Hypertensive Emergencies in Acute Ischemic Stroke: Pathophysiology and

Management Robert A. Felberg, MD

Stroke Program DirectorDepartment of NeurologyGeisinger Medical Center

Danville, Pennsylvania

Objectives

• To define hypertensive emergencies and identify the major risk factors involved

• To explain key principles of cerebrovascular pathophysiology in the stroke patient, reinforcing the importance of gradual downward titration of elevated blood pressure to prevent complications

• To examine current guidelines and treatment options for managing hypertensive emergencies in patients with acute ischemic stroke, focusing on the role of intravenously administered vasoactive agents

• To discuss the specific management of a hypertensive emergency in acute ischemic stroke using a case study that follows a patient from presentation to posttreatment

Defining Hypertensive Crises and Understanding the

Scope of the Problem

Hypertensive Crisis: Emergency vs Urgency• Hypertensive emergency1,2

– Evidence of end-organ damage• Kidney• Retina • Heart• Brain

– About 500,000 cases annually in US due to high prevalenceof HTN

• Hypertensive urgency1,2

– No evidence of end-organ damage– BP reduction over several hours to days– Usually treated with oral antihypertensives

1. Mansoor GA, Frishman WH. Heart Dis. 2002;4:358-371.

2. Varon J, Marik PE. Chest. 2000;118:214-227.

End-Organ Damage Characterizes Hypertensive Emergencies

BrainHypertensive encephalopathy

StrokeRetinaHemorrhagesExudatesPapilledema

Cardiovascular SystemUnstable angina

Acute heart failureAcute myocardial infarction

Acute aortic dissection Dissecting aortic aneurysm

KidneyHematuriaProteinuriaDecreasing renal function

Adapted from Varon J, Marik PE. Chest. 2000;118:214-227.

Major Risk Factors for Hypertensive Emergencies

• Antihypertensive therapy failing to provide adequate blood pressure control

• Failure to adhere to prescribed antihypertensive regimens

• Lack of a primary care physician• Illicit drug use

Varon J, Marik PE. Critical Care. 2003;7:374-384.

Current State of Hypertensive Emergency Management• Accelerated hypertension is among the most

misunderstood and mismanaged of acute medical problems seen in clinical practice1

• Delays in initiating therapy can cause severe complications in target end organs2

• Overzealous therapy resulting in a too-rapid reduction in blood pressure is equally damaging2

• Many clinicians fail to consider the pathophysiologic principles involved in managing hypertensive emergencies1

1. Varon J, Marik PE. Chest. 2000;118:214-227.2. Epstein M. Clin Cornerstone. 1999;2:41-54.

Pathophysiologic Principles at Work in the Hypertensive Milieu

Pathophysiology of the Hypertensive Emergency1-4

Vasoconstriction, often with intravascular hypovolemia– Increased circulating

catecholamines– Activation of renin-

angiotensin-aldosterone system

– Altered autoregulatory function

Circulating vasoconstrictors

Abrupt SVR

Abrupt BP

Endothelialdamage

Loss of autoregulatory function

End organischemia

HypertensiveEmergency

1. Ault NJ, et al. Am J Emerg Med. 1985;3(6 suppl):10-15. 2. Wallach R, et al. Am J Cardiol. 1980;46:559-565. 3. Varon J, et al. Chest. 2000;118:214-227. 4. Kincaid-Smith P. J Hypertens. 1991;9:893-899.

SVR = systemic vascular resistance.

Endothelial/Vascular Smooth Muscle Interactions

• Triggers of acute changes in vascular resistance– Excess catecholamines (CAT)– Angiotensin II (ATII)– Vasopressin (ADH)– Aldosterone– Thromboxane (TxA2)– Endothelin (ET1)– Low nitric oxide (NO) or

prostaglandin (PGI2)

• Abrupt rise in BP– Promotes expression of cellular

adhesion molecules (CAMs)

Vaughan CJ, Delanty N. Lancet. 2000;356:411-417.

TxA2

PGI2

NO

CAMs CAMs

PGI2

CAT ET1

ATII ADH

Endothelium

Vascular Smooth Muscle

Endothelium

NO

Vascular Smooth Muscle Contraction Is Calcium Dependent

Ca++

Ca++ plus calmodulin

Myosin kinaseMyosin kinase

Actin-myosin interaction Contraction

Ca++

Calcium influx into vascular smooth musclemay occur via opening of L-type calcium channels

Release of intracellular storesmay also be a source of Ca++

Adapted with permission from Frishman WH, et al. Curr Probl Cardiol. 1987;12:285-346.

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

Ischemia

Cerebral Blood Flow

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

MAP (mm Hg)

0

Patients with chronic hypertension autoregulate cerebral blood flow

around higher set points

Hypertension Can Drive Elevated Intracranial Pressure

15012510075502500

25

50

75

Cerebral Perfusion Pressure (mm Hg)

Cer

ebra

l Blo

od

Flo

w (

mL

/100

g/m

in)

Zone of Normal Autoregulation

MaximumConstriction

MaximumDilatation

PassiveCollapse

0

25

50

Intr

acra

nia

l Pre

ssu

re (

mm

Hg

)

Vasodilatory Cascade Zone

Autoregulation Breakthrough Zone

Courtesy of Stephan A. Mayer, MD.

Cerebral Blood Flow Is Controlled by Arterioles

Arteries

Veins

Hypertensive Emergencies in Acute Ischemic Stroke: Treatment

Principles and Guidelines

Stroke Epidemiology and Outcomes

88% IS

9% ICH

3% SAH

ICH = intracerebral hemorrhage; IS = ischemic stroke; SAH = subarachnoid hemorrhage.

Incidence of Stroke by Type

American Heart Association. Heart Disease and Stroke Statistics—2005 Update. Dallas, Tex: American Heart Association; 2005.

High or Low Admission SBPin IS Patients Correlates With Increased Early and Late Mortality

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.

SBP = systolic blood pressure; IS = ischemic stroke.*P<0.001 vs SBP 121-140 mm Hg on admission.†P<0.05 vs SBP 121-140 mm Hg on admission.

<101

n=23

101-120

n=87

121-140

n=268

141-160

n=248

161-180

n=162

181-200

n=82

201-220

n=43

>220

n=17

0

10

20

30

40

50

60

70

80 * †

N=930

Ischemic Penumbra: Hypoperfused Area of Focal Ischemia Can Be Salvaged by Timely Intervention

Infarct<8 mL/100 g/min

Penumbra8-23 mL/100 g/min

Normal50 mL/100 g/min

Ahmed SH, et al. In: Fisher M, ed. Stroke Therapy. 2nd ed. Woburn, Mass: Butterworth-Heinemann; 2001:25-57. Ullman JS. In: Andrews BT, ed. Intensive Care in Neurosurgery. New York, NY: Thieme; 2003:29-46.

Treatment of Hypertension in Acute Ischemic Stroke: Concerns

• Without treatment– Formation of brain edema– Hemorrhagic transformation– Further vascular damage

• Overly aggressive treatment– Secondary reduction in perfusion to ischemic area

Adams HP, et al. Stroke. 2005;36:916-923.

Hypertensive Crisis: Goals of Therapy

• Immediate and controlled BP reduction1

– Reduce BP 25% within minutes to 1 hour– If BP is then stable, target toward 160/100-110 mm Hg over

the next 2-6 hours– If this level of BP is well tolerated and the patient is clinically

stable, further gradual reductions toward normal BP can be targeted over the next 24-48 hours

• Increased caution in acute ischemic stroke patients2

– Not indicated if DBP ≤120 mm Hg or SBP ≤220 mm Hg– Lower cutoffs in certain circumstances

1. The 7th Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. US Dept of HHS; NIH publication No. 03-5233; 2003:54.

2. Adams HP, et al. Stroke. 2005;36:916-923.

Should Acute Hypertension Be Treated in Ischemic Stroke?

NoIncreased BP

necessary

YesIncreased BP

harmful

↑ BP ↓ BP

Hemorrhagic transformation2,3

Brain edema2

HTN post–rt-PA ↑ ICH risk4

Maintain CBF toischemic penumbra1

1. Powers WJ. Neurology. 1993;43:461-467. 2. Adams HP, et al. Stroke. 2005;36:916-923. 3. Hornig CR, et al. Stroke. 1986;17:179-185. 4. NINDS t-PA Stroke Study Group. Stroke. 1997;28:2109-2118.

CBF = cerebral blood flow; rt-PA = recombinant tissue plasminogen activator; ICH = intracerebral hemorrhage.

AHA/ASA 2007 Treatment Guidelines for Arterial Hypertension: Ischemic Stroke Not Eligible for Thrombolytic Therapy

BP Level(mm Hg)

Treatment

SBP ≤220 or

DBP ≤120

Emergency administration of antihypertensive agents to be withheld

SBP >230 or

DBP 121-140

Nicardipine or labetalol to 15% -25% ↓ in BP within the first day

DBP >140Nitroprusside to 15% -25% ↓ in BP within the first day

Adapted from Adams HP, et al. Stroke. 2007;38:1655-1711.

ASA = American Stroke Association; IS = ischemic stroke; SBP = systolic blood pressure; DBP = diastolic blood pressure.

Time Is Brain

Minutes From Stroke Onset to Start of Treatment

Od

ds

Rat

io f

or

Fav

ora

ble

Ou

tco

me

at 3

Mo

nth

s

Benefit for rt-PA

No benefit for rt-PA

60 70 80 90 100 110 120 130 140 150 160 170 1800

1

2

3

4

5

6

7

8

μ

Marler JR, et al. Neurology. 2000;55:1649-1655.

rt-PA = recombinant tissue plasminogen activator.

BP Level (mm Hg) Treatment

PretreatmentSBP >185 or DBP >110

Labetalol (may repeat once) or nitropaste or nicardipineIf BP not reduced and maintained, do not administer rtPA

During and after rt-PA

SBP 180-230 OR

DBP 105-120Labetalol

SBP >230OR

DBP 121-140

Nicardipine or labetalol If BP not controlled, consider nitroprusside

DBP >140 NitroprussideAdapted from Adams HP, et al. Stroke. 2005;36:916-923.

AHA/ASA 2007 Treatment Guidelines for Arterial Hypertension: Ischemic Stroke Eligible for Thrombolytic Therapy

JNC 7: Special Considerations in Hypertensive Emergencies

• Patients with marked BP elevations and acute target-organ damage– Should be admitted to an ICU for continuous

monitoring of BP– Should receive parenteral antihypertensive therapy

with an agent appropriate for the individual patient• Patients with ischemic stroke in which no clear evidence from

clinical trials exists to support the use of immediate antihypertensive therapy are an exception

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. US Dept of HHS; NIH publication No. 04-5230; 2004:54.

Pharmacologic Profile of Commonly Administered IV Agents to Treat

Hypertensive Emergencies

Properties of an Ideal Parenteral Antihypertensive Agent

• Rapid onset of action

• Predictable dose response

• Titratable to desired BP

• Minimal dosage adjustments

• Minimal adverse effects

• Not associated with coronary steal

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

• Clonidine• Diazoxide• Enalaprilat• Esmolol• Fenoldopam• Hydralazine• Labetalol

• Nicardipine• Nifedipine• Nitroglycerin• Nitroprusside• Phentolamine• Trimethaphan

Antihypertensive Agents Used in Hypertensive Crises*

*Highlights denote more commonly used intravenous agents for hypertensive emergencies that are discussed in this presentation.

Enalaprilat

• ACE inhibitor1

• Onset of action: 15-30 minutes2

• Duration: 6-12 hours2

• Adverse effects: precipitous fall in pressure in high-renin states; variable response2

• Special indications/contraindications– Appropriate in acute left ventricular failure2

– Contraindicated in acute myocardial infarction2 or a history of angioedema1

– Also contraindicated in MAP insufficient for renal perfusion, low cardiac output, volume depletion, renal vascular disease, and therapy with vasoconstrictor agents (eg, NSAIDs, cyclosporine A)

1. Vasotec® I.V. injection (enalaprilat). Physician’s Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005:2170-2172. Enalaprit IV prescribing information.

2. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. US Dept of HHS; NIH publication No. 04-5230; 2004:55.

Esmolol

• Beta1-blocker1

• Onset of action: 1-2 minutes2 • Duration: 10-30 minutes per bolus—may necessitate use of

multiple boluses2 • Adverse effects: hypotension, nausea, asthma, first-degree heart

block, and heart failure2

• Special indications/contraindications– Appropriate in aortic dissection and perioperative management2;

supraventricular tachycardia, intraoperative and postoperative tachycardia and/or hypertension1

– Contraindicated in sinus bradycardia, heart block greater than first degree, and cardiogenic shock or overt heart failure1

– Use with caution in bronchospastic diseases, since beta1 selectivity is not absolute1

2. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. US Dept of HHS; NIH publication No. 04-5230; 2004:55.

1. Brevibloc injection (esmolol hydrochloride). Physician’s Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005:804-808.

• Combined nonselective beta-blocker and alpha1-blocker1 – Beta-blockade is 7 times greater than alpha1-blockade

with IV administration1

– Not associated with decreased cardiac output seen withpure beta-blockers2

• Onset of action: 5-10 minutes per bolus—may necessitate use of multiple boluses2,3

• Duration: 3-6 hours3

• Adverse effects: vomiting, scalp tingling, brochoconstriction, dizziness, nausea, heart block, and orthostatic hypotension3

• Special indications/contraindications– Appropriate in most hypertensive emergencies except acute heart

failure3

– Contraindicated in bronchial asthma, severe bradycardia, heart block greater than first degree, overt cardiac failure, and cardiogenic shock1

Labetalol

1. Labetalol hydrochloride injection. Prescribing information. Corona, Calif: Watson Laboratories, Inc.

2. Varon J, et al. Chest. 2000;118:214-227.

3. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. US Dept of HHS; NIH publication No. 04-5230; 2004:55.

Nitroprusside

• Vasodilator―venous and arterial• Onset of action: immediate • Duration: 1-2 minutes• Adverse effects: nausea, vomiting, muscle twitching, sweating,

thiocyanate and cyanide toxicity– Doses >10 μg/kg/min for >10 minutes increase the risk of

cyanide toxicity• Special indications/contraindications

– Appropriate for most hypertensive emergencies– Use with caution with high ICP or azotemia

• Requires special delivery system• Usually requires direct artery pressure monitoring

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. US Dept of HHS; NIH publication No. 04-5230; 2004:55.

Nicardipine • Selective arteriolar vasodilator1,2

• Calcium ion channel inhibitor2

• Onset of action: 5-10 minutes3

• Duration: 15-30 minutes; may exceed 4 hours3

• Adverse effects: tachycardia, headache, flushing, and local phlebitis3

– No significant effect on ICP4

• Special indications/contraindications

– Appropriate in most hypertensive emergencies except acute heart failure1-3

– Use with caution in coronary ischemia3

• Other considerations: more selective for vascular smooth muscle than cardiac muscle2; only IV CCB indicated for short-term treatment of HTN2; maintains or increases cardiac output2; as effective as sodium nitroprusside with fewer dose adjustments5; not associated with coronary steal2

1. Rose JC, et al. Neurocrit Care. 2004;1:287-299. 2. Cardene I.V. (nicardipine hydrochloride). Prescribing information. Fremont, Calif: PDL BioPharma Inc; 2006. 3.The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. US Dept of HHS; NIH publication No. 04-5230; 2004:55. 4. Nishiyama T, et al. Can J Anesth. 2000;47:1196-1201. 5. Neutel JM, et al. Am J Hypertens. 1994;7:623-628.

Case Study in Acute Ischemic Stroke

Patient Presentation• A 78-year-old woman presents with acute-onset aphasia

and right hemiparesis

• CT scan did not reveal any intracranial hemorrhage

• The patient presented 4 hours after symptom onset and was eligible for intra-arterial thrombolysis

• An emergent cerebral angiogram revealed 2 occlusions in distal branches of the superior and inferior divisions of the left middle cerebral artery

• Initial blood pressure was 162/80 mm Hg but rose to 256/77 mm Hg prior to treatment

2 Sites of Occlusion (Arrows) on the Initial Angiogram (Qureshi Grade 1)

Treatment

• Intra-arterial thrombolysis was contemplated but required lowering of blood pressure to reduce the risk of intracranial hemorrhage

• Intravenous nicardipine was initiated at 5 mg/h to achieve and maintain SBP <185 mm Hg and DBP <110 mm Hg consistent with AHA guidelines

• Subsequently, a total of 1.5 units of reteplase* was administered through a microcatheter placed in the right middle cerebral artery

• Intravenous eptifibatide* also was initiated after the procedure to prevent reocclusion

*Use of reteplase and eptifibatide in stroke patients is still investigational.

Blood Pressure Recordings After Administration of IV Nicardipine

0

50

100

150

200

250

300

0 5 10 15

SBP (mm Hg)

DBP (mm Hg)

HR (min)

Minutes

Blo

od

Pre

ssu

re (

mm

Hg

)

Partial Recanalization After Administration of Intra-arterial Reteplase (Arrows)

Postthrombolysis and Acute Hypertension Treatment

• CT scan at 24 hours revealed a small infarction without any intracranial hemorrhage

Baseline 24 Hours

Clinical Recap

Algorithm for Managing Blood Pressure in the ED Following Ischemic or Hemorrhagic Stroke

• In the first 24 hours post stroke– Stop oral medications– Do not treat hypertension unless

• SBP >220 mm Hg and DBP >120 mm Hg on repeated readings

• ICH • Need for TPA • Myocardial ischemia

– If you treat hypertension in ICH• Go to MAP 130 mm Hg, SBP 185 mm Hg,

DBP 110 mm Hg• Maybe go a little lower if the situation warrants• Use titratable drugs: IV labetalol or nicardipine

• After the first 24 hours post stroke– Do not reduce MAP by more than 15 mm Hg/day– Start ACE inhibitor

Key Points to Remember

• Patients who experience an acute ischemic stroke are at risk of an acute hypertensive emergency in the aftermath

• A patient’s eligibility to undergo thrombolysis must be assessed before an appropriate course of therapy can be selected

• Selection of a therapy must consider the clinical idiosyncrasies of the individual patient as well as the cerebrovascular and cardiovascular pathophysiology involved

• Antihypertensive therapy with an IV vasodilator may be essential to countering a hypertensive emergency