Hypertensive Emergencies
in Acute Ischemic Stroke:
Pathophysiology and Management
Robert A. Felberg, MD
Stroke Program Director
Department of Neurology
Geisinger 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 prevalence
of 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
Brain
Hypertensive encephalopathy
Stroke
Retina
Hemorrhages
Exudates
Papilledema
Cardiovascular System
Unstable angina
Acute heart failure
Acute myocardial infarction
Acute aortic dissection
Dissecting aortic aneurysm
Adapted from Varon J, Marik PE. Chest. 2000;118:214-227.
Kidney
Hematuria
Proteinuria
Decreasing renal function
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
Hypertensive
Emergency
Circulating vasoconstrictors
End organ
ischemia
Abrupt
Loss of
autoregulatory function
Abrupt
Endothelial
damage
SVR
BP
Vasoconstriction, often
with intravascular
hypovolemia
– Increased circulating
catecholamines
– Activation of reninangiotensin-aldosterone
system
– Altered autoregulatory
function
SVR = systemic vascular resistance.
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.
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.
Endothelium
NO
ATII
ADH
PGI2
CAT
CAMs
PGI2
ET1
TxA2
CAMs
Endothelium
NO
Vascular Smooth Muscle
Vascular Smooth Muscle Contraction Is
Calcium Dependent
Ca++


Ca++ plus calmodulin

Myosin kinase

Calcium influx into vascular
smooth muscle
may occur via opening of
L-type calcium channels
Release of intracellular stores
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.
Cerebral Autoregulation Is Central to
Treatment of Hypertensive Crises
Patients with chronic hypertension
autoregulate cerebral blood flow
around higher set points
Cerebral Blood Flow
Patients with cerebral ischemia
lose their ability to autoregulate
Increasing risk of
hypertensive
encephalopathy
Ischemia
Normotensive
Chronic hypertensive
Increasing risk
of ischemia
0
50
100
150
MAP (mm Hg)
Adapted with permission from Varon J, Marik PE. Chest. 2000;118:214-227.
200
250
Hypertension Can Drive Elevated
Intracranial Pressure
75
Autoregulation
Maximum
Breakthrough
Zone
Constriction
Zone of Normal
Autoregulation
50
50
25
25
0
0
0
25
50
75
100
Cerebral Perfusion Pressure (mm Hg)
Courtesy of Stephan A. Mayer, MD.
125
150
Intracranial Pressure (mm Hg)
Cerebral Blood Flow
(mL/100 g/min)
Passive
Collapse
Vasodilatory
Maximum
Cascade
Zone
Dilatation
Cerebral Blood Flow Is Controlled
by Arterioles
Veins
Arteries
Hypertensive Emergencies in
Acute Ischemic Stroke: Treatment
Principles and Guidelines
Stroke Epidemiology and Outcomes
Incidence of Stroke by Type
9% ICH
3% SAH
88% IS
ICH = intracerebral hemorrhage; IS = ischemic stroke; SAH = subarachnoid hemorrhage.
American Heart Association. Heart Disease and Stroke Statistics—2005 Update. Dallas, Tex: American Heart Association;
2005.
High or Low Admission SBP
in IS Patients Correlates With
Increased Early and Late Mortality
1 month
Mortality Rate (%)
80
12 months
*
†
70
60
50
40
30
20
10
0
N=930
<101
101-120
121-140
n=23
n=87
n=268
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.
141-160 161-180
n=248
n=162
SBP (mm Hg)
Adapted from Vemmos KN, et al. J Intern Med. 2004;255:257-265.
181-200
201-220
>220
n=82
n=43
n=17
Ischemic Penumbra: Hypoperfused Area
of Focal Ischemia Can Be Salvaged by
Timely Intervention
Infarct
<8 mL/100 g/min
Normal
50 mL/100 g/min
Penumbra
8-23 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?
No
Increased BP
necessary
Yes
Increased BP
harmful
↑ BP
↓ BP
Maintain CBF to
ischemic penumbra1
Hemorrhagic transformation2,3
Brain edema2
HTN post–rt-PA  ↑ ICH risk4
CBF = cerebral blood flow; rt-PA = recombinant tissue plasminogen activator; ICH = intracerebral hemorrhage.
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.
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 >140
Nitroprusside to 15% -25% ↓ in BP within
the first day
ASA = American Stroke Association; IS = ischemic stroke; SBP = systolic blood pressure; DBP = diastolic blood pressure.
Adapted from Adams HP, et al. Stroke. 2007;38:1655-1711.
Odds Ratio for Favorable Outcome at 3 Months
Time Is Brain
8
7
6
5
4
3
2
1
Benefit for rt-PA
No benefit for rt-PA
μ
0
60
70
80
90
100
110
120
130
140
150
160
Minutes From Stroke Onset to Start of Treatment
rt-PA = recombinant tissue plasminogen activator.
Marler JR, et al. Neurology. 2000;55:1649-1655.
170
180
AHA/ASA 2007 Treatment Guidelines for
Arterial Hypertension: Ischemic Stroke
Eligible for Thrombolytic Therapy
BP Level (mm Hg)
Pretreatment
SBP >185 or
DBP >110
Treatment
Labetalol (may repeat once) or nitropaste
or nicardipine
If BP not reduced and maintained,
do not administer rtPA
During and after
rt-PA
SBP 180-230
OR
DBP 105-120
Labetalol
SBP >230
OR
DBP 121-140
Nicardipine or labetalol
If BP not controlled, consider nitroprusside
DBP >140
Nitroprusside
Adapted from Adams HP, et al. Stroke. 2005;36:916-923.
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.
Antihypertensive Agents Used in
Hypertensive Crises*
•
•
•
•
•
•
•
Clonidine
Diazoxide
Enalaprilat
Esmolol
Fenoldopam
Hydralazine
Labetalol
•
•
•
•
•
•
Nicardipine
Nifedipine
Nitroglycerin
Nitroprusside
Phentolamine
Trimethaphan
*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
1. Brevibloc injection (esmolol hydrochloride). Physician’s Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005:804808.
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.
Labetalol
• 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 with
pure 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
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
Blood Pressure (mm Hg)
300
250
200
SBP (mm Hg)
DBP (mm Hg)
HR (min)
150
100
50
0
0
5
10
Minutes
15
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