Neurol Clin 26 (2008) 565–583

Blood Pressure Management

in Acute Stroke
Victor C. Urrutia, MD*, Robert J. Wityk, MD
Cerebrovascular Division, Department of Neurology, Johns Hopkins University School
of Medicine, 601 N. Caroline Street, Suite 5073A, Baltimore, MD 21287, USA

The optimal management of arterial blood pressure in the setting of an

acute stroke has not been defined [1–3]. Many articles have been published
on this topic in the past few years, but definitive evidence from clinical trials
continues to be lacking [4–7]. This situation is complicated further because
stroke is a heterogeneous disease. The best management of arterial blood
pressure may differ, depending on the type of stroke (ischemic or hemor-
rhagic) and the subtype of ischemic or hemorrhagic stroke [1,8].
This article reviews the relationship between arterial blood pressure and
the pathophysiology specific to ischemic stroke, primary intracerebral hemor-
rhage (ICH), and aneurysmal subarachnoid hemorrhage (SAH), elaborating
on the concept of ischemic penumbra and the role of cerebral autoregulation.
The article also examines the impact of blood pressure and its management
on outcome. Finally, an agenda for research in this field is outlined.

Cerebral autoregulation
Cerebral autoregulation is the mechanism by which cerebral blood flow
(CBF) remains constant across a wide range of cerebral perfusion pressures
(CPP), achieved by reflex vasoconstriction or vasodilation of the cerebral
arterioles in response to changes in perfusion pressure. CPP is defined by
the following relationship:

CPP ¼ MAP  ICP

where MAP is mean arterial pressure and ICP is intracranial pressureIf ICP
is constant and not elevated, MAP and CPP are proportional; they can be

This is an updated version of an article that originally appeared in Critical Care Clinics,
volume 22, issue 4.
* Corresponding author.
E-mail address: vurruti1@jhmi.edu (V.C. Urrutia).

0733-8619/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ncl.2008.02.002 neurologic.theclinics.com
566 URRUTIA & WITYK

used interchangeably when talking about autoregulation. CBF is

determined by CPP and cerebrovascular resistance (CVR). CVR is governed
primarily by arteriolar diameter, although larger vessels also may contrib-
ute. To maintain a constant CBF of approximately 50 mL/100 g/min, CVR
increases through arteriolar constriction if CPP increases, and decreases by
arteriolar dilation if CPP decreases. The autoregulatory system in the brain
can maintain essentially constant CBF between a MAP of 50 to 60 mm Hg
to 150 to 160 mm Hg. When MAP decreases to less than 50 to 60 mm Hg,
maximum vasodilation is reached, and CBF decreases proportionally with
the MAP, resulting in ischemia. On the other extreme, when MAP exceeds
150 to 160 mm Hg, arteriolar vasoconstriction is exhausted, and hydrostatic
pressure increases continuously, resulting in cerebral edema and breakdown
of the blood–brain barrier (ie, hypertensive encephalopathy or ICH) (Fig. 1).
Segmental vasodilation or a ‘‘sausage-string’’ appearance of the arteries
comes first, followed by massive cerebrovascular dilation [9]. In chronically
hypertensive individuals, the autoregulation curve is shifted as a result of
the elevated MAP levels; the lower and upper inflection points are higher
than in normal individuals. A normal CBF and oxygen consumption are
maintained at the expense of a marked increase in the CVR [9]. These changes
result in a decreased tolerance for relative hypotension because the capacity
to maintain a constant CBF at the lower end of the blood pressure spectrum
is impaired.
Evidence indicates that autoregulation is dysfunctional after a stroke. If
capacity for autoregulation does not exist, CBF increases or decreases
proportionally to the MAP, exposing the brain to ischemia from

Fig. 1. CBF remains constant across a wide range of CPP owing to cerebral autoregulation,
achieved primarily through arteriolar vasoconstriction and vasodilation in response to changes
in CPP. (Data from Rose JC, Mayer SA. Optimizing blood pressure in neurologic emergencies.
Neurocrit Care 2004;1:287–99.)
 BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE 567

hypoperfusion, or edema and hemorrhage in the case of hypertension

(Fig. 2). Eames and colleagues [10] measured dynamic cerebral autoregula-
tion by analyzing beat-to-beat, spontaneous blood pressure variability and
CBF velocities with transcranial Doppler in 56 patients who had stroke
and 56 matched controls. They found global impairment in dynamic autor-
egulation in patients who had stroke but not in controls, and this dysfunc-
tion occurred not only in the hemisphere ipsilateral to the infarct, but also
contralaterally [10,11].

Ischemic penumbra
CBF in the area of a cerebral infarction is not homogeneous. In animal
experiments, Astrup and colleagues [12] showed a critical threshold of
CBF, below which neurons cease to function but continue to survive for
a time. These neurons can potentially return to a normal functional state
with restoration of blood flow. Jones and colleagues [13] replicated these
findings and suggested that the time window in which ischemia is reversible
is in the range of several hours. The current concept of the ischemic penum-
bra is a region of brain with a gradient of decreased CBF. Tissue with the
lowest CBF would be irreversibly damaged and constitute the core of the
infarct [14,15]; this area will become an infarct even if CBF is restored.
The regions surrounding the core, the ‘‘penumbra’’ (Fig. 3), are ischemic
and dysfunctional, but potentially salvageable. With timely reperfusion,
the region of ischemic penumbra may be rescued from infarction. The length
of time during which tissue in the ischemic penumbra remains viable is
controversial, but is likely to depend on the location of the cerebral vessel

Fig. 2. In chronic hypertension, the autoregulatory curve is ‘‘shifted’’ to the right, maintaining
constant CBF at higher CPP than normal and resulting in a decreased tolerance to relative
hypotension. In the setting of cerebral ischemia, autoregulation is impaired, and CBF becomes
proportional to CPP. (Data from Rose JC, Mayer SA. Optimizing blood pressure in neurologic
emergencies. Neurocrit Care 2004;1:287–99.)
568 URRUTIA & WITYK

Fig. 3. In an arterial bed distal to an acute occlusion, a ‘‘core’’ of irreversibly damaged tissue is
surrounded by an area of decreased perfusion. The region of hypoperfusion associated with
functional impairment that potentially can be salvaged by reperfusion is operationally consid-
ered the ‘‘ischemic penumbra.’’ (Adapted from Wityk RJ, Lewin JJ III. Blood pressure manage-
ment during acute ischemic stroke. Expert Opin Pharmacother 2006;7:247–58; with permission.)

occlusion, the rapidity of occlusion, and the adequacy of collateral blood

flow [14]. It widely believed that blood pressure is a crucial parameter in
the setting of acute ischemic stroke and that its reduction may worsen hypo-
perfusion of the penumbra and hasten extension of the infarct [16].
It has been suggested that diffusion-weighted and perfusion-weighted
MRI (DWI and PWI) constitute a clinically useful analogy to the concept
of ischemic penumbra. According to this view, DWI reveals areas of
cerebral injury developing within minutes to hours after onset of ischemia;
although reversible in exceptional circumstances, the DWI lesion represents,
for practical purposes, the core of the infarct. PWI uses tracking of a bolus
of gadolinium to generate relative CBF maps that can demonstrate regions
of hypoperfusion. The subtraction of PWI and DWI volumes, the diffusion–
perfusion mismatch, can be operationally used as a representation of the
ischemic penumbra (Fig. 4) [17].

Ischemic stroke
Natural history of blood pressure after ischemic stroke
Increased blood pressure is common in patients presenting with acute
stroke, particularly in patients who have pre-existing hypertension [18]. In
most cases, blood pressure spontaneously declines in the first few days after
stroke onset, but in about one third of patients, a significant decline can be
seen even in the first few hours after onset [19]. Numerous studies have
examined the relationship between admission or early changes in blood
 BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE 569

Fig. 4. An example of diffusion–perfusion mismatch and the concept of ‘‘penumbra.’’ The im-
ages labeled ‘‘before Rx’’ show a marked mismatch between a small DWI lesion (brighter signal)
and a large area of hypoperfusion in PWI (darker signal). The area of hypoperfusion decreases
after treatment with induced hypertension (‘‘during Rx’’), whereas the DWI lesion remains the
same.

pressure and outcome after stroke [20–27]. These studies are contradictory.
Some studies note an association of poor outcome with patients who have
high blood pressure on hospital admission [20,25]. Others have noted a de-
creased risk for neurologic deterioration from stroke with higher blood pres-
sure [22] and worse outcomes in patients who have a decrease in blood
pressure after admission [24]. The argument can be made that a higher blood
pressure may reflect greater stroke severity, rather than causing worse
outcomes [28]. Mattle and colleagues [27] reported a greater spontaneous
decrease in blood pressure after admission in patients who recanalized after
intra-arterial thrombolysis, compared with patients who had inadequate
recanalization. Semplicini and colleagues [29] found that 77% of patients
had an elevated blood pressure on admission and noted that in patients
who had lacunar, large artery atherosclerotic, and cardioembolic strokes,
higher blood pressures (systolic blood pressures [SBP] of 140–220 mm Hg
570 URRUTIA & WITYK

and diastolic blood pressures [DBP] of 70–110 mm Hg) were associated with
a better prognosis.
The International Stroke Trial, evaluating more than 17,000 patients,
showed a ‘‘U-shaped’’ relationship between blood pressure and mortality,
with low or high admission blood pressures linked to poor outcome [30]. In
the first 48 hours, 54% of the patients had an SBP greater than 160 mm Hg.
It was found that for every increase of SBP of 10 mm Hg over 150 mm Hg,
early mortality increased by 3.8%, and for every decrease of 10 mm Hg below
SBP of 150 mm Hg, mortality increased by 17.9% [30,31]. These findings were
replicated subsequently in a hospital-based stroke registry [32].
These studies show a physiologic relationship between acute stroke and
elevation of blood pressure; thus, elevated blood pressure may be a marker
of stroke severity and not causally related to worse outcomes. They also sug-
gest the possibility of a range of SBP that may be more favorable to patients
who have stroke. It has been postulated that patients who have a significant
ischemic penumbra may benefit from a higher blood pressure. Some patients
may benefit from higher blood pressures, whereas in others, the opposite may
be true. Studies evaluating the role of blood pressure modification (elevating
or lowering it) in acute ischemic stroke are presented in the next section.

Modifying blood pressure in acute stroke

Blood pressure reduction
Only a few studies have examined the effect of blood pressure reduction
in patients who have acute ischemic stroke [33–36]. In a Cochrane Review,
five trials with a total of 218 subjects were identified [37]. The data were
deemed insufficient to make a recommendation on lowering or elevating
blood pressure in acute stroke. The most recent American Heart Associa-
tion/American Stroke Association guidelines affirm that in most cases it is
not imperative to lower blood pressure in the acute setting and that hyper-
tension should only be treated carefully in cases were the blood pressure is
markedly elevated (SBPR220 mm Hg or DBPR120 mm Hg). They have
recommended a goal of a 15% reduction in the first 24 hours after a stroke
[1]. However, these guidelines also state that a patient’s previous antihyper-
tensive regimen can be safely restarted within 24 hours of stroke onset in
patients who have mild-to-moderate stroke and are neurologically stable
[1]. This apparent discrepancy is due to conflicting data from recent studies.
Numerous case reports and series describe neurologic worsening with exces-
sive blood pressure lowering [38,39], whereas other studies have shown that
antihypertensive therapy may be safe in patients who have acute stroke and
may, in fact, be beneficial through mechanisms related and unrelated to the
blood pressure–lowering effect.
The Intravenous Nimodipine West European Trial (INWEST) [40] was
designed to test whether nimodipine had a neuroprotective effect in stroke.
 BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE 571

The target population was 600 subjects, but the trial was stopped after
recruiting 295 subjects because of worse outcomes in the groups treated
with nimodipine. Ahmed and colleagues [35] reanalyzed the data and found
that the poorer outcome in the nimodipine groups was associated with
lowering of blood pressure, even after adjusting for known risk factors for
poor outcome. Willmot and collaborators [41] performed a study involving
18 patients, 12 randomized to transdermal glyceryl trinitrate (GTN) and
6 serving as controls. The patients were enrolled within 5 days of their stroke
and were hypertensive (SBP 140–220 mm Hg), and the treatment continued
for 7 days. The patients received a baseline xenon CT scan and the scan was
repeated 1 hour after administration of GTN. Likewise, the blood pressure
was measured before the first scan and after the second. GTN lowered SBP
by 14% without any significant change in global, ipsilateral, or contralateral
CBF, and 90-day outcomes were similar in both groups. Although the study
population is small, the patients in this study, with the same blood pressure
reduction, did not have an unfavorable outcome, as in the INWEST study.
This difference may be due to a drug- or class-specific differential effect on
systemic blood pressure and CBF favoring GTN over nimodipine.
The Acute Candesartan Cilexetil Therapy in Stroke Survivors Study
(ACCESS) [33] used candesartan cilexetil, an angiotensin type 1 receptor an-
tagonist, in patients who had ischemic stroke, with a goal of blood pressure
reduction of 10% to 15% in the first 24 hours. Patients were included in the
study if they had elevated blood pressures, as follows: SBP greater than or
equal to 200 mm Hg; DBP greater than or equal to 100 mm Hg within the
first 6 to 24 hours; SBP greater than or equal to 180 mm Hg; or DBP greater
than or equal to 105 mm Hg 24 to 36 hours after stroke onset. Patients who
had more than 70% carotid stenosis and were older than 85 years of age,
and patients who had a decreased level of consciousness or signs of aortic
dissection, acute coronary syndrome, or malignant hypertension, were
excluded. No significant difference was found in blood pressure between
candesartan cilexetil and placebo groups in the first week or the year of fol-
low-up, and functional outcome assessed by the Barthel index at 3 months,
which was the primary outcome of the study, was not significantly different
between groups. Nevertheless, improved 1-year outcomes were observed in
the candesartan cilexetil group, compared with placebo; mortality was 2.9%
and 7.2% (P ¼ .07) and stroke recurrence was 9.8% and 18.7% (P ¼ .026)
in the candesartan and placebo groups, respectively. This trial suggests that
in patients who do not have evolving neurologic deficits, who have elevated
blood pressures, treatment with an angiotensin II type 1 receptor antagonist
may be safe and may improve survival and recurrence of stroke by mecha-
nisms independent of blood pressure reduction.
Several animal studies support the notion that angiotensin II type 1 recep-
tor antagonism may be beneficial in stroke [42,43]. Postulated mechanisms
include increased CBF through stimulation of endothelial nitric oxide
synthetase or direct activation of the angiotensin II type 2 receptor, or an
572 URRUTIA & WITYK

anti-inflammatory effect. A recent meta-analysis found an association be-

tween antihypertensive agents that increase angiotensin II (angiotensin II
type 1 receptor blockers, diuretics, and calcium channel blockers) and better
cerebrovascular outcomes, compared with agents that decrease angiotensin
II (beta blockers and angiotensin-converting enzyme [ACE] inhibitors)
[44]. Studies showing a beneficial effect of ACE inhibitors in stroke may be
explained by improved CBF despite a reduction of systemic blood pressure
[31,45,46].
Elewa and collaborators [42] recently reported their experience with
a temporary middle cerebral artery occlusion model in rats treated with
candesartan, low- and high-dose enalapril, or hydralazine. Candesartan
reduced infarct volumes and improved outcome when compared with saline.
Hydralazine and the higher dose enalapril produced a reduction in mean
arterial pressure (MAP) and in infarct size but no functional improvement,
whereas low-dose enalapril did not change MAP and had no impact on
outcome measures.
Boutitie and collaborators [44] conducted a meta-analysis of 26 prospec-
tive randomized trials. They included trials testing antihypertensive agents
that either increased or decreased angiotensin II levels. The total number
of patients studied was 206,632, with 7,505 strokes. They found that the
cumulative relative risk for stroke with angiotensin II–reducing agents
was 0.87 (95% CI 0.80–0.95), compared with 0.67 (95% CI 0.60–0.74)
with angiotensin II–increasing agents (P ¼ .00001).
Eveson and collaborators [45] conducted a phase II randomized placebo-
controlled trial of lisinopril versus placebo in patients who had acute stroke.
They enrolled 40 patients within 24 hours of stroke onset and an SBP greater
than or equal to 140 mm Hg or a DBP greater than or equal to 90 mm Hg.
They excluded patients who had significant swallowing dysfunction, known
carotid stenosis greater than 70%, history of Myocardial Infarction, conges-
tive heart failure, or renal insufficiency, and ICH. The patients were random-
ized to receive lisinopril (5 mg daily) or placebo for 7 days; at that point, if
they had an SBP greater than or equal to 140 mm Hg or a DBP greater than
or equal to 90 mm Hg, enalapril was increased to 10 mg daily to complete
14 days. After 14 days, blood pressure management was at the discretion
of the treating physician. Blood pressure reduction was significantly different
between the groups, with the lisinopril group being lower. No adverse effects
due to blood pressure lowering were observed, and functional outcomes at 14
days and 90 days showed no difference.
These studies suggest that blood pressure reduction in acute stroke may be
safe and that a drug/class-specific effect may exist related to angiotensin II
levels or angiotensin II type 1 receptor antagonist and outcome after stroke.
The mechanism of improved CBF is proposed to be related to inducing en-
dothelial nitric oxide synthase and may be the final common mechanism for
the effect observed with angiotensin receptor blockers, ACE inhibitors and
GTN. Alternatively, the beneficial effect of antihypertensives may relate to
 BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE 573

the optimum blood pressure level. Data from the International Stroke Trial
suggest a range of SBP of between 140 mm Hg and 180 mm Hg as being the
optimum for patients who have stroke, whereas lower and higher SBP values
increase mortality and morbidity, to a higher degree with lower blood pres-
sure than with higher [30].
Currently, several clinical trials are attempting to resolve some of the per-
sisting questions regarding blood pressure management in acute stroke [47]:
Controlling Hypertension and Hypotension Immediately Post Stroke
(CHHIPS) trial. This trial has a vasopressor arm where hypotensive
patients (SBP%140 mm Hg) are randomized to phenylephrine versus
placebo within 12 hours of onset, and a antihypertensive arm where
hypertensive patients (SBPO180 mm Hg) are randomized to lisinopril,
labetalol, or placebo.
Scandinavian Candesartan Acute Stroke Trial (SCAST). In this study,
patients who have acute stroke within 30 hours of onset and an SBP
greater than or equal to 140 mm Hg will be randomized to Candesar-
tan versus placebo for 7 days.
Continue Or Stop post-Stroke Anti-hypertensives Collaborative Study
(COSSACS). Patients who have acute stroke or ICH within 24 hours
of onset and 24 hours from last dose of antihypertensives will be
randomized to continuing antihypertensive therapy, versus not con-
tinuing, for 2 weeks.
Efficacy of Nitric Oxide in Stroke trial (ENOS). A randomized trial with
factorial design, with the following interventions: GTN versus placebo
and stopping or continuing antihypertensive therapy for 7 days in
patients who have acute stroke within 48 hours of onset and an SBP
greater than or equal to 140 mm Hg.

Blood pressure augmentation

Reports of induced hypertension to treat acute ischemic stroke date back
to the 1950s. Shanbrom and Levy [48] reported on 2 patients (1 who had an
internal carotid artery occlusion and 1 who had basilar artery thrombosis)
who had fluctuating neurologic deficits followed by persistent neurologic de-
terioration. Both showed transient improvement in neurologic function after
systemic blood pressure was elevated using intravenous norepinephrine.
Farhat and Schneider [49] reported clinical improvement with induced hy-
pertension in 4 patients who had stroke secondary to large vessel occlusion
from various causes (eg, tumor compression of the internal carotid artery
and occlusion of the internal carotid artery for treatment of an intracranial
aneurysm). Patients seemed to have a blood pressure threshold below which
neurologic deficits returned. Wise [50] reported on the use of induced
hypertension in 2 patients who had acute ischemic stroke complicating an-
giography. In the first patient, induced hypertension was discontinued after
5 hours without recurrence of neurologic deficit. The second patient was
574 URRUTIA & WITYK

treated for 2 days, until he could undergo carotid endarterectomy. Wise and
collaborators [51] reported on 13 patients who had acute ischemic stroke
whose blood pressure was augmented within several hours of onset of symp-
toms. Rapid clinical improvement (eg, within 1 hour of induced hyperten-
sion) was noted in 5 of 13 patients, and improvement was maintained in
3 of 5 patients when assessed 24 hours later. In many of these patients,
neurologic deficits returned when hypertensive treatment was stopped,
and improved again when reinstated. Baseline MAP was 65 to 100 mm Hg
in the 5 responders, and a clinical response was seen after MAP elevation
of 13 to 30 mm Hg above baseline. No systemic complications were re-
ported. Olsen and collaborators [11] and Agnoli and colleagues [52] exam-
ined the effects of induced hypertension on CBF using intracarotid tracer
injection methods. Areas of cerebral hypoperfusion showed improved
perfusion with elevation of systemic blood pressure, demonstrating the
loss of autoregulation in ischemic brain [11,52]. Despite these early positive
reports, induced hypertension did not achieve widespread use because of
concerns of a high risk for ICH and worsening of brain edema.
Several groups have reported on patients who had ischemic stroke who
were treated with induced hypertension in the neurologic intensive care set-
ting. Rordorf and collaborators [53] reviewed 30 patients who had ischemic
stroke treated with induced hypertension and compared them with 30 similar
patients who had stroke treated with standard therapy. Intravenous phenyl-
ephrine was used to increase blood pressure until neurologic deficits improved.
Treatment was started within 24 hours of stroke onset and was continued for
a mean of 110 hours (range 7–576 hours). Neurologic improvement occurred
in 10 of the 30 treated patients and occurred at an SBP threshold of 130 to
180 mm Hg. Improvements in neurologic deficits occurred within 2 to
30 minutes of raising blood pressure. At follow-up, 4 of the 10 patients who
responded had no neurologic deficit and no infarct on brain imaging, despite
the fact that they had had an average of 10 hours of neurologic deficit before
improvement. No overall difference was seen in neurologic or cardiac compli-
cations between the patients treated with and without induced hypertension.
In contrast, the group assigned to standard therapy had higher rates of ICH
and cerebral edema on CT scan. Because this review was nonrandomized
and retrospective, it is possible that CT findings biased patient selection.
The same investigators subsequently performed a prospective study of
induced hypertension in 13 subjects who had acute ischemic stroke within
12 hours of onset of symptoms [54]. Exclusion criteria included recent cardiac
ischemia, congestive heart failure, ICH, or cerebral edema on initial head CT
scan. All patients had admission SBP of less than 200 mm Hg. The goal was to
increase SBP to at least 160 mm Hg or to 20% above the admission SBP, with
a maximum allowed SBP of 200 mm Hg. Neurologic improvement was defined
as a reduction by at least two points in the National Institutes of Health stroke
scale (NIHSS) performed by two independent examiners. To avoid misinter-
pretation of spontaneous improvement as treatment-related improvement,
 BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE 575

phenylephrine was discontinued in all responders. After SBP returned to base-

line for 20 minutes, the patient was examined for neurologic deterioration. A
beneficial neurologic response was seen in 7 of 13 patients who had blood pres-
sure elevation. Induced hypertension therapy was continued for 1 to 6 days
and eventually weaned successfully in all patients. In the responders, the
neurologic deficit did not worsen between discontinuation of induced hyper-
tension and time of discharge. At the time of discharge, the mean NIHSS
was 7.4 (range 2–15) among responders compared with an NIHSS of 10 (range
5–15) among nonresponders. Despite the presence of multiple cardiovascular
risk factors in the patients enrolled, no cardiac or neurologic complications
were associated with treatment.
Hillis and colleagues [55,56] have used DWI and PWI to study the neural
basis of aphasia and cognitive function in patients who had acute stroke.
One patient studied was a 55-year-old, right-handed man who had a left
carotid artery occlusion and a left middle cerebral artery territory infarct
primarily involving the frontal lobe [57]. Neurologic examination revealed
a transcortical motor aphasia with telegraphic speech and frequent parapha-
sias. DWI revealed a large region of restricted diffusion in the left frontal
lobe, but PWI showed an even larger area of hypoperfusion also involving
the anterior left temporal lobe (Wernicke’s area). On serial testing, it was
noted that his language ability worsened with a relative decrease in blood
pressure. When his MAP was increased from a baseline of 88 mm Hg to
a maximum of 100 mm Hg using phenylephrine, PWI showed reperfusion
of Wernicke’s area, and a marked improvement in word and sentence com-
prehension was noted. The patient eventually was transitioned from intrave-
nous phenylephrine to oral medications (fludrocortisone, salt tablets, and
midodrine) to maintain an elevated MAP. By 2 months after stroke onset,
these oral medications had been tapered without worsening of aphasia
and with return to his normal blood pressure. A repeat PWI at that time
showed normal perfusion to Wernicke’s area and no expansion of the infarct
beyond the original DWI abnormality. A remarkable feature of this case
was that induced hypertension resulted in partial, but objective, neurologic
improvement when started 7 days after onset of stroke. Similar findings were
subsequently reported in 5 other patients treated with induced hypertension
1 to 9 days after ischemic stroke [58].
With this preliminary experience, Hillis and colleagues [59] went on to
perform a prospective, unblinded study of induced hypertension in 15 sub-
jects who were randomly assigned in a 2:1 ratio to receive induced hyperten-
sion or standard stroke care. Patients were included if they had acute
ischemic stroke presenting within 1 and 7 days of onset of symptoms,
a quantifiable neurologic deficit, and a diffusion–perfusion mismatch of
20% or greater on baseline MRI scan. Exclusion criteria included recent
cardiac ischemia, congestive heart failure, hemorrhage on CT scan, or con-
traindication to intravenous phenylephrine use. MAP was increased initially
by discontinuing antihypertensive medications, then with intravascular
576 URRUTIA & WITYK

volume expansion, and finally with intravenous phenylephrine. MAP was

increased in increments of 10% to 20% above baseline with a goal of im-
proving NIHSS by two or more points. The maximum allowed MAP was
140 mm Hg. All patients treated with induced hypertension were admitted
to the neurologic ICU. Nine patients were randomly assigned to induced hy-
pertension and 6 to standard care. The two groups were similar in terms of
age, baseline NIHSS, and volume of DWI and PWI lesions on baseline MRI
scan. By day 3, patients in the induced hypertension treatment arm had a sig-
nificantly better mean NIHSS (5.6 versus 12.3; P!.02) compared with the
standard treatment group, and this difference persisted until follow-up at
6 to 8 weeks (mean NIHSS 2.8 versus 9.7; P!.04). No patient in the study
experienced a serious adverse event. Six of 9 patients treated with induced
hypertension were classified as responders (ie, they showed a reduction of
more than two points on the NIHSS, which was associated with an increase
in MAP of between 14 and 27 mm Hg [13%–30%]). Neither treatment
group showed a significant difference in the volume of DWI lesion, whereas
patients treated with induced hypertension had a significant reduction in
PWI lesion volume (from mean 132 mL to 58 mL; P!.02) and a significant
reduction in the volume of diffusion–perfusion mismatch (from mean 83 mL
to 53 mL; P!.005). Independent of treatment, improvements in NIHSS
seemed to correlate with a significant reduction in hypoperfused volume
in PWI on serial scans [60].
Marzan and colleagues [61] used norepinephrine to induce hypertension
in 34 patients who had ischemic stroke, in a study that included patients
who would have been excluded from most of the other published investiga-
tions [62]. Among the 34 subjects, 14 had infarcts on baseline CT involving
more than one third of the middle cerebral artery territory, 8 were concom-
itantly treated with thrombolytic agents, and 17 received intravenous
heparin. Nine of 34 patients (26%) were responders (more than a two-point
improvement in NIHSS); however, among patients not treated with throm-
bolytic therapy, 5 of 26 (19%) were responders. Serious complications
potentially related to induced hypertension occurred in 2 patients (cardiac
arrhythmia and symptomatic ICH). The investigators believed this rate of
complications was acceptable, particularly given the severity of stroke and
the aggressive nature of the interventions. Koenig and colleagues [62] re-
viewed the outcomes and adverse events associated with the use of any
form of blood pressure elevation in patients who had acute ischemic stroke
who had baseline DWI and PWI studies and were treated within 7 days of
onset of symptoms. Forty-six treated patients were compared with 54 pa-
tients from the same time period who received ‘‘standard therapy.’’ Treated
patients were more likely to have a larger volume of diffusion–perfusion
mismatch and the presence of large-artery atherosclerosis and were more
likely to be treated in the neurologic ICU. Treated patients had a decrease
in median NIHSS by the time of discharge, but it was not statistically signif-
icant. Serious adverse events occurred in 4 patients in each group.
 BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE 577

Several other approaches to blood pressure manipulation in patients who

have stroke have been reported. In a study of diaspirin cross-linked hemoglo-
bin (DCLHb), a hemoglobin-based oxygen carrier, in patients who had acute
stroke, a dose-dependent elevation of MAP was noted in the DCLHb-treated
subjects [63]. The treated group showed no excess of hemorrhagic transfor-
mation, cerebral edema, or hypertensive encephalopathy. The overall clinical
outcome was not improved, however, in the treated patients. Finally, Camp-
bell and associates [64] reported on the use of intra-aortic balloon pumps
placed above and below the renal arteries, causing partial aortic obstruction
and resulting in increased cerebral perfusion, sometimes with no systemic
blood pressure elevation. CBF assessed by transcranial Doppler, angio-
graphy, or positron emission tomography (PET)/single-photon emission
computed tomography (SPECT) improved in 12 of 16 patients.

Summary: blood pressure and acute ischemic stroke

Currently, the optimal management of blood pressure in acute stroke re-
mains poorly defined. From a review of the literature, the following conclu-
sions can be made: (1) At the onset of acute stroke, most patients have an
elevated blood pressure, and this elevated blood pressure tends to return to
prestroke levels in approximately 7 days. (2) No conclusive evidence supports
lowering the blood pressure in acute stroke. However, findings in animal
studies and small clinical trials suggest that blood pressure can be lowered
safely in the acute setting and that it may have a beneficial effect. Large ran-
domized clinical trials are currently underway to help answer these questions.
Moreover, the early use of angiotensin II type 1 receptor blocking agents may
be beneficial because of a mechanism not directly related to reducing blood
pressure (ie, their effects on CBF) and the induction of endothelial nitric ox-
ide. (3) In selected cases, blood pressure augmentation may be beneficial and
safe in the management of acute ischemic stroke. (4) More research is needed
to identify effective strategies for blood pressure management in acute ische-
mic stroke. It is possible that patients may benefit from active management to
maintain blood pressure within a specified range. Clinical trials such as the
proposed CHHIPS may help answer these questions, specifically whether
achieving a target blood pressure by reducing or augmenting blood pressure
is beneficial [31]. Until such data are available, the guidelines of the American
Heart Association provide a reasonable approach to this problem [1].

Hemorrhagic stroke
Intracerebral hemorrhage
The role of blood pressure management in the acute phase of primary ICH
is equally not well defined. Elevated blood pressure is seen in 46% to 56% of
patients presenting with ICH [65]. Outcomes after ICH are closely related to
578 URRUTIA & WITYK

hematoma size and hematoma expansion [66,67]. Ohwaki and colleagues [68]
studied 76 patients and used a multiple logistic regression model to show that
SBP of more than 160 mm Hg was independently associated with hematoma
growth. Studies have shown that hematoma expansion occurs early within
the first 24 hours in 38% of patients [69]. The hypothesis has been advanced
that lowering blood pressure in the acute setting may decrease the hematoma
expansion rate and improve prognosis, yet this theory remains to be tested in
clinical trials. The concept of decreasing blood pressure after ICH has been
opposed because of concerns about reducing CBF and promoting ischemia
in the perihematomal brain tissue. This concept has been studied in a few
patients using SPECT, PET, and DWI. Recent results suggest that in the
acute setting, regional CBF is reduced around the hematoma, with a matching
decrease in the cerebral metabolic rate of oxygen. The oxygen extraction
fraction remains low, indicating no region of ischemia [70–72]. Stages of
CBF have been proposed in the perihematomal area, as follows [73]:
Hibernation: decreased CBF, decreased cerebral metabolic rate of oxygen,
and decreased oxygen extraction fraction (0–48 hours)
Reperfusion: blood flow is heterogeneous and can be decreased, normal,
or augmented (48 hours to 14 days)
Normalization (O14 days)
In a study by Powers and colleagues [71], 14 patients who had ICH were
evaluated with a baseline PET scan 6 to 22 hours after onset of symptoms.
Blood pressure was lowered by 15%, from a MAP of 143 to 119 mm Hg
with either nicardipine or labetalol, and repeat PET showed that the CBF
remained stable in the perihematomal area. Studies such as this and the
one done by Ohwaki and colleagues [68,71] suggest that reducing blood
pressure in the first 24 hours after ICH is safe. In a study by Qureshi and
coworkers [65], 27 patients who had ICH were treated to reduce SBP to
less than 160 mm Hg and DBP to less than 110 mm Hg. Only 2 of 27 pa-
tients deteriorated neurologically, and only 9.1% had hematoma expansion
(defined as a growth of the hematoma of O33%).
These data indicate that treatment of hypertension could be beneficial to
reduce hematoma expansion and clinical deterioration in the acute period
after ICH. The recent guidelines from the American Heart Association/
American Stroke Association, published in 2007 [8], recognize that the evi-
dence is still not sufficient to guide management of blood pressure in ICH;
the recommendation is to treat patients aggressively with an SBP greater
than 200 mm Hg or MAP greater than150 mm Hg; to consider ICP moni-
toring to guide therapy, with the goal of maintaining a CPP between 60 and
80 mm Hg in patients who have suspected elevation of ICP and an SBP
greater than 180 mm Hg or MAP greater than 130 mm Hg; and to consider
treatment to a goal of SBP of 160 mm Hg or MAP of 110 mm Hg in patients
who have an SBP greater than 160 mm Hg or MAP greater than 130 mm Hg
without suspicion of elevated ICP.
 BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE 579

Two trials are currently underway to evaluate these questions. In the An-
tihypertensive Treatment in Acute Cerebral Hemorrhage (ATACH) study,
patients are randomly assigned to three treatment groups with a specified
target blood pressure level [47]. In the INTEnsive blood pressure Reduction
in Acute Cerebral hemorrhage Trial (INTERACT), patients are randomized
to a protocol of intensive blood pressure lowering versus ASA guideline
blood pressure management as control [47].

Aneurysmal subarachnoid hemorrhage

Aneurysmal SAH occurs in more than 30,000 individuals per year in the
United States, and 30-day mortality is 25% to 50% [74]. Management of
SAH is governed by different priorities and paradigms, depending on the
time after onset of the hemorrhage. The biggest concern in the first few
days after rupture is rebleeding, which occurs in 9% to 30% of patients.
The risk is 20% in the first 2 weeks and 30% in the first month if the aneu-
rysm remains untreated. Mortality in patients who rebleed increases to 50%
to 80% [75,76]. After the aneurysm has been secured by clipping or coiling,
the next major concern is vasospasm. Symptomatic vasospasm occurs in
30% of patients and is a major cause of morbidity and mortality in SAH.
Its incidence peaks between days 10 and 14 after SAH [74].
Blood pressure may be an important determinant of rebleeding and vaso-
spasm. The risk for rebleeding is highest in the first 24 hours after SAH
[75,77]. Ohkuma and colleagues [75] studied 273 patients and found aneu-
rysmal rerupture in 13.6% within the first 24 hours. In the same study,
they found a statistically significant higher risk for rebleeding in patients
who had SBP greater than 160 mm Hg. Claassen and coworkers [78] found,
in a group of 467 patients who had SAH studied within the first 3 days, that
MAP less than 70 mm Hg, or greater than 130 mm Hg, was an independent
predictor of death and disability at 3 months. Hypotension with MAP of
less than 70 mm Hg is seen in 4% of all patients who have SAH in the acute
period, whereas 33% to 50% of patients present with elevated blood pres-
sure. In this study, however, hypertension was not independently associated
with rerupture.
In patients within days 1 to 4 of the onset of a SAH and without vaso-
spasm, hydrocephalus, or ICH, PET shows a decrease in the cerebral
metabolic rate of oxygen, CBF, and cerebral blood volume with normal ox-
ygen extraction fraction. Metabolism and CBF show a coupled reduction
[70], which is similar to the pattern in the perihematomal region in an
ICH, discussed earlier. One could postulate, based on the experience with
ICH, that lowering blood pressure would not cause an increase in ischemia
if the criteria mentioned earlier are met. Early studies of blood pressure
management after SAH, which were completed before the adoption of early
aneurysm surgery as a standard of care, suggested that patients who
benefited from treatment of hypertension to prevent rebleed subsequently
580 URRUTIA & WITYK

had a higher rate of ischemic stroke later in the course when vasospasm was
more prevalent [79]. This change in priority as the patient evolves from a sit-
uation of high rebleed risk to a high vasospasm risk makes interpretation of
these studies difficult. Wijdicks and colleagues [79] studied 134 patients
enrolled in a trial of tranexamic acid in which 80 (60%) were treated with
antihypertensive medication. Rebleeding occurred in 12 of 80 (15%)
patients treated with antihypertensives, compared with 18 of 54 patients
(33%) who did not receive antihypertensives. Cerebral infarction occurred
in 43% of patients who had antihypertensive treatment versus 22% in those
who did not [79].
A randomized controlled trial of blood pressure management in early
SAH has not been conducted. Data from observational studies suggest
a benefit in avoiding the extremes of blood pressure. Also, in the absence
of vasospasm, hydrocephalus, or ICH with increased ICP, blood pressure
reduction may be safe. Based on expert opinion and accumulated experi-
ence, it seems reasonable to maintain SBP at less than 160 mm Hg before
treatment of the aneurysm, provided that the conditions outlined earlier
are met [74]. A well-designed, randomized, controlled trial is needed to
address this important question. After definitive aneurysm treatment by
clipping or coiling, a strategy of permissive or induced hypertension is com-
monly implemented to improve CBF in the setting of vasospasm; however,
clinical trials are also needed to support this practice.

References
[1] Adams HP Jr, Del ZG, Alberts MJ, et al. Guidelines for the early management of adults
with ischemic stroke: a guideline from the American Heart Association/American Stroke
Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and
Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of
Care Outcomes in Research Interdisciplinary Working Groups: the American Academy
of Neurology affirms the value of this guideline as an educational tool for neurologists.
Stroke 2007;38(5):1655–711.
[2] Adams H, Adams R, Del ZG, 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(4):916–23.
[3] Adams HP Jr, Adams RJ, Brott T, et al. Guidelines for the early management of patients
with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke
Association. Stroke 2003;34(4):1056–83.
[4] Markus H. Acute stroke. Int Psychogeriatr 2003;(15 Suppl 1):161–6.
[5] Goldstein LB. Blood pressure management in patients with acute ischemic stroke. Hyperten-
sion 2004;43(2):137–41.
[6] Wityk RJ, Lewin JJ III. Blood pressure management during acute ischaemic stroke. Expert
Opin Pharmacother 2006;7(3):247–58.
[7] Verstappen A, Thijs V. What do we (not) know about the management of blood pressure in
acute stroke? Curr Neurol Neurosci Rep 2004;4(6):505–9.
[8] Broderick J, Connolly S, Feldmann E, et al. Guidelines for the management of spontaneous
intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart
Association/American Stroke Association Stroke Council, High Blood Pressure Research
 BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE 581

Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working
Group. Circulation 2007;116(16):e391–413.
[9] Chillon J-M, Baumbach G. Autoregulation: arterial and intracranial pressure. In: Edvinsson
L, Krause DN, editors. Cerebral blood flow and metabolism. 2nd edition. Philadelphia: Lip-
pincott, Williams, Wilkins; 2002. p. 395–406.
[10] Eames PJ, Blake MJ, Dawson SL, et al. Dynamic cerebral autoregulation and beat to beat
blood pressure control are impaired in acute ischaemic stroke. J Neurol Neurosurg Psychi-
atry 2002;72(4):467–72.
[11] Olsen TS, Larsen B, Herning M, et al. Blood flow and vascular reactivity in collaterally
perfused brain tissue. Evidence of an ischemic penumbra in patients with acute stroke. Stroke
1983;14(3):332–41.
[12] Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia - the ischemic penumbra.
Stroke 1981;12(6):723–5.
[13] Jones TH, Morawetz RB, Crowell RM, et al. Thresholds of focal cerebral ischemia in awake
monkeys. J Neurosurg 1981;54(6):773–82.
[14] Fisher M, Garcia JH. Evolving stroke and the ischemic penumbra. Neurology 1996;47(4):
884–8.
[15] Marchal G, Beaudouin V, Rioux P, et al. Prolonged persistence of substantial volumes of
potentially viable brain tissue after stroke: a correlative PET-CT study with voxel-based
data analysis. Stroke 1996;27(4):599–606.
[16] Hakim AM. Ischemic penumbra: the therapeutic window. Neurology 1998;51(3 Suppl 3):
S44–6.
[17] Fisher M, Albers GW. Applications of diffusion-perfusion magnetic resonance imaging in
acute ischemic stroke. Neurology 1999;52(9):1750–6.
[18] Wallace JD, Levy LL. Blood pressure after stroke. JAMA 1981;246(19):2177–80.
[19] Broderick J, Brott T, Barsan W, et al. Blood pressure during the first minutes of focal
cerebral ischemia. Ann Emerg Med 1993;22(9):1438–43.
[20] Carlberg B, Asplund K, Hagg E. The prognostic value of admission blood pressure in
patients with acute stroke. Stroke 1993;24(9):1372–5.
[21] Demchuk AM, Tanne D, Hill MD, et al. Predictors of good outcome after intravenous tPA
for acute ischemic stroke. Neurology 2001;57(3):474–80.
[22] Jorgensen HS, Nakayama H, Raaschou HO, et al. Effect of blood pressure and diabetes on
stroke in progression. Lancet 1994;344(8916):156–9.
[23] Aslanyan S, Fazekas F, Weir CJ, et al. Effect of blood pressure during the acute period of
ischemic stroke on stroke outcome: a tertiary analysis of the GAIN International Trial.
Stroke 2003;34(10):2420–5.
[24] Oliveira-Filho J, Silva SC, Trabuco CC, et al. Detrimental effect of blood pressure reduction
in the first 24 hours of acute stroke onset. Neurology 2003;61(8):1047–51.
[25] Willmot M, Leonardi-Bee J, Bath PM. High blood pressure in acute stroke and subsequent
outcome: a systematic review. Hypertension 2004;43(1):18–24.
[26] Vemmos KN, Tsivgoulis G, Spengos K, et al. Pulse pressure in acute stroke is an independent
predictor of long-term mortality. Cerebrovasc Dis 2004;18(1):30–6.
[27] Mattle HP, Kappeler L, Arnold M, et al. Blood pressure and vessel recanalization in the first
hours after ischemic stroke. Stroke 2005;36(2):264–8.
[28] Christensen H, Meden P, Overgaard K, et al. The course of blood pressure in acute
stroke is related to the severity of the neurological deficits. Acta Neurol Scand 2002;
106(3):142–7.
[29] Semplicini A, Maresca A, Boscolo G, et al. Hypertension in acute ischemic stroke: a compen-
satory mechanism or an additional damaging factor? Arch Intern Med 2003;163(2):211–6.
[30] Leonardi-Bee J, Bath PM, Phillips SJ, et al. Blood pressure and clinical outcomes in the
International Stroke Trial. Stroke 2002;33(5):1315–20.
[31] Potter J, Robinson T, Ford G, et al. CHHIPS (Controlling Hypertension and Hypotension
Immediately Post-Stroke) pilot trial: rationale and design. J Hypertens 2005;23(3):649–55.
582 URRUTIA & WITYK

[32] 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(2):257–65.
[33] Schrader J, Luders S, Kulschewski A, et al. The ACCESS study: evaluation of Acute
Candesartan Cilexetil Therapy in Stroke Survivors. Stroke 2003;34(7):1699–703.
[34] Bath PM, Pathansali R, Iddenden R, et al. The effect of transdermal glyceryl trinitrate,
a nitric oxide donor, on blood pressure and platelet function in acute stroke. Cerebrovasc
Dis 2001;11(3):265–72.
[35] Ahmed N, Nasman P, Wahlgren NG. Effect of intravenous nimodipine on blood pressure
and outcome after acute stroke. Stroke 2000;31(6):1250–5.
[36] Lisk DR, Grotta JC, Lamki LM, et al. Should hypertension be treated after acute stroke? A
randomized controlled trial using single photon emission computed tomography. Arch
Neurol 1993;50(8):855–62.
[37] Blood Pressure in Acute Stroke Collaboration (BASC). Interventions for deliberately
altering blood pressure in acute stroke (Cochrane Review). Cochrane Database Syst Rev
2001;(3). Available at: http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/
CD000039/frame.html. Accessed May 13, 2006.
[38] Graham DI. Ischaemic brain damage of cerebral perfusion failure type after treatment of
severe hypertension. Br Med J 1975;4(5999):739.
[39] Fischberg GM, Lozano E, Rajamani K, et al. Stroke precipitated by moderate blood
pressure reduction. J Emerg Med 2000;19(4):339–46.
[40] Wahlgren NG, MacMahon DG, Keyser JD, et al, for the INWEST Study Group. The
Intravenous Nimodipine West European Trial of Nimodipine in the Treatment of Acute
Ischemic Stroke. Cerebrovasc Dis 1994;4:204–10.
[41] Willmot M, Ghadami A, Whysall B, et al. Transdermal glyceryl trinitrate lowers blood pres-
sure and maintains cerebral blood flow in recent stroke. Hypertension 2006;47(6):1209–15.
[42] Elewa HF, Kozak A, Johnson MH, et al. Blood pressure lowering after experimental
cerebral ischemia provides neurovascular protection. J Hypertens 2007;25(4):855–9.
[43] Sigurdsson ST, Strandgaard S. Blood pressure lowering in acute ischaemic stroke: an update
on the role of angiotensin receptor blockers. J Hypertens 2007;25(4):743–5.
[44] Boutitie F, Oprisiu R, Achard JM, et al. Does a change in angiotensin II formation caused by
antihypertensive drugs affect the risk of stroke? A meta-analysis of trials according to treat-
ment with potentially different effects on angiotensin II. J Hypertens 2007;25(8):1543–53.
[45] Eveson DJ, Robinson TG, Potter JF. Lisinopril for the treatment of hypertension within the
first 24 hours of acute ischemic stroke and follow-up. Am J Hypertens 2007;20(3):270–7.
[46] Walters MR, Bolster A, Dyker AG, et al. Effect of perindopril on cerebral and renal perfu-
sion in stroke patients with carotid disease. Stroke 2001;32(2):473–8.
[47] Stroke Trials Registry. The Internet Stroke Center. 2007. Ref Type: Internet Communication.
[48] Shanbrom E, Levy L. The role of systemic blood pressure in cerebral circulation in carotid
and basilar artery thromboses. Am J Med 1957;23:197–204.
[49] Farhat SM, Schneider RC. Observations on the effect of systemic blood pressure on
intracranial circulation in patients with cerebrovascular insufficiency. J Neurosurg 1967;
27(5):441–5.
[50] Wise GR. Vasopressor-drug therapy for complications of cerebral arteriography. N Engl
J Med 1970;282(11):610–2.
[51] Wise G, Sutter R, Burkholder J. The treatment of brain ischemia with vasopressor drugs.
Stroke 1972;3(2):135–40.
[52] Agnoli A, Fieschi C, Bozzao L, et al. Autoregulation of cerebral blood flow. Studies during
drug-induced hypertension in normal subjects and in patients with cerebral vascular diseases.
Circulation 1968;38(4):800–12.
[53] Rordorf G, Cramer SC, Efird JT, et al. Pharmacological elevation of blood pressure in acute
stroke. Clinical effects and safety. Stroke 1997;28(11):2133–8.
[54] Rordorf G, Koroshetz WJ, Ezzeddine MA, et al. A pilot study of drug-induced hypertension
for treatment of acute stroke. Neurology 2001;56(9):1210–3.
 BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE 583

[55] Hillis AE, Barker PB, Beauchamp NJ, et al. MR perfusion imaging reveals regions of hypo-
perfusion associated with aphasia and neglect. Neurology 2000;55(6):782–8.
[56] Hillis AE, Wityk RJ, Tuffiash E, et al. Hypoperfusion of Wernicke’s area predicts severity of
semantic deficit in acute stroke. Ann Neurol 2001;50(5):561–6.
[57] Hillis AE, Barker PB, Beauchamp NJ, et al. Restoring blood pressure reperfused Wernicke’s
area and improved language. Neurology 2001;56(5):670–2.
[58] Hillis AE, Kane A, Tuffiash E, et al. Reperfusion of specific brain regions by raising blood pres-
sure restores selective language functions in subacute stroke. Brain Lang 2001;79(3):495–510.
[59] Hillis AE, Ulatowski JA, Barker PB, et al. A pilot randomized trial of induced blood pressure
elevation: effects on function and focal perfusion in acute and subacute stroke. Cerebrovasc
Dis 2003;16(3):236–46.
[60] Hillis AE, Wityk RJ, Beauchamp NJ, et al. Perfusion-weighted MRI as a marker of response
to treatment in acute and subacute stroke. Neuroradiology 2004;46(1):31–9.
[61] Marzan AS, Hungerbuhler HJ, Studer A, et al. Feasibility and safety of norepinephrine-
induced arterial hypertension in acute ischemic stroke. Neurology 2004;62(7):1193–5.
[62] Koenig MA, Geocadin RG, de GM, et al. Safety of induced hypertension therapy in patients
with acute ischemic stroke. Neurocrit Care 2006;4(1):3–7.
[63] Saxena R, Wijnhoud AD, Koudstaal PJ, et al. Induced elevation of blood pressure in the
acute phase of ischemic stroke in humans. Stroke 2000;31(2):546–8.
[64] Campbell MS, Grotta JC, Gomez CR, et al. NeuroFlo Investigators. Abstract presented at
the 29th International Stroke Conference, San Diego, CA, 2004. Stroke 2004;35:291.
[65] Qureshi AI, Mohammad YM, Yahia AM, et al. A prospective multicenter study to evaluate
the feasibility and safety of aggressive antihypertensive treatment in patients with acute
intracerebral hemorrhage. J Intensive Care Med 2005;20(1):34–42.
[66] Hallevy C, Ifergane G, Kordysh E, et al. Spontaneous supratentorial intracerebral hemor-
rhage. Criteria for short-term functional outcome prediction. J Neurol 2002;249(12):1704–9.
[67] Kazui S, Naritomi H, Yamamoto H, et al. Enlargement of spontaneous intracerebral
hemorrhage. Incidence and time course. Stroke 1996;27(10):1783–7.
[68] Ohwaki K, Yano E, Nagashima H, et al. Blood pressure management in acute intracerebral
hemorrhage: relationship between elevated blood pressure and hematoma enlargement.
Stroke 2004;35(6):1364–7.
[69] Aronowski J, Hall CE. New horizons for primary intracerebral hemorrhage treatment:
experience from preclinical studies. Neurol Res 2005;27(3):268–79.
[70] Powers WJ, Zazulia AR. The use of positron emission tomography in cerebrovascular
disease. Neuroimaging Clin N Am 2003;13(4):741–58.
[71] Powers WJ, Zazulia AR, Videen TO, et al. Autoregulation of cerebral blood flow surround-
ing acute (6 to 22 hours) intracerebral hemorrhage. Neurology 2001;57(1):18–24.
[72] Zazulia AR, Diringer MN, Videen TO, et al. Hypoperfusion without ischemia surrounding
acute intracerebral hemorrhage. J Cereb Blood Flow Metab 2001;21(7):804–10.
[73] Qureshi AI, Hanel RA, Kirmani JF, et al. Cerebral blood flow changes associated with
intracerebral hemorrhage. Neurosurg Clin N Am 2002;13(3):355–70.
[74] Ropper AH, Gress DR, Diringer MN, et al. Neurological and neurosurgical intensive care.
4th edition. Philadelphia: Lippincot Williams & Wilkins; 2003. p. 231–42.
[75] Ohkuma H, Tsurutani H, Suzuki S. Incidence and significance of early aneurysmal rebleed-
ing before neurosurgical or neurological management. Stroke 2001;32(5):1176–80.
[76] Rose JC, Mayer SA. Optimizing blood pressure in neurological emergencies. Neurocrit Care
2004;1(3):287–99.
[77] Fujii Y, Takeuchi S, Sasaki O, et al. Ultra-early rebleeding in spontaneous subarachnoid
hemorrhage. J Neurosurg 1996;84(1):35–42.
[78] Claassen J, Vu A, Kreiter KT, et al. Effect of acute physiologic derangements on outcome
after subarachnoid hemorrhage. Crit Care Med 2004;32(3):832–8.
[79] Wijdicks EF, Vermeulen M, Murray GD, et al. The effects of treating hypertension following
aneurysmal subarachnoid hemorrhage. Clin Neurol Neurosurg 1990;92(2):111–7.