BP Control and Stroke

Pro Calcium Blockers“Melee Mayer”

Con Calcium Blockers“Power-Punch Pancioli”

Stephan A. “Melee”

Mayer, MD

Calcium Channel Blockers for Stroke: PRO

Stephan A. Mayer, MDAssociate Professor of Neurology & NeurosurgeryColumbia University Director, Neuro-ICUNew York Presbyterian HospitalNew York, NY

Outcome after Acute Ischemic Stroke by Admission Blood Pressure

90 –

80 –

70 –

60 –

50 –

40 –

30 –

20 –

10 –

0 –n = 18< 120

n = 29121 -140

n = 39141 -160

n = 78161 -180

n = 49181 -200

n = 87> 200

Pos

t neu

rolo

gica

l out

com

e %

Systolic BP on admission (mm Hg)

C

90 –

80 –

70 –

60 –

50 –

40 –

30 –

20 –

10 –

0 –n = 18< 120

n = 29121 -140

n = 39141 -160

n = 78161 -180

n = 49181 -200

n = 87> 200

Ear

ly n

euro

logi

cal d

eter

iora

tion

%

Systolic BP on admission (mm Hg)

A

90 –

80 –

70 –

60 –

50 –

40 –

30 –

20 –

10 –

0 –Pos

t neu

rolo

gica

l out

com

e %

Diastolic BP on admission (mm Hg)

D

n = 38< 70

n = 3971 -80

n = 4881 -90

n = 4391 -100

n = 30101 -110

n = 102> 110

90 –

80 –

70 –

60 –

50 –

40 –

30 –

20 –

10 –

0 –n = 38< 70

n = 3971 -80

n = 4881 -90

n = 4391 -100

n = 30101 -110

n = 102> 110

Ear

ly n

euro

logi

cal d

eter

iora

tion

%

Diastolic BP on admission (mm Hg)

B

Castillo J, et al. Stroke. 2004;35:520–526.

Management of Hypertension in Acute Ischemic Stroke: Patients Not Eligible for

tPA

• SBP <220 mm Hg or DBP <120 mm Hg– No antihypertensive therapy

• SBP >220 mm Hg or DBP >120 mm Hg– Labetalol 20, 40, 60, 80 mg IVP– Nicardipine 5–15 mg/h

Adams HP, et al. Stroke. 2003;34:1056–1083.

SBP, systolic blood pressure; DBP, diastolic blood pressure.

Management of Hypertension in Acute Ischemic Stroke: Patients Eligible for tPA (Pre and Post)

Adams HP, et al. Stroke. 2003;34:1056–1083.

• SBP <180 mm Hg and DBP <105 mm Hg– No antihypertensive therapy

• SBP >180 mm Hg or DBP >105 mm Hg– Labetalol 20, 40, 60, 80 mg IVP– Nicardipine 5–15 mg/h

Treatment of Hypertension in Acute ICH (1999)

Recommendations• Maintain MAP <130 mm Hg and SBP

<180 mm Hg if history of hypertension

• If ICP monitored, keep CPP (MAP – ICP) >70 mm Hg

CPP, cerebral perfusion pressure; MAP, mean arterial pressure; ICP, intracranial pressure. Broderick JP, et al. Stroke. 1999;30:905–915.

High or Low Admission SBP in ICH Patients Correlates with Increased

Mortality

<120 121-140 141-160 161-180 181-200 201-220 >220

n = 7 n = 24 n = 34 n = 50 n = 39 N = 24 n = 13

0

10

20

30

40

50

60

70

80

90

100†NC

*

N = 191.*P < 0.001 vs SBP 141–160 mm Hg on admission.†P < 0.05 vs SBP 141–160 mm Hg on admission.NC, confidence interval not calculated due to <8 cases.

1 month 12 months

Mo

rtal

ity

Rat

e (%

)

SBP (mm Hg)

Adapted from: Vemmos KN, et al. J Intern Med. 2004;255:257-265.

Cerebral Autoregulation Is Central to Treatment of Hypertensive Crises

100 200

normotensive

chronic hypertensive

Increasing risk of hypertensive

encephalopathy

Increasing risk of ischemia

50 150 250

Patients with cerebral ischemia lose their ability to autoregulate

vasoparalysis

Cerebral Blood Flow

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

MAP (mm Hg)

Specific Agents

Antihypertensive Agents Used in Hypertensive Crisis

• Clonidine• Diazoxide• Enalaprilat• Esmolol• Fenoldopam• Hydralazine• Labetalol• Nicardipine• Nifedipine• Nitroglycerin• Nitroprusside• Phentolamine• Trimethaphan

Antihypertensive Agents Used in Hypertensive Crisis

• Clonidine• Diazoxide• Enalaprilat• Esmolol• Fenoldopam• Hydralazine• Labetalol• Nicardipine• Nifedipine• Nitroglycerin• Nitroprusside• Phentolamine• Trimethaphan

Antihypertensive “Escalation” for Emergency Treatment of Hypertension

• Nitroprusside– Cerebral vasodilation may

produce or aggravate increased ICP

• Nicardipine• Labetalol or esmolol

– May worsen bronchospasm– Causes bradycardia– May worsen heart failure

• Nitropaste

Increasing Severity of Hypertension

Nitroprusside: NOT the Greatest BP Agent for Patients with Stroke

• Unstable dose-response relationship

• Directly increases ICP via cerebral vasodilation

• Toxicity with longer infusions (>72 hours)

Nicardipine vs Nitroprusside:Postoperative Hypertension Titration

of Study Medications

Halpern NA, et al. Crit Care Med. 1992;20:1637–1643.

Time to Response

(min)

Number of Dose

ChangesAdverse Events

Nicardipine

(n = 71)14.1 ± 1 1.5 ± 0.2 7%

Nitroprusside

(n = 68)30 ± 3.5 5.1 ± 1.4 18%

P = 0.003 P < 0.05

Mean ± SEM.

Nicardipine: Pharmacokinetics of IV Bolus Administration

Adapted from Cheung AT, et al. Anesth Analg. 1999;89:1116.

-50

-40

-30

-20

-10

0

10

0 20 40 60 80 100

Ch

ang

e i

n M

AP

(m

m H

g)

Nicardipine Concentration (ng/mL)120 140

0

50

100

150

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5Time after Drug Administration (h)

Pla

sma

Nic

ard

ipin

e C

on

cen

trat

ion

(n

g/m

L)

Group 1: 0.25 mgGroup 2: 0.5 mgGroup 3: 1.0 mgGroup 4: 2.0 mg

Nicardipine vs Adrenergic BlockersDrug

Nicardipine(Cardene® IV)

Esmolol(Brevibloc®)

Labetalol

Administration Continuous infusion*

Bolus,

continuous

infusion

Bolus,

continuous infusion

Onset + offset Rapid Rapid Slower

Contractility 0 Decreased Decreased

HR Minimal increase Decreased Decreased

SVR Decreased 0 Decreased

Cardiac output Increased Decreased +/-

Myocardial O2 balance

Positive Positive Positive

Contraindications Advanced aortic stenosis

Bradycardia

Heart block >1°

CHF

Bronchospasm

COPD

Bradycardia

Heart block >1°

CHF

Bronchospasm

COPD

Nicardipine

Labetalol

The Evidence Base

Randomized controlled trials comparing nicardipine and labetalol for BP control in ED-treated stroke patients

HA HA HA!

Acute Intracerebral Hemorrhage

Approximately 2 hours after onset of symptoms

“Soft Landing” in a Narrow Target Range

0

20

40

60

80

100

120

140

160

180

200

3:00 4:00 5:00 6:00 7:00 8:00 9:00

Time

mm

Hg

10

Nicardipine Infusion Dose (mg/h)

15 8

SBP MAP DBPTarget SBPTarget MAP Range

“Jagged” BP Profile with Intermittent IVP

0

20

40

60

80

100

120

140

160

180

200

3:00 4:00 5:00 6:00 7:00 8:00 9:00

Time

mm

Hg

Labetalol 40 mg IVP

SBP MAP DBPTarget SBPTarget MAP Range

Calcium Channel Blockers for Acute Stroke?

• Calcium channel blockers directly counteract the neurogenic pressor response

• Consider the IV infusion approach

• This is what we will do in the ICU

• EDs need to function as ICUs

Neurocritical Care Societywww.neurocriticalcare.org

Arthur M. “Power-Punch”

Pancioli, MD

Con: Blood Pressure Management in Stroke Calcium Channel Blockers

Arthur M. Pancioli, MD, FACEP

Associate Professor and Vice Chairman for Research

Department of Emergency Medicine

University of Cincinnati, College of Medicine

Director of Emergency Cerebrovascular Research

Greater Cincinnati/Northern Kentucky Stroke Team

Outline

• The Disease States

• Why Lower Blood Pressure?

• How to Do It?

The Disease States

• Acute ischemic stroke

• ICH

• Subarachnoid hemorrhage

Acute Ischemic Stroke

ICHICH

Early Hemorrhage Growth in Patients With ICH

Growth at 1 hour on CTGrowth at 1 hour on CT >33% Growth>33% Growth 33% Growth33% Growth

Change in NIH Stroke ScaleChange in NIH Stroke Scale 3.7 3.7 ± ± 5.25.2 0.4 ± 2.60.4 ± 2.6

Rankin Scale (4Rankin Scale (4––6 weeks)6 weeks) 4.5 4.5 ± ± 0.90.9 3.8 3.8 ± ± 1.61.6

30-Day mortality30-Day mortality 44%44% 34%34%

Brott T, et al. Stroke. 1997;28:1–5.

Aneurysmal Subarachnoid Hemorrhage

Outcome If You “Rebleed” After Sentinel Subarachnoid Hemorrhage

• Rebleeding significantly increased the odds of death (OR, 2.6; 95% CI, 1.1 to 6.3; P = 0.048)

• Reduced the odds of survival with good outcome (OR, 0.34; 95% CI, 0.13 to 0.92; P = 0.041)

Beck J, et al. Stroke. 2006;37:2733–2737.

The Dance

CPP = MAP – (ICP or CVP)

When is MAP high enough?

When is MAP too high?

My Experience with Calcium Channel Blockers

Should a moratorium be placed on sublingual

nifedipine capsules given for hypertensive emergencies and

pseudoemergencies?

JAMA, Volume 276, Number 16, October 23, 1996

Nimodipine: Subarachnoid Nimodipine: Subarachnoid HemorrhageHemorrhage

• Nimotop® (nimodipine) is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (ie, Hunt and Hess Grades I-V).

DO NOT ADMINISTER NIMOTOP INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES. DEATHS AND SERIOUS, LIFE-THREATENING ADVERSE EVENTS HAVE OCCURRED WHEN THE CONTENTS OF NIMOTOP CAPSULES HAVE BEEN INJECTED PARENTERALLY.

• (See WARNINGS and DOSAGE AND ADMINISTRATION.)

Titratable Agents for Hypertensive Cerebrovascular Emergencies

What Do I Want?

• Predictability

• Speed

• Ease

Let’s Go Disease by Disease

Acute Ischemic Stroke:

SBP >220 mm Hg / DBP >120 mm Hg

OR - when using tPA:

SBP <185 mm Hg / DBP <110 mm Hg

• IF I MUST – Then I have a lot more experience with labetalol and it reliably does BOTH the things I want

Let’s Go Disease by Disease

ICH:Keep MAP <130 mm Hg but >70 mm Hg

Subarachnoid Hemorrhage:Keep MAP <130 mm Hg but >70 mm HgGeneral rule: keep SBP <160 mm Hg

• WHEN I CAN – I Like labetalol or esmolol; they do everything I want and I can choose how to do it

Pro Calcium Blockers“Melee Mayer”

Con Calcium Blockers“Power-Punch Pancioli”

My Memories of Your Therapy

By The Way

• If we haven’t said it yet:

• I am NOT a hydralazine fan– It has defined unpredictable in my world

By the Way,Nitroprusside

and ICP

Changes in Intracranial

Pressure with Nitroprusside

Therapy

Time for a CONFESSION