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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
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
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
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
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-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
Investigation Investigation ●● Innovation ● Application Innovation ● Application
““A man is as old as his arteries”A man is as old as his arteries”““A man is as old as his arteries”A man is as old as his arteries”
Sir William Osler
Sir William OslerSir William Osler
Investigation Investigation ●● Innovation ● Application Innovation ● Application
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
Investigation Investigation ●● Innovation ● Application Innovation ● Application
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
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
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)
Clevidipine(n = 296)
Sodiumnitroprusside
(n = 283)
Clevidipine(n = 188)
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 et al. ACC 2007.
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
ClevidipineClevidipinen=269n=269
NTGNTGn=278n=278
ClevidipineClevidipinen=295n=295
SNPSNPn=284n=284
ClevidipineClevidipinen=187n=187
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)
Aronson et al. ACC 2007.
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
Data on file, The Medicines Company.
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.
aMAP = mean arterial pressure.bp < 0.05, nicardipine group versus all patients.
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
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
aMAP = mean arterial pressure.bp < 0.05, nicardipine group versus all patients.
cp < 0.05, nicardipine group versus nitroprusside group.dOne patient was excluded from the analysis.
aMAP = mean arterial pressure.bp < 0.05, nicardipine group versus all patients.
cp < 0.05, nicardipine group versus nitroprusside group.dOne patient was excluded from the analysis.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.
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
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
Data on file, The Medicines Company.
"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)
Levy JH: Management of systemic and pulmonary hypertension. Tex Heart Inst J 2005;32:467-471.
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
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
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
‡‡††
††††
mcg/kg/minmcg/kg/min
C2 C2
††
Mean Arterial PressureMean Arterial Pressure
9090
8080
7070
**††
††
C1C1 0.3750.375 0.750.75 1.51.5 33
mcg/kg/minmcg/kg/min
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
Data on file. The Medicines Company.
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
Data on file. The Medicines Company.
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
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%
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
Comparators Comparators n=754n=754
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
Data on file. The Medicines Company.
ECLIPSE SNP: Drug AdministrationECLIPSE SNP: Drug Administration
Timing and DurationTiming and Duration ClevidipineClevidipineN=296N=296
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)
Overall Infusion Overall Infusion Duration (median)Duration (median) 4.03 hr4.03 hr 3.25 hr3.25 hr
Data on file. The Medicines Company.
ECLIPSE NIC: Drug AdministrationECLIPSE NIC: Drug Administration
Timing and DurationTiming and Duration ClevidipineClevidipineN=188N=188
NicardipineNicardipineN=193N=193
Dosed DuringDosed DuringPost-OpPost-Op 188 (100)188 (100) 193 (100)193 (100)
Overall Infusion Overall Infusion Duration (median)Duration (median) 5.55 hr5.55 hr 5.12 hr5.12 hr
Data on file. The Medicines Company.
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
Investigation Investigation ●● Innovation ● Application Innovation ● Application
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
Neurovascular ProtectionNeurovascular Protection
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
Neurovascular ProtectionNeurovascular Protection
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
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
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
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
Neurovascular ProtectionNeurovascular Protection
Neurovascular ProtectionNeurovascular Protection
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
Neurovascular ProtectionNeurovascular Protection
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?
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