1. Blood Pressure Control in
Neuro Critical Care
PJ Papadakos MD FCCM
Director CCM
Professor Anesthesiology, Surgery and
Neurosurgery
Rochester NY USA

2. Disclaimer
Speakers Bureau Medicines Company

NIH, Erasmus University


3. Hypertension
Common clinical problem

1 billion people worldwide

 60 million Americans
At least 15% of African-Americans

Increases with age

Male +/- higher than females?

30% undiagnosed

15%-30% adequate BP control


4. The Seventh Report of the Joint National
Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood
Pressure
The JNC 7 Report
BP Classification Systolic BP mm Hg Diastolic BP mm Hg
Normal < 120 < 80
Prehypertension 120-139 80-89
Stage 1 140-159 90-99
160  100
Stage 2
JAMA. 2003;289:2560-2572.

5. STAT Registry Analysis
50 45
Patient outcomes (%)
37.2
40
30
20
9.4
8.8
6.9
10
0
New End-Organ In-Hospital Admit to 90-Day 90-Day 90-Day
Readmission †
Damage* Death* Death* Readmission
†
Due to HTN
*N=1,588 (all patients); †n=1,405 (patients alive at discharge and with 90-day follow-up).
HTN=hypertension.
Kleinschmidt K, et al. Society for Academic Emergency Medicine 2008 Annual Meeting. Poster #140.

6. Acute Hypertensive Crises
Require Rapid BP Control
Acute Hypertensive Crises
Perioperative
Hypertensive Hypertensive
Hypertension2
Urgency1 Emergency1
Severe BP elevation
Severe BP elevation Severe BP elevation occurring before,
WITHOUT WITH during, or after
end-organ damage end-organ damage surgical procedures
BP=blood pressure.
1. Chobanian AV, et al. Hypertension. 2003;42:1206-1252;
2. Varon J, Marik PE. Vasc Health Risk Manag. 2008;4:615-627.

7. Pathophysiology

8. Regulation of Blood Pressure
CNS Adrenal
Gland
Baroreceptor Adrenergic
Reflexes Tone Catecholamines
Veins Arteries
Capacitance Resistance
Afterload
Preload Volume/Pressure
Cardiac Output Renin/Angiotensin
Heart Kidney
Blood Pressure

9. Understanding the Pathophysiology of Acute
Hypertension Is Key to Effective Treatment
• Hypertensive crisis is
thought to be initiated by an
abrupt increase in systemic
vascular resistance likely
related to humoral
vasoconstrictors
– Mechanical stress
– Endothelial injury
• Permeability
• Coagulation
• Fibrinoid necrosis
Marik P, Varon J. Chest. 2007;131:1949-1962.

10. Examples of End-Organ Damage
in Hypertensive Emergencies
Retina Brain
Retinopathy Acute neurologic syndromes
Papilledema Hypertensive encephalopathy
Cerebral infarction
Subarachnoid or intracranial
hemorrhage
Cardiovascular System Kidney
Myocardial ischemia and infarction Renal insufficiency
Acute left ventricular dysfunction
Acute pulmonary edema
Aortic dissection
Aggarwal M, Khan IA. Cardiol Clin. 2006;24:135-146.

11. Fibrinoid Necrosis

12. CT SCANS and X-rays

13. Reversible high T2 signal
abnormalities in pre-eclampsia

14. Hypertensive
Encephalopathy/Retinopathy

16. Current Drugs in the ICU

18. Traditionally Used IV Antihypertensive
AgentsClass of Therapy
Drug
Esmolol Beta-blocker
Fenoldopam Dopamine agonist
Hydralazine Vasodilator
Labetalol Beta-blocker with alpha-blocking activity
Nicardipine Dihydropyridine calcium channel blocker
Nitroglycerin Nitrovasodilator
Sodium nitroprusside Nitrovasodilator
The Merck Manual. http://www.merck.com/mmpe/sec07/ch071/ch071c.html#sec07-ch071-ch071c-464.

19. Gold Standard ?

20. Sodium Nitroprusside
NO+
-
CN -
CN
-
CN
2 ++
Na+ Fe
-
CN
-
CN
4 of the 5 CN– ions are promptly released

44% of fractional weight is cyanide


21. Metabolism of Sodium
Nitroprusside
Oxyhemoglobin
Nitroprusside
Non-
Methemoglobin
enzymatic
Nitroprusside Radical
- Cyanmethemoglobin
CN
Thiosulfate
Cytochrome Oxidases
Hepatic
Rhodanase
Inactive Cytochromes
-
Thiocyanate (SCN )
Renal Excretion TOXICITY
Tinker JH, Michenfelder JD. Anesthesiology. 1976;45:340-354.

22. Nitrovasodilators Dilate Both Arterial and Venous Vessels
- Hypotension
- Reflex tachycardia
NITROVASODILATORS
- Exacerbated by volume depletion

23. Nitrovasodilators in Patients With Recent Stroke and
Compromised Coronary Blood Flow
Coronary Steal
Syndrome

24. Nitrovasodilators in Patients With Decreased Cerebral Circulation
and Compromised Coronary Blood Flow
Decreased Cerebral
Blood Flow

26. A Precipitous and Uncontrolled Fall in
BP Can Have Lethal Consequences
Infarct …. brain, heart, kidney
Cerebral
Blood
Flow
Acute
Chronic
60 mm Hg 180 mm Hg
120 mm Hg
Mean Arterial Blood Pressure

28. Calcium Receptor Modulation

29. Vascular Smooth Muscle Contraction Is
Calcium Dependent
Ca++
Calcium influx into vascular

smooth muscle may occur via
 opening of
L-type calcium channels
Ca++ plus calmodulin

Release of intracellular stores
Myosin kinase
may also be a source of Ca++

Actin-myosin interaction
 Contraction

Ca++
Adapted with permission from Frishman WH, et al. Curr Probl Cardiol. 1987;12:285-346.

30. Ca2+ influx
Plasma membrane channels
Ligand-Operated
Voltage-Operated Receptor-Operated
Ca2+/Cation
Ca2+ specific Ca2+ / Cation
Ca2+
Mitochondrial Sarco-/Endo-plasmic
Ca Uptake reticulum Ca Uptake
Ca/Mg pump
Na-Ca exchg.
Papadakos and Sayeed New Horizions Calcium Homeostasis 1997

31. Voltage-operated Ca2+ Channel
(VOCC)
Electrical Impulse
L-type Ca2+
Channel
ICa
Ca2+
Ca-pump
CICR
Ca2+
Sarcoplasmic reticulum Myofilament
Papadakos and Sayeed New Horizons Calcium Homeostasis 1997

32. Vascular Smooth Muscle Contraction Is
Calcium Dependent
Calcium influx into
vascular smooth
muscle may occur
via opening of
L-type calcium
channels

33. Nicardipine
2nd generation dihydropyridine Ca++ blocker with

high vascular selectivity
100 times more water soluble than nifedipine; easily

titratable IV formulation
Onset within 5-10 min; duration of action

4-6 h
Decreases cardiac and cerebral ischemia in hypertensive

emergencies
No significant rebound once infusion is stopped

5 mg/h up to 30 mg/h


34. IV Calcium Channel Blockers
Suppression of
Coronary Suppression of Suppression of
Compound Cardiac
Vasodilatation SA Node AV Node
Contractility
Verapamil ++++ ++++ +++++ +++++
Diltiazem +++ ++ +++++ ++++
Nicardipine +++++ 0 + 0
The relative effects are ranked from no effect (0) to most prominent (+++++).
Adapted from Goodman and Gilman, 9th ed. McGraw-Hill;1996 and Massie, Am J Cardiol.
1997;80:231-321.

35. Dihydropyridine CCBs
Drug Brand Name
Oral preparations
1st Generation: nifedipine Procardia®, Adalat®
2nd Generation: nicardipine Cardene®
amlodipine Norvasc®
isradipine DynaCirc®
felodipine Plendil®
nimodipine Nimotop®
nisoldipine Sular®
Intravenous preparations
2nd Generation: nicardipine Cardene® IV

36. Cleviprex™ (clevidipine
butyrate) injectable emulsion

37. Cleviprex™ (clevidipine butyrate):
Metabolism
Cl
Cl
Cl
O
Cl O
O
O
O
O OH
O HO
O
+ +
O
H
Esterases H
O O
N
N H
H
Primary metabolite
Cleviprex
Figure adapted from Ericsson H, et al. Drug Metab Dispos. 1999;27:558-564.
Cleviprex is rapidly metabolized by hydrolysis of the ester linkage primarily by

esterases in the blood and extravascular tissues
 Elimination is unlikely to be affected by hepatic or renal dysfunction
 The potential of Cleviprex to interact with other drugs is low
 No dosage adjustment is required in patients with underlying hepatic or
renal impairment

38. Rapid pharmacokinetics of
clevidipine
Approximate half-life: 1 min

T 1/2 (triphasic): alpha, 48

100 arterial
sec; beta, 2.3 min; terminal,
venous
Blood [clevidipine] (nmol/L)
21.7 min
85%–90% eliminated in first

10
T½
After 72 hrs cont. infusion

No tachyphylaxis

No rebound
1 
No drug accumulation

Rapid offset maintained

20 minute infusion
(12 nmol/kg/min)
0.1
0 20 40 60 80
Time (min)
*Redrawn from Ericsson et al. Anesthesiology, 2000

39. Clevidipine: Linear
Pharmacokinetics
120
At steady state,

Clevidipine Concentration
there is a linear 100
at Css (nmol/L)*
relationship between 80
dosage and arterial 60
blood 40
concentrations
20
Linear relationship

0
maintained for 0 5 10 15 20 25 30 35
dosages as high as Dose Rate (nmol/kg/min)
21.9 mcg/kg/min
*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.

40. Clevidipine: Rapid Onset
SBP Changes
10
BP-lowering effects seen
 5
within ~1 minute of
% Change From Baseline
0
clevidipine infusion –5
–10
–15
–20
SBP
–25
–30
0 5 10 15 20 25 30
Time (min)
SBP changes for patients receiving clevidipine during a 30-minute treatment period.
Levy JH, et al. Anesthesiology. 2005;103:A354.

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

42. Effects on Central Hemodynamics:
Clevidipine Pharmacodynamically
Friendly vs. SNP
“The blood pressure reduction caused by clevidipine is due
to profound lowering of TPR with associated increased CO,
40 while the effects of SNP results mainly from a reduction in
Change from pre-drug (%)
CO, which is due to its venodilatory effect and leads to
reduced ventricular filling”
30
*
20
* *
10
* Clevidipine
0
SNP
MAP CO TPR dP/dt LVEDP
-10
-20
-30
-40
Experiment in anesthetized dogs
* p < 0.05
Norlander, M.B, etal. B J Aneasth 1996;

43. Coronary and Systemic
Hemodynamic Effects of Clevidipine
After CABG surgery
Objective: Compare the hemodynamic effects of

Clevidipine in a cross-over design vs Sodium
Nitroprusside (SNP)
Methods: The effects of clevidipine on central

hemodynamics, myocardial blood flow and metabolism
were studied at two different phases after CABG.
Phase 1 (n=13), the hypertensive phase, the effects of

clevidipine were compared to those of SNP when used
to control postoperative hypertension in a crossover
fashion
Phase 2 (n=9), the normotensive phase, clevidipine

dose-response relationship was established.
N. Kieler-Jensen et al. Acta Anesthesiol Scand 2000; 44: 186-193

44. Phase 1: Vasoselective Effects
Clev/SNP
Heart Rate
Mean Arterial Pressure
mm Hg bpm
*
80 85
80
70
75
Cardiac Filling Pressures
Systemic Vascular Resistance Stroke Volume
mm Hg
units
15
1200
PCWP
*
*
ml
1100
70
* 10
1000 CVP
*
60
900 5
0 0
0
SNP 1 Clevidipine SNP 2 SNP 1 Clevidipine SNP 2
SNP 1 Clevidipine SNP 2
: N. Kieler-Jensen et al. Acta Anesthesiol Scand 2000; 44: 186-193

45. Phase 2: DOSE RESPONSE:
Clevidipine
Rapid onset, linear relationship
•mm Hg •bmp
•Mean Arterial Pressure •Heart Rate
•90 •90
•*
•80 •80
•* •*
•*
•* •*
•*
•* •*
•*
•70 •70
•units
•Systemic Vascular Resistance •Stroke Volume
•1400
•ml/min
•* •*
•*
•*
•*
•75
•1200
•*
•* •70
•* •*
•*
•* •*
•*
•1000 •65
•* •*
•*
•0 •0
•0 •m
•C1 •0.375 •0.75 •1.5 •3 •g/kg/min
•3 •µg/kg/min
•0.375 •0.75 •1.5
N = 9. N. Kieler-Jensen et al. Acta Anesthesiol Scand 2000; 44: 186-193

46. Clinical Studies

47. Efficacy Study of Clevidipine Assessing Its
Preoperative Antihypertensive Effect in Cardiac
Surgery-1 (ESCAPE-1)
Efficacy Study of Clevidipine Assessing Its
Postoperative Antihypertensive Effect in Cardiac
Surgery-2 (ESCAPE-2)

48. ESCAPE Results: Onset and
Time-to-Target Effect
Onset of BP-lowering effect: within 1–2 minutes of

infusion
Time to target BP (15% reduction): ESCAPE-1 = 6.0

min*; ESCAPE-2 = 5.3 min†
ESCAPE- ESCAPE-
1 2
10 5
% Change From Baseline
% Change From Baseline
5 0
0 –5
–5
–10
–10
–15
–15
SBP
–20
–20
SBP –25
–25
–30 –30
0 5 10 15 20 25 30 0 5 10 15 20 25 30
Time (min) Time (min)
SBP Changes SBP Changes
Levy JH et al. Anesth Analg. 2007;105:918-925.
Data on file, The Medicines Company.
*Reproduced from Levy JH, et al. Anesthesiology. 2005;103:A354.
†Reproduced from Singla N, et al. Anesthesiology. 2005;103:A292.

49. Tight Control

50. Excursions Outside Target BP Range
Define Control
BP control was assessed as a prespecified secondary end point by

measuring the magnitude and duration of SBP excursions
outside the predefined pre- and postoperative target range (75-
145 mmHg) and intraoperative SBP target range (65-135 mmHg)
Illustration of a single
Upper limit
Upper limit
patient’s excursions
SBP
SBP
(mmHg)
(mmHg)
used to assess BP
control
Lower limit
Lower limit
0 6 12 18 24
Time (hours)
BP=blood pressure; SBP=systolic blood pressure.
Aronson S, et al. Anesth Analg. 2008;107:1111-1122.

51. EValuation of the Effect of ULtraShOrt
Acting Clevidipine In the Treatment of
Severe HYpertension

52. Overview and Enrollment Criteria
Multicenter, phase 3, open-label, single-arm study to confirm the safety and

efficacy of Cleviprex™ (clevidipine butyrate) using a predefined, non–weight-
based dosing algorithm in patients presenting in the ED or ICU with severe
HTN
Inclusion criteria

 Age ≥18 years
 SBP >180 mmHg and/or DBP >115 mmHg assessed on 2 successive
occasions, 15 minutes apart
Exclusion criteria

 SBP ≤180 mmHg and DBP ≤115 mmHg
 Expectation that the patient will not tolerate IV antihypertensive therapy
for a minimum of 18 hours
 Known or suspected aortic dissection
DBP=diastolic blood pressure; ED=emergency department; HTN=hypertension; ICU=intensive care unit;
IV=intravenous; SBP=systolic blood pressure.
Pollack CV, et al. Ann Emerg Med. 2008; Jun 6. [Epub ahead of print].

53. Objectives
Primary end points

 Patients (%) in whom SBP fell to within the SBP ITR within
30 minutes of initiating infusion
 Patients (%) in whom SBP fell below the lower limit of the SBP ITR
within 3 minutes of initiating infusion
Secondary end points

 Time to achieve SBP ITR within the initial 30 minutes
 Proportion of patients successfully transitioned to
oral antihypertensive therapy
 Safety of prolonged (≥18 hours) Cleviprex™
(clevidipine butyrate) infusion
ITR=initial target range; SBP=systolic blood pressure.
Pollack CV, et al. Ann Emerg Med. 2008; Jun 6. [Epub ahead of print].
Please see Important Safety Information and accompanying full Prescribing Information.

54. Titration Algorithm
Initiate Cleviprex™
(clevidipine butyrate) BP and HR measured with cuff every 3 min pre-ITR
I
infusion at initial rate BP and HR measured with cuff every 15 min post-ITR
T
of 2 mg/h (4 mL/h) for 2 h, then hourly until oral therapy
R
2h
45 60 75 90
0 3 6 9 12 15 18 21 24 27 30
18-96 h
Time postinfusion (min)
Determine ITR Maintain or further titrate after
for each patient first 30 min to achieve desired
prior to infusion long-term reduction in SBP;
Titrate every 3 min in doubling
continue treatment for 18-96 h
increments (2-4, 4-8,
up to 32 mg/h maximum)
to achieve prespecified ITR*
*Downward titration was also permitted.
BP=blood pressure; HR=heart rate; ITR=initial target range (specific for each patient; 20-40 mmHg
between upper and lower limits); SBP=systolic blood pressure.
Pollack CV, et al. Ann Emerg Med. 2008; Jun 6. [Epub ahead of print].

55. Baseline Characteristics
Medical History Patients (%)
End-organ injury 81
Myocardial infarction 5
Renal disease 25
Dialysis dependent 11
Coronary artery disease 28
HTN 97
Previous hospitalization for 31
HTN
Congestive heart failure 18
Dyslipidemia 37
Smoker (current/former) 39/21
Diabetes 31
Safety population, N=126.
HTN=hypertension.
Stroke 11
Pollack CV, et al. Ann Emerg Med. 2008; Jun 6. [Epub ahead of print].

56. Cleviprex™ (clevidipine butyrate) Rapidly
Lowered BP to Target in ~90% of Patients
Primary end point results: Kaplan-Meier curve demonstrating probability
of attaining SBP ITR within 30 minutes (mITT population*, n=117)
attainment in 30 minutes (%)
100
91%
90
Probability of SBP ITR
80
70
60
50
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Minutes
*Patients whose SBP was above their prespecified ITR at the time of Cleviprex initiation.
BP=blood pressure; ITR=initial target range; mITT=modified intent-to-treat; SBP=systolic blood pressure.
Pollack CV, et al. Ann Emerg Med. 2008; Jun 6. [Epub ahead of print].

57. Cleviprex™ (clevidipine butyrate)
Minimized Overshoot
2 patients (1.6%) fell below the lower ITR limit within the

first 3 minutes
 In 1 patient, the ITR was narrower than specified by protocol
(205-195 mmHg), with SBP 15 mmHg below the lower limit
 In 1 patient, the lower limit was 160 mmHg and the SBP fell
4 mmHg below this
 Both patients continued Cleviprex infusion beyond 18 hours
without AEs
AEs=adverse events; ITR=initial target range; SBP=systolic blood pressure.
Pollack CV, et al. Ann Emerg Med. 2008; Jun 6. [Epub ahead of print].

58. Rapid, Sustained BP Control
• Per protocol, patients were infused for a
0
minimum of 18 h
• Dose adjustments2
–5 – On average, 2 dose adjustments were
from baseline (%)1
Mean SBP reduction
needed to attain ITR
30-minute
–10 – Mean number of adjustments needed after
titration to ITR attainment of ITR through 18 h = 0.33/h
–15
–20
Additional titration
BP adjustment
–25 and maintenance
–30
0 3 6 9 12 15 18
Time after start of infusion (h)
BP=blood pressure; ITR=initial target range; SBP=systolic blood pressure.
1. Pollack CV, et al. Ann Emerg Med. 2008; Jun 6. [Epub ahead of print].
2. Data on file. The Medicines Company.

59. Cleviprex™ (clevidipine butyrate)
in Patients With Renal Impairment
Cleviprex reduced systolic blood pressure (SBP) in a post hoc

analysis of patients with renal dysfunction (dialysis dependent and
nondialysis dependent)
5 With renal dysfunction (n=22)
0 Without renal dysfunction (n=95)
from baseline (%)
–5
Mean SBP change
–10
–15
–20
–25
–30
–35
3 6 9 12 15 18 21 24 27 30
Time (min)
Peacock WF, et al. Society of Critical Care Medicine 37th Critical Care Congress; 2008. Poster #310.

60. Cleviprex™ (clevidipine butyrate)
in Patients With Acute Heart Failure
Cleviprex decreased systolic blood pressure (SBP) in a post hoc

analysis of patients with acute heart failure and severe hypertension,
without causing hypotension
5
With acute heart failure (n=17)
0
from baseline (%)
Without acute heart failure (n=100)
Mean SBP change
–5
–10
–15
–20
–25
–30
–35
3 6 9 12 15 18 21 24 27 30
Time (min)
Peacock WF, et al. Society of Critical Care Medicine 37th Critical Care Congress; 2008. Poster #302.

61. clevidipine butyrate
May be the esmolol of calcium blockers
