Investigations ● Advances ● Applications
Emerging Perspectives and Strategies for
Optimizing Perioperative Blood Pressure Management
Jerrold H. Levy, MD
Program Co-Chairman
Professor and Deputy Chair for Research
Emory University School of Medicine
Director of Cardiothoracic Anesthesiology
Cardiothoracic Anesthesiology and Critical Care
Emory Healthcare
Atlanta, Georgia
Solomon Aronson, MD
Program Co-Chairman
Professor of Anesthesiology
Duke University Medical Center
Executive Vice Chair
Department of Anesthesiology
Durham, North Carolina

CME-accredited symposium jointly sponsored by the University of
Massachusetts Medical School and CMEducation Resources, LLC
Commercial Support: Sponsored by an independent educational grant from The Medicines Company
Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management
Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies
COI: Full faculty disclosures provided in syllabus and at the beginning of the program

As a result of this educational activity, participants 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 are indicated 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.
► Understand the efficacy and safety profiles of specific pharmacologic agents used for anesthesiology-based control of systemic blood pressure.

Solomon Aronson, MD
Program Co-Chairman
Professor of Anesthesiology
Duke University Medical Center
Executive Vice Chair
Department of Anesthesiology
Durham, North Carolina
Edwin G. Avery, MD, CPI
Assistant Professor of Anesthesiology
Department of Anesthesia and
Critical Care
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts
Jerrold H. Levy, MD
Program Co-Chairman
Professor and Deputy Chair for Research
Emory University School of Medicine
Director of Cardiothoracic Anesthesiology
Cardiothoracic Anesthesiology and Critical Care
Emory Healthcare
Atlanta, Georgia

Solomon Aronson, MD
Grant/Research Support: Abbott
Consultant: The Medicines Company, Regado Bioscience
Speaker’s Bureau: Baxter
Major Shareholder: Medwave
Jerrold H. Levy, MD
Grant/Research Support: Alexion
Consultant: Bayer HealthCare, Dyax, Novo Nordisk, and Organon
Edwin G. Avery, MD
Consultant: The Medicines Company, Covidien, Cubist
Speakers Bureau : The Medicines Company
Research Funding: The Medicines Company, Covidien, Cubist

Investigations ● Advances ● Applications
Solomon Aronson, MD
Program Co-Chairman
FACC, FCCP, FAHA, FASE
Professor and Executive Vice Chairman
Dept of Anesthesiology
Duke University Health System

►
►
►
►
►
3 prospective, randomized, open-label, parallel comparisons
Clevidipine to NTG or SNP periop, or NIC postop in pts undergoing cardiac surgery
61 medical centers
Primary Safety Endpoint: (death, myocardial infarction, stroke, renal)
Secondary endpoints: Other AEs, BP control
Clevidipine vs Nitroglycerin
1:1
Clevidipine vs Sodium
Nitroprusside
1:1
Clevidipine vs Nicardipine
1:1
Clevidipine
(n = 268)
Nitroglycerin
(n = 278)
Clevidipine
(n = 296)
Sodium nitroprusside
(n = 283)
Perioperative
Aronson, et al. Anesth Analg . 2008 Oct;107(4):1110-21
Clevidipine
(n = 188)
Nicardipine
(n = 193)
Postoperative

Incidence Death, MI, Stroke,
Renal Dysfunction
10% Clevidipine
Comparators
8%
6%
2.8%
3.8%
4%
2%
0%
(n = 719) (n = 729)
Death
2.3% 2.4%
(n = 700) (n = 707)
Myocardial
Infarction
1.1%
1.7%
(n = 700) (n = 705)
Stroke
7.9% 7.9%
(n = 712) (n = 710)
Renal
Dysfunction
Aronson, et al. Anesth Analg . 2008 Oct;107(4):1110-21

BP Control Assessed via
AUC Analysis
Upper
SBP
(mm Hg)
Lower
0
AUC = area under the curve
Cumulative AUC calculated for excursions outside prespecified range.
Lower AUC = tighter BP control.
6 12
Time (hours)
18
Aronson, et al. Anesth Analg . 2008 Oct;107(4):1110-21
24

p = 0.0006
44.48
p = 0.0027
p = NS p = 0.0004
24.33
39.51
40.40
CLV v SNP;
35.84
Above (2.97 v 6.61
, p=0.03)
Below (2.30 v 8.38, p=0.0006)
22.37
16.30
10.50
8.87
4.14
4.37
Clevidipine n=269
NTG n=278
ECLIPSE
NTG
Clevidipine n=295
SNP n=284
ECLIPSE
SNP
7.79
CLV v NTG;
3.79
Above (2.76 v 7.94 p=0.0002)
Below target range similar.
n=187
NIC n=194
Clevidipine n=751
All Comparators n=756
ECLIPSE
NIC
ECLIPSE
NTG/SNP/NIC
Anesth and Analg 2008, 107; 1111-22

SBP
Upper
Lower
Lower
0 6 12
Time (hours)
18 24

140
120
100
80
60
40
20
83.74
Peri-operative p = 0.0068
127.87
p = 0.0556
108.57
100.17
0
Clevidipine n=269
NTG n=278
ECLIPSE
NTG
Median AUC
Range = Pre-/post-op SBP 105-145, Intra-op SBP 95-135
Clevidipine n=295
SNP n=284
ECLIPSE
SNP
Post-operative
Only p = 0.0231
101.59
76.95
Clevidipine n=187
NIC n=194
ECLIPSE
NIC

P=0.0068
P=0.0027
n=295 n=284
P=0.0003
P=0.0009
specified
Intra-op SBP (mmHg) 65
Pre/post SBP (mmHg) 75 n=278 n=269
P=0.0006
P=0.0002
P=0.0016
P=0.0556
+10
75
85
85
95
+20 +30
95
105 n=194 n=187
P=0.8508
P=0.8949
P=0.3086
P=0.0231

AUC Predictive of Mortality at 30 Days
Surgery duration (hour)
Age (year)
Preop creatinine ≥1.2 mg/dL
AUC (1 mm Hg*min)
Additional surgical procedures
Preop Hgb (g/dL)
Preop SBP >160 or DBP >105
History of COPD
History of recent MI (<6 months prior)
P value
Odds ratio
<0.0001
1.517
0.0003
1.070
0.0031
0.0069
0.0089
2.670
1.003
2.409
0.0135
0.0228
0.824
2.386
0.0228
0.0312
2.326
2.197
95% CI
(Lower limit,
Upper limit)
(1.240, 1.856)
(1.031, 1.110)
(1.392, 5.122)
(1.001, 1.004)
(1.246, 4.655)
(0.707, 0.961)
(1.147, 4.963)
(1.125, 4.812)
(1.073, 4.497)
Aronson S et al. ACC Annual Meeting. 2007.

Excursions in Perioperative BP
Control Related to Increased 30-day Mortality
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
0 1 2 3
Odds
Ratio
1.20
1.43
1.71
2.05
2.46
4
95% CI
[Lower Limit,
Upper Limit]
[1.06, 1.27]
[1.13, 1.61]
[1.20, 2.05]
[1.27, 2.61]
[1.35, 3.31]
Data on file, The Medicines Company.

Predicted Probability of 30-day Mortality
Low-risk Patients High-risk Patients
Increase from 0.006 to 0.013
Increase from 0.186 to 0.325

N=7808 pts
3.1M BP measured
Duke population
Above 5 min +/- 4
Below 11 min +/- 9
Combined 8 min
Minutes SBP > 130 or < 105 mmHg per incident
8 min predicted mortality 1.9%;
10 min = 2.1%; 15 min = 2.8%; 20 min = 3.5%
Aronson S et al . Critical Care Medicine . 2008; 36 (Suppl); 557
P-Value < 0.0001, O.R.-1.07 (1.04-1.102)
Min<95 mmHg (min)
P-Value
0.004
OR
95% CI
1.025
1.008-1.042
Min>135 mmHg (min) 0.013
1.033
1.007-1.059

Multiple logistic regression analysis
P value
Odds
Ratio
95%
Confidence
Interval
Pre-op serum Cr
≥1.2 mg/dl <0.0001 5.466 3.506, 8.521
Pre-op hemoglobin (g/dL) <0.0001 0.785 0.699, 0.881
Body mass index 0.0074 1.049 1.013, 1.087
Surgery duration (hour) 0.0077 1.292 1.070, 1.559
Age (year) 0.0086 1.033 1.008, 1.059
BP (4 th
quartile of AUC*) 0.0126 1.785 1.132, 2.815
Candidate variables;
Demographics
Baseline characteristics
Medical history
Treatment group
Proc characteristics
AUC p<0.05 required.
Race (African American) 0.0151 2.164 1.161, 4.035
Primary CABG + valve 0.0165 1.944 1.129, 3.348
Total AUC of SBP excursions outside the range of 85-145 mmHg pre- and postoperatively, and 75-135 mmHg intraoperatively;
AUC ≥75th percentile analyzed.
Aronson S, et al. Anesthesiology . 2007; 107: A1253

Avery EG, et al. Anesthesia and Analgesia . 2008; 106 (SCA Supp); 69 xxxxx

BP excursions
> 60 min
O.R.
1 mmHg/min 1.17
2 mmHg/min 1.38
95% C I
1.02-1.34
1.05-1.81
3 mmHg/min 1.61
1.07-2.43
4 mmHg/min
5 mmHg/min
1.89
2.22
1.10-3.27
1.12-4.39
Myocardial infarction
Quartile 1
Quartile 2
Quartile 3
Quartile 4
Multiple Logistic Regression Analysis ECLIPSE trial:
AUC calc for excursions outside sBP range of 85-145 mmHg pre, post-op, & 75-135 mmHg intra-op
Avery EG, et al. Anesthesia and Analgesia . 2008; 106 (SCA Supp); 69

BP Fluctuations Predict Short-Term Mortality in
Patients Undergoing Cardiac Valve Surgery
Logistic Regression Results: Predictor of 30-Day Mortality
Screening SBP (per 1 mm Hg increment)
AUC (per 1 mm Hg ×min/hr increment)
AUC (per 1mmHg ×min/hr increment), narrow range
P Value OR 95% C.I.
0.0013
1.038
1.014
–1.061
0.0146
1.004
1.001
–1.007
0.0078
1.002
1.001
–1.004
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.
Minimizing SBP fluctuations within a narrow range improved 30-day mortality.
ACCP 2009

1.
Tight control of perioperative hypertension is an important objective
2.
Tightening blood pressure control zone during perioperative CV surgery may improve clinical outcomes
3.
Clevidipine possesses pharmacokinetic and pharmacodynamic properties that are consistent with optimizing blood pressure control during cardiovascular surgery.
4.
Landmark trials support new approaches to blood pressure therapy

Investigations ● Advances ● Applications
Challenges, Innovations, and
Landmark Trials for the CV Anesthesiologist
Jerrold H Levy, MD, FAHA
Professor of Anesthesiology
Emory University School of Medicine
Deputy Chairman for Research
Director, Cardiothoracic Anesthesiology
Cardiothoracic Anesthesiology and Critical Care
Emory Healthcare
Atlanta, Georgia

Trends and Observations
► Older patients with comorbidities presenting for surgery and to ICUs with vascular and endothelial dysfunction due to multiple causes
► Endothelial, vascular, and circulatory dysfunction common across this cardiac, neurological, and critically ill patient populations —acute and chronic disease
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.

Endothelial and Vascular Dysfunction are the
Hallmarks of our Patients
Angina
Plaque Rupture
Renal Failure
Calcification
Albumin Shunting
Through
Membrane Pores
Glomerular Sclerosis
Release of ET-1
Production of TGF b
NO
Tubulointerstitial Damage
Altered
Extracellular Matrix
(mesangium)
Endothelial Dysfunction
Coronary Artery Disease
Atherosclerosis
Endothelial Dysfunction
Myocardial
Ischemia
Unstable Angina
Myocardial Infarction
Sudden Death
Fibrosis And
Muscle Loss
ROS
Inflammation
Cell Injury
Glycosylated Proteins
Oxidative Stress
Inflammation
Heart Failure
P
GC
Aldosterone
Endothelin-1
Angiotensin II
Hypertension
Diabetes
Insulin Resistance
Dyslipidemia
Death
Schiffrin EL. Am J Hypertens 2004;17(12):1192-1200

Principles and Practice Considerations
► Patients who are normotensive may become hypertensive
► Most blood pressure changes develop acutely and require rapid intervention with IV agents
► Characterized by systemic vasoconstriction with intravascular hypovolemia
► Patients may have preoperative biventricular dysfunction
Levy JH: Management of systemic and pulmonary hypertension. Tex Heart Inst J 2005;32:467-471.

Hypertension in Cardiac Surgical Patients (2)
Principles and Practice Considerations
► BP may be maintained at lower levels to avoid graft/suture line disruption
► Patients are being “Fast Tracked”
► Mechanical manipulation, suturing with potential risk for vascular spasm
► Ventricular dysfunction is common in patients with normal preop function due to stunning/ reperfusion injury
Levy JH: Management of systemic and pulmonary hypertension. Tex Heart Inst J 2005;32:467-471.

► Metabolized to CN, then thiocyanate
Problematic Aspects
• Pregnancy
• Coronary steal
• Dose dependent
 in CBF
– Caution with high ICP
• Hypoxemia (

V/Q mismatch)
• Requires special delivery system
• Usually requires direct arterial pressure monitoring

Na +
Na +
Sodium Nitroprusside
NO +
CN
CN
CN
Fe ++
CN
CN

► Potent venodilator/arterial vasodilator
► Cardiac output is often affected due to venodilation
► Volume replacement is often required for venodilation
Levy JH: Management of systemic and pulmonary hypertension. Tex Heart Inst J 2005;32:467-471.

Selectivity of Calcium Channel Antagonists
O
O
Cl
*
O
Cl
O
N
H
Clevidipine
O
O
H
3
C
O
H
3
COC
H
N CH
3
O CH
3
COCH
2
CH
2
NCH
2
NO
2
Nicardipine
H
3
C
O
CH
3
OC
H
N CH
3
COCH
3
O
NO
2
Nifedipine
IV Agent
Clevidipine
Nicardipine
Diltiazem
Verapamil
Vasodilation
3
4
5
5
Myocardial
Depression
0
0
2
4
SA Node
Suppression
0
0
5
5
*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.
AV Node
Suppression
4
5
0
0

► Arterial vasodilator 1
► Decreases SVR 2-6
► More selective for vascular smooth muscle than cardiac muscle 1
► No significant increase in ICP 7
► No direct inotropic or dromotropic effects 2-6
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.

►
►
►
►
Loss of endothelial function via vascular injury and platelet activation is potential mechanism
Other mechanisms include NO scavenging by hemoglobin
Thromboxane, a potent constrictor, has been implicated
Only certain drugs will completely reverse arterial spasm

Vasospasm/Vascular Dysfunction Studies
►
►
►
►
►
►
►
Salmenperra MT: Effects of PDE inhibitors on the human IMA. Anesth
Analg 1996; 82: 954-957.
Huraux C: Vasodilator effects of clevidipine on human IMA. Anesth Analg
1997; 85: 1000-1004.
Huraux C: A comparative eval of multiple vasodilators on human IMA.
Anesthesiology 1998;88:1654-1659.
Huraux C: Superoxide production, risk factors, and EDRF relaxations in human IMAs. Circulation 1999;99:53-59.
Tsuda A: Reversal of histamine-induced vasodilation in the human IMA.
Anesth Analg 2001;93:1453-1459.
Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin and fenoldopam in the human umbilical artery. Anesth Analg 2003;96:539-544.
Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)induced vasoconstriction in human IMA. Br J Anaesth 2004;93:257-262.

Vasodilator Effects of
Clevidipine on Human IMA
► Clevidipine was effective antivasospasm agent at therapeutically used doses
Huraux C, Makita T, Szlam F, Nordlander M, Levy JH: Anesth Analg 1997; 85: 1000-1004.

CH
3
OOC
Cl
Cl
H
COOCH
2
OOCC
3
H
7
H
3
C N
H
CH
3
Clevidipine is the first ultrashort acting dihydropyridine intravenous calcium channel blocker

Clevidipine — Metabolized by
Plasma and Tissue Esterases
► Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive carboxylic acid metabolite
Cl
O
O
Cl
O
O
N
H
*
Clevidipine
O
O
Cl
Esterases
O
O
Cl
O H
O
N
H
Primary metabolite
+
H
O
H
+
H O
O
*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.

Perioperative BP Control:
ESCAPE Trials
► Design: 2 double-blind, randomized, placebo-controlled trials
ESCAPE-1
Preoperative HTN
(SBP ≥160 mmHg)
ESCAPE-2
Postoperative HTN
(SBP ≥140 mmHg)
Clevidipine
(n=53)
Placebo
(n=52)
Clevidipine
(n=61)
Placebo
(n=49)
► Primary end point: comparison of the incidence of treatment failure* between the clevidipine butyrate and placebo treatment groups over 30 minutes from initiation of study drug
*Treatment failure was defined as the premature and permanent discontinuation of study drug infusion for any reason, or the failure to decrease SBP by 15% from baseline at any time within the 30-minute period from study drug initiation.
BP=blood pressure; HTN=hypertension; SBP=systolic blood pressure.
Levy JH, et al. Anesth Analg.
2007;105:918-925;
Singla N, et al. Anesth Analg.
2008;107:59-67.
Please see Important Safety Information and accompanying full Prescribing Information.

Clevidipine butyrate
Rapidly Controlled BP
ESCAPE-1
(N=105)
ESCAPE-2
(N=110)
0
-5
-10
-15
-20
-25
-30
0
Clevidipine
Placebo
0
-5
-10
-15
-20
-25
-30
0
Clevidipine
Placebo *
5 10 15
Time (minutes)
20 25 30 5 10 15
Time (minutes)
20 25
Target BP reached in ~6 minutes
Target BP reached in ~5 minutes
*In ESCAPE-2, the decrease in placebo group SBP reflects the number of placebo patients (n=49 at baseline) who bailed out during the 30-minute infusion period (n=10 remaining at 30 minutes).
BP=blood pressure; SBP=systolic blood pressure.
Levy JH, et al. Anesth Analg.
2007;105:918-925;
Singla N, et al. Anesth Analg.
2008;107:59-67;
Data on file. The Medicines Company.
Please see Important Safety Information and accompanying full Prescribing Information.
30

Clevidipine — Linear Pharmacokinetics
► At steady state, there is a linear relationship between dosage and arterial blood concentrations
► Linear relationship maintained for dosages as high as 21.9 mcg/kg/min
120
100
80
60
40
20
0
0 5 10 15 20
Dose Rate (nmol/kg/min)
25 30 35
*Css = concentration at steady state; median blood concentration of clevidipine obtained during the last 10 minutes of infusion.
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 — Ultrashort Half-Life
► Clinically relevant half-life: Approximately 1 minute
Arterial and venous clevidipine blood samples
Reproduced from Ericsson H, et al. Anesthesiology . 2000;92:993-1001.

Clevidipine — Rapid Offset
► After discontinuation of clevidipine infusion, there was rapid clearance
► BP returned to baseline in <10 minutes in healthy volunteers
100
Clevidipine Infusion
90 MAP
80
70
60
50
40
–5
0 5 10 15
Time (min)
20 25 30 35
Reproduced from Ericsson H, et al. Anesthesiology . 2000;92:993-1001.

Mean Arterial Pressure
90
*
80
†
†
70
†
Central Venous Pressure
Systemic Vascular Resistance
C2
2
0
6
4
12
10
8
0 0.375
0.75
1.5
1400 mcg/kg/min
3
C1 0.375
0.75
1.5
mcg/kg/min
3
1200 ‡
†
1000
†
†
0
C1 0.375
0.75
1.5
3 mcg/kg/min
C2
* 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.
0
Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193.

Clevidipine:
Minimal Effect on Heart Rate
Preoperative HR Changes in Non-Anesthetized Patients
Postoperative HR Changes in Anesthetized Patients
5
10
0
–5
HR
0 5 10 15 20 25 30
Time (min)
HR changes for patients during the
30-minute treatment period
5
0
–5
HR
0 5 10 15 20 25 30
Time (min)
HR changes for patients during the
30-minute treatment period
Levy JH, et al. Anesth Analg . 2007;105(4):918.
Singla N, et al. Anesthesiology.
2005;103:A292.

► Clevidipine
● Initiated 2 mg/hr
● Titrated doubling increments Q 90s to 16 mg/hr
● 40 mg/hr maximum
► Comparators (NTG, SNP, NIC) administered per institutional practice
► Treatment duration up to discharge from the
ICU
► Concomitant antihypertensives discouraged
Aronson, et al. Anesth Analg . 2008 Oct;107(4):1110-21

Primary End Points* (Cumulative rate of clinical outcomes at 30 days):
● Death
● MI: Symptomatic presentation, enzyme release, and/or new ECG changes
● Stroke: Hemorrhagic or ischemic
●
Renal Dysfunction: Cr >2.0 with min absolute change of 0.7
Secondary End Points
● SAEs through day 7
● BP control during the first 24 h
* Blinded CEC adjudication of all primary measures
Aronson, et al. Anesth Analg . 2008 Oct;107(4):1110-21

Procedural Characteristics
Surgery Duration: Median Hours
Procedure
CABG
Valve replacement/repair
CABG & Valve replacement/repair
Other
Aronson, et al. Anesth Analg . 2008 Oct;107(4):1110-21
Clevidipine n=752
3.32
Comparators n=754
3.23
77%
14%
9%
0.3%
77%
12%
11%
0.1%

ECLIPSE NTG — Drug Administration
Timing and Duration
Initiated Pre-Op
Initiated Intra-Op
Initiated Post-Op
Overall Infusion
Duration (median)
Clevidipine
N=268
92 (34.3)
145 (54.1)
31 (11.6)
3.35 hr
Nitroglycerin
N=278
119 (42.8)
132 (47.5)
27 (9.7)
8.13 hr
Aronson, et al. Anesth Analg . 2008 Oct;107(4):1110-21

ECLIPSE SNP: Drug Administration
Timing and Duration
Initiated Pre-Op
Initiated Intra-Op
Initiated Post-Op
Overall Infusion
Duration (median)
Clevidipine
N=296
52 (17.6)
161 (54.4)
83 (28.0)
4.03 hr
Nitroprusside
N=283
34 (12.0)
158 (55.8)
90 (31.8)
3.25 hr
Aronson, et al. Anesth Analg . 2008 Oct;107(4):1110-21

ECLIPSE NIC: Drug Administration
Timing and Duration
Dosed During
Post-Op
Overall Infusion
Duration (median)
Clevidipine
N=188
188 (100)
5.55 hr
Nicardipine
N=193
193 (100)
5.12 hr
Aronson, et al. Anesth Analg . 2008 Oct;107(4):1110-21

10%
8%
Clevidipine
Comparators
6%
4%
2.8%
3.8%
2%
2.3% 2.4%
7.9% 7.9%
1.1%
1.7%
0% n=719 n=729
Death n=700 n=707
MI n=700 n=705
Stroke n=712 n=710
Renal
Dysfunction
Aronson, et al. Anesth Analg . 2008 Oct;107(4):1110-21

Primary End Points by
Treatment Comparison
End
Points
Death
Clevidipine NTG Clevidipine SNP Clevidipine NIC
2.8% 3.4% 1.7% 4.7%* 4.4% 3.2%
MI 3.3% 3.5%
2.3%
1.4%
1.1%
2.3% 2.3%
1.5% 0.6%
1.1%
1.1% Stroke
Renal
Dysfunction
1.6%
6.9%
* p = 0.045
8.1% 8.5% 9.1% 8.3% 5.9%
Aronson, et al. Anesth Analg . 2008 Oct;107(4):1110-21

Serious Adverse Events
Total
Atrial fibrillation (AF)
Respiratory failure
Acute renal failure (ARF)
Ventricular fibrillation
Cardiac arrest
CVA
Post-procedural hemorrhage
Clevidipine n=752
17.7%
2.4%
1.1%
2.3%
0.9%
0.5%
0.5%
0.5%
Comparators n=754
20.0%
2.4%
2.5%
1.7%
1.5%
1.1%
1.1%
1.1%
Aronson, et al. Anesth Analg . 2008 Oct;107(4):1110-21

Non –Weight-Based Dosing Regimen
Initiate clevidipine butyrate IV infusion at 1-2 mg/h
Double the dose every 90 sec initially, then as BP approaches goal, increase dose by less than double and lengthen time between dose adjustments to every 5-10 min
~1- to 2-mg/h increase will generally produce an additional 2- to 4-mmHg decrease in SBP
Monitor BP and heart rate continuously during infusion, and then until vital signs are stable
BP=blood pressure; IV=intravenous; SBP=systolic blood pressure.
Prescribing Information; August 1, 2008.
Please see Important Safety Information and accompanying full Prescribing Information.

Non –Weight-Based Dosing Regimen (cont’d)
► The desired therapeutic response for most patients occurs at doses of 4-6 mg/h
●
●
Most patients were treated with maximum doses of
16 mg/h or less
There is limited short-term experience with doses up to
32 mg/h
► Because of lipid load restrictions, no more than 1,000 mL or an average of 21 mg/h of clevidipine infusion is recommended per 24-hour period
● In clinical trials, 55 hypertensive patients were treated with
>500 mL of clevidipine infusion per 24-hour period
► There is little experience with infusion durations beyond
72 hours at any dose
Prescribing Information; August 1, 2008.
Please see Important Safety Information and accompanying full Prescribing Information.

=“Full” loading dose = [Cp] x Vdss
= Smaller loading dose =[Cp] x Vc
= No loading dose
60
50
40
30
20
10
0
0 1 2 3
Time (Half-life)
4 5 6
Therapeutic
Concentration
Range

► Multiple pharmacologic agents produce vasodilation via different mechanisms.
► Arterial vasoconstriction is characteristic of perioperative hypertension with intravascular hypovolemia.
► Nitrovasodilators decrease both preload and resistance vessels
► DHP CCBs produce arterial selective vasodilation that controls BP without producing venodilation or negative inotropic and conduction effects, and reverses vasospasm in the IMA and other vascular beds.

►
►
ECLIPSE is the largest safety program ever performed with an intravenous antihypertensive (n=1,512) agents that examine management of acute, severe hypertension in the perioperative setting
AUC data suggests better overall BP control with clevidipine compared with SNP and NTG
► Clevidipine represents a safe alternative to commonly used antihypertensive agents in the cardiovascular surgery setting, and demonstrated superior blood pressure control as assessed by integral analysis of excursions outside specified ranges over time
► Data supports importance of precise blood pressure control in a critically ill patient population
► Clevidipine represents the first potential nitroprusside replacement for clinicians

Bleeding
Vascular damage
Extent
BP
Duration
Efficacy Threshold
Duration
Threshold is higher with pre-existing bleeding or vascular injury
(ICH, Aortic dissection, etc)
Threshold is higher with pre-existing end-organ damage
(kidney, heart, brain)
Safety Threshold
Extent
Ischemia
Hypoperfusion
Time
Courtesy of J. Ferguson, MD

Investigations ● Advances ● Applications
Assistant Professor of Anesthesiology
Massachusetts General Hospital Heart Center
Harvard Medical School

www.radpod.org

Case Study 1: Type A Aortic Dissection
44-year-old female presents for surgical correction of a Type A dissection
► HPI: presented to ED complaining of sudden onset of severe chest pain and shortness of breath.
► PHM/PSH: obesity
► Allergies: NKDA
► Medications: none
► Fam Hx: noncontributory
► ROS: unremarkable www.edpma.com

Case Study 1: Type A Aortic Dissection
► General: anxious, grossly obese.
► Ht: 62 inches Wt: 102 kg
► VS: 141/45 (R=L)
; HR 80’s reg ; Resp 18;
SpO2 96% RA
► Neuro: alert & oriented x3; no gross deficits
► Pulmonary: B/L rales
► Cardiac: S
1
S
2 reg, grade IV syst.
murmur
► Extrem: 2+ palpable B/L UE & LE; no edema turbosquid.com

Case Study 1: Type A Aortic Dissection
Chem:
Heme:
141 112 20
4.0 24 1.2
< 110
>
12.3
39
ECG: no ischemic changes
CT: TEE:
LFTs Coags
WNL WNL

Case Study 1: Type A Aortic Dissection
Diagnosis
Type A Aortic Dissection w/severe aortic insufficiency
Management
► Immediate β-blockade www.radiologyassistant.nl
► Control SBP with IV antihypertensive to prevent aortic rupture & further extension of dissection
► Proceed to the OR for immediate surgical correction
(ascending aortic replacement, +/- AVR)

Case Study 1: Type A Aortic Dissection
Management
► β-blockade: reduces dP/dt
► IV antihypertensive: reduces shear forces on the weakened aortic wall
► Surgical correction: reduces observed
Type A dissection mortality (~↑2% per hour). Uncorrected in-hospital mortality (58%) vs. surgically corrected (27.4
%)1.
www.radiologyassistant.nl
Hagan et al. Jama 2000;283:897

Case Study 1: Type A Aortic Dissection

Case Study 1: Type A Aortic Dissection
SBP Values (mm Hg) v. Time
180
160
140
120
100
80
60
40
20
0
8:
45
8:
55
9:
05
9:
15
9:
25
9:
35
9:
45
9:
55
10
:0
5
Time (HH:MM)
10
:1
5
10
:2
5
10
:3
5
10
:4
5
10
:5
5
SBP Values (mm Hg) v. Time

Case Study 1: Type A Aortic Dissection
180
160
140
120
100
80
60
40
20
0
SBP Values (mm Hg) v. Time
Induction Incision
8:
45
8:
55
9:
05
9:
15
9:
25
9:
35
9:
45
9:
55
10
:0
5
Time (HH:MM)
10
:1
5
10
:2
5
10
:3
5
10
:4
5
CPB
10
:5
5
SBP Values (mm Hg) v. Time

Case Study 1: Type A Aortic Dissection
180
160
140
120
100
80
60
40
20
0
8:
45
SBP Values (mm Hg) v. Time
Induction Incision
8:
55
9:
05
9:
15
9:
25
CPB
9:
35
9:
45
9:
55
10
:0
5
Time (HH:MM)
10
:1
5
10
:2
5
10
:3
5
10
:4
5
10
:5
5
SBP Values (mm Hg) v. Time

Case Study 1: Type A Aortic Dissection
CPB
Induction Incision
180
160
140
120
100
80
60
40
20
0
NTG
SNP
8:
45
8:
55
9:
05
9:
15
9:
25
SNP sodium nitroprusside
CLV clevidipine
CLV
9:
35
9:
45
9:
55
10
:0
5
Time (HH:MM)
10
:1
5
10
:2
5
10
:3
5
10
:4
5
10
:5
5
SBP Values (mm Hg) v. Time

Case Study 1: Type A Aortic Dissection
CPB
Induction Incision
180
160
140
120
100
80
60
40
20
0
NTG
SNP
10 0 2 4 6
8:
45
8:
55
9:
05
9:
15
9:
25
9:
35
8
CLV
9:
45
SNP sodium nitroprusside
CLV clevidipine
9:
55
10
:0
5
10
:1
5
10
:2
5
10
:3
5
10
:4
5
10
:5
5
SBP Values (mm Hg) v. Time

Case Study 1: Type A Aortic Dissection
The ultra-short acting dihydropyridine calcium channel blocker, clevidipine, can be used to safely and effectively manage the acute hypertension that accompanies one of the most morbid and potentially mortal disorders of the cardiovascular system.

Case Studies of Acute Hypertension
http://library.med.utah.edu

Case Studies of Acute Hypertension

Case Study #2: Acute Coronary Syndrome
► 58 y/o male presents to ED with chest pain of acute onset radiating to left jaw and shoulder, accompanied by SOB
► Triage vital signs were pulse
92/min, resp 24/min, and BP
212/126 mm Hg
► PMH included known CAD, CHF, and hyperlipidemia
► ECG performed in Triage http://mykentuckyheart.com

Case Study #2: Acute Coronary Syndrome
Acute Anterior STE Myocardial Infarction

Case Study #2: Acute Coronary Syndrome
► Physical examination: symmetrical bounding pulses, diaphoresis, and rales in both lung bases
► Management:




ASA 325 mg
Clopidogrel 600 mg
Unfractionated heparin by IV infusion
Nitroglycerin by IV infusion
 Beta-blockers are held because of concern over heart failure
► Prior to cath lab transfer: recheck BP is
196/118; and patient is diagnosed with www.etopiamedia.net

Case Study #2: Acute Coronary Syndrome
Blood Pressure vs. Time & Heart Rate
225
170
175
125
160
75
0 2 4 6 8 10
Time (minutes)
12 14 16
SBP
DBP
HR

Case Study #2: Acute Coronary Syndrome
225
175
125
75
0
196
2
Blood Pressure vs. Time & Heart Rate
192
4
188
176
168
6 8 10
Time (minutes)
166
12
162
14
162
16
8
6
4
2
0
12
10
SBP
DBP
HR

Case Study #2: Acute Coronary Syndrome
Clevidipine can be used safely and effectively to care for a patient with an acute coronary syndrome using a peripheral IV and a blood pressure cuff. There was no evidence of coronary steal or worsening of this patient’s chest pain. Target BP control was obtained in less than
10 minutes.

Case Studies of Acute Hypertension

Case Study 3: Aortic Valve Replacement
78-year-old male presents for aortic valve replacement
► HPI: presented with symptoms of
 shortness of breath and DOE.
► PHM/PSH: AS, MI, CAD (stents x2), HTN
( brittle ),

Chol, TIAs secondary to spontaneous cholesterol emboli
► Allergies: NKDA
► Medications: metoprolol
► Fam Hx: noncontributory
► ROS: as per HPI o/w unremarkable

Case Study 3: Aortic Valve Replacement
► General: fatigued appearing
► Ht: 72 inches Wt: 90 kg
► VS: 128/62 (R=L)
; HR 60’s reg ; Resp 18;
SpO2 98% RA
► Neuro: alert & oriented x3; no gross deficits
► Pulmonary: CTA bilaterally
► Cardiac: S
1
S
2 reg, grade IV syst.
murmur
► Extrem: 2+ palpable B/L UE & LE; no edema

Case Study 3: Aortic Valve Replacement
Chem:
Heme:
139 103 25
4.5 24 1.3
ECG: no ischemic changes
< 91
> 14.1
41.2
TEE:
Aortic stenosis (AVA 0.7 cm 2 ), gradient (P 51/M 32 mmHg w/CI 2.9
L/min/m 2 )
LFTs Coags
WNL WNL

Case Study 3: Aortic Valve Replacement
Diagnosis
Severe Aortic Stenosis with left ventricular hypertrophy
Management
► Surgical aortic valve replacement with a bioprosthesis
► Control heart rate, maintain NSR, manage SBP with an IV antihypertensive to prevent

LV wall stress and

MVO
2
, avoid hypotensive overshoots

Case Study 3: Aortic Valve Replacement

250
200
150
100
50
0
Case Study 3: Aortic Valve Replacement
SBP
DBP
Heart Rate

Case Study 3: Aortic Valve Replacement
100
50
0
Induction
250
Intubation
200
F
150
2 4
8 16 2
Incision
F
0 2 4
CPB
0
SBP
DBP
Heart Rate
Clevidipine (mg/hr) F - Fentanyl bolus

Case Study 3: Aortic Valve Replacement
Clevidipine can be used safely and effectively to provide hemodynamic support for patients with complex cardiovascular disease profiles (i.e. need to strictly ovoid overshoot hypotension [AS] & reflex tachycardia [AS, LVH, CAD]). Target BP control was expeditiously obtained and maintained in this patient.

Case Study #2: Acute Coronary Syndrome