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

Program ChairmanProgram ChairmanJoseph Varon, MD, FACP, FCCP, FCCMJoseph Varon, MD, FACP, FCCP, FCCM

Clinical Professor of MedicineClinical Professor of MedicineThe University of Texas Health Science Center at HoustonThe University of Texas Health Science Center at Houston

Professor, Acute and Continuing CareProfessor, Acute and Continuing CareThe University of Texas Health Science Center at HoustonThe University of Texas Health Science Center at Houston

Clinical Professor of MedicineClinical Professor of MedicineThe University of Texas Medical Branch – GalvestonThe University of Texas Medical Branch – Galveston

Professor of Medicine and SurgeryProfessor of Medicine and SurgeryUAT, UDEM, UPAEP, UABC, UNE MexicoUAT, UDEM, UPAEP, UABC, UNE Mexico






Vascular Dysfunction and Vascular Dysfunction and Acute Pressure Syndromes Acute Pressure Syndromes Vascular Dysfunction and Vascular Dysfunction and Acute Pressure Syndromes Acute Pressure Syndromes

From Threat to Therapy—Optimizing Management of From Threat to Therapy—Optimizing Management of Blood Pressure Across the Cardiovascular Disease Blood Pressure Across the Cardiovascular Disease

Continuum Continuum

From Threat to Therapy—Optimizing Management of From Threat to Therapy—Optimizing Management of Blood Pressure Across the Cardiovascular Disease Blood Pressure Across the Cardiovascular Disease

Continuum Continuum

Investigation Investigation ●● Innovation ● Application Innovation ● Application

CME-accredited symposiumCME-accredited symposium jointly sponsored by the University of jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLCMassachusetts Medical School and CMEducation Resources, LLC

Commercial Support:Commercial Support: Sponsored by an independent educational grant Sponsored by an independent educational grant from The Medicines Companyfrom The Medicines Company

Mission statement:Mission statement: Improve patient care through evidence-based Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management

Processes:Processes: Strives for fair balance, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies

COI:COI: Full faculty disclosures provided in syllabus and at the beginning Full faculty disclosures provided in syllabus and at the beginning of the programof the program

CME-accredited symposiumCME-accredited symposium jointly sponsored by the University of jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLCMassachusetts Medical School and CMEducation Resources, LLC

Commercial Support:Commercial Support: Sponsored by an independent educational grant Sponsored by an independent educational grant from The Medicines Companyfrom The Medicines Company

Mission statement:Mission statement: Improve patient care through evidence-based Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management

Processes:Processes: Strives for fair balance, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies

COI:COI: Full faculty disclosures provided in syllabus and at the beginning Full faculty disclosures provided in syllabus and at the beginning of the programof the program

Welcome and Program OverviewWelcome and Program Overview

Program Educational ObjectivesProgram Educational Objectives

As a result of this educational activity, physicians will: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: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.

Program Educational ObjectivesProgram 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.

Program FacultyProgram FacultyProgram FacultyProgram Faculty

Joseph Varon, MD, FACP, FCCP, FCCMJoseph Varon, MD, FACP, FCCP, FCCMClinical Professor of MedicineClinical Professor of MedicineThe University of Texas Health Science Center at HoustonThe University of Texas Health Science Center at HoustonProfessor, Acute and Continuing CareProfessor, Acute and Continuing CareThe University of Texas Health Science Center at HoustonThe University of Texas Health Science Center at HoustonClinical Professor of MedicineClinical Professor of MedicineThe University of Texas Medical Branch – GalvestonThe University of Texas Medical Branch – GalvestonProfessor of Medicine and SurgeryProfessor of Medicine and SurgeryUAT, UDEM, UPAEP, UABC, UNE MexicoUAT, UDEM, UPAEP, UABC, UNE Mexico

Charles V. Pollack Jr, MA, MD, FACEP, FAAEMChairman, Department of Emergency MedicinePennsylvania HospitalProfessor of Emergency MedicineUniversity of Pennsylvania School of Medicine

Solomon Aronson, MDSolomon Aronson, MDProfessor of AnesthesiologyProfessor of AnesthesiologyExecutive Vice ChairmanExecutive Vice ChairmanDuke University Medical CenterDuke University Medical CenterDurham, NCDurham, NC

Joseph Varon, MD, FACP, FCCP, FCCMJoseph Varon, MD, FACP, FCCP, FCCMClinical Professor of MedicineClinical Professor of MedicineThe University of Texas Health Science Center at HoustonThe University of Texas Health Science Center at HoustonProfessor, Acute and Continuing CareProfessor, Acute and Continuing CareThe University of Texas Health Science Center at HoustonThe University of Texas Health Science Center at HoustonClinical Professor of MedicineClinical Professor of MedicineThe University of Texas Medical Branch – GalvestonThe University of Texas Medical Branch – GalvestonProfessor of Medicine and SurgeryProfessor of Medicine and SurgeryUAT, UDEM, UPAEP, UABC, UNE MexicoUAT, UDEM, UPAEP, UABC, UNE Mexico

Charles V. Pollack Jr, MA, MD, FACEP, FAAEMChairman, Department of Emergency MedicinePennsylvania HospitalProfessor of Emergency MedicineUniversity of Pennsylvania School of Medicine

Solomon Aronson, MDSolomon Aronson, MDProfessor of AnesthesiologyProfessor of AnesthesiologyExecutive Vice ChairmanExecutive Vice ChairmanDuke University Medical CenterDuke University Medical CenterDurham, NCDurham, NC

Faculty COI DisclosuresFaculty COI Disclosures Faculty COI DisclosuresFaculty COI Disclosures

Joseph Varon, MD, FACP, FCCP, FCCMJoseph Varon, MD, FACP, FCCP, FCCMGrant/Research Support: The Medicines Company Consultant: The Medicines Company, ESP/PDL LaboratoriesSpeaker’s Bureau: ESP/PDL Laboratories

Charles V. Pollack Jr, MA, MD, FACEP, FAAEMCharles V. Pollack Jr, MA, MD, FACEP, FAAEMGrant/Research Support: GlaxoSmithKlineConsultant: The Medicines Company., Schering-Plough, Sanofi-Aventis,BMS, Genentech, Speaker’s Bureau: Schering-Plough, Sanofi-Aventis, BMS, Genentech

Solomon Aronson, MDSolomon Aronson, MDGrant/Research Support: AbbottGrant/Research Support: AbbottConsultant: The Medicines CompanyConsultant: The Medicines CompanySpeaker’s Bureau: BaxterSpeaker’s Bureau: BaxterMajor Shareholder: MedwaveMajor Shareholder: Medwave

Joseph Varon, MD, FACP, FCCP, FCCMJoseph Varon, MD, FACP, FCCP, FCCMGrant/Research Support: The Medicines Company Consultant: The Medicines Company, ESP/PDL LaboratoriesSpeaker’s Bureau: ESP/PDL Laboratories

Charles V. Pollack Jr, MA, MD, FACEP, FAAEMCharles V. Pollack Jr, MA, MD, FACEP, FAAEMGrant/Research Support: GlaxoSmithKlineConsultant: The Medicines Company., Schering-Plough, Sanofi-Aventis,BMS, Genentech, Speaker’s Bureau: Schering-Plough, Sanofi-Aventis, BMS, Genentech

Solomon Aronson, MDSolomon Aronson, MDGrant/Research Support: AbbottGrant/Research Support: AbbottConsultant: The Medicines CompanyConsultant: The Medicines CompanySpeaker’s Bureau: BaxterSpeaker’s Bureau: BaxterMajor Shareholder: MedwaveMajor Shareholder: Medwave

Acute Pressure Syndromes — Acute Pressure Syndromes — From Threat to TherapyFrom Threat to Therapy

Characterization, Epidemiology, and Approach to Acute Blood Pressure Characterization, Epidemiology, and Approach to Acute Blood Pressure Elevations Across the Cardiovascular Disease ContinuumElevations Across the Cardiovascular Disease Continuum

Giving “Acute Hypertension the Hyperattention” it DeservesGiving “Acute Hypertension the Hyperattention” it Deserves

Acute Pressure Syndromes — Acute Pressure Syndromes — From Threat to TherapyFrom Threat to Therapy

Characterization, Epidemiology, and Approach to Acute Blood Pressure Characterization, Epidemiology, and Approach to Acute Blood Pressure Elevations Across the Cardiovascular Disease ContinuumElevations Across the Cardiovascular Disease Continuum

Giving “Acute Hypertension the Hyperattention” it DeservesGiving “Acute Hypertension the Hyperattention” it Deserves

Investigation Investigation ●● Innovation Innovation ●● Application ApplicationInvestigation Investigation ●● Innovation Innovation ●● Application Application











J Varon ACCP Oct 2007F Peacock ACEP Oct 2007J Varon ACCP Oct 2007

F Peacock ACEP Oct 2007S Aronson ACC 2007S Aronson ACC 2007


Severe HypertensionSevere Hypertension

► CommonCommon

► Deadly and disablingDeadly and disabling

► Poorly studiedPoorly studied

► Poorly managedPoorly managed

► Evidence that speed and degree of Evidence that speed and degree of control relate to outcomecontrol relate to outcome

► Needs more attentionNeeds more attention

► Observed across multiple settingsObserved across multiple settings

► CommonCommon

► Deadly and disablingDeadly and disabling

► Poorly studiedPoorly studied

► Poorly managedPoorly managed

► Evidence that speed and degree of Evidence that speed and degree of control relate to outcomecontrol relate to outcome

► Needs more attentionNeeds more attention

► Observed across multiple settingsObserved across multiple settings

Prevalence of high blood pressure in adultsPrevalence of high blood pressure in adultsby age and sexby age and sex

Prevalence of high blood pressure in adultsPrevalence of high blood pressure in adultsby age and sexby age and sex

11.2

37.4

55.4

73.9

23.2

37.5

49.1

63.669.5

6.4

83.8

18.3

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

20-34 35-44 45-54 55-64 65-74 75+

Per

cent

of P

opul

atio

n

Men Women

Prevalence of HypertensionPrevalence of Hypertension

NHANES: 1999-2004. Source: NCHS and NHLBI.

Extent of awareness, treatment and control of Extent of awareness, treatment and control of high blood pressure by age high blood pressure by age

Extent of awareness, treatment and control of Extent of awareness, treatment and control of high blood pressure by age high blood pressure by age

52.3

35.8

24.6

62.5

39.8

68.474.6

34.3

75.3

01020304050607080

Awareness Treatment Controlled

Pe

rce

nt

of

Po

pu

lati

on

20-39 40-59 60+

NHANES: 1999-2004. Source: NCHS and NHLBI.

Hypertension: Awareness and ControlHypertension: Awareness and Control

► 5,026 emergency departments5,026 emergency departments

► 113.9 million visits in 2003113.9 million visits in 2003

► Presentation with severe hypertension in up to Presentation with severe hypertension in up to 25% of patients in busy urban EDs25% of patients in busy urban EDs

► 5,026 emergency departments5,026 emergency departments

► 113.9 million visits in 2003113.9 million visits in 2003

► Presentation with severe hypertension in up to Presentation with severe hypertension in up to 25% of patients in busy urban EDs25% of patients in busy urban EDs

Sullivan AF. Acad Emerg Med 2004;11:454; IOM Emergency Medical Care Report 2006.

Emergency Care of SevereEmergency Care of SevereBlood Pressure ElevationBlood Pressure Elevation

Short-Term (2 to 6 month) OutcomesShort-Term (2 to 6 month) Outcomes

Acute ConditionAcute Condition DeathDeath RehospitalizationRehospitalization

Acute ConditionAcute Condition DeathDeath RehospitalizationRehospitalization

1. OASIS-5 NEJM 2006. 2. GUSTO IIb NEJM 1996.3. GRACE JAMA 2007.4. IMPACT-HF J Cardiac Failure 2004.5. Cline DM. Acad Emerg Med 2006.

ACSACS1,2,31,2,3 5-7% 5-7% 30% 30%

CHFCHF44 8.5% 8.5% 26% 26%

Severe HypertensionSevere Hypertension55 5-6% 5-6% 30% 30%

ACSACS1,2,31,2,3 5-7% 5-7% 30% 30%

CHFCHF44 8.5% 8.5% 26% 26%

Severe HypertensionSevere Hypertension55 5-6% 5-6% 30% 30%

Terminology and DefinitionsTerminology and Definitions


► JNC VII >JNC VII > 180/110 180/110


► JNC VII >JNC VII > 180/110 180/110End-organ DamageEnd-organ Damage

► CHFCHF

► ACS/AMIACS/AMI

► Renal failureRenal failure

► Stroke and ICHStroke and ICH

► EncephalopathyEncephalopathy

► Aortic dissectionAortic dissection

► Pre-eclampsiaPre-eclampsia

► Other?Other?

End-organ DamageEnd-organ Damage

► CHFCHF

► ACS/AMIACS/AMI

► Renal failureRenal failure

► Stroke and ICHStroke and ICH

► EncephalopathyEncephalopathy

► Aortic dissectionAortic dissection

► Pre-eclampsiaPre-eclampsia

► Other?Other?

plus

UrgencyUrgencyUrgencyUrgency EmergencyEmergency EmergencyEmergency

Severe Hypertension, End-Organ Damage, Severe Hypertension, End-Organ Damage, and Comorbiditiesand Comorbidities

AorticDissection

Stroke,Enceph-alopathy

Renal dysfunction

MI

CHFPulm Edema

SevereHTN

ICHPre-eclampsiaPeri-operative

Spectrum of End-Organ DamageSpectrum of End-Organ Damage

End-Organ Damage Type No. of Cases (%)End-Organ Damage Type No. of Cases (%)

Cerebral infarction Cerebral infarction 26 26 (24.5) (24.5) ICH or SAH ICH or SAH 5 5 (4.5) (4.5)

EncephalopathyEncephalopathy 18 18 (16.3) (16.3)

Acute Pulmonary EdemaAcute Pulmonary Edema 24 24 (22.5) (22.5)Acute CHF Acute CHF 15 15 (14.3) (14.3)Acute MIAcute MI 13 13 (12.0) (12.0)

Aortic DissectionAortic Dissection 2 2 (2.0) (2.0)

EclampsiaEclampsia 5 5 (4.5) (4.5)

End-Organ Damage Type No. of Cases (%)End-Organ Damage Type No. of Cases (%)

Cerebral infarction Cerebral infarction 26 26 (24.5) (24.5) ICH or SAH ICH or SAH 5 5 (4.5) (4.5)

EncephalopathyEncephalopathy 18 18 (16.3) (16.3)

Acute Pulmonary EdemaAcute Pulmonary Edema 24 24 (22.5) (22.5)Acute CHF Acute CHF 15 15 (14.3) (14.3)Acute MIAcute MI 13 13 (12.0) (12.0)

Aortic DissectionAortic Dissection 2 2 (2.0) (2.0)

EclampsiaEclampsia 5 5 (4.5) (4.5)

Zampaglione, B. Hypertension 1996;27:144-147.

341 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*All Caucasians

Acute Severe Hypertension Acute Severe Hypertension Epidemiology and MortalityEpidemiology and Mortality

► 1939: First study of the natural 1939: First study of the natural history of hypertensive history of hypertensive emergencies publishedemergencies published

• • Untreated hypertensive emergencies Untreated hypertensive emergencies had a 1-year mortality rate of 79%, had a 1-year mortality rate of 79%, with median survival of 10.5 monthswith median survival of 10.5 months

► 1939: First study of the natural 1939: First study of the natural history of hypertensive history of hypertensive emergencies publishedemergencies published

• • Untreated hypertensive emergencies Untreated hypertensive emergencies had a 1-year mortality rate of 79%, had a 1-year mortality rate of 79%, with median survival of 10.5 monthswith median survival of 10.5 months

Varon J. CHEST 2007; 131:1949–1962.

Risk FactorsRisk Factors

► History of History of hypertensionhypertension

► African AmericansAfrican Americans

► ElderlyElderly

► MenMen

► NoncomplianceNoncompliance

Risk FactorsRisk Factors

► History of History of hypertensionhypertension

► African AmericansAfrican Americans

► ElderlyElderly

► MenMen

► NoncomplianceNoncompliance

Historical StudyHistorical Study

Sokolow & Perloff. Circulation 1961;23:697-713.

100100

8080

6060

4040

2020

00

100100

8080

6060

4040

2020

00

439 patients total439 patients total439 patients total439 patients total

CumulativeCumulative% Mortality% MortalityCumulativeCumulative% Mortality% Mortality

1 2 3 4 51 2 3 4 5Time in YearsTime in YearsTime in YearsTime in Years

BP I – 150-200/90-110BP I – 150-200/90-110BP II – 200-250/110-130BP II – 200-250/110-130BP III – Over 250/130BP III – Over 250/130

BP I – 150-200/90-110BP I – 150-200/90-110BP II – 200-250/110-130BP II – 200-250/110-130BP III – Over 250/130BP III – Over 250/130

BP IIIBP IIIBP IIIBP III

BP IIBP II

BP IBP I

38%38%38%38%

18%18%18%18%

8%8%8%8%

Mortality and Severe HypertensionMortality and Severe Hypertension

Hypertensive Urgency or EmergencyHypertensive Urgency or Emergency

► Total Total 865865

► Reviews Reviews 190190

► Randomized Randomized

Clinical Trials Clinical Trials 4646

► Total Total 865865

► Reviews Reviews 190190

► Randomized Randomized

Clinical Trials Clinical Trials 4646

ACSACS

55,35355,353

3,5183,518

HU or HEHU or HE

An Evaluation of Pharmacotherapeutic An Evaluation of Pharmacotherapeutic Regimens — Inadequately StudiedRegimens — Inadequately Studied

Medline 1966-2001Medline 1966-2001References from aboveReferences from aboveExperts contactedExperts contactedCochrane Library checkedCochrane Library checked

Randomized controlled trialsRandomized controlled trialsSystematic review of cohort studiesSystematic review of cohort studiesIndividual cohort studyIndividual cohort studyOutcome ResearchOutcome Research

600 Studies600 StudiesIdentifiedIdentified

ExcludedExcludedNon-HumanNon-HumanBlood pressures too lowBlood pressures too lowSafety or Tolerability studiesSafety or Tolerability studiesCase Series or Case ReportsCase Series or Case Reports

39 Studies39 Studies

Excluded Excluded ► Did not include a target BP & Did not include a target BP &

thus could not do comparisonsthus could not do comparisons► Methodologic FlawsMethodologic Flaws

19 Studies Remained 19 Studies Remained (8 were Open label or Not blinded)(8 were Open label or Not blinded)Only 4 HTN Emergency (236 patients)Only 4 HTN Emergency (236 patients)Only 15 HTN Urgency (1074 patients)Only 15 HTN Urgency (1074 patients)

19 Studies Remained 19 Studies Remained (8 were Open label or Not blinded)(8 were Open label or Not blinded)Only 4 HTN Emergency (236 patients)Only 4 HTN Emergency (236 patients)Only 15 HTN Urgency (1074 patients)Only 15 HTN Urgency (1074 patients)

J Gen Intern Med 2002;17:937-945.

► Definitions and DistinctionsDefinitions and Distinctions● Emergencies always included “end organ damage” Emergencies always included “end organ damage” ● Urgencies “without”end organ involvementUrgencies “without”end organ involvement

► Emergency – Could NOT determine:Emergency – Could NOT determine:● Optimal rate to Optimal rate to BP BP ● Mortality benefitMortality 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 How quickly should BP BP● The timing to begin maintenance therapyThe timing to begin maintenance therapy● If observation is needed during treatmentIf observation is needed during treatment

► Definitions and DistinctionsDefinitions and Distinctions● Emergencies always included “end organ damage” Emergencies always included “end organ damage” ● Urgencies “without”end organ involvementUrgencies “without”end organ involvement

► Emergency – Could NOT determine:Emergency – Could NOT determine:● Optimal rate to Optimal rate to BP BP ● Mortality benefitMortality 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 How quickly should BP BP● The timing to begin maintenance therapyThe timing to begin maintenance therapy● If observation is needed during treatmentIf observation is needed during treatment

An Evaluation of Pharmacotherapeutic An Evaluation of Pharmacotherapeutic Regimens — Questions UnansweredRegimens — Questions Unanswered

J Gen Intern Med 2002;17:937-945.

U.S. Departmentof Health and

Human Services

NationalInstitutes of Health

National Heart, Lung, and Blood

Institute

The Seventh Report of the The Seventh Report of the Joint National Committee onJoint National Committee onPrevention, Detection, Prevention, Detection, Evaluation, and Treatment of High Evaluation, and Treatment of High Blood Pressure (JNC 7)Blood Pressure (JNC 7)

The Seventh Report of the The Seventh Report of the Joint National Committee onJoint National Committee onPrevention, Detection, Prevention, Detection, Evaluation, and Treatment of High Evaluation, and Treatment of High Blood Pressure (JNC 7)Blood Pressure (JNC 7)

National Initiatives — HypertensionNational Initiatives — Hypertension

Hypertension. 2003;42:1206–1252.

National Heart, Lung, and Blood InstituteNational Heart, Lung, and Blood InstituteNational High Blood Pressure Education ProgramNational High Blood Pressure Education ProgramNational Heart, Lung, and Blood InstituteNational Heart, Lung, and Blood Institute

National High Blood Pressure Education ProgramNational High Blood Pressure Education Program

Hypertensive Urgencies Hypertensive Urgencies and Emergenciesand Emergencies

Hypertensive Urgencies Hypertensive Urgencies and Emergenciesand Emergencies

STAT — Inclusion CriteriaSTAT — Inclusion Criteria

► >18 years of age>18 years of age

► Presenting to the hospital with acute severe Presenting to the hospital with acute severe HTNHTN

► Treated in a critical care settingTreated in a critical care setting

► Acute severe HTN treated with anAcute severe HTN treated with anIV agentIV agent

► Severe hypertensionSevere hypertension● At least one SBP >180 mmHg and/orAt least one SBP >180 mmHg and/or● At least one DBP >110 mmHgAt least one DBP >110 mmHg

► SAH patients with SBP >140 and/or DBP >90SAH patients with SBP >140 and/or DBP >90

► >18 years of age>18 years of age

► Presenting to the hospital with acute severe Presenting to the hospital with acute severe HTNHTN

► Treated in a critical care settingTreated in a critical care setting

► Acute severe HTN treated with anAcute severe HTN treated with anIV agentIV agent

► Severe hypertensionSevere hypertension● At least one SBP >180 mmHg and/orAt least one SBP >180 mmHg and/or● At least one DBP >110 mmHgAt least one DBP >110 mmHg

► SAH patients with SBP >140 and/or DBP >90SAH patients with SBP >140 and/or DBP >90

The GoalThe GoalThe GoalThe Goal

Improve understanding of clinical conditions Improve understanding of clinical conditions characterized by acute severe hypertension, characterized by acute severe hypertension,

managed in a critical care setting, and treated managed in a critical care setting, and treated with IV antihypertensive drugswith IV antihypertensive drugs

Improve understanding of clinical conditions Improve understanding of clinical conditions characterized by acute severe hypertension, characterized by acute severe hypertension,

managed in a critical care setting, and treated managed in a critical care setting, and treated with IV antihypertensive drugswith IV antihypertensive drugs

A New Registry to Study Conditions and IV Treatment of Severe Hypertension

A New Registry to Study Conditions and IV Treatment of Severe Hypertension

Primary Objectives of Registry Primary Objectives of Registry

► Describe patient characteristics:Describe patient characteristics:Who are these patients?Who are these patients?

► Describe contemporary practice:Describe contemporary practice:How are they treated?How are they treated?

● Timing of initiating IV treatmentTiming of initiating IV treatment● Medications used (IV and oral transition)Medications used (IV and oral transition)● Control of BPControl of BP● Time to achieve controlTime to achieve control

► Describe in-hospital patient outcomesDescribe in-hospital patient outcomes::How do they fare?How do they fare?

► Link practice and patient variations with Link practice and patient variations with outcome: outcome: How does management relate to outcome?How does management relate to outcome?

► Describe patient characteristics:Describe patient characteristics:Who are these patients?Who are these patients?

► Describe contemporary practice:Describe contemporary practice:How are they treated?How are they treated?

● Timing of initiating IV treatmentTiming of initiating IV treatment● Medications used (IV and oral transition)Medications used (IV and oral transition)● Control of BPControl of BP● Time to achieve controlTime to achieve control

► Describe in-hospital patient outcomesDescribe in-hospital patient outcomes::How do they fare?How do they fare?

► Link practice and patient variations with Link practice and patient variations with outcome: outcome: How does management relate to outcome?How does management relate to outcome?

► DiagnosisDiagnosis● Clarify the definition of “end organ dysfunction”Clarify the definition of “end organ dysfunction”● Differentiate those whose end organ dysfunctionDifferentiate those whose end organ dysfunction

is acute and due to the severe hypertension from those with is acute and due to the severe hypertension from those with chronic dysfunctionchronic dysfunction

● Gain insight into what measurements matter most and have Gain insight into what measurements matter most and have most predictive value on outcomes: (1most predictive value on outcomes: (1stst BP, highest BP) BP, highest BP)

► TreatmentTreatment● How fast to How fast to BP? BP?● How much to How much to BP? 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 Does the speed and degree of BP change and the agent used

depend upon which end organ is dysfunctional?depend upon which end organ is dysfunctional?

► DiagnosisDiagnosis● Clarify the definition of “end organ dysfunction”Clarify the definition of “end organ dysfunction”● Differentiate those whose end organ dysfunctionDifferentiate those whose end organ dysfunction

is acute and due to the severe hypertension from those with is acute and due to the severe hypertension from those with chronic dysfunctionchronic dysfunction

● Gain insight into what measurements matter most and have Gain insight into what measurements matter most and have most predictive value on outcomes: (1most predictive value on outcomes: (1stst BP, highest BP) BP, highest BP)

► TreatmentTreatment● How fast to How fast to BP? BP?● How much to How much to BP? 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 Does the speed and degree of BP change and the agent used

depend upon which end organ is dysfunctional?depend upon which end organ is dysfunctional?

Questions Addressed by RegistryQuestions Addressed by Registry

Summary of Acute Pressure Syndromes Summary of Acute Pressure Syndromes — An Evolving Landscape— An Evolving Landscape

► Major public health concernMajor public health concern● Huge resources used in ED aloneHuge resources used in ED alone● Mortality and morbidity similar to ACS, CHFMortality and morbidity similar to ACS, CHF● Paucity of careful study of nature of problemPaucity of careful study of nature of problem

► Best management is unclearBest management is unclear● Little knowledge of what treatment goals Little knowledge of what treatment goals

should be and how control relates to should be and how control relates to outcomeoutcome

● Opportunity to improve outcome with better Opportunity to improve outcome with better follow-up care and focus on adherencefollow-up care and focus on adherence

► Needs more attention!Needs more attention!

► Major public health concernMajor public health concern● Huge resources used in ED aloneHuge resources used in ED alone● Mortality and morbidity similar to ACS, CHFMortality and morbidity similar to ACS, CHF● Paucity of careful study of nature of problemPaucity of careful study of nature of problem

► Best management is unclearBest management is unclear● Little knowledge of what treatment goals Little knowledge of what treatment goals

should be and how control relates to should be and how control relates to outcomeoutcome

● Opportunity to improve outcome with better Opportunity to improve outcome with better follow-up care and focus on adherencefollow-up care and focus on adherence

► Needs more attention!Needs more attention!

Hypertensive UrgenciesHypertensive Urgenciesand Emergencies:and Emergencies:

The Current Challenge for The Current Challenge for Emergency PhysiciansEmergency Physicians

Hypertensive UrgenciesHypertensive Urgenciesand Emergencies:and Emergencies:

The Current Challenge for The Current Challenge for Emergency PhysiciansEmergency Physicians

Charles V. Pollack, Jr., M.A., M.D., FACEP, FAHACharles V. Pollack, Jr., M.A., M.D., FACEP, FAHAChairman, Emergency MedicineChairman, Emergency Medicine

Pennsylvania HospitalPennsylvania HospitalProfessor of Emergency MedicineProfessor of Emergency Medicine

University of PennsylvaniaUniversity of PennsylvaniaPhiladelphiaPhiladelphia

Charles V. Pollack, Jr., M.A., M.D., FACEP, FAHACharles V. Pollack, Jr., M.A., M.D., FACEP, FAHAChairman, Emergency MedicineChairman, Emergency Medicine

Pennsylvania HospitalPennsylvania HospitalProfessor of Emergency MedicineProfessor of Emergency Medicine

University of PennsylvaniaUniversity of PennsylvaniaPhiladelphiaPhiladelphia

Investigation Investigation ●● Innovation ● Application Innovation ● Application

Hypertensive Urgencies and EmergenciesHypertensive Urgencies and Emergencies

► Epidemiologic data are largely lackingEpidemiologic data are largely lacking

► It is thought that ~ 1% of patients with htn will It is thought that ~ 1% of patients with htn will eventually present to the ED in hypertensive crisiseventually present to the ED in hypertensive crisis

► In a single-center Italian study, HU or HE In a single-center Italian study, HU or HE accounted for 3% of all medicine admissions and accounted for 3% of all medicine admissions and 27.5% of all medical emergencies27.5% of all medical emergencies● HU:HE 3:1 in that studyHU:HE 3:1 in that study● Patients with HU much more likely to be unaware of their Patients with HU much more likely to be unaware of their

htn dx than those with HEhtn dx than those with HE



► In a single-center Italian study, HU or HE In a single-center Italian study, HU or HE accounted for 3% of all medicine admissions and accounted for 3% of all medicine admissions and 27.5% of all medical emergencies27.5% of all medical emergencies● HU:HE 3:1 in that studyHU:HE 3:1 in that study● Patients with HU much more likely to be unaware of their Patients with HU much more likely to be unaware of their


Zampaglione et al, Hypertension 1996;27:144Zampaglione et al, Hypertension 1996;27:144

Presenting SymptomsPresenting Symptoms

► Hypertensive UrgenciesHypertensive Urgencies● ArrhythmiaArrhythmia● EpistaxisEpistaxis● HeadacheHeadache● Psychomotor agitationPsychomotor agitation

► Usual Primary ED Usual Primary ED DiagnosisDiagnosis● HypertensionHypertension



► Hypertensive EmergenciesHypertensive Emergencies● Chest painChest pain● DyspneaDyspnea● Neurologic deficitsNeurologic deficits

► Usual Primary ED Usual Primary ED DiagnosisDiagnosis● CVACVA● APEAPE● Hypertensive Hypertensive

encephalopathyencephalopathy● Acute heart failureAcute heart failure


► Usual Primary ED Usual Primary ED DiagnosisDiagnosis● CVACVA● APEAPE● Hypertensive Hypertensive


Zampaglione et al, Hypertension 1996;27:144Zampaglione et al, Hypertension 1996;27:144

JNC 7 NomenclatureJNC 7 Nomenclature

► Normal BP: S < 120, D < 80Normal BP: S < 120, D < 80

► Prehypertension: S 120-139, D 80-89Prehypertension: S 120-139, D 80-89

► Stage 1 hypertension: S 140-159, D 90-99Stage 1 hypertension: S 140-159, D 90-99

► Stage 2 hypertension: S Stage 2 hypertension: S >> 160, D 160, D >> 100 100

► Stage 3 hypertension (JNC 6):Stage 3 hypertension (JNC 6):● S > 180, D > 110S > 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 < 80Normal BP: S < 120, D < 80

► Prehypertension: S 120-139, D 80-89Prehypertension: S 120-139, D 80-89

► Stage 1 hypertension: S 140-159, D 90-99Stage 1 hypertension: S 140-159, D 90-99

► Stage 2 hypertension: S Stage 2 hypertension: S >> 160, D 160, D >> 100 100

► Stage 3 hypertension (JNC 6):Stage 3 hypertension (JNC 6):● S > 180, D > 110S > 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; 289:2560-2572JNC 7, JAMA 2003; 289:2560-2572

JNC 7 NomenclatureJNC 7 Nomenclature

► Using JNC 7 nomenclature, “hypertensive crisis” is Using JNC 7 nomenclature, “hypertensive crisis” is an acute, severe, stage 2 elevation in blood an acute, severe, stage 2 elevation in blood pressurepressure

► Crisis is then differentiated into hypertensive Crisis is then differentiated into hypertensive “emergencies” (involving some end-organ damage) “emergencies” (involving some end-organ damage) and “urgencies” (no end-organ damageand “urgencies” (no end-organ damage

► Using JNC 7 nomenclature, “hypertensive crisis” is Using JNC 7 nomenclature, “hypertensive crisis” is an acute, severe, stage 2 elevation in blood an acute, severe, stage 2 elevation in blood pressurepressure

► Crisis is then differentiated into hypertensive Crisis is then differentiated into hypertensive “emergencies” (involving some end-organ damage) “emergencies” (involving some end-organ damage) and “urgencies” (no end-organ damageand “urgencies” (no end-organ damage

JNC 7, JAMA 2003; 289:2560-2572JNC 7, JAMA 2003; 289:2560-2572

““End-Organ Damage”End-Organ Damage”

► CardiopulmonaryCardiopulmonary● Acute heart failureAcute heart failure● Acute coronary syndromeAcute coronary syndrome● Acute pulmonary edema with respiratory failureAcute pulmonary edema with respiratory failure● Dissecting aortaDissecting aorta

► CNSCNS● Hypertensive encephalopathyHypertensive encephalopathy● CVACVA

► OcularOcular● ExudatesExudates● PapilledemaPapilledema● Retinal hemorrhagesRetinal hemorrhages

► RenalRenal● Acute renal failureAcute renal failure




► RenalRenal● Acute renal failureAcute renal failure JNC 7, JAMA 2003; 289:2560-2572JNC 7, JAMA 2003; 289:2560-2572

Causes of Hypertensive CrisesCauses of Hypertensive Crises

► Essential hypertensionEssential hypertension● Medication noncomplianceMedication noncompliance

► Secondary hypertensionSecondary hypertension● Aortic coarctationAortic coarctation● Cushing’s syndromeCushing’s syndrome● Elevated ICPElevated ICP● Renal dysfunctionRenal dysfunction● Pregnancy Pregnancy ● HyperparathyroidismHyperparathyroidism● HyperthyroidismHyperthyroidism● PheochromocytomaPheochromocytoma● Primary aldosteronismPrimary aldosteronism

► Essential hypertensionEssential hypertension● Medication noncomplianceMedication noncompliance

► Secondary hypertensionSecondary hypertension● Aortic coarctationAortic coarctation● Cushing’s syndromeCushing’s syndrome● Elevated ICPElevated ICP● Renal dysfunctionRenal dysfunction● Pregnancy Pregnancy ● HyperparathyroidismHyperparathyroidism● HyperthyroidismHyperthyroidism● PheochromocytomaPheochromocytoma● Primary aldosteronismPrimary aldosteronism

JNC 7, JAMA 2003; 289:2560-2572JNC 7, JAMA 2003; 289:2560-2572

Goals of ED Tx of Hypertensive CrisesGoals of ED Tx of Hypertensive Crises

► HU can generally be managed with oral HU can generally be managed with oral medications and requires BP lowering over 24-48 medications and requires BP lowering over 24-48 hourshours

● Important to prevent too-rapid lowering due to autoregulation of Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneysflow by pressure in brain, heart, and kidneys

► Goal in HE is to reduce MAP by 10-15% and/or to a Goal in HE is to reduce MAP by 10-15% and/or to a DBP of 110 . . . within one hourDBP of 110 . . . within one hour

● Aortic dissection requires even more rapid loweringAortic dissection requires even more rapid lowering● Once initial reduction achieved, transition to oral agentsOnce initial reduction achieved, transition to oral agents● Dug of choice for initial therapy often depends on which end-Dug of choice for initial therapy often depends on which end-

organ system is affected and on comorbiditiesorgan system is affected and on comorbidities

► HU can generally be managed with oral HU can generally be managed with oral medications and requires BP lowering over 24-48 medications and requires BP lowering over 24-48 hourshours

● Important to prevent too-rapid lowering due to autoregulation of Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneysflow by pressure in brain, heart, and kidneys

► Goal in HE is to reduce MAP by 10-15% and/or to a Goal in HE is to reduce MAP by 10-15% and/or to a DBP of 110 . . . within one hourDBP of 110 . . . within one hour

● Aortic dissection requires even more rapid loweringAortic dissection requires even more rapid lowering● Once initial reduction achieved, transition to oral agentsOnce initial reduction achieved, transition to oral agents● Dug of choice for initial therapy often depends on which end-Dug of choice for initial therapy often depends on which end-

organ system is affected and on comorbiditiesorgan system is affected and on comorbidities

JNC 7, JAMA 2003; 289:2560-2572JNC 7, JAMA 2003; 289:2560-2572

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

CategoryCategory FrequencyFrequency► Emergencies Emergencies 1 cerebral and 1 cardiac/shift)1 cerebral and 1 cardiac/shift)

► Urgencies Urgencies ????????????

► Mild, uncomplicated Mild, uncomplicated 1/shift1/shift

► TransientTransient Who cares?Who cares?

CategoryCategory FrequencyFrequency► Emergencies Emergencies 1 cerebral and 1 cardiac/shift)1 cerebral and 1 cardiac/shift)

► Urgencies Urgencies ????????????

► Mild, uncomplicated Mild, uncomplicated 1/shift1/shift

► TransientTransient Who cares?Who cares?

CVACVA

► > 75% of acute CVA patients present with SBP > > 75% of acute CVA patients present with SBP > 140, and cerebral autoregulation may be disturbed, 140, and cerebral autoregulation may be disturbed, resulting in increased ICPresulting in increased ICP

► There appears to be a U-curve relationship between There appears to be a U-curve relationship between BP and neurologic outcomesBP and neurologic outcomes

● ↓ ↓ of SBP of 10 below 180 is associated with 25% ↑d risk of poor 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 neuro outcomes; ↑ of 10 above 180 is associated with a 40% ↑ in early neuro deterioration and a 23% ↑d risk of poor outcomeearly neuro deterioration and a 23% ↑d risk of poor outcome

● Based on this finding, the usual recommendation is to try to Based on this finding, the usual recommendation is to try to maintain SBP in 150-180 range and not attempt to “normalize”maintain SBP in 150-180 range and not attempt to “normalize”

► > 75% of acute CVA patients present with SBP > > 75% of acute CVA patients present with SBP > 140, and cerebral autoregulation may be disturbed, 140, and cerebral autoregulation may be disturbed, resulting in increased ICPresulting in increased ICP

► There appears to be a U-curve relationship between There appears to be a U-curve relationship between BP and neurologic outcomesBP and neurologic outcomes

● ↓ ↓ of SBP of 10 below 180 is associated with 25% ↑d risk of poor 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 neuro outcomes; ↑ of 10 above 180 is associated with a 40% ↑ in early neuro deterioration and a 23% ↑d risk of poor outcomeearly neuro deterioration and a 23% ↑d risk of poor outcome

● Based on this finding, the usual recommendation is to try to Based on this finding, the usual recommendation is to try to maintain SBP in 150-180 range and not attempt to “normalize”maintain SBP in 150-180 range and not attempt to “normalize”

Adams et al, Stroke 2003; 34:1056-83Adams et al, Stroke 2003; 34:1056-83

Autoregulation of Cerebral Blood Flow Autoregulation of Cerebral Blood Flow is Affected by Hypertensionis Affected by Hypertension

100 200

Normotensive

Poorly controlledhypertensive

Mean Arterial Pressure (MAP)

Cerebral Blood FlowCerebral Blood FlowCerebral Blood FlowCerebral Blood Flow

Risk of hypertensive

encephalopathy

Risk of ischemia

50 150 250

Loss of AutoregulationLoss of Autoregulation

Adapted with permission from Varon J, Marik PE. Chest. 2000;118:214-227.

CVACVA

► American Stroke Association guidelines (2003):American Stroke Association guidelines (2003):● No treatment of S < 220 or D < 120 unless end-organ No treatment of S < 220 or D < 120 unless end-organ

damagedamage● If end-organ damage or S > 220 or DBP 121-140, labetolol If end-organ damage or S > 220 or DBP 121-140, labetolol

or nicardipine is recommendedor nicardipine is recommended● If D > 140, NTP recommended, with caution that If D > 140, NTP recommended, with caution that ↑CBF may ↑CBF may

lead to ↑ICPlead to ↑ICP● If considering lytic treatment, labetolol should be started if If considering lytic treatment, labetolol should be started if

S > 185 or D > 110S > 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 No treatment of S < 220 or D < 120 unless end-organ

damagedamage● If end-organ damage or S > 220 or DBP 121-140, labetolol If end-organ damage or S > 220 or DBP 121-140, labetolol

or nicardipine is recommendedor nicardipine is recommended● If D > 140, NTP recommended, with caution that If D > 140, NTP recommended, with caution that ↑CBF may ↑CBF may

lead to ↑ICPlead to ↑ICP● If considering lytic treatment, labetolol should be started if If considering lytic treatment, labetolol should be started if

S > 185 or D > 110S > 185 or D > 110

Adams et al, Stroke 2003; 34:1056-83Adams et al, Stroke 2003; 34:1056-83

Aortic DissectionAortic Dissection

► Treatment of htn should begin before confirmation of Treatment of htn should begin before confirmation of dx, if suspecteddx, if suspected

► Goal of therapy is to Goal of therapy is to ↓ aortic stress by rapidly lowering ↓ aortic stress by rapidly lowering DBP and controlling pulse rateDBP and controlling pulse rate

► Target is 10-15% ↓ in MAP, or reduction from baseline Target is 10-15% ↓ in MAP, or reduction from baseline to SBP to 110, in 5-30 minutesto SBP to 110, in 5-30 minutes

► Usual drugs are vasodilator + beta blocker, usually Usual drugs are vasodilator + beta blocker, usually NTP + esmololNTP + esmolol

● Labetalol as sole agent limited by tachyphylaxisLabetalol as sole agent limited by tachyphylaxis

► Treatment of htn should begin before confirmation of Treatment of htn should begin before confirmation of dx, if suspecteddx, if suspected

► Goal of therapy is to Goal of therapy is to ↓ aortic stress by rapidly lowering ↓ aortic stress by rapidly lowering DBP and controlling pulse rateDBP and controlling pulse rate

► Target is 10-15% ↓ in MAP, or reduction from baseline Target is 10-15% ↓ in MAP, or reduction from baseline to SBP to 110, in 5-30 minutesto SBP to 110, in 5-30 minutes

► Usual drugs are vasodilator + beta blocker, usually Usual drugs are vasodilator + beta blocker, usually NTP + esmololNTP + esmolol

● Labetalol as sole agent limited by tachyphylaxisLabetalol as sole agent limited by tachyphylaxis

Varon J, Chest 2000;118:214-227Varon J, Chest 2000;118:214-227

Acute Renal FailureAcute Renal Failure

► Goal of therapy is to treat htn without further Goal of therapy is to treat htn without further ↓ing renal ↓ing renal perfusionperfusion

► Target is 10-20% ↓ in MAP over 1-2h, then by 10-15% Target is 10-20% ↓ in MAP over 1-2h, then by 10-15% more in next 6-12h; accelerating this process may ↓ more in next 6-12h; accelerating this process may ↓ renal function renal function

► Fenoldopam appears to be preferred drugFenoldopam appears to be preferred drug● Maintains GFRMaintains GFR● Dilates the renal arteryDilates the renal artery● Causes natriuresisCauses natriuresis

► NTP should be avoided because of accumulation of NTP should be avoided because of accumulation of metabolites and development of acidosismetabolites and development of acidosis

► Goal of therapy is to treat htn without further Goal of therapy is to treat htn without further ↓ing renal ↓ing renal perfusionperfusion

► Target is 10-20% ↓ in MAP over 1-2h, then by 10-15% Target is 10-20% ↓ in MAP over 1-2h, then by 10-15% more in next 6-12h; accelerating this process may ↓ more in next 6-12h; accelerating this process may ↓ renal function renal function

► Fenoldopam appears to be preferred drugFenoldopam appears to be preferred drug● Maintains GFRMaintains GFR● Dilates the renal arteryDilates the renal artery● Causes natriuresisCauses natriuresis

► NTP should be avoided because of accumulation of NTP should be avoided because of accumulation of metabolites and development of acidosismetabolites and development of acidosis

Vaughn, Lancet 2000;356:411-417Vaughn, Lancet 2000;356:411-417

Acute Cardiopulmonary CompromiseAcute Cardiopulmonary Compromise

► Goal of therapy is to treat htn and improve cardiac Goal of therapy is to treat htn and improve cardiac functionfunction

► Target is 10-20% ↓ in MAP over 1-2h, guided by clinical Target is 10-20% ↓ in MAP over 1-2h, guided by clinical findings, followed by transition to oral agentsfindings, 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 Morphine is a venodilator that may help both control both anginal pain and pulmonary congestionboth anginal pain and pulmonary congestion

► Must be cautious not to overshoot; NTP often avoided Must be cautious not to overshoot; NTP often avoided for this reasonfor this reason

► Goal of therapy is to treat htn and improve cardiac Goal of therapy is to treat htn and improve cardiac functionfunction

► Target is 10-20% ↓ in MAP over 1-2h, guided by clinical Target is 10-20% ↓ in MAP over 1-2h, guided by clinical findings, followed by transition to oral agentsfindings, 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 Morphine is a venodilator that may help both control both anginal pain and pulmonary congestionboth anginal pain and pulmonary congestion

► Must be cautious not to overshoot; NTP often avoided Must be cautious not to overshoot; NTP often avoided for this reasonfor this reason

Vaughn, Lancet 2000;356:411-417Vaughn, Lancet 2000;356:411-417

Hemodynamics and Myocardial IschemiaHemodynamics and Myocardial Ischemia

Adapted from Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. W.B.Saunders Co.; 2001.

Afterload or SVR

Work

O2 consumption

↓ Myocardial Blood Flow

O2 delivery

↑ Left Ventricular (LV) Wall Tension

Afterload or SVR

Myocardial Ischemia

Increased Afterload Increases OIncreased Afterload Increases O22 Consumption Consumption

and Decreases Oand Decreases O22 Delivery to the Heart Delivery to the HeartIncreased Afterload Increases OIncreased Afterload Increases O22 Consumption Consumption

and Decreases Oand Decreases O22 Delivery to the Heart Delivery to the Heart

Common Therapeutic AgentsCommon Therapeutic Agents

► ACE InhibitorsACE Inhibitors

► DiazoxideDiazoxide

► EsmololEsmolol

► HydralazineHydralazine

► NicardipineNicardipine

► NitroglycerinNitroglycerin



► EsmololEsmolol




► ClonidineClonidine

► DiureticsDiuretics

► FenoldopamFenoldopam

► LabetalolLabetalol

► NifedipineNifedipine

► NitroprussideNitroprusside







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

ACE InhibitorsACE Inhibitors

► Reduce vasoconstriction and circulating Reduce vasoconstriction and circulating catecholamine levelscatecholamine levels

► Many oral options; enalaprilat is IV formMany oral options; enalaprilat is IV form

► May cause hypotension, acute renal failure, May cause hypotension, acute renal failure, hyperkalemia, cough, angioedema, and rashhyperkalemia, cough, angioedema, and rash

► Reduce vasoconstriction and circulating Reduce vasoconstriction and circulating catecholamine levelscatecholamine levels

► Many oral options; enalaprilat is IV formMany oral options; enalaprilat is IV form

► May cause hypotension, acute renal failure, May cause hypotension, acute renal failure, hyperkalemia, cough, angioedema, and rashhyperkalemia, cough, angioedema, and rash


ClonidineClonidine

► Reduces central sympathetic outflow, thereby Reduces central sympathetic outflow, thereby increasing vagal tone, reducing PVR and HRincreasing vagal tone, reducing PVR and HR

► Only available orally; onset of effect is 1-3hOnly available orally; onset of effect is 1-3h

► May cause orthostasis (especially in volume-May cause orthostasis (especially in volume-depleted patients, bradycardia, and AV block; depleted patients, bradycardia, and AV block; associated with withdrawal in patients taking more associated with withdrawal in patients taking more than 0.3mg/dthan 0.3mg/d

► Reduces central sympathetic outflow, thereby Reduces central sympathetic outflow, thereby increasing vagal tone, reducing PVR and HRincreasing vagal tone, reducing PVR and HR

► Only available orally; onset of effect is 1-3hOnly available orally; onset of effect is 1-3h

► May cause orthostasis (especially in volume-May cause orthostasis (especially in volume-depleted patients, bradycardia, and AV block; depleted patients, bradycardia, and AV block; associated with withdrawal in patients taking more associated with withdrawal in patients taking more than 0.3mg/dthan 0.3mg/d


DiazoxideDiazoxide

► Direct peripheral arteriolar vasodilatorDirect peripheral arteriolar vasodilator

► Given IV, slowly to avoid excessive hypotension, as Given IV, slowly to avoid excessive hypotension, as an infusion or with repeated bolusesan infusion or with repeated boluses

► May cause tachycardia, hypotension, N/V, May cause tachycardia, hypotension, N/V, hyperglycemia, and hyperuricemia; with repeated hyperglycemia, and hyperuricemia; with repeated doses may cause sodium and fluid retention with doses may cause sodium and fluid retention with edema and frank heart failureedema and frank heart failure

► Direct peripheral arteriolar vasodilatorDirect peripheral arteriolar vasodilator

► Given IV, slowly to avoid excessive hypotension, as Given IV, slowly to avoid excessive hypotension, as an infusion or with repeated bolusesan infusion or with repeated boluses

► May cause tachycardia, hypotension, N/V, May cause tachycardia, hypotension, N/V, hyperglycemia, and hyperuricemia; with repeated hyperglycemia, and hyperuricemia; with repeated doses may cause sodium and fluid retention with doses may cause sodium and fluid retention with edema and frank heart failureedema and frank heart failure


DiureticsDiuretics

► Loop diuretics are often used in chronic management Loop diuretics are often used in chronic management of hypertensionof hypertension

► Acute management limited to pulmonary edemaAcute management limited to pulmonary edema● Diminished effectiveness in renal insufficiency or decreased Diminished effectiveness in renal insufficiency or decreased

cardiac outputcardiac output

► May cause ototoxicity with rapid IV administration; may May cause ototoxicity with rapid IV administration; may induce or exacerbate hypokalemia (also induce or exacerbate hypokalemia (also ↓ Na, Ca, and ↓ Na, Ca, and Mg); furosemide, bumetanide, and torsemide can all Mg); furosemide, bumetanide, and torsemide can all cause allergic reactions in sulfa-sensitive patientscause allergic reactions in sulfa-sensitive patients

► Loop diuretics are often used in chronic management Loop diuretics are often used in chronic management of hypertensionof hypertension

► Acute management limited to pulmonary edemaAcute management limited to pulmonary edema● Diminished effectiveness in renal insufficiency or decreased Diminished effectiveness in renal insufficiency or decreased

cardiac outputcardiac output

► May cause ototoxicity with rapid IV administration; may May cause ototoxicity with rapid IV administration; may induce or exacerbate hypokalemia (also induce or exacerbate hypokalemia (also ↓ Na, Ca, and ↓ Na, Ca, and Mg); furosemide, bumetanide, and torsemide can all Mg); furosemide, bumetanide, and torsemide can all cause allergic reactions in sulfa-sensitive patientscause allergic reactions in sulfa-sensitive patients


EsmololEsmolol

► Blocks Blocks ββ-1 receptors of heart and vasculature-1 receptors of heart and vasculature

► Given IV, onset of action is 6-10min after bolus, and Given IV, onset of action is 6-10min after bolus, and activity persists 20min after infusion d/c’d; must be activity persists 20min after infusion d/c’d; must be carefully titratedcarefully titrated

► May cause bradycardia and hypotension, May cause bradycardia and hypotension, bronchospasm, seizures, and pulmonary edemabronchospasm, seizures, and pulmonary edema

► Chest pain may occur after abrupt withdrawalChest pain may occur after abrupt withdrawal

► Blocks Blocks ββ-1 receptors of heart and vasculature-1 receptors of heart and vasculature

► Given IV, onset of action is 6-10min after bolus, and Given IV, onset of action is 6-10min after bolus, and activity persists 20min after infusion d/c’d; must be activity persists 20min after infusion d/c’d; must be carefully titratedcarefully titrated

► May cause bradycardia and hypotension, May cause bradycardia and hypotension, bronchospasm, seizures, and pulmonary edemabronchospasm, seizures, and pulmonary edema

► Chest pain may occur after abrupt withdrawalChest pain may occur after abrupt withdrawal


LabetalolLabetalol

► ↓↓s PVR by blocking s PVR by blocking αα-1 receptors and prevents -1 receptors and prevents reflex tachycardia by blocking reflex tachycardia by blocking ββ-1 receptors, -1 receptors, resulting in a ↓BPresulting in a ↓BP

► Given as repeated IV boluses and can be carefully Given as repeated IV boluses and can be carefully given as a short-term infusion given as a short-term infusion

► Optimally used when a gradual Optimally used when a gradual ↓ in BP is needed ↓ in BP is needed with minimal effects on HR, and in CVA (labetolol with minimal effects on HR, and in CVA (labetolol has minimal effects on CBF)has minimal effects on CBF)

► Should be avoided in significant asthma/COPD; Should be avoided in significant asthma/COPD; may cause bradycardia, AV block, hypotensionmay cause bradycardia, AV block, hypotension

► ↓↓s PVR by blocking s PVR by blocking αα-1 receptors and prevents -1 receptors and prevents reflex tachycardia by blocking reflex tachycardia by blocking ββ-1 receptors, -1 receptors, resulting in a ↓BPresulting in a ↓BP

► Given as repeated IV boluses and can be carefully Given as repeated IV boluses and can be carefully given as a short-term infusion given as a short-term infusion

► Optimally used when a gradual Optimally used when a gradual ↓ in BP is needed ↓ in BP is needed with minimal effects on HR, and in CVA (labetolol with minimal effects on HR, and in CVA (labetolol has minimal effects on CBF)has minimal effects on CBF)

► Should be avoided in significant asthma/COPD; Should be avoided in significant asthma/COPD; may cause bradycardia, AV block, hypotensionmay cause bradycardia, AV block, hypotension


-Blocker vs Combined -Blocker vs Combined - and - and -Blocker-Blocker

Esmolol Esmolol -Blocker-Blocker

LabetalolLabetalol

- and - and -Blocker-Blocker

AdministrationAdministration BolusBolusContinuous infusionContinuous infusion

BolusBolusContinuous infusionContinuous infusion

OnsetOnset Rapid (60 s)Rapid (60 s)22 Intermediate (peak 5-15 min)Intermediate (peak 5-15 min)22

Offset (Duration of action)Offset (Duration of action) Rapid (10-20 min)Rapid (10-20 min)22 Slower (2-4 h)Slower (2-4 h)22

HRHR DecreasedDecreased +/-+/-

SVRSVR 00 DecreasedDecreased

Cardiac outputCardiac output DecreasedDecreased +/-+/-

Myocardial OMyocardial O22 balance balance PositivePositive PositivePositive

ContraindicationsContraindications Sinus bradycardiaSinus bradycardiaHeart block >1°Heart block >1°

Overt heart failureOvert heart failureCardiogenic shockCardiogenic shock

Severe bradycardiaSevere bradycardiaHeart block >1°Heart block >1°

Overt heart failureOvert heart failureCardiogenic shockCardiogenic shock

1. Hoffman BB. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:215-268.

2. Varon J, Malik PE. Chest. 2000;118:214-227.

HydralazineHydralazine

► Directly relaxes arteriolar smooth muscleDirectly relaxes arteriolar smooth muscle

► Used primarily in management of preeclampsia and Used primarily in management of preeclampsia and eclampsiaeclampsia

► Many adverse effects that limit its use in other Many adverse effects that limit its use in other situations, so not discussed further heresituations, so not discussed further here

► Directly relaxes arteriolar smooth muscleDirectly relaxes arteriolar smooth muscle

► Used primarily in management of preeclampsia and Used primarily in management of preeclampsia and eclampsiaeclampsia

► Many adverse effects that limit its use in other Many adverse effects that limit its use in other situations, so not discussed further heresituations, so not discussed further here


FenoldopamFenoldopam

► Selective dopamine-1 receptor agonist, Selective dopamine-1 receptor agonist, ↓ing PVR ↓ing PVR while ↑ing RBF, natriuresis, and diuresiswhile ↑ing RBF, natriuresis, and diuresis

► 6x more potent than dopamine in producing renal 6x more potent than dopamine in producing renal vasodilationvasodilation

► Given IV and titrated; onset of action 10 min and Given IV and titrated; onset of action 10 min and effects persist for an hour after d/ceffects persist for an hour after d/c

► May cause T-wave flattening, angina, atrial May cause T-wave flattening, angina, atrial fib/flutter, and reflex tachycardiafib/flutter, and reflex tachycardia

► Selective dopamine-1 receptor agonist, Selective dopamine-1 receptor agonist, ↓ing PVR ↓ing PVR while ↑ing RBF, natriuresis, and diuresiswhile ↑ing RBF, natriuresis, and diuresis

► 6x more potent than dopamine in producing renal 6x more potent than dopamine in producing renal vasodilationvasodilation

► Given IV and titrated; onset of action 10 min and Given IV and titrated; onset of action 10 min and effects persist for an hour after d/ceffects persist for an hour after d/c



Calcium Channel BlockersCalcium Channel Blockers

NicardipineNicardipine(dihydropyridine)(dihydropyridine)

DiltiazemDiltiazem(benzothiazepine)(benzothiazepine)

VerapamilVerapamil(phenylalkylamine)(phenylalkylamine)

Peripheral Peripheral VasodilationVasodilation11 ++++++++++ ++++++ ++++++

CoronaryCoronaryVasodilationVasodilation22 ++++++++++ ++++++ ++++++++

SuppressionSuppressionof SA Nodeof SA Node22 ++ ++++++++++ ++++++++++

SuppressionSuppressionof AV Nodeof AV Node22 00 ++++++++ ++++++++++

SuppressionSuppressionof Cardiac of Cardiac

ContractilityContractility2200 ++++ ++++++++

1. Frishman WH, et al. Med Clin North Am. 1988;72:523-547. 2. Adapted from Goodman and Gilman’s: The Pharmacologic Basis of Therapeutics. 9th ed. 2001.

NicardipineNicardipine

► As a CCB, relaxes arteriolar smooth muscle and ↓s As a CCB, relaxes arteriolar smooth muscle and ↓s PVR by a baroreceptor-mediated sympathetic PVR by a baroreceptor-mediated sympathetic dischargedischarge

► Seems to be selective for L-type, voltage-sensitive Ca Seems to be selective for L-type, voltage-sensitive Ca channels of the heart, and works by decreasing channels of the heart, and works by decreasing afterload afterload

► Given by IV infusion with careful titrationGiven by IV infusion with careful titration

► May cause tachycardia, flushing, headache, dizziness, May cause tachycardia, flushing, headache, dizziness, hypotension, and digital dysesthesiashypotension, and digital dysesthesias

► As a CCB, relaxes arteriolar smooth muscle and ↓s As a CCB, relaxes arteriolar smooth muscle and ↓s PVR by a baroreceptor-mediated sympathetic PVR by a baroreceptor-mediated sympathetic dischargedischarge

► Seems to be selective for L-type, voltage-sensitive Ca Seems to be selective for L-type, voltage-sensitive Ca channels of the heart, and works by decreasing channels of the heart, and works by decreasing afterload afterload

► Given by IV infusion with careful titrationGiven by IV infusion with careful titration

► May cause tachycardia, flushing, headache, dizziness, May cause tachycardia, flushing, headache, dizziness, hypotension, and digital dysesthesiashypotension, and digital dysesthesias



► Onset to effect is about 10min, and lasts 2-6h after Onset to effect is about 10min, and lasts 2-6h after d/cd/c

► Abrupt withdrawal can cause rebound angina and Abrupt withdrawal can cause rebound angina and hypertensionhypertension

► Still, in at least one head-to-head trial, better Still, in at least one head-to-head trial, better tolerated than NTPtolerated than NTP

► Onset to effect is about 10min, and lasts 2-6h after Onset to effect is about 10min, and lasts 2-6h after d/cd/c

► Abrupt withdrawal can cause rebound angina and Abrupt withdrawal can cause rebound angina and hypertensionhypertension

► Still, in at least one head-to-head trial, better Still, in at least one head-to-head trial, better tolerated than NTPtolerated than NTP

Neutel et al, Am J Hypertens 1994;7:623-8Neutel et al, Am J Hypertens 1994;7:623-8

Safety Profiles of Nicardipine Safety Profiles of Nicardipine and Nitroprussideand Nitroprusside

Adverse EventsAdverse Events NicardipineNicardipine11 NitroprussideNitroprusside22

HypotensionHypotension 5.6%5.6% 36.9%36.9%

FlushingFlushing NANA 9.8%9.8%

NauseaNausea 4.9%4.9% 11.0%11.0%

DizzinessDizziness 1.4%1.4% 6.8%6.8%

HeadacheHeadache 14.6%14.6% 27.6%27.6%

ThiocyanateThiocyanate NANA 14.0%14.0%

Injection site painInjection site pain 1.4%1.4% NANA

1. Cardene IV [package insert]. 2. Nitropress [package insert].

Nicardipine vs Adrenergic BlockersNicardipine vs Adrenergic Blockers

DrugDrug NicardipineNicardipine EsmololEsmolol LabetalolLabetalol

AdministrationAdministration Continuous infusionContinuous infusionBolusBolus

Continuous infusionContinuous infusion

BolusBolus

Continuous infusion Continuous infusion

OnsetOnset RapidRapid RapidRapid IntermediateIntermediate

OffsetOffset RapidRapid RapidRapid SlowerSlower

HRHR11 Minimal increaseMinimal increase DecreasedDecreased +/–+/–

SVRSVR DecreasedDecreased 00 DecreasedDecreased

Cardiac outputCardiac output11 IncreasedIncreased DecreasedDecreased +/–+/–

Myocardial OMyocardial O22 balancebalance22 PositivePositive PositivePositive PositivePositive

Contra-indicationsContra-indications Advanced aortic Advanced aortic stenosisstenosis

Sinus bradycardiaSinus bradycardia

Heart block >1°Heart block >1°

Overt heart failureOvert heart failure

Cardiogenic shockCardiogenic shock

Severe bradycardiaSevere bradycardia

Heart block >1°Heart block >1°

Overt heart failureOvert heart failure

Cardiogenic shockCardiogenic shock

NifedipineNifedipine

► Formerly given sublingually or as bite-and-swallow Formerly given sublingually or as bite-and-swallow (in fact, there is only negligible absorption (in fact, there is only negligible absorption sublingually)sublingually)

► Erratic and unpredictable effect on BPErratic and unpredictable effect on BP

► Many documented cases of CVA and even death Many documented cases of CVA and even death from rapid ↓ BPfrom rapid ↓ BP

► Should be avoided in hypertensive crisesShould be avoided in hypertensive crises

► Formerly given sublingually or as bite-and-swallow Formerly given sublingually or as bite-and-swallow (in fact, there is only negligible absorption (in fact, there is only negligible absorption sublingually)sublingually)

► Erratic and unpredictable effect on BPErratic and unpredictable effect on BP

► Many documented cases of CVA and even death Many documented cases of CVA and even death from rapid ↓ BPfrom rapid ↓ BP

► Should be avoided in hypertensive crisesShould be avoided in hypertensive crises


NitroglycerinNitroglycerin

► Useful in managing BP in patients with angina or Useful in managing BP in patients with angina or pulmonary edemapulmonary edema

► At lower doses, works primarily by ↓ing preloadAt lower doses, works primarily by ↓ing preload● Affects venous system predominantlyAffects venous system predominantly● Reduces myocardial oxygen demandReduces myocardial oxygen demand

► At higher doses, works primarily by ↓ing afterloadAt higher doses, works primarily by ↓ing afterload● Affects arterioles and coronary arteries predominantlyAffects arterioles and coronary arteries predominantly

► Useful in managing BP in patients with angina or Useful in managing BP in patients with angina or pulmonary edemapulmonary edema

► At lower doses, works primarily by ↓ing preloadAt lower doses, works primarily by ↓ing preload● Affects venous system predominantlyAffects venous system predominantly● Reduces myocardial oxygen demandReduces myocardial oxygen demand

► At higher doses, works primarily by ↓ing afterloadAt higher doses, works primarily by ↓ing afterload● Affects arterioles and coronary arteries predominantlyAffects arterioles and coronary arteries predominantly


NitroglycerinNitroglycerin

► Given in hypertensive crisis by continuous IV Given in hypertensive crisis by continuous IV infusioninfusion

► Onset of action 2-5 minOnset of action 2-5 min

► Tolerance tends to develop over 12-72 hoursTolerance tends to develop over 12-72 hours

► Dose-limiting adverse effects include tachycardia, Dose-limiting adverse effects include tachycardia, bradycardia, and headachebradycardia, and headache

► Given in hypertensive crisis by continuous IV Given in hypertensive crisis by continuous IV infusioninfusion

► Onset of action 2-5 minOnset of action 2-5 min

► Tolerance tends to develop over 12-72 hoursTolerance tends to develop over 12-72 hours

► Dose-limiting adverse effects include tachycardia, Dose-limiting adverse effects include tachycardia, bradycardia, and headachebradycardia, and headache


NitroprussideNitroprusside

► A direct vasodilator that dilates both arteriolar and A direct vasodilator that dilates both arteriolar and venous capacitance vesselsvenous capacitance vessels

► Reduces PVR, venous return, and preloadReduces PVR, venous return, and preload

► Can Can ↑ CO in patients with LVF↑ CO in patients with LVF

► Mechanism: metabolized to nitric oxide→ ↑ cGMP Mechanism: metabolized to nitric oxide→ ↑ cGMP → vasodilation→ vasodilation● From nitric oxide is metabolized to cyanide, which can From nitric oxide is metabolized to cyanide, which can

cause lactic acidosis, N/V, anorexia, disorientation, and cause lactic acidosis, N/V, anorexia, disorientation, and psychosispsychosis

► A direct vasodilator that dilates both arteriolar and A direct vasodilator that dilates both arteriolar and venous capacitance vesselsvenous capacitance vessels

► Reduces PVR, venous return, and preloadReduces PVR, venous return, and preload

► Can Can ↑ CO in patients with LVF↑ CO in patients with LVF

► Mechanism: metabolized to nitric oxide→ ↑ cGMP Mechanism: metabolized to nitric oxide→ ↑ cGMP → vasodilation→ vasodilation● From nitric oxide is metabolized to cyanide, which can From nitric oxide is metabolized to cyanide, which can

cause lactic acidosis, N/V, anorexia, disorientation, and cause lactic acidosis, N/V, anorexia, disorientation, and psychosispsychosis



► Effects are immediate, and persist 3-5 minutesEffects are immediate, and persist 3-5 minutes

► Reported to ↑ CBF, although this may be offset by ↓ Reported to ↑ CBF, although this may be offset by ↓ MAP, so must be used with caution in suspected MAP, so must be used with caution in suspected CVACVA

► Effects are immediate, and persist 3-5 minutesEffects are immediate, and persist 3-5 minutes

► Reported to ↑ CBF, although this may be offset by ↓ Reported to ↑ CBF, although this may be offset by ↓ MAP, so must be used with caution in suspected MAP, so must be used with caution in suspected CVACVA



► Also reported to cause “coronary steal Also reported to cause “coronary steal syndrome,” causing or worsening myocardial syndrome,” causing or worsening myocardial ischemiaischemia

► Toxicity usually not a problem unless larger Toxicity usually not a problem unless larger infusion rates ( > 2infusion rates ( > 2μμg/kg/min) are used for g/kg/min) are used for long periods ( > 48h)long periods ( > 48h)

► Nurses find it difficult to administerNurses find it difficult to administer

► Also reported to cause “coronary steal Also reported to cause “coronary steal syndrome,” causing or worsening myocardial syndrome,” causing or worsening myocardial ischemiaischemia

► Toxicity usually not a problem unless larger Toxicity usually not a problem unless larger infusion rates ( > 2infusion rates ( > 2μμg/kg/min) are used for g/kg/min) are used for long periods ( > 48h)long periods ( > 48h)

► Nurses find it difficult to administerNurses find it difficult to administer


Cyanide ToxicityCyanide Toxicity

► Tachyphylaxis — Important sign of impending Tachyphylaxis — Important sign of impending toxicitytoxicity

► Neurological manifestationsNeurological manifestations● HyperpneaHyperpnea● Headache, VertigoHeadache, Vertigo● Altered mental statusAltered mental status● Coma, SeizuresComa, Seizures

► Laboratory manifestationsLaboratory manifestations● Lactic acidosisLactic acidosis● Increased base deficitIncreased base deficit

► Tachyphylaxis — Important sign of impending Tachyphylaxis — Important sign of impending toxicitytoxicity

► Neurological manifestationsNeurological manifestations● HyperpneaHyperpnea● Headache, VertigoHeadache, Vertigo● Altered mental statusAltered mental status● Coma, SeizuresComa, Seizures

► Laboratory manifestationsLaboratory manifestations● Lactic acidosisLactic acidosis● Increased base deficitIncreased base deficit

Sipe EK, et al. Am Surg. 2001;67:685-686.

NitrovasodilatorsNitrovasodilatorsNitroprusside versus NitroglycerinNitroprusside versus Nitroglycerin

DrugDrug NitroprussideNitroprusside NitroglycerinNitroglycerin

Rapid onset of peak effectRapid onset of peak effect ++++++++ ++++++

Afterload reductionAfterload reduction ++++++++ ++

Preload reductionPreload reduction ++++ ++++++++

Coronary steal reportedCoronary steal reported ++ 00

Coronary dilation – large vesselCoronary dilation – large vessel ++ ++++++++

Coronary dilation – small vesselCoronary dilation – small vessel +/-+/- +/-+/-

TachycardiaTachycardia ++++ ++++

Potential for symptomatic hypotensionPotential for symptomatic hypotension ++++ ++++++

Ease of administrationEase of administration ++++ ++++++

Cyanide toxicityCyanide toxicity ++++++++ 00

Pepine CJ. Clin Ther. 1988;10:316-325.

Limitations and Pitfalls of AgentsLimitations 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):2579-82.

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):2579-82.

Baseline Characteristics of Study PopulationBaseline Characteristics of Study Population

Brooks, et al. Brooks, et al. Am J Health Syst PharmAm J Health Syst Pharm. Dec 15, 2007;64(24):2579-82 . Dec 15, 2007;64(24):2579-82 Brooks, et al. Brooks, et al. Am J Health Syst PharmAm J Health Syst Pharm. Dec 15, 2007;64(24):2579-82 . Dec 15, 2007;64(24):2579-82

Primary and Secondary EndpointsPrimary and Secondary Endpoints


aMAP = mean arterial pressure.bp < 0.05, nicardipine group versus all patients.cp < 0.05, nicardipine group versus nitroprusside group.dOne patient was excluded from the analysis.

aMAP = mean arterial pressure.bp < 0.05, nicardipine group versus all patients.cp < 0.05, nicardipine group versus nitroprusside group.dOne patient was excluded from the analysis.

Treatment-Related Adverse EventsTreatment-Related Adverse Events


ap < 0.05, nicardipine group versus nitroprusside group; p < 0.05, nitroprusside group versus all patients.ap < 0.05, nicardipine group versus nitroprusside group; p < 0.05, nitroprusside group versus all patients.

SummarySummary

► Hypertension is extremely prevalent in US society, and Hypertension is extremely prevalent in US society, and as population ages, hypertensive crises will become as population ages, hypertensive crises will become increasingly common in the EDincreasingly common in the ED● Debate over terminology and numerical definitions is too Debate over terminology and numerical definitions is too

prevalent in the literatureprevalent in the literature

► Choices among available agents often difficult, and Choices among available agents often difficult, and none is ideal across the spectrumnone is ideal across the spectrum● Must balance effective reduction with avoidance of over-Must balance effective reduction with avoidance of over-

reduction and its complicationsreduction and its complications

► As ED LOS increases, care of BP derangements will fall As ED LOS increases, care of BP derangements will fall ever more in the purview of the emergency physicianever more in the purview of the emergency physician

► Hypertension is extremely prevalent in US society, and Hypertension is extremely prevalent in US society, and as population ages, hypertensive crises will become as population ages, hypertensive crises will become increasingly common in the EDincreasingly common in the ED● Debate over terminology and numerical definitions is too Debate over terminology and numerical definitions is too




► As ED LOS increases, care of BP derangements will fall As ED LOS increases, care of BP derangements will fall ever more in the purview of the emergency physicianever more in the purview of the emergency physician

Acute Severe HypertensionAcute Severe HypertensionEvolving Strategies and New Dimensions of Evolving Strategies and New Dimensions of

Emergency Cardiovascular CareEmergency Cardiovascular Care

Acute Severe HypertensionAcute Severe HypertensionEvolving Strategies and New Dimensions of Evolving Strategies and New Dimensions of

Emergency Cardiovascular CareEmergency Cardiovascular Care












HypertensionHypertension

► Affects at least 72 million AmericansAffects at least 72 million Americans

► Affects at least 1 BILLION individuals worldwideAffects at least 1 BILLION individuals worldwide

► Most current (2003) evidence basis for management—Most current (2003) evidence basis for management—The Seventh Report of the Joint National Committee The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Hypertension Treatment of High Blood Pressure Hypertension (JNC 7)—(JNC 7)—lacks guidance on acute management of lacks guidance on acute management of patients presenting to an ED with hypertensionpatients presenting to an ED with hypertension

► Affects at least 72 million AmericansAffects at least 72 million Americans

► Affects at least 1 BILLION individuals worldwideAffects at least 1 BILLION individuals worldwide

► Most current (2003) evidence basis for management—Most current (2003) evidence basis for management—The Seventh Report of the Joint National Committee The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Hypertension Treatment of High Blood Pressure Hypertension (JNC 7)—(JNC 7)—lacks guidance on acute management of lacks guidance on acute management of patients presenting to an ED with hypertensionpatients presenting to an ED with hypertension

JNC 7, JAMA 2003; 289:2560-2572.

Hypertensive UrgenciesHypertensive Urgenciesand Emergencies — What We Knowand Emergencies — What We Know



► In a single-center Italian study, HU or HE accounted In a single-center Italian study, HU or HE accounted for 3% of all medicine admissions and 27.5% of all for 3% of all medicine admissions and 27.5% of all medical emergenciesmedical emergencies● HU:HE 3:1 in that studyHU:HE 3:1 in that study● Patients with HU much more likely to be unaware of their Patients with HU much more likely to be unaware of their




► In a single-center Italian study, HU or HE accounted In a single-center Italian study, HU or HE accounted for 3% of all medicine admissions and 27.5% of all for 3% of all medicine admissions and 27.5% of all medical emergenciesmedical emergencies● HU:HE 3:1 in that studyHU:HE 3:1 in that study● Patients with HU much more likely to be unaware of their Patients with HU much more likely to be unaware of their


Zampaglione et al, Hypertension 1996;27:144.

Acute Pressure Syndromes — Management Acute Pressure Syndromes — Management ConsiderationsConsiderations

► 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 What improved outcome is there for the patient?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 What improved outcome is there for the patient?the patient?

Goals of Emergency TherapyGoals of Emergency Therapy of Hypertensive Crises of Hypertensive Crises

► HU can generally be managed with oral medications and HU can generally be managed with oral medications and requires BP lowering over 24-48 hoursrequires BP lowering over 24-48 hours

● Important to prevent too-rapid lowering due to autoregulation of flow Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneysby pressure in brain, heart, and kidneys

► Goal in hypertensive emergency is to reduce MAP by 10-Goal in hypertensive emergency is to reduce MAP by 10-15% and/or to a DBP of 110 as rapidly as possible15% and/or to a DBP of 110 as rapidly as possible

● Aortic dissection requires Aortic dissection requires especially rapid loweringespecially rapid lowering● Once initial reduction achieved, transition to oral agentsOnce initial reduction achieved, transition to oral agents● Drug of choice for initial therapy often depends on which end-organ Drug of choice for initial therapy often depends on which end-organ

system is affected and on comorbiditiessystem is affected and on comorbidities

► HU can generally be managed with oral medications and HU can generally be managed with oral medications and requires BP lowering over 24-48 hoursrequires BP lowering over 24-48 hours

● Important to prevent too-rapid lowering due to autoregulation of flow Important to prevent too-rapid lowering due to autoregulation of flow by pressure in brain, heart, and kidneysby pressure in brain, heart, and kidneys

► Goal in hypertensive emergency is to reduce MAP by 10-Goal in hypertensive emergency is to reduce MAP by 10-15% and/or to a DBP of 110 as rapidly as possible15% and/or to a DBP of 110 as rapidly as possible

● Aortic dissection requires Aortic dissection requires especially rapid loweringespecially rapid lowering● Once initial reduction achieved, transition to oral agentsOnce initial reduction achieved, transition to oral agents● Drug of choice for initial therapy often depends on which end-organ Drug of choice for initial therapy often depends on which end-organ

system is affected and on comorbiditiessystem is affected and on comorbidities

JNC 7, JAMA 2003; 289:2560-2572.

““End Organ Damage”End Organ Damage”









JNC 7, JAMA 2003; 289:2560-2572.

Presenting SymptomsPresenting Symptoms






► Usual Primary ED DiagnosisUsual Primary ED Diagnosis● CVACVA● APEAPE● Hypertensive Hypertensive



► Usual Primary ED DiagnosisUsual Primary ED Diagnosis● CVACVA● APEAPE● Hypertensive Hypertensive


Zampaglione et al, Hypertension 1996;27:144.

Why Are We Here Today?Why Are We Here Today?

► Severe hypertension is increasingly prevalent as Severe hypertension is increasingly prevalent as population ages and obesity and diabetes become population ages and obesity and diabetes become more commonmore common

► Currently available agents for the management of Currently available agents for the management of acute severe BP elevation leave much to be acute severe BP elevation leave much to be desireddesired

► Advancements in therapy are possibleAdvancements in therapy are possible

► There is a new agent on the horizon that has been There is a new agent on the horizon that has been tested specifically in the EDtested specifically in the ED

► Severe hypertension is increasingly prevalent as Severe hypertension is increasingly prevalent as population ages and obesity and diabetes become population ages and obesity and diabetes become more commonmore common

► Currently available agents for the management of Currently available agents for the management of acute severe BP elevation leave much to be acute severe BP elevation leave much to be desireddesired

► Advancements in therapy are possibleAdvancements in therapy are possible

► There is a new agent on the horizon that has been There is a new agent on the horizon that has been tested specifically in the EDtested specifically in the ED

Therapeutic Agents Currently UsedTherapeutic Agents Currently Used



► EsmololEsmolol






► EsmololEsmolol
















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

ArmamentariumArmamentarium

FenoldopamFenoldopam

► Selective dopamine-1 receptor agonist, Selective dopamine-1 receptor agonist, decreasing PVR while increasing RBF, natriuresis, decreasing PVR while increasing RBF, natriuresis, and diuresisand diuresis

► Six times more potent than dopamine in producing Six times more potent than dopamine in producing renal vasodilationrenal vasodilation

► Given IV and titrated; onset of action 10 minutes Given IV and titrated; onset of action 10 minutes and effects persist for an hour after and effects persist for an hour after discontinuationdiscontinuation


► Selective dopamine-1 receptor agonist, Selective dopamine-1 receptor agonist, decreasing PVR while increasing RBF, natriuresis, decreasing PVR while increasing RBF, natriuresis, and diuresisand diuresis

► Six times more potent than dopamine in producing Six times more potent than dopamine in producing renal vasodilationrenal vasodilation

► Given IV and titrated; onset of action 10 minutes Given IV and titrated; onset of action 10 minutes and effects persist for an hour after and effects persist for an hour after discontinuationdiscontinuation


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

Principles of UsePrinciples of UsePrinciples of UsePrinciples of Use

Nitropusside: Issues and ConcernsNitropusside: Issues and Concerns

► Common Side Effects Common Side Effects ► BP BP ► May cause N/V, twitching, sweatingMay cause N/V, twitching, sweating► Metabolized to CN, then thiocyanateMetabolized to CN, then thiocyanate

● Renal issue Renal issue

► Problematic AspectsProblematic Aspects• PregnancyPregnancy• Coronary stealCoronary steal• Dose dependent Dose dependent in CBF in CBF

– Caution with high ICP Caution with high ICP

• Hypoxia (Hypoxia ( Va/Q mismatch) Va/Q mismatch)• Requires special delivery systemRequires special delivery system• Usually requires direct Usually requires direct

artery pressure monitoringartery pressure monitoring

► Common Side Effects Common Side Effects ► BP BP ► May cause N/V, twitching, sweatingMay cause N/V, twitching, sweating► Metabolized to CN, then thiocyanateMetabolized to CN, then thiocyanate

● Renal issue Renal issue

► Problematic AspectsProblematic Aspects• PregnancyPregnancy• Coronary stealCoronary steal• Dose dependent Dose dependent in CBF in CBF

– Caution with high ICP Caution with high ICP

• Hypoxia (Hypoxia ( Va/Q mismatch) Va/Q mismatch)• Requires special delivery systemRequires special delivery system• Usually requires direct Usually requires direct

artery pressure monitoringartery pressure monitoring

So What’s New for Emergency So What’s New for Emergency Medicine- and Critical Care-Based Medicine- and Critical Care-Based Therapy of Acute, Severe Blood Therapy of Acute, Severe Blood

Pressure Elevations in the Setting Pressure Elevations in the Setting of Cardiovascular Disease, of Cardiovascular Disease,

Stroke, and Associated Stroke, and Associated Conditions?Conditions?

So What’s New for Emergency So What’s New for Emergency Medicine- and Critical Care-Based Medicine- and Critical Care-Based Therapy of Acute, Severe Blood Therapy of Acute, Severe Blood

Pressure Elevations in the Setting Pressure Elevations in the Setting of Cardiovascular Disease, of Cardiovascular Disease,

Stroke, and Associated Stroke, and Associated Conditions?Conditions?

Acute Pressure SyndromesAcute Pressure Syndromes

Clevidipine: The First Third-Generation Clevidipine: The First Third-Generation Calcium Channel BlockerCalcium Channel Blocker

Generic Name Brand Name

First Generation Nifedipine Procardia®, Adalat®

Second Generation

Nicardipine/Nicardipine I.V.AmlodipineIsradipineFelodipineNisoldipine

Cardene®/Cardene I.V.Norvasc®

DynaCirc®

Plendil®

Sular®

Third Generation Clevidipine Cleviprex™

Whiting RL, et al. Angiology. 1990;41:987-991.

Metabolism by PlasmaMetabolism by Plasmaand Tissue Esterasesand Tissue Esterases

► Clevidipine is rapidly metabolized by esterases Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive in blood and extravascular tissue to an inactive carboxylic acid metabolite, carboxylic acid metabolite, independent of independent of renal or hepatic function!renal or hepatic function!

► Clevidipine is rapidly metabolized by esterases Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive in blood and extravascular tissue to an inactive carboxylic acid metabolite, carboxylic acid metabolite, independent of independent of renal or hepatic function!renal or hepatic function!

+OH

OHH

O

Clevidipine

Cl

OO

O

O

NH

Cl

O

O

*Esterases

+O

O

NH

Cl

O

O

Cl

H

Primary metabolite

Responders = treatment success: >10% decrease in MAP or >20% decrease in MAP at each measured concentration.

Bailey JM, et al. Anesthesiology. 2002;96:1086-1094.

Linear Dose ResponseLinear Dose Response

► Linear dose response in postoperative cardiac surgery Linear dose response in postoperative cardiac surgery patientspatients

► 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 Linear dose response in postoperative cardiac surgery patientspatients

► 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)

0

10

20

30

40

50

60

70

80

90

100

0 0.05 0.18 0.32 1.37 3.19

Re

sp

on

de

rs (

%)

n=0

n=1

n=4

n=6

n=9

Selectivity of Calcium Channel AntagonistsSelectivity of Calcium Channel Antagonists

MyocardialMyocardial SA NodeSA Node AV NodeAV Node IV AgentIV Agent VasodilationVasodilation DepressionDepression SuppressionSuppression SuppressionSuppression ClevidipineClevidipine 55 00 00 00

NicardipineNicardipine 55 00 00 00

DiltiazemDiltiazem 33 22 55 44

VerapamilVerapamil 44 44 55 55

*The chiral center of clevidipine; SA = sinoatrial; AV = atrioventricular.

Kerins DM, et al. In: Goodman and Gilman’s Pharmacological Basis of Therapeutics. 2001:843-870. Massie BM. Am J CardioI. 1997;80:23I-32I.

ClevidipineClevidipine

Cl

OO

O

O

NH

Cl

O

O

*

COCH2CH2NCH2

NO2

CH3

O CH3

N

H

OH3C

H3COC

NifedipineNifedipine

NO2

COCH3

CH3

O

N

H

OH3C

CH3OC


Multi-center, Phase III, open-label, single-arm, study to confirm Multi-center, Phase III, open-label, single-arm, study to confirm the safety of IV clevidipine for patients who present to the the safety of IV clevidipine for patients who present to the

emergency department (ED) or intensive care unit (ICU) with emergency department (ED) or intensive care unit (ICU) with acute, severe hypertension requiring parenteral treatment for acute, severe hypertension requiring parenteral treatment for

at least 18 hoursat least 18 hours

Multi-center, Phase III, open-label, single-arm, study to confirm Multi-center, Phase III, open-label, single-arm, study to confirm the safety of IV clevidipine for patients who present to the the safety of IV clevidipine for patients who present to the

emergency department (ED) or intensive care unit (ICU) with emergency department (ED) or intensive care unit (ICU) with acute, severe hypertension requiring parenteral treatment for acute, severe hypertension requiring parenteral treatment for

at least 18 hoursat least 18 hours

New Dimensions and AdvancesNew Dimensions and Advances

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 AdvancesNew Dimensions and Advances

VELOCITY — RationaleVELOCITY — Rationale

► Multi-center, Phase III, open-label, single-arm, Multi-center, Phase III, open-label, single-arm, study to confirm the safety of IV clevidipine for study to confirm the safety of IV clevidipine for patients with acute hypertension requiring patients with acute hypertension requiring parenteral treatment for at least 18 hoursparenteral treatment for at least 18 hours

► Phase III safety and efficacy studyPhase III safety and efficacy study ● Evaluation:Evaluation: to confirm the safety and efficacy to confirm the safety and efficacy

of clevidipine in patients with acute of clevidipine in patients with acute hypertension using a predefined, non-weight hypertension using a predefined, non-weight based dosing algorithmbased dosing algorithm

● Population:Population: patients with acute hypertension patients with acute hypertension (SBP >180 mmHg or DBP >115 mmHg) (SBP >180 mmHg or DBP >115 mmHg) assessed at 2 successive occasions 15 min assessed at 2 successive occasions 15 min apart at baselineapart at baseline

► Multi-center, Phase III, open-label, single-arm, Multi-center, Phase III, open-label, single-arm, study to confirm the safety of IV clevidipine for study to confirm the safety of IV clevidipine for patients with acute hypertension requiring patients with acute hypertension requiring parenteral treatment for at least 18 hoursparenteral treatment for at least 18 hours

► Phase III safety and efficacy studyPhase III safety and efficacy study ● Evaluation:Evaluation: to confirm the safety and efficacy to confirm the safety and efficacy

of clevidipine in patients with acute of clevidipine in patients with acute hypertension using a predefined, non-weight hypertension using a predefined, non-weight based dosing algorithmbased dosing algorithm

● Population:Population: patients with acute hypertension patients with acute hypertension (SBP >180 mmHg or DBP >115 mmHg) (SBP >180 mmHg or DBP >115 mmHg) assessed at 2 successive occasions 15 min assessed at 2 successive occasions 15 min apart at baselineapart at baseline

VELOCITY — ObjectivesVELOCITY — Objectives

► PrimaryPrimary

► Confirm the safety of a titration dosing regimen of Confirm the safety of a titration dosing regimen of an IV infusion of clevidipine for the treatment of an IV infusion of clevidipine for the treatment of acute hypertensionacute hypertension● Efficacy:Efficacy: Percentage of patients in whom SBP Percentage of patients in whom SBP

fell within the SBP target range within 30 min of fell within the SBP target range within 30 min of initiating infusioninitiating infusion

● Safety:Safety: Percentage of patients in whom SBP Percentage of patients in whom SBP fell below the lower limit of the initial SBP target fell below the lower limit of the initial SBP target range within 3 min of initiating infusionrange within 3 min of initiating infusion

► PrimaryPrimary

► Confirm the safety of a titration dosing regimen of Confirm the safety of a titration dosing regimen of an IV infusion of clevidipine for the treatment of an IV infusion of clevidipine for the treatment of acute hypertensionacute hypertension● Efficacy:Efficacy: Percentage of patients in whom SBP Percentage of patients in whom SBP

fell within the SBP target range within 30 min of fell within the SBP target range within 30 min of initiating infusioninitiating infusion

● Safety:Safety: Percentage of patients in whom SBP Percentage of patients in whom SBP fell below the lower limit of the initial SBP target fell below the lower limit of the initial SBP target range within 3 min of initiating infusionrange within 3 min of initiating infusion

VELOCITY — ObjectivesVELOCITY — Objectives

► SecondarySecondary► 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 Change in heart rate during the 30-min period from

initiation of infusioninitiation of infusion● Dose of clevidipine during the treatment periodDose of clevidipine during the treatment period● Of the patients converted to oral antihypertensive Of the patients converted to oral antihypertensive

therapy, the proportion of those with successful therapy, the proportion of those with successful transition, defined as SBP within the last specified target transition, defined as SBP within the last specified target range at 6 hr after cessation of clevidipine infusionrange at 6 hr after cessation of clevidipine infusion

● Safety of prolonged infusion of clevidipine (≥18 hr) Safety of prolonged infusion of clevidipine (≥18 hr)

► SecondarySecondary► 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 Change in heart rate during the 30-min period from

initiation of infusioninitiation of infusion● Dose of clevidipine during the treatment periodDose of clevidipine during the treatment period● Of the patients converted to oral antihypertensive Of the patients converted to oral antihypertensive

therapy, the proportion of those with successful therapy, the proportion of those with successful transition, defined as SBP within the last specified target transition, defined as SBP within the last specified target range at 6 hr after cessation of clevidipine infusionrange at 6 hr after cessation of clevidipine infusion

● Safety of prolonged infusion of clevidipine (≥18 hr) Safety of prolonged infusion of clevidipine (≥18 hr)

VELOCITY — CriteriaVELOCITY — Criteria

► Inclusion CriteriaInclusion Criteria● Age 18 years and olderAge 18 years and older● Systolic BP >180 mmHg and/or diastolic BP >115 Systolic BP >180 mmHg and/or diastolic BP >115

mmHg assessed on two successive occasions, mmHg assessed on two successive occasions, 15 minutes apart15 minutes apart

● Provide written informed consent before initiation of any Provide written informed consent before initiation of any study-related proceduresstudy-related procedures

► Exclusion CriteriaExclusion Criteria● SBP ≤180 mmHg and DBP ≤115 mmHgSBP ≤180 mmHg and DBP ≤115 mmHg● Expectation that the patient will not tolerate Expectation that the patient will not tolerate

IV antihypertensive therapy for a minimum of 18 hourzIV antihypertensive therapy for a minimum of 18 hourz● Known or suspected aortic dissectionKnown or suspected aortic dissection

► Inclusion CriteriaInclusion Criteria● Age 18 years and olderAge 18 years and older● Systolic BP >180 mmHg and/or diastolic BP >115 Systolic BP >180 mmHg and/or diastolic BP >115

mmHg assessed on two successive occasions, mmHg assessed on two successive occasions, 15 minutes apart15 minutes apart

● Provide written informed consent before initiation of any Provide written informed consent before initiation of any study-related proceduresstudy-related procedures

► Exclusion CriteriaExclusion Criteria● SBP ≤180 mmHg and DBP ≤115 mmHgSBP ≤180 mmHg and DBP ≤115 mmHg● Expectation that the patient will not tolerate Expectation that the patient will not tolerate

IV antihypertensive therapy for a minimum of 18 hourzIV antihypertensive therapy for a minimum of 18 hourz● Known or suspected aortic dissectionKnown or suspected aortic dissection

VELOCITY — TreatmentVELOCITY — Treatment

► ClevidipineClevidipine

● Selection of Initial Target Range (ITR) for Selection of Initial Target Range (ITR) for systolic blood pressure determined prior systolic blood pressure determined prior to the initiation of clevidipine for each to the initiation of clevidipine for each individual patientindividual patient

● Difference between the upper and lower Difference between the upper and lower ITR was 20-40 mmHgITR was 20-40 mmHg

► ClevidipineClevidipine

● Selection of Initial Target Range (ITR) for Selection of Initial Target Range (ITR) for systolic blood pressure determined prior systolic blood pressure determined prior to the initiation of clevidipine for each to the initiation of clevidipine for each individual patientindividual patient

● Difference between the upper and lower Difference between the upper and lower ITR was 20-40 mmHgITR was 20-40 mmHg

VELOCITY — TreatmentVELOCITY — Treatment

► Clevidipine initiated at 2 mg/h via Clevidipine initiated at 2 mg/h via peripheral veinperipheral vein

► Titrated up to 32 mg/h in doubling Titrated up to 32 mg/h in doubling increments Q3 min to achieve increments Q3 min to achieve pre-specified ITRpre-specified ITR

► Infusion rate could be decreased Infusion rate could be decreased if neededif needed

► Clevidipine initiated at 2 mg/h via Clevidipine initiated at 2 mg/h via peripheral veinperipheral vein

► Titrated up to 32 mg/h in doubling Titrated up to 32 mg/h in doubling increments Q3 min to achieve increments Q3 min to achieve pre-specified ITRpre-specified ITR

► Infusion rate could be decreased Infusion rate could be decreased if neededif needed

► Infusion maintained or further titrated after the first 30 Infusion maintained or further titrated after the first 30 min to reach ITRmin 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 Infusion maintained or further titrated after the first 30 min to reach ITRmin 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

VELOCITY — Transition to Oral TherapyVELOCITY — Transition to Oral Therapy

► If transition to an oral antihypertensive agent was If transition to an oral antihypertensive agent was required, the agent could be given after 18h of required, the agent could be given after 18h of clevidipine, starting 1 hr prior toclevidipine, starting 1 hr prior toending infusionending infusion

► After administration of the oral agent, clevidipine After administration of the oral agent, clevidipine could be down-titrated or terminatedcould be down-titrated or terminated

► If the BP rose to an undesirable level upon If the BP rose to an undesirable level upon cessation of the infusion, additional oral therapy cessation of the infusion, additional oral therapy or restarting of clevidipine infusion were optionsor restarting of clevidipine infusion were options

► If transition to an oral antihypertensive agent was If transition to an oral antihypertensive agent was required, the agent could be given after 18h of required, the agent could be given after 18h of clevidipine, starting 1 hr prior toclevidipine, starting 1 hr prior toending infusionending infusion

► After administration of the oral agent, clevidipine After administration of the oral agent, clevidipine could be down-titrated or terminatedcould be down-titrated or terminated

► If the BP rose to an undesirable level upon If the BP rose to an undesirable level upon cessation of the infusion, additional oral therapy cessation of the infusion, additional oral therapy or restarting of clevidipine infusion were optionsor restarting of clevidipine infusion were options

VELOCITY – Patient DemographicsVELOCITY – Patient Demographics

ParameterParameter ValueValue

Age (yrs)Age (yrs) 53.5 53.5 ± 15± 15

Gender (%)Gender (%)

MaleMale 4848

FemaleFemale 5252

BMI (kg/mBMI (kg/m22)) 30 30 ± 7.6± 7.6

Race (%)Race (%)

African AmericanAfrican American 7777

WhiteWhite 1616

HispanicHispanic 66

AsianAsian 11

SBP (mmHg)SBP (mmHg) 202 202 ± 22± 22

DBP (mmHg)DBP (mmHg) 111 111 ± 21± 21

ITR (high, low)ITR (high, low) 175, 143175, 143Mean ± SDSafety Population, N=126.

Medical History, Comorbidity, and Medical History, Comorbidity, and End-Organ Dysfunction End-Organ Dysfunction

Medical History Medical History Percent (%)Percent (%)

End organ injuryEnd organ injury 8181

Myocardial infarctionMyocardial infarction 55

Renal diseaseRenal disease 2525

Dialysis dependentDialysis dependent 1111

Coronary artery diseaseCoronary artery disease 2828

HypertensionHypertension 9797

Previous hospitalization for HBPPrevious hospitalization for HBP 3131

Congestive heart failureCongestive heart failure 1818

DyslipidemiaDyslipidemia 3737

SmokerSmoker

Current / FormerCurrent / Former 39 / 2139 / 21

DiabetesDiabetes 3131

StrokeStroke 1111

Safety Population, N=126.

VELOCITY — Patient DispositionVELOCITY — Patient Disposition

DNC=did not complete.

mITT Population(patients with

SBP >UL of target range)N=117

Total patients enrolledN=131

Safety Population(patients who

received at least 1 dose)N=126

No No clevidipineclevidipine

n=5n=5

SBP SBP ≤UL of target ≤UL of target rangerangen=14n=14

≥≥18 hr continuous 18 hr continuous infusioninfusionn=117

<18 hr treatment<18 hr treatmentn=9n=9

VELOCITY — Efficacy ResultsVELOCITY — 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 Time to first achievement to Initial Target Range (ITR)(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 Time to first achievement to Initial Target Range (ITR)(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

VELOCITY — Efficacy ResultsVELOCITY — Efficacy Results

► 89% of patients achieved pre-specified ITR within 89% of patients achieved pre-specified ITR within 30 minutes30 minutes● An additional 7% of patients achieved ITR after An additional 7% of patients achieved ITR after

30 minutes30 minutes● Of the 96% of patients who did not have Of the 96% of patients who did not have

protocol violations with selection of ITR, protocol violations with selection of ITR, 90% 90% achieved the ITR within 30 minachieved the ITR within 30 min

► From drug initiation to 30 minutesFrom 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 minTime to a 15% drop in blood pressure 9.5 min

► 89% of patients achieved pre-specified ITR within 89% of patients achieved pre-specified ITR within 30 minutes30 minutes● An additional 7% of patients achieved ITR after An additional 7% of patients achieved ITR after

30 minutes30 minutes● Of the 96% of patients who did not have Of the 96% of patients who did not have

protocol violations with selection of ITR, protocol violations with selection of ITR, 90% 90% achieved the ITR within 30 minachieved the ITR within 30 min

► From drug initiation to 30 minutesFrom 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 minTime to a 15% drop in blood pressure 9.5 min

VELOCITY VELOCITY

K-M Analysis

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

0

10

20

30

40

50

60

70

80

90

10091%

Minutes

Per

cent

of

Pat

ient

sP

erce

nt o

f P

atie

nts

Probability of Having Attained SBP Probability of Having Attained SBP Initial Target RangeInitial Target Range

Probability of Having Attained SBP Probability of Having Attained SBP Initial Target RangeInitial Target Range

VELOCITY: Efficacy Results VELOCITY: Efficacy Results

mITT population

Time after start of infusion (min.)

% R

educ

tion

from

Bas

elin

e S

BP

(Mea

n ±

SE

)

3 6 9 12 15 18 21 24 27 30-25

-20

-15

-10

-5

0

-6%-6%

-16.5%-16.5%-21%-21%

Change in BP (30 minutes)Change in BP (30 minutes)Change in BP (30 minutes)Change in BP (30 minutes)

VELOCITY: Results VELOCITY: Results

► 92.9% of patients were administered clevidipine 92.9% of patients were administered clevidipine for for ≥18 hours≥18 hours● The infusion rate was maintained or further The infusion rate was maintained or further

titrated after 30 min to the desired long-term titrated after 30 min to the desired long-term (≥18 h) SBP target (≥18 h) SBP target

● SBP reduction at 18 hours was -27% (-55 SBP reduction at 18 hours was -27% (-55 mmHg) from baseline mmHg) from baseline

● Patients were maintained on a steady infusion of Patients were maintained on a steady infusion of clevidipine without evidence of tachyphylaxis or clevidipine without evidence of tachyphylaxis or drug accumulationdrug accumulation

► 92.9% of patients were administered clevidipine 92.9% of patients were administered clevidipine for for ≥18 hours≥18 hours● The infusion rate was maintained or further The infusion rate was maintained or further

titrated after 30 min to the desired long-term titrated after 30 min to the desired long-term (≥18 h) SBP target (≥18 h) SBP target

● SBP reduction at 18 hours was -27% (-55 SBP reduction at 18 hours was -27% (-55 mmHg) from baseline mmHg) from baseline

● Patients were maintained on a steady infusion of Patients were maintained on a steady infusion of clevidipine without evidence of tachyphylaxis or clevidipine without evidence of tachyphylaxis or drug accumulationdrug accumulation

Long-Term InfusionLong-Term Infusion Long-Term InfusionLong-Term Infusion

VELOCITY: Efficacy Results VELOCITY: Efficacy Results

Time after start of infusion (hours)

% S

BP

Red

uctio

n fr

om B

asel

ine

(Mea

n ±

SE

)%

SB

P R

educ

tion

from

Bas

elin

e(M

ean

± S

E)

0 3 6 9 12 15 18

0

-5

-10

-15

-20

-25

-30

Additional Additional TitrationTitration

BP AdjustmentBP Adjustmentand Maintenanceand Maintenance

30 min.30 min.Titration to ITRTitration to ITR

Change in BP (18 hours)Change in BP (18 hours)Change in BP (18 hours)Change in BP (18 hours)

VELOCITY: Results VELOCITY: Results

► 92.3% of all patients were maintained on 92.3% of all patients were maintained on clevidipine monotherapy without the need for clevidipine monotherapy without the need for additional IV antihypertensive therapyadditional IV antihypertensive therapy

► Clevidipine was well tolerated for a median Clevidipine was well tolerated for a median duration of 21 hours (max 60 hours)duration of 21 hours (max 60 hours)

► 118 patients were eligible for transition to oral 118 patients were eligible for transition to oral antihypertensive therapyantihypertensive therapy● 97.5% did so to a defined target BP within 6 hours of 97.5% did so to a defined target BP within 6 hours of

cessation of clevidipine infusioncessation of clevidipine infusion

► 92.3% of all patients were maintained on 92.3% of all patients were maintained on clevidipine monotherapy without the need for clevidipine monotherapy without the need for additional IV antihypertensive therapyadditional IV antihypertensive therapy

► Clevidipine was well tolerated for a median Clevidipine was well tolerated for a median duration of 21 hours (max 60 hours)duration of 21 hours (max 60 hours)

► 118 patients were eligible for transition to oral 118 patients were eligible for transition to oral antihypertensive therapyantihypertensive therapy● 97.5% did so to a defined target BP within 6 hours of 97.5% did so to a defined target BP within 6 hours of

cessation of clevidipine infusioncessation of clevidipine infusion

Long-Term InfusionLong-Term InfusionLong-Term InfusionLong-Term Infusion

VELOCITY: Safety ResultsVELOCITY: Safety Results

► 2 patients (1.6%) fell below the lower ITR limit within 2 patients (1.6%) fell below the lower ITR limit within first 3 min. of clevidipine infusionfirst 3 min. of clevidipine infusion● One patient had a narrower than specified ITR (205-195 One patient had a narrower than specified ITR (205-195

mmHg), SBP was 15 mmHg below the lower limit mmHg), SBP was 15 mmHg below the lower limit ● One patient lower limit was 160 mmHg and SBP fell One patient lower limit was 160 mmHg and SBP fell

4 mmHg below this4 mmHg below this● Both patients continued clevidipine infusion beyond Both patients continued clevidipine infusion beyond

18 hr without AEs18 hr without AEs

► No clinical hypotensive events related to clevidipine No clinical hypotensive events related to clevidipine were reported throughout the studywere reported throughout the study

► 2 patients (1.6%) fell below the lower ITR limit within 2 patients (1.6%) fell below the lower ITR limit within first 3 min. of clevidipine infusionfirst 3 min. of clevidipine infusion● One patient had a narrower than specified ITR (205-195 One patient had a narrower than specified ITR (205-195

mmHg), SBP was 15 mmHg below the lower limit mmHg), SBP was 15 mmHg below the lower limit ● One patient lower limit was 160 mmHg and SBP fell One patient lower limit was 160 mmHg and SBP fell

4 mmHg below this4 mmHg below this● Both patients continued clevidipine infusion beyond Both patients continued clevidipine infusion beyond

18 hr without AEs18 hr without AEs

► No clinical hypotensive events related to clevidipine No clinical hypotensive events related to clevidipine were reported throughout the studywere reported throughout the study

mITT population

VELOCITY VELOCITY Transition to Oral TherapyTransition to Oral Therapy

► Transition successful in 91.3% of patientsTransition successful in 91.3% of patients

► Of the 11 not transitioning to oral therapy Of the 11 not transitioning to oral therapy within 6 hr of IV terminationwithin 6 hr of IV termination::● 2.4% could not be converted from clevidipine2.4% could not be converted from clevidipine● 3.2% did not reach the 18-hr endpoint for 3.2% did not reach the 18-hr endpoint for

transition eligibilitytransition eligibility

● 3.2% had contraindications to oral transition3.2% had contraindications to oral transition

► Of 118 patients eligible for transition, Of 118 patients eligible for transition, 97.5% did so within 6 hr97.5% did so within 6 hr

► Transition successful in 91.3% of patientsTransition successful in 91.3% of patients

► Of the 11 not transitioning to oral therapy Of the 11 not transitioning to oral therapy within 6 hr of IV terminationwithin 6 hr of IV termination::● 2.4% could not be converted from clevidipine2.4% could not be converted from clevidipine● 3.2% did not reach the 18-hr endpoint for 3.2% did not reach the 18-hr endpoint for

transition eligibilitytransition eligibility

● 3.2% had contraindications to oral transition3.2% had contraindications to oral transition

► Of 118 patients eligible for transition, Of 118 patients eligible for transition, 97.5% did so within 6 hr97.5% did so within 6 hr

ConclusionsConclusions

► Clevidipine lowered BP to pre-specified target range Clevidipine lowered BP to pre-specified target range in ~90% of patients within 30 minutesin ~90% of patients within 30 minutes

► Patients reached target BP without overshoot in a Patients reached target BP without overshoot in a median 10.9 minutesmedian 10.9 minutes

► Clevidipine was easy to administer and well toleratedClevidipine was easy to administer and well tolerated● Peripheral venous administrationPeripheral venous administration● BP monitoring via a cuff BP monitoring via a cuff ● Non-weight based dosing regimenNon-weight based dosing regimen

► Clevidipine was effective and well tolerated after Clevidipine was effective and well tolerated after prolonged infusion and maintained BP in patients with prolonged infusion and maintained BP in patients with acute and severe hypertensionacute and severe hypertension

► Clevidipine lowered BP to pre-specified target range Clevidipine lowered BP to pre-specified target range in ~90% of patients within 30 minutesin ~90% of patients within 30 minutes

► Patients reached target BP without overshoot in a Patients reached target BP without overshoot in a median 10.9 minutesmedian 10.9 minutes

► Clevidipine was easy to administer and well toleratedClevidipine was easy to administer and well tolerated● Peripheral venous administrationPeripheral venous administration● BP monitoring via a cuff BP monitoring via a cuff ● Non-weight based dosing regimenNon-weight based dosing regimen

► Clevidipine was effective and well tolerated after Clevidipine was effective and well tolerated after prolonged infusion and maintained BP in patients with prolonged infusion and maintained BP in patients with acute and severe hypertensionacute and severe hypertension

What We Learned From VELOCITYWhat We Learned From VELOCITYWhat We Learned From VELOCITYWhat We Learned From VELOCITY

SummarySummary

► Hypertension is extremely prevalent in US society, Hypertension is extremely prevalent in US society, and as population ages, hypertensive crises will and as population ages, hypertensive crises will become increasingly common in the EDbecome increasingly common in the ED● Debate over terminology and numerical definitions is too Debate over terminology and numerical definitions is too




► Hypertension is extremely prevalent in US society, Hypertension is extremely prevalent in US society, and as population ages, hypertensive crises will and as population ages, hypertensive crises will become increasingly common in the EDbecome increasingly common in the ED● Debate over terminology and numerical definitions is too Debate over terminology and numerical definitions is too




SummarySummary

► As ED LOS increases, care of BP derangements As ED LOS increases, care of BP derangements will fall ever more in the purview of the emergency will fall ever more in the purview of the emergency physicianphysician

► Even with prompt transfer of HU/HE patients to Even with prompt transfer of HU/HE patients to the inpatient setting, this is one of the few areas the inpatient setting, this is one of the few areas where emergency physicians and cardiologists where emergency physicians and cardiologists approach definitive care in much the same wayapproach definitive care in much the same way

► Clevidipine may soon afford a novel, safe, and Clevidipine may soon afford a novel, safe, and multi-setting, multidisciplinary approach to acute multi-setting, multidisciplinary approach to acute severe hypertensionsevere hypertension

► As ED LOS increases, care of BP derangements As ED LOS increases, care of BP derangements will fall ever more in the purview of the emergency will fall ever more in the purview of the emergency physicianphysician

► Even with prompt transfer of HU/HE patients to Even with prompt transfer of HU/HE patients to the inpatient setting, this is one of the few areas the inpatient setting, this is one of the few areas where emergency physicians and cardiologists where emergency physicians and cardiologists approach definitive care in much the same wayapproach definitive care in much the same way

► Clevidipine may soon afford a novel, safe, and Clevidipine may soon afford a novel, safe, and multi-setting, multidisciplinary approach to acute multi-setting, multidisciplinary approach to acute severe hypertensionsevere hypertension

Optimizing Blood Pressure Management Optimizing Blood Pressure Management in the Perioperative andin the Perioperative and

Cardiothoracic Surgery SettingCardiothoracic Surgery Setting

Relationship and Relevance of Acute Pressure Control and Emerging Agents - Relationship and Relevance of Acute Pressure Control and Emerging Agents - The ECLIPSE TrialThe ECLIPSE Trial

Optimizing Blood Pressure Management Optimizing Blood Pressure Management in the Perioperative andin the Perioperative and

Cardiothoracic Surgery SettingCardiothoracic Surgery Setting

Relationship and Relevance of Acute Pressure Control and Emerging Agents - Relationship and Relevance of Acute Pressure Control and Emerging Agents - The ECLIPSE TrialThe ECLIPSE Trial

Solomon Aronson, M.D., FACC, FAHA, FACCP, FASEFACC, FAHA, FACCP, FASEFACC,FCCP,FAHA,FASE

Professor and Executive Vice ChairmanDept of Anesthesiology

Duke University Health System

Solomon Aronson, M.D., FACC, FAHA, FACCP, FASEFACC, FAHA, FACCP, FASEFACC,FCCP,FAHA,FASE

Professor and Executive Vice ChairmanDept of Anesthesiology

Duke University Health System

Investigation Investigation ●● Innovation Innovation ●● Application Application

““A man is as old as his arteries”A man is as old as his arteries”““A man is as old as his arteries”A man is as old as his arteries”

Sir William OslerSir William Osler

Investigation Investigation ●● Innovation Innovation ●● Application Application

0

20

40

60

80

1990 2000 2010 2020 2030 2040 2050

The Aging PopulationThe Aging PopulationP

op

ula

tion

(in

m

illion

s)

30 35 40 45 50 55 60 70 65 75

Age (Years)

0

2

4

6

8

10

Per

cen

t1976-19801988-1991

CHF mortality

National Health & Nutrition Examination Survey II 1976-1980 and 1988-1991National Health & Nutrition Examination Survey II 1976-1980 and 1988-1991

Risk Risk >> 115/75 115/75 90% pts 90% pts >> 55 years of age 55 years of age

Risk Risk >> 115/75 115/75 90% pts 90% pts >> 55 years of age 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; 2413-46,1997JAMA 289; 2560-72,2003

Joint National Committee (JNC-6 & 7) On Prevention, Detection, Evaluation, & Treatment of Hypertension:Arch Int Med 157; 2413-46,1997JAMA 289; 2560-72,2003

Hypertension: Costs and ConsequencesHypertension: Costs and Consequences

JNC 7: BP ClassificationJNC 7: BP Classification

BP level (mmHg)*BP level (mmHg)*

SystolicSystolic Diastolic Diastolic

< 120 and < 80< 120 and < 80

120-139 or 80-89120-139 or 80-89

140-159 or 90-99140-159 or 90-99

> 160 or > 100> 160 or > 100

BP level (mmHg)*BP level (mmHg)*

SystolicSystolic Diastolic Diastolic

< 120 and < 80< 120 and < 80

120-139 or 80-89120-139 or 80-89

140-159 or 90-99140-159 or 90-99

> 160 or > 100> 160 or > 100

CategoryCategory

NormalNormal

Pre-hypertensionPre-hypertension

Stage 1 HypertensionStage 1 Hypertension


CategoryCategory

NormalNormal

Pre-hypertensionPre-hypertension



* Use higher value for classification* Use higher value for classification

BPBP typetype Systolic Systolic mmHgmmHg Diastolic Diastolic mmHgmmHg

► OptimalOptimal < 115< 115 && < 75< 75

► Pre – HTNPre – HTN < 140< 140 && < 90< 90

► Isolated DBP HTNIsolated DBP HTN < 140< 140 && > 90> 90

► Isolated SBP HTNIsolated SBP HTN > 140> 140 && < 90< 90

► Pulse Pressure HTNPulse Pressure HTN > 60 mmHg> 60 mmHg

► Orthostatic changesOrthostatic changes Hyper Hyper responseresponse > 20 mmHg > 20 mmHgHypo Hypo responseresponse < 20 < 20

HypertensionHypertension

Mu

scle

sym

pat

het

ic n

erve

act

ivit

y

JACC. 2002;40;119-25.

““White Coat” HypertensionWhite Coat” Hypertension

0

20

40

60

80

NT WHT EHT0

20

40

60

80

NT WHT EHT

Bar

ore

cep

tor

sen

siti

vity

0

2

4

6

8

10

NT WHT EHT

*

†

*†

Chronic HTNChronic HTN

HTN Emergencies

HTN Emergencies

Acute Circulatory Dysfunction

Acute Circulatory Dysfunction

Physiology: Perioperative HTNPhysiology: Perioperative HTN

► Increase SVR , increase preloadIncrease SVR , increase preload► Rapid intravascular volume shiftsRapid intravascular volume shifts► Renin angiotensin activationRenin angiotensin activation► Adrenergic stimulation (cardiac & neural)Adrenergic stimulation (cardiac & neural)► Serotonergic overproductionSerotonergic overproduction► Baroreceptor denervationBaroreceptor denervation► Altered cardiac reflexesAltered cardiac reflexes► Depth anesthesia inadeqDepth anesthesia inadeq► Cross clampCross clamp

► Increase SVR , increase preloadIncrease SVR , increase preload► Rapid intravascular volume shiftsRapid intravascular volume shifts► Renin angiotensin activationRenin angiotensin activation► Adrenergic stimulation (cardiac & neural)Adrenergic stimulation (cardiac & neural)► Serotonergic overproductionSerotonergic overproduction► Baroreceptor denervationBaroreceptor denervation► Altered cardiac reflexesAltered cardiac reflexes► Depth anesthesia inadeqDepth anesthesia inadeq► Cross clampCross clamp

Periop Triggers for Adverse Physiologic StatePeriop Triggers for Adverse Physiologic State

TraumaAnesthesiaStressHypoxiaFastingPainTachycardiaHypo / HyperthermiaHyper / HypotensionHyper / HypoglycemiaAnemia / Bleeding / Transfusion

TraumaAnesthesiaStressHypoxiaFastingPainTachycardiaHypo / HyperthermiaHyper / HypotensionHyper / HypoglycemiaAnemia / Bleeding / Transfusion

InflammatoryHypercoagulableInflammatoryHypercoagulable

Diastolic BPDiastolic BPDiastolic BPDiastolic BPHistorically; perioperative risk defined by this indexHistorically; perioperative risk defined by this index

Systolic BPSystolic BP

Adverse events > with isolated SBP HTN, than DBP HTNAdverse events > with isolated SBP HTN, than DBP HTNAdverse events > with isolated SBP HTN, than DBP HTNAdverse events > with isolated SBP HTN, than DBP HTN

Pulse PressurePulse PressureAdverse events highest with increased PPAdverse events highest with increased PP

Risk of CV Events by Type of HTNRisk of CV Events by Type of HTN

Age Adjusted Risk Ratio*Age Adjusted Risk Ratio* 35-64 yrs 65-94 yrs35-64 yrs 65-94 yrs

Men Women Men WomenMen Women Men Women

Isolated diastolicIsolated diastolic 1.8 1.2 1.2 1.61.8 1.2 1.2 1.6

Isolated systolicIsolated systolic 2.4 1.9 1.9 1.4 2.4 1.9 1.9 1.4

CombinedCombined 2.7 2.2 2.7 2.2 2.2 1.6 2.2 1.6

**Reference groups consist of normotensive personsReference groups consist of normotensive persons

Age Adjusted Risk Ratio*Age Adjusted Risk Ratio* 35-64 yrs 65-94 yrs35-64 yrs 65-94 yrs

Men Women Men WomenMen Women Men Women

Isolated diastolicIsolated diastolic 1.8 1.2 1.2 1.61.8 1.2 1.2 1.6

Isolated systolicIsolated systolic 2.4 1.9 1.9 1.4 2.4 1.9 1.9 1.4

CombinedCombined 2.7 2.2 2.7 2.2 2.2 1.6 2.2 1.6

**Reference groups consist of normotensive personsReference groups consist of normotensive persons

36 Year Follow-Up (Framingham Study According to Age & Sex)

Am Jour of Card; 85, 2000

Negative outcome* O.R. 2.1 p=0.01Negative outcome* O.R. 2.1 p=0.01

Anesth Analg 94;1079- 84,2002Anesth Analg 94;1079- 84,2002Anesth Analg 95;273-7,2002Anesth Analg 95;273-7,2002

*LOS > 10 days, or death SBP > 160 mmHg

Renal O.R. 1.3 (1.0-1.9)Stroke 1.7 (1.2-2.3)LV dysfunction 1.3 (1.0-1.6)Combined 1.4 (1.1-1.7)

Renal O.R. 1.3 (1.0-1.9)Stroke 1.7 (1.2-2.3)LV dysfunction 1.3 (1.0-1.6)Combined 1.4 (1.1-1.7)

Intraoperative Intraoperative

PreoperativePreoperative

Systolic BP: HypertensionSystolic BP: Hypertension

0

10

20

30

20 30 40 50 60 70 80 90

Age

Pre

vale

nce

%P

reva

lenc

e %

WomenWomen

MenMen

Prevalence of IsolatedPrevalence of IsolatedSystolic HypertensionSystolic Hypertension

Circulation 2006;114:2780-7Circulation 2006;114:2780-7

FLOWFLOWFLOWFLOW

PRESSUREPRESSUREPRESSUREPRESSURE

HR x SV = CO

*BP/ CO = SVR

CO x MAP = work

MAP = 1/3 PP + DBP

All in the absence of pulsationsAll in the absence of pulsations

(*BP = MAP -RAP)

Pressure/Flow RelationshipsPressure/Flow Relationships

Rate /1,000 Rate /1,000

35-64 yrs 65-94yrs35-64 yrs 65-94yrs

Pulse Pressure Pulse Pressure (mm Hg)(mm Hg) Women Women Men Men Women Women Men Men

2-392-39 9 9 44 2 2 17 17

40-4940-49 13 13 6 6 16 16 1919

50-5950-59 16 7 32 2216 7 32 22

60-6960-69 22 10 39 2522 10 39 25

70-18270-182 33 16 58 3233 16 58 32

Regression 0.024 0.025 0.024 0.014Regression 0.024 0.025 0.024 0.014

Risk factor 0.018 0.019 0.021 0.010Risk factor 0.018 0.019 0.021 0.010

Rate /1,000 Rate /1,000

35-64 yrs 65-94yrs35-64 yrs 65-94yrs

Pulse Pressure Pulse Pressure (mm Hg)(mm Hg) Women Women Men Men Women Women Men Men

2-392-39 9 9 44 2 2 17 17

40-4940-49 13 13 6 6 16 16 1919

50-5950-59 16 7 32 2216 7 32 22

60-6960-69 22 10 39 2522 10 39 25

70-18270-182 33 16 58 3233 16 58 32

Regression 0.024 0.025 0.024 0.014Regression 0.024 0.025 0.024 0.014

Risk factor 0.018 0.019 0.021 0.010Risk factor 0.018 0.019 0.021 0.010

Framingham Study (30 Year Follow-Up)

The American Journal of Cardiology Vol 85, January 15, 2000

Pulse Pressure and Cardiac RiskPulse Pressure and Cardiac Risk

Wave PropagationWave Propagation

Proximal Aorta:Proximal Aorta: Compliant Compliant (accepts SV with low SBP)(accepts SV with low SBP)

FemoralFemoral

Brach.Brach. stifferstiffer

RadialRadial

Proximal Aorta:Proximal Aorta: Compliant Compliant (accepts SV with low SBP)(accepts SV with low SBP)

FemoralFemoral

Brach.Brach. stifferstiffer

RadialRadial

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 distendingEnergy distendingarterial tree in systole arterial tree in systole returned in diastolereturned in diastole

due to proximal aorta due to proximal aorta elasticityelasticity

Energy distendingEnergy distendingarterial tree in systole arterial tree in systole returned in diastolereturned in diastole

due to proximal aorta due to proximal aorta elasticityelasticity

Aronson et al; Circulation 115,733-42,2007

PP and Renal RISK INDEXPP and Renal RISK INDEX

Preoperative Risk Factors Score Intraoperative Risk Factors Score

Age > 75 years 7 > Inotropes 10

Pulse Pressure (mm HG) Intra-aortic Balloon Pump 15 40 0 41-60 4 Cardiopulmonary Bypass 6 61-80 8 >122 min 81-100 12 >100 16

History CHF 9 MI 6 Renal Disease 13

Preoperative Risk Factors Score Intraoperative Risk Factors Score

Age > 75 years 7 > Inotropes 10

Pulse Pressure (mm HG) Intra-aortic Balloon Pump 15 40 0 41-60 4 Cardiopulmonary Bypass 6 61-80 8 >122 min 81-100 12 >100 16

History CHF 9 MI 6 Renal Disease 13

Each 20 mmHg increase PP > 40mmHg additive risk (OR 1.49; CI, 1.17-1.89 (P = 0.001)

Each 20 mmHg increase PP > 40mmHg additive risk (OR 1.49; CI, 1.17-1.89 (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 = 0.0003) renal dysfunction [5 % vs. 3 %; P = 0.0004 renal failure 5.5 % vs. 2.5 %; P = 0.001]

Renal injury doubled if PP > 80mmHg (8.6 % vs. 4.5 %; P = 0.0003) renal dysfunction [5 % vs. 3 %; P = 0.0004 renal failure 5.5 % vs. 2.5 %; P = 0.001]

Renal RISK INDEXRenal RISK INDEX

Aronson et al; Circulation 115,733-42,2007

Fontes, Aronson, Mathew, et al. Analg Anes 2007Benjo, Thompson, Fine, et al Hypertension 2007

Fontes, Aronson, Mathew, et al. Analg Anes 2007Benjo, 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 PPCardiac & 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, 1.13-1.62) (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, 1.13-1.62) (P = 0.001)

Blood Pressure ComponentsBlood 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)

Hypertension and RiskHypertension and Risk

The situation The situation ((type of surgery, CHF, stroke, etctype of surgery, CHF, stroke, etc.).)

The patient The patient (Type of HTN)(Type of HTN)

The condition The condition (Treatment effectiveness)(Treatment effectiveness)

The situation The situation ((type of surgery, CHF, stroke, etctype of surgery, CHF, stroke, etc.).)

The patient The patient (Type of HTN)(Type of HTN)

The condition The condition (Treatment effectiveness)(Treatment effectiveness)

The situation The situation (type of surgery)(type of surgery)The situation The situation (type of surgery)(type of surgery)


ECLIPSE Secondary Endpoint ECLIPSE Secondary Endpoint Systolic Blood Pressure Control Over 24 HoursSystolic Blood Pressure Control Over 24 Hours

Time (hours)

SBP

Lower

Upper

0 6 12 2418

Lower

ECLIPSE Trial; Presented at ACC, March 27, 2007.

Logistic Regression Results Logistic Regression Results Predictors of MortalityPredictors of Mortality

Mortality Predictors

P-Value

Odds Ratio

95% CI [Lower Limit, Upper Limit]

Surgery Duration (hour) <0.0001 1.517 [1.240, 1.856]

Age (year) 0.0003 1.070 [1.031, 1.110]

Pre-op Creatinine ≥ 1.2 mg/dL 0.0031 2.670 [1.392, 5.122]

AUC (area outside the range)AUC (area outside the range) 0.00690.0069 1.0031.003 [1.001, 1.004][1.001, 1.004]

Additional surgical procedures 0.0089 2.409 [1.246, 4.655]

Pre-op Hgb (g/dL) 0.0135 0.824 [0.707, 0.961]

Pre-op SBP >160 or DBP > 105 0.0228 2.386 [1.147, 4.963]

History of COPD 0.0228 2.326 [1.125, 4.812]

History of recent MI (<6 months prior) 0.0312 2.197 [1.073, 4.497]

I mmHg x 60 min I mmHg x 60 min

2 mmHg x 60 min

3 mmHg x 60 min3 mmHg x 60 min

4 mmHg x 60 min4 mmHg x 60 min

5 mmHg x 60 min

30-Day Mortality by Magnitude of AUC30-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]

Perioperative BP lability predicts mortality in Perioperative BP lability predicts mortality in pts undergoing cardiac surgerypts undergoing cardiac surgery

5238 pts 3.1 million BP evaluations (P=0.0139, OR =1.02 per100mmHg.min, 95% CI [1.004-1.037]

SCCM 2008, Hawaii

P-Value Odds Ratio95% CI

[Lower Limit, Upper Limit]

Minutes > 135 or < 95 mmHg per incident (min)

<0.0001 1.068 1.036-1.102

Surgery length (min) 0.475 0.999 0.997-1.002

Parsonnet <0.0001 1.069 1.045-1.094

Mean Duration of IncursionsMean Duration of Incursions

Minutes <95 mmHg (min) 0.004 1.025 1.008-1.042

Minutes >135 mmHg (min) 0.013 1.033 1.007-1.059

Adverse Events & BP ControlAdverse Events & BP Control

AUC Quartile

All agents* n/N (%)

MI 1st 6/380 (1.6)

4th 11/378 (2.9)

Stroke 1st 4/380 (1.1)

4th 6/378 (1.6)

Renal 1st 24/380 (6.3)

4th 39/378 (10.3)

*ECLIPSE clinical trials, N=1512 SBP range of 75 – 145 (pre & post-op), 65-135 (intra-op)

Predictors of postop renal dysfunction

Aronson et al ASA 2007

Odds ratio (95% CI)Odds ratio (95% CI) pp

Preop serum Cr > 1.2 mg/dLPreop serum Cr > 1.2 mg/dL 4.71 (3.067-7.235)4.71 (3.067-7.235) <0.0001<0.0001

Race (African American)Race (African American) 2.166 (1.19-3.943)2.166 (1.19-3.943) 0.01140.0114

Primary CABG + valvePrimary CABG + valve 1.957 (1.158-3.307)1.957 (1.158-3.307) 0.01220.0122

BP (4BP (4thth quartile AUC*) quartile AUC*) 1.725 (1.111-2.68)1.725 (1.111-2.68) 0.01520.0152

Surgery duration (hours)Surgery duration (hours) 1.263 (1.054-1.515)1.263 (1.054-1.515) 0.01160.0116

Age (years)Age (years) 1.037 (1.013-1.062)1.037 (1.013-1.062) 0.00230.0023

BMIBMI 1.05 (1.016-1.086)1.05 (1.016-1.086) 0.00420.0042

Odds ratio (95% CI)Odds ratio (95% CI) pp

Preop serum Cr > 1.2 mg/dLPreop serum Cr > 1.2 mg/dL 4.71 (3.067-7.235)4.71 (3.067-7.235) <0.0001<0.0001

Race (African American)Race (African American) 2.166 (1.19-3.943)2.166 (1.19-3.943) 0.01140.0114

Primary CABG + valvePrimary CABG + valve 1.957 (1.158-3.307)1.957 (1.158-3.307) 0.01220.0122

BP (4BP (4thth quartile AUC*) quartile AUC*) 1.725 (1.111-2.68)1.725 (1.111-2.68) 0.01520.0152

Surgery duration (hours)Surgery duration (hours) 1.263 (1.054-1.515)1.263 (1.054-1.515) 0.01160.0116

Age (years)Age (years) 1.037 (1.013-1.062)1.037 (1.013-1.062) 0.00230.0023

BMIBMI 1.05 (1.016-1.086)1.05 (1.016-1.086) 0.00420.0042

Vasodilator Effects of Vasodilator Effects of Clevidipine on Human IMAClevidipine on Human IMA

► Clevidipine was effective Clevidipine was effective anti-vasospasm agent at anti-vasospasm agent at therapeuticallytherapeuticallyused dosesused doses

► Clevidipine was effective Clevidipine was effective anti-vasospasm agent at anti-vasospasm agent at therapeuticallytherapeuticallyused dosesused doses

Huraux C, Makita T, Szlam F, Nordlander M, Levy JH: Anesth Analg 1997; 85: 1000-1004.

The condition The condition (Treatment effectiveness)(Treatment effectiveness)The condition The condition (Treatment effectiveness)(Treatment effectiveness)


RESULTS — Primary EndpointRESULTS — Primary Endpoint

2.8%2.3%

1.1%

7.9%

3.8%

2.4%1.7%

7.9%

0%

2%

4%

6%

8%

10%

Clevidipine

Comparators

DeathDeath

30-D

ay E

vent

s (%

)

n=729 n=700 n=707 n=700 n=705 n=712 n=710n=719

MIMI StrokeStroke RenalDysfunction

RenalDysfunction

AUC Targeted BP Range by TreatmentAUC Targeted BP Range by Treatment

4.14 4.37

1.76

8.87

10.50

1.69

0

2

4

6

8

10

12

ECLIPSENTG

ECLIPSENTG

ECLIPSESNP

ECLIPSESNP ECLIPSE

NICECLIPSE

NIC

mm

Hg

x m

in/h

p = 0.0006

p = 0.0027

p = 0.8508

Clevidipinen=269

NTGn=278

Clevidipinen=295

SNPn=284

Clevidipinen=187

NICn=194

Median AUC

Range = Pre-/post-op SBP 75-145, Intra-op SBP 65-135

Median AUC


Peri-operative Post-operativeOnly

AUC Narrowed BP Range by TreatmentAUC Narrowed BP Range by Treatment

83.74

100.17

76.95

108.57

127.87

101.59

0

20

40

60

80

100

120

140

ECLIPSENTG

ECLIPSESNP

ECLIPSENIC

mm

Hg

x m

in/h

p = 0.0556

p = 0.0068

p = 0.0231

Clevidipinen=269

NTGn=278

Clevidipinen=295

SNPn=284

Clevidipinen=187

NICn=194

Median AUC


Peri-operative Post-operativeOnly

SNP or NTG assoc with increased 30d mortality compared to Clevidipine: SNP or NTG assoc with increased 30d mortality compared to Clevidipine:

ECLIPSE Trials

Preoperative BP ControlPreoperative BP Control

p-value O.R 95% CI

Treatment CLV v SNP/NTG 0.0155 7.5 1.5, 38.4

Additional procedure 0.0085 5.8 1.6, 21.2

Pre-op Scr > 1.2mg/dl 0.0168 4.9 1.3, 17.8

Effects on Central Hemodynamics: Clevidipine Effects on Central Hemodynamics: Clevidipine Pharmacodynamically Friendly vs. SNPPharmacodynamically Friendly vs. SNP

-40

-30

-20

-10

0

10

20

30

40

MAP CO TPR dP/dt LVEDP

Clevidipine

SNP

Experiment in anesthetized dogs* p < 0.05Norlander, M.B, etal. B J Aneasth 1996;

*

*

* *

100

90

80

70

60

110

120

130

140

Cha

nge

from

pre

-dru

g (%

)C

hang

e fr

om p

re-d

rug

(%)

“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”

Clevidipine — Metabolized by Clevidipine — Metabolized by Plasma and Tissue EsterasesPlasma and Tissue Esterases

► Clevidipine is rapidly metabolized by Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue esterases in blood and extravascular tissue to an inactive carboxylic acid metaboliteto an inactive carboxylic acid metabolite

► Clevidipine is rapidly metabolized by Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue esterases in blood and extravascular tissue to an inactive carboxylic acid metaboliteto an inactive carboxylic acid metabolite

+OH

OHH

O

Clevidipine

Cl

OO

O

O

NH

Cl

O

O

*Esterases +O

O

NH

Cl

O

O

Cl

H

Primary metabolite

*The chiral center of clevidipine.Reproduced from Ericsson H, et al. Eur J Clin Pharmacol. 1999;55:61-67.Bailey JM, et al. Anesthesiology. 2002;96:1086-1094.Ericsson H, et al. Drug Metab Dispos. 1999;27:558-564.Ericsson H et al. Eur J Clin Pharmacol. 1999;55:61-67.Ericsson H, et al. Eur J Pharm Sci. 1999;8:29-37.

SBP changes for patients receiving

clevidipine during a 30-minute treatment period.

SBP changes for patients receiving

clevidipine during a 30-minute treatment period.

10

5

0

–5

–10

–15

–20

–25

–300 5 10 15 20 25 30

% C

han

ge

Fro

m B

asel

ine

Time (min)

SBP

SBP Changes SBP Changes

ClevidipineClevidipine

► BP-lowering effects are seen within 2–3 min of infusionBP-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 infusionBP-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;92:993-1001.Ericsson H, et al. Anesthesiology. 2000;92:993-1001.Ericsson H, et al. Br J Clin Pharmacol. 1999;47:531-538.

120

100

80

60

40

20

0

0 5 10 15 20 35

Cle

vid

ipin

e C

on

ce

ntr

ati

on

at

Cs

s (

nm

ol/

L)*

Dose Rate (nmol/kg/min)25 30

Clinically relevant half-life: approx 1 minute

Arterial & venous blood samplesArterial & venous blood samples

Clevidipine — Rapid OffsetClevidipine — Rapid Offset

► After discontinuation of clevidipine infusion, there After discontinuation of clevidipine infusion, there was rapid clearancewas rapid clearance

► BP returned to baseline in <10 minutes in healthy BP returned to baseline in <10 minutes in healthy volunteersvolunteers

► After discontinuation of clevidipine infusion, there After discontinuation of clevidipine infusion, there was rapid clearancewas rapid clearance

► BP returned to baseline in <10 minutes in healthy BP returned to baseline in <10 minutes in healthy volunteersvolunteers

Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001.

100

90

80

70

60

50

40–5 0 5 10 15 20 35

MA

P (

mm

Hg

) a

nd

H

R (

be

ats

/min

)

Time (min)

25 30

Clevidipine InfusionClevidipine InfusionMAP

The patient The patient (Type of HTN)(Type of HTN)The patient The patient (Type of HTN)(Type of HTN)


Hypertension,1999;34:375-80Hypertension,1999;34:375-80

• • Each 10 mm Hg increase in PP:Each 10 mm Hg increase in PP: 11% increase in stroke11% increase in stroke• • Each 10 mm Hg increase in PP:Each 10 mm Hg increase in PP: 11% increase in stroke11% increase in stroke

DBP, MAP, SBP and PPDBP, 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 stroke20% increase in stroke• • Each 10 mm Hg rise in MAP:Each 10 mm Hg rise in MAP: 20% increase in stroke20% increase in stroke

• • Each 10 mm Hg increase in PP:Each 10 mm Hg increase in PP: 16% increase 16% increase in death and 12% increase in recurrent MIin death and 12% increase in recurrent MI• • Each 10 mm Hg increase in PP:Each 10 mm Hg increase in PP: 16% increase 16% increase in death and 12% increase in recurrent MIin death and 12% increase in recurrent MI

Cardiac mass associated with SPBCardiac mass associated with SPB Work to drive blood = SBPWork to drive blood = SBP despite MAP & SVRdespite MAP & SVRCardiac mass associated with SPBCardiac mass associated with SPB Work to drive blood = SBPWork to drive blood = SBP despite MAP & SVRdespite MAP & SVR

Increase PP associated with decreased coronary BFIncrease PP associated with decreased coronary BF Increase PP associated with decreased coronary BFIncrease PP associated with decreased coronary BF

J – Curve HypothesisJ – Curve Hypothesis

Lowering DBP Lowering DBP (too much)(too much) increases risk for coronary events increases risk for coronary events … in pts CAD & wide pulse pressures (> 60 mmHg)… in pts CAD & wide pulse pressures (> 60 mmHg)

Lowering DBP Lowering DBP (too much)(too much) increases risk for coronary events increases risk for coronary events … in pts CAD & wide pulse pressures (> 60 mmHg)… in pts CAD & wide pulse pressures (> 60 mmHg)

Farnett et al. JAMA, 265:489-95, 1991Farnett et al. JAMA, 265:489-95, 1991Farnett et al. JAMA, 265:489-95, 1991Farnett et al. JAMA, 265:489-95, 1991

J – Curve HypothesisJ – Curve Hypothesis

-40

-30

-20

-10

0

10

Esmolol

Nitroprusside

Gray Rj. Am J Cardiol 1985;56:49F-56FGray Rj. Am J Cardiol 1985;56:49F-56FGray Rj. Am J Cardiol 1985;56:49F-56FGray Rj. Am J Cardiol 1985;56:49F-56F

*P < 0.05 vs baseline*P < 0.05 vs baseline

+P < 0.05 vs. esmolol+P < 0.05 vs. esmolol

*P < 0.05 vs baseline*P < 0.05 vs baseline

+P < 0.05 vs. esmolol+P < 0.05 vs. esmolol

PercentPercentChangeChangePercentPercentChangeChange

HRHR SBPSBP DBPDBP PaOPaO22HRHR SBPSBP DBPDBP PaOPaO22

CAFÉ CAFÉ ((conduit artery function evaluation )conduit artery function evaluation )

Sub-study ofSub-study of ASCOT ASCOT (Anglo-Scandinavian cardiac outcomes trial)`(Anglo-Scandinavian cardiac outcomes trial)`

Circulation 113;1213-25,2006

2199 pts (5 centers)

2 regimes atenolol+/- thiazide amlodipine +/- perindopril

Central v Brach BPCV, renal outcomes

2199 pts (5 centers)

2 regimes atenolol+/- thiazide amlodipine +/- perindopril

Central v Brach BPCV, renal outcomes

BP drugs effect central & brachial differentCentral PP principal determinant in outcomes BP drugs effect central & brachial differentCentral PP principal determinant in outcomes

115

120

125

130

135

140

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7

Time (Years)

mm

HG

Atenolol

Amlodipine

Brachial SBP Diff Mean (AUC) = 0.7 (-0.4,1.7) mmHG

Central SBPDiff Mean (AUC) = 4.3 (3.3, 5.4) mmHG

AUC

133.9

133.2

121.2

125.5

Atenolol 86 243 324 356 445 372 462 270 339 128 85 1031

Amlodipine 88 248 329 369 475 406 508 278 390 126 101 1042

p=0.07

p<0.0001

Ao. Stiffness betterAo. Stiffness better predictor of CV mortality predictor of CV mortality than age, BP & cardiac massthan 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 1987Am J Cardiol 1987

Summary ECLIPSE Trial ECLIPSE Trial

► Largest safety intravenous anti-htn program (n=1,512) Largest safety intravenous anti-htn program (n=1,512) examined management of acute, severe periop htn examined management of acute, severe periop htn

► Balanced demographics and baseline characteristicsBalanced demographics and baseline characteristics

► Met primary end points with adverse event rates Met primary end points with adverse event rates comparable across groups incd Afib rates comparable across groups incd Afib rates

► Better BP control compared with SNP and NTGBetter BP control compared with SNP and NTG

► Largest safety intravenous anti-htn program (n=1,512) Largest safety intravenous anti-htn program (n=1,512) examined management of acute, severe periop htn examined management of acute, severe periop htn

► Balanced demographics and baseline characteristicsBalanced demographics and baseline characteristics

► Met primary end points with adverse event rates Met primary end points with adverse event rates comparable across groups incd Afib rates comparable across groups incd Afib rates

► Better BP control compared with SNP and NTGBetter BP control compared with SNP and NTG

Documents

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