Hypertensive Emergencies in Acute Ischemic Stroke: Pathophysiology and Management

1
Hypertensive Emergencies
in Acute Ischemic Stroke
Pathophysiology and Management

• Robert A. Felberg, MD
• Stroke Program Director
• Department of Neurology
• Geisinger Medical Center
• Danville, Pennsylvania

2
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

3
Defining Hypertensive Crises
and Understanding the
Scope of the Problem
4
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.
20024358-371. 2. Varon J, Marik PE. Chest.
2000118214-227.
5
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
Kidney Hematuria Proteinuria Decreasing renal
function
Adapted from Varon J, Marik PE. Chest.
2000118214-227.
6
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. 20037374-384.
7
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. 2000118214-227. 2.
Epstein M. Clin Cornerstone. 1999241-54.
8
Pathophysiologic Principles at Work in the
Hypertensive Milieu
9
Pathophysiology of the Hypertensive Emergency1-4

• Vasoconstriction, often with intravascular
  hypovolemia
• Increased circulating catecholamines
• Activation of renin-angiotensin-aldosterone
  system
• Altered autoregulatory function

SVR systemic vascular resistance.
1. Ault NJ, et al. Am J Emerg Med. 19853(6
suppl)10-15. 2. Wallach R, et al. Am J Cardiol.
198046559-565. 3. Varon J, et al. Chest.
2000118214-227. 4. Kincaid-Smith P. J
Hypertens. 19919893-899.
10
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)

Endothelium
NO
ATII
ADH
PGI2
PGI2
CAT
ET1
TxA2
CAMs
CAMs
Endothelium
NO
Vascular Smooth Muscle
Vaughan CJ, Delanty N. Lancet. 2000356411-417.
11
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 may also be a
source of Ca
Myosin kinase
? ? ?
Actin-myosin interaction ? Contraction
?
Ca
Adapted with permission from Frishman WH, et al.
Curr Probl Cardiol. 198712285-346.
12
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
200
150
250
100
50
0
MAP (mm Hg)
Adapted with permission from Varon J, Marik PE.
Chest. 2000118214-227.
13
Hypertension Can Drive Elevated Intracranial
Pressure
75

Vasodilatory Cascade Zone
Autoregulation Breakthrough Zone
Zone of Normal
Maximum
Maximum
Passive
Dilatation
Collapse
Autoregulation
Constriction
50
50
25
25
Cerebral Blood Flow (mL/100 g/min)
Intracranial Pressure (mm Hg)
0
0
150
125
100
75
50
25
0
Cerebral Perfusion Pressure (mm Hg)
Courtesy of Stephan A. Mayer, MD.
14
Cerebral Blood Flow Is Controlled by Arterioles
Veins
Arteries
15
Hypertensive Emergencies in Acute
Ischemic Stroke Treatment Principles and
Guidelines
16
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 Statistics2005 Update. Dallas, Tex
American Heart Association 2005.
17
High or Low Admission SBPin IS Patients
Correlates With Increased Early and Late Mortality
1 month
12 months
Mortality Rate ()
N930
SBP (mm Hg)
SBP systolic blood pressure IS ischemic
stroke. Plt0.001 vs SBP 121-140 mm Hg on
admission. Plt0.05 vs SBP 121-140 mm Hg on
admission.
Adapted from Vemmos KN, et al. J Intern Med.
2004255257-265.
18
Ischemic Penumbra Hypoperfused Area of Focal
Ischemia Can Be Salvaged by Timely Intervention
Infarct lt8 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-Heinema
nn 200125-57. Ullman JS. In Andrews BT, ed.
Intensive Care in Neurosurgery. New York, NY
Thieme 200329-46.
19
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. 200536916-923.
20
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 200354. 2. Adams
HP, et al. Stroke. 200536916-923.
21
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
postrt-PA ? ? ICH risk4
CBF cerebral blood flow rt-PA recombinant
tissue plasminogen activator ICH intracerebral
hemorrhage.
1. Powers WJ. Neurology. 199343461-467. 2.
Adams HP, et al. Stroke. 200536916-923. 3.
Hornig CR, et al. Stroke. 198617179-185. 4.
NINDS t-PA Stroke Study Group. Stroke.
1997282109-2118.
22
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 gt230 or DBP 121-140 Nicardipine or labetalol to 15 -25 ? in BP within the first day
DBP gt140 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.
2007381655-1711.
23
Time Is Brain
8
7
6
5
Odds Ratio for Favorable Outcome at 3 Months
4
3
Benefit for rt-PA
2
No benefit for rt-PA
1
µ
0
140
60
70
80
90
100
110
120
130
150
160
170
180
Minutes From Stroke Onset to Start of Treatment
rt-PA recombinant tissue plasminogen activator.
Marler JR, et al. Neurology. 2000551649-1655.
24
AHA/ASA 2007 Treatment Guidelines for Arterial
Hypertension Ischemic Stroke Eligible for
Thrombolytic Therapy
BP Level (mm Hg) Treatment
Pretreatment SBP gt185 or DBP gt110 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 gt230 OR DBP 121-140 Nicardipine or labetalol If BP not controlled, consider nitroprusside
DBP gt140 Nitroprusside
Adapted from Adams HP, et al. Stroke.
200536916-923.
25
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 200454.
26
Pharmacologic Profile of Commonly Administered IV
Agents to Treat Hypertensive
Emergencies
27
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. 199912653-664.
28
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.
29
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).
Physicians Desk Reference. 59th ed. Montvale,
NJ Thomson PDR 20052170-2172. 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 200455.
30
Esmolol

• Beta1-blocker1
• Onset of action 1-2 minutes2
• Duration 10-30 minutes per bolusmay 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).
Physicians Desk Reference. 59th ed. Montvale,
NJ Thomson PDR 2005804-808.
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 200455.
31
Labetalol

• Combined nonselective beta-blocker and
  alpha1-blocker1
• Beta-blockade is 7 times greater than
  alpha1-blockadewith IV administration1
• Not associated with decreased cardiac output seen
  withpure beta-blockers2
• Onset of action 5-10 minutes per bolusmay
  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. 2000118214-227.


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 200455.
32
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 gt10 µg/kg/min for gt10 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 200455.
33
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.
20041287-299. 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 200455. 4. Nishiyama T,
et al. Can J Anesth. 2000471196-1201. 5. Neutel
JM, et al. Am J Hypertens. 19947623-628.
34
Case Study in
Acute Ischemic Stroke
35
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

36
2 Sites of Occlusion (Arrows) on the Initial
Angiogram (Qureshi Grade 1)
37
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 lt185 mm Hg and
  DBP lt110 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.
38
Blood Pressure Recordings After Administration of
IV Nicardipine
Blood Pressure (mm Hg)
Minutes
39
Partial Recanalization After Administration of
Intra-arterial Reteplase (Arrows)
40
Postthrombolysis and Acute Hypertension Treatment

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

Baseline
24 Hours
41
Clinical Recap
42
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 gt220 mm Hg and DBP gt120 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

43
Key Points to Remember

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