The Relationship between Acute Pressure Derangements & Comprehensive Vascular Protection in the Setting of CT Surgery Solomon Aronson, MD Program Co-Chairman.

The Relationship between Acute Pressure The Relationship between Acute Pressure Derangements & Comprehensive Derangements & Comprehensive

Vascular Protection in the Setting of Vascular Protection in the Setting of CT SurgeryCT Surgery



Solomon Aronson, MDSolomon Aronson, MDProgram Co-ChairmanProgram Co-ChairmanFACC, FCCP, FAHA, FASEFACC, FCCP, FAHA, FASE

Professor and Executive Vice ChairmanProfessor and Executive Vice ChairmanDept of AnesthesiologyDept of Anesthesiology

Duke University Health System Duke University Health System




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 manage the hemodynamic derangements and complications of serious and/or life-threatening elevations in systolic and/or diastolic blood pressure in the perioperative setting.

► Learn how to select among intravenous pharmacologic agents, including calcium channel blockers/dihydropyridines, that offer unique benefits for blood pressure control in the setting of cardiovascular disease.

► Learn how landmark trials and analyses focusing on BP reduction may have an impact on current and future strategies for management of BP elevations in the setting of cardiovascular surgery.

► Be able to assess the need for and implement optimal BP-lowering strategies for patients with serious and/or life-threatening elevations in systolic and/or diastolic BP in the setting of cardiothoracic surgery, with a special focus on neurologic end point optimization.

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

► Learn to manage the hemodynamic derangements and complications of serious and/or life-threatening elevations in systolic and/or diastolic blood pressure in the perioperative setting.

► Learn how to select among intravenous pharmacologic agents, including calcium channel blockers/dihydropyridines, that offer unique benefits for blood pressure control in the setting of cardiovascular disease.

► Learn how landmark trials and analyses focusing on BP reduction may have an impact on current and future strategies for management of BP elevations in the setting of cardiovascular surgery.

► Be able to assess the need for and implement optimal BP-lowering strategies for patients with serious and/or life-threatening elevations in systolic and/or diastolic BP in the setting of cardiothoracic surgery, with a special focus on neurologic end point optimization.

Program FacultyProgram FacultyProgram FacultyProgram Faculty

Solomon Aronson, MDSolomon Aronson, MDProgram Co-ChairmanProgram Co-ChairmanProfessor of AnesthesiologyProfessor of AnesthesiologyDuke University Medical CenterDuke University Medical CenterExecutive Vice ChairExecutive Vice ChairDepartment of AnesthesiologyDepartment of AnesthesiologyDurham, North CarolinaDurham, North Carolina

Jerrold H. Levy, MDJerrold H. Levy, MDProgram Co-ChairmanProgram Co-ChairmanProfessor and Deputy Chair for ResearchProfessor and Deputy Chair for ResearchEmory University School of MedicineEmory University School of MedicineDirector of Cardiothoracic AnesthesiologyDirector of Cardiothoracic AnesthesiologyCardiothoracic Anesthesiology and Critical CareCardiothoracic Anesthesiology and Critical CareEmory HealthcareEmory HealthcareAtlanta, GeorgiaAtlanta, Georgia

Solomon Aronson, MDSolomon Aronson, MDProgram Co-ChairmanProgram Co-ChairmanProfessor of AnesthesiologyProfessor of AnesthesiologyDuke University Medical CenterDuke University Medical CenterExecutive Vice ChairExecutive Vice ChairDepartment of AnesthesiologyDepartment of AnesthesiologyDurham, North CarolinaDurham, North Carolina

Jerrold H. Levy, MDJerrold H. Levy, MDProgram Co-ChairmanProgram Co-ChairmanProfessor and Deputy Chair for ResearchProfessor and Deputy Chair for ResearchEmory University School of MedicineEmory University School of MedicineDirector of Cardiothoracic AnesthesiologyDirector of Cardiothoracic AnesthesiologyCardiothoracic Anesthesiology and Critical CareCardiothoracic Anesthesiology and Critical CareEmory HealthcareEmory HealthcareAtlanta, GeorgiaAtlanta, Georgia

Charles W. Hogue, Jr., MDCharles W. Hogue, Jr., MDAssociate Professor of AnesthesiologyAssociate Professor of AnesthesiologyDepartment of Anesthesiology and Critical Care Department of Anesthesiology and Critical Care Medicine Medicine Johns Hopkins University Medical SchoolJohns Hopkins University Medical SchoolBaltimore, MarylandBaltimore, Maryland

Charles W. Hogue, Jr., MDCharles W. Hogue, Jr., MDAssociate Professor of AnesthesiologyAssociate Professor of AnesthesiologyDepartment of Anesthesiology and Critical Care Department of Anesthesiology and Critical Care Medicine Medicine Johns Hopkins University Medical SchoolJohns Hopkins University Medical SchoolBaltimore, MarylandBaltimore, Maryland

Faculty COI DisclosuresFaculty COI Disclosures Faculty COI DisclosuresFaculty COI Disclosures

Solomon Aronson, MDSolomon Aronson, MDGrant/Research Support:Grant/Research Support: Abbott Abbott

Consultant:Consultant: The Medicines Company, Regado Bioscience The Medicines Company, Regado Bioscience Speaker’s Bureau:Speaker’s Bureau: Baxter BaxterMajor ShareholderMajor Shareholder: Medwave: Medwave

Jerrold H. Levy, MDGrant/Research SupportGrant/Research Support: Alexion : Alexion Consultant:Consultant: Bayer HealthCare, Dyax, Novo Nordisk, and Organon Bayer HealthCare, Dyax, Novo Nordisk, and Organon

Charles W. Hogue, Jr., MDCharles W. Hogue, Jr., MD Advisory Committee: Advisory Committee: The Medicines CompanyThe Medicines CompanySpeakers Bureau: Speakers Bureau: The Medicines Company and HospiraThe Medicines Company and HospiraResearch Funding: Research Funding: NIH, American Heart AssociationNIH, American Heart Association

Solomon Aronson, MDSolomon Aronson, MDGrant/Research Support:Grant/Research Support: Abbott Abbott

Consultant:Consultant: The Medicines Company, Regado Bioscience The Medicines Company, Regado Bioscience Speaker’s Bureau:Speaker’s Bureau: Baxter BaxterMajor ShareholderMajor Shareholder: Medwave: Medwave

Jerrold H. Levy, MDGrant/Research SupportGrant/Research Support: Alexion : Alexion Consultant:Consultant: Bayer HealthCare, Dyax, Novo Nordisk, and Organon Bayer HealthCare, Dyax, Novo Nordisk, and Organon

Charles W. Hogue, Jr., MDCharles W. Hogue, Jr., MD Advisory Committee: Advisory Committee: The Medicines CompanyThe Medicines CompanySpeakers Bureau: Speakers Bureau: The Medicines Company and HospiraThe Medicines Company and HospiraResearch Funding: Research Funding: NIH, American Heart AssociationNIH, American Heart Association





Solomon Aronson, MDSolomon Aronson, MDProgram Co-ChairmanProgram Co-Chairman

FACC,FCCP,FAHA,FASEFACC,FCCP,FAHA,FASEProfessor and Executive Vice ChairmanProfessor and Executive Vice Chairman

Dept of AnesthesiologyDept of AnesthesiologyDuke University Health System Duke University Health System

Solomon Aronson, MDSolomon Aronson, MDProgram Co-ChairmanProgram Co-Chairman

FACC,FCCP,FAHA,FASEFACC,FCCP,FAHA,FASEProfessor and Executive Vice ChairmanProfessor and Executive Vice Chairman

Dept of AnesthesiologyDept of AnesthesiologyDuke University Health System Duke University Health System


““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 Osler

Sir William OslerSir William Osler


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 HTN by AgePrevalence of HTN by Age

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

HTN Risk HTN Risk >> 115/75 115/75

52.3

35.8

24.6

62.5

39.8

68.474.6

34.3

75.3

01020304050607080

Awareness Treatment Controlled

Pe

rce

nt o

f Po

pu

latio

n

20-39 40-59 60+

52.3

35.8

24.6

62.5

39.8

68.474.6

34.3

75.3

01020304050607080

Awareness Treatment Controlled

Pe

rce

nt o

f Po

pu

latio

n

20-39 40-59 60+

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

Hypertension: Awareness and Control by AgeHypertension: Awareness and Control by Age

Chronic Chronic HypertensionHypertension

Hypertension Hypertension EmergenciesEmergencies

Acute Acute Hypertension Hypertension

SyndromesSyndromes

Acute and Chronic Hypertension: Acute and Chronic Hypertension: Clinical ContextClinical Context

Physiology Perioperative HypertensionPhysiology Perioperative Hypertension

► Hyperadrenergic response to surgeryHyperadrenergic response to surgery ► Increase SVR, decrease preloadIncrease SVR, decrease 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► Inadequate anesthesia Inadequate anesthesia ► Cross clampCross clamp

► Hyperadrenergic response to surgeryHyperadrenergic response to surgery ► Increase SVR, decrease preloadIncrease SVR, decrease 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► Inadequate anesthesia Inadequate anesthesia ► Cross clampCross clamp

SVRSVR;; Humoral Humoral vasoconstrictorsvasoconstrictorsMechanical stressMechanical stressEndothelial injuryEndothelial injuryPermeabilityPermeabilityCoagulationCoagulationFibrinoid necrosisFibrinoid necrosis

Marik P. Chest. 2007;131:1949-1962.

Perioperative Antihypertension Therapy Perioperative Antihypertension Therapy During Cardiac SurgeryDuring Cardiac Surgery

Vuylsteke A et al. J Cardiothorac Vasc Anesth. 2000;14:269-73.

N = 1660 patients, (N = 191 anesthesiologistsN = 1660 patients, (N = 191 anesthesiologists))

Mean MAP threshold for treatmentMean MAP threshold for treatment

106.0106.0 86.386.3 97.197.1 109.0109.0

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

PreoperativePreoperative IntraoperativeIntraoperative PostoperativePostoperative ICUICU

Patients Patients (%)(%)

Prior hypertension (n = 845)Prior hypertension (n = 845)

No prior hypertension (n = 815)No prior hypertension (n = 815)

Blood Pressure “Phenotypes”Blood Pressure “Phenotypes”

Steady Component Steady Component (MAP,SBP,DBP)(MAP,SBP,DBP)

Dynamic Component Dynamic Component (Pulse Pres.)(Pulse Pres.)

Steady Component Steady Component (MAP,SBP,DBP)(MAP,SBP,DBP)

Dynamic Component Dynamic Component (Pulse Pres.)(Pulse Pres.)

Determinants MAP

LV ejection PVR

Determinants PP

LV ejection Viscoelasticity Wave Reflection

Determinants SBP

Stroke Volume LV ejection Distensibility Wave Reflection

Remodeling Remodeling

Courtesy of Schiffrin EL.

NormalNormalNormalNormal

Inward Inward Eutrophic Eutrophic remodelingremodeling

Outward Outward Hypertrophic Hypertrophic remodelingremodeling

SmallSmall ArteriesArteries (eutrophic)(eutrophic) in diastolic HTNin diastolic HTN

LargeLarge ArteriesArteries (hypertrophic) (hypertrophic) inin PPHPPH

Courtesy of Schiffrin EL.Courtesy of Schiffrin EL.

Pathogenic Role of Mechanical ForcesPathogenic Role of Mechanical Forces

Oscillatory Shear Stress*Oscillatory Shear Stress*Oscillatory Shear Stress*Oscillatory Shear Stress* Occurs sites prone to lesion formationOccurs sites prone to lesion formation Carotid bulbCarotid bulb Prox. CoronariesProx. Coronaries Distal aortaDistal aortaHigh Shear High Shear Atheroprotective AtheroprotectiveLow Shear Low Shear Atherogenic Atherogenic

Occurs sites prone to lesion formationOccurs sites prone to lesion formation Carotid bulbCarotid bulb Prox. CoronariesProx. Coronaries Distal aortaDistal aortaHigh Shear High Shear Atheroprotective AtheroprotectiveLow Shear Low Shear Atherogenic Atherogenic

**Wide PP Wide PP Augments Oscillatory Shear Augments Oscillatory Shear**Wide PP Wide PP Augments Oscillatory Shear Augments Oscillatory Shear

Elevated Stretch with Hypertension Elevated Stretch with Hypertension Pro-Inflammatory / AtherogenicPro-Inflammatory / Atherogenic

Elevated Stretch with Hypertension Elevated Stretch with Hypertension Pro-Inflammatory / AtherogenicPro-Inflammatory / Atherogenic

Pressure/StretchPressure/StretchPressure/StretchPressure/Stretch

O

NO

PGI2

CatecholaminesCatecholaminesAT-IIAT-II

ADH (vasopressin)ADH (vasopressin)AldosteroneAldosterone

TxATxA22

EndotheliumEndotheliumEndogenous

vasoconstrictors

The Endothelium Modulates Vascular ToneThe Endothelium Modulates Vascular Tone

Courtesy of JJ Ferguson III, MD.

Endogenous vasodilators

O2-

X

Proposed Vascular Pathophysiology Proposed Vascular Pathophysiology of Hypertensive Urgencyof Hypertensive Urgency

Vaughan CJ, Delanty N. Lancet. 2000;356:411-7.Courtesy of JJ Ferguson III, MD.

Acute ↑ BP triggers ↑ cellular adhesion molecular expression

NO

PGI2

CatecholaminesCatecholaminesAT-IIAT-II

ADH (vasopressin)ADH (vasopressin)AldosteroneAldosterone

TxA2

ETET11( - ) ( + )

CAMs

Endogenous vasodilators

Endogenous vasoconstrictors

O2-

• Overwhelmed control of vascular tone leads to coagulation cascade activationOverwhelmed control of vascular tone leads to coagulation cascade activation• Loss of endothelial activity coupled with coagulation and platelets promotes DICLoss of endothelial activity coupled with coagulation and platelets promotes DIC

Proposed Vascular Pathophysiology Proposed Vascular Pathophysiology of Hypertensive Emergencyof Hypertensive Emergency

Vaughan CJ, Delanty N. Lancet. 2000;356:411-7. Courtesy of JJ Ferguson III, MD.

TxA2, PAI-1, TF

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

EachEach 1010mmHgmmHg increase PP increase PP 11% 11% increaseincrease stroke, 16% stroke, 16% increase death & 12% increase in recurrent MI*increase death & 12% increase in recurrent MI*

EachEach 1010mmHgmmHg rise MAP rise MAP 20% 20% increaseincrease stroke stroke

Cardiac mass Cardiac mass assocassoc withwith SBPSBP Work to drive blood = SBPWork to drive blood = SBP despite MAP & SVRdespite MAP & SVR

EachEach 1010mmHgmmHg increase PP increase PP 11% 11% increaseincrease stroke, 16% stroke, 16% increase death & 12% increase in recurrent MI*increase death & 12% increase in recurrent MI*

EachEach 1010mmHgmmHg rise MAP rise MAP 20% 20% increaseincrease stroke stroke

Cardiac mass Cardiac mass assocassoc withwith SBPSBP Work to drive blood = SBPWork to drive blood = SBP despite MAP & SVRdespite MAP & SVR

*Increase PP assoc. decreased CBF

MAP, SBP & PP Independently Predict RiskMAP, SBP & PP Independently Predict Risk

SBP HTN SBP HTN and Adverse Eventsand Adverse Events

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

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

Event rate %Event rate %N = 2069 scheduled for CABG

No ISH No ISH (n = 1457)(n = 1457)

ISH ISH (n=612)(n=612)

Odds RatioOdds Ratio

Renal failure/insufficiencyRenal failure/insufficiency 6.76.7 8.88.8 1.3 (0.9-1.9)1.3 (0.9-1.9)

StrokeStroke 6.36.3 10.110.1 1.7 (1.2-2.3)1.7 (1.2-2.3)

LV dysfunctionLV dysfunction 29.129.1 34.334.3 1.3 (1.0-1.6)1.3 (1.0-1.6)

Renal failure/insufficiency, Renal failure/insufficiency, stroke, LV dysfunction, deathstroke, LV dysfunction, death 33.233.2 40.940.9 1.4 (1.1-1.7)1.4 (1.1-1.7)

Dependent on;Dependent on;

Ventricular EjectionVentricular Ejection

Viscoelastic properties Lg. arteriesViscoelastic properties Lg. arteries

Wave ReflectionWave Reflection

Pulse PressurePulse Pressure

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

Renal RISK INDEX

PP HTN PP HTN and Adverse Eventsand Adverse Events

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

Aronson et al; Circulation 115,733-42,2007Aronson et al; Circulation 115,733-42,2007Fontes, Aronson, Mathew, et al. Analg Anes 2007Fontes, Aronson, Mathew, et al. Analg Anes 2007Benjo, Thompson, Fine, et al Hypertension 2007Benjo, Thompson, Fine, et al Hypertension 2007

CerebralCerebral (5.5 % vs. 2.8 %; P = 0.004)(5.5 % vs. 2.8 %; P = 0.004)

CHFCHF (12.8 % vs. 7.8 %; P = 0.003), (12.8 % vs. 7.8 %; P = 0.003), Cardiac deathCardiac death (4.7 % vs. 2.4 %; P = 0.001)(4.7 % vs. 2.4 %; P = 0.001)

CV surgery outcome ( PP > 80)CV surgery outcome ( PP > 80)

StrokeStroke (81.2 v 64.5 mmHg) (81.2 v 64.5 mmHg) eacheach 10mmHg10mmHg additive riskadditive risk (OR 1.35; (OR 1.35; CI, 1.13-1.62CI, 1.13-1.62) (P = 0.001)) (P = 0.001)

RenalRenal (8.6 % vs. 4.5 %; P = 0.0003), (8.6 % vs. 4.5 %; P = 0.0003), Renal deathRenal death (3.7% vs. 1.1%)(3.7% vs. 1.1%)

PP HTN PP HTN and Adverse Eventsand Adverse Events

Pathophysiology of Acute Hypertensive Pathophysiology of Acute Hypertensive SyndromesSyndromes

Mechanical Mechanical stress on the stress on the vessel wallvessel wall

↑ ↑BPBPRelease of Local Release of Local

humoral humoral vasoconstrictorsvasoconstrictors

Augments HTNAugments HTN

Endothelial Endothelial damagedamage

Activation of the Activation of the clotting cascadeclotting cascade

Further release of Further release of humoral humoral

vasoconstrictorsvasoconstrictors

Fibrinoid necrosis of Fibrinoid necrosis of small blood vesselssmall blood vessels

Pressure Pressure natriuresisnatriuresis

Volume Volume depletiondepletion

RAAS RAAS activationactivation

VasopressinVasopressinendothelinendothelin

catecholaminescatecholaminesMajorMajor physiologic physiologic

derangementsderangements

Courtesy of JJ Ferguson III, MD.Courtesy of JJ Ferguson III, MD.

"Zoned Out“"Zoned Out“Blood Pressure Control in CT SurgeryBlood Pressure Control in CT Surgery

What Do RCT & Registries Tell Us About Acute Pressure What Do RCT & Registries Tell Us About Acute Pressure Management and OutcomesManagement and Outcomes

"Zoned Out“"Zoned Out“Blood Pressure Control in CT SurgeryBlood Pressure Control in CT Surgery

What Do RCT & Registries Tell Us About Acute Pressure What Do RCT & Registries Tell Us About Acute Pressure Management and OutcomesManagement and Outcomes








Acute HypertensionAcute Hypertension

Acute HypertensionAcute Hypertension

Hypertensive Hypertensive UrgencyUrgency

Severe HTN Severe HTN WITHOUT acute WITHOUT acute end-organ damageend-organ damage

Requires BP control Requires BP control over severalover severaldays-weeksdays-weeks

Hypertensive Hypertensive EmergencyEmergency

Severe HTN Severe HTN (BP >180/120 mm Hg) (BP >180/120 mm Hg)

WITH end-organ WITH end-organ damagedamage

Requires immediate, Requires immediate, aggressive BP controlaggressive BP control

Perioperative Perioperative HypertensionHypertension

HTN*HTN* occurring prior occurring prior to, during, or following to, during, or following surgical proceduressurgical procedures

Requires immediate Requires immediate BP controlBP control

* Poorly defined* Poorly defined

ECLIPSE: Trial DesignECLIPSE: Trial Design

► 3 prospective, randomized, open-label, parallel comparisons of clevidipine to NTG or 3 prospective, randomized, open-label, parallel comparisons of clevidipine to NTG or SNP periop, or NIC postop in pts undergoing cardiac surgery - 61 medical centersSNP periop, or NIC postop in pts undergoing cardiac surgery - 61 medical centers

► Primary endpoint: Safety of clevidipine (death, myocardial infarction, stroke, renal) Primary endpoint: Safety of clevidipine (death, myocardial infarction, stroke, renal)

► Secondary endpoints: Other AEs, BP controlSecondary endpoints: Other AEs, BP control

► 3 prospective, randomized, open-label, parallel comparisons of clevidipine to NTG or 3 prospective, randomized, open-label, parallel comparisons of clevidipine to NTG or SNP periop, or NIC postop in pts undergoing cardiac surgery - 61 medical centersSNP periop, or NIC postop in pts undergoing cardiac surgery - 61 medical centers

► Primary endpoint: Safety of clevidipine (death, myocardial infarction, stroke, renal) Primary endpoint: Safety of clevidipine (death, myocardial infarction, stroke, renal)

► Secondary endpoints: Other AEs, BP controlSecondary endpoints: Other AEs, BP control

Clevidipinevs Nitroglycerin

Clevidipine vs Sodium

Nitroprusside

Clevidipinevs Nicardipine

Clevidipine(n = 268)

Nitroglycerin(n = 278)


Sodiumnitroprusside

(n = 283)


Nicardipine(n = 193)

Perioperative Postoperative

1:1 1:1 1:1

Aronson et al. ACC 2007.

ECLIPSE Baseline CharacteristicsECLIPSE Baseline Characteristics

ClevidipineClevidipinen=752n=752

Comparators Comparators n=754n=754

Age, median (range)Age, median (range) 65 (24-87)65 (24-87) 66 (19-89)66 (19-89)

MaleMale 72%72% 74%74%

CaucasianCaucasian 82%82% 83%83%

Hx HTNHx HTN 88%88% 85%85%

CHFCHF 19%19% 18%18%

Insulin dependent diabetesInsulin dependent diabetes 11%11% 11%11%

COPDCOPD 14%14% 15%15%

Recent MI (< 6 mos)Recent MI (< 6 mos) 17%17% 18%18%

Prior CABGPrior CABG 3%3% 6%6%

Data on file, The Medicines Company.

Incidence of Death, MI, Stroke, Renal Incidence of Death, MI, Stroke, Renal DysfunctionDysfunction

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 (%

)30

-Day

Eve

nts

(%)

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

MyocardialMyocardialInfarctionInfarction

StrokeStroke RenalRenalDysfunctionDysfunction


Aronson S et al. Presented at ACC. 2007.

BP Control Assessed viaBP Control Assessed viaAUC AnalysisAUC Analysis

Time (hours)Time (hours)

LowerLower

UpperUpper

00 66 1212 24241818

SBPSBP(mm Hg)(mm Hg)

Cumulative AUC calculated for excursions outside Cumulative AUC calculated for excursions outside prespecified range. prespecified range. Lower AUC = tighter BP control.Lower AUC = tighter BP control.

AUC = area under the curveAUC = area under the curve

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

ECLIPSEECLIPSENTGNTG

ECLIPSEECLIPSESNPSNP

ECLIPSEECLIPSENICNIC

mm

Hg

x m

in/h

mm

Hg

x m

in/h

p = 0.0006

p = 0.0027

p = 0.8508


NTGNTGn=278n=278


SNPSNPn=284n=284


NICNICn=194n=194

Median AUC Median AUC

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

Peri-operative Post-operativeOnly

SNP pts were outside the target BP range > compared to CLV pts[above and below (overshoot)] AUC above [CLV vs. SNP ] = 2.97 vs. 6.61 mmHg min/h, p=0.03. AUC below [CLV vs. SNP ] = 2.30 vs. 8.38 mmHg min/h, p=0.0006.

NTG pts did not meet target BP range as often compared with CLV AUC above [CLV vs. NTG ] = 2.76 vs. 7.94 mmHg min/h, p=0.0002 AUC below the target range was similar between these groups.

SNP pts were outside the target BP range > compared to CLV pts[above and below (overshoot)] AUC above [CLV vs. SNP ] = 2.97 vs. 6.61 mmHg min/h, p=0.03. AUC below [CLV vs. SNP ] = 2.30 vs. 8.38 mmHg min/h, p=0.0006.

NTG pts did not meet target BP range as often compared with CLV AUC above [CLV vs. NTG ] = 2.76 vs. 7.94 mmHg min/h, p=0.0002 AUC below the target range was similar between these groups.

ECLIPSEECLIPSE

AUC Predictive of Mortality AUC Predictive of Mortality at 30 Daysat 30 Days

P P valuevalue Odds Odds ratioratio

95% CI 95% CI (Lower limit, (Lower limit, Upper limit)Upper limit)

Surgery duration (hour)Surgery duration (hour) <0.0001<0.0001 1.5171.517 (1.240, 1.856)(1.240, 1.856)

Age (year)Age (year) 0.00030.0003 1.0701.070 (1.031, 1.110)(1.031, 1.110)

Preop creatinine ≥1.2 mg/dLPreop creatinine ≥1.2 mg/dL 0.00310.0031 2.6702.670 (1.392, 5.122)(1.392, 5.122)

AUC (1 mm Hg*min)AUC (1 mm Hg*min) 0.00690.0069 1.0031.003 (1.001, 1.004)(1.001, 1.004)

Additional surgical proceduresAdditional surgical procedures 0.00890.0089 2.4092.409 (1.246, 4.655)(1.246, 4.655)

Preop Hgb (g/dL)Preop Hgb (g/dL) 0.01350.0135 0.8240.824 (0.707, 0.961)(0.707, 0.961)

Preop SBP >160 or DBP >105Preop SBP >160 or DBP >105 0.02280.0228 2.3862.386 (1.147, 4.963)(1.147, 4.963)

History of COPDHistory of COPD 0.02280.0228 2.3262.326 (1.125, 4.812)(1.125, 4.812)

History of recent MI (<6 months prior)History of recent MI (<6 months prior) 0.03120.0312 2.1972.197 (1.073, 4.497)(1.073, 4.497)


I mm Hg x 60 min

2 mm Hg x 60 min

3 mm Hg x 60 min

4 mm Hg x 60 min

5 mm Hg x 60 min

Odds Odds RatioRatio

95% CI 95% CI [Lower Limit, [Lower Limit, Upper Limit]Upper Limit]

1.201.20 [1.06, 1.27][1.06, 1.27]

1.431.43 [1.13, 1.61][1.13, 1.61]

1.711.71 [1.20, 2.05][1.20, 2.05]

2.052.05 [1.27, 2.61][1.27, 2.61]

2.462.46 [1.35, 3.31][1.35, 3.31]

Excursions in Perioperative BP Excursions in Perioperative BP Control Related to Increased 30-day MortalityControl Related to Increased 30-day Mortality


0 1 2 3 4

Systolic BP Control Over 24 HoursSystolic BP Control Over 24 Hours

Time (hours)

SBP

Lower

Upper

0 6 12 2418

Lower

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 AUCMedian AUC

Range = Pre-/post-op SBP 105-145, Intra-op SBP 95-135Range = Pre-/post-op SBP 105-145, Intra-op SBP 95-135

Peri-operative Post-operativeOnly

Aronson S et al. SCCM 2008. Poster #557.Aronson S et al. SCCM 2008. Poster #557.

Perioperative BP Lability Predicts Mortality in Perioperative BP Lability Predicts Mortality in Patients Undergoing Cardiac SurgeryPatients Undergoing Cardiac Surgery

► Analysis of DUKE Analysis of DUKE Heart Center Heart Center database in pts database in pts undergoing CT undergoing CT surgerysurgery● N =5238N =5238● 3.1M BP 3.1M BP

evaluationsevaluations

► AUC (95-AUC (95-135mmHg) 135mmHg) predictive of 30-predictive of 30-day mortalityday mortality

► Analysis of DUKE Analysis of DUKE Heart Center Heart Center database in pts database in pts undergoing CT undergoing CT surgerysurgery● N =5238N =5238● 3.1M BP 3.1M BP

evaluationsevaluations

► AUC (95-AUC (95-135mmHg) 135mmHg) predictive of 30-predictive of 30-day mortalityday mortality

P=0.0139

OR =1.02 per 100 mm Hg x min

95% CI [1.004-1.037]

Mean Duration of ExcursionsMean Duration of Excursions

Minutes SBP > 135 or < 95mmHg per incidentMinutes SBP > 135 or < 95mmHg per incident

P-Value < 0.0001, O.R.-1.068 (1.036-1.102)

Samples (n=7187)Samples (n=7187)

DUKE patient populationDUKE patient population

Development & validationDevelopment & validationdatasetsdatasets

P-ValueP-Value Odds Odds RatioRatio 95% CI 95% CI

Minutes SBP > 135 or < 95mmHg Minutes SBP > 135 or < 95mmHg per incidentper incident <0.0001<0.0001 1.0681.068 1.036-1.1021.036-1.102

Surgery length (min)Surgery length (min) 0.4750.475 0.9990.999 0.997-1.0020.997-1.002

ParsonnetParsonnet <0.0001<0.0001 1.0691.069 1.045-1.0941.045-1.094

Mean Duration of IncursionsMean Duration of Incursions

Minutes <95 mmHg (min)Minutes <95 mmHg (min) 0.0040.004 1.0251.025 1.008-1.0421.008-1.042

Minutes >135 mmHg (min)Minutes >135 mmHg (min) 0.0130.013 1.0331.033 1.007-1.0591.007-1.059

Predictors of Postoperative Renal DysfunctionPredictors of Postoperative Renal Dysfunction

Odds ratio (95% CI)Odds ratio (95% CI) PP value value

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

Aronson S et al. Presented at ASA. 2007.

‡‡ UnadjustedUnadjusted*Excursions outside SBP 85-145 mm Hg pre/postoperatively or 75-135 mm Hg intraoperatively*Excursions outside SBP 85-145 mm Hg pre/postoperatively or 75-135 mm Hg intraoperatively

N = 1512 undergoing cardiac surgeryN = 1512 undergoing cardiac surgery

Logistic Regression Results: Predictor of 30-Day MortalityLogistic Regression Results: Predictor of 30-Day Mortality

PP Value Value OROR 95% C.I.95% C.I.

Screening SBP (per 1 mm Hg increment)Screening SBP (per 1 mm Hg increment) 0.00130.0013 1.0381.038 1.014–1.0611.014–1.061

AUC (per 1 mm Hg×min/hr increment)AUC (per 1 mm Hg×min/hr increment) 0.01460.0146 1.0041.004 1.001–1.0071.001–1.007

AUC (per 1mmHg×min/hr increment), narrow AUC (per 1mmHg×min/hr increment), narrow rangerange 0.00780.0078 1.0021.002 1.001–1.0041.001–1.004

BP Fluctuations Predict Short-Term Mortality in BP Fluctuations Predict Short-Term Mortality in Patients Undergoing Cardiac Valve SurgeryPatients Undergoing Cardiac Valve Surgery

Minimizing SBP fluctuations within a narrow range improved 30-day mortality.Minimizing SBP fluctuations within a narrow range improved 30-day mortality.

Screening SBP was defined as the SBP within 24 hours prior to randomization. AUC calculated for excursions outside SBP range of 85–145 mmHg pre- and postoperatively, 75–135 mmHg intraoperatively.

ACCP 2009ACCP 2009

Cardiac Surgery Patients – Cardiac Surgery Patients – Inadequate BP ControlInadequate BP Control

The worse the control, the poorer the outcomes. The worse the control, the poorer the outcomes.

SCA 2008

Increased risk of 30-day Increased risk of 30-day death, CVA, MI and renal dysfunction vs patients with tight BP controldeath, CVA, MI and renal dysfunction vs patients with tight BP control

► 1500 pts, 21 hospitals, 1500 pts, 21 hospitals, 79% therapy in ED79% therapy in ED

► Median age 58, Women 49%, AA 58%Median age 58, Women 49%, AA 58%

► Initial BP 201/110Initial BP 201/110

► 90% HTN, 33% kidney history , 17% drug 90% HTN, 33% kidney history , 17% drug abuseabuse

► 1500 pts, 21 hospitals, 1500 pts, 21 hospitals, 79% therapy in ED79% therapy in ED

► Median age 58, Women 49%, AA 58%Median age 58, Women 49%, AA 58%

► Initial BP 201/110Initial BP 201/110

► 90% HTN, 33% kidney history , 17% drug 90% HTN, 33% kidney history , 17% drug abuseabuse

Granger et al. SCCM February 2008

HTN

Neuro

ACS

CHF

Reason for AdmissionReason for Admission

45.3%

72.4%

87.4%

96.7%100.0%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Within 1Hour

Within 3Hours

Within 6Hours

Within 12Hours

Within 24Hours

Time to Initiation of IV Therapy

Systolic BP Control Over 24 Hours by First Systolic BP Control Over 24 Hours by First IV AntihypertensiveIV Antihypertensive

-40

-30

-20

-10

0

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

Time since IV initiation (h)

Ch

an

ge

fro

m q

ua

lify

ing

(%

)

Enalapril* Hydralazine* Labetolol*

Metoprolol* Nicardapine* Nipride*

Nitroglycerin*

n=982n=982

*Median*MedianGranger et al. SCCM February 2008

Regardless of 1st antihypertensiveRegardless of 1st antihypertensive

50-75% of pts required > one agent50-75% of pts required > one agent

Systolic BP Control Over 24 Hours by First Systolic BP Control Over 24 Hours by First IV AntihypertensiveIV Antihypertensive

-40

-30

-20

-10

0

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

Time since IV initiation (h)

Ch

an

ge

fro

m q

ua

lify

ing

(%

)

Enalapril* Nipride*

n=982n=982

*Median*MedianGranger et al. SCCM February 2008

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.



OutcomeOutcomeaa All Patients All Patients (n=47)(n=47)

Nicardipine Nicardipine Group Group (n=21)(n=21)

Nitroprusside Nitroprusside Group Group (n=18)(n=18)

PrimaryPrimary

No (%) patients with No (%) patients with appropriate MAP appropriate MAP reduction at 2 hrreduction at 2 hr

15 (32)15 (32) 4 (19)4 (19) 7 (39)7 (39)

No. (%) patients with No. (%) patients with excessive MAP excessive MAP

reduction at 2 hrreduction at 2 hrbb27 (57)27 (57) 16 (76)16 (76) 9 (50)9 (50)

No. (5) treatment failures No. (5) treatment failures at 2 hrat 2 hr 5 (11)5 (11) 1 (5)1 (5) 2 (11)2 (11)

Primary and Secondary EndpointsPrimary and Secondary Endpoints


cp < 0.05, nicardipine group versus nitroprusside group.dOne patient was excluded from the analysis.


cp < 0.05, nicardipine group versus nitroprusside group.dOne patient was excluded from the analysis.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

OutcomeOutcomeaaAll All

Patients Patients (n=47)(n=47)

Nicardipine Nicardipine Group Group (n=21)(n=21)

Nitroprusside Nitroprusside Group Group (n=18)(n=18)

SecondarySecondary

No. (%) of patients with appropriate No. (%) of patients with appropriate blood-pressure reduction at 6 hrblood-pressure reduction at 6 hr 6 (13)6 (13) 1 (5)1 (5) 4 (22)4 (22)

Mean no. (range) of additional p.r.n. Mean no. (range) of additional p.r.n. antihypertensive doses per patientantihypertensive doses per patientcc 4 (0-33)4 (0-33) 6 (0-33)6 (0-33)dd 2 (0-5)2 (0-5)

Mean length of stay (range), daysMean length of stay (range), dayscc 9 (2-41)9 (2-41) 13 (2-41)13 (2-41)dd 7 (2-14)7 (2-14)

Mean duration (range) of i.v. therapy, hrMean duration (range) of i.v. therapy, hr 20 (1-74)20 (1-74) 21 (3-74)21 (3-74)dd 16 (1-67)16 (1-67)

Mean time (range) until scheduled oral Mean time (range) until scheduled oral antihypertensives were started, hrantihypertensives were started, hr 14 (0-72)14 (0-72) 16 (0-48)16 (0-48) 10 (0-72)10 (0-72)

No. (%) of patients meeting 2- or 6-hour No. (%) of patients meeting 2- or 6-hour goalgoalb,cb,c 26 (28)26 (28) 5 (12)5 (12) 11 (31)11 (31)

Treatment-Related Adverse EventsTreatment-Related Adverse Events

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


No. (%)No. (%)

Adverse Adverse EventEvent

All Patients All Patients (n=47)(n=47)

Nicardipine Nicardipine (n=21)(n=21)

Nitroprusside Nitroprusside (n=18)(n=18)

Hypotension*Hypotension* 42 (89)42 (89) 21 (100)21 (100) 14 (78)14 (78)

TachycardiaTachycardia 15 (32)15 (32) 9 (43) 9 (43) 5 (28)5 (28)

BradycardiaBradycardia 9 (19)9 (19) 2 (10) 2 (10) 4 (22)4 (22)

Acute Renal Acute Renal FailureFailure 2 (4)2 (4) 1 (5)1 (5) 1 (6)1 (6)

Major IschemiaMajor Ischemia 2 (4) 2 (4) 1 (5) 1 (5) 1 (6)1 (6)

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

SCA 2008SCA 2008

Pre-operative BP ControlPre-operative BP Control

p-valuep-value O.RO.R 95% CI95% CI

Treatment CLP v SNP/NTGTreatment CLP v SNP/NTG 0.01550.0155 7.57.5 1.5, 38.41.5, 38.4

Additional procedure Additional procedure 0.00850.0085 5.85.8 1.6, 21.21.6, 21.2

Pre-op Scr > 1.2mg/dlPre-op Scr > 1.2mg/dl 0.01680.0168 4.94.9 1.3, 17.81.3, 17.8


"Under Pressure"—Vascular Dysfunction and Acute "Under Pressure"—Vascular Dysfunction and Acute Pressure Syndromes in the Setting of Cardiovascular Pressure Syndromes in the Setting of Cardiovascular

SurgerySurgery

Challenges, Innovations, and Landmark Trials (ECLIPSE)—From Challenges, Innovations, and Landmark Trials (ECLIPSE)—From Threat to Therapy Threat to Therapy

"Under Pressure"—Vascular Dysfunction and Acute "Under Pressure"—Vascular Dysfunction and Acute Pressure Syndromes in the Setting of Cardiovascular Pressure Syndromes in the Setting of Cardiovascular

SurgerySurgery

Challenges, Innovations, and Landmark Trials (ECLIPSE)—From Challenges, Innovations, and Landmark Trials (ECLIPSE)—From Threat to Therapy Threat to Therapy

Jerrold H Levy, MD, FAHAJerrold H Levy, MD, FAHAProfessor of AnesthesiologyProfessor of Anesthesiology

Emory University School of MedicineEmory University School of MedicineDeputy Chairman for ResearchDeputy Chairman for Research

Director, Cardiothoracic AnesthesiologyDirector, Cardiothoracic AnesthesiologyCardiothoracic Anesthesiology and Critical CareCardiothoracic Anesthesiology and Critical Care

Emory HealthcareEmory HealthcareAtlanta, GeorgiaAtlanta, Georgia

Jerrold H Levy, MD, FAHAJerrold H Levy, MD, FAHAProfessor of AnesthesiologyProfessor of Anesthesiology

Emory University School of MedicineEmory University School of MedicineDeputy Chairman for ResearchDeputy Chairman for Research

Director, Cardiothoracic AnesthesiologyDirector, Cardiothoracic AnesthesiologyCardiothoracic Anesthesiology and Critical CareCardiothoracic Anesthesiology and Critical Care

Emory HealthcareEmory HealthcareAtlanta, GeorgiaAtlanta, Georgia

Investigation Investigation ●● Innovation Innovation ●● Application Application

Evolution of Perioperative CareEvolution of Perioperative Care

► Changing demographics and increasing use Changing demographics and increasing use of stenting and platelet inhibitors of stenting and platelet inhibitors

► Older patients with comorbidities presenting Older patients with comorbidities presenting for surgery and to ICUs with vascular and for surgery and to ICUs with vascular and endothelial dysfunction due to multiple causesendothelial dysfunction due to multiple causes

► Endothelial and vascular dysfunction common Endothelial and vascular dysfunction common across this cardiac, neurological, and critically across this cardiac, neurological, and critically ill patient populations—acute and chronic ill patient populations—acute and chronic diseasedisease

► Changing demographics and increasing use Changing demographics and increasing use of stenting and platelet inhibitors of stenting and platelet inhibitors

► Older patients with comorbidities presenting Older patients with comorbidities presenting for surgery and to ICUs with vascular and for surgery and to ICUs with vascular and endothelial dysfunction due to multiple causesendothelial dysfunction due to multiple causes

► Endothelial and vascular dysfunction common Endothelial and vascular dysfunction common across this cardiac, neurological, and critically across this cardiac, neurological, and critically ill patient populations—acute and chronic ill patient populations—acute and chronic diseasedisease

Estafanous FG, et al. Ann Thorac Surg. 1998;65:383-389.Fontana GP. Chest Surg Clin N Am. 1998;8:871-890.Verrier ED. J Am Coll Surg. 1999;188:104-110.

Trends and ObservationsTrends and Observations

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

55.4

73.9

23.2

37.5

49.1

63.669.5

37.4

6.4

83.8

18.3

0.0

10.020.0

30.0

40.050.0

60.0

70.080.0

90.0

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

Per

cent

of P

opul

atio

n

Men Women

11.2

55.4

73.9

23.2

37.5

49.1

63.669.5

37.4

6.4

83.8

18.3

0.0

10.020.0

30.0

40.050.0

60.0

70.080.0

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.

Endothelial and Vascular Dysfunction are the Endothelial and Vascular Dysfunction are the Hallmarks of our PatientsHallmarks of our Patients

AnginaAngina

Fibrosis AndFibrosis AndMuscle LossMuscle Loss

Heart FailureHeart Failure

DeathDeath

Sudden DeathSudden DeathMyocardialMyocardial IschemiaIschemia

PPGCGC

Glomerular SclerosisGlomerular Sclerosis

HypertensionDiabetes

Insulin ResistanceDyslipidemia

Endothelial Dysfunction

ROSROSInflammationInflammation

Cell InjuryCell Injury

Angiotensin II

Aldosterone

Endothelin-1

Glycosylated ProteinsGlycosylated Proteins

Release of ET-1Release of ET-1 Production of TGFProduction of TGF NONO

Unstable Angina Unstable Angina Myocardial InfarctionMyocardial Infarction

Coronary Artery DiseaseCoronary Artery Disease

Plaque RupturePlaque Rupture

AlteredAlteredExtracellular MatrixExtracellular Matrix

(mesangium)(mesangium)

AtherosclerosisAtherosclerosis

Tubulointerstitial DamageTubulointerstitial Damage

Albumin ShuntingAlbumin ShuntingThroughThrough

Membrane PoresMembrane Pores Oxidative Stress Oxidative Stress InflammationInflammation

Schiffrin EL. Am J Hypertens 2004;17(12):1192-1200

CalcificationCalcification

Renal FailureRenal Failure

Endothelial Dysfunction

Perioperative HypertensionPerioperative HypertensionThe Cardiothoracic Surgery SettingThe Cardiothoracic Surgery Setting

► Patients with preoperative hypertension are at increased Patients with preoperative hypertension are at increased risk for perioperative complicationsrisk for perioperative complications11

► Approximately 30% to 56% of patients undergoing routine Approximately 30% to 56% of patients undergoing routine cardiac surgery experience acute rises in blood pressure cardiac surgery experience acute rises in blood pressure that require administration of a parenteral that require administration of a parenteral antihypertensive agentantihypertensive agent22

► Antihypertensive therapy is often needed to manage life-Antihypertensive therapy is often needed to manage life-threatening arterial bleeding, myocardial ischemia, or threatening arterial bleeding, myocardial ischemia, or cardiac failurecardiac failure33

► Patients with preoperative hypertension are at increased Patients with preoperative hypertension are at increased risk for perioperative complicationsrisk for perioperative complications11

► Approximately 30% to 56% of patients undergoing routine Approximately 30% to 56% of patients undergoing routine cardiac surgery experience acute rises in blood pressure cardiac surgery experience acute rises in blood pressure that require administration of a parenteral that require administration of a parenteral antihypertensive agentantihypertensive agent22

► Antihypertensive therapy is often needed to manage life-Antihypertensive therapy is often needed to manage life-threatening arterial bleeding, myocardial ischemia, or threatening arterial bleeding, myocardial ischemia, or cardiac failurecardiac failure33

1. Sladen, IARS Rev Course Lectures, 2002, p100; DeQuattro, J Cardiovasc Pharmacol Ther, 1997.2. Cheung, J Card Surg, 2006, S8; Estafanous, Am J Cardiol, 1980, p685; Landymore, Can J Surg, 1980.3. Cheung, J Card Surg, 2006, S8.

The ProblemsThe ProblemsThe ProblemsThe Problems

Considerations for Perioperative BP Control Considerations for Perioperative BP Control During Cardiac SurgeryDuring Cardiac Surgery

Acute, Severe Elevations in Blood Pressure are Acute, Severe Elevations in Blood Pressure are Triggered by Multiple Perioperative EventsTriggered by Multiple Perioperative Events

Intraoperative EventsIntraoperative Events► InductionInduction► CannulationCannulation► Protamine and hemostasis (aortotomy/suture lines)Protamine and hemostasis (aortotomy/suture lines)► Chest closureChest closure► TransportTransport

Postoperative EventsPostoperative Events► Temperature management (warming and shivering)Temperature management (warming and shivering)► EmergenceEmergence► Weaning and extubationWeaning and extubation► Volume statusVolume status

Acute, Severe Elevations in Blood Pressure are Acute, Severe Elevations in Blood Pressure are Triggered by Multiple Perioperative EventsTriggered by Multiple Perioperative Events

Intraoperative EventsIntraoperative Events► InductionInduction► CannulationCannulation► Protamine and hemostasis (aortotomy/suture lines)Protamine and hemostasis (aortotomy/suture lines)► Chest closureChest closure► TransportTransport

Postoperative EventsPostoperative Events► Temperature management (warming and shivering)Temperature management (warming and shivering)► EmergenceEmergence► Weaning and extubationWeaning and extubation► Volume statusVolume status

Goals for an Ideal Antihypertensive Agent in Goals for an Ideal Antihypertensive Agent in Setting of Cardiac SurgerySetting of Cardiac Surgery

► Rapid onset of actionRapid onset of action

► Predictable dose responsePredictable dose response

► Titratable to desired BPTitratable to desired BP

► Highly vascular selectiveHighly vascular selective

► Maintain stroke volume and cardiac outputMaintain stroke volume and cardiac output

► Rapidly reversibleRapidly reversible

► Low risk of overshoot hypotension Low risk of overshoot hypotension

► Low risk of adverse reactionsLow risk of adverse reactions

► Rapid onset of actionRapid onset of action

► Predictable dose responsePredictable dose response

► Titratable to desired BPTitratable to desired BP

► Highly vascular selectiveHighly vascular selective

► Maintain stroke volume and cardiac outputMaintain stroke volume and cardiac output

► Rapidly reversibleRapidly reversible

► Low risk of overshoot hypotension Low risk of overshoot hypotension

► Low risk of adverse reactionsLow risk of adverse reactions

Levy JH. Anesthesiol Clin North Am. 1988;17:587-678.

Oparil S et al. Am J Hypertens. 1999;12:653-664.

Desirable Properties for Intravenous Agent Desirable Properties for Intravenous Agent

Therapeutic Approaches to Arterial Therapeutic Approaches to Arterial Vasodilation: ArmamentariumVasodilation: Armamentarium

► ACE inhibition ACE inhibition

► Alpha-1 adrenergic blockadeAlpha-1 adrenergic blockade

► Calcium channel blockadeCalcium channel blockade

► Dopamine-1 stimulationDopamine-1 stimulation

► Ganglionic blockadeGanglionic blockade

► Cyclic nucleotide stimulationCyclic nucleotide stimulation

► PDE inhibitionPDE inhibition

► Potassium channel modulationPotassium channel modulation

► ACE inhibition ACE inhibition

► Alpha-1 adrenergic blockadeAlpha-1 adrenergic blockade

► Calcium channel blockadeCalcium channel blockade

► Dopamine-1 stimulationDopamine-1 stimulation

► Ganglionic blockadeGanglionic blockade

► Cyclic nucleotide stimulationCyclic nucleotide stimulation

► PDE inhibitionPDE inhibition

► Potassium channel modulationPotassium channel modulation

Levy JH: The ideal agent for perioperative hypertension. Acta Anaesth Scand 1993; 37(S):20-25.

Treatment OptionsTreatment Options Treatment OptionsTreatment Options

Hypertension in Surgical Patients (1)Hypertension in Surgical Patients (1)

► Patients who are normotensive may become Patients who are normotensive may become hypertensivehypertensive

► Most blood pressure changes develop acutely Most blood pressure changes develop acutely and require rapid intervention with IV agentsand require rapid intervention with IV agents

► Characterized by systemic vasoconstriction with Characterized by systemic vasoconstriction with intravascular hypovolemiaintravascular hypovolemia

► Patients may have preoperative biventricular Patients may have preoperative biventricular dysfunctiondysfunction

► Patients who are normotensive may become Patients who are normotensive may become hypertensivehypertensive

► Most blood pressure changes develop acutely Most blood pressure changes develop acutely and require rapid intervention with IV agentsand require rapid intervention with IV agents

► Characterized by systemic vasoconstriction with Characterized by systemic vasoconstriction with intravascular hypovolemiaintravascular hypovolemia

► Patients may have preoperative biventricular Patients may have preoperative biventricular dysfunctiondysfunction

Levy JH: Management of systemic and pulmonary hypertension. Tex Heart Inst J 2005;32:467-471.

Principles and Practice ConsiderationsPrinciples and Practice ConsiderationsPrinciples and Practice ConsiderationsPrinciples and Practice Considerations

► BP may be maintained at lower levels to avoid BP may be maintained at lower levels to avoid graft/suture line disruptiongraft/suture line disruption

► Patients are being “Fast Tracked”Patients are being “Fast Tracked”

► Mechanical manipulation, suturing with potential Mechanical manipulation, suturing with potential risk for vascular spasmrisk for vascular spasm

► Ventricular dysfunction is common in patients Ventricular dysfunction is common in patients with normal preop function due to stunning/ with normal preop function due to stunning/ reperfusion injuryreperfusion injury

► BP may be maintained at lower levels to avoid BP may be maintained at lower levels to avoid graft/suture line disruptiongraft/suture line disruption

► Patients are being “Fast Tracked”Patients are being “Fast Tracked”

► Mechanical manipulation, suturing with potential Mechanical manipulation, suturing with potential risk for vascular spasmrisk for vascular spasm

► Ventricular dysfunction is common in patients Ventricular dysfunction is common in patients with normal preop function due to stunning/ with normal preop function due to stunning/ reperfusion injuryreperfusion injury

Hypertension in Cardiac Surgical Patients (2)Hypertension in Cardiac Surgical Patients (2)


Principles and Practice ConsiderationsPrinciples and Practice Considerations

Nitropusside: Issues and ConcernsNitropusside: Issues and Concerns

► Metabolized to CN, then thiocyanateMetabolized to CN, then thiocyanate

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

– Caution with high ICP Caution with high ICP

• Hypoxemia (Hypoxemia ( V/Q mismatch) V/Q mismatch)• Requires special delivery systemRequires special delivery system• Usually requires direct arterial pressure monitoringUsually requires direct arterial pressure monitoring

► Metabolized to CN, then thiocyanateMetabolized to CN, then thiocyanate

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

– Caution with high ICP Caution with high ICP

• Hypoxemia (Hypoxemia ( V/Q mismatch) V/Q mismatch)• Requires special delivery systemRequires special delivery system• Usually requires direct arterial pressure monitoringUsually requires direct arterial pressure monitoring

NitrovasodilatorsNitrovasodilators

Na+

CN

NO+

CN

Fe++

CN

CN

CNNa+

SodiumSodium NitroprussideNitroprussideSodiumSodium NitroprussideNitroprusside

Nitroprusside TherapyNitroprusside Therapy

► Potent venodilator/arterial vasodilatorPotent venodilator/arterial vasodilator

► Cardiac output is often affected due to Cardiac output is often affected due to venodilationvenodilation

► Volume replacement is often required for Volume replacement is often required for venodilationvenodilation

► Potent venodilator/arterial vasodilatorPotent venodilator/arterial vasodilator

► Cardiac output is often affected due to Cardiac output is often affected due to venodilationvenodilation

► Volume replacement is often required for Volume replacement is often required for venodilationvenodilation


Principles and Practice ConsiderationsPrinciples and Practice ConsiderationsPrinciples and Practice ConsiderationsPrinciples and Practice Considerations

IV DHP Calcium Channel BlockersIV DHP Calcium Channel Blockers

► 1st Generation: Nifedipine1st Generation: Nifedipine

► 2nd Generation: Nicardipine, isradipine2nd Generation: Nicardipine, isradipine

► 3rd Generation: Clevidipine3rd Generation: Clevidipine

► 1st Generation: Nifedipine1st Generation: Nifedipine

► 2nd Generation: Nicardipine, isradipine2nd Generation: Nicardipine, isradipine

► 3rd Generation: Clevidipine3rd Generation: Clevidipine

Evolution of Therapeutic OptionsEvolution of Therapeutic OptionsEvolution of Therapeutic OptionsEvolution of Therapeutic Options

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

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

ClCl

OOOO

OO

OO

NNHH

ClCl

OO

OO

**

COCH2CH2NCH2

NO2

CH3

O CH3

N

H

OH3C

H3COC

NifedipineNifedipine

NO2NO2

COCH3COCH3

CH3CH3

OO

NNHH

OOH3CH3C

CH3OCCH3OC

NicardipineNicardipineNicardipineNicardipine

Properties of DihydropyridinesProperties of Dihydropyridines

► Arterial vasodilatorArterial vasodilator11

► Decreases SVRDecreases SVR2-62-6

► More selective for vascular smooth muscle More selective for vascular smooth muscle than cardiac musclethan cardiac muscle11

► No significant increase in ICPNo significant increase in ICP77

► No direct inotropic or dromotropic effectsNo direct inotropic or dromotropic effects2-62-6

► Arterial vasodilatorArterial vasodilator11

► Decreases SVRDecreases SVR2-62-6

► More selective for vascular smooth muscle More selective for vascular smooth muscle than cardiac musclethan cardiac muscle11

► No significant increase in ICPNo significant increase in ICP77

► No direct inotropic or dromotropic effectsNo direct inotropic or dromotropic effects2-62-6

1. Clarke B, et al. Br J Pharmacol. 1983;79:333P. 2. Lambert CR, et al. Am J Cardiol. 1987;60:471-476. 3. Silke B, et al. Br J Clin Pharmacol. 1985;20:169S-176S. 4. Lambert CR, et al Am J Cardiol. 1985;55:652-656. 5. Visser CA, et al. Postgrad Med J. 1984;60:17-20. 6. Silke B, et al. Br J Clin Pharmacol. 1985;20:169S-176S. 7. Nishiyama MT, et al. Can J Anaesth. 2000;47:1196-1201.

Hemodynamic Effects of NicardipineHemodynamic Effects of Nicardipine

Lambert CR: Am J Cardiol 1993;71:420.

ControlControl NicardipineNicardipine

HRHR 71 71 ± ± 1313 70 70 ± 14± 14

MAPMAP 107 107 ± 14± 14 80 80 ± 9± 9

PAOPPAOP 9 9 ± 4± 4 8 8 ± 3± 3

MPAPMPAP 15 15 ± 3± 3 16 16 ± 4± 4

RAPRAP 8 8 ± 3± 3 8 8 ± 2± 2

CICI 2.2 2.2 ± 0.3± 0.3 2.8 2.8 ± 0.4± 0.4

LVdP/dTLVdP/dT 1509 1509 ± 376± 376 1680 1680 ± 485± 485

LVEF %LVEF % 57 57 ± 9± 9 68 68 ± 7± 7

Arterial SpasmArterial Spasm

► Loss of endothelial function via vascular injury Loss of endothelial function via vascular injury and platelet activation is potential mechanismand platelet activation is potential mechanism

► Other mechanisms include NO scavenging by Other mechanisms include NO scavenging by hemoglobinhemoglobin

► Thromboxane, a potent constrictor, has been Thromboxane, a potent constrictor, has been implicatedimplicated

► Only certain drugs will completely reverse arterial Only certain drugs will completely reverse arterial spasmspasm

► Loss of endothelial function via vascular injury Loss of endothelial function via vascular injury and platelet activation is potential mechanismand platelet activation is potential mechanism

► Other mechanisms include NO scavenging by Other mechanisms include NO scavenging by hemoglobinhemoglobin

► Thromboxane, a potent constrictor, has been Thromboxane, a potent constrictor, has been implicatedimplicated

► Only certain drugs will completely reverse arterial Only certain drugs will completely reverse arterial spasmspasm

MechanismMechanism MechanismMechanism

Vasospasm/Vascular Dysfunction StudiesVasospasm/Vascular Dysfunction Studies

► Salmenperra MT: Effects of PDE inhibitors on the human IMA. Salmenperra MT: Effects of PDE inhibitors on the human IMA. Anesth Anesth AnalgAnalg 1996; 82: 954-957. 1996; 82: 954-957.

► Huraux C: Vasodilator effects of clevidipine on human IMA. Huraux C: Vasodilator effects of clevidipine on human IMA. Anesth AnalgAnesth Analg 1997; 85: 1000-1004.1997; 85: 1000-1004.

► Huraux C: A comparative eval of multiple vasodilators on human IMA. Huraux C: A comparative eval of multiple vasodilators on human IMA. AnesthesiologyAnesthesiology 1998;88:1654-1659. 1998;88:1654-1659.

► Huraux C: Superoxide production, risk factors, and EDRF relaxations in Huraux C: Superoxide production, risk factors, and EDRF relaxations in human IMAs. human IMAs. CirculationCirculation 1999;99:53-59. 1999;99:53-59.

► Tsuda A: Reversal of histamine-induced vasodilation in the human IMA. Tsuda A: Reversal of histamine-induced vasodilation in the human IMA. Anesth AnalgAnesth Analg 2001;93:1453-1459. 2001;93:1453-1459.

► Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin and Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin and fenoldopam in the human umbilical artery. fenoldopam in the human umbilical artery. Anesth AnalgAnesth Analg 2003;96:539-544. 2003;96:539-544.

► Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)-Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)-induced vasoconstriction in human IMA. induced vasoconstriction in human IMA. Br J AnaesthBr J Anaesth 2004;93:257-262. 2004;93:257-262.

► Salmenperra MT: Effects of PDE inhibitors on the human IMA. Salmenperra MT: Effects of PDE inhibitors on the human IMA. Anesth Anesth AnalgAnalg 1996; 82: 954-957. 1996; 82: 954-957.

► Huraux C: Vasodilator effects of clevidipine on human IMA. Huraux C: Vasodilator effects of clevidipine on human IMA. Anesth AnalgAnesth Analg 1997; 85: 1000-1004.1997; 85: 1000-1004.

► Huraux C: A comparative eval of multiple vasodilators on human IMA. Huraux C: A comparative eval of multiple vasodilators on human IMA. AnesthesiologyAnesthesiology 1998;88:1654-1659. 1998;88:1654-1659.

► Huraux C: Superoxide production, risk factors, and EDRF relaxations in Huraux C: Superoxide production, risk factors, and EDRF relaxations in human IMAs. human IMAs. CirculationCirculation 1999;99:53-59. 1999;99:53-59.

► Tsuda A: Reversal of histamine-induced vasodilation in the human IMA. Tsuda A: Reversal of histamine-induced vasodilation in the human IMA. Anesth AnalgAnesth Analg 2001;93:1453-1459. 2001;93:1453-1459.

► Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin and Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin and fenoldopam in the human umbilical artery. fenoldopam in the human umbilical artery. Anesth AnalgAnesth Analg 2003;96:539-544. 2003;96:539-544.

► Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)-Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)-induced vasoconstriction in human IMA. induced vasoconstriction in human IMA. Br J AnaesthBr J Anaesth 2004;93:257-262. 2004;93:257-262.

Studies on Arteriolar VasodilatorsStudies on Arteriolar Vasodilators

Nitroglycerin is the most potent; but Nitroglycerin is the most potent; but nitrate tolerance occurnitrate tolerance occur

Milrinone, dihydropyridines, PGE1, Milrinone, dihydropyridines, PGE1, were also effective at therapeutically were also effective at therapeutically used dosesused doses

Nitroglycerin is the most potent; but Nitroglycerin is the most potent; but nitrate tolerance occurnitrate tolerance occur

Milrinone, dihydropyridines, PGE1, Milrinone, dihydropyridines, PGE1, were also effective at therapeutically were also effective at therapeutically used dosesused doses

Huraux: Anesthesiology 1998;88:1654.

A Comparative Evaluation of the Effects of A Comparative Evaluation of the Effects of Multiple Vasodilators on Human IMAMultiple Vasodilators on Human IMA

A Comparative Evaluation of the Effects of A Comparative Evaluation of the Effects of Multiple Vasodilators on Human IMAMultiple Vasodilators on Human IMA

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.

Simulated Drug Level CurvesSimulated Drug Level Curves

=“Full” loading dose = [Cp] x Vdss= Smaller loading dose =[Cp] x Vc= No loading dose

Time (Half-life)Time (Half-life)

0

10

20

30

40

50

60

0 1 2 3 4 5 6

TherapeuticConcentration

Range

TherapeuticConcentration

Range

Pla

sma

Dru

g L

eve

lP

lasm

a D

rug

Le

vel

Cl

ClH

CH3OOC

H3C

COOCH2OOCC3H7

CH3N

H

The Clevidipine MoleculeThe Clevidipine Molecule

Clevidipine is the first ultrashort acting dihydropyridine intravenous calcium channel blocker

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

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

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

+OH

OHH

O

ClevidipineClevidipine

Cl

OO

O

O

NH

Cl

O

O

*EsterasesEsterases +O

O

NH

Cl

O

O

Cl

H

Primary metabolitePrimary 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

hang

e F

rom

Ba

selin

e

Time (min)

SBP

SBP ChangesSBP Changes SBP ChangesSBP Changes

Clevidipine — Rapid Onset of ActionClevidipine — Rapid Onset of Action

► BP-lowering effects are seen within 2–3 minutes of BP-lowering effects are seen within 2–3 minutes of clevidipine infusionclevidipine infusion

► BP-lowering effects are seen within 2–3 minutes of BP-lowering effects are seen within 2–3 minutes of clevidipine infusionclevidipine infusion

Levy JH, et al. Anesth Analg. 2007;105(4):918 .

*Css = concentration at steady state; median blood concentration of clevidipine obtainedduring the last 10 minutes of infusion.

Clevidipine — Linear PharmacokineticsClevidipine — Linear Pharmacokinetics

► At steady state, there is a linear relationship between dosage At steady state, there is a linear relationship between dosage and arterial blood concentrationsand arterial blood concentrations

► Linear relationship maintained for dosages as high as 21.9 Linear relationship maintained for dosages as high as 21.9 mcg/kg/minmcg/kg/min

► At steady state, there is a linear relationship between dosage At steady state, there is a linear relationship between dosage and arterial blood concentrationsand arterial blood concentrations

► Linear relationship maintained for dosages as high as 21.9 Linear relationship maintained for dosages as high as 21.9 mcg/kg/minmcg/kg/min

120

100

80

60

40

20

0

0 5 10 15 20 35

Cle

vid

ipin

e C

on

ce

ntr

ati

on

Cle

vid

ipin

e C

on

ce

ntr

ati

on

at

Cs

s (

nm

ol/

L)*

at

Cs

s (

nm

ol/

L)*

Dose Rate (nmol/kg/min)Dose Rate (nmol/kg/min)25 30

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.

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

M

AP

(m

m H

g)

an

d

HR

(b

ea

ts/m

in)

HR

(b

ea

ts/m

in)

Time (min)Time (min)

25 30

Clevidipine InfusionClevidipine InfusionMAPMAP

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

Clevidipine — Ultrashort Half-LifeClevidipine — Ultrashort Half-Life

► Clinically relevant half-life: Approximately 1 Clinically relevant half-life: Approximately 1 minuteminute

► Clinically relevant half-life: Approximately 1 Clinically relevant half-life: Approximately 1 minuteminute

Arterial and venous clevidipine blood samplesArterial and venous clevidipine blood samples

*P<0.05, †P<0.001, ‡P<0.01, control vs 0.375, 0.75, 1.5, and 3.0 mcg/kg /min–1

and post-drug control. Values are mean ± SEM.

1212

mm

Hg

mm

Hg 88

44

0000 0.3750.375 0.750.75 1.51.5 33 00

1010

66

22

mcg/kg/minmcg/kg/min

Central Venous Pressure Central Venous Pressure

Clevidipine and Arterial SelectivityClevidipine and Arterial Selectivity

14001400

Uni

tsU

nits

12001200

10001000

00C1C1 0.3750.375 0.750.75 1.51.5 33 C2 C2

Systemic Vascular ResistanceSystemic Vascular Resistance

‡‡††

††††


C2 C2

††

Mean Arterial PressureMean Arterial Pressure

9090

8080

7070

**††

††

C1C1 0.3750.375 0.750.75 1.51.5 33


mm

Hg

mm

Hg

Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193.

Preoperative HR Changes in Non-Anesthetized Patients

Preoperative HR Changes in Non-Anesthetized Patients

Postoperative HR Changesin Anesthetized Patients

Postoperative HR Changesin Anesthetized Patients

Clevidipine: Clevidipine: Minimal Effect on Heart Rate Minimal Effect on Heart Rate

1010

55

00

––55

00 55 1010 1515 2020 2525 3030

% C

hang

e F

rom

Ba

selin

e%

Cha

nge

Fro

m B

ase

line

Time (min)Time (min)

HRHR

HR changes for patients during the HR changes for patients during the 30-minute treatment period30-minute treatment period

55

00

––55

00 55 1010 1515 2020 2525 3030%

Cha

nge

Fro

m B

ase

line

% C

hang

e F

rom

Ba

selin

eTime (min)Time (min)

HRHR

HR changes for patients during the HR changes for patients during the 30-minute treatment period30-minute treatment period

Levy JH, et al. Anesth Analg. 2007;105(4):918. Singla N, et al. Anesthesiology. 2005;103:A292.

Clevidipine Clinical DevelopmentClevidipine Clinical Development

Tolerability, Tolerability, Safety, PKSafety, PK

DoseDose ResponseResponseESCAPE: EfficacyESCAPE: Efficacy

Clevidipine Clevidipine vs Placebovs Placebo

VELOCITYSevere Hypertension

PK, Metabolism, PK, Metabolism, Rates and Routes Rates and Routes

of Excretionof ExcretionPK/BPPK/BP

ESCAPE: EfficacyESCAPE: EfficacyClevidipine Clevidipine vs Placebovs Placebo

PKPKPK/PD:PK/PD:

Clevidipine Clevidipine vs Placebovs Placebo

ECLIPSE: Safety vs NTG

QTc StudyQTc StudyECLIPSE:

Safety vs SNP

ECLIPSE: Safety vs NIC

DoseDose Response:Response:Clevidipine Clevidipine vs Placebovs Placebo

Hemodynamics:Hemodynamics:Clevidipine vs SNPClevidipine vs SNP

BP, HR:BP, HR:Clevidipine vs SNPClevidipine vs SNP

BP, Dose/PKBP, Dose/PK

BP: Clevidipine BP: Clevidipine vs Placebovs Placebo

Phase IPhase IN=89N=89

Phase II Phase II N=300N=300

Phase II Phase II N=300N=300

Healthy VolunteersHealthy VolunteersPatients: Mild to Patients: Mild to

Moderate HypertensionModerate HypertensionN=86N=86

Phase III Phase III N=1821N=1821

Perioperative Perioperative Hypertension Hypertension

N=1721 N=1721

SevereSevereHypertensionHypertension

N=100N=100

Patients: Patients: Perioperative Perioperative

N=214N=214

Data on file. The Medicines Company.

Acknowledgements — ECLIPSE TrialAcknowledgements — ECLIPSE Trial

Cornelius Dyke, MDCornelius Dyke, MD Dean Kereiakes, MDDean Kereiakes, MD

Jerrold H. Levy, MDJerrold H. Levy, MD Philip Lumb, MDPhilip Lumb, MD

Albert Cheung, MDAlbert Cheung, MD Howard Corwin, MDHoward Corwin, MD

Solomon Aronson, MD*Solomon Aronson, MD* Mark Newman, MDMark Newman, MD

**Acknowledgement and thanks to Dr. Solomon Aronson, whoAcknowledgement and thanks to Dr. Solomon Aronson, who first presented much of this material as a Late Breaker at first presented much of this material as a Late Breaker at ACC 2007 Scientific Assembly on March 27, 2007ACC 2007 Scientific Assembly on March 27, 2007

**Acknowledgement and thanks to Dr. Solomon Aronson, whoAcknowledgement and thanks to Dr. Solomon Aronson, who first presented much of this material as a Late Breaker at first presented much of this material as a Late Breaker at ACC 2007 Scientific Assembly on March 27, 2007ACC 2007 Scientific Assembly on March 27, 2007

ECLIPSE — RationaleECLIPSE — Rationale

► Clevidipine is an IV dihydropyridine calcium channel Clevidipine is an IV dihydropyridine calcium channel blocker with an ultrashort half-life (~1 min)blocker with an ultrashort half-life (~1 min)

► Phase I and II studies (300 pts) demonstrated:Phase I and II studies (300 pts) demonstrated:

● Dose: 2–16 mg/hr effectiveDose: 2–16 mg/hr effective11

► Phase III safety program required for FDA registrationPhase III safety program required for FDA registration

● Evaluation: Death, MI, Stroke, Renal DysfunctionEvaluation: Death, MI, Stroke, Renal Dysfunction

● Comparators: Nitroglycerin (NTG), Sodium nitroprusside (SNP), Comparators: Nitroglycerin (NTG), Sodium nitroprusside (SNP), Nicardipine (NIC)Nicardipine (NIC)

● Rapid onset: BP control in 5 minRapid onset: BP control in 5 min22

► Clevidipine is an IV dihydropyridine calcium channel Clevidipine is an IV dihydropyridine calcium channel blocker with an ultrashort half-life (~1 min)blocker with an ultrashort half-life (~1 min)

► Phase I and II studies (300 pts) demonstrated:Phase I and II studies (300 pts) demonstrated:

● Dose: 2–16 mg/hr effectiveDose: 2–16 mg/hr effective11

► Phase III safety program required for FDA registrationPhase III safety program required for FDA registration

● Evaluation: Death, MI, Stroke, Renal DysfunctionEvaluation: Death, MI, Stroke, Renal Dysfunction

● Comparators: Nitroglycerin (NTG), Sodium nitroprusside (SNP), Comparators: Nitroglycerin (NTG), Sodium nitroprusside (SNP), Nicardipine (NIC)Nicardipine (NIC)

● Rapid onset: BP control in 5 minRapid onset: BP control in 5 min22

1Bailey J. Anesthesiology 2002;96:1086-94. 2Levy J. Anesth Analg. 2007;105(4):918.

ECLIPSEECLIPSE

► Randomized (1:1), open-label, parallel group with Randomized (1:1), open-label, parallel group with active comparators: nitroglycerin (NTG), sodium active comparators: nitroglycerin (NTG), sodium nitroprusside (SNP), or nicardipine (NIC)nitroprusside (SNP), or nicardipine (NIC)

• • NTG and SNP studies are perioperative and NIC is NTG and SNP studies are perioperative and NIC is postoperativepostoperative

► Treatment with study drug allowed until discharge from Treatment with study drug allowed until discharge from ICUICU

► Patients undergoing cardiac surgery; CABG, OPCAB, Patients undergoing cardiac surgery; CABG, OPCAB, Valve, MIDCABValve, MIDCAB

► Randomized (1:1), open-label, parallel group with Randomized (1:1), open-label, parallel group with active comparators: nitroglycerin (NTG), sodium active comparators: nitroglycerin (NTG), sodium nitroprusside (SNP), or nicardipine (NIC)nitroprusside (SNP), or nicardipine (NIC)

• • NTG and SNP studies are perioperative and NIC is NTG and SNP studies are perioperative and NIC is postoperativepostoperative

► Treatment with study drug allowed until discharge from Treatment with study drug allowed until discharge from ICUICU

► Patients undergoing cardiac surgery; CABG, OPCAB, Patients undergoing cardiac surgery; CABG, OPCAB, Valve, MIDCABValve, MIDCAB


ProtocolsProtocols ProtocolsProtocols

ECLIPSE: Trial DesignECLIPSE: Trial Design

Clevidipinevs nitroglycerin

Clevidipinevs nitroglycerin

Clevidipine vs sodium

nitroprusside

Clevidipine vs sodium

nitroprusside

ClevidipineClevidipinevs nicardipinevs nicardipine

PerioperativePerioperative Perioperative PostoperativePostoperative

ClevidipineN=268

NitroglycerinN=278

ClevidipineN=296

Sodiumnitroprusside

N=283

ClevidipineClevidipineN=188N=188

NicardipineNicardipineN=193N=193

1:1 1:1 1:1


Treatment ProtocolTreatment Protocol

► ClevidipineClevidipine● Initiated 2 mg/hr Initiated 2 mg/hr

● Titrated doubling increments Q 90s to 16 mg/hrTitrated doubling increments Q 90s to 16 mg/hr

● 40 mg/hr maximum 40 mg/hr maximum

► Comparators (NTG, SNP, NIC) administered Comparators (NTG, SNP, NIC) administered per institutional practiceper institutional practice

► Treatment duration up to discharge from the Treatment duration up to discharge from the ICUICU

► Concomitant antihypertensives discouragedConcomitant antihypertensives discouraged

► ClevidipineClevidipine● Initiated 2 mg/hr Initiated 2 mg/hr

● Titrated doubling increments Q 90s to 16 mg/hrTitrated doubling increments Q 90s to 16 mg/hr

● 40 mg/hr maximum 40 mg/hr maximum

► Comparators (NTG, SNP, NIC) administered Comparators (NTG, SNP, NIC) administered per institutional practiceper institutional practice

► Treatment duration up to discharge from the Treatment duration up to discharge from the ICUICU

► Concomitant antihypertensives discouragedConcomitant antihypertensives discouraged

Outcome EndpointsOutcome Endpoints

Primary End Points*Primary End Points* (Cumulative rate of clinical (Cumulative rate of clinical outcomes at 30 days):outcomes at 30 days):

● DeathDeath

● MI:MI: Symptomatic presentation, enzyme release, and/or Symptomatic presentation, enzyme release, and/or new ECG changesnew ECG changes

● Stroke:Stroke: Hemorrhagic or ischemic Hemorrhagic or ischemic

● Renal Dysfunction:Renal Dysfunction: Cr >2.0 with min absolute Cr >2.0 with min absolute changechange of 0.7of 0.7

Secondary End PointsSecondary End Points● SAEs through day 7 SAEs through day 7

● BP control during the first 24 hBP control during the first 24 h

Primary End Points*Primary End Points* (Cumulative rate of clinical (Cumulative rate of clinical outcomes at 30 days):outcomes at 30 days):

● DeathDeath

● MI:MI: Symptomatic presentation, enzyme release, and/or Symptomatic presentation, enzyme release, and/or new ECG changesnew ECG changes

● Stroke:Stroke: Hemorrhagic or ischemic Hemorrhagic or ischemic

● Renal Dysfunction:Renal Dysfunction: Cr >2.0 with min absolute Cr >2.0 with min absolute changechange of 0.7of 0.7

Secondary End PointsSecondary End Points● SAEs through day 7 SAEs through day 7

● BP control during the first 24 hBP control during the first 24 h

* Blinded CEC adjudication of all primary measures

Patient DispositionPatient Disposition

PopulationsPopulations ClevidipineClevidipine ComparatorsComparators

Randomized patientsRandomized patients 971971 993993

Met post-randomization criteriaMet post-randomization criteria 755755 757757

Safety populationSafety population 752752 754754

Completed studyCompleted study 715715 719719

Did not complete studyDid not complete study Withdrew consentWithdrew consent Physician decisionPhysician decision Lost to follow upLost to follow up Adverse experienceAdverse experience Patient deathPatient death OtherOther

3737 00 111515 002020 11

3535 11 00 66 002828 00

Baseline CharacteristicsBaseline Characteristics

Historical FeaturesHistorical Features ClevidipineClevidipinen=752n=752


Age, median (range)Age, median (range) 65 (24-87)65 (24-87) 66 (19-89)66 (19-89)

MaleMale 72%72% 74%74%

CaucasianCaucasian 82%82% 83%83%

History of HypertensionHistory of Hypertension 88%88% 85%85%

CHFCHF 19%19% 18%18%

Insulin dependent diabetesInsulin dependent diabetes 11%11% 11%11%

COPDCOPD 14%14% 15%15%

Recent MI (< 6 mos)Recent MI (< 6 mos) 17%17% 18%18%

Prior CABGPrior CABG 3%3% 6%6%

Procedural CharacteristicsProcedural Characteristics

Procedural CharacteristicsProcedural Characteristics ClevidipineClevidipinen=752n=752


Surgery Duration: Median HoursSurgery Duration: Median Hours 3.323.32 3.233.23

ProcedureProcedure CABGCABG

Valve replacement/repairValve replacement/repair

CABG & Valve replacement/repairCABG & Valve replacement/repair

OtherOther

77%77%

14%14%

9%9%

0.3%0.3%

77%77%

12%12%

11%11%

0.1%0.1%

ECLIPSE NTG — Drug AdministrationECLIPSE NTG — Drug Administration

Timing and DurationTiming and Duration ClevidipineClevidipineN=268N=268

NitroglycerinNitroglycerinN=278N=278

Initiated Pre-OpInitiated Pre-Op 92 (34.3)92 (34.3) 119 (42.8)119 (42.8)

Initiated Intra-OpInitiated Intra-Op 145 (54.1)145 (54.1) 132 (47.5)132 (47.5)

Initiated Post-OpInitiated Post-Op 31 (11.6)31 (11.6) 27 (9.7)27 (9.7)

Overall Infusion Overall Infusion Duration (median)Duration (median) 3.35 hr3.35 hr 8.13 hr8.13 hr


ECLIPSE SNP: Drug AdministrationECLIPSE SNP: Drug Administration


NitroprussideNitroprussideN=283N=283

Initiated Pre-OpInitiated Pre-Op 52 (17.6)52 (17.6) 34 (12.0)34 (12.0)

Initiated Intra-OpInitiated Intra-Op 161 (54.4)161 (54.4) 158 (55.8)158 (55.8)

Initiated Post-OpInitiated Post-Op 83 (28.0)83 (28.0) 90 (31.8)90 (31.8)



ECLIPSE NIC: Drug AdministrationECLIPSE NIC: Drug Administration


NicardipineNicardipineN=193N=193

Dosed DuringDosed DuringPost-OpPost-Op 188 (100)188 (100) 193 (100)193 (100)



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

Primary End Points byPrimary End Points byTreatment ComparisonTreatment Comparison

End PointsEnd Points ClevidipineClevidipine NTGNTG ClevidipineClevidipine SNPSNP ClevidipineClevidipine NICNIC

DeathDeath 2.8%2.8% 3.4%3.4% 1.7%1.7% 4.7%*4.7%* 4.4%4.4% 3.2%3.2%

MIMI 3.3%3.3% 3.5%3.5% 1.4%1.4% 2.3%2.3% 2.3%2.3% 1.1%1.1%

StrokeStroke 1.6%1.6% 2.3%2.3% 1.1%1.1% 1.5%1.5% 0.6%0.6% 1.1%1.1%

Renal Renal DysfunctionDysfunction 6.9%6.9% 8.1%8.1% 8.5%8.5% 9.1%9.1% 8.3%8.3% 5.9%5.9%

* p = 0.045

Serious Adverse EventsSerious Adverse Events

Serious Adverse EventsSerious Adverse Events ClevidipineClevidipinen=752n=752

ComparatorsComparatorsn=754n=754

TotalTotal 17.7%17.7% 20.0%20.0%

Atrial fibrillation (AF)Atrial fibrillation (AF) 2.4%2.4% 2.4%2.4%

Respiratory failureRespiratory failure 1.1%1.1% 2.5%2.5%

Acute renal failure (ARF)Acute renal failure (ARF) 2.3%2.3% 1.7%1.7%

Ventricular fibrillationVentricular fibrillation 0.9%0.9% 1.5%1.5%

Cardiac arrestCardiac arrest 0.5%0.5% 1.1%1.1%

CVACVA 0.5%0.5% 1.1%1.1%

Post-procedural hemorrhagePost-procedural hemorrhage 0.5%0.5% 1.1%1.1%

ECLIPSE: Atrial FibrillationECLIPSE: Atrial Fibrillation

ArrhythmiaArrhythmia CLVCLVn/N (%)n/N (%)

NTGNTGn/N (%)n/N (%)

SNPSNPn/N (%)n/N (%)

NICNICn/N (%)n/N (%)

Atrial fibrillation Atrial fibrillation (Total)(Total)

275/752 275/752 (36.6)(36.6)

91/278 91/278 (32.7)(32.7)

95/283 95/283 (33.6)(33.6)

71/193 71/193 (36.8)(36.8)

Atrial fibrillation Atrial fibrillation (before March 25, (before March 25,

2005)2005)

108/296 108/296 (36.5)(36.5)

91/278 91/278 (32.7)(32.7)

25/111 25/111 (22.5)(22.5) 16/50 (32.0)16/50 (32.0)

Atrial fibrillation Atrial fibrillation (after March(after March

25, 2005)25, 2005)

67/188 67/188 (35.6)(35.6) N/AN/A 70/172 70/172

(40.7)(40.7)55/143 55/143 (38.5)(38.5)

►ECLIPSE was put on hold due to higher AF rates in clevidipine in March 2004 and restarted in December 2005

►No statistically significant differences in any of the arms or in overall comparison

..

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 PredictorsMortality Predictors P-ValueP-Value Odds Odds RatioRatio

95% CI95% CI [Lower Limit, [Lower Limit, Upper Limit]Upper Limit]

Surgery Duration (hour)Surgery Duration (hour) <0.0001<0.0001 1.5171.517 [1.240, 1.856][1.240, 1.856]

Age (year)Age (year) 0.00030.0003 1.0701.070 [1.031, 1.110][1.031, 1.110]

Pre-op Creatinine Pre-op Creatinine ≥ ≥ 1.2 mg/dL1.2 mg/dL 0.00310.0031 2.6702.670 [1.392, 5.122][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 proceduresAdditional surgical procedures 0.00890.0089 2.4092.409 [1.246, 4.655][1.246, 4.655]

Pre-op Hgb (g/dL)Pre-op Hgb (g/dL) 0.01350.0135 0.8240.824 [0.707, 0.961][0.707, 0.961]

Pre-op SBP >160 or DBP > 105Pre-op SBP >160 or DBP > 105 0.02280.0228 2.3862.386 [1.147, 4.963][1.147, 4.963]

History of COPDHistory of COPD 0.02280.0228 2.3262.326 [1.125, 4.812][1.125, 4.812]

History of recent MI History of recent MI (<6 months prior)(<6 months prior) 0.03120.0312 2.1972.197 [1.073, 4.497] [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 Odds RatioRatio

95% CI 95% CI [Lower Limit, [Lower Limit, Upper Limit]Upper Limit]

1.201.20 [1.06, 1.27][1.06, 1.27]

1.431.43 [1.13, 1.61][1.13, 1.61]

1.711.71 [1.20, 2.05][1.20, 2.05]

2.052.05 [1.27, 2.61][1.27, 2.61]

2.462.46 [1.35, 3.31][1.35, 3.31]

0 1 2 3 4

SUMMARY (1)SUMMARY (1)

► Multiple pharmacologic agents produce vasodilation via Multiple pharmacologic agents produce vasodilation via different mechanisms.different mechanisms.

► Arterial vasoconstriction is characteristic of perioperative Arterial vasoconstriction is characteristic of perioperative hypertension with intravascular hypovolemia.hypertension with intravascular hypovolemia.

► Nitrovasodilators decrease both preload and resistance Nitrovasodilators decrease both preload and resistance vessels vessels

► DHP CCBs produce arterial selective vasodilation that DHP CCBs produce arterial selective vasodilation that controls BP without producing venodilation or negative controls BP without producing venodilation or negative inotropic and conduction effects, and reverses vasospasm inotropic and conduction effects, and reverses vasospasm in the IMA and other vascular beds.in the IMA and other vascular beds.

SUMMARY (2)SUMMARY (2)

► ECLIPSE is the largest safety program ever performed with an ECLIPSE is the largest safety program ever performed with an intravenous antihypertensive (n=1,512) agents that examine intravenous antihypertensive (n=1,512) agents that examine management of acute, severe hypertension in the perioperative management of acute, severe hypertension in the perioperative settingsetting

► AUC data suggests better overall BP control with clevidipine AUC data suggests better overall BP control with clevidipine compared with SNP and NTGcompared with SNP and NTG

► Clevidipine represents a safe alternative to commonly Clevidipine represents a safe alternative to commonly used antihypertensive agents in the cardiovascular used antihypertensive agents in the cardiovascular surgery setting, and demonstrated superior blood surgery setting, and demonstrated superior blood pressure control as assessed by integral analysis of pressure control as assessed by integral analysis of excursions outside specified ranges over timeexcursions outside specified ranges over time

► Data supports importance of precise blood pressure Data supports importance of precise blood pressure control in a critically ill patient populationcontrol in a critically ill patient population

► Clevidipine represents the first potential nitroprusside Clevidipine represents the first potential nitroprusside replacement for cliniciansreplacement for clinicians

Comprehensive Neurovascular Protection in Comprehensive Neurovascular Protection in Patients Undergoing Cardiac Surgery Patients Undergoing Cardiac Surgery

Comprehensive Neurovascular Protection in Comprehensive Neurovascular Protection in Patients Undergoing Cardiac Surgery Patients Undergoing Cardiac Surgery


Charles W. Hogue, Jr., MDCharles W. Hogue, Jr., MDAssociate Professor of AnesthesiologyAssociate Professor of Anesthesiology

Department of Anesthesiology and Critical Care Medicine Department of Anesthesiology and Critical Care Medicine Johns Hopkins University Medical SchoolJohns Hopkins University Medical School

Baltimore, MarylandBaltimore, Maryland

Charles W. Hogue, Jr., MDCharles W. Hogue, Jr., MDAssociate Professor of AnesthesiologyAssociate Professor of Anesthesiology

Department of Anesthesiology and Critical Care Medicine Department of Anesthesiology and Critical Care Medicine Johns Hopkins University Medical SchoolJohns Hopkins University Medical School

Baltimore, MarylandBaltimore, Maryland

Neurovascular ProtectionNeurovascular Protection

Vascular Stiffness and Cardiovascular Vascular Stiffness and Cardiovascular OutcomesOutcomes

• Reflected pulse wave returns early Reflected pulse wave returns early in systolein systole

• Rising systolic blood but declining Rising systolic blood but declining diastolic B/P (rising diastolic B/P (rising pulse pulse pressurepressure) )

• Increases strain on Increases strain on myocardium myocardium

• Exposes micro-circulation Exposes micro-circulation of brain and kidney to of brain and kidney to chronically high pressures chronically high pressures and resultant and resultant pathophysiologic changespathophysiologic changes

• Reflected pulse wave returns early Reflected pulse wave returns early in systolein systole

• Rising systolic blood but declining Rising systolic blood but declining diastolic B/P (rising diastolic B/P (rising pulse pulse pressurepressure) )

• Increases strain on Increases strain on myocardium myocardium

• Exposes micro-circulation Exposes micro-circulation of brain and kidney to of brain and kidney to chronically high pressures chronically high pressures and resultant and resultant pathophysiologic changespathophysiologic changes

Pulsatile Pressure Changes Pulsatile Pressure Changes in the Vascular Treein the Vascular Tree

O’Rourke. J Am Coll Cardiol 2006;50:1-13

Pulse Pressure Predicts Stroke DevelopmentPulse Pressure Predicts Stroke DevelopmentAfter Cardiac Surgery After Cardiac Surgery

Benjo et al. Hyperten 2007;50:630-35

0 50 100 150

4

3

2

1

0

Pulse Pressure

Pre

dict

ed P

roba

bilit

y of

Str

oke

DWI and PWI in Acute StrokeDWI and PWI in Acute Stroke

• DWI identifies densely ischemic tissue/infarctDWI identifies densely ischemic tissue/infarct

• PWI identifies area surrounding the core infarct getting enough PWI identifies area surrounding the core infarct getting enough blood to survive, not enough to functionblood to survive, not enough to function

• PWI-DWI (diffusion-perfusion mismatch) PWI-DWI (diffusion-perfusion mismatch) ~ “ischemic penumbra”~ “ischemic penumbra”

• DWI identifies densely ischemic tissue/infarctDWI identifies densely ischemic tissue/infarct

• PWI identifies area surrounding the core infarct getting enough PWI identifies area surrounding the core infarct getting enough blood to survive, not enough to functionblood to survive, not enough to function

• PWI-DWI (diffusion-perfusion mismatch) PWI-DWI (diffusion-perfusion mismatch) ~ “ischemic penumbra”~ “ischemic penumbra”

Densely Ischemic TissueDensely Ischemic TissueMarginally Perfused Marginally Perfused

BrainBrain

DWIDWI PWIPWI

Acute aphasic deficits are due to both areas of structural Acute aphasic deficits are due to both areas of structural damage and areas of hypoperfusiondamage and areas of hypoperfusion

Before BP ElevationBefore BP Elevation After BP ElevationAfter BP Elevation

BA 22

BA 37

0102030405060708090

100

Day 1 Day 3

% c

orre

ct

Word/PictureMatching

Oral Naming


SPECT Imaging Before CABGSPECT Imaging Before CABG

Moraca et al. J Thorac Cardiovasc Surg 2006;131:540-6

Watershed Strokes Detected with Watershed Strokes Detected with DWI After Cardiac SurgeryDWI After Cardiac Surgery

► Watershed infarcts present in Watershed infarcts present in 68% of 98 strokes 68% of 98 strokes

► MAP MAP ≥ 10 mm Hg during ≥ 10 mm Hg during CPB CPB risk 4 fold for bilateral risk 4 fold for bilateral watershed infarct c/w other watershed infarct c/w other infarct patternsinfarct patterns

► Watershed infarcts present in Watershed infarcts present in 68% of 98 strokes 68% of 98 strokes

► MAP MAP ≥ 10 mm Hg during ≥ 10 mm Hg during CPB CPB risk 4 fold for bilateral risk 4 fold for bilateral watershed infarct c/w other watershed infarct c/w other infarct patternsinfarct patterns

Gottesman et al. Stroke 2006;37:2306Gottesman et al. Stroke 2006;37:2306Gottesman et al. Stroke 2006;37:2306Gottesman et al. Stroke 2006;37:2306

Blood Pressure Management During CPBBlood Pressure Management During CPB

► CBF-BP autoregulation believed intact (CBF-BP autoregulation believed intact (-stat)-stat)• Lower limit MAP of 50 mmHg? Lower limit MAP of 50 mmHg?

► Higher CBF might be deleteriousHigher CBF might be deleterious• Increase cerebral embolic loadIncrease cerebral embolic load• ““Wash-out” cardioplegia via non-coronary collateralsWash-out” cardioplegia via non-coronary collaterals

► CBF-BP autoregulation believed intact (CBF-BP autoregulation believed intact (-stat)-stat)• Lower limit MAP of 50 mmHg? Lower limit MAP of 50 mmHg?

► Higher CBF might be deleteriousHigher CBF might be deleterious• Increase cerebral embolic loadIncrease cerebral embolic load• ““Wash-out” cardioplegia via non-coronary collateralsWash-out” cardioplegia via non-coronary collaterals

TCDTCDTCDTCD

Arterial B/PArterial B/PArterial B/PArterial B/P

NIRSNIRSNIRSNIRS A/D A/D ConversionConversion

A/D A/D ConversionConversion PCPCPCPC

Continuous moving Continuous moving Pearson correlation Pearson correlation coefficient*:coefficient*:

CBFv and MAPCBFv and MAP Mx Mx

NIRs and MAP NIRs and MAP COx COx

Continuous moving Continuous moving Pearson correlation Pearson correlation coefficient*:coefficient*:

CBFv and MAPCBFv and MAP Mx Mx

NIRs and MAP NIRs and MAP COx COx

* Non-overlapping 10 sec values sampled at 0.1 Hz to eliminate high frequency noise from respiration * Non-overlapping 10 sec values sampled at 0.1 Hz to eliminate high frequency noise from respiration and pulse according to Nyquist theorem. Correlations are 10 sec averaged data over 300 secand pulse according to Nyquist theorem. Correlations are 10 sec averaged data over 300 sec* Non-overlapping 10 sec values sampled at 0.1 Hz to eliminate high frequency noise from respiration * Non-overlapping 10 sec values sampled at 0.1 Hz to eliminate high frequency noise from respiration and pulse according to Nyquist theorem. Correlations are 10 sec averaged data over 300 secand pulse according to Nyquist theorem. Correlations are 10 sec averaged data over 300 sec


Autoregulation Monitoring using ICM+Autoregulation Monitoring using ICM+

CBF: MAP r < 0CBF: MAP r < 0CBF: MAP r < 0CBF: MAP r < 0

CBF: MAP r > 0CBF: MAP r > 0CBF: MAP r > 0CBF: MAP r > 0


0 20 40 60 80 1000

20

40

60

80

MAP

LM

CA

CB

F V

Cerebral AutoregulationCerebral Autoregulation

100 200

Chronic hypertensivePrior Stroke

50 150 250

Cerebral Blood Flow

MAP (mm Hg)

0

CBF: MAP r < 0CBF: MAP r < 0CBF: MAP r < 0CBF: MAP r < 0



Autoregulatory Threshold: COx vs Doppler Autoregulatory Threshold: COx vs Doppler

Brady et al. Stroke. 2007;38:2818-25 Brady et al. Stroke. 2007;38:2818-25 Brady et al. Stroke. 2007;38:2818-25 Brady et al. Stroke. 2007;38:2818-25



Approach to High Risk PatientApproach to High Risk Patient

• We don’t know where to keep MAPWe don’t know where to keep MAP

• MAP > 70 mmHg (???)MAP > 70 mmHg (???)

• NIRS monitoringNIRS monitoring

• We don’t know where to keep MAPWe don’t know where to keep MAP

• MAP > 70 mmHg (???)MAP > 70 mmHg (???)

• NIRS monitoringNIRS monitoring

Preload Preload SensitiveSensitivePreload Preload

SensitiveSensitive

Pulse Pressure

V

P


ConclusionsConclusions

► Cerebral vascular disease is prevalent in Cerebral vascular disease is prevalent in contemporary cardiac surgery practicecontemporary cardiac surgery practice

► Blood pressures during CPB deemed Blood pressures during CPB deemed “safe” in the past may expose patients to “safe” in the past may expose patients to cerebral hypoperfusion and brain injurycerebral hypoperfusion and brain injury

► Blood pressure within a “tight” range Blood pressure within a “tight” range may be preferablemay be preferable

► Individualized blood pressure Individualized blood pressure management based on NIRS?management based on NIRS?

► Cerebral vascular disease is prevalent in Cerebral vascular disease is prevalent in contemporary cardiac surgery practicecontemporary cardiac surgery practice

► Blood pressures during CPB deemed Blood pressures during CPB deemed “safe” in the past may expose patients to “safe” in the past may expose patients to cerebral hypoperfusion and brain injurycerebral hypoperfusion and brain injury

► Blood pressure within a “tight” range Blood pressure within a “tight” range may be preferablemay be preferable

► Individualized blood pressure Individualized blood pressure management based on NIRS?management based on NIRS?

The Relationship between Acute Pressure Derangements & Comprehensive Vascular Protection in the Setting of CT Surgery Solomon Aronson, MD Program Co-Chairman.

Documents

md program cochairman

md grantresearch support

program welcome

program overview slide

md advisory committee

systolic andor diastolic

management of bp elevations

perioperative setting