131
Clinical Conference
Pathophysiology and Management of
Hypertension in Acute Ischemic Stroke
Principal Discussant
Stephen J. Phillips
Camp Hill Medical Centre and Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
H ypertension, defined in different ways by vari-
ous investigators over a period of many years,
has been shown to be a major risk factor for
stroke.1-2 In fact, the strength of the evidence suggests
that hypertension causes stroke. But by what mecha-
nisms? The value of treating chronic hypertension to
prevent stroke is well established, but what should be
done about blood pressure elevations in the setting of
acute stroke?
Stroke is a generic term for a clinical syndrome that
includes focal cerebral infarction (ischemic stroke),
focal hemorrhage in the brain, and subarachnoid hem-
orrhage.3 Hypertension is an important precursor of
cerebral infarction and intracerebral hemorrhage.
Whether hypertension predisposes to subarachnoid
hemorrhage is less certain because of conflicting evi-
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dence from epidemiologic, clinical, and laboratory
investigations.47
This article will focus on the pathophysiology and
management of elevated blood pressure in the setting of
acute ischemic stroke. A review of the subject seems
timely given the frequency of the problem, the paucity
of clinically relevant scientific data,8 and contemporary
interest in salvaging ischemic brain before infarction
occurs.9-10
How Does Hypertension Cause
Cerebral Infarction?
Attempts to answer this question have tended to
focus on the pathoanatomic effects of chronic hyperten-
sion, mainly because they are more amenable to study
than the pathophysiological mechanisms of hyperten-
sion and cerebral ischemia during the acute phase of
stroke. Clearly, one would expect both types of mecha-
nism to be involved, but unfortunately, the picture is
incomplete and our knowledge fragmentary. Insights
into pathoanatomic mechanisms come from epidemio-
logic investigations, autopsy studies, and clinical trials.
Study of the pathophysiological mechanisms of acute
focal cerebral ischemia has been enhanced by the
development of new techniques such as positron emis-
sion tomography and diffusion-weighted magnetic reso-
Reccived October 27,1992; accepted in revised form October 5,
1993.
Correspondence to Dr S.J. Phillips, Camp Hill Medical Centre,
Department of Medicine, 5303 Morris St, Halifax, Nova Scotia B3J
1B6, Canada.
nance imaging.11-'2 Animal models of stroke permit
rigorous scientific study of the mechanisms of cerebral
infarction, but the relevance of such laboratory findings
to human stroke is not always clear.
Chronic hypertension aggravates atherosclerosis13
and induces complex pathological changes in the medias
of arteries and arterioles.1415 These structural changes
increase vascular resistance and protect the cerebral
microcirculation from the deleterious effects of systemic
hypertension.16 Paradoxically, however, the structural
changes may predispose to cerebral ischemia by impair-
ing vasodilator responsiveness.17-18
The small-diameter penetrating end arteries in the
brain have been considered particularly vulnerable to
the deleterious effects of elevated blood pressure be-
cause they arise directly from main arterial trunks.19
The hypertension-associated morphological changes1-20
that occur in these vessels include microaneurysm for-
mation,2123 lipohyalinosis,24 and microatheroma.25 Ap-
parently as a consequence of these changes but by
mechanisms not fully understood, either rupture or
occlusion of the diseased vessel may occur, producing
intracerebral hemorrhage or infarction. The small in-
farcts that occur deep in the cerebral hemispheres or
brain stem as a consequence of occlusion of these
diseased vessels have been postulated to represent a
specific complication of hypertension (lacunar infarc-
tion), recognizable clinically as lacunar syndromes.25-26
More recent clinical and epidemiologic data, 2729 how-
ever, suggest that hypertension is no more important in
the pathogenesis of lacunar infarction (small-vessel
territory stroke) than in the development of large-vessel
territory stroke caused by presumed atherothromboem-
bolic mechanisms (Table). Cerebral small-vessel disease
also occurs in aged normotensive subjects. Collectively,
the data suggest that hypertension has an aggravating
and accelerating but nonspecific influence on degener-
ative cerebrovascular disease, and the existence of a
unique cerebrovascular lesion attributable to hyperten-
sion remains in question.30
An overview analysis of 14 randomized trials of
antihypertensive drug therapy31 showed that coronary
heart disease events were reduced by only 14% (95%
confidence interval, 4% to 22%). A reduction of 20% to
25% would have been expected on the basis of evidence
from observational epidemiologic studies.32 In contrast,
stroke was reduced by 42% (95% confidence interval,
33% to 50%). The disparate effect of antihypertensive
 132 Hypertension Vol 23, No 1 January 1994
Comparison of Frequency of Prestroke Hypertension
Among Patients With Flrst-Ever Ischemic Stroke in the
Rochester Epidemiology Project 37 and Oxfordshire
Community Stroke Project 28
Prestroke Hypertension
Rochester* Oxfordshire!
Lacunar infarction, % 80 44
Nonlacunar infarction, % 70 47
Prestroke hypertension was defined by two blood pressure
readings a 160/95 mmHg in the Rochester project and two
blood pressure readings > 160/90 in the Oxfordshire project.
Difference between proportions within studies: *P=.O5 (P=.11
if patients with a cardiac source of emboli are excluded); tP=-6.
treatment on apparently similar pathological processes
has generated considerable debate and has not been
fully explained. Because myocardial infarction (the ma-
jor contributor to the end point "coronary heart dis-
ease" in clinical trials) is almost invariably a complica-
tion of coronary artery atherosclerosis, whereas
cerebral infarction has several causes, the data suggest
that the effect of antihypertensive therapy on stroke
incidence was not mediated solely through an effect on
atherothromboembolic mechanisms.
The results of the antihypertensive treatment trials
indicate that both fatal and nonfatal strokes are pre-
vented within just a few years of blood pressure lower-
ing, even among chronically hypertensive elderly sub-
jects33 who would be expected to have advanced
irreversible structural arterial disease. This suggests
that differences in the physiological regulatory mecha-
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nisms of the cerebral and myocardial circulations and
their dynamic adaptation to changes in perfusion pres-
sure may be important determinants of the effects of
antihypertensive treatment.34
Functional brain imaging studies using positron emis-
sion tomography have helped reveal the pathophysio-
logical consequences of acute cerebral arterial occlu-
sion.35-3* Some compensatory responses to reduced
cerebral perfusion pressure are shown in Fig 1. The
influence of blood pressure on these responses is not
well understood. In a recent study37 of 16 patients who
had hypertension and an acute middle cerebral artery
territory infarct, blood flow in the ischemic region (as
estimated by single-photon emission computed tomog-
raphy) increased as blood pressure fell in patients
treated with captopril (n=3) or clonidine hydrochloride
(n=2). In the patients who were given placebo (n=6) or
nicardipine hydrochloride (n=5), the fall in blood pres-
sure was not associated with a significant change in
cerebral blood flow. The nicardipine-treated patients
had the greatest fall in blood pressure from baseline.
These data are difficult to interpret because of the small
number of patients studied.
The time interval between arterial occlusion and
irreversible brain injury may be as long as 6 to 9
hours.35-38-39 Conceptualized as the ischemic penum-
bra,40"42 this period is viewed as a "window of opportu-
nity" for therapeutic intervention to restore regional
cerebral blood flow.43-44 The window would be expected
to be widest in zones of cortical ischemia where the
potential for collateral flow is greatest, and narrowest in
the territory of small-diameter penetrating end arteries,
CBF
Perfusion Pressure
(mm Hg)
FKB 1. Rot shows compensatory responses to reduced cere-
bral perfusion pressure. As cerebral perfusion pressure falls,
cerebral blood flow (CBF) Is initially maintained by dilation of
precapillary resistance vessels. As a result, cerebral blood
volume (CBV) increases. When vasodilation can no longer
compensate, cerebral autoregulation fails, and blood flow be-
gins to fall (vertical line at 60 mm Hg). If perfusion pressure
continues to fall, an increase in the oxygen extraction fraction
(OEF) maintains cerebral oxygen metabolism (CMRO2). Once
this mechanism becomes maximal (vertical line at 30 mm Hg),
further decline in blood flow leads to substrate depletion, energy
failure, disruption of cellular homeostasis, and ultimately, isch-
emic necrosis (ie, infarction). Dashed lines indicate conditions
for which data are inadequate to draw firm conclusions. (Used
with permission from Powers.38)
occlusion of which results in small, deep (lacunar)
cerebral infarcts. The influence of blood pressure on
this window is, clearly, worthy of further study.
Acute increases in blood pressure superimposed on a
chronic hypertensive state ("acute-on-chronic hyperten-
sion") is common in acute ischemic stroke; about half of
all patients have a history of preexisting hyperten-
sion,45"48 and on average these individuals have higher
blood pressures than those who were previously nor-
motensrve.48"50 After 3 or 4 days in the hospital, blood
pressure falls spontaneously (Fig 2).45"47-50-51
The reasons for acute hypertension in the setting of
acute stroke are poorly understood. Because it occurs in
patients with transient ischemic attacks as well as stroke
patients,50-51 Cushing's phenomenon (increased blood
pressure secondary to elevated intracranial pressure)
cannot be responsible, except in cases of massive cere-
bral infarction. There seems to be no definite correla-
tion with lesion size or location.49 Therefore, it is
difficult to incriminate ischemic damage to the insular
cortex,52 nucleus tracrus solitarius, or other structures
involved in the physiological regulation of blood pres-
sure.53 Most explanations are based on the premise that
the hypertension is secondary to the stroke, eg, a
response to increased plasma catecholamines,54 or the
stress of hospital admission.48-50
How Should Elevated Blood Pressure Be
Managed in the Setting of Acute
Ischemic Stroke?
The answer to this question is "rarely and cautiously"
according to the recent report of the Emergency Car-
diac Care Committee and Subcommittees of the Amer-
ican Heart Association.55 This statement stems mainly

200 a b
2 190 E 105
1 1
i 180 | 100
K
1 170
' D1
I stroke, 11% had a transient ischemic attack, and
•D
160 1 90
s
z 1 | 1
a 150
D = ash
D
I 140
First diy Fourth day
D
Discharge
80
from the fact that there had been no randomized trials
of antihypertensive treatment in acute ischemic stroke.
The single trial37 reported since these recommendations
were published was too small to provide any definitive
data. Therefore, clinical decision making depends on
extrapolation from animal experiments, study of indi-
viduals or series of patients, fashions and trends stimu-
lated by the development and use of new drugs, and the
experience and recommendations of experts. Not sur-
prisingly, then, considerable controversy surrounds this
issue.
Although severe hypertension during acute ischemic
stroke is an indicator of poor prognosis,5* there is no
convincing evidence that rapid lowering of elevated
blood pressure is beneficial in this situation. On the
contrary, there are several published reports of patients
in whom neurological deterioration was associated with
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precipitous falls in blood pressure induced by emer-
gency antihypertensive treatment.57-58 Although cere-
bral blood flow was not measured in these patients, it is
generally assumed that neurological deterioration oc-
curred because blood pressure dropped below the lower
limit of cerebral blood flow autoregulation and caused
more widespread cerebral hypoperfusion. The fre-
quency of this occurrence in clinical practice has not
been established. It has been suggested59 that such
complications are more common than reported in the
literature. The risk of causing harm, together with the
lack of evidence of benefit, and knowledge that elevated
blood pressure settles spontaneously in a few days
suggest that rapid lowering of blood pressure is best
avoided during the acute phase of an uncomplicated
ischemic stroke.60*63
However, given the quality of the evidence, the
absence of proof of benefit does not mean that antihy-
pertensive therapy is of no value. Some clinical investi-
gators64"66 have argued persuasively in favor of aggres-
sive blood pressure management (particularly if the
diastolic pressure is in excess of 120 mm Hg) to atten-
uate edema formation and reduce the risk of hemor-
rhage into ischemic brain. In addition, comorbid condi-
tions may be present, such as aortic dissection or acute
myocardial ischemia, that would require antihyperten-
sive treatment in their own right.
The clinician who elects to treat a hypertensive stroke
patient has to decide next which drug to use and how far
to lower the blood pressure. Two recent reviews67'68 of
the management of hypertensive urgencies and emer-
gencies recommended sodium nitroprusside as the drug
of first choice for patients with acute ischemic stroke.
Phillips Hypertension in Acute Ischemic Stroke 133
F G 2. Graphs show systolic (a) and diastolic (b)
blood pressure course in 755 stroke patients with
(solid bars) and without (open bars) previous hy-
pertension admitted to a nonintensive stroke unit.
Bars indicate 95% confidence limits of group mean
1 values. Of the 755 patients, 79% had an ischemic
7% had an intracerebral hemorrhage. Patients con-
. D1 tinued their previous antihypertensive therapy un-
less symptomatic hypotension developed. Antihy-
pertensive therapy was started or intensified in 5%
D 1 (2% within the first 4 days of admission) and
Admission First day
D
Fourth d»y
D
Hscturoe
decreased or stopped in 8% (2% within the first 4
days of admission). (Used with permission from
Carlberg et al.M)
Others34 have objected to the use of sodium nitroprus-
side in this setting because cerebral vasodilatation
caused by the drug may compromise cerebral perfusion
pressure by increasing intracranial pressure. This risk is
probably more theoretical than real, except in patients
who have poor intracranial compliance caused by a
massive stroke. Therefore, intracranial pressure should
be monitored if it is decided to lower elevated blood
pressure in a patient who has had a massive stroke.69
Alternatives to sodium nitroprusside include labe-
talol, diazoxide, and nifedipine. The effect of intrave-
nously administered labetalol on cerebral blood flow in
humans has not been well studied. Chronic oral therapy
with labetalol has been shown not to reduce cerebral
blood flow in hypertensive patients.70 Diazoxide does
not cross the blood-brain barrier and so does not cause
direct cerebral vasodilatation.58 Nifedipine is frequently
used to treat hypertensive urgencies and emergencies
and has been shown to lower blood pressure without
causing a reduction in cerebral blood flow71 but may not
be an option for acute stroke patients who cannot
swallow because it has to be administered orally.
Intravenous phentolamine or sodium nitroprusside is
recommended for rapid control of severe hypertension
associated with the purposeful or accidental ingestion or
injection of sympathomimetic agents such as cocaine.68
Drug use or abuse is becoming increasingly recognized
as an important cause of stroke in young adults.72
Hydralazine is contraindicated in patients with acute
ischemic stroke because it causes cerebral vasodilata-
tion and impaired autoregulation.34'58'68 Clonidine and
methyldopa are relatively contraindicated because of
their tendency to depress higher cerebral functions.67
How far should blood pressure be lowered? Most
authorities34'64'67'68 agree that mean arterial blood pres-
sure (calculated as diastolic pressure plus one third of
the pulse pressure) should be reduced by about 20% to
25% over 24 hours. This recommendation is largely
based on the results of a study73 of global cerebral blood
flow in 22 hypertensive patients and 10 normotensive
control subjects which showed that mean arterial blood
pressure could be reduced by about 25% before the
lower limit of autoregulation was reached and by about
50% before symptoms of cerebral hypoperfusion oc-
curred. The 24-hour time frame is somewhat arbitrary;
positron emission tomography has shown that cerebral
blood flow is unstable for a few days after stroke onset.35
Closing Comments
We do not know exactly how hypertension causes
stroke, and we do not understand the pathophysiologi-
 134 Hypertension Vol 23, No 1 January 1994
cal mechanisms producing elevated blood pressure dur-
ing acute focal cerebral ischemia. Nor do we know the
relative risks and benefits of antihypertensive treatment
in patients who present with an acute ischemic stroke or
whether one antihypertensive agent is better than
another.
Fortunately, the new wave of interest in salvaging
ischemic brain is likely to change this dismal state of
affairs because of the realization that blood pressure
and its pharmacological manipulation have the poten-
tial to interact —directly or indirectly, beneficially or
detrimentally—with other treatments currently being
evaluated for acute ischemic stroke. For example, in the
recently published pilot studies74-76 of tissue plasmino-
gen activator administered within minutes to hours of
stroke onset, patients with severe hypertension were
excluded because they were considered to be at high
risk of hemorrhage into the region of reperfused isch-
emic brain.
It is hoped that future research will bridge the gaps
between laboratory science and clinical investigation
and between the theory and practice of antihyperten-
sive treatment in acute ischemic stroke.
Ack nowledgmen t
Dr Phillips receives support from the W. Garfield Weston
Foundation.
Questions and Answers
Dr Gerald DiBona (University of Iowa, Iowa City):
Given the impressive return of blood pressure to near
normal levels by day 4 after acute stroke in the Swedish
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study50 (Fig 2), is there a cutoff value for admission
blood pressure that should be treated?
Dr Phillips: No, the authors did not make any recom-
mendations for treatment. Other authors have done so,
but cutoff values do not take into account the prestroke
blood pressure. For example, a stroke patient with a
blood pressure of 190/115 mm Hg and a premorbid
blood pressure of 170/90 mm Hg would probably be
considered to require different management than an-
other stroke patient with the same level of acute hyper-
tension but a premorbid blood pressure of 140/90
mm Hg. Unfortunately, the premorbid blood pressure is
usually unknown to the treating physician when a
patient presents to the emergency room because of a
stroke.
Dr Donald Heistad (University of Iowa, Iowa City): Is
there a way to individualize treatment for patients? Are
neurological symptoms or other approaches useful in
evaluating responses to reduction of blood pressure in
acute stroke?
Dr Phillips: Currently, no. Physicians tend to feel
compelled to act when the systolic pressure is 180
mm Hg or more, particularly if the patient's neurologi-
cal status is deteriorating. Conversely, if a patient's
neurological status deteriorates because of or despite
antihypertensive treatment, then the treatment would
usually be discontinued. However, because of the tre-
mendous variation in the clinical severity and course of
acute focal cerebral ischemia, it is difficult to tell in an
individual patient whether the administration of antihy-
pertensive treatment influences outcome. Although this
is apparently paradoxical to many clinicians, we are
likely to learn more about the treatment of individuals
by studying large numbers of patients in randomized
trials.
Dr William Lawton (University of Iowa, Iowa City): Are
there different effects of various calcium blockers in
terms of efficacy; eg, does nimodipine or nicardipine
have special properties to commend their use over other
dihydropyridines?
Dr Phillips: Not as far as we know. Nimodipine is of
proven value for the prevention of secondary cerebral
ischemic damage in patients with acute subarachnoid
hemorrhage but has not been shown to be of definite
value in patients with acute ischemic stroke.77 The
benefit of nimodipine therapy in subarachnoid hemor-
rhage patients is probably due to a cytoprotective effect
rather than a blood pressure-lowering effect. In two
randomized placebo-controlled trials of nimodipine in
patients with acute ischemic stroke,78-79 there were no
significant differences in blood pressure between the
nimodipine- and placebo-treated groups. Different cal-
cium channel blockers have not been compared in
clinical stroke trials.
Dr William Lawton (University of Iowa, Iowa City): Do
calcium channel blockers or other vasodilators produce
a "steal syndrome" in acute stroke and worsen ischemic
areas?
Dr Phillips: Possibly. Vorstrup et al80 measured regional
cerebral blood flow using the xenon-133 inhalation
method before and after the intravenous administration
of PY 108-068 (a dihydropyridine calcium antagonist
developed by Sandoz Ltd) in 11 patients who had a
cerebral infarct confirmed by computed tomography in
the preceding 1 to 9 days. Cerebral blood flow in the
ischemic areas did not improve. In 3 patients, cerebral
blood flow decreased even further in the ischemic area.
In 1 other patient, cerebral blood flow increased in part
of the peri-infarct area. These changes in cerebral blood
flow were not accompanied by any change in the pa-
tients' clinical status. The results are difficult to inter-
pret because the experiment was uncontrolled, a small
number of patients were studied, and the cerebral blood
flow measurements were made at different times after
each stroke. The investigators did not clearly demon-
strate an increase in blood flow in one area of the brain
and a concomitant decrease in another (ie, a "steal"
phenomenon).
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KEY WORDS • antihypertensive agents • cerebral ischemia •
cerebral infarction • hypertension, chronic • hypertension, acute