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
[Program title]

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
Objectives
Following completion of the grand rounds CME course, participants should be able to accomplish the 4 objectives stated in the slide.

3. Defining Hypertensive Crises and Understanding the Scope of the Problem
[Section 1]

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 prevalence of HTN
Hypertensive urgency1,2
No evidence of end-organ damage
BP reduction over several hours to days
Usually treated with oral antihypertensives
Hypertensive Crisis: Emergency vs Urgency
A number of clinical circumstances may require rapid reduction of blood pressure (BP).
These circumstances, termed hypertensive crises, may be classified as emergencies, which require immediate (within minutes to a few hours) lowering of BP to safe levels, and urgencies, which can be safely treated with oral antihypertensive drugs with early follow-up.1
The distinction between emergencies and urgencies is based on the presence of end organ damage and not on a specific level of BP, although organ dysfunction is uncommon with diastolic blood pressure (DBP) <130 mm Hg. In addition, the absolute level of BP may not be as important as the rate of increase.2
Hypertensive emergencies are uncommon and probably occur in less than 1% to 2% of the hypertensive population.1
Nevertheless, due to the prevalence of poorly controlled hypertension (HTN) in the United States, approximately 500,000 patients experience a hypertensive emergency annually.1
1. Mansoor GA, Frishman WH. Heart Dis. 2002;4:
2. Varon J, Marik PE. Chest. 2000;118:
1. Mansoor GA, Frishman WH. Comprehensive management of hypertensive emergencies and urgencies. Heart Dis. 2002;4:
2. Varon J, Marik PE. The diagnosis and management of hypertensive crises. Chest. 2000;118:

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
End-Organ Damage Characterizes Hypertensive Emergencies
The end organs most frequently affected in a hypertensive emergency are shown on this slide. Patients may experience any one of the following :
Hypertensive encephalopathy with or without stroke
Unstable angina, acute heart failure, acute myocardial infarction, or dissecting aortic aneurysm
Retinal hemorrhages, exudates, or papilledema
Hematuria, proteinuria, or decreasing renal function
Kidney
Hematuria
Proteinuria
Decreasing renal function
Adapted from Varon J, Marik PE. Chest. 2000;118:
Varon J, Marik PE. The diagnosis and management of hypertensive crises. Chest. 2000;118:

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
Major Risk Factors for Hypertensive Emergencies
Most patients who experience a hypertensive crisis already have been diagnosed as hypertensive. Although many patients take an antihypertensive regimen, the level of blood pressure control is often inadequate.1
Hypertensive emergencies often are attributed to lack of a primary care physician, as well as failure of a patient to adhere to a prescribed antihypertensive regimen.1 One study revealed that only 54% of patients who presented to an emergency medicine department with a hypertensive emergency actually had taken their medication during the preceding week.2
Illicit drug use is another major risk factor.1
Varon J, Marik PE. Critical Care. 2003;7:
Varon J, Marik PE. Clinical review: the management of hypertensive crises. Critical Care. 2003;7:
Tumlin JA, Dunbar LM, Oparil S, et al. Fenoldopam: a dopamine agonist, for hypertensive emergency: a multicenter trial. Fenoldopam Study Group. Acad Emerg Med. 2000;7:

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
Current State of Hypertensive Emergency Management
Appropriate management of accelerated hypertension must consider fundamental principles in cerebrovascular pathophysiology so that treatment delays or overzealous approaches are avoided to ensure a better outcome for the patient.
1. Varon J, Marik PE. Chest. 2000;118:
2. Epstein M. Clin Cornerstone. 1999;2:41-54.
Varon J, Marik PE. The diagnosis and management of hypertensive crises. Chest. 2000;118:
Epstein M. Diagnosis and management of hypertensive emrgencies. Clin Cornerstone. 1999;2:41-54.

8. Pathophysiologic Principles at Work in the Hypertensive Milieu
[Section 2]

9. Pathophysiology of the Hypertensive Emergency1-4
Circulating vasoconstrictors
Abrupt SVR
Abrupt BP
Endothelial
damage
Loss of
autoregulatory function
End organ
ischemia
Hypertensive
Emergency
Vasoconstriction, often with intravascular hypovolemia
Increased circulating catecholamines
Activation of renin-angiotensin-aldosterone system
Altered autoregulatory function
Pathophysiology of the Hypertensive Emergency
Regardless of the underlying cause of the hypertensive emergency, it is thought that the final common pathway is a sudden increase in systemic vascular resistance (SVR) and consequently BP owing to the action of circulating vasoconstrictors such as catecholamines and angiotensin on arterioles.1-4
The resulting increase in BP damages the endothelium, leading to the release of local vasoconstrictors, such as endothelin, which cause further vasoconstriction, often with intravascular hypovolemia.1-4
Damage to the endothelium impairs autoregulatory function. Autoregulation refers to the inherent ability of arteries to dilate or constrict in response to changing perfusion pressures in order to maintain a relatively constant blood flow. Further release of humoral vasoconstrictors perpetuates the vicious cycle.1-4
It is important to note that, in this setting, patients are often hypovolemic because of 2 factors1:
― An initial pressure natriuresis and diuresis accompanies the onset of the hypertensive episode
Fluid intake usually decreases as the episode and symptoms progress
The resultant hypovolemia contributes to end-organ damage.1
SVR = systemic vascular resistance.
1. Ault NJ, et al. Am J Emerg Med. 1985;3(6 suppl): Wallach R, et al. Am J Cardiol. 1980;46: Varon J, et al. Chest. 2000;118: Kincaid-Smith P. J Hypertens. 1991;9:
Ault NJ, Ellrodt AG. Pathophysiological events leading to the end-organ effects of acute hypertension. Am J Emerg Med. 1985;3(6 suppl):10-15.
Wallach R,Karp RB, Reves JG, et al. Pathogenesis of paroxysmal hypertension developing during and after coronary bypass surgery: a study of hemodynamic and humoral factors. Am J Cardiol.1980;46:
Varon J, Marik PE. The diagnosis and management of hypertensive crises. Chest. 2000;118:
Kincaid-Smith P. Malignant hypertension. J Hypertens. 1991;9:

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
Endothelial/Vascular Smooth Muscle Contractions
At the level of the arterial wall, vascular tone is modulated by a complex interaction between the endothelium and the vascular smooth muscle cells. Under stable conditions, the endothelium secretes nitric oxide (NO), prostacyclin, and related vasoactive substances to modulate the extent of vasoconstriction.1 NO is a potent vasodilator that is released under the influence of endothelial-derived agonists, including acetylcholine, norepinephrine, and substance P, as well as in response to mechanical shear stress. Activation of the RAAS leads to reduced synthesis of NO.2
An abrupt rise in BP appears to trigger a number of compensatory responses, including activation of the RAAS. When the initial rise in BP is severe or prolonged, the capacity of the endothelium to compensate is lost. This decompensation leads to further rises in BP and the release of inflammatory cytokines, starting a cycle of homeostatic failure.1
Endothelium NO
Vascular Smooth Muscle
Vaughan CJ, Delanty N. Lancet. 2000;356:
1. Vaughan CJ, Delanty N. Hypertensive emergencies. Lancet. 2000;356:
2. Enseleit F, Hurlimann D, Luscher TF. Vascular protective effects of angiotensin converting enzyme inhibitors and their relation to clinical events. J Cardiovasc Pharmacol. 2001;37(suppl 1):S21-S30.

11. Vascular Smooth Muscle Contraction Is Calcium Dependent
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
Vascular Smooth Muscle Contraction Is Calcium Dependent
Contraction of vascular smooth muscle cells depends on increased intracellular-free calcium concentrations. This increase can be accomplished through increased influx of calcium through L-type calcium channels, release of intracellular stores, or a decrease in efflux of calcium.
  
Actin-myosin interaction
 Contraction 
Ca++
Adapted with permission from Frishman WH, et al. Curr Probl Cardiol. 1987;12:
Frishman WH, Stroh JA, Greenberg SM, et al. Calcium-channel blockers in systemic hypertension. Curr Probl Cardiol. 1987;12:1-346.

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
Cerebral Autoregulation Is Central to the Treatment of Hypertensive Crises
Autoregulation refers to the inherent regulation of arterial diameter to allow maintenance of a relatively constant amount of blood flow in different vascular beds and is most frequently discussed in terms of cerebral tissue.1
Autoregulation is lost in ischemic tissue. In patients with chronic hypertension, the structure of the arterioles thickens and the entire autoregulatory curve is shifted to the right. When BP is increased beyond the upper limits of autoregulation, “breakthrough” hyperperfusion occurs. In previously normotensive patients, whose vessels have not been altered by prior exposure to high pressures, breakthrough typically occurs at a MAP of about 120 mm Hg. In chronic hypertensive patients, the breakthrough may occur at 160 mm Hg.2
As such, a normotensive patient would be expected to develop end-organ damage at a lower BP than a chronic hypertensive. Lowering BP into the normal range in a poorly controlled, chronic hypertensive patient may actually accelerate end-organ damage.2
This difference in autoregulatory set points has important implications for the management of hypertensive urgency and emergency. The majority of the complications seen in the management of hypertensive emergency are actually from overly aggressive BP reductions. Care should be exercised in patients with chronic hypertension, or patients whose previous BP status is unknown, so that their MAP is not lowered to the point where they suffer from ischemia (“fall off the left side of the curve”).2
1. Berne RM, Levy MN. Cardiovascular Physiology. 8th ed. Philadelphia, Pa: Mosby; 2001.
2. Strandgaard S. Autoregulation of cerebral blood flow in hypertensive patients: the modifying influence of prolonged antihypertensive treatment on the tolerance to acute, drug-induced hypotension. Circulation. 1976;53: 50
100
150
200
250
MAP (mm Hg)
Adapted with permission from Varon J, Marik PE. Chest. 2000;118:

13. Hypertension Can Drive Elevated Intracranial Pressure75
Vasodilatory Cascade Zone
Autoregulation Breakthrough Zone
Passive
Maximum
Zone of Normal
Maximum
Collapse
Dilatation
Autoregulation
Constriction 50 50 25 25
Cerebral Blood Flow
(mL/100 g/min)
Intracranial Pressure (mm Hg)
Hypertension Can Drive Elevated Intracranial Pressure
The arterial dynamics of cerebroautoregulation are impacted by hypertension.
With excessively high blood pressure, the capacity of the brain to autoregulate the blood flow is challenged and increased intracranial pressure (ICP) is exacerbated.
Conversely, hypotension may lead to further ischemic damage in marginally perfused tissue, triggering cerebral vasodilation and ICP plateau waves. 25 50 75
100
125
150
Cerebral Perfusion Pressure (mm Hg)
Courtesy of Stephan A. Mayer, MD.
Rose JC, Mayer SA. Optimizing blood pressure in neurological emergencies. Neurocrit Care. 2004;1:

14. Cerebral Blood Flow Is Controlled by Arterioles
Veins
Arteries
Cerebral Blood Flow Is Controlled by Arterioles
The arterioles are the critical conduit in cerebral blood flow, as they are the last smooth muscle structure in the arterial system and control the release of blood into the capillaries. With the capability of closing completely or dilating several times their normal size, the arterioles can vastly alter blood flow to the capillaries.
An acute elevation in cerebral blood pressure to the point of disrupting cerebral autoregulation results in excessively high capillary pressure or damage to the capillary endothelium, which leads to brain edema, eventual depression of blood flow, and, finally, ischemia.
The ischemia causes arteriolar dilatation with increased capillary pressure, consequently leading to a vicious cycle characterized by more edema and more ischemic damage if the blood pressure is not brought under control.
Guyton AC. Textbook of Medical Physiology. 7th ed. Philadelphia, Pa: WB Saunders Co; 1986:218.

15. Hypertensive Emergencies in Acute Ischemic Stroke: Treatment Principles and Guidelines
[Section 3]

16. Stroke Epidemiology and Outcomes
Incidence of Stroke by Type
9% ICH
3% SAH
88% IS
Stroke Epidemiology and Outcomes
According to the American Heart Association Heart and Stroke Statistics―2005 Update, the incidence of stroke in the United States is approximately 700,000 new and recurrent attacks per year, making stroke the third leading cause of death at an estimated cost of $56.8 billion.1
While the majority of these strokes are ischemic, the mortality for hemorrhagic stroke is approximately four-fold higher.1 Mortality at 30 days ranges from 8% to 12% for ischemic stroke and from 37% to 38% for hemorrhagic stroke.
Approximately 88% of strokes are nonhemorrhagic as indicated on the slide,1 and a substantially elevated BP is not sustained in most patients who have an ischemic stroke (IS).2
Hypertension is often associated with stroke syndromes. In most of these patients, elevated blood pressure is the result of the physiologic response to the stroke itself and is not the immediate cause.2
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.
American Heart Association. Heart Disease and Stroke Statistics—2005 Update. Dallas, Tex: American Heart Association; 2005.
Blecic SA, Devuyst G. General management of acute stroke. In: Fisher M, ed. Stroke Therapy. 2nd ed. Woburn, Mass: Butterworth-Heinemann; 2001:

17. High or Low Admission SBP in IS Patients Correlates With Increased Early and Late Mortality
1 month
12 months 10 20 30 40 50 60 70 80 * †
Mortality Rate (%)
High or Low Admission SBP in IS Patients Correlates With Increased Early and Late Mortality
Vemmos and associates conducted a prospective study evaluating the relationship between systolic blood pressure (SBP) and diastolic blood pressure (DBP) [data not shown] and mortality at 1 month and 12 months in 1121 patients with acute stroke admitted within hours of stroke onset.
In 930 patients with ischemic stroke, early and late mortality in relation to SBP (and DBP) followed a U-shaped curve pattern, with patients at either end of the curve experiencing an increased risk of mortality.
The most common causes of early and late mortality in the study population with low SBP values on admission were congestive heart failure and coronary artery disease.
<101
n=23
n=87
n=268
n=248
n=162
n=82
n=43
>220
n=17
N=930
SBP (mm Hg)
SBP = systolic blood pressure; IS = ischemic stroke.
*P<0.001 vs SBP mm Hg on admission.
†P<0.05 vs SBP mm Hg on admission.
Adapted from Vemmos KN, et al. J Intern Med. 2004;255:
Vemmos KN, Tsivgoulis G, Spengos K, et al. U-shaped relationship between mortality and admission blood pressure in patients with acute stroke. J Intern Med. 2004;255:

18. 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
Ischemic Penumbra: Hypoperfused Area of Focal Ischemia Can Be Salvaged by Timely Intervention
In ischemic stroke, 2 components are important to remember:
― Infarct (area depicted in white): the area where blood flow is so diminished that necrosis occurs quickly.1
― Ischemic penumbra (area depicted in yellow): the area immediately surrounding the core infarct, where blood flow is momentarily sufficient to maintain neuronal viability but insufficient for normal cellular function.1,2
Depending on the amount of blood flow to the ischemic area, the ischemic penumbra may remain viable for as little as 1 hour or as long as 2 weeks.2
The ischemic penumbra, therefore, is at risk of infarction if blood flow remains critically low for a long enough period or if blood flow decreases further.
Normal cerebral blood flow approximates 50 mL/100 g/min. Infarction typically occurs when blood flow is <8 mL/100 g/min, and ischemia when flow is between 8 and 23 mL/100 g/min.1,2
Existence of the ischemic penumbra necessitates a cautious approach to the treatment of hypertension, as any decrease in mean arterial pressure may result in a decrease in blood flow to this already ischemic area, risking infarction.3
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.
Ahmed SH, Hu CJ, Paczynski R, et al. Pathophysiology of ischemic injury. In: Fisher M, ed. Stroke Therapy. 2nd ed. Woburn, Mass: Butterworth-Heinemann; 2001:25-57.
Ullman JS. Cerebrovascular pathophysiology and monitoring in the neurosurgical intensive care unit. In: Andrews BT, ed. Intensive Care in Neurosurgery. New York, NY: Thieme; 2003:29-46.
Lindenauer PK, Mathew MC, Ntuli TS, et al. Use of antihypertensive agents in the management of patients with acute ischemic stroke. Neurology. 2004;63:

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
Treatment of Hypertension in Acute Ischemic Stroke
The theoretical basis for treating hypertension, which is common following ischemic stroke, includes reducing the risk of brain edema formation, hemorrhagic transformation, more extensive vascular damage, and recurrent stroke in the early postevent period. However, these needs must be balanced against the consequences of overly aggressive blood pressure reduction. When the reduction of blood pressure is not gradual and controlled, the size of the infarction can be increased by secondary reduction in the ischemic area.
In the absence of convincing evidence for clinical benefit in lowering blood pressure in stroke patients who do not have evidence of end-organ damage, treatment is not advised unless the DBP is >120 mm Hg or the SBP is >220 mm Hg. The preferred parenteral drugs are those that are easily titrated and that have a minimal effect on cerebral blood vessels, such as labetalol or nicardipine.
Sublingual use of a calcium antagonist is to be avoided because of rapid absorption and secondary precipitous decline in blood pressure.
Adams HP, et al. Stroke. 2005;36:
Adams H, Adams R, Del Zoppo G, et al. Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update. A scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke. 2005;36:

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/ 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 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
Hypertensive Crisis: Goals of Therapy
The objective of treating hypertensive crisis is to reduce blood pressure without further compromise of blood flow to critical organs. Cerebral autoregulation is an important consideration.
The JNC 7 Report recommends a blood pressure reduction of no more than 25% within the first few minutes to 1 hour. If the blood pressure stabilizes, then lowering it toward a target of 160/ mm Hg over the next 2 to 6 hours should be the goal.1
In cases of aortic dissection, the reduction of blood pressure should be within 5 to 10 minutes, as shear forces on the arterial wall directly correlate with extension.2 If patients develop signs of hypoperfusion (eg, worsening angina, declining mental status), therapy should be reduced. Most complications that are seen in the management of hypertensive emergency are actually due to an overly aggressive reduction in blood pressure.
The use of short-acting and easily titratable IV drug therapy is essential in this situation. Once signs and symptoms of end-organ damage improve, oral therapy should be initiated for long-term treatment.2
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 ; 2003:54.
2. Adams HP, et al. Stroke. 2005;36:
1. 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 ; 2004:54-55.
2. Marx J, Hockberger R. Rosen's Emergency Medicine: Concepts and Clinical Practice. 5th ed. St Louis, Mo: Mosby Inc; 2001.

21. Should Acute Hypertension Be Treated in Ischemic Stroke?No
Increased BP
necessary
Yes
Increased BP
harmful
↑ BP
↓ BP
Should Acute Hypertension Be Treated in Ischemic Stroke?
On the “No” side of this scale:
Lowering BP may decrease blood flow to an already ischemic area1,2
On the “Yes” side of this scale, untreated hypertension:
May cause transformation of an ischemic stroke to a hemorrhagic stroke, which is associated with worse outcomes2
In a clinical study, 5% of cases showed clinical deterioration caused by hemorrhagic transformation3
May cause brain edema2
According to the American Heart Association/American Stroke Association (AHA/ASA) guidelines, if recombinant tissue plasminogen activator (rt-PA) is utilized, it is imperative to maintain SBP ≤185 mm Hg and DBP ≤110 mm Hg to reduce the risk of ICH. In this instance, precise BP control is critical.2
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: Adams HP, et al. Stroke. 2005;36: Hornig CR, et al. Stroke. 1986;17: NINDS t-PA Stroke Study Group. Stroke. 1997;28:
Powers WJ. Acute hypertension after stroke: the scientific basis for treatment decisions. Neurology. 1993;43:
Adams H, Adams R, Del Zoppo G, et al. Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update. A scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke. 2005;36:
Hornig CR, Dorndorf W, Agnoli AL. Hemorrhagic cerebral infarction—a prospective study. Stroke. 1986;17:

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 >230
DBP
Nicardipine or labetalol to 15% -25% ↓ in BP within the first day
DBP >140
Nitroprusside to 15% -25% ↓ in BP within the first day
AHA/ASA Treatment Guidelines for 2005: Ischemic Stroke Not Eligible for Thrombolytic Therapy
The 2005 AHA/ASA guidelines were based on definitive data from controlled clinical trials and, when no definitive data were available, on customary practice.
Regarding patients NOT eligible for thrombolytic therapy, the following recommendations were made: blood pressure is not treated unless SBP >220 mm Hg or DBP >120 mm Hg, at which time the recommendation is to reduce BP by 10% to 15% with nicardipine, labetalol, or nitroprusside (nitroprusside only if the DBP is >140 mm Hg).1
The AHA/ASA consensus guidelines further recommend that antihypertensive agents should be withheld unless the DBP is >120 mm Hg or unless the SBP is >220 mm Hg.1
Nicardipine had been added to the guidelines in 2003 while enalapril had been deleted.2
The AHA/ASA treatment guidelines for ischemic stroke (2005) should be consulted for specific dosages of each agent.
ASA = American Stroke Association; IS = ischemic stroke; SBP = systolic blood pressure; DBP = diastolic blood pressure.
Adapted from Adams HP, et al. Stroke. 2007;38:
Adams H, Adams R, Del Zoppo G, et al. Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update. A scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke. 2005;36:
Cardene I.V. (nicardipine hydrochloride). Package insert. Edison, NJ: PDL BioPharma; 2006.

23. Time Is Brain Odds Ratio for Favorable Outcome at 3 Months8 7 6 5
Odds Ratio for Favorable Outcome at 3 Months 4 3
Time Is Brain
The National Institute of Neurologic Diseases and Stroke (NINDS) rt-PA stroke study was a randomized, placebo-controlled, multicenter trial conducted to assess the benefit of administering rt-PA within hours following the onset of ischemic stroke.1
Results demonstrated that at 24 hours, no significant difference in short-term outcomes was seen between rt-PA and placebo, although a benefit for rt-PA was seen at 3 months.1 Patients treated with rt-PA were at least 30% more likely to have minimal or no disability at months.1
A reanalysis of the NINDS data showed that the benefit of treatment was higher when rt-PA was given earlier in the 3-hour time window, the results of which are shown in this slide.2
Patients treated with rt-PA demonstrated increased odds of improvement at 24 hours (if treated within 90 minutes, odds ratio [OR]: 1.71, P=0.02; if treated within 91 to 180 minutes, OR: 1.12, P=0.62) and a favorable 3-month outcome (if treated within 90 minutes, OR: 2.11, P=0.002; if treated within 91 to 180 minutes, OR: 1.69, P=0.02). The time of treatment had no effect on the ICH rate.2
Benefit for rt-PA 2
No benefit for rt-PA 1 μ 60 70 80 90
100
110
120
130
140
150
160
170
180
Minutes From Stroke Onset to Start of Treatment
rt-PA = recombinant tissue plasminogen activator.
Marler JR, et al. Neurology. 2000;55:
NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:
Marler JR, Tilley BC, Lu M, et al. Early stroke treatment associated with better outcome. Neurology. 2000;55:

24. AHA/ASA 2007 Treatment Guidelines for Arterial Hypertension: Ischemic Stroke Eligible for Thrombolytic Therapy
BP Level (mm Hg)
Treatment
Pretreatment
SBP >185 or
DBP >110
Labetalol (may repeat once) or nitropaste or nicardipine
If BP not reduced and maintained, do not administer rtPA
During and after
rt-PA
SBP OR
DBP
Labetalol
SBP >230
DBP
Nicardipine or labetalol
If BP not controlled, consider nitroprusside
DBP >140
Nitroprusside
AHA/ASA Treatment Guidelines for 2005: Ischemic Stroke Eligible for Thrombolytic Therapy
The 2005 AHA/ASA guidelines were based on definitive data from controlled clinical trials and, when no definitive data were available, on customary practice.
Regarding patients eligible for thrombolytic therapy, note that the blood pressure treatment thresholds are reduced and blood pressure tightly controlled.
If the pretreatment blood pressure levels as outlined above cannot be achieved, rt-PA should not be administered.
The recommended treatment options are nicardipine, labetalol, or nitroprusside.
The AHA/ASA treatment guidelines for ischemic stroke (2005) should be consulted for specific dosages of each agent.
Adapted from Adams HP, et al. Stroke. 2005;36:
Adams H, Adams R, Del Zoppo G, et al. Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update. A scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke. 2005;36:

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
JNC 7: Special Considerations in Hypertensive Emergencies
Patients with hypertensive emergencies should be placed in an intensive care unit for continuous monitoring of blood pressure.
Parenteral antihypertensive therapy with a vasodilator or adrenergic inhibitor will depend on the needs of the individual patient.
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 ; 2004:54.
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 ; 2003:54-55.

26. Pharmacologic Profile of Commonly Administered IV Agents to Treat Hypertensive Emergencies
[Section 5]

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
Properties of an Ideal Parenteral Antihypertensive Agent
No parenteral antihypertensive agent is ideal for every hypertensive patient.
The ideal parenteral antihypertensive drug would have the following key properties:
Is rapid acting1
Provides a predictable dose response
Is easy to titrate1
Requires minimal dosage adjustments
Has minimal adverse effects1
Is not associated with coronary steal
In addition, this agent should preserve the patient’s mental status, selectively dilate vascular beds in vital organs such as the brain, and be easy to administer and monitor.2
Oparil S, et al. Am J Hypertens. 1999;12:
Oparil S, Aronson, S, Deeb GM, et al. Fenoldopam: a new parenteral antihypertensive: consensus roundtable on the management of perioperative hypertension and hypertensive crises. Am J Hypertens. 1999;12:
Garcia JY, Vidt DG. Current management of hypertensive emergencies. Drugs. 1987;34:

28. Antihypertensive Agents Used in Hypertensive Crises*
Clonidine
Diazoxide
Enalaprilat
Esmolol
Fenoldopam
Hydralazine
Labetalol
Nicardipine
Nifedipine
Nitroglycerin
Nitroprusside
Phentolamine
Trimethaphan
Antihypertensive Agents Used in Hypertensive Crises
Several parenteral vasodilators and adrenergic inhibitors are being used to manage hypertensive emergencies.
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure lists parenteral drugs that may be used for the treatment of hypertensive emergencies. Each has its own special indications.
According to the JNC 7 Report, the initial goal of therapy is to reduce mean arterial blood pressure by no more than 25% over the course of minutes to 1 hour. If the blood pressure then stabilizes, further lowering to 160/100 mm Hg within the next 2 to 6 hours is then recommended. Excessive drops in pressure should be avoided because they may lead to renal, coronary, or cerebral ischemia. If this level is well tolerated and the patient is clinically stable, then further gradual reductions of the blood pressure toward normalcy may be instituted in the next 24 to 48 hours.
The agents highlighted in the slide will be discussed in this presentation.
*Highlights denote more commonly used intravenous agents for hypertensive emergencies that are discussed in this presentation.
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 ; 2003:54-55.

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)
Enalaprilat
Enalaprilat is an angiotensin-converting enzyme (ACE) inhibitor. It is the active metabolite of the orally administered prodrug enalapril. It is given as a 5-minute IV infusion every 6 hours.
Because enalaprilat has a long half-life lasting 11 hours, this agent should not be administered in situations where tight control of blood pressure is critically important.
As with all ACE inhibitors, the risk of angioedema is associated with with enalaprilat.
1. Vasotec® I.V. injection (enalaprilat). Physician’s Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005: 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 ; 2004:55.
Vasotec® I.V. injection (enalaprilat). Physician’s Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005:

30. Esmolol Beta1-blocker1 Onset of action: 1-2 minutes2
Duration: 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
Esmolol
Esmolol is a selective beta1-blocker. It is administered by IV bolus, which may be followed by a continuous infusion. It is indicated for the treatment of supraventricular tachycardia and for intraoperative and postoperative tachycardia and/or hypertension.
Esmolol has a very rapid onset and offset of action.
It has the same contraindications as all beta-blockers. In addition, sloughing of the skin and necrosis have been reported in association with infiltration and extravasation of the IV infusion.
1. Brevibloc injection (esmolol hydrochloride). Physician’s Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005:
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 ; 2004:55.
Brevibloc (esmolol hydrochloride). Physician’s Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005:

31. 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
Labetalol
Labetalol is a combination of a nonselective beta-blocker and an alpha1-blocker.1
The beta-blocker effects are 7 times greater than the alpha-blocker effects.1 The onset of action is 5 to15 minutes per bolus dose, but multiple doses may be required to achieve blood pressure control.2
Labetalol is not associated with the reduction in cardiac output associated with pure beta-blockers, but the adverse effects are similar.1,2
Therefore, caution should be exercised in patients with reactive airway disease, bradycardia, heart block, etc.1
1. Labetalol hydrochloride injection. Prescribing information. Corona, Calif: Watson Laboratories, Inc.
2. Varon J, et al. Chest. 2000;118:
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 ; 2004:55.
Labetalol hydrochloride Injection. Package Insert. Corona, Calif: Watson Laboratories, Inc.
Varon J, Marik PE. The diagnosis and management of hypertensive crises. Chest. 2000;118:

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 >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
Nitroprusside
Nitroprusside, like nitroglycerin, provides a rapid onset of effect with short duration of action.
Nitroprusside is recommended for most hypertensive emergencies. However, caution must be exercised in cases of high intracranial pressure (ICP) or azotemia.
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 ; 2004:55.
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 ; 2004:54-55.

33. Nicardipine Selective arteriolar vasodilator1,2
Calcium ion channel inhibitor2
Onset of action: 5-10 minutes3
Duration: 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
Nicardipine
Nicardipine is the only IV calcium-channel blocker (CCB) approved in the United States for the short-term treatment of hypertension.
It is a selective arteriolar vasodilator1,2 that does not cause venodilation and does not have significant negative cardiac effects.2
In addition to having no significant effect on ICP,3,4 nicardipine maintains or increases cardiac output2 and it is not associated with coronary steal.2
Nicardipine provides rapid or gradual control of BP with minimal dose adjustments.5-7
1. Rose JC, et al. Neurocrit Care. 2004;1: Cardene I.V. (nicardipine hydrochloride). Prescribing information. Fremont, Calif: PDL BioPharma Inc; 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 ; 2004: Nishiyama T, et al. Can J Anesth. 2000;47: Neutel JM, et al. Am J Hypertens. 1994;7:
Rose JC, Mayer SA. Optimizing blood pressure in neurological emergencies. Neurocrit Care. 2004;1:
Cardene I.V. (nicardipine hydrochloride). Prescribing information. Fremont, Calif: PDL BioPharma Inc; 2006.
Nishiyama T, Yokoyama T, Matsukawa T, et al. Continuous nicardipine infusion to control blood pressure after evacuation of acute cerebral hemorrhage. Can J Anesth. 2000;47:
Combes P, Durand M. Combined effects of nicardipine and hypocapnic alkalosis on cerebral vasomotor activity and intracranial pressure in man. Eur J Clin Pharmacol. 1991;41:
Halpern NA, Goldberg M, Neely C, et al. Postoperative hypertension: a multicenter, prospective, randomized comparison between intravenous nicardipine and sodium nitroprusside. Crit Care Med. 1992;20:
Varon J, Marik TE. The diagnosis and management of hypertensive crises. Chest. 2000;118:
Neutel JM, Smith DHG, Wallin D, et al. A comparison of intravenous nicardipine and sodium nitroprusside in the immediate treatment of severe hypertension. Am J Hypertens. 1994;7:

34. Case Study in Acute Ischemic Stroke
[Section 6]

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 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
[Please review the clinical findings upon the patient’s presentation to the emergency department.]

36. 2 Sites of Occlusion (Arrows) on the Initial Angiogram (Qureshi Grade 1)
An emergent cerebral angiogram revealed 2 occlusions in the distal branches of the superior and inferior divisions of the left middle cerebral artery. The occlusions were categorized as Qureshi grade 1.
The Qureshi grading scheme was proposed to evaluate the severity of arterial occlusion in acute ischemic stroke. This system assigns a score from 0 to 5 on the basis of occlusion site and collateral supply as evidenced on initial angiography.
Mohammad Y, Xavier AR, Christoforidis G, et al. Qureshi grading system for angiographic occlusions strongly correlates with the initial severity and in-hospital outcome of acute ischemic stroke. J Neuroimaging. 2004;14:

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 <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
Treatment
Although this patient had been deemed eligible to receive thrombolytic therapy, lowering the blood pressure with intravenously administered nicardipine was an essential preliminary step to reduce the risk of intracranial hemorrhage.
Once systolic and diastolic blood pressures were lowered and maintained at levels consistent with the American Heart Association guidelines, reteplase was administered through a microcatheter inserted in the right middle cerebral artery.
To prevent reocclusion, epitifibatide also was intravenously administered.
At this time, the use of reteplase and eptifibatide in patients with acute ischemic stroke is still considered investigational.
*Use of reteplase and eptifibatide in stroke patients is still investigational.

38. Blood Pressure Recordings After Administration of IV Nicardipine50
100
150
200
250
300 5 10 15
SBP (mm Hg)
DBP (mm Hg)
HR (min)
Blood Pressure (mm Hg)
Blood Pressure Recordings After Administration of IV Nicardipine
Nicardipine was intravenously administered at a rate of 5 mg/h in this patient.
Approximately 8 minutes after administration of the vasodilator, systolic blood pressure leveled off at <185 mm Hg and diastolic blood pressure at <110 mm Hg.
Minutes

39. Partial Recanalization After Administration of Intra-arterial Reteplase (Arrows)
Once the patient was able to undergo thrombolytic therapy, 1.5 units of reteplase was administered through the right middle cerebral artery.
A cerebral angiogram taken postthrombolysis revealed partial recanalization, necessitating subsequent administration of eptifibatide to prevent reocclusion.

40. Postthrombolysis and Acute Hypertension Treatment
CT scan at 24 hours revealed a small infarction without any intracranial hemorrhage
Postthrombolysis and Acute Hypertension Treatment
Comparison of baseline and 24-hour postthrombolysis CT scans revealed a small infarction without any intracranial hemorrhage.
Baseline
24 Hours

41. Clinical Recap
[Section 7]

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 >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
Algorithm for Managing Blood Pressure in the ED Following Ischemic or Hemorrhagic Stroke
In managing blood pressure in the emergency department following ischemic or hemorrhagic stroke, the risk of a hypertensive emergency must be minimized.
In the first 24 hours following a stroke, all oral medications must be discontinued. Hypertension should not be treated unless systolic and diastolic blood pressure readings repeatedly meet the levels recommended by the American Heart Association. Intracranial hemorrhage, the need for tissue plasminogen activator, and myocardial ischemia are situations also warranting hypertension treatment.
After the first 24 hours following a stroke, the mean arterial pressure should not be reduced by more than 15 mm Hg/day. Therapy with an angiotensin-converting enzyme inhibitor should be initiated.

43. 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
Key Points to Remember
Acute hypertensive emergencies frequently develop in patients who have experienced an ischemic stroke.
The course of therapy will be dictated by a patient’s eligibility to undergo thrombolysis. Treatment selection also must consider the clinical nuances of the individual patient as well as the pathophysiology involved.
Intravenous administration of a vasodilator may be essential to controlling blood pressure following a stroke and avoiding a hypertensive emergency.