q mismatch)Hypoxia ( Va/Q mismatch) Requires special delivery systemRequires special delivery system Usually requires direct artery pressure monitoringUsually requires direct artery pressure monitoring BP BP May cause N/V, twitching, sweating May cause N/V, twitching, sweating Metabolized to CN, then thiocyanate Metabolized to CN, then thiocyanate l RF issue BADNESS BADNESS PregnancyPregnancy Coronary steal?Coronary steal? Dose dependent in CBFDose dependent in CBF –Caution with high ICP Hypoxia ( Va/Q mismatch)Hypoxia ( Va/Q mismatch) Requires special delivery systemRequires special delivery system Usually requires direct artery pressure monitoringUsually requires direct artery pressure monitoring

43 Nitrovasodilators Nitroprusside versus Nitroglycerin DrugNitroprussideNitroglycerin Rapid onset of peak effect Afterload reduction Preload reduction Coronary steal reported +0 Coronary dilation – large vessel Coronary dilation – small vessel +/-+/- Tachycardia++++ Potential for symptomatic hypotension Ease of administration Cyanide toxicity Pepine CJ. Clin Ther. 1988;10:

44 Cyanide Toxicity Tachyphylaxis Important sign of impending toxicity Tachyphylaxis Important sign of impending toxicity Neurological manifestations Neurological manifestations l Hyperpnea l Headache, Vertigo l Altered mental status l Coma, Seizures Laboratory manifestations Laboratory manifestations l Lactic acidosis l Increased base deficit Tachyphylaxis Important sign of impending toxicity Tachyphylaxis Important sign of impending toxicity Neurological manifestations Neurological manifestations l Hyperpnea l Headache, Vertigo l Altered mental status l Coma, Seizures Laboratory manifestations Laboratory manifestations l Lactic acidosis l Increased base deficit Sipe EK, et al. Am Surg. 2001;67:

45 Very dyspneic BP 160/97 Rales Cool skin Very dyspneic BP 160/97 Rales Cool skin 61-Year-Old Female

46 Profiles and Therapies of Advanced Heart Failure Yes R. Bourge, UAB Cardiology Stevenson LW. Eur J Heart Failure 1999;1: R. Bourge, UAB Cardiology Stevenson LW. Eur J Heart Failure 1999;1: No Warm and Dry PCW and CI normal Warm and Dry PCW and CI normal Warm and Wet PCW elevated CI normal Warm and Wet PCW elevated CI normal Cold and Wet PCW elevated CI decreased Cold and Wet PCW elevated CI decreased Cold and Dry PCW low/normal CI decreased Cold and Dry PCW low/normal CI decreased Vasodilators Nitroprusside Nitroglycerine Nesiritide Vasodilators Nitroprusside Nitroglycerine Nesiritide Inotropic Drugs Dobutamine Milrinone Calcium Sensitizers Inotropic Drugs Dobutamine Milrinone Calcium Sensitizers Nl SVR High SVR Congestion at Rest LowPerfusion at Rest LowPerfusion No Yes 49% with BP>140 mmHg 49% with BP>140 mmHg

47 Acute Pulmonary Edema: Algorithm Nitroglycerin 1 sublingual q 1 min Nitroglycerin 1 sublingual q 1 min l Until patient improves, IV is in, or requires intubation Start at 30 g/min Start at 30 g/min l titrate up to 200 g/min within 5-10 minutes l Until dyspnea improves or BP drops If NTG reaches >200 g/min, change to nitroprusside If NTG reaches >200 g/min, change to nitroprusside Careful if: HOCM, volume depleted Careful if: HOCM, volume depleted Nitroglycerin 1 sublingual q 1 min Nitroglycerin 1 sublingual q 1 min l Until patient improves, IV is in, or requires intubation Start at 30 g/min Start at 30 g/min l titrate up to 200 g/min within 5-10 minutes l Until dyspnea improves or BP drops If NTG reaches >200 g/min, change to nitroprusside If NTG reaches >200 g/min, change to nitroprusside Careful if: HOCM, volume depleted Careful if: HOCM, volume depleted

48 HD NTG Controls P value Mech vent 20.7 %46.7 %0.023 ICU admit 37.9 %80.0 %<0.001 Hosp LOS (days) NSTEMI17.2 %28.9 %0.254 Low BP 3.4 %0 %0.210 Levy PD, et al, Acad EM, 13 (5) S107, Systolic BP 160 mmHg or MAP 120 Systolic BP 160 mmHg or MAP 120 Failed: O2, SL NTG x 3, furosemide Failed: O2, SL NTG x 3, furosemide 2 mg IV NTG bolus, titration and repeat q3 minutes, May repeat x 10 2 mg IV NTG bolus, titration and repeat q3 minutes, May repeat x 10 N = 29 HD nitroglycerin, 45 controls N = 29 HD nitroglycerin, 45 controls Patient: 61-Year-Old Female

49 D R I M K R G S S S S G L G F C C S S G S GQ V M K V L R R H K P S Cardiac 3 l Ventricular relaxation (lusitropy) (lusitropy) l Antifibrotic ( TGF ) l Antiremodeling Cardiac 3 l Ventricular relaxation (lusitropy) (lusitropy) l Antifibrotic ( TGF ) l Antiremodeling Hemodynamic 1,2 (balanced vasodilation) l Veins l Arteries l Coronary arteries Hemodynamic 1,2 (balanced vasodilation) l Veins l Arteries l Coronary arteries Neurohumoral 2 aldosterone 4 aldosterone 4 endothelin 2 endothelin 2 norepinephrine 5 norepinephrine 5 Neurohumoral 2 aldosterone 4 aldosterone 4 endothelin 2 endothelin 2 norepinephrine 5 norepinephrine 5 Renal 1,5 DiuresisDiuresis NatriuresisNatriuresis Renal 1,5 DiuresisDiuresis NatriuresisNatriuresis 1 Marcus LS et al. Circulation. 1996;94:3184; 2 Zellner C et al. Am J Physiol. 1999;276(3 pt 2):H1049; 3 Tamura N et al. Proc Natl Acad Sci U S A. 2000;97:4239; 4 Abraham WT et al. J Card Fail. 1998;4:37; 5 Clemens LE et al. J Pharmacol Exp Ther. 1998;287:67. Recombinant hBNP

50 Proaction BP Based on Baseline Thirds SBP is a function of the baseline SBP SBP is a function of the baseline SBP NES NES l Baseline SBP 100 mmHg 1.24% decline l SBP 140 mmHg 18% decline Standard care Standard care l Baseline SBP 100 mmHg 17% increase l SBP 140 mmHg 5.3% decrease Heart rate at 6 hours Nesiritide 5% decrease Nesiritide 5% decrease Standard care 1% decrease Standard care 1% decrease (p=0.029) (p=0.029) SBP is a function of the baseline SBP SBP is a function of the baseline SBP NES NES l Baseline SBP 100 mmHg 1.24% decline l SBP 140 mmHg 18% decline Standard care Standard care l Baseline SBP 100 mmHg 17% increase l SBP 140 mmHg 5.3% decrease Heart rate at 6 hours Nesiritide 5% decrease Nesiritide 5% decrease Standard care 1% decrease Standard care 1% decrease (p=0.029) (p=0.029) Peacock, et al, Cardiology, 2007.

51 JD Sackner-Bernstein, et al. JAMA April 20, 2005; 293 (15) Nesiritide Meta-Analyses Sackner-Bernstein JD et al. Circulation 2005;111: NAPA: Prospective study of 305 patients demonstrating nesiritide is actually renal protective Fusion II: Prospective study of 911 patients demonstrating NO mortality effect

52 ECG is normal, BP 180/95 54-Year-Old Male, Collapsed At Work

53 Aortic Dissection Strategy Must decrease shear forces Must decrease shear forces l Shear force dP/dT l Do not use inotropics Esmolol Esmolol Labetolol Labetolol Must decrease shear forces Must decrease shear forces l Shear force dP/dT l Do not use inotropics Esmolol Esmolol Labetolol Labetolol Tintinalli, 4th ed.

54 Labetalol Mechanism Competitive, selective 1 and non-selective -blocker Competitive, selective 1 and non-selective -blocker l > blockade (4-8 Xs more) l blockade is 1/10 of clonidine l blockade is ¼ propranolol Treatment Considerations Treatment Considerations l Elimination t½ = 8 hours: Clinical effect ~ 4-6 hrs l 5%: orthostatic hypotension l Paradoxical HTN with low doses ( block only, unopposed ) Competitive, selective 1 and non-selective -blocker Competitive, selective 1 and non-selective -blocker l > blockade (4-8 Xs more) l blockade is 1/10 of clonidine l blockade is ¼ propranolol Treatment Considerations Treatment Considerations l Elimination t½ = 8 hours: Clinical effect ~ 4-6 hrs l 5%: orthostatic hypotension l Paradoxical HTN with low doses ( block only, unopposed )

55 No in CBF: Good if h/o cerebrovascular disease No in CBF: Good if h/o cerebrovascular disease No in HR: MV0 2 unchanged No in HR: MV0 2 unchanged Indications Indications l Catechol excess: Pheo, MAOI emergencies clonidine withdrawal l Pregnancy-induced HTN Dose Dose l mg IV, q 30 mins, max 300 mg –BP drops w/in 5 mins, max response in 10 mins l IV 2 mg/min (may start w/ 20 mg bolus) l PO 200 mg Labetalol Strategy

56 Labetalol: Combined - and -Blocker Issues to consider Issues to consider l No in cerebral, renal, or coronary blood flow l Intermediate time to onset l Moderate effect l Negative chronotropic effects 1 l Negative inotropic effects 2 l May exacerbate reactive airway disease Issues to consider Issues to consider l No in cerebral, renal, or coronary blood flow l Intermediate time to onset l Moderate effect l Negative chronotropic effects 1 l Negative inotropic effects 2 l May exacerbate reactive airway disease 1.Hoffman BB. In: Hardman JG, Limbird LE, eds. Goodman and Gilmans Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill;1997: Le Bret F, et al. J Cardiothorac Vasc Anesth. 1992;6:433.

57 Esmolol Strategy Load: 500 mcg/kg over one minute Load: 500 mcg/kg over one minute Then four-minute maintenance infusion of 50 mcg/kg/min Then four-minute maintenance infusion of 50 mcg/kg/min If inadequate: If inadequate: l Repeat loading dose over one minute l Increase maintenance infusion by 50 mcg/kg/min l Max maintenance dose 200 mcg/kg/min As BP target is approached, omit subsequent loading doses and titrate the maintenance dosage up or down to endpoint As BP target is approached, omit subsequent loading doses and titrate the maintenance dosage up or down to endpoint

58 -Blocker Treatment Issues Esmolol -Blocker Treatment Issues Esmolol Advantages Advantages l Treats tachycardia and hypertension l Cardioprotective l Short duration of effect Disadvantages Disadvantages l Bradycardia l Reactive airway disease Advantages Advantages l Treats tachycardia and hypertension l Cardioprotective l Short duration of effect Disadvantages Disadvantages l Bradycardia l Reactive airway disease Oparil S, et al. Am J Hypertension. 1999;12:

59 -Blocker vs Combined - and -Blocker -Blocker vs Combined - and -Blocker Esmolol -Blocker Labetalol - and -Blocker - and -Blocker AdministrationBolus Continuous infusion Bolus Onset Rapid (60 s) 2 Intermediate (peak 5-15 min) 2 Offset (Duration of action) Rapid (10-20 min) 2 Slower (2-4 h) 2 HRDecreased+/- SVR0Decreased Cardiac output Decreased+/- Myocardial O 2 balance PositivePositive Contraindications Sinus bradycardia Heart block >1° Overt heart failure Cardiogenic shock Severe bradycardia Heart block >1° Overt heart failure Cardiogenic shock 1.Hoffman BB. In: Hardman JG, Limbird LE, eds. Goodman and Gilmans Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997: Varon J, Malik PE. Chest. 2000;118:

60 Pregnancy-Induced HTN ULN BP 3 rd Trimester: 125/75 mmHg ULN BP 3 rd Trimester: 125/75 mmHg l Emergency: BP> 140/90 WITH l Hyper-reflexia, altered MS, H/A, epigastric pain, seizures Eclampsia Eclampsia l Most often in primips, or old multips (> 35 yrs) l Usually 3 rd trimester, unless molar preg, or h/o hypertension or renal disease l Post-partum: Up to 2 weeks later Tx: Nitroprusside (short), hydralazine, MgSO 4 Tx: Nitroprusside (short), hydralazine, MgSO 4 Dont Use: ACEI (inhib fetal AII) Diuretics (already hypovol) Dont Use: ACEI (inhib fetal AII) Diuretics (already hypovol) ULN BP 3 rd Trimester: 125/75 mmHg ULN BP 3 rd Trimester: 125/75 mmHg l Emergency: BP> 140/90 WITH l Hyper-reflexia, altered MS, H/A, epigastric pain, seizures Eclampsia Eclampsia l Most often in primips, or old multips (> 35 yrs) l Usually 3 rd trimester, unless molar preg, or h/o hypertension or renal disease l Post-partum: Up to 2 weeks later Tx: Nitroprusside (short), hydralazine, MgSO 4 Tx: Nitroprusside (short), hydralazine, MgSO 4 Dont Use: ACEI (inhib fetal AII) Diuretics (already hypovol) Dont Use: ACEI (inhib fetal AII) Diuretics (already hypovol)

61 Hydralazine Mechanism and Strategy Indications: Pregnancy Indications: Pregnancy Direct arteriolar vasodilator Direct arteriolar vasodilator Concerns Concerns l Reflex tachycardia Increases MVO 2 ?, MI?Increases MVO 2 ?, MI? l Chronically causes SLE syndrome IV Onset: 10 mins, IV Onset: 10 mins, Duration: 3-8 hrs Duration: 3-8 hrs Metabolism: hepatic acetylation and renal elimination Metabolism: hepatic acetylation and renal elimination l 50% of pop is slow acetylator & get complications l Decrease dose in renal failure Eclamptic dose: mg iv, repeat in 30 minutes prn Eclamptic dose: mg iv, repeat in 30 minutes prn Indications: Pregnancy Indications: Pregnancy Direct arteriolar vasodilator Direct arteriolar vasodilator Concerns Concerns l Reflex tachycardia Increases MVO 2 ?, MI?Increases MVO 2 ?, MI? l Chronically causes SLE syndrome IV Onset: 10 mins, IV Onset: 10 mins, Duration: 3-8 hrs Duration: 3-8 hrs Metabolism: hepatic acetylation and renal elimination Metabolism: hepatic acetylation and renal elimination l 50% of pop is slow acetylator & get complications l Decrease dose in renal failure Eclamptic dose: mg iv, repeat in 30 minutes prn Eclamptic dose: mg iv, repeat in 30 minutes prn

62 This Is Your Brain….. Any questions………..??

63 HTN enc ISC CVA ICHSAHTIA OnsetOver Hr rapidrapidrapid CNSProgressYes Over hrs Mins- hrs MinsNo LOC LOCLate Only if bilat or brainstem Usually Usually, but +/- No Other sx H/A, sz, lethargy Prior TIA, p sleep H/A & vomit No Focal Transient migratory FixedFixedNoBrief CSF ICP ICP Normal, unless edema Blood, ICP No, or blood & ICP Normal Neurovascular Insults

64 Neurologic Insult Hypertensive encephalopathy Hypertensive encephalopathy l Waxing and waning symptoms l H/A, nausea, vomiting l Retinal findings l CBF is constant from MAP 60 to 125 mmHg Overwhelmed in HTN encephalopathyOverwhelmed in HTN encephalopathy CBF can be dangerously decreased if BP lowered too muchCBF can be dangerously decreased if BP lowered too much l Isolated H/A IS NOT a focal finding Hypertensive encephalopathy Hypertensive encephalopathy l Waxing and waning symptoms l H/A, nausea, vomiting l Retinal findings l CBF is constant from MAP 60 to 125 mmHg Overwhelmed in HTN encephalopathyOverwhelmed in HTN encephalopathy CBF can be dangerously decreased if BP lowered too muchCBF can be dangerously decreased if BP lowered too much l Isolated H/A IS NOT a focal finding

65 Autoregulation of Cerebral Blood Flow is Affected by Hypertension Normotensive Poorly controlled hypertensive Mean Arterial Pressure (MAP) Cerebral Blood Flow Risk of hypertensive encephalopathy Risk of ischemia Loss of Autoregulation Adapted with permission from Varon J, Marik PE. Chest. 2000;118:

66 Calcium Channel Blockers Nicardipine(dihydropyridine)Diltiazem(benzothiazepine)Verapamil(phenylalkylamine) Peripheral Vasodilation Coronary Vasodilation Suppression of SA Node Suppression of AV Node Suppression of Cardiac Contractility Frishman WH, et al. Med Clin North Am. 1988;72: Adapted from Goodman and Gilmans: The Pharmacologic Basis of Therapeutics. 9th ed

67 Dihydropyridine CCB: Nicardipine Arterial selective vasodilator 1 Arterial selective vasodilator 1 l Significant SVR 2-6 l Cerebral and coronary vasodilator Vascular smooth muscle selective 1 Vascular smooth muscle selective 1 l Minimal myocardial depression l No AV nodal depression No significant in ICP 7 No significant in ICP 7 Oates JA. Brown NJ. In: Hardman JG, Limbird LE, eds. Goodman and Gilmans Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997: Clarke B, et al. Br J Pharmacol. 1983;79:333P. 2.Lambert CR, et al. Am J Cardiol. 1987;60: Silke B, et al. Br J Clin Pharmacol. 1985;20:169S-176S. 4.Lambert CR, et al Am J Cardiol. 1985;55: Visser CA, et al. Postgrad Med J. 1984;60: Silke B, et al. Br J Clin Pharmacol. 1985;20:169S-176S. 7. Nishiyama MT, et al. Can J Anaesth. 2000;47:

68 Nicardipine Strategy Start at 5 mg/h: Titrate by 2.5 mg/h q5 minutes 15 mg/h max Start at 5 mg/h: Titrate by 2.5 mg/h q5 minutes 15 mg/h max Half life: Half life: l Redistribution: t½ = 2.7 minutes l Intermediate: t½ = 44 minutes l Terminal after long infusion = 14.4 hours After d/c, concentration declines rapidly, at least 50% in 1 st 2 hrs After d/c, concentration declines rapidly, at least 50% in 1 st 2 hrs Start at 5 mg/h: Titrate by 2.5 mg/h q5 minutes 15 mg/h max Start at 5 mg/h: Titrate by 2.5 mg/h q5 minutes 15 mg/h max Half life: Half life: l Redistribution: t½ = 2.7 minutes l Intermediate: t½ = 44 minutes l Terminal after long infusion = 14.4 hours After d/c, concentration declines rapidly, at least 50% in 1 st 2 hrs After d/c, concentration declines rapidly, at least 50% in 1 st 2 hrs Cardene IV [package insert] Onset of Action Duration Adverse Events Special Considerations 5-10 min minutes: May exceed 4 hours HR, H/A, flushing HR, H/A, flushing local phlebitis Most hypertensive emergencies; caution with ACS The 7th Report of the JNC. JAMA 2003;289:

69 Safety Profiles of Nicardipine and Nitroprusside Adverse Events Nicardipine 1 Nitroprusside 2 Hypotension5.6%36.9% FlushingNA9.8% Nausea4.9%11.0% Dizziness1.4%6.8% Headache14.6%27.6% ThiocyanateNA14.0% Injection site pain 1.4%NA 1.Cardene IV [package insert]. 2.Nitropress [package insert].

70 Nicardipine vs Adrenergic Blockers DrugNicardipineEsmololLabetalol Administration Continuous infusion Bolus Bolus OnsetRapidRapidIntermediate OffsetRapidRapidSlower HR 1 Minimal increase Decreased+/– SVRDecreased0Decreased Cardiac output 1 IncreasedDecreased+/– Myocardial O 2 balance 2 PositivePositivePositive Contra-indications Advanced aortic stenosis Sinus bradycardia Heart block >1° Overt heart failure Cardiogenic shock Severe bradycardia Heart block >1° Overt heart failure Cardiogenic shock

71 AHA Stroke Guidelines Key Points The management of arterial hypertension remains controversial The management of arterial hypertension remains controversial l Data is inconclusive or conflicting l Many patients have spontaneous BP declines in the 1st 24 hrs after a stroke Until more definitive data are available, it is generally agreed that a cautious approach to the treatment of arterial hypertension should be recommended Until more definitive data are available, it is generally agreed that a cautious approach to the treatment of arterial hypertension should be recommended (Class I, Level of Evidence C) (Class I, Level of Evidence C) Patients who have other medical indications for aggressive treatment of blood pressure should be treated Patients who have other medical indications for aggressive treatment of blood pressure should be treated The management of arterial hypertension remains controversial The management of arterial hypertension remains controversial l Data is inconclusive or conflicting l Many patients have spontaneous BP declines in the 1st 24 hrs after a stroke Until more definitive data are available, it is generally agreed that a cautious approach to the treatment of arterial hypertension should be recommended Until more definitive data are available, it is generally agreed that a cautious approach to the treatment of arterial hypertension should be recommended (Class I, Level of Evidence C) (Class I, Level of Evidence C) Patients who have other medical indications for aggressive treatment of blood pressure should be treated Patients who have other medical indications for aggressive treatment of blood pressure should be treated

72 AHA Stroke Guidelines If Patient is a Lytic Candidate Class I, Level of Evidence B Blood Pressure Level Systolic > 185 mm Hg or diastolic > 110 mm Hg ___________________________________________________ Labetalol 10 to 20 mg IV over 1 to 2 minutes, may repeat x 1 or or Nitropaste 1 to 2 inches or or Nicardipine infusion, 5 mg/h, titrate up by 0.25 mg/h at 5- to 15- minute intervals, maximum dose 15 mg/h; when desired blood pressure obtained, reduce to 3 mg/h

73 Fini ! Thank you ! ACUTE PRESSURE SYNDROMES

74 Acute Severe Hypertension An Emerging Agent for Possible ED Use From Threat to Therapy A Year 2007 EM Update From Threat to Therapy A Year 2007 EM Update Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Program Chairman Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine Philadelphia, Pennsylvania

75 Common Therapeutic Agents ACE Inhibitors ACE Inhibitors Diazoxide Diazoxide Esmolol Esmolol Hydralazine Hydralazine Nicardipine Nicardipine Nitroglycerin Nitroglycerin ACE Inhibitors ACE Inhibitors Diazoxide Diazoxide Esmolol Esmolol Hydralazine Hydralazine Nicardipine Nicardipine Nitroglycerin Nitroglycerin Clonidine Clonidine Diuretics Diuretics Fenoldopam Fenoldopam Labetalol Labetalol Nifedipine Nifedipine Nitroprusside Nitroprusside Clonidine Clonidine Diuretics Diuretics Fenoldopam Fenoldopam Labetalol Labetalol Nifedipine Nifedipine Nitroprusside Nitroprusside Rynn et al, J Pharm Pract 2005;18:

76 Common Therapeutic Agents Dr. Peacock has just reviewed their limitations ACE Inhibitors ACE Inhibitors Diazoxide Diazoxide Esmolol Esmolol Hydralazine Hydralazine Nicardipine Nicardipine Nitroglycerin Nitroglycerin Clonidine Clonidine Diuretics Diuretics Fenoldopam Fenoldopam Labetalol Labetalol Nifedipine Nifedipine Nitroprusside Nitroprusside Rynn et al, J Pharm Pract 2005;18:

77 So Whats New? Emerging Therapy for Acute Pressure Syndromes

78 Disclaimer The following slides will discuss clinical trials for an agent (clevidipine) that is not currently available or approved for treatment of acute, severe hypertension. The following slides will discuss clinical trials for an agent (clevidipine) that is not currently available or approved for treatment of acute, severe hypertension. The agent is currently under FDA review, and therefore, it cannot be recommended for clinical use until additional, defining guidance is available. This information is presented for scientific purposes. The agent is currently under FDA review, and therefore, it cannot be recommended for clinical use until additional, defining guidance is available. This information is presented for scientific purposes.Disclaimer The following slides will discuss clinical trials for an agent (clevidipine) that is not currently available or approved for treatment of acute, severe hypertension. The following slides will discuss clinical trials for an agent (clevidipine) that is not currently available or approved for treatment of acute, severe hypertension. The agent is currently under FDA review, and therefore, it cannot be recommended for clinical use until additional, defining guidance is available. This information is presented for scientific purposes. The agent is currently under FDA review, and therefore, it cannot be recommended for clinical use until additional, defining guidance is available. This information is presented for scientific purposes. Emerging Therapy for Acute Pressure Syndromes

79 Clevidipine: The First Third-Generation Calcium Channel Blocker Generic Name Brand Name First Generation Nifedipine Procardia ®, Adalat ® Second Generation Nicardipine/Nicardipine I.V. AmlodipineIsradipineFelodipineNisoldipine Cardene ® /Cardene I.V. Norvasc ® DynaCirc ® Plendil ® Sular ® Third Generation Clevidipine Cleviprex Whiting RL, et al. Angiology. 1990;41:

80 Cl H CH 3 OOC H3CH3C COOCH 2 OOCC 3 H 7 CH 3 N H The Clevidipine Molecule A rationally designed dihydropyridine calcium channel blocker A rationally designed dihydropyridine calcium channel blocker t ½ ~1 minute t ½ ~1 minute Steady state achieved in ~ 2 minutes Steady state achieved in ~ 2 minutes Protein binding >99.5% Protein binding >99.5% High clearance rate (independent of dosing rate, metabolized by extrahepatic tissues) High clearance rate (independent of dosing rate, metabolized by extrahepatic tissues) Small Vol/dist = 0.17 L/kg Small Vol/dist = 0.17 L/kg A rationally designed dihydropyridine calcium channel blocker A rationally designed dihydropyridine calcium channel blocker t ½ ~1 minute t ½ ~1 minute Steady state achieved in ~ 2 minutes Steady state achieved in ~ 2 minutes Protein binding >99.5% Protein binding >99.5% High clearance rate (independent of dosing rate, metabolized by extrahepatic tissues) High clearance rate (independent of dosing rate, metabolized by extrahepatic tissues) Small Vol/dist = 0.17 L/kg Small Vol/dist = 0.17 L/kg

81 Metabolism by Plasma and Tissue Esterases Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive carboxylic acid metabolite, independent of renal or hepatic function! Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive carboxylic acid metabolite, independent of renal or hepatic function! + 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

82 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 104 mg/hr (21.9 mcg/kg/min) Linear relationship maintained for dosages as high as 104 mg/hr (21.9 mcg/kg/min) 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 104 mg/hr (21.9 mcg/kg/min) Linear relationship maintained for dosages as high as 104 mg/hr (21.9 mcg/kg/min) Clevidipine Concentration at Css (nmol/L)* Dose Rate (nmol/kg/min) 2530 Reproduced from Ericsson H, et al. Anesthesiology. 2000;92: Ericsson H, et al. Anesthesiology. 2000;92: Ericsson H, et al. Br J Clin Pharmacol. 1999;47:

83 Responders = treatment success: >10% decrease in MAP or >20% decrease in MAP at each measured concentration. Bailey JM, et al. Anesthesiology. 2002;96: Linear Dose Response 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 16 mg/hr Effective in 95% of patients at 16 mg/hr Linear dose response in postoperative cardiac surgery patients Linear dose response in postoperative cardiac surgery patients Effective in 95% of patients at 16 mg/hr Effective in 95% of patients at 16 mg/hr n=19 Infusion Rate (mcg/kg/min) Responders (%) n=0 n=1 n=4 n=6 n=9

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

85 % return BP to baseline SBP in minutes 50% return BP to baseline SBP in minutes Data on file, The Medicines Company Rapid Cessation of Effect MAP, % of baseline (Mean + SE) Time after stop of infusion (minutes) Recovery of Mean Arterial Pressure (MAP) Recovery of Mean Arterial Pressure (MAP) Following Cessation of Clevidipine Infusion Following Cessation of Clevidipine Infusion Recovery of Mean Arterial Pressure (MAP) Recovery of Mean Arterial Pressure (MAP) Following Cessation of Clevidipine Infusion Following Cessation of Clevidipine Infusion

86 Selectivity of Calcium Channel Antagonists MyocardialSA NodeAV Node MyocardialSA NodeAV Node IV AgentVasodilationDepressionSuppressionSuppression IV AgentVasodilationDepressionSuppressionSuppression Clevidipine5000 Clevidipine5000 Nicardipine5000 Nicardipine5000 Diltiazem3254 Diltiazem3254 Verapamil4455 Verapamil4455 *The chiral center of clevidipine SA = sinoatrial; AV = atrioventricular Clevidipine Cl O O O O N H O O * COCH 2 CH 2 NCH 2 NO 2 CH 3 O N H O H3CH3C H 3 COC Nifedipine NO 2 COCH 3 CH 3 O N H O H3CH3C CH 3 OC Nicardipine Kerins DM, et al. In: Goodman and Gilmans Pharmacological Basis of Therapeutics. 2001: Massie BM. Am J CardioI. 1997;80:23I-32I.

87 Multi-center, Phase III, open-label, single-arm, study to confirm the safety of IV clevidipine for patients who present to the ED (or ICU) with severe hypertension requiring parenteral treatment for at least 18 hours The VELOCITY Trial

88 VELOCITY Trial Objectives Primary End Points Confirm the safety of a titration-based dosing regimen of an IV infusion of clevidipine for ED- and critical care unit- based treatment of severe HTN Confirm the safety of a titration-based dosing regimen of an IV infusion of clevidipine for ED- and critical care unit- based treatment of severe HTN l Efficacy: Percentage of patients in whom SBP fell within the initial SBP target range within 30 min of initiating infusion l Safety: Percentage of patients in whom SBP fell below the lower limit of the initial SBP target range within 3 min of initiating infusion Primary End Points Confirm the safety of a titration-based dosing regimen of an IV infusion of clevidipine for ED- and critical care unit- based treatment of severe HTN Confirm the safety of a titration-based dosing regimen of an IV infusion of clevidipine for ED- and critical care unit- based treatment of severe HTN l Efficacy: Percentage of patients in whom SBP fell within the initial SBP target range within 30 min of initiating infusion l Safety: Percentage of patients in whom SBP fell below the lower limit of the initial SBP target range within 3 min of initiating infusion

89 Secondary End Points Efficacy Efficacy l Time to attainment of 30-minute SBP target range Safety Safety l Change in heart rate during the 30-minute period from initiation of infusion l Dose of clevidipine during the treatment period l Of the patients converted to oral antihypertensive therapy, the proportion of those with successful transition, defined as SBP within the last specified target range at 6 hr after cessation of clevidipine infusion l Safety of prolonged infusion of clevidipine (18 hr) Secondary End Points Efficacy Efficacy l Time to attainment of 30-minute SBP target range Safety Safety l Change in heart rate during the 30-minute period from initiation of infusion l Dose of clevidipine during the treatment period l Of the patients converted to oral antihypertensive therapy, the proportion of those with successful transition, defined as SBP within the last specified target range at 6 hr after cessation of clevidipine infusion l Safety of prolonged infusion of clevidipine (18 hr) VELOCITY: Secondary Objectives

90 VELOCITY Patient Enrollment Criteria Inclusion Criteria Inclusion Criteria l Age 18 years and older l Systolic BP >180 mmHg and/or diastolic BP >115 mmHg, assessed on 2 successive occasions, 15 minutes apart Exclusion Criteria Exclusion Criteria l SBP 180 mmHg and DBP 115 mmHg l Expectation that the patient will not tolerate IV antihypertensive therapy for a minimum of 18 hours l Known or suspected aortic dissection Inclusion Criteria Inclusion Criteria l Age 18 years and older l Systolic BP >180 mmHg and/or diastolic BP >115 mmHg, assessed on 2 successive occasions, 15 minutes apart Exclusion Criteria Exclusion Criteria l SBP 180 mmHg and DBP 115 mmHg l Expectation that the patient will not tolerate IV antihypertensive therapy for a minimum of 18 hours l Known or suspected aortic dissection

91 VELOCITY Treatment Clevidipine Clevidipine l Selection of Initial Target Range (ITR) for systolic blood pressure determined prior to the initiation of clevidipine for each individual patient l Difference between the upper and lower ITR was mmHg Clevidipine Clevidipine l Selection of Initial Target Range (ITR) for systolic blood pressure determined prior to the initiation of clevidipine for each individual patient l Difference between the upper and lower ITR was mmHg

92 VELOCITY Treatment Clevidipine initiated at 2 mg/h via peripheral veinClevidipine initiated at 2 mg/h via peripheral vein Titrated up to 32 mg/h in doubling increments Q3 min to achieve pre-specified ITRTitrated up to 32 mg/h in doubling increments Q3 min to achieve pre-specified ITR Infusion rate could be decreased if neededInfusion rate could be decreased if needed Clevidipine initiated at 2 mg/h via peripheral veinClevidipine initiated at 2 mg/h via peripheral vein Titrated up to 32 mg/h in doubling increments Q3 min to achieve pre-specified ITRTitrated up to 32 mg/h in doubling increments Q3 min to achieve pre-specified ITR Infusion rate could be decreased if neededInfusion rate could be decreased if needed Infusion maintained or further titrated after the first 30 min to reach ITRInfusion maintained or further titrated after the first 30 min to reach ITR Treatment duration for at least 18 h, up to 96 hTreatment duration for at least 18 h, up to 96 h BP monitoring with BP cuffBP monitoring with BP cuff Infusion maintained or further titrated after the first 30 min to reach ITRInfusion maintained or further titrated after the first 30 min to reach ITR Treatment duration for at least 18 h, up to 96 hTreatment duration for at least 18 h, up to 96 h BP monitoring with BP cuffBP monitoring with BP cuff

93 VELOCITY Transition to Oral Therapy If transition to an oral antihypertensive agent was required, the agent could be given after 18h of clevidipine, starting 1 hr prior to ending infusion If transition to an oral antihypertensive agent was required, the agent could be given after 18h of clevidipine, starting 1 hr prior to ending infusion After administration of the oral agent, clevidipine could be down-titrated or terminated After administration of the oral agent, clevidipine could be down-titrated or terminated If the BP rose to an undesirable level upon cessation of the infusion, additional oral therapy or restarting of clevidipine infusion were options If the BP rose to an undesirable level upon cessation of the infusion, additional oral therapy or restarting of clevidipine infusion were options If transition to an oral antihypertensive agent was required, the agent could be given after 18h of clevidipine, starting 1 hr prior to ending infusion If transition to an oral antihypertensive agent was required, the agent could be given after 18h of clevidipine, starting 1 hr prior to ending infusion After administration of the oral agent, clevidipine could be down-titrated or terminated After administration of the oral agent, clevidipine could be down-titrated or terminated If the BP rose to an undesirable level upon cessation of the infusion, additional oral therapy or restarting of clevidipine infusion were options If the BP rose to an undesirable level upon cessation of the infusion, additional oral therapy or restarting of clevidipine infusion were options

94 VELOCITY Sites

95 VELOCITY: Patient Demographics ParameterValue Age (yrs) 53.5 ± 15 Gender (%) Male Male48 Female Female52 BMI (kg/m 2 ) 30 ± 7.6 Race (%) African American African American77 White White16 Hispanic Hispanic6 Asian Asian1 SBP (mmHg) 202 ± 22 DBP (mmHg) 111 ± 21 ITR (high, low) 175, 143 Mean ± SD Safety Population, N=126

96 VELOCITY: Results Medical History Percent (%) End organ injury 81 Myocardial infarction 5 Renal disease 25 Dialysis dependent Dialysis dependent11 Coronary artery disease 28 Hypertension97 Previous hospitalization for hypertension 31 Congestive heart failure 18 Dyslipidemia37 Smoker Current / Former Current / Former 39 / 21 Diabetes31 Stroke11 Safety Population, N=126

97 VELOCITY: Patient Disposition DNC = Did Not Complete Data on file. The Medicines Company. mITT (patients with SBP >UL of target range) N=117 ITT (patients enrolled) N=131 Completed Patients n=105 n=114 n=110 Safety (patients who received at least 1 dose) N=126 No clevidipine n=5 SBP UL of target range n=14 18 hr continuous infusion n=117 <18 hr treatment n=9 DNCn=12 DNCn=7

98 VELOCITY: Results Initial infusion rate 2 mg/hr (4 mL/hr) Initial infusion rate 2 mg/hr (4 mL/hr) Time to first achievement to Initial Target Range (ITR) Time to first achievement to Initial Target Range (ITR) l 10.9 min (95% CI 9.0, 15.0) l Median dose 4 mg/hr (max 11 mg/hr) Initial infusion rate 2 mg/hr (4 mL/hr) Initial infusion rate 2 mg/hr (4 mL/hr) Time to first achievement to Initial Target Range (ITR) Time to first achievement to Initial Target Range (ITR) l 10.9 min (95% CI 9.0, 15.0) l Median dose 4 mg/hr (max 11 mg/hr) mITT population

99 89% achieved pre-specified ITR within 30 min 89% achieved pre-specified ITR within 30 min l 7% more achieved ITR after 30 min l Of the 96% of patients who did not have protocol violations with selection of ITR, 90% achieved the ITR within 30 min From drug initiation to 30 min From drug initiation to 30 min l Median infusion rate 7 mg/hr (max 15 mg/hr) Time to a 15% drop in blood pressure was 9.5 min Time to a 15% drop in blood pressure was 9.5 min VELOCITY: Results

100 VELOCITY: Probability of Having Attained ITR K-M Analysis 91% Minutes Percent of Patients

101 VELOCITY Change in BP Over First 30 min Time after start of infusion (min.) % Reduction from Baseline SBP (Mean ± SE) % -16.5% -21% mITT population

102 VELOCITY: Safety Only 2 patients (1.6%) fell below the lower ITR limit within first 3 min Only 2 patients (1.6%) fell below the lower ITR limit within first 3 min l One had narrower than specified ITR ( mmHg); SBP was 15 mmHg below the lower limit l One lower limit was 160 mmHg and SBP fell to 156 l Both patients continued clevidipine infusion beyond 18 hr without AEs l No clinical hypotensive events were reported mITT population

103 VELOCITY Transition to Oral Therapy Transition successful in 91.3% of patients Transition successful in 91.3% of patients Of the 11 not transitioning to oral therapy within 6 hr of IV termination: Of the 11 not transitioning to oral therapy within 6 hr of IV termination: l 2.4% could not be converted from clevidipine l 3.2% did not reach the 18-hr endpoint for transition eligibility l 3.2% had contraindications to oral transition Of 118 patients eligible for transition, 97.5% did so within 6 hr Of 118 patients eligible for transition, 97.5% did so within 6 hr Transition successful in 91.3% of patients Transition successful in 91.3% of patients Of the 11 not transitioning to oral therapy within 6 hr of IV termination: Of the 11 not transitioning to oral therapy within 6 hr of IV termination: l 2.4% could not be converted from clevidipine l 3.2% did not reach the 18-hr endpoint for transition eligibility l 3.2% had contraindications to oral transition Of 118 patients eligible for transition, 97.5% did so within 6 hr Of 118 patients eligible for transition, 97.5% did so within 6 hr

104 What We Learned From VELOCITY Clevidipine reliably lowered BP to pre- specified target range in 90% of patients within 30 minutes Clevidipine reliably lowered BP to pre- specified target range in 90% of patients within 30 minutes Predictably reached target BP without overshoot in a median 10.9 min Predictably reached target BP without overshoot in a median 10.9 min Clevidipine was easy to administer and well tolerated Clevidipine was easy to administer and well tolerated l Peripheral venous administration and BP monitoring via a cuff was safe and feasible in the ED Clevidipine reliably lowered BP to pre- specified target range in 90% of patients within 30 minutes Clevidipine reliably lowered BP to pre- specified target range in 90% of patients within 30 minutes Predictably reached target BP without overshoot in a median 10.9 min Predictably reached target BP without overshoot in a median 10.9 min Clevidipine was easy to administer and well tolerated Clevidipine was easy to administer and well tolerated l Peripheral venous administration and BP monitoring via a cuff was safe and feasible in the ED

105 Summary Hypertension is extremely prevalent in US society, and as population ages, hypertensive crises will become increasingly common in the ED Hypertension is extremely prevalent in US society, and as population ages, hypertensive crises will become increasingly common in the ED l Debate over terminology and numerical definitions is all too prevalent in the literature Choices among available agents are often difficult, and none is ideal across the spectrum Choices among available agents are often difficult, and none is ideal across the spectrum l Must balance effective reduction with avoidance of over-reduction and its complications Hypertension is extremely prevalent in US society, and as population ages, hypertensive crises will become increasingly common in the ED Hypertension is extremely prevalent in US society, and as population ages, hypertensive crises will become increasingly common in the ED l Debate over terminology and numerical definitions is all too prevalent in the literature Choices among available agents are often difficult, and none is ideal across the spectrum Choices among available agents are often difficult, and none is ideal across the spectrum l Must balance effective reduction with avoidance of over-reduction and its complications

106 Summary As ED LOS increases, care of BP derangements will fall ever more in the purview of the emergency physician As ED LOS increases, care of BP derangements will fall ever more in the purview of the emergency physician Even with prompt transfer of HU/HE patients to the inpatient setting, this is one of the few areas where emergency physicians and intensivists actually approach definitive care in much the same way Even with prompt transfer of HU/HE patients to the inpatient setting, this is one of the few areas where emergency physicians and intensivists actually approach definitive care in much the same way Clevidipine may soon afford a novel, safe, multi- setting, multi-disciplinary approach to management of acute severe hypertension Clevidipine may soon afford a novel, safe, multi- setting, multi-disciplinary approach to management of acute severe hypertension As ED LOS increases, care of BP derangements will fall ever more in the purview of the emergency physician As ED LOS increases, care of BP derangements will fall ever more in the purview of the emergency physician Even with prompt transfer of HU/HE patients to the inpatient setting, this is one of the few areas where emergency physicians and intensivists actually approach definitive care in much the same way Even with prompt transfer of HU/HE patients to the inpatient setting, this is one of the few areas where emergency physicians and intensivists actually approach definitive care in much the same way Clevidipine may soon afford a novel, safe, multi- setting, multi-disciplinary approach to management of acute severe hypertension Clevidipine may soon afford a novel, safe, multi- setting, multi-disciplinary approach to management of acute severe hypertension


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