Journal of Human Hypertension (2009) 23, 559–569
& 2009 Macmillan Publishers Limited All rights reserved 0950-9240/09 $32.00
REVIEW
Blood pressure management in acute
stroke
MT Mullen, JS McKinney and SE Kasner
Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
Blood pressure (BP) is the major determinant of cerebral
perfusion yet blood pressure management in acute
stroke is complex and controversial. Optimized blood
pressure management may improve outcomes in pa-
tients with ischemic and hemorrhagic stroke although
the available data are conflicting and target BP goals are
Keywords: blood pressure; stroke; infarct; intracerebral hemorrhage
Introduction
Blood pressure (BP) is the major determinant of
cerebral perfusion, yet BP management in acute
stroke is complex and controversial. Stroke is the
third leading cause of death and a leading cause of
disability in the United States, with an annual
incidence of 700–800 000 cases per year.1–3 Stroke is
extremely expensive and is estimated to cost the
United States 65.5 billion dollars in 2008.2 The
global burden of stroke is even more staggering, with
an estimated incidence of 15 million cases per year.4
Five million of these patients die and another five
million are left permanently disabled.4 Optimized
BP management may improve outcomes in these
patients. Unfortunately, the data are conflicting and
target BP goals are not well defined.
Elevated BP is incredibly common during an
acute stroke, with 60–80% of patients having a
systolic blood pressure (SBP) 4140 mm Hg.5–8 In
20% of these patients this represents the first
diagnosis of hypertension.9 The acute hypertensive
response is partially due to changes in cerebral
perfusion, and may serve to increase blood flow to
ischaemic portions of the brain. There are many
other contributing factors, including undiagnosed
hypertension, inadequately treated hypertension,
damage to autonomic centres in the brain, stress
response and elevated intracranial pressure (ICP).10
This early elevation in BP spontaneously decreases
over days, with an average decline of 20/10 mm Hg
Correspondence: Dr SE Kasner, Department of Neurology,
University of Pennsylvania Medical Center, 3 West Gates Build-
ing, 3400 Spruce Street, Philadelphia, PA 19104, USA.
E-mail: kasner@mail.med.upenn.edu
Received 23 October 2008; revised 11 December 2008; accepted
12 December 2008; published online 15 January 2009
www.nature.com/jhh
not well defined. We review the current literature,
published guidelines, and emerging research on this
important topic. Additionally, the treatment algorithm
which we employ is discussed.
Journal of Human Hypertension (2009) 23, 559–569;
doi:10.1038/jhh.2008.164; published online 15 January 2009
by day 10.7,11 This spontaneous resolution appears
to be facilitated by arterial recanalization.12
Unfortunately, increased cerebral perfusion comes
at a cost. Increased blood flow through infarcted
tissue may worsen cerebral oedema and increase the
risk of haemorrhagic transformation. A meta-analy-
sis incorporating over 10 000 ischaemic and haemor-
rhagic stroke patients showed that elevated SBP,
diastolic blood pressure (DBP) and mean arterial
pressure (MAP) were all associated with worse
outcome.8 Clearly, there is a fine balance between
optimal perfusion and adverse events. We will
review the pathophysiology of cerebral perfusion,
the management of BP after acute stroke, published
treatment guidelines and emerging clinical data.
Pathophysiology
Cerebral perfusion pressure (CPP) is equal to MAP
minus ICP. Under normal circumstances, ICP is
negligible and therefore CPP is determined almost
entirely by MAP. Cerebral blood flow (CBF) is a
function of CPP and cerebrovascular resistance
(CVR), where CBF ¼ CPP/CVR. Although MAP may
fluctuate dramatically over time, CBF is normally
held constant at 50 ml/100 g brain tissue per
minute.13 CBF is maintained by adjusting CVR. This
is cerebral autoregulation; it is depicted graphically
in Figure 1a.
Autoregulation is the incompletely understood
ability of the brain’s resistance vessels to dilate or
constrict in response to changes in MAP. This
vasomotor response occurs primarily at the level of
the arteriole. Autoregulation maintains a constant
CBF between an MAP of 60–150 mm Hg.14–16 As
MAP falls, arteriolar dilation occurs to decrease CVR
and maintain CBF. When these vessels become
 Blood pressure management in acute stroke
MT Mullen et al
560

Figure 1 Autoregulation of cerebral blood flow (CBF). (a) Under

normal conditions, CBF is held constant at 50 ml/100 g brain
tissue per minute despite fluctuations in mean arterial pressure
(MAP) from 60 to 150 mm Hg. This is accomplished by constric-
tion and dilation of cerebral arterioles. When MAP falls below
60 mm Hg, CBF falls and brain tissue becomes ischaemic. When
MAP rises above 150 mm Hg, CBF rises, there is cerebral oedema,
elevated intracranial pressure (ICP) and intracranial haemorrhage.
(b) With chronic hypertension, the normal autoregulatory curve is
shifted to the right, making the brain intolerant of relative Figure 2 This figure represents a patient with a complete middle
hypotension. (c) In acute stroke, autoregulation is impaired, and cerebral artery syndrome. The infarcted core is tissue that has
the relationship between CBF and MAP becomes linear. been irreversibly damaged and cannot be salvaged. The ischaemic
penumbra is tissue that may be salvaged by restoring cerebral
perfusion and blood flow.

maximally dilated, oxygen extraction fraction (OEF)

may increase to satisfy high cerebral metabolic
demands. If MAP continues to fall after vessel
dilation and OEF have been maximized, metabolic
needs are not met and brain tissue becomes
ischaemic.
When MAP is increased, arterioles constrict to
raise CVR and maintain a constant CBF. However,
as MAP surpasses the upper threshold of auto-
regulation, arterioles are forced open by high
intra-luminal pressures. Forced dilation causes
disruption of the blood–brain barrier, vasogenic
oedema, increased ICP and haemorrhage. In patients
with chronic hypertension, the entire autoregulatory Figure 3 Tissue at risk in acute stroke progresses from reversible
curve is shifted to the right (Figure 1b).15 Constantly ischaemia to permanent infarction over time. The speed of
increased CVR leads to hypertrophy and stiffening progression depends on the severity of cerebral blood flow
of vessel walls. This makes the brain intolerant of (CBF) reduction.
relative hypotension and causes decreased CBF at
MAPs that would otherwise be well tolerated.
In the setting of an acute stroke, the ability to
adjust CVR is decreased and autoregulation is surrounding area that is not yet irreversibly
impaired. This impairment is most prominent with- damaged, the ischaemic penumbra (Figure 2). If
in and around the stroke, but may be present normal CBF is restored to the penumbra before the
globally.17,18 As a result, the relationship between tissue dies, it may regain function. The time window
CBF and CPP becomes more linear (Figure 1c). for saving this tissue at risk depends on how
Changes in MAP may cause dramatic changes in severely CBF is impaired (Figure 3). The primary
CBF. This puts the brain at risk for further infarction goal of stroke care is to preserve as much of the
when MAP falls and cerebral oedema, elevated ICP penumbra as possible, which means optimizing BP
and haemorrhage when MAP rises. and CBF.
The relationship between BP and outcome after
ischaemic stroke is complicated. Elevated BP may
be a marker for stroke severity.19 It can also serve as a
Ischaemic stroke prognostic factor. Studies have shown an associa-
Ischaemic stroke is due to the abrupt loss of CBF tion between low BP and poor outcome, as well as
to a portion of the brain. At presentation, clinic an association between elevated BP and poor
deficits in acute ischaemic stroke represent both an outcome.8,20–22 BP variability is another important
infracted core, which has already died, and a consideration that may impact outcome.11,23,24 These

Journal of Human Hypertension


seemingly contradictory findings can be explained
by a U-shaped relationship between BP and out-
come after ischaemic stroke.5,25 This relationship is
expected given the physiology of CBF and the loss of
autoregulation that accompanies acute stroke.
There is a small range of BP that is optimal for
the penumbra; above and below this range further
damage ensues. The International Stroke Trial (IST)
demonstrated this in over 17 000 patients. There
was a 17.9% increase in early death for every
10 mm Hg rise in SBP above 150 mm Hg and a
3.8% increase for every 10 mm Hg drop in SBP
below 150 mm Hg.5 A smaller study found a similar
U-shaped relationship between BP and outcome.25
However, in this study the inflection point was
higher, and SBP above and below 180 mm Hg were
associated with neurologic deterioration and worse
outcome. The optimal BP is not known, and
may differ among individuals and across stroke
subtypes.26
Evidence against treating hypertension in acute
ischaemic stroke
Low BP decreases cerebral perfusion and may
potentiate infarction in the ischaemic penumbra.
SBP may drop by as much as 28% in the first 24 h
after acute stroke, independent of treatment, and
this decline is associated with poor outcome.27
There are a multitude of case reports with
patients experiencing neurologic deterioration after
moderate BP reduction.28
Several clinical trials have found an association
between antihypertensive therapy in acute stroke
and worse outcome. The Beta-Blocker Stroke Trial
looked at low dose b-blockade in acute stroke.
Patients presenting within 48 h were randomized
to placebo, atenolol 50 mg daily or slow release
propranolol 80 mg daily.29 The trial was stopped
early because of an increased risk of death in the
treatment groups. The Intravenous Nimodipine
West European Stroke Trial (INWEST) showed that
treatment with nimodipine was associated with
decreased BP and increased chance of death or
dependency.30 This study had a very high rate of
hypotension, with 60% of patients having one or
more drop in DBP o60 mm Hg. This undoubtedly
contributed to the effect on outcome. A meta-
analysis of calcium channel blockers in acute stroke
evaluating 29 trials and 7665 patients found that
among published trials there was no effect of
treatment.31 Subgroup analysis of methodologically
sound and unpublished trials (identified by contacts
with investigators and pharmaceutical companies)
found a negative effect, with worse outcomes in the
treatment group.31 A 2000 Cochrane Review using
data from 32 trials encompassing 5368 patients
found that b-blockers and calcium channel blockers
appeared to increase disability and case fatality.
However, they noted significant variability in base-
line BP between studies and concluded that there
Blood pressure management in acute stroke
MT Mullen et al
561
was insufficient evidence to reliably evaluate the
effect of vasoactive drugs.32
Evidence in favour of treating hypertension
in acute ischaemic stroke
Elevated BP may increase cerebral oedema after an
acute infarction and raise the risk of haemorrhagic
conversion.33–35 Antihypertensive medications may
limit this process. Animal data suggest that BP
reduction may reduce infarct size.36 In addition to
their haemodynamic effects, antihypertensive med-
ications may have class-specific effects that further
benefit stroke patients. It has been postulated
that angiotensin receptor antagonism may increase
CBF and vasomotor reactivity.36–38 Antihypertensive
therapies have been used in acute cardiac and renal
disease for tissue protection, and these agents may
have neuroprotective properties as well.
The Acute Candesartan Cilexetil Evaluation in
Stroke Survivors (ACCESS) study was a double-
blinded, placebo-controlled evaluation of candesartan
in acute stroke.39 Enrolled patients had to have two
BP readings with a mean SBP X200 mm Hg and/or a
DBP X110 mm Hg 6–24 h after admission or SBP
X180 mm Hg and/or DBP X105 mm Hg 24–36 h after
admission. Patients with internal carotid artery
stenosis 470% were excluded. There was no
difference in the primary end point of disability at
90 days, but 12 month mortality and the incidence
of vascular events were significantly lower in the
treatment group, with an odds ratio of 0.475 (95% CI
0.252–0.895).39 The authors proposed that cande-
sartan facilitated vascular growth and remodelling,
thus counterbalancing the haemodynamic effects
of lower BP. These results must be interpreted
cautiously. The mean BP in ACCESS was signifi-
cantly higher than in INWEST (SBP 196 versus
162 mm Hg).30,39 This difference may account for
the difference in outcome. Also, a large portion of
the benefit in ACCESS was due to lower rates of
cardiovascular events in the treatment group rather
than neurologic recovery.
A smaller study of lisinopril, given within 24 h of
acute ischaemic stroke, showed a significant reduc-
tion in BP at 4 h, but no difference in functional
outcome at 90 days.40 A meta-analysis of two studies
evaluating transdermal nitroglycerin in a total of
127 patients also showed a statistically significant
reduction in BP with no difference in outcome.41
Post hoc analysis of the National Institute of
Neurological Disorders and Stroke (NINDS) recom-
binant tissue plasminogen activator (rt-PA) treat-
ment trial showed no significant difference between
placebo-treated patients who received antihyperten-
sives and those who did not.42 These trials together
imply that antihypertensive therapy may be safe in
the setting of acute stroke, but do not show a benefit
to the patient. Timing is another critical considera-
tion that has not been addressed in these, or any
other, trials. There may be a window of time acutely
Journal of Human Hypertension
 Blood pressure management in acute stroke
MT Mullen et al
562
when BP reduction exacerbates cell death in the
penumbra. There may also be intervals when drug-
specific neuroprotective and/or vascular growth
promoting properties can be exploited. There are
unfortunately no good clinical data to guide timing
of early antihypertensive medication administration
after acute stroke.
Blood pressure and thrombolysis
Patients who receive intravenous or intra-arterial
thrombolysis are at increased risk for haemorrhagic
conversion. Tight BP control is very important in
these patients. In the Australian streptokinase
study, SBP 4165 mm Hg was associated with a 25%
increased risk of major intracranial haemorrhage.43
In the second European Cooperative Acute Stroke
Study, SBP and systolic variability were associated
with an increased risk of petechial haemorrhage
after thrombolysis.24 The NINDS rt-PA stroke treat-
ment trial recommended a BP of p185/110 mm Hg
before treatment and p180/105 mm Hg after treat-
ment.44 In the trial, elevated BP was associated with
an increased risk of symptomatic haemorrhage.45
Failure to adhere to these guidelines in routine
clinical practice has also been shown to increase the
rate of symptomatic haemorrhage.46–48
It has been suggested that patients who require
aggressive measures to maintain a BP lower than 185/
110 mm Hg should not receive thrombolysis. How-
ever, there is growing evidence to support the use of
thrombolytics in these patients. Martin-Shild et al.49
conducted a retrospective cohort study of 178
patients with acute ischaemic stroke who were
treated with rt-PA. Fifty of these patients required
BP lowering, 24 of whom received intravenous
nicardipine. There was no difference in outcome in
those who required treatment compared to those who
did not. When comparing those treated with intra-
venous nicardipine to those treated with labetalol
alone, there was no significant difference between
groups. Because recanalization by rt-PA may cause a
spontaneous decline in BP, patients require close
monitoring and medication titration to ensure their
BP does not fall to an unacceptable level.12
Induced hypertension
In acute ischaemic stroke, low BP is associated with
worse outcomes.5,25 Severe hypotension is rare after
stroke. In the IST, only 5% of the 17 398 patients had
an SBP o120 mm Hg.5,25 If an acute stroke patient is
hypotensive, clinicians should search for an under-
lying aetiology, including volume depletion, myo-
cardial infarction, cardiac arrhythmia, blood loss
and aortic dissection. If any of these entities are
found, they must be treated rapidly. If there is no
correctable cause for hypotension, the patient fails
to respond to volume resuscitation, and/or there is
fluctuation in neurologic symptoms, induced
hypertension may be considered.
Journal of Human Hypertension
Pharmacologically induced hypertension for
acute ischaemic stroke has been used since
1950s.50 More recently, studies have shown that
induced hypertension may increase CBF and restore
perfusion to the penumbra.18,51 Small studies have
demonstrated clinical improvement with induced
hypertension as late as 9 days after stroke onset.52
Koenig et al.53 conducted a clinical trial of induced
hypertension in 100 patients with acute ischaemic
stroke and diffusion–perfusion mismatch on mag-
netic resonance imaging (MRI), which is believed
to represent viable penumbral tissue. Forty-six
patients were treated with induced hypertension
and 54 received standard therapy. The stated goal
was to raise BP by 10–20%. There was a trend
towards higher MAP in the induced hypertension
group with a statistically significant difference at
day 3 (103±14 versus 96±13 mm Hg). The induced
hypertension group had an increased frequency of
carotid stenosis and a larger volume of restricted
perfusion on baseline MRI. There was a non-
significant reduction in stroke severity (three point
median decrease on the National Institutes of Health
Stroke Scale) in the induced hypertension group.
Adverse events were similar between groups. Pa-
tients treated with induced hypertension were more
likely to be admitted to the neurologic intensive care
unit and had a longer length of stay by an average of
4 days. Mistri and colleagues performed a systemic
review of induced hypertension, including 12
studies and 319 patients. Included studies varied
considerably with respect to inclusion/exclusion
criteria, duration/method of induced hypertension
and outcome measures. As a result, formal meta-
analysis was not possible. The authors concluded
that although induced hypertension appears safe,
larger scale clinical trials are needed to address this
issue.54
Current guidelines
Current treatment guidelines, published by the
European Stroke Organization (ESO) and American
Heart Association (AHA), generally do not recom-
mend antihypertensive therapy in acute stroke.
These recommendations acknowledge the conflict-
ing and incomplete nature of the evidence. Both the
ESO and the AHA recommend BP lowering to below
185/110 mm Hg in patients eligible for thrombolysis
(Evidence Class I Level B).55,56 After rt-PA, BP
should be maintained below 180/105 mm Hg.55,56
Labetalol, nitropaste and nicardipine are all first-
line options in these patients, and the use of
intravenous nicardipine is not a contraindication
to rt-PA.56 For patients not undergoing thrombolysis,
cautious BP lowering is recommended when SBP
4220 mm Hg and/or DBP 4120 mm Hg (Evidence
Class I Level C).55,56 The AHA guidelines conclude
that there is no sufficient evidence to recommend a
specific agent, but the goal should be to reduce BP
by no more than 15% during the first 24 h.

Hypotension after acute stroke should prompt
the clinician to search for and treat the under-
lying aetiology, as noted above. Initial treatment
should be with volume expansion as dehydration
is common in acute ischaemic stroke.55,56 The
AHA guidelines specifically address induced hy-
pertension and conclude that it should be
reserved for ‘exceptional cases’; it is not recom-
mended outside of clinical trials (Evidence Class III
Level B).
For patients with a history of hypertension, there
are almost no data on management of their pre-
existing antihypertensive medications. European
guidelines do not address this issue at all. The
AHA guidelines recommend restarting home med-
ications at 24 h if the patient is stable. The seventh
report of the Joint National Committee on the
Detection, Evaluation and Treatment of High Blood
Pressure recommends that BP be maintained at
approximately 160/100 mm Hg until the patient is
neurologically stable.57
Emerging clinical data
Both the ESO and AHA guidelines comment on the
need for large, well-designed trials to guide BP
management in acute ischaemic stroke. The Con-
trolling Hypertension and Hypotension Immediately
Post-Stroke study is a multi-centre, placebo-con-
trolled, double-blinded study enrolling patients
with acute ischaemic strokes. Hypertensive patients,
defined by an SBP 4160 mm Hg, enrolled within
36 h are randomized to treatment with lisinopril,
labetalol or placebo.58 Hypotensive patients, defined
by an SBP o140 mm Hg, enrolled within 12 h are
randomized to treatment with phenylephrine or
placebo to a target SBP of 150 mm Hg. The primary
outcome measure is death and dependency at day
14. Pilot data from the hypertension arm of the
study, with 179 patients, was presented at the 2008
International Stroke Conference. Patients in the
placebo arm were 2.2 times more likely to be dead
at 90 days.59 A larger, phase III trial is required to
confirm these interesting early results and will
hopefully help to define the optimal BP for patients
with acute ischaemic stroke.
Another important ongoing study is the Continue
Or Stop Post-Stroke Antihypertensives Collabora-
tive Study.60 This study is designed to evaluate the
optimal management of pre-existing antihyper-
tensives. In the study patients will be randomized
to either continue or discontinue pre-existing anti-
hypertensives. The primary outcome will be death
and disability at 2 weeks and 6 months. The
Scandinavian Candesartan Acute Stroke Trial is a
larger trial of candesartan in acute stroke, with a goal
of 2500 patients, and it may confirm the findings of
ACCESS.61 Finally, the Efficacy of Nitric Oxide in
Stroke trial is looking at the effects of transdermal
nitroglycerin as well as discontinuing pre-existing
antihypertensives on outcome.61
Blood pressure management in acute stroke
MT Mullen et al
563
These studies will hopefully add greatly to our
ability to manage BP in acute ischaemic stroke,
answering important questions about whether hyper-
tension should be treated, what agents to use, when
to start them and what to do with pre-existing
antihypertensive drugs.
Intracerebral haemorrhage
Spontaneous intracerebral haemorrhage (ICH) ac-
counts for 10–15% of all strokes with an estimated
worldwide incidence of 10–20 cases per 100 000
population.62,63 This is a highly morbid disease with
an estimated 1-year mortality of 38%.62 The aetio-
logy of spontaneous ICH is divided into primary and
secondary causes. Primary ICH is most often the
sequela of chronic hypertension or cerebral amyloid
angiopathy, which together account for 78–88% of
cases.64 Secondary ICH may result from disorders
of coagulation, vascular malformations or neo-
plasms. Elevations in SBP greater than 140 mm Hg
are reported in the majority (75%) of patients with
acute spontaneous ICH.6 Elevations in BP in acute
ICH have been correlated with poor outcomes in
some, but not all studies.8,65–67 Treatment of elevated
BP in the setting of spontaneous primary ICH
remains controversial because there are unclear data
to guide therapeutic decision-making.
Evidence against treating hypertension in acute ICH
Arguments against lowering elevated BP in acute
ICH are based on the theoretical risk that lowering
BP will lower CPP and induce ischaemia in a zone
of hypoperfused tissue surrounding the haemato-
ma.68 The CBF in normotensive and chronically
hypertensive people is the same. However, chronic
hypertensive changes in the vessel wall limit its
ability to vasodilate in response to hypotension so
that CBF falls and tissue becomes ischaemic. A few
animal studies have demonstrated a global decrease
in CBF after ICH, with the lowest flow reported in
the area adjacent to the haematoma.69,70 Kidwell
et al.71 reported MRI apparent diffusion coefficient
data that indicated there may be a perihaematomal
area of ischaemia, similar to the penumbra of
ischaemic stroke. A retrospective study showed an
increase in mortality in ICH patients that had a rapid
decline in BP in the first 24 h.72 These studies
suggest that aggressive BP lowering could pose a risk
of perihaematomal infarction or other major adverse
events and should be avoided.
Evidence for aggressive BP management in acute
spontaneous ICH
The primary reason for early and aggressive BP
control in patients with acute ICH is to reduce
the risk of haemorrhagic expansion. Approximately
38% of patients with acute ICH have haemorrhagic
expansion within the first 24 h, 20–25% within the
Journal of Human Hypertension
 Blood pressure management in acute stroke
MT Mullen et al
564
first hour of presentation.73,74 Studies have shown a
relationship between BP at presentation and hae-
morrhagic expansion.75,76 Whether hypertension is
the cause of haematoma growth or the effect of
elevated ICP remains unclear. Although intuitively
beneficial, reducing or preventing haemorrhagic
expansion has not been clearly associated with
acute hypertension or shown to affect clinical
outcomes that may be affected by a myriad of
potential confounders including cerebral oedema,
elevated ICP or systemic medical complications.
Despite early evidence to the contrary, multiple
neuroimaging studies have not demonstrated
an area of ischaemia surrounding the haematoma.
Using positron emission tomography (PET), investi-
gators have shown no change in CBF, cerebral
metabolic rate for oxygen or OEF both in dogs and
in humans with ICH.77–79 This correlates with MRI
studies that have shown no perihaematomal
ischaemia.80–82 One small prospective study of
14 ICH patients showed that a 15% pharmaco-
logic reduction in MAP (mean 142±10 to
119±11 mm Hg) using nicardipine or labetalol did
not reduce global or regional perihaematomal CBF
measured with PET and 15O-water.83
In an observational cohort of 98 patients with ICH,
there was no relationship between BP or heart rate
parameters, individually or in combination, with
haematoma growth.84 In a trial of recombinant factor
VIIa for ICH involving 382 patients with CT scans
within 3 h and at 24 h after symptom onset, there
was also no relationship between baseline BP and
haemorrhagic expansion.85
The INTERACT (Intensive Blood Pressure Reduc-
tion in Acute Cerebral Hemorrhage) trial rando-
mized 404 patients with spontaneous ICH and
hypertension (SBP ¼ 150–220 mm Hg) within 6 h of
presentation to either ‘guideline-based’ therapy
(target SBP ¼ 180 mm Hg) or ‘early intensive’ treat-
ment (target SBP ¼ 140 mm Hg).86 There was a sig-
nificant reduction in haematoma growth from 36.3%
in the guideline group to 13.7% in the intensive
group (difference 22.6%, 95% CI 0.6–44.5%;
P ¼ 0.04) at 24 h. This reduction was slightly
dampened when it was corrected for initial haema-
toma volume; the absolute risk reduction for
haematoma expansion 433% or 12.5 ml was de-
creased from 23% in the guideline group to 15% in
the intensive treatment arm (difference 8, 95% CI
1.0–17%; P ¼ 0.05). However, intensive BP lowering
did not alter the chances of having an adverse event,
and there was no significant change in the second-
ary end points, including death or dependency.
Current guidelines
Current treatment guidelines, published by the AHA
and the European Stroke Initiative (EUSI), recom-
mend individualized treatment for acute elevations
of BP in patients with ICH based on underlying
factors such as chronic baseline hypertension, ICP,
Journal of Human Hypertension
patient age, aetiology and timing of the haemor-
rhage.87,88 The current recommendations were based
on the available incomplete and conflicting data
from animal models, small uncontrolled trials and
the traumatic brain injury literature.
The 2007 AHA guidelines for management of
spontaneous ICH in adults suggest the following
treatment goals for elevated BP (Evidence Class
IIb Level C).87 Aggressive reduction of BP with
continuous infusion of intravenous (i.v.) antihyper-
tensive medications should be considered for an
SBP 4200 mm Hg or MAP 4150 mm Hg. If SBP
4180 mm Hg or MAP 4130 mm Hg and there is
clinical suspicion for elevated ICP, then anti-
hypertensive treatment with either continuous or
intermittent bolus i.v. doses to maintain CPP
60–80 mm Hg is advised. If there is no clinical
suspicion of raised ICP and SBP 4180 mm Hg or
MAP 4130 mm Hg, then BP may be lowered to a
goal MAP of 110 mm Hg or BP of 160/90 mm Hg
using continuous or bolus i.v. medication.
The 2006 EUSI guidelines for managing sponta-
neous ICH suggest the following treatment goals for
elevated BP.88 In patients with known or suspected
chronic hypertension, an upper BP limit of 180/
105 mm Hg should be treated to a target of 160/
100 mm Hg or MAP of 120 mm Hg using short acting
i.v. antihypertensive medications. In patients with
no prior history and no clinical suspicion of chronic
hypertension, an upper BP limit of 160/90 mm Hg
should be used with treatment goals of 150/
90 mm Hg or an MAP of 110 mm Hg. The guidelines
further recommend adjusting these treatment para-
meters to keep CPP 60–70 mm Hg in patients with
elevated ICP.
Both the AHA and EUSI guidelines for manage-
ment of patients with spontaneous ICH recommend
initiating antihypertensive therapy in an intensive
care or dedicated stroke unit with continuous intra-
arterial pressure monitoring if available (Evidence
Class I Level B). There are several intravenous drugs
in either bolus or continuous infusion preparations
recommended in the AHA and EUSI guidelines for
the treatment of elevated BP in ICH patients.87–89
These medications are detailed in Table 1.
Emerging clinical data
The available treatment guidelines are limited
because they were published before the completion
of two relatively large randomized trials, INTERACT
(described above) and ATACH (Antihypertensive
Treatment of Acute Cerebral Hemorrhage).
The ATACH pilot trial was designed to assess the
tolerability of goal directed BP therapy in ICH
patients presenting within 6 h of their symptoms
with SBP 4200 mm Hg.90 A total of 58 patients were
enrolled in ATACH and randomized to treatment
with an i.v. nicardipine infusion for 24 h targeted to
one of three different predefined SBP goals (170–
200, 140–170 or 110–140 mm Hg). The results of
 Blood pressure management in acute stroke
MT Mullen et al
565
Table 1 Antihypertensive medications for blood pressure control in acute stroke

Drug Infusion dose Bolus dose Onset Duration Comments

of action of action

Vasodilators
Nicardipine 5–15 mg h1 infusion NA 1–5 min 3–6 h Reflex tachycardia
Enalaprilat NA 0.625–5 mg q 6 h 5–15 min 6h Caution with impaired renal function
Hydralazine 1.5–5 mg kg1  min 5–20 mg q 30 min 15–30 min 3–4 h Drug-induced lupus syndrome,
serum sickness-like syndrome
Nitroprusside 0.1–10 mg kg1  min NA Immediate 2–3 min May cause or exacerbate high ICP,
cyanide toxicity with prolonged use
Nitroglycerine 20–400 mg min1 NA 1–2 min 3–5 min May cause or exacerbate high ICP,
methaemoglobinaemia
Fenoldopam 0.1–0.3 mg kg1  min NA 15 min 10–20 min Caution in hypokalaemia

Anti-adrenergic
Labetalol 2 mg min1 5–20 mg q 15 min 5–10 min 2–12 h Caution in reactive airway disease,
congestive heart failure
Urapadil 5–40 mg h1 12.5–25 mg q 15 min 3–5 min 4–6 h Caution in ischaemic coronary disease
Esmolol 25–350 mg kg1  min NA Immediate o15 min Caution in congestive heart failure

Diuretic
Furosemide NA 20–80 mg q 1 h 2–5 min 2–3 h Caution in hypokalaemia

Abbreviations: ICP, intracranial pressure; q, every.

ATACH were presented at the 2008 International
Stroke Conference but have only been published in
abstract form.91 There were no significant differ-
ences in safety end points or in-hospital mortality
between the three treatment arms. The presenters
concluded that aggressive SBP control to a goal of
110–140 mm Hg in the first 24 h following an ICH is
safe, well tolerated and has a low risk of haematoma
expansion, neurologic worsening or in-hospital
mortality.
The current evidence is leading towards early,
aggressive management of elevated BP in the setting
of acute ICH. This strategy seems to prevent ICH
expansion, though has not been proven to improve
clinical outcomes. Though not perfect, the current
guidelines provide a good starting place for devel-
oping treatment paradigms for hypertension in acute
ICH. The recent data provided by the INTERACT
and ATACH trials indicate that it may be safe to
aggressively lower SBP below 140 mm Hg in these
patients.86,91 INTERACT 2 is now recruiting patients
and ATACH 2 is being planned. INTERACT 2 plans
to enrol 2800 patients with the primary outcome
being a composite of death and dependency at 3
months. These larger phase III studies will be
designed to better demonstrate whether aggressive
BP control can improve clinical outcomes.
Conclusions
Decisions about the management of hypertension
after stroke are limited by a lack of high-level
evidence from clinical trials. In both ischaemic
and haemorrhagic stroke, the optimum BP range in
the first hours to days is not known. It is not clear
when oral agents should be started and which
agents should be first-line drugs. Whether pre-
existing antihypertensives should be continued is
not known. Published practice guidelines and our
recommendations (presented in Figure 4) are based
at least as much on pathophysiology as on the
available evidence.
In ischaemic stroke, the data consistently demon-
strate that elevated BP after thrombolysis is harmful.
We agree with published guidelines and recommend
that BP be less than 185/110 mm Hg before throm-
bolysis and 180/105 mm Hg for at least the first 24 h
after thrombolysis. In the absence of thrombolysis,
we agree with the AHA guidelines and prefer to
withhold treatment unless SBP 4220 mm Hg or DBP
4120 mm Hg. The AHA guidelines do not comment
on MAP, but we recommend treatment if MAP
4140 mm Hg. We initially treat with short acting i.v.
agents such as labetalol, enalaprilat or nicardipine.
We transition to oral agents when the patient has
been neurologically stable for 24 h. We hold all
pre-existing antihypertensives acutely, except for
b-blockers that we continue at 50% of the home dose
to prevent rebound tachycardia. Induced hyperten-
sion is not used routinely, but may be reserved for
hypotension that is refractory to aggressive fluid
resuscitation and/or fluctuation in the neurologic
exam that is clearly dependent on haemodynamic
parameters.
For haemorrhagic stroke, we recommend an
aggressive approach, based on the data from INTER-
ACT and ATACH. If ICP is normal, SBP at presenta-
tion is o160/90 mm Hg, and there is no pre-existing
history of hypertension, we maintain BP o140/
80 mm Hg. If BP at presentation is 4160/90 mm Hg
or there is a history of hypertension, we maintain BP
o160/90 and/or MAP o110 mm Hg. If there is a
clinical concern for elevated ICP, a monitor is placed

Journal of Human Hypertension

 Blood pressure management in acute stroke
MT Mullen et al
566

Acute
Stroke

Ischemic or
Hemorrhagic?

Ischemic Hemorrhagic

Thrombolysis • If ICP is normal, BP

candidate?
Yes
• BP<185/110 mm Hg
prior to thrombolysis.
• Post-treatment maintain
BP<180/105 mm Hg.
• IV labetalol 10-20 mg or
continuous infusion of
nicardipine (5 mg/hr
initial dose) preferred.
No
• If on beta blocker, reduce
dose by 50%.
• Hold all other pre-existing
antihypertensives.
• If SBP>220, DBP>120, or
MAP>140 mm Hg lower BP
by no more than 15%.
• IV labetalol 10-20 mg, IV
enalaprilat 1.25-2.5 mg, or
continuous infusion of
nicardipine (5 mg/hr initial
dose) preferred.
<160/90 at presentation,
and no prior history of
HTN maintain
BP<140/80.
• If BP at presentation
>160/90 and/or there is a
prior history of HTN
maintain BP<160/90
and/or MAP<110 mm
Hg.
• If ICP is increased,
consider ICP monitor
and maintain CPP 60-80
mm Hg.
• Nicardipine continuous
infusion (5 mg/hr initial
dose) preferred.

Consider oral antihypertensives when neurologically stable for 24 hours.

Figure 4 Blood pressure management in acute stroke (authors’ recommended treatment algorithm).

and we maintain CPP 60–80 mm Hg. Nicardipine downloadable/heart/1201543457735FS06INT08.pdf.

infusion is the preferred agent for BP control in the
acute setting. When the patient has been neurologi-
cally stable for 24 h, oral agents may be started.
References
1 Qureshi AI, Suri MF, Nasar A, Kirmani JF, Ezzeddine
MA, Divani AA et al. Changes in cost and outcome
among US patients with stroke hospitalized in 1990–
1991 and those hospitalized in 2000–2001. Stroke
2007; 38(7): 2180–2184.
2 Rosamond W, Flegal K, Furie K, Go A, Greenlund K,
Haase N et al. Heart disease and stroke statistics—2008
update: a report from the American Heart Association
Statistics Committee and Stroke Statistics Sub-
committee. Circulation 2008; 117(4): e25–e146.
3 Williams GR. Incidence and characteristics of total
stroke in the United States. BMC Neurol 2001; 1: 2.
4 International cardiovascular disease statistics (2008
Update). Available at: http://www.americanheart.org/
Accessed 30 September 2008.
5 Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock PA.
Blood pressure and clinical outcomes in the Interna-
tional Stroke Trial. Stroke 2002; 33(5): 1315–1320.
6 Qureshi AI, Ezzeddine MA, Nasar A, Suri MF, Kirmani
JF, Hussein HM et al. Prevalence of elevated blood
pressure in 563 704 adult patients with stroke present-
ing to the ED in the United States. Am J Emerg Med
2007; 25(1): 32–38.
7 Wallace JD, Levy LL. Blood pressure after stroke. JAMA
1981; 246(19): 2177–2180.
8 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.
9 Rodriguez-Yanez M, Castellanos M, Blanco M,
Garcia MM, Nombela F, Serena J et al. New-onset
hypertension and inflammatory response/poor out-
come in acute ischemic stroke. Neurology 2006;
67(11): 1973–1978.
10 Qureshi AI. Acute hypertensive response in patients
with stroke: pathophysiology and management. Circu-
lation 2008; 118(2): 176–187.

Journal of Human Hypertension


11 Aslanyan S, Fazekas F, Weir CJ, Horner S, Lees KR.
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):
2420–2425.
12 Mattle HP, Kappeler L, Arnold M, Fischer U, Nedelt-
chev K, Remonda L et al. Blood pressure and vessel
recanalization in the first hours after ischemic stroke.
Stroke 2005; 36(2): 264–268.
13 Obrist WD, Langfitt TW, Jaggi JL, Cruz J, Gennarelli TA.
Cerebral blood flow and metabolism in comatose
patients with acute head injury. Relationship to
intracranial hypertension. J Neurosurg 1984; 61(2):
241–253.
14 Lassen NA. Cerebral blood flow and oxygen consump-
tion in man. Physiol Rev 1959; 39(2): 183–238.
15 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(4): 720–727.
16 Strandgaard S, Olesen J, Skinhoj E, Lassen NA.
Autoregulation of brain circulation in severe arterial
hypertension. Br Med J 1973; 1(5852): 507–510.
17 Dawson SL, Panerai RB, Potter JF. Serial changes in
static and dynamic cerebral autoregulation after acute
ischaemic stroke. Cerebrovasc Dis 2003; 16(1): 69–75.
18 Olsen TS, Larsen B, Herning M, Skriver EB, Lassen
NA. Blood flow and vascular reactivity in collaterally
perfused brain tissue. Evidence of an ischemic pe-
numbra in patients with acute stroke. Stroke 1983;
14(3): 332–341.
19 Christensen H, Meden P, Overgaard K, Boysen G. The
course of blood pressure in acute stroke is related to
the severity of the neurological deficits. Acta Neurol
Scand 2002; 106(3): 142–147.
20 Jorgensen HS, Nakayama H, Raaschou HO, Olsen TS.
Effect of blood pressure and diabetes on stroke in
progression. Lancet 1994; 344(8916): 156–159.
21 Stead LG, Gilmore RM, Decker WW, Weaver AL,
Brown Jr RD. Initial emergency department blood
pressure as predictor of survival after acute ischemic
stroke. Neurology 2005; 65(8): 1179–1183.
22 Carlberg B, Asplund K, Hagg E. The prognostic value
of admission blood pressure in patients with acute
stroke. Stroke 1993; 24(9): 1372–1375.
23 Stead LG, Gilmore RM, Vedula KC, Weaver AL, Decker
WW, Brown Jr RD. Impact of acute blood pressure
variability on ischemic stroke outcome. Neurology
2006; 66(12): 1878–1881.
24 Yong M, Kaste M. Association of characteristics of
blood pressure profiles and stroke outcomes in the
ECASS-II trial. Stroke 2008; 39(2): 366–372.
25 Castillo J, Leira R, Garcia MM, Serena J, Blanco M,
Davalos A. Blood pressure decrease during the acute
phase of ischemic stroke is associated with brain
injury and poor stroke outcome. Stroke 2004; 35(2):
520–526.
26 Semplicini A, Maresca A, Boscolo G, Sartori M, Rocchi
R, Giantin V et al. Hypertension in acute ischemic
stroke: a compensatory mechanism or an additional
damaging factor? Arch Intern Med 2003; 163(2):
211–216.
27 Oliveira-Filho J, Silva SC, Trabuco CC, Pedreira BB,
Sousa EU, Bacellar A. Detrimental effect of blood
pressure reduction in the first 24 h of acute stroke
onset. Neurology 2003; 61(8): 1047–1051.
Blood pressure management in acute stroke
MT Mullen et al
567
28 Fischberg GM, Lozano E, Rajamani K, Ameriso S,
Fisher MJ. Stroke precipitated by moderate
blood pressure reduction. J Emerg Med 2000; 19(4):
339–346.
29 Barer DH, Cruickshank JM, Ebrahim SB, Mitchell JR.
Low dose beta blockade in acute stroke (‘BEST’ trial):
an evaluation. Br Med J (Clin Res Ed) 1988; 296(6624):
737–741.
30 Ahmed N, Nasman P, Wahlgren NG. Effect of intrave-
nous nimodipine on blood pressure and outcome after
acute stroke. Stroke 2000; 31(6): 1250–1255.
31 Horn J, Limburg M. Calcium antagonists for ischemic
stroke: a systematic review. Stroke 2001; 32(2):
570–576.
32 The Blood pressure in Acute Stroke Collaboration
(BASC). Vasoactive drugs for acute stroke. Cochrane
Database Syst Rev 2000; (4): CD002839.
33 Krieger DW, Demchuk AM, Kasner SE, Jauss M,
Hantson L. Early clinical and radiological predictors
of fatal brain swelling in ischemic stroke. Stroke 1999;
30(2): 287–292.
34 Bowes MP, Zivin JA, Thomas GR, Thibodeaux H,
Fagan SC. Acute hypertension, but not thrombolysis,
increases the incidence and severity of hemorrhagic
transformation following experimental stroke in rab-
bits. Exp Neurol 1996; 141(1): 40–46.
35 Fagan SC, Bowes MP, Lyden PD, Zivin JA. Acute
hypertension promotes hemorrhagic transformation in
a rabbit embolic stroke model: effect of labetalol. Exp
Neurol 1998; 150(1): 153–158.
36 Elewa HF, Kozak A, Johnson MH, Ergul A, Fagan SC.
Blood pressure lowering after experimental cerebral
ischemia provides neurovascular protection. J Hyper-
tens 2007; 25(4): 855–859.
37 Di Napoli M, Papa F. Angiotensin-converting enzyme
inhibitor use is associated with reduced plasma
concentration of C-reactive protein in patients
with first-ever ischemic stroke. Stroke 2003; 34(12):
2922–2929.
38 Sigurdsson ST, Strandgaard S. Blood pressure low-
ering in acute ischaemic stroke: an update on the role
of angiotensin receptor blockers. J Hypertens 2007;
25(4): 743–745.
39 Schrader J, Luders S, Kulschewski A, Berger J, Zidek
W, Treib J et al. The ACCESS Study: evaluation of
Acute Candesartan Cilexetil Therapy in Stroke Survi-
vors. Stroke 2003; 34(7): 1699–1703.
40 Eveson DJ, Robinson TG, Potter JF. Lisinopril for the
treatment of hypertension within the first 24 h of acute
ischemic stroke and follow-up. Am J Hypertens 2007;
20(3): 270–277.
41 Bath PM, Willmot M, Leonardi-Bee J, Bath FJ. Nitric
oxide donors (nitrates), L-arginine, or nitric oxide
synthase inhibitors for acute stroke. Cochrane Data-
base Syst Rev 2002; (4): CD000398.
42 Brott T, Lu M, Kothari R, Fagan SC, Frankel M,
Grotta JC et al. Hypertension and its treatment
in the NINDS rt-PA Stroke Trial. Stroke 1998; 29(8):
1504–1509.
43 Gilligan AK, Markus R, Read S, Srikanth V, Hirano T,
Fitt G et al. Baseline blood pressure but not early
computed tomography changes predicts major hemor-
rhage after streptokinase in acute ischemic stroke.
Stroke 2002; 33(9): 2236–2242.
44 NINDS rt-PA Stroke Study Group. Tissue plasminogen
activator for acute ischemic stroke. N Engl J Med 1995;
333: 1581–1588.
Journal of Human Hypertension
 Blood pressure management in acute stroke
MT Mullen et al
568
45 The NINDS t-PA Stroke Study Group. Intracerebral
hemorrhage after intravenous t-PA therapy for is-
chemic stroke. The NINDS t-PA Stroke Study Group.
Stroke 1997; 28(11): 2109–2118.
46 Katzan IL, Furlan AJ, Lloyd LE, Frank JI, Harper DL,
Hinchey JA et al. Use of tissue-type plasminogen
activator for acute ischemic stroke: the Cleveland area
experience. JAMA 2000; 283(9): 1151–1158.
47 Katzan IL, Hammer MD, Furlan AJ, Hixson ED,
Nadzam DM. Quality improvement and tissue-type
plasminogen activator for acute ischemic stroke: a
Cleveland update. Stroke 2003; 34(3): 799–800.
48 Lopez-Yunez AM, Bruno A, Williams LS, Yilmaz E,
Zurru C, Biller J. Protocol violations in community-
based rTPA stroke treatment are associated with
symptomatic intracerebral hemorrhage. Stroke 2001;
32(1): 12–16.
49 Martin-Schild S, Hallevi H, Albright KC, Khaja AM,
Barreto AD, Gonzales NR et al. Aggressive blood
pressure-lowering treatment before intravenous tissue
plasminogen activator therapy in acute ischemic
stroke. Arch Neurol 2008; 65(9): 1174–1178.
50 Shanbrom E, Levy L. The role of systemic blood
pressure in cerebral circulation in carotid and basilar
artery thromboses; clinical observations and therapeu-
tic implications of vasopressor agents. Am J Med 1957;
23(2): 197–204.
51 Shin HK, Nishimura M, Jones PB, Ay H, Boas DA,
Moskowitz MA et al. Mild induced hypertension
improves blood flow and oxygen metabolism in
transient focal cerebral ischemia. Stroke 2008; 39(5):
1548–1555.
52 Hillis AE, Kane A, Tuffiash E, Ulatowski JA, Barker PB,
Beauchamp NJ et al. Reperfusion of specific brain
regions by raising blood pressure restores selective
language functions in subacute stroke. Brain Lang
2001; 79(3): 495–510.
53 Koenig MA, Geocadin RG, de Grouchy M, Glasgow J,
Vimal S, Restrepo L et al. Safety of induced hyperten-
sion therapy in patients with acute ischemic stroke.
Neurocrit Care 2006; 4(1): 3–7.
54 Mistri AK, Robinson TG, Potter JF. Pressor therapy in
acute ischemic stroke: systematic review. Stroke 2006;
37(6): 1565–1571.
55 European Stroke Organisation (ESO) Executive Com-
mittee; ESO Writing Committee. Guidelines for man-
agement of ischaemic stroke and transient ischaemic
attack 2008. Cerebrovasc Dis 2008; 25(5): 457–507.
56 Adams Jr HP, del Zoppo G, Alberts MJ, Bhatt DL, Brass
L, Furlan A et al. Guidelines for the early management
of adults with ischemic stroke: a guideline from the
American Heart Association/American Stroke Associa-
tion Stroke Council, Clinical Cardiology Council,
Cardiovascular Radiology and Intervention Council,
and the Atherosclerotic Peripheral Vascular Disease
and Quality of Care Outcomes in Research Interdisci-
plinary Working Groups: The American Academy of
Neurology affirms the value of this guideline as an
educational tool for neurologists. Circulation 2007;
115(20): e478–e534.
57 Chobanian AV, Bakris GL, Black HR, Cushman WC,
Green LA, Izzo Jr JL et al. The Seventh Report of the
Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure: the
JNC 7 report. JAMA 2003; 289(19): 2560–2572.
58 Potter J, Robinson T, Ford G, James M, Jenkins D,
Mistri A et al. CHHIPS (Controlling Hypertension and
Journal of Human Hypertension
Hypotension Immediately Post-Stroke) Pilot Trial:
rationale and design. J Hypertens 2005; 23(3): 649–655.
59 Rosendorff C. New insights into hypertension manage-
ment in acute stroke: let the CHHIPS fall where they
may. J Clin Hypertens (Greenwich) 2008; 10(6):
425–426.
60 COSSACS Trial Group. COSSACS (Continue or Stop
post-Stroke Antihypertensives Collaborative Study):
rationale and design. J Hypertens 2005; 23(2): 455–458.
61 Clinicaltrials.gov—Registry of federally and privately
supported clinical trials conducted in the United
States and around the world. Available at: www.
clinicaltrials.gov. Accessed 30 September 2008.
62 Dennis MS, Burn JP, Sandercock PA, Bamford JM,
Wade DT, Warlow CP. Long-term survival after
first-ever stroke: the Oxfordshire Community Stroke
Project. Stroke 1993; 24(6): 796–800.
63 Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo
H, Hanley DF. Spontaneous intracerebral hemorrhage.
N Engl J Med 2001; 344(19): 1450–1460.
64 Foulkes MA, Wolf PA, Price TR, Mohr JP, Hier DB. The
Stroke Data Bank: design, methods, and baseline
characteristics. Stroke 1988; 19(5): 547–554.
65 Fogelholm R, Avikainen S, Murros K. Prognostic value
and determinants of first-day mean arterial pressure in
spontaneous supratentorial intracerebral hemorrhage.
Stroke 1997; 28(7): 1396–1400.
66 Qureshi AI, Safdar K, Weil J, Barch C, Bliwise DL,
Colohan AR et al. Predictors of early deterioration
and mortality in black Americans with sponta-
neous intracerebral hemorrhage. Stroke 1995; 26(10):
1764–1767.
67 Terayama Y, Tanahashi N, Fukuuchi Y, Gotoh F.
Prognostic value of admission blood pressure in
patients with intracerebral hemorrhage. Keio Coopera-
tive Stroke Study. Stroke 1997; 28(6): 1185–1188.
68 Meyer JS, Bauer RB. Medical treatment of spontaneous
intracranial hemorrhage by the use of hypotensive
drugs. Neurology 1962; 12: 36–47.
69 Bullock R, Brock-Utne J, van Dellen J, Blake G.
Intracerebral hemorrhage in a primate model: effect
on regional cerebral blood flow. Surg Neurol 1988;
29(2): 101–107.
70 Nath FP, Kelly PT, Jenkins A, Mendelow AD,
Graham DI, Teasdale GM. Effects of experimental
intracerebral hemorrhage on blood flow, capillary
permeability, and histochemistry. J Neurosurg 1987;
66(4): 555–562.
71 Kidwell CS, Saver JL, Mattiello J, Warach S, Liebeskind
DS, Starkman S et al. Diffusion-perfusion MR
evaluation of perihematomal injury in hyperacute
intracerebral hemorrhage. Neurology 2001; 57(9):
1611–1617.
72 Qureshi AI, Bliwise DL, Bliwise NG, Akbar MS, Uzen
G, Frankel MR. Rate of 24-h blood pressure decline and
mortality after spontaneous intracerebral hemorrhage:
a retrospective analysis with a random effects regres-
sion model. Crit Care Med 1999; 27(3): 480–485.
73 Brott T, Broderick J, Kothari R, Barsan W, Tomsick T,
Sauerbeck L et al. Early hemorrhage growth in patients
with intracerebral hemorrhage. Stroke 1997; 28(1): 1–5.
74 Kazui S, Naritomi H, Yamamoto H, Sawada T,
Yamaguchi T. Enlargement of spontaneous intracereb-
ral hemorrhage. Incidence and time course. Stroke
1996; 27(10): 1783–1787.
75 Kazui S, Minematsu K, Yamamoto H, Sawada T,
Yamaguchi T. Predisposing factors to enlargement of

spontaneous intracerebral hematoma. Stroke 1997;
28(12): 2370–2375.
76 Ohwaki K, Yano E, Nagashima H, Hirata M, Nakagomi
T, Tamura A. Blood pressure management in acute
intracerebral hemorrhage: relationship between ele-
vated blood pressure and hematoma enlargement.
Stroke 2004; 35(6): 1364–1367.
77 Hirano T, Read SJ, Abbott DF, Sachinidis JI, Tochon-
Danguy HJ, Egan GF et al. No evidence of hypoxic
tissue on 18F-fluoromisonidazole PET after intracer-
ebral hemorrhage. Neurology 1999; 53(9): 2179–2182.
78 Qureshi AI, Wilson DA, Hanley DF, Traystman RJ.
No evidence for an ischemic penumbra in massive
experimental intracerebral hemorrhage. Neurology
1999; 52(2): 266–272.
79 Zazulia AR, Diringer MN, Videen TO, Adams RE,
Yundt K, Aiyagari V et al. Hypoperfusion without
ischemia surrounding acute intracerebral hemorrhage.
J Cereb Blood Flow Metab 2001; 21(7): 804–810.
80 Butcher KS, Baird T, MacGregor L, Desmond P, Tress B,
Davis S. Perihematomal edema in primary intracereb-
ral hemorrhage is plasma derived. Stroke 2004; 35(8):
1879–1885.
81 Carhuapoma JR, Wang PY, Beauchamp NJ, Keyl PM,
Hanley DF, Barker PB. Diffusion-weighted MRI and
proton MR spectroscopic imaging in the study of
secondary neuronal injury after intracerebral hemor-
rhage. Stroke 2000; 31(3): 726–732.
82 Schellinger PD, Fiebach JB, Hoffmann K, Becker K,
Orakcioglu B, Kollmar R et al. Stroke MRI in
intracerebral hemorrhage: is there a perihemorrhagic
penumbra? Stroke 2003; 34(7): 1674–1679.
83 Powers WJ, Zazulia AR, Videen TO, Adams RE, Yundt
KD, Aiyagari V et al. Autoregulation of cerebral blood
flow surrounding acute (6 to 22 h) intracerebral
hemorrhage. Neurology 2001; 57(1): 18–24.
84 Jauch EC, Lindsell CJ, Adeoye O, Khoury J, Barsan W,
Broderick J et al. Lack of evidence for an association
Blood pressure management in acute stroke
MT Mullen et al
569
between hemodynamic variables and hematoma
growth in spontaneous intracerebral hemorrhage.
Stroke 2006; 37(8): 2061–2065.
85 Broderick JP, Diringer MN, Hill MD, Brun NC, Mayer
SA, Steiner T et al. Determinants of intracerebral
hemorrhage growth: an exploratory analysis. Stroke
2007; 38(3): 1072–1075.
86 Anderson CS, Huang Y, Wang JG, Arima H, Neal B,
Peng B et al. Intensive blood pressure reduction in
acute cerebral haemorrhage trial (INTERACT): a ran-
domised pilot trial. Lancet Neurol 2008; 7(5): 391–399.
87 Broderick J, Connolly S, Feldmann E, Hanley D, Kase
C, Krieger D et al. Guidelines for the management of
spontaneous intracerebral hemorrhage in adults: 2007
update: a guideline from the American Heart Associa-
tion/American Stroke Association Stroke Council,
High Blood Pressure Research Council, and the
Quality of Care and Outcomes in Research Interdisci-
plinary Working Group. Circulation 2007; 116(16):
e391–e413.
88 Steiner T, Kaste M, Forsting M, Mendelow D, Kwie-
cinski H, Szikora I et al. Recommendations for the
management of intracranial haemorrhage—part I:
spontaneous intracerebral haemorrhage. The European
Stroke Initiative Writing Committee and the Writing
Committee for the EUSI Executive Committee.
Cerebrovasc Dis 2006; 22(4): 294–316.
89 Tietjen CS, Hurn PD, Ulatowski JA, Kirsch JR. Treat-
ment modalities for hypertensive patients with intra-
cranial pathology: options and risks. Crit Care Med
1996; 24(2): 311–322.
90 Qureshi AI. Antihypertensive Treatment of Acute
Cerebral Hemorrhage (ATACH): rationale and design.
Neurocrit Care 2007; 6(1): 56–66.
91 Qureshi AI, The ATACH Investigators. Antihyper-
tensive Treatment of Acute Cerebral Hemorrhage
(ATACH) Trial. International Stroke Conference. New
Orleans, LA, February 2008.
Journal of Human Hypertension