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Program Chairman Joseph Varon, MD, FACP, FCCP, FCCM Clinical Professor of Medicine The University of Texas Health Science Center at Houston Professor,

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Presentation on theme: "Program Chairman Joseph Varon, MD, FACP, FCCP, FCCM Clinical Professor of Medicine The University of Texas Health Science Center at Houston Professor,"— Presentation transcript:

1 Program Chairman Joseph Varon, MD, FACP, FCCP, FCCM Clinical Professor of Medicine The University of Texas Health Science Center at Houston Professor, Acute and Continuing Care The University of Texas Health Science Center at Houston Clinical Professor of Medicine The University of Texas Medical Branch – Galveston Professor of Medicine and Surgery UAT, UDEM, UPAEP, UABC, UNE Mexico Program Chairman Joseph Varon, MD, FACP, FCCP, FCCM Clinical Professor of Medicine The University of Texas Health Science Center at Houston Professor, Acute and Continuing Care The University of Texas Health Science Center at Houston Clinical Professor of Medicine The University of Texas Medical Branch – Galveston Professor of Medicine and Surgery UAT, UDEM, UPAEP, UABC, UNE Mexico Vascular Dysfunction and Acute Pressure Syndromes Vascular Dysfunction and Acute Pressure Syndromes From Threat to TherapyOptimizing Management of Blood Pressure Across the Cardiovascular Disease Continuum Investigation Innovation Application

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 Welcome and Program Overview Welcome and Program Overview

3 Program Educational Objectives As a result of this educational activity, physicians will: Learn to identify underlying chronic, acute, and perioperative precipitants of acute elevations in systemic blood pressure and how this syndrome presents across multiple cardiovascular disease states and patient populations. Learn to assess and implement optimal pharmacologic interventions for patients presenting with manifestations of vascular dysfunction and 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 CV 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 educational activity, physicians will: Learn to identify underlying chronic, acute, and perioperative precipitants of acute elevations in systemic blood pressure and how this syndrome presents across multiple cardiovascular disease states and patient populations. Learn to assess and implement optimal pharmacologic interventions for patients presenting with manifestations of vascular dysfunction and 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 CV 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.

4 Program Educational Objectives Learn to understand the specific advantages and potential disadvantages of currently available intravenously administered pharmacologic agents used to manage acute, serious, and/or life-threatening elevations in systemic blood pressure. Learn to identify the ideal properties of intravenous agents used to provide cardiology-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 cardiovascular disease and acute pressure syndromes. Learn to apply national guidelines and expert, consensus-based recommendations in order to optimize 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 to manage acute, serious, and/or life-threatening elevations in systemic blood pressure. Learn to identify the ideal properties of intravenous agents used to provide cardiology-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 cardiovascular disease and acute pressure syndromes. Learn to apply national guidelines and expert, consensus-based recommendations in order to optimize therapy of patients with serious, systemic elevations in blood pressure.

5 Program Faculty Joseph Varon, MD, FACP, FCCP, FCCM Clinical Professor of Medicine The University of Texas Health Science Center at Houston Professor, Acute and Continuing Care The University of Texas Health Science Center at Houston Clinical Professor of Medicine The University of Texas Medical Branch – Galveston Professor of Medicine and Surgery UAT, UDEM, UPAEP, UABC, UNE Mexico Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine Solomon Aronson, MD Professor of Anesthesiology Executive Vice Chairman Duke University Medical Center Durham, NC Joseph Varon, MD, FACP, FCCP, FCCM Clinical Professor of Medicine The University of Texas Health Science Center at Houston Professor, Acute and Continuing Care The University of Texas Health Science Center at Houston Clinical Professor of Medicine The University of Texas Medical Branch – Galveston Professor of Medicine and Surgery UAT, UDEM, UPAEP, UABC, UNE Mexico Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine Solomon Aronson, MD Professor of Anesthesiology Executive Vice Chairman Duke University Medical Center Durham, NC

6 Faculty COI Disclosures Faculty COI Disclosures Joseph Varon, MD, FACP, FCCP, FCCM Grant/Research Support: The Medicines Company Consultant: The Medicines Company, ESP/PDL Laboratories Speakers Bureau: ESP/PDL Laboratories Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Grant/Research Support: GlaxoSmithKline Consultant: The Medicines Company., Schering-Plough, Sanofi-Aventis, BMS, Genentech, Speakers Bureau: Schering-Plough, Sanofi-Aventis, BMS, Genentech Solomon Aronson, MD Grant/Research Support: Abbott Consultant: The Medicines Company Speakers Bureau: Baxter Major Shareholder: Medwave Joseph Varon, MD, FACP, FCCP, FCCM Grant/Research Support: The Medicines Company Consultant: The Medicines Company, ESP/PDL Laboratories Speakers Bureau: ESP/PDL Laboratories Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Grant/Research Support: GlaxoSmithKline Consultant: The Medicines Company., Schering-Plough, Sanofi-Aventis, BMS, Genentech, Speakers Bureau: Schering-Plough, Sanofi-Aventis, BMS, Genentech Solomon Aronson, MD Grant/Research Support: Abbott Consultant: The Medicines Company Speakers Bureau: Baxter Major Shareholder: Medwave

7 Acute Pressure Syndromes From Threat to Therapy Characterization, Epidemiology, and Approach to Acute Blood Pressure Elevations Across the Cardiovascular Disease Continuum Giving Acute Hypertension the Hyperattention it Deserves Acute Pressure Syndromes From Threat to Therapy Characterization, Epidemiology, and Approach to Acute Blood Pressure Elevations Across the Cardiovascular Disease Continuum Giving Acute Hypertension the Hyperattention it Deserves Investigation Innovation Application Program Chairman Joseph Varon, MD, FACP, FCCP, FCCM Clinical Professor of Medicine The University of Texas Health Science Center at Houston Professor, Acute and Continuing Care The University of Texas Health Science Center at Houston Clinical Professor of Medicine The University of Texas Medical Branch – Galveston Professor of Medicine and Surgery UAT, UDEM, UPAEP, UABC, UNE Mexico Program Chairman Joseph Varon, MD, FACP, FCCP, FCCM Clinical Professor of Medicine The University of Texas Health Science Center at Houston Professor, Acute and Continuing Care The University of Texas Health Science Center at Houston Clinical Professor of Medicine The University of Texas Medical Branch – Galveston Professor of Medicine and Surgery UAT, UDEM, UPAEP, UABC, UNE Mexico

8 J Varon ACCP Oct 2007 F Peacock ACEP Oct 2007 J Varon ACCP Oct 2007 F Peacock ACEP Oct 2007 S Aronson ACC 2007 Investigation Innovation Application

9 Severe Hypertension Common Common Deadly and disabling Deadly and disabling Poorly studied Poorly studied Poorly managed Poorly managed Evidence that speed and degree of control relate to outcome Evidence that speed and degree of control relate to outcome Needs more attention Needs more attention Observed across multiple settings Observed across multiple settings Common Common Deadly and disabling Deadly and disabling Poorly studied Poorly studied Poorly managed Poorly managed Evidence that speed and degree of control relate to outcome Evidence that speed and degree of control relate to outcome Needs more attention Needs more attention Observed across multiple settings Observed across multiple settings

10 Prevalence of high blood pressure in adults by age and sex Prevalence of Hypertension NHANES: Source: NCHS and NHLBI.

11 Extent of awareness, treatment and control of high blood pressure by age Extent of awareness, treatment and control of high blood pressure by age NHANES: Source: NCHS and NHLBI. Hypertension: Awareness and Control

12 5,026 emergency departments 5,026 emergency departments million visits in million visits in 2003 Presentation with severe hypertension in up to 25% of patients in busy urban EDs Presentation with severe hypertension in up to 25% of patients in busy urban EDs 5,026 emergency departments 5,026 emergency departments million visits in million visits in 2003 Presentation with severe hypertension in up to 25% of patients in busy urban EDs Presentation with severe hypertension in up to 25% of patients in busy urban EDs Sullivan AF. Acad Emerg Med 2004;11:454; IOM Emergency Medical Care Report Emergency Care of Severe Blood Pressure Elevation

13 Short-Term (2 to 6 month) Outcomes Acute ConditionDeath Rehospitalization 1.OASIS-5 NEJM GUSTO IIb NEJM GRACE JAMA IMPACT-HF J Cardiac Failure Cline DM. Acad Emerg Med ACS 1,2,3 5-7% 30% CHF 4 8.5% 26% Severe Hypertension 5 5-6% 30% ACS 1,2,3 5-7% 30% CHF 4 8.5% 26% Severe Hypertension 5 5-6% 30%

14 Terminology and Definitions Severe Hypertension JNC VII > 180/110 JNC VII > 180/110 Severe Hypertension JNC VII > 180/110 JNC VII > 180/110 End-organ Damage CHF CHF ACS/AMI ACS/AMI Renal failure Renal failure Stroke and ICH Stroke and ICH Encephalopathy Encephalopathy Aortic dissection Aortic dissection Pre-eclampsia Pre-eclampsia Other? Other? End-organ Damage CHF CHF ACS/AMI ACS/AMI Renal failure Renal failure Stroke and ICH Stroke and ICH Encephalopathy Encephalopathy Aortic dissection Aortic dissection Pre-eclampsia Pre-eclampsia Other? Other? plus UrgencyUrgency Emergency Emergency

15 Severe Hypertension, End-Organ Damage, and Comorbidities ICH Pre-eclampsia Peri-operative

16 Spectrum of End-Organ Damage End-Organ Damage Type No. of Cases (%) Cerebral infarction 26 (24.5) ICH or SAH 5 (4.5) Encephalopathy18 (16.3) Cerebral infarction 26 (24.5) ICH or SAH 5 (4.5) Encephalopathy18 (16.3) Acute Pulmonary Edema24 (22.5) Acute CHF 15 (14.3) Acute MI13 (12.0) Aortic Dissection2 (2.0) Eclampsia5 (4.5) End-Organ Damage Type No. of Cases (%) Cerebral infarction 26 (24.5) ICH or SAH 5 (4.5) Encephalopathy18 (16.3) Cerebral infarction 26 (24.5) ICH or SAH 5 (4.5) Encephalopathy18 (16.3) Acute Pulmonary Edema24 (22.5) Acute CHF 15 (14.3) Acute MI13 (12.0) Aortic Dissection2 (2.0) Eclampsia5 (4.5) Zampaglione, B. Hypertension 1996;27: Hypertensive Urgencies* 341 Hypertensive Urgencies* 108 Hypertensive Emergencies* 108 Hypertensive Emergencies* 341 Hypertensive Urgencies* 341 Hypertensive Urgencies* 108 Hypertensive Emergencies* 108 Hypertensive Emergencies* *All Caucasians

17 Acute Severe Hypertension Epidemiology and Mortality 1939: First study of the natural history of hypertensive emergencies published 1939: First study of the natural history of hypertensive emergencies published Untreated hypertensive emergencies had a 1-year mortality rate of 79%, with median survival of 10.5 months Untreated hypertensive emergencies had a 1-year mortality rate of 79%, with median survival of 10.5 months 1939: First study of the natural history of hypertensive emergencies published 1939: First study of the natural history of hypertensive emergencies published Untreated hypertensive emergencies had a 1-year mortality rate of 79%, with median survival of 10.5 months Untreated hypertensive emergencies had a 1-year mortality rate of 79%, with median survival of 10.5 months Varon J. CHEST 2007; 131:1949–1962. Risk Factors History of hypertension History of hypertension African Americans African Americans Elderly Elderly Men Men Noncompliance Noncompliance Risk Factors History of hypertension History of hypertension African Americans African Americans Elderly Elderly Men Men Noncompliance Noncompliance Historical Study

18 Sokolow & Perloff. Circulation 1961;23: patients total Cumulative % Mortality Cumulative Time in Years BP I – / BP II – / BP III – Over 250/130 BP I – / BP II – / BP III – Over 250/130 BP III BP II BP I 38%38% 18%18% 8%8% Mortality and Severe Hypertension

19 Hypertensive Urgency or Emergency Total 865 Total 865 Reviews 190 Reviews 190 Randomized Randomized Clinical Trials 46 Clinical Trials 46 Total 865 Total 865 Reviews 190 Reviews 190 Randomized Randomized Clinical Trials 46 Clinical Trials 46 ACS ACS 55,353 55,3533,518 HU or HE

20 An Evaluation of Pharmacotherapeutic Regimens Inadequately Studied Medline References from above Experts contacted Cochrane Library checked Randomized controlled trials Systematic review of cohort studies Individual cohort study Outcome Research 600 Studies Identified ExcludedNon-Human Blood pressures too low Safety or Tolerability studies Case Series or Case Reports 39 Studies Excluded Did not include a target BP & thus could not do comparisons Did not include a target BP & thus could not do comparisons Methodologic Flaws Methodologic Flaws 19 Studies Remained (8 were Open label or Not blinded) Only 4 HTN Emergency (236 patients) Only 15 HTN Urgency (1074 patients) 19 Studies Remained (8 were Open label or Not blinded) Only 4 HTN Emergency (236 patients) Only 15 HTN Urgency (1074 patients) J Gen Intern Med 2002;17:

21 Definitions and Distinctions Definitions and Distinctions Emergencies always included end organ damage Emergencies always included end organ damage Urgencies withoutend organ involvement Urgencies withoutend organ involvement Emergency – Could NOT determine: Emergency – Could NOT determine: Optimal rate to BP Optimal rate to BP Mortality benefit Mortality benefit Urgency Could NOT determine: Urgency Could NOT determine: The optimal BP to define (DBP > 120 most common) The optimal BP to define (DBP > 120 most common) How quickly should BP How quickly should BP The timing to begin maintenance therapy The timing to begin maintenance therapy If observation is needed during treatment If observation is needed during treatment Definitions and Distinctions Definitions and Distinctions Emergencies always included end organ damage Emergencies always included end organ damage Urgencies withoutend organ involvement Urgencies withoutend organ involvement Emergency – Could NOT determine: Emergency – Could NOT determine: Optimal rate to BP Optimal rate to BP Mortality benefit Mortality benefit Urgency Could NOT determine: Urgency Could NOT determine: The optimal BP to define (DBP > 120 most common) The optimal BP to define (DBP > 120 most common) How quickly should BP How quickly should BP The timing to begin maintenance therapy The timing to begin maintenance therapy If observation is needed during treatment If observation is needed during treatment An Evaluation of Pharmacotherapeutic Regimens Questions Unanswered J Gen Intern Med 2002;17:

22 U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) National Initiatives Hypertension Hypertension. 2003;42:1206–1252. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program

23 Hypertensive Urgencies and Emergencies

24

25 STAT Inclusion Criteria >18 years of age >18 years of age Presenting to the hospital with acute severe HTN Presenting to the hospital with acute severe HTN Treated in a critical care setting Treated in a critical care setting Acute severe HTN treated with an IV agent Acute severe HTN treated with an IV agent Severe hypertension Severe hypertension At least one SBP >180 mmHg and/or At least one SBP >180 mmHg and/or At least one DBP >110 mmHg At least one DBP >110 mmHg SAH patients with SBP >140 and/or DBP >90 SAH patients with SBP >140 and/or DBP >90 >18 years of age >18 years of age Presenting to the hospital with acute severe HTN Presenting to the hospital with acute severe HTN Treated in a critical care setting Treated in a critical care setting Acute severe HTN treated with an IV agent Acute severe HTN treated with an IV agent Severe hypertension Severe hypertension At least one SBP >180 mmHg and/or At least one SBP >180 mmHg and/or At least one DBP >110 mmHg At least one DBP >110 mmHg SAH patients with SBP >140 and/or DBP >90 SAH patients with SBP >140 and/or DBP >90

26 The Goal Improve understanding of clinical conditions characterized by acute severe hypertension, managed in a critical care setting, and treated with IV antihypertensive drugs A New Registry to Study Conditions and IV Treatment of Severe Hypertension

27 Primary Objectives of Registry Describe patient characteristics: Who are these patients? Describe patient characteristics: Who are these patients? Describe contemporary practice: How are they treated? Describe contemporary practice: How are they treated? Timing of initiating IV treatment Timing of initiating IV treatment Medications used (IV and oral transition) Medications used (IV and oral transition) Control of BP Control of BP Time to achieve control Time to achieve control Describe in-hospital patient outcomes: How do they fare? Describe in-hospital patient outcomes: How do they fare? Link practice and patient variations with outcome: How does management relate to outcome? Link practice and patient variations with outcome: How does management relate to outcome? Describe patient characteristics: Who are these patients? Describe patient characteristics: Who are these patients? Describe contemporary practice: How are they treated? Describe contemporary practice: How are they treated? Timing of initiating IV treatment Timing of initiating IV treatment Medications used (IV and oral transition) Medications used (IV and oral transition) Control of BP Control of BP Time to achieve control Time to achieve control Describe in-hospital patient outcomes: How do they fare? Describe in-hospital patient outcomes: How do they fare? Link practice and patient variations with outcome: How does management relate to outcome? Link practice and patient variations with outcome: How does management relate to outcome?

28 Diagnosis Diagnosis Clarify the definition of end organ dysfunction Clarify the definition of end organ dysfunction Differentiate those whose end organ dysfunction is acute and due to the severe hypertension from those with chronic dysfunction Differentiate those whose end organ dysfunction is acute and due to the severe hypertension from those with chronic dysfunction Gain insight into what measurements matter most and have most predictive value on outcomes: (1 st BP, highest BP) Gain insight into what measurements matter most and have most predictive value on outcomes: (1 st BP, highest BP) Treatment Treatment How fast to BP? How fast to BP? How much to BP? How much to BP? Which agents by which route should be used? Which agents by which route should be used? Does the speed and degree of BP change and the agent used depend upon which end organ is dysfunctional? Does the speed and degree of BP change and the agent used depend upon which end organ is dysfunctional? Diagnosis Diagnosis Clarify the definition of end organ dysfunction Clarify the definition of end organ dysfunction Differentiate those whose end organ dysfunction is acute and due to the severe hypertension from those with chronic dysfunction Differentiate those whose end organ dysfunction is acute and due to the severe hypertension from those with chronic dysfunction Gain insight into what measurements matter most and have most predictive value on outcomes: (1 st BP, highest BP) Gain insight into what measurements matter most and have most predictive value on outcomes: (1 st BP, highest BP) Treatment Treatment How fast to BP? How fast to BP? How much to BP? How much to BP? Which agents by which route should be used? Which agents by which route should be used? Does the speed and degree of BP change and the agent used depend upon which end organ is dysfunctional? Does the speed and degree of BP change and the agent used depend upon which end organ is dysfunctional? Questions Addressed by Registry

29 Summary of Acute Pressure Syndromes An Evolving Landscape Major public health concern Major public health concern Huge resources used in ED alone Huge resources used in ED alone Mortality and morbidity similar to ACS, CHF Mortality and morbidity similar to ACS, CHF Paucity of careful study of nature of problem Paucity of careful study of nature of problem Best management is unclear Best management is unclear Little knowledge of what treatment goals should be and how control relates to outcome Little knowledge of what treatment goals should be and how control relates to outcome Opportunity to improve outcome with better follow-up care and focus on adherence Opportunity to improve outcome with better follow-up care and focus on adherence Needs more attention! Needs more attention! Major public health concern Major public health concern Huge resources used in ED alone Huge resources used in ED alone Mortality and morbidity similar to ACS, CHF Mortality and morbidity similar to ACS, CHF Paucity of careful study of nature of problem Paucity of careful study of nature of problem Best management is unclear Best management is unclear Little knowledge of what treatment goals should be and how control relates to outcome Little knowledge of what treatment goals should be and how control relates to outcome Opportunity to improve outcome with better follow-up care and focus on adherence Opportunity to improve outcome with better follow-up care and focus on adherence Needs more attention! Needs more attention!

30 Hypertensive Urgencies and Emergencies: The Current Challenge for Emergency Physicians Charles V. Pollack, Jr., M.A., M.D., FACEP, FAHA Chairman, Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania Philadelphia Charles V. Pollack, Jr., M.A., M.D., FACEP, FAHA Chairman, Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania Philadelphia Investigation Innovation Application

31 Hypertensive Urgencies and Emergencies Epidemiologic data are largely lacking Epidemiologic data are largely lacking It is thought that ~ 1% of patients with htn will eventually present to the ED in hypertensive crisis It is thought that ~ 1% of patients with htn 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 HU:HE 3:1 in that study HU:HE 3:1 in that study Patients with HU much more likely to be unaware of their htn dx than those with HE Patients with HU much more likely to be unaware of their htn dx than those with HE Epidemiologic data are largely lacking Epidemiologic data are largely lacking It is thought that ~ 1% of patients with htn will eventually present to the ED in hypertensive crisis It is thought that ~ 1% of patients with htn 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 HU:HE 3:1 in that study HU:HE 3:1 in that study Patients with HU much more likely to be unaware of their htn dx than those with HE Patients with HU much more likely to be unaware of their htn dx than those with HE Zampaglione et al, Hypertension 1996;27:144

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

33 JNC 7 Nomenclature Normal BP: S < 120, D < 80 Normal BP: S < 120, D < 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): S > 180, D > 110 S > 180, D > 110 Functionally, this is hypertensive urgency Functionally, this is hypertensive urgency What about crisis, emergency, and urgency? What about crisis, emergency, and urgency? Normal BP: S < 120, D < 80 Normal BP: S < 120, D < 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): S > 180, D > 110 S > 180, D > 110 Functionally, this is hypertensive urgency Functionally, this is hypertensive urgency What about crisis, emergency, and urgency? What about crisis, emergency, and urgency? JNC 7, JAMA 2003; 289:

34 JNC 7 Nomenclature Using JNC 7 nomenclature, hypertensive crisis is an acute, severe, stage 2 elevation in blood pressure Using JNC 7 nomenclature, hypertensive crisis is an acute, severe, stage 2 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 elevation in blood pressure Using JNC 7 nomenclature, hypertensive crisis is an acute, severe, stage 2 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:

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

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

37 Goals of ED Tx 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 Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneys Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneys Goal in HE is to reduce MAP by 10-15% and/or to a DBP of within one hour Goal in HE is to reduce MAP by 10-15% and/or to a DBP of within one hour Aortic dissection requires even more rapid lowering Aortic dissection requires even more rapid lowering Once initial reduction achieved, transition to oral agents Once initial reduction achieved, transition to oral agents Dug of choice for initial therapy often depends on which end- organ system is affected and on comorbidities 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 Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneys Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneys Goal in HE is to reduce MAP by 10-15% and/or to a DBP of within one hour Goal in HE is to reduce MAP by 10-15% and/or to a DBP of within one hour Aortic dissection requires even more rapid lowering Aortic dissection requires even more rapid lowering Once initial reduction achieved, transition to oral agents Once initial reduction achieved, transition to oral agents Dug of choice for initial therapy often depends on which end- organ system is affected and on comorbidities Dug of choice for initial therapy often depends on which end- organ system is affected and on comorbidities JNC 7, JAMA 2003; 289:

38 How Often Do We See It in the ED? 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?

39 CVA > 75% of acute CVA patients present with SBP > 140, and cerebral autoregulation may be disturbed, resulting in increased ICP > 75% of acute CVA patients present with SBP > 140, and cerebral autoregulation may be disturbed, resulting in increased ICP There appears to be a U-curve relationship between BP and neurologic outcomes There appears to be a U-curve relationship between BP and neurologic outcomes of SBP of 10 below 180 is associated with 25% d risk of poor neuro outcomes; of 10 above 180 is associated with a 40% in early neuro deterioration and a 23% d risk of poor outcome of SBP of 10 below 180 is associated with 25% d risk of poor neuro outcomes; of 10 above 180 is associated with a 40% in early neuro deterioration and a 23% d risk of poor outcome Based on this finding, the usual recommendation is to try to maintain SBP in range and not attempt to normalize Based on this finding, the usual recommendation is to try to maintain SBP in range and not attempt to normalize > 75% of acute CVA patients present with SBP > 140, and cerebral autoregulation may be disturbed, resulting in increased ICP > 75% of acute CVA patients present with SBP > 140, and cerebral autoregulation may be disturbed, resulting in increased ICP There appears to be a U-curve relationship between BP and neurologic outcomes There appears to be a U-curve relationship between BP and neurologic outcomes of SBP of 10 below 180 is associated with 25% d risk of poor neuro outcomes; of 10 above 180 is associated with a 40% in early neuro deterioration and a 23% d risk of poor outcome of SBP of 10 below 180 is associated with 25% d risk of poor neuro outcomes; of 10 above 180 is associated with a 40% in early neuro deterioration and a 23% d risk of poor outcome Based on this finding, the usual recommendation is to try to maintain SBP in range and not attempt to normalize Based on this finding, the usual recommendation is to try to maintain SBP in range and not attempt to normalize Adams et al, Stroke 2003; 34:

40 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:

41 CVA American Stroke Association guidelines (2003): American Stroke Association guidelines (2003): No treatment of S < 220 or D < 120 unless end-organ damage No treatment of S < 220 or D < 120 unless end-organ damage If end-organ damage or S > 220 or DBP , labetolol or nicardipine is recommended If end-organ damage or S > 220 or DBP , labetolol or nicardipine is recommended If D > 140, NTP recommended, with caution that CBF may lead to ICP If D > 140, NTP recommended, with caution that CBF may lead to ICP If considering lytic treatment, labetolol should be started if S > 185 or D > 110 If considering lytic treatment, labetolol should be started if S > 185 or D > 110 American Stroke Association guidelines (2003): American Stroke Association guidelines (2003): No treatment of S < 220 or D < 120 unless end-organ damage No treatment of S < 220 or D < 120 unless end-organ damage If end-organ damage or S > 220 or DBP , labetolol or nicardipine is recommended If end-organ damage or S > 220 or DBP , labetolol or nicardipine is recommended If D > 140, NTP recommended, with caution that CBF may lead to ICP If D > 140, NTP recommended, with caution that CBF may lead to ICP If considering lytic treatment, labetolol should be started if S > 185 or D > 110 If considering lytic treatment, labetolol should be started if S > 185 or D > 110 Adams et al, Stroke 2003; 34:

42 Aortic Dissection Treatment of htn should begin before confirmation of dx, if suspected Treatment of htn should begin before confirmation of dx, if suspected Goal of therapy is to aortic stress by rapidly lowering DBP and controlling pulse rate Goal of therapy is to aortic stress by rapidly lowering DBP and controlling pulse rate Target is 10-15% in MAP, or reduction from baseline to SBP to 110, in 5-30 minutes Target is 10-15% in MAP, or reduction from baseline to SBP to 110, in 5-30 minutes Usual drugs are vasodilator + beta blocker, usually NTP + esmolol Usual drugs are vasodilator + beta blocker, usually NTP + esmolol Labetalol as sole agent limited by tachyphylaxis Labetalol as sole agent limited by tachyphylaxis Treatment of htn should begin before confirmation of dx, if suspected Treatment of htn should begin before confirmation of dx, if suspected Goal of therapy is to aortic stress by rapidly lowering DBP and controlling pulse rate Goal of therapy is to aortic stress by rapidly lowering DBP and controlling pulse rate Target is 10-15% in MAP, or reduction from baseline to SBP to 110, in 5-30 minutes Target is 10-15% in MAP, or reduction from baseline to SBP to 110, in 5-30 minutes Usual drugs are vasodilator + beta blocker, usually NTP + esmolol Usual drugs are vasodilator + beta blocker, usually NTP + esmolol Labetalol as sole agent limited by tachyphylaxis Labetalol as sole agent limited by tachyphylaxis Varon J, Chest 2000;118:

43 Acute Renal Failure Goal of therapy is to treat htn without further ing renal perfusion Goal of therapy is to treat htn without further ing renal perfusion Target is 10-20% in MAP over 1-2h, then by 10-15% more in next 6-12h; accelerating this process may renal function Target is 10-20% in MAP over 1-2h, then by 10-15% more in next 6-12h; accelerating this process may renal function Fenoldopam appears to be preferred drug Fenoldopam appears to be preferred drug Maintains GFR Maintains GFR Dilates the renal artery Dilates the renal artery Causes natriuresis Causes natriuresis NTP should be avoided because of accumulation of metabolites and development of acidosis NTP should be avoided because of accumulation of metabolites and development of acidosis Goal of therapy is to treat htn without further ing renal perfusion Goal of therapy is to treat htn without further ing renal perfusion Target is 10-20% in MAP over 1-2h, then by 10-15% more in next 6-12h; accelerating this process may renal function Target is 10-20% in MAP over 1-2h, then by 10-15% more in next 6-12h; accelerating this process may renal function Fenoldopam appears to be preferred drug Fenoldopam appears to be preferred drug Maintains GFR Maintains GFR Dilates the renal artery Dilates the renal artery Causes natriuresis Causes natriuresis NTP should be avoided because of accumulation of metabolites and development of acidosis NTP should be avoided because of accumulation of metabolites and development of acidosis Vaughn, Lancet 2000;356:

44 Acute Cardiopulmonary Compromise Goal of therapy is to treat htn and improve cardiac function Goal of therapy is to treat htn and improve cardiac function Target is 10-20% in MAP over 1-2h, guided by clinical findings, followed by transition to oral agents Target is 10-20% in MAP over 1-2h, guided by clinical findings, followed by transition to oral agents Diuretics can be used to manage fluid overload Diuretics can be used to manage fluid overload Morphine is a venodilator that may help both control both anginal pain and pulmonary congestion Morphine is a venodilator that may help both control both anginal pain and pulmonary congestion Must be cautious not to overshoot; NTP often avoided for this reason Must be cautious not to overshoot; NTP often avoided for this reason Goal of therapy is to treat htn and improve cardiac function Goal of therapy is to treat htn and improve cardiac function Target is 10-20% in MAP over 1-2h, guided by clinical findings, followed by transition to oral agents Target is 10-20% in MAP over 1-2h, guided by clinical findings, followed by transition to oral agents Diuretics can be used to manage fluid overload Diuretics can be used to manage fluid overload Morphine is a venodilator that may help both control both anginal pain and pulmonary congestion Morphine is a venodilator that may help both control both anginal pain and pulmonary congestion Must be cautious not to overshoot; NTP often avoided for this reason Must be cautious not to overshoot; NTP often avoided for this reason Vaughn, Lancet 2000;356:

45

46 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

47 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 Rynn et al, J Pharm Pract 2005;18:363-76

48 ACE Inhibitors Reduce vasoconstriction and circulating catecholamine levels Reduce vasoconstriction and circulating catecholamine levels Many oral options; enalaprilat is IV form Many oral options; enalaprilat is IV form May cause hypotension, acute renal failure, hyperkalemia, cough, angioedema, and rash May cause hypotension, acute renal failure, hyperkalemia, cough, angioedema, and rash Reduce vasoconstriction and circulating catecholamine levels Reduce vasoconstriction and circulating catecholamine levels Many oral options; enalaprilat is IV form Many oral options; enalaprilat is IV form May cause hypotension, acute renal failure, hyperkalemia, cough, angioedema, and rash May cause hypotension, acute renal failure, hyperkalemia, cough, angioedema, and rash Rynn et al, J Pharm Pract 2005;18:363-76

49 Clonidine Reduces central sympathetic outflow, thereby increasing vagal tone, reducing PVR and HR Reduces central sympathetic outflow, thereby increasing vagal tone, reducing PVR and HR Only available orally; onset of effect is 1-3h Only available orally; onset of effect is 1-3h May cause orthostasis (especially in volume- depleted patients, bradycardia, and AV block; associated with withdrawal in patients taking more than 0.3mg/d May cause orthostasis (especially in volume- depleted patients, bradycardia, and AV block; associated with withdrawal in patients taking more than 0.3mg/d Reduces central sympathetic outflow, thereby increasing vagal tone, reducing PVR and HR Reduces central sympathetic outflow, thereby increasing vagal tone, reducing PVR and HR Only available orally; onset of effect is 1-3h Only available orally; onset of effect is 1-3h May cause orthostasis (especially in volume- depleted patients, bradycardia, and AV block; associated with withdrawal in patients taking more than 0.3mg/d May cause orthostasis (especially in volume- depleted patients, bradycardia, and AV block; associated with withdrawal in patients taking more than 0.3mg/d Rynn et al, J Pharm Pract 2005;18:363-76

50 Diazoxide Direct peripheral arteriolar vasodilator Direct peripheral arteriolar vasodilator Given IV, slowly to avoid excessive hypotension, as an infusion or with repeated boluses Given IV, slowly to avoid excessive hypotension, as an infusion or with repeated boluses May cause tachycardia, hypotension, N/V, hyperglycemia, and hyperuricemia; with repeated doses may cause sodium and fluid retention with edema and frank heart failure May cause tachycardia, hypotension, N/V, hyperglycemia, and hyperuricemia; with repeated doses may cause sodium and fluid retention with edema and frank heart failure Direct peripheral arteriolar vasodilator Direct peripheral arteriolar vasodilator Given IV, slowly to avoid excessive hypotension, as an infusion or with repeated boluses Given IV, slowly to avoid excessive hypotension, as an infusion or with repeated boluses May cause tachycardia, hypotension, N/V, hyperglycemia, and hyperuricemia; with repeated doses may cause sodium and fluid retention with edema and frank heart failure May cause tachycardia, hypotension, N/V, hyperglycemia, and hyperuricemia; with repeated doses may cause sodium and fluid retention with edema and frank heart failure Rynn et al, J Pharm Pract 2005;18:363-76

51 Diuretics Loop diuretics are often used in chronic management of hypertension Loop diuretics are often used in chronic management of hypertension Acute management limited to pulmonary edema Acute management limited to pulmonary edema Diminished effectiveness in renal insufficiency or decreased cardiac output Diminished effectiveness in renal insufficiency or decreased cardiac output May cause ototoxicity with rapid IV administration; may induce or exacerbate hypokalemia (also Na, Ca, and Mg); furosemide, bumetanide, and torsemide can all cause allergic reactions in sulfa-sensitive patients May cause ototoxicity with rapid IV administration; may induce or exacerbate hypokalemia (also Na, Ca, and Mg); furosemide, bumetanide, and torsemide can all cause allergic reactions in sulfa-sensitive patients Loop diuretics are often used in chronic management of hypertension Loop diuretics are often used in chronic management of hypertension Acute management limited to pulmonary edema Acute management limited to pulmonary edema Diminished effectiveness in renal insufficiency or decreased cardiac output Diminished effectiveness in renal insufficiency or decreased cardiac output May cause ototoxicity with rapid IV administration; may induce or exacerbate hypokalemia (also Na, Ca, and Mg); furosemide, bumetanide, and torsemide can all cause allergic reactions in sulfa-sensitive patients May cause ototoxicity with rapid IV administration; may induce or exacerbate hypokalemia (also Na, Ca, and Mg); furosemide, bumetanide, and torsemide can all cause allergic reactions in sulfa-sensitive patients Rynn et al, J Pharm Pract 2005;18:363-76

52 Esmolol Blocks β-1 receptors of heart and vasculature Blocks β-1 receptors of heart and vasculature Given IV, onset of action is 6-10min after bolus, and activity persists 20min after infusion d/cd; must be carefully titrated Given IV, onset of action is 6-10min after bolus, and activity persists 20min after infusion d/cd; must be carefully titrated May cause bradycardia and hypotension, bronchospasm, seizures, and pulmonary edema May cause bradycardia and hypotension, bronchospasm, seizures, and pulmonary edema Chest pain may occur after abrupt withdrawal Chest pain may occur after abrupt withdrawal Blocks β-1 receptors of heart and vasculature Blocks β-1 receptors of heart and vasculature Given IV, onset of action is 6-10min after bolus, and activity persists 20min after infusion d/cd; must be carefully titrated Given IV, onset of action is 6-10min after bolus, and activity persists 20min after infusion d/cd; must be carefully titrated May cause bradycardia and hypotension, bronchospasm, seizures, and pulmonary edema May cause bradycardia and hypotension, bronchospasm, seizures, and pulmonary edema Chest pain may occur after abrupt withdrawal Chest pain may occur after abrupt withdrawal Rynn et al, J Pharm Pract 2005;18:363-76

53 Labetalol s PVR by blocking α-1 receptors and prevents reflex tachycardia by blocking β-1 receptors, resulting in a BP s PVR by blocking α-1 receptors and prevents reflex tachycardia by blocking β-1 receptors, resulting in a BP Given as repeated IV boluses and can be carefully given as a short-term infusion Given as repeated IV boluses and can be carefully given as a short-term infusion Optimally used when a gradual in BP is needed with minimal effects on HR, and in CVA (labetolol has minimal effects on CBF) Optimally used when a gradual in BP is needed with minimal effects on HR, and in CVA (labetolol has minimal effects on CBF) Should be avoided in significant asthma/COPD; may cause bradycardia, AV block, hypotension Should be avoided in significant asthma/COPD; may cause bradycardia, AV block, hypotension s PVR by blocking α-1 receptors and prevents reflex tachycardia by blocking β-1 receptors, resulting in a BP s PVR by blocking α-1 receptors and prevents reflex tachycardia by blocking β-1 receptors, resulting in a BP Given as repeated IV boluses and can be carefully given as a short-term infusion Given as repeated IV boluses and can be carefully given as a short-term infusion Optimally used when a gradual in BP is needed with minimal effects on HR, and in CVA (labetolol has minimal effects on CBF) Optimally used when a gradual in BP is needed with minimal effects on HR, and in CVA (labetolol has minimal effects on CBF) Should be avoided in significant asthma/COPD; may cause bradycardia, AV block, hypotension Should be avoided in significant asthma/COPD; may cause bradycardia, AV block, hypotension Rynn et al, J Pharm Pract 2005;18:363-76

54 -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:

55 Hydralazine Directly relaxes arteriolar smooth muscle Directly relaxes arteriolar smooth muscle Used primarily in management of preeclampsia and eclampsia Used primarily in management of preeclampsia and eclampsia Many adverse effects that limit its use in other situations, so not discussed further here Many adverse effects that limit its use in other situations, so not discussed further here Directly relaxes arteriolar smooth muscle Directly relaxes arteriolar smooth muscle Used primarily in management of preeclampsia and eclampsia Used primarily in management of preeclampsia and eclampsia Many adverse effects that limit its use in other situations, so not discussed further here Many adverse effects that limit its use in other situations, so not discussed further here Rynn et al, J Pharm Pract 2005;18:363-76

56 Fenoldopam Selective dopamine-1 receptor agonist, ing PVR while ing RBF, natriuresis, and diuresis Selective dopamine-1 receptor agonist, ing PVR while ing RBF, natriuresis, and diuresis 6x more potent than dopamine in producing renal vasodilation 6x more potent than dopamine in producing renal vasodilation Given IV and titrated; onset of action 10 min and effects persist for an hour after d/c Given IV and titrated; onset of action 10 min and effects persist for an hour after d/c May cause T-wave flattening, angina, atrial fib/flutter, and reflex tachycardia May cause T-wave flattening, angina, atrial fib/flutter, and reflex tachycardia Selective dopamine-1 receptor agonist, ing PVR while ing RBF, natriuresis, and diuresis Selective dopamine-1 receptor agonist, ing PVR while ing RBF, natriuresis, and diuresis 6x more potent than dopamine in producing renal vasodilation 6x more potent than dopamine in producing renal vasodilation Given IV and titrated; onset of action 10 min and effects persist for an hour after d/c Given IV and titrated; onset of action 10 min and effects persist for an hour after d/c May cause T-wave flattening, angina, atrial fib/flutter, and reflex tachycardia May cause T-wave flattening, angina, atrial fib/flutter, and reflex tachycardia Rynn et al, J Pharm Pract 2005;18:363-76

57 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

58 Nicardipine As a CCB, relaxes arteriolar smooth muscle and s PVR by a baroreceptor-mediated sympathetic discharge As a CCB, relaxes arteriolar smooth muscle and s PVR by a baroreceptor-mediated sympathetic discharge Seems to be selective for L-type, voltage-sensitive Ca channels of the heart, and works by decreasing afterload Seems to be selective for L-type, voltage-sensitive Ca channels of the heart, and works by decreasing afterload Given by IV infusion with careful titration Given by IV infusion with careful titration May cause tachycardia, flushing, headache, dizziness, hypotension, and digital dysesthesias May cause tachycardia, flushing, headache, dizziness, hypotension, and digital dysesthesias As a CCB, relaxes arteriolar smooth muscle and s PVR by a baroreceptor-mediated sympathetic discharge As a CCB, relaxes arteriolar smooth muscle and s PVR by a baroreceptor-mediated sympathetic discharge Seems to be selective for L-type, voltage-sensitive Ca channels of the heart, and works by decreasing afterload Seems to be selective for L-type, voltage-sensitive Ca channels of the heart, and works by decreasing afterload Given by IV infusion with careful titration Given by IV infusion with careful titration May cause tachycardia, flushing, headache, dizziness, hypotension, and digital dysesthesias May cause tachycardia, flushing, headache, dizziness, hypotension, and digital dysesthesias Rynn et al, J Pharm Pract 2005;18:363-76

59 Nicardipine Onset to effect is about 10min, and lasts 2-6h after d/c Onset to effect is about 10min, and lasts 2-6h after d/c Abrupt withdrawal can cause rebound angina and hypertension Abrupt withdrawal can cause rebound angina and hypertension Still, in at least one head-to-head trial, better tolerated than NTP Still, in at least one head-to-head trial, better tolerated than NTP Onset to effect is about 10min, and lasts 2-6h after d/c Onset to effect is about 10min, and lasts 2-6h after d/c Abrupt withdrawal can cause rebound angina and hypertension Abrupt withdrawal can cause rebound angina and hypertension Still, in at least one head-to-head trial, better tolerated than NTP Still, in at least one head-to-head trial, better tolerated than NTP Neutel et al, Am J Hypertens 1994;7:623-8

60 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].

61 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

62 Nifedipine Formerly given sublingually or as bite-and-swallow (in fact, there is only negligible absorption sublingually) Formerly given sublingually or as bite-and-swallow (in fact, there is only negligible absorption sublingually) Erratic and unpredictable effect on BP Erratic and unpredictable effect on BP Many documented cases of CVA and even death from rapid BP Many documented cases of CVA and even death from rapid BP Should be avoided in hypertensive crises Should be avoided in hypertensive crises Formerly given sublingually or as bite-and-swallow (in fact, there is only negligible absorption sublingually) Formerly given sublingually or as bite-and-swallow (in fact, there is only negligible absorption sublingually) Erratic and unpredictable effect on BP Erratic and unpredictable effect on BP Many documented cases of CVA and even death from rapid BP Many documented cases of CVA and even death from rapid BP Should be avoided in hypertensive crises Should be avoided in hypertensive crises Rynn et al, J Pharm Pract 2005;18:363-76

63 Nitroglycerin Useful in managing BP in patients with angina or pulmonary edema Useful in managing BP in patients with angina or pulmonary edema At lower doses, works primarily by ing preload At lower doses, works primarily by ing preload Affects venous system predominantly Affects venous system predominantly Reduces myocardial oxygen demand Reduces myocardial oxygen demand At higher doses, works primarily by ing afterload At higher doses, works primarily by ing afterload Affects arterioles and coronary arteries predominantly Affects arterioles and coronary arteries predominantly Useful in managing BP in patients with angina or pulmonary edema Useful in managing BP in patients with angina or pulmonary edema At lower doses, works primarily by ing preload At lower doses, works primarily by ing preload Affects venous system predominantly Affects venous system predominantly Reduces myocardial oxygen demand Reduces myocardial oxygen demand At higher doses, works primarily by ing afterload At higher doses, works primarily by ing afterload Affects arterioles and coronary arteries predominantly Affects arterioles and coronary arteries predominantly Rynn et al, J Pharm Pract 2005;18:363-76

64 Nitroglycerin Given in hypertensive crisis by continuous IV infusion Given in hypertensive crisis by continuous IV infusion Onset of action 2-5 min Onset of action 2-5 min Tolerance tends to develop over hours Tolerance tends to develop over hours Dose-limiting adverse effects include tachycardia, bradycardia, and headache Dose-limiting adverse effects include tachycardia, bradycardia, and headache Given in hypertensive crisis by continuous IV infusion Given in hypertensive crisis by continuous IV infusion Onset of action 2-5 min Onset of action 2-5 min Tolerance tends to develop over hours Tolerance tends to develop over hours Dose-limiting adverse effects include tachycardia, bradycardia, and headache Dose-limiting adverse effects include tachycardia, bradycardia, and headache Rynn et al, J Pharm Pract 2005;18:363-76

65 Nitroprusside A direct vasodilator that dilates both arteriolar and venous capacitance vessels A direct vasodilator that dilates both arteriolar and venous capacitance vessels Reduces PVR, venous return, and preload Reduces PVR, venous return, and preload Can CO in patients with LVF Can CO in patients with LVF Mechanism: metabolized to nitric oxide cGMP vasodilation Mechanism: metabolized to nitric oxide cGMP vasodilation From nitric oxide is metabolized to cyanide, which can cause lactic acidosis, N/V, anorexia, disorientation, and psychosis From nitric oxide is metabolized to cyanide, which can cause lactic acidosis, N/V, anorexia, disorientation, and psychosis A direct vasodilator that dilates both arteriolar and venous capacitance vessels A direct vasodilator that dilates both arteriolar and venous capacitance vessels Reduces PVR, venous return, and preload Reduces PVR, venous return, and preload Can CO in patients with LVF Can CO in patients with LVF Mechanism: metabolized to nitric oxide cGMP vasodilation Mechanism: metabolized to nitric oxide cGMP vasodilation From nitric oxide is metabolized to cyanide, which can cause lactic acidosis, N/V, anorexia, disorientation, and psychosis From nitric oxide is metabolized to cyanide, which can cause lactic acidosis, N/V, anorexia, disorientation, and psychosis Rynn et al, J Pharm Pract 2005;18:363-76

66 Nitroprusside Effects are immediate, and persist 3-5 minutes Effects are immediate, and persist 3-5 minutes Reported to CBF, although this may be offset by MAP, so must be used with caution in suspected CVA Reported to CBF, although this may be offset by MAP, so must be used with caution in suspected CVA Effects are immediate, and persist 3-5 minutes Effects are immediate, and persist 3-5 minutes Reported to CBF, although this may be offset by MAP, so must be used with caution in suspected CVA Reported to CBF, although this may be offset by MAP, so must be used with caution in suspected CVA Rynn et al, J Pharm Pract 2005;18:363-76

67 Nitroprusside Also reported to cause coronary steal syndrome, causing or worsening myocardial ischemia Also reported to cause coronary steal syndrome, causing or worsening myocardial ischemia Toxicity usually not a problem unless larger infusion rates ( > 2μg/kg/min) are used for long periods ( > 48h) Toxicity usually not a problem unless larger infusion rates ( > 2μg/kg/min) are used for long periods ( > 48h) Nurses find it difficult to administer Nurses find it difficult to administer Also reported to cause coronary steal syndrome, causing or worsening myocardial ischemia Also reported to cause coronary steal syndrome, causing or worsening myocardial ischemia Toxicity usually not a problem unless larger infusion rates ( > 2μg/kg/min) are used for long periods ( > 48h) Toxicity usually not a problem unless larger infusion rates ( > 2μg/kg/min) are used for long periods ( > 48h) Nurses find it difficult to administer Nurses find it difficult to administer Rynn et al, J Pharm Pract 2005;18:363-76

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

69 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:

70 Limitations and Pitfalls of Agents Blood Pressure Management in Acute Hypertensive Emergency Brooks TW, Finch CK, Lobo BL, Deaton PR, Varner CF. Am J Health Syst Pharm, 2007 Dec 15;64(24): Blood Pressure Management in Acute Hypertensive Emergency Brooks TW, Finch CK, Lobo BL, Deaton PR, Varner CF. Am J Health Syst Pharm, 2007 Dec 15;64(24):

71 Baseline Characteristics of Study Population Brooks, et al. Am J Health Syst Pharm. Dec 15, 2007;64(24):

72 Primary and Secondary Endpoints Brooks, et al. Am J Health Syst Pharm. Dec 15, 2007;64(24): a MAP = mean arterial pressure. b p < 0.05, nicardipine group versus all patients. c p < 0.05, nicardipine group versus nitroprusside group. d One patient was excluded from the analysis. a MAP = mean arterial pressure. b p < 0.05, nicardipine group versus all patients. c p < 0.05, nicardipine group versus nitroprusside group. d One patient was excluded from the analysis.

73 Treatment-Related Adverse Events Brooks, et al. Am J Health Syst Pharm. Dec 15, 2007;64(24): a p < 0.05, nicardipine group versus nitroprusside group; p < 0.05, nitroprusside group versus all patients.

74 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 Debate over terminology and numerical definitions is too prevalent in the literature Debate over terminology and numerical definitions is too prevalent in the literature Choices among available agents often difficult, and none is ideal across the spectrum Choices among available agents often difficult, and none is ideal across the spectrum Must balance effective reduction with avoidance of over- reduction and its complications Must balance effective reduction with avoidance of over- reduction and its complications 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 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 Debate over terminology and numerical definitions is too prevalent in the literature Debate over terminology and numerical definitions is too prevalent in the literature Choices among available agents often difficult, and none is ideal across the spectrum Choices among available agents often difficult, and none is ideal across the spectrum Must balance effective reduction with avoidance of over- reduction and its complications Must balance effective reduction with avoidance of over- reduction and its complications 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

75 Acute Severe Hypertension Evolving Strategies and New Dimensions of Emergency Cardiovascular Care Acute Severe Hypertension Evolving Strategies and New Dimensions of Emergency Cardiovascular Care Investigation Innovation Application Program Chairman Joseph Varon, MD, FACP, FCCP, FCCM Clinical Professor of Medicine The University of Texas Health Science Center at Houston Professor, Acute and Continuing Care The University of Texas Health Science Center at Houston Clinical Professor of Medicine The University of Texas Medical Branch – Galveston Professor of Medicine and Surgery UAT, UDEM, UPAEP, UABC, UNE Mexico Program Chairman Joseph Varon, MD, FACP, FCCP, FCCM Clinical Professor of Medicine The University of Texas Health Science Center at Houston Professor, Acute and Continuing Care The University of Texas Health Science Center at Houston Clinical Professor of Medicine The University of Texas Medical Branch – Galveston Professor of Medicine and Surgery UAT, UDEM, UPAEP, UABC, UNE Mexico

76 Hypertension Affects at least 72 million Americans Affects at least 72 million Americans Affects at least 1 BILLION individuals worldwide Affects at least 1 BILLION individuals worldwide Most current (2003) evidence basis for management The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Hypertension (JNC 7)lacks guidance on acute management of patients presenting to an ED with hypertension Most current (2003) evidence basis for management The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Hypertension (JNC 7)lacks guidance on acute management of patients presenting to an ED with hypertension Affects at least 72 million Americans Affects at least 72 million Americans Affects at least 1 BILLION individuals worldwide Affects at least 1 BILLION individuals worldwide Most current (2003) evidence basis for management The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Hypertension (JNC 7)lacks guidance on acute management of patients presenting to an ED with hypertension Most current (2003) evidence basis for management The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Hypertension (JNC 7)lacks guidance on acute management of patients presenting to an ED with hypertension JNC 7, JAMA 2003; 289:

77 Hypertensive Urgencies and Emergencies What We Know Epidemiologic data are largely lacking Epidemiologic data are largely lacking It is thought that ~ 1% of patients with htn will eventually present to the ED in hypertensive crisis It is thought that ~ 1% of patients with htn 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 HU:HE 3:1 in that study HU:HE 3:1 in that study Patients with HU much more likely to be unaware of their htn dx than those with HE Patients with HU much more likely to be unaware of their htn dx than those with HE Epidemiologic data are largely lacking Epidemiologic data are largely lacking It is thought that ~ 1% of patients with htn will eventually present to the ED in hypertensive crisis It is thought that ~ 1% of patients with htn 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 HU:HE 3:1 in that study HU:HE 3:1 in that study Patients with HU much more likely to be unaware of their htn dx than those with HE Patients with HU much more likely to be unaware of their htn dx than those with HE Zampaglione et al, Hypertension 1996;27:144.

78 Acute Pressure Syndromes Management Considerations What is the magnitude of: What is the magnitude of: Disease risk? Disease risk? Treatment benefit? Treatment benefit? Treatment risk? 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: Disease risk? Disease risk? Treatment benefit? Treatment benefit? Treatment risk? 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?

79 Goals of Emergency 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 Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneys Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneys Goal in hypertensive emergency is to reduce MAP by % and/or to a DBP of 110 as rapidly as possible Goal in hypertensive emergency is to reduce MAP by % and/or to a DBP of 110 as rapidly as possible Aortic dissection requires especially rapid lowering Aortic dissection requires especially rapid lowering Once initial reduction achieved, transition to oral agents Once initial reduction achieved, transition to oral agents Drug of choice for initial therapy often depends on which end-organ system is affected and on comorbidities Drug 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 Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneys Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneys Goal in hypertensive emergency is to reduce MAP by % and/or to a DBP of 110 as rapidly as possible Goal in hypertensive emergency is to reduce MAP by % and/or to a DBP of 110 as rapidly as possible Aortic dissection requires especially rapid lowering Aortic dissection requires especially rapid lowering Once initial reduction achieved, transition to oral agents Once initial reduction achieved, transition to oral agents Drug of choice for initial therapy often depends on which end-organ system is affected and on comorbidities Drug of choice for initial therapy often depends on which end-organ system is affected and on comorbidities JNC 7, JAMA 2003; 289:

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

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

82 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 Currently available agents for the management of acute severe BP elevation leave much to be desired Advancements in therapy are possible Advancements in therapy 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 Currently available agents for the management of acute severe BP elevation leave much to be desired Advancements in therapy are possible Advancements in therapy 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

83 Therapeutic Agents Currently Used 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 Rynn et al, J Pharm Pract 2005;18: Armamentarium

84 Fenoldopam Selective dopamine-1 receptor agonist, decreasing PVR while increasing RBF, natriuresis, and diuresis Selective dopamine-1 receptor agonist, decreasing PVR while increasing RBF, natriuresis, and diuresis Six times more potent than dopamine in producing renal vasodilation Six times more potent than dopamine in producing renal vasodilation Given IV and titrated; onset of action 10 minutes and effects persist for an hour after discontinuation Given IV and titrated; onset of action 10 minutes and effects persist for an hour after discontinuation May cause T-wave flattening, angina, atrial fib/flutter, and reflex tachycardia May cause T-wave flattening, angina, atrial fib/flutter, and reflex tachycardia Selective dopamine-1 receptor agonist, decreasing PVR while increasing RBF, natriuresis, and diuresis Selective dopamine-1 receptor agonist, decreasing PVR while increasing RBF, natriuresis, and diuresis Six times more potent than dopamine in producing renal vasodilation Six times more potent than dopamine in producing renal vasodilation Given IV and titrated; onset of action 10 minutes and effects persist for an hour after discontinuation Given IV and titrated; onset of action 10 minutes and effects persist for an hour after discontinuation May cause T-wave flattening, angina, atrial fib/flutter, and reflex tachycardia May cause T-wave flattening, angina, atrial fib/flutter, and reflex tachycardia Rynn et al, J Pharm Pract 2005;18: Principles of Use

85 Nitropusside: Issues and Concerns Nitropusside: Issues and Concerns Common Side Effects Common Side Effects BP BP May cause N/V, twitching, sweating May cause N/V, twitching, sweating Metabolized to CN, then thiocyanate Metabolized to CN, then thiocyanate Renal issue Renal issue Problematic Aspects Problematic Aspects Pregnancy Pregnancy Coronary steal Coronary steal Dose dependent in CBF Dose dependent in CBF –Caution with high ICP Hypoxia ( Va/Q mismatch) Hypoxia ( Va/Q mismatch) Requires special delivery system Requires special delivery system Usually requires direct artery pressure monitoring Usually requires direct artery pressure monitoring Common Side Effects Common Side Effects BP BP May cause N/V, twitching, sweating May cause N/V, twitching, sweating Metabolized to CN, then thiocyanate Metabolized to CN, then thiocyanate Renal issue Renal issue Problematic Aspects Problematic Aspects Pregnancy Pregnancy Coronary steal Coronary steal Dose dependent in CBF Dose dependent in CBF –Caution with high ICP Hypoxia ( Va/Q mismatch) Hypoxia ( Va/Q mismatch) Requires special delivery system Requires special delivery system Usually requires direct artery pressure monitoring Usually requires direct artery pressure monitoring

86 So Whats New for Emergency Medicine- and Critical Care-Based Therapy of Acute, Severe Blood Pressure Elevations in the Setting of Cardiovascular Disease, Stroke, and Associated Conditions? Acute Pressure Syndromes

87 Clevidipine: The First Third-Generation Calcium Channel Blocker Generic NameBrand Name First Generation NifedipineProcardia ®, Adalat ® Second Generation Nicardipine/Nicardipine I.V. Amlodipine Isradipine Felodipine Nisoldipine Cardene ® /Cardene I.V. Norvasc ® DynaCirc ® Plendil ® Sular ® Third Generation ClevidipineCleviprex Whiting RL, et al. Angiology. 1990;41:

88 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

89 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 in postoperative cardiac surgery patients Linear dose response in postoperative cardiac surgery patients Effective in 95% of patients at 3.2 mcg/kg/min (16 mg/hr) Effective in 95% of patients at 3.2 mcg/kg/min (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 3.2 mcg/kg/min (16 mg/hr) Effective in 95% of patients at 3.2 mcg/kg/min (16 mg/hr) n=19 Infusion Rate (mcg/kg/min) Responders (%) n=0 n=1 n=4 n=6 n=9

90 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. Kerins DM, et al. In: Goodman and Gilmans Pharmacological Basis of Therapeutics. 2001: Massie BM. Am J CardioI. 1997;80:23I-32I. 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

91 Multi-center, Phase III, open-label, single-arm, study to confirm the safety of IV clevidipine for patients who present to the emergency department (ED) or intensive care unit (ICU) with acute, severe hypertension requiring parenteral treatment for at least 18 hours New Dimensions and Advances

92 Presented in part at American College of Emergency Physicians Scientific Assembly, Oct 5, 07: Pollack CV and Peacock WF Presented in part at American College of Chest Physicians Annual Conference, Oct 23, 2007: Varon J Presented in part at American College of Emergency Physicians Scientific Assembly, Oct 5, 07: Pollack CV and Peacock WF Presented in part at American College of Chest Physicians Annual Conference, Oct 23, 2007: Varon J New Dimensions and Advances

93 VELOCITY Rationale Multi-center, Phase III, open-label, single-arm, study to confirm the safety of IV clevidipine for patients with acute hypertension requiring parenteral treatment for at least 18 hours Multi-center, Phase III, open-label, single-arm, study to confirm the safety of IV clevidipine for patients with acute hypertension requiring parenteral treatment for at least 18 hours Phase III safety and efficacy study Phase III safety and efficacy study Evaluation: to confirm the safety and efficacy of clevidipine in patients with acute hypertension using a predefined, non-weight based dosing algorithm Evaluation: to confirm the safety and efficacy of clevidipine in patients with acute hypertension using a predefined, non-weight based dosing algorithm Population: patients with acute hypertension (SBP >180 mmHg or DBP >115 mmHg) assessed at 2 successive occasions 15 min apart at baseline Population: patients with acute hypertension (SBP >180 mmHg or DBP >115 mmHg) assessed at 2 successive occasions 15 min apart at baseline Multi-center, Phase III, open-label, single-arm, study to confirm the safety of IV clevidipine for patients with acute hypertension requiring parenteral treatment for at least 18 hours Multi-center, Phase III, open-label, single-arm, study to confirm the safety of IV clevidipine for patients with acute hypertension requiring parenteral treatment for at least 18 hours Phase III safety and efficacy study Phase III safety and efficacy study Evaluation: to confirm the safety and efficacy of clevidipine in patients with acute hypertension using a predefined, non-weight based dosing algorithm Evaluation: to confirm the safety and efficacy of clevidipine in patients with acute hypertension using a predefined, non-weight based dosing algorithm Population: patients with acute hypertension (SBP >180 mmHg or DBP >115 mmHg) assessed at 2 successive occasions 15 min apart at baseline Population: patients with acute hypertension (SBP >180 mmHg or DBP >115 mmHg) assessed at 2 successive occasions 15 min apart at baseline

94 VELOCITY Objectives Primary Primary Confirm the safety of a titration dosing regimen of an IV infusion of clevidipine for the treatment of acute hypertension Confirm the safety of a titration dosing regimen of an IV infusion of clevidipine for the treatment of acute hypertension Efficacy: Percentage of patients in whom SBP fell within the SBP target range within 30 min of initiating infusion Efficacy: Percentage of patients in whom SBP fell within the SBP target range within 30 min of initiating infusion Safety: Percentage of patients in whom SBP fell below the lower limit of the initial SBP target range within 3 min of initiating infusion 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 Primary Confirm the safety of a titration dosing regimen of an IV infusion of clevidipine for the treatment of acute hypertension Confirm the safety of a titration dosing regimen of an IV infusion of clevidipine for the treatment of acute hypertension Efficacy: Percentage of patients in whom SBP fell within the SBP target range within 30 min of initiating infusion Efficacy: Percentage of patients in whom SBP fell within the SBP target range within 30 min of initiating infusion Safety: Percentage of patients in whom SBP fell below the lower limit of the initial SBP target range within 3 min of initiating infusion Safety: Percentage of patients in whom SBP fell below the lower limit of the initial SBP target range within 3 min of initiating infusion

95 VELOCITY Objectives Secondary Secondary Efficacy: Efficacy: Time to attainment of 30-min SBP target range Time to attainment of 30-min SBP target range Safety: Safety: Change in heart rate during the 30-min period from initiation of infusion Change in heart rate during the 30-min period from initiation of infusion Dose of clevidipine during the treatment period Dose of clevidipine during the treatment period 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 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 Safety of prolonged infusion of clevidipine (18 hr) Safety of prolonged infusion of clevidipine (18 hr) Secondary Secondary Efficacy: Efficacy: Time to attainment of 30-min SBP target range Time to attainment of 30-min SBP target range Safety: Safety: Change in heart rate during the 30-min period from initiation of infusion Change in heart rate during the 30-min period from initiation of infusion Dose of clevidipine during the treatment period Dose of clevidipine during the treatment period 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 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 Safety of prolonged infusion of clevidipine (18 hr) Safety of prolonged infusion of clevidipine (18 hr)

96 VELOCITY Criteria Inclusion Criteria Inclusion Criteria Age 18 years and older Age 18 years and older Systolic BP >180 mmHg and/or diastolic BP >115 mmHg assessed on two successive occasions, 15 minutes apart Systolic BP >180 mmHg and/or diastolic BP >115 mmHg assessed on two successive occasions, 15 minutes apart Provide written informed consent before initiation of any study-related procedures Provide written informed consent before initiation of any study-related procedures Exclusion Criteria Exclusion Criteria SBP 180 mmHg and DBP 115 mmHg SBP 180 mmHg and DBP 115 mmHg Expectation that the patient will not tolerate IV antihypertensive therapy for a minimum of 18 hourz Expectation that the patient will not tolerate IV antihypertensive therapy for a minimum of 18 hourz Known or suspected aortic dissection Known or suspected aortic dissection Inclusion Criteria Inclusion Criteria Age 18 years and older Age 18 years and older Systolic BP >180 mmHg and/or diastolic BP >115 mmHg assessed on two successive occasions, 15 minutes apart Systolic BP >180 mmHg and/or diastolic BP >115 mmHg assessed on two successive occasions, 15 minutes apart Provide written informed consent before initiation of any study-related procedures Provide written informed consent before initiation of any study-related procedures Exclusion Criteria Exclusion Criteria SBP 180 mmHg and DBP 115 mmHg SBP 180 mmHg and DBP 115 mmHg Expectation that the patient will not tolerate IV antihypertensive therapy for a minimum of 18 hourz Expectation that the patient will not tolerate IV antihypertensive therapy for a minimum of 18 hourz Known or suspected aortic dissection Known or suspected aortic dissection

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

98 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

99 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

100 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 ± SDSafety Population, N=126.

101 Medical History, Comorbidity, and End-Organ Dysfunction 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 HBP 31 Congestive heart failure 18 Dyslipidemia37 Smoker Current / Former Current / Former 39 / 21 Diabetes31 Stroke11 Safety Population, N=126.

102 VELOCITY Patient Disposition VELOCITY Patient Disposition DNC=did not complete. mITT Population (patients with SBP >UL of target range) N=117 Total patients enrolled N=131 Safety Population (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

103 VELOCITY Efficacy 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) 10.9 min (95% CI 9.0, 15.0) 10.9 min (95% CI 9.0, 15.0) Median dose rate 4 mg/hr (mean 6 mg/hr) Median dose rate 4 mg/hr (mean 6 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) 10.9 min (95% CI 9.0, 15.0) 10.9 min (95% CI 9.0, 15.0) Median dose rate 4 mg/hr (mean 6 mg/hr) Median dose rate 4 mg/hr (mean 6 mg/hr) mITT population

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

105 VELOCITY K-M Analysis % Minutes Percent of Patients Probability of Having Attained SBP Initial Target Range

106 VELOCITY: Efficacy Results mITT population Time after start of infusion (min.) % Reduction from Baseline SBP (Mean ± SE) % -16.5% -21% Change in BP (30 minutes)

107 VELOCITY: Results 92.9% of patients were administered clevidipine for 18 hours 92.9% of patients were administered clevidipine for 18 hours The infusion rate was maintained or further titrated after 30 min to the desired long-term (18 h) SBP target The infusion rate was maintained or further titrated after 30 min to the desired long-term (18 h) SBP target SBP reduction at 18 hours was -27% (-55 mmHg) from baseline SBP reduction at 18 hours was -27% (-55 mmHg) from baseline Patients were maintained on a steady infusion of clevidipine without evidence of tachyphylaxis or drug accumulation Patients were maintained on a steady infusion of clevidipine without evidence of tachyphylaxis or drug accumulation 92.9% of patients were administered clevidipine for 18 hours 92.9% of patients were administered clevidipine for 18 hours The infusion rate was maintained or further titrated after 30 min to the desired long-term (18 h) SBP target The infusion rate was maintained or further titrated after 30 min to the desired long-term (18 h) SBP target SBP reduction at 18 hours was -27% (-55 mmHg) from baseline SBP reduction at 18 hours was -27% (-55 mmHg) from baseline Patients were maintained on a steady infusion of clevidipine without evidence of tachyphylaxis or drug accumulation Patients were maintained on a steady infusion of clevidipine without evidence of tachyphylaxis or drug accumulation Long-Term Infusion Long-Term Infusion

108 VELOCITY: Efficacy Results Time after start of infusion (hours) % SBP Reduction from Baseline (Mean ± SE) % SBP Reduction from Baseline (Mean ± SE) Additional Titration BP Adjustment and Maintenance 30 min. Titration to ITR Change in BP (18 hours)

109 VELOCITY: Results 92.3% of all patients were maintained on clevidipine monotherapy without the need for additional IV antihypertensive therapy 92.3% of all patients were maintained on clevidipine monotherapy without the need for additional IV antihypertensive therapy Clevidipine was well tolerated for a median duration of 21 hours (max 60 hours) Clevidipine was well tolerated for a median duration of 21 hours (max 60 hours) 118 patients were eligible for transition to oral antihypertensive therapy 118 patients were eligible for transition to oral antihypertensive therapy 97.5% did so to a defined target BP within 6 hours of cessation of clevidipine infusion 97.5% did so to a defined target BP within 6 hours of cessation of clevidipine infusion 92.3% of all patients were maintained on clevidipine monotherapy without the need for additional IV antihypertensive therapy 92.3% of all patients were maintained on clevidipine monotherapy without the need for additional IV antihypertensive therapy Clevidipine was well tolerated for a median duration of 21 hours (max 60 hours) Clevidipine was well tolerated for a median duration of 21 hours (max 60 hours) 118 patients were eligible for transition to oral antihypertensive therapy 118 patients were eligible for transition to oral antihypertensive therapy 97.5% did so to a defined target BP within 6 hours of cessation of clevidipine infusion 97.5% did so to a defined target BP within 6 hours of cessation of clevidipine infusion Long-Term Infusion

110 VELOCITY: Safety Results 2 patients (1.6%) fell below the lower ITR limit within first 3 min. of clevidipine infusion 2 patients (1.6%) fell below the lower ITR limit within first 3 min. of clevidipine infusion One patient had a narrower than specified ITR ( mmHg), SBP was 15 mmHg below the lower limit One patient had a narrower than specified ITR ( mmHg), SBP was 15 mmHg below the lower limit One patient lower limit was 160 mmHg and SBP fell 4 mmHg below this One patient lower limit was 160 mmHg and SBP fell 4 mmHg below this Both patients continued clevidipine infusion beyond 18 hr without AEs Both patients continued clevidipine infusion beyond 18 hr without AEs No clinical hypotensive events related to clevidipine were reported throughout the study No clinical hypotensive events related to clevidipine were reported throughout the study 2 patients (1.6%) fell below the lower ITR limit within first 3 min. of clevidipine infusion 2 patients (1.6%) fell below the lower ITR limit within first 3 min. of clevidipine infusion One patient had a narrower than specified ITR ( mmHg), SBP was 15 mmHg below the lower limit One patient had a narrower than specified ITR ( mmHg), SBP was 15 mmHg below the lower limit One patient lower limit was 160 mmHg and SBP fell 4 mmHg below this One patient lower limit was 160 mmHg and SBP fell 4 mmHg below this Both patients continued clevidipine infusion beyond 18 hr without AEs Both patients continued clevidipine infusion beyond 18 hr without AEs No clinical hypotensive events related to clevidipine were reported throughout the study No clinical hypotensive events related to clevidipine were reported throughout the study mITT population

111 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: 2.4% could not be converted from clevidipine 2.4% could not be converted from clevidipine 3.2% did not reach the 18-hr endpoint for transition eligibility 3.2% did not reach the 18-hr endpoint for transition eligibility 3.2% had contraindications to oral transition 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: 2.4% could not be converted from clevidipine 2.4% could not be converted from clevidipine 3.2% did not reach the 18-hr endpoint for transition eligibility 3.2% did not reach the 18-hr endpoint for transition eligibility 3.2% had contraindications to oral transition 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

112 Conclusions Clevidipine lowered BP to pre-specified target range in ~90% of patients within 30 minutes Clevidipine lowered BP to pre-specified target range in ~90% of patients within 30 minutes Patients reached target BP without overshoot in a median 10.9 minutes Patients reached target BP without overshoot in a median 10.9 minutes Clevidipine was easy to administer and well tolerated Clevidipine was easy to administer and well tolerated Peripheral venous administration Peripheral venous administration BP monitoring via a cuff BP monitoring via a cuff Non-weight based dosing regimen Non-weight based dosing regimen Clevidipine was effective and well tolerated after prolonged infusion and maintained BP in patients with acute and severe hypertension Clevidipine was effective and well tolerated after prolonged infusion and maintained BP in patients with acute and severe hypertension Clevidipine lowered BP to pre-specified target range in ~90% of patients within 30 minutes Clevidipine lowered BP to pre-specified target range in ~90% of patients within 30 minutes Patients reached target BP without overshoot in a median 10.9 minutes Patients reached target BP without overshoot in a median 10.9 minutes Clevidipine was easy to administer and well tolerated Clevidipine was easy to administer and well tolerated Peripheral venous administration Peripheral venous administration BP monitoring via a cuff BP monitoring via a cuff Non-weight based dosing regimen Non-weight based dosing regimen Clevidipine was effective and well tolerated after prolonged infusion and maintained BP in patients with acute and severe hypertension Clevidipine was effective and well tolerated after prolonged infusion and maintained BP in patients with acute and severe hypertension What We Learned From VELOCITY

113 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 Debate over terminology and numerical definitions is too prevalent in the literature Debate over terminology and numerical definitions is too prevalent in the literature Choices among available agents often difficult, and none is ideal across the spectrum Choices among available agents often difficult, and none is ideal across the spectrum Must balance effective reduction with avoidance of over- reduction and its complications 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 Debate over terminology and numerical definitions is too prevalent in the literature Debate over terminology and numerical definitions is too prevalent in the literature Choices among available agents often difficult, and none is ideal across the spectrum Choices among available agents often difficult, and none is ideal across the spectrum Must balance effective reduction with avoidance of over- reduction and its complications Must balance effective reduction with avoidance of over- reduction and its complications

114 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 cardiologists 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 cardiologists approach definitive care in much the same way Clevidipine may soon afford a novel, safe, and multi-setting, multidisciplinary approach to acute severe hypertension Clevidipine may soon afford a novel, safe, and multi-setting, multidisciplinary approach to 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 cardiologists 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 cardiologists approach definitive care in much the same way Clevidipine may soon afford a novel, safe, and multi-setting, multidisciplinary approach to acute severe hypertension Clevidipine may soon afford a novel, safe, and multi-setting, multidisciplinary approach to acute severe hypertension

115 Optimizing Blood Pressure Management in the Perioperative and Cardiothoracic Surgery Setting Relationship and Relevance of Acute Pressure Control and Emerging Agents - The ECLIPSE Trial FACC, FAHA, FACCP, FASE Solomon Aronson, M.D., FACC, FAHA, FACCP, FASE FACC,FCCP,FAHA,FASE Professor and Executive Vice Chairman Dept of Anesthesiology Duke University Health System FACC, FAHA, FACCP, FASE Solomon Aronson, M.D., FACC, FAHA, FACCP, FASE FACC,FCCP,FAHA,FASE Professor and Executive Vice Chairman Dept of Anesthesiology Duke University Health System Investigation Innovation Application

116 A man is as old as his arteries Sir William Osler Investigation Innovation Application

117 The Aging Population Population (in millions) Age (Years) Percent CHF mortality National Health & Nutrition Examination Survey II and

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

119 JNC 7: BP Classification BP level (mmHg)* BP level (mmHg)* Systolic Diastolic < 120 and < or or > 160 or > 100 BP level (mmHg)* BP level (mmHg)* Systolic Diastolic < 120 and < or or > 160 or > 100 CategoryNormalPre-hypertension Stage 1 Hypertension Stage 2 Hypertension * Use higher value for classification

120 BP type Systolic mmHg Diastolic mmHg Optimal< 115&< 75 Optimal< 115&< 75 Pre – HTN< 140&< 90 Pre – HTN< 140&< 90 Isolated DBP HTN 90 Isolated DBP HTN 90 Isolated SBP HTN> 140& 140&< 90 Pulse Pressure HTN> 60 mmHg Pulse Pressure HTN> 60 mmHg Orthostatic changesHyper response > 20 mmHg Hypo response 20 mmHg Hypo response < 20 BP type Systolic mmHg Diastolic mmHg Optimal< 115&< 75 Optimal< 115&< 75 Pre – HTN< 140&< 90 Pre – HTN< 140&< 90 Isolated DBP HTN 90 Isolated DBP HTN 90 Isolated SBP HTN> 140& 140&< 90 Pulse Pressure HTN> 60 mmHg Pulse Pressure HTN> 60 mmHg Orthostatic changesHyper response > 20 mmHg Hypo response 20 mmHg Hypo response < 20 Hypertension

121 Muscle sympathetic nerve activity JACC. 2002;40; White Coat Hypertension Baroreceptor sensitivity * *

122 Chronic HTN HTN Emergencies HTN Emergencies Acute Circulatory Dysfunction Acute Circulatory Dysfunction

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

124 Periop Triggers for Adverse Physiologic State Trauma Anesthesia Stress Hypoxia Fasting Pain Tachycardia Hypo / Hyperthermia Hyper / Hypotension Hyper / Hypoglycemia Anemia / Bleeding / Transfusion Trauma Anesthesia Stress Hypoxia Fasting Pain Tachycardia Hypo / Hyperthermia Hyper / Hypotension Hyper / Hypoglycemia Anemia / Bleeding / Transfusion Inflammatory Hypercoagulable Inflammatory Hypercoagulable

125 Diastolic BP Historically; perioperative risk defined by this index Systolic BP Adverse events > with isolated SBP HTN, than DBP HTN Pulse Pressure Adverse events highest with increased PP

126 Risk of CV Events by Type of HTN Age Adjusted Risk Ratio* Age Adjusted Risk Ratio* yrs yrs yrs yrs Men Women Men Women Men Women Men Women Isolated diastolic Isolated systolic Combined * Reference groups consist of normotensive persons Age Adjusted Risk Ratio* Age Adjusted Risk Ratio* yrs yrs yrs yrs Men Women Men Women Men Women Men Women Isolated diastolic Isolated systolic Combined * Reference groups consist of normotensive persons 36 Year Follow-Up (Framingham Study According to Age & Sex) Am Jour of Card; 85, 2000

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

128 Age Prevalence % Women Men Prevalence of Isolated Systolic Hypertension Circulation 2006;114:2780-7

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

130 Rate /1, yrs 65-94yrs Pulse Pressure (mm Hg) Women Men Women Men Regression Risk factor Rate /1, yrs 65-94yrs Pulse Pressure (mm Hg) Women Men Women Men Regression Risk factor Framingham Study (30 Year Follow-Up) The American Journal of Cardiology Vol 85, January 15, 2000 Pulse Pressure and Cardiac Risk

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

132 Aronson et al; Circulation 115,733-42,2007 PP and Renal RISK INDEX Preoperative Risk FactorsScoreIntraoperative Risk FactorsScore Age > 75 years7> Inotropes10 Pulse Pressure (mm HG)Intra-aortic Balloon Pump Cardiopulmonary Bypass >122 min >10016 History CHF9 MI6 Renal Disease13 Preoperative Risk FactorsScoreIntraoperative Risk FactorsScore Age > 75 years7> Inotropes10 Pulse Pressure (mm HG)Intra-aortic Balloon Pump Cardiopulmonary Bypass >122 min >10016 History CHF9 MI6 Renal Disease13

133 Each 20 mmHg increase PP > 40mmHg additive risk (OR 1.49; CI, (P = 0.001) Each 20 mmHg increase PP > 40mmHg additive risk (OR 1.49; CI, (P = 0.001) PPH > 80 mmHg assoc 3X renal related death (3.7% vs. 1.1%) PPH > 80 mmHg assoc 3X renal related death (3.7% vs. 1.1%) Renal injury doubled if PP > 80mmHg (8.6 % vs. 4.5 %; P = ) renal dysfunction [5 % vs. 3 %; P = renal failure 5.5 % vs. 2.5 %; P = 0.001] Renal injury doubled if PP > 80mmHg (8.6 % vs. 4.5 %; P = ) renal dysfunction [5 % vs. 3 %; P = renal failure 5.5 % vs. 2.5 %; P = 0.001] Renal RISK INDEX Aronson et al; Circulation 115,733-42,2007

134 Fontes, Aronson, Mathew, et al. Analg Anes 2007 Benjo, Thompson, Fine, et al Hypertension 2007 Fontes, Aronson, Mathew, et al. Analg Anes 2007 Benjo, Thompson, Fine, et al Hypertension 2007 Cerebral (5.5 % vs. 2.8 %; P = 0.004) CHF (12.8 % vs. 7.8 %; P = 0.003) Cardiac death (4.7 % vs. 2.4 %; P = 0.001) Cerebral (5.5 % vs. 2.8 %; P = 0.004) CHF (12.8 % vs. 7.8 %; P = 0.003) Cardiac death (4.7 % vs. 2.4 %; P = 0.001) Cardiac & Cerebral RISK and PP Mean PP predicts stroke following card surg 81.2 mmHg v 64.5 mmHg each 10 mmHg additive risk (OR 1.35; CI, ) (P = 0.001) Mean PP predicts stroke following card surg 81.2 mmHg v 64.5 mmHg each 10 mmHg additive risk (OR 1.35; CI, ) (P = 0.001)

135 Blood Pressure Components Steady Component (MAP) Steady Component (MAP) Pulsatile Component (Pulse Pressure) Pulsatile Component (Pulse Pressure) Steady Component (MAP) Steady Component (MAP) Pulsatile Component (Pulse Pressure) Pulsatile Component (Pulse Pressure)

136 Hypertension and Risk The situation ( type of surgery, CHF, stroke, etc.) The patient (Type of HTN) The condition (Treatment effectiveness) The situation ( type of surgery, CHF, stroke, etc.) The patient (Type of HTN) The condition (Treatment effectiveness)

137 The situation (type of surgery) Hypertension and Risk

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

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

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

141 Perioperative BP lability predicts mortality in pts undergoing cardiac surgery 5238 pts 3.1 million BP evaluations (P=0.0139, OR =1.02 per100mmHg.min, 95% CI [ ] SCCM 2008, Hawaii

142 P-ValueOdds Ratio 95% CI [Lower Limit, Upper Limit] Minutes > 135 or < 95 mmHg per incident (min) < Surgery length (min) Parsonnet < Mean Duration of Incursions Minutes <95 mmHg (min) Minutes >135 mmHg (min)

143 Adverse Events & BP Control AUC Quartile All agents* n/N (%) MI1st6/380 (1.6) 4th11/378 (2.9) Stroke1st4/380 (1.1) 4th6/378 (1.6) Renal1st24/380 (6.3) 4th39/378 (10.3) *ECLIPSE clinical trials, N=1512 SBP range of 75 – 145 (pre & post-op), (intra-op) Predictors of postop renal dysfunction Aronson et al ASA 2007 Odds ratio (95% CI)p Preop serum Cr > 1.2 mg/dL4.71 ( ) 1.2 mg/dL4.71 ( )< Race (African American)2.166 ( ) Primary CABG + valve1.957 ( ) BP (4 th quartile AUC*)1.725 ( ) Surgery duration (hours)1.263 ( ) Age (years)1.037 ( ) BMI1.05 ( ) Odds ratio (95% CI)p Preop serum Cr > 1.2 mg/dL4.71 ( ) 1.2 mg/dL4.71 ( )< Race (African American)2.166 ( ) Primary CABG + valve1.957 ( ) BP (4 th quartile AUC*)1.725 ( ) Surgery duration (hours)1.263 ( ) Age (years)1.037 ( ) BMI1.05 ( )0.0042

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

145 The condition (Treatment effectiveness) Hypertension and Risk

146 RESULTS Primary Endpoint Death 30-Day Events (%) n=729n=700n=707n=700n=705n=712n=710n=719 MI Stroke Renal Dysfunction Renal Dysfunction

147 AUC Targeted BP Range by Treatment ECLIPSE NTG ECLIPSE NTG ECLIPSE SNP ECLIPSE SNP ECLIPSE NIC ECLIPSE NIC mm Hg x min/h p = p = p = Clevidipine n=269 NTG n=278 Clevidipine n=295 SNP n=284 Clevidipine n=187 NIC n=194 Median AUC Range = Pre-/post-op SBP , Intra-op SBP Median AUC Range = Pre-/post-op SBP , Intra-op SBP Peri-operativePost-operative Only

148 AUC Narrowed BP Range by Treatment ECLIPSE NTG ECLIPSE SNP ECLIPSE NIC mm Hg x min/h p = p = p = Clevidipine n=269 NTG n=278 Clevidipine n=295 SNP n=284 Clevidipine n=187 NIC n=194 Median AUC Range = Pre-/post-op SBP , Intra-op SBP Peri-operativePost-operative Only

149 SNP or NTG assoc with increased 30d mortality compared to Clevidipine: ECLIPSE Trials Preoperative BP Control p-valueO.R95% CI Treatment CLV v SNP/NTG , 38.4 Additional procedure , 21.2 Pre-op Scr > 1.2mg/dl , 17.8

150 Effects on Central Hemodynamics: Clevidipine Pharmacodynamically Friendly vs. SNP Experiment in anesthetized dogs * p < 0.05 Norlander, M.B, etal. B J Aneasth 1996; * * ** Change from pre-drug (%) The blood pressure reduction caused by clevidipine is due to profound lowering of TPR with associated increased CO, while the effects of SNP results mainly from a reduction in CO, which is due to its venodilatory effect and leads to reduced ventricular filling

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

152 SBP changes for patients receiving clevidipine during a 30-minute treatment period. SBP changes for patients receiving clevidipine during a 30-minute treatment period –5 –10 –15 –20 –25 – % Change From Baseline Time (min) SBP SBP Changes Clevidipine BP-lowering effects are seen within 2–3 min of infusion BP-lowering effects are seen within 2–3 min of infusion Linear dose - response as high as 21.9 mcg/kg/min BP-lowering effects are seen within 2–3 min of infusion BP-lowering effects are seen within 2–3 min of infusion Linear dose - response as high as 21.9 mcg/kg/min Levy JH, et al. Anesth Analg. 2007t;105(4):918. 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: Clevidipine Concentration at Css (nmol/L)* Dose Rate (nmol/kg/min) 2530 Clinically relevant half-life: approx 1 minute Arterial & venous blood samples

153 Clevidipine Rapid Offset After discontinuation of clevidipine infusion, there was rapid clearance After discontinuation of clevidipine infusion, there was rapid clearance BP returned to baseline in <10 minutes in healthy volunteers BP returned to baseline in <10 minutes in healthy volunteers After discontinuation of clevidipine infusion, there was rapid clearance After discontinuation of clevidipine infusion, there was rapid clearance BP returned to baseline in <10 minutes in healthy volunteers BP returned to baseline in <10 minutes in healthy volunteers Reproduced from Ericsson H, et al. Anesthesiology. 2000;92: – MAP (mm Hg) and HR (beats/min) Time (min) 2530 Clevidipine Infusion MAP

154 The patient (Type of HTN) Hypertension and Risk

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

156 J – Curve Hypothesis Lowering DBP (too much) increases risk for coronary events … in pts CAD & wide pulse pressures (> 60 mmHg) 4Farnett et al. JAMA, 265:489-95, 1991

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

158 CAFÉ (conduit artery function evaluation ) Sub-study of ASCOT (Anglo-Scandinavian cardiac outcomes trial)` Circulation 113; , pts (5 centers) 2 regimes atenolol+/- thiazide amlodipine +/- perindopril Central v Brach BP CV, renal outcomes 2199 pts (5 centers) 2 regimes atenolol+/- thiazide amlodipine +/- perindopril Central v Brach BP CV, renal outcomes BP drugs effect central & brachial different Central PP principal determinant in outcomes BP drugs effect central & brachial different Central PP principal determinant in outcomes

159 Ao. Stiffness better predictor of CV mortality than age, BP & cardiac mass Ao. Stiffness better predictor of CV mortality than age, BP & cardiac mass ESRD undergoing dialysis, increased aortic stiffness is major and independent predictor of Mortality ESRD undergoing dialysis, increased aortic stiffness is major and independent predictor of Mortality Am J Cardiol 1987

160 ECLIPSE Trial Summary ECLIPSE Trial Largest safety intravenous anti-htn program (n=1,512) examined management of acute, severe periop htn Largest safety intravenous anti-htn program (n=1,512) examined management of acute, severe periop htn Balanced demographics and baseline characteristics Balanced demographics and baseline characteristics Met primary end points with adverse event rates comparable across groups incd Afib rates Met primary end points with adverse event rates comparable across groups incd Afib rates Better BP control compared with SNP and NTG Better BP control compared with SNP and NTG Largest safety intravenous anti-htn program (n=1,512) examined management of acute, severe periop htn Largest safety intravenous anti-htn program (n=1,512) examined management of acute, severe periop htn Balanced demographics and baseline characteristics Balanced demographics and baseline characteristics Met primary end points with adverse event rates comparable across groups incd Afib rates Met primary end points with adverse event rates comparable across groups incd Afib rates Better BP control compared with SNP and NTG Better BP control compared with SNP and NTG


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