Anda di halaman 1dari 13

Acute Hypertensive Response in Patients With Stroke: Pathophysiology and Management

Adnan I. Qureshi
Circulation. 2008;118:176-187
doi: 10.1161/CIRCULATIONAHA.107.723874
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2008 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/118/2/176

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/

Downloaded from http://circ.ahajournals.org/ by guest on February 27, 2014

Contemporary Reviews in Cardiovascular Medicine


Acute Hypertensive Response in Patients With Stroke
Pathophysiology and Management
Adnan I. Qureshi, MD

cute hypertensive response is the elevation of blood


pressure (BP) above normal and premorbid values that
initially occurs within the first 24 hours of symptom onset in
patients with stroke. This phenomenon was reported in 60%
of patients presenting with stroke in a nationally representative study from the United States.1 With 980 000 patients2
admitted with stroke each year in the United States, the
estimated annual prevalence of acute hypertensive response is
more than half a million patients. With 15 million patients
experiencing stroke worldwide each year,3 the acute hypertensive response may be expected in 10 million patients per
year. The acute hypertensive response in stroke patients is
managed by a diverse group of physicians, including emergency physicians, intensivists, internists, primary care physicians, neurologists, neurosurgeons, and cardiologists. Previous audits suggest that antihypertensive agents and
management strategies vary considerably and are not always
consistent with recommended guidelines.4 Data from 1181
acute ischemic stroke patients enrolled in the Project for
Improvement of Stroke Care Management suggested that
administration of antihypertensive medication within 24
hours in 56% of the patients was inconsistent with guidelines
provided by the American Stroke Association (ASA).5 The
present review article summarizes the current concepts pertaining to treatment of the acute hypertensive response
derived from recent guidelines provided by professional
organizations and best available evidence derived from
experimental and clinical studies and discusses incorporation
of these concepts into clinical practice. Randomized trials,
nonrandomized controlled studies, and selected observational
studies were identified with multiple searches on Medline
from 1980 to 2007 by cross-referencing the key words of
stroke, acute hypertension, antihypertensive agents, acute
stroke, and hypertension. Pertinent articles identified from
bibliographies of selected articles were also reviewed. Treatment targets and strategies were identified by review of
existing guidelines from professional organizations.

Definition of Acute Hypertensive Response


The 2003 World Health Organization (WHO)/International
Society of Hypertension (ISH) statement6 and the Seventh
Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure

(JNC 7)7 define hypertension on the basis of the presence of


consistent BP 140/90 mm Hg (multiple readings on separate days). This definition of hypertension is a threshold for
the use of long-term antihypertensive treatment that is supported by evidence derived from randomized trials and clinicor population-based data that demonstrate reduction in cardiovascular events with this threshold for treatment. The
same definition cannot be applied in the case of acute
hypertensive response, because the above-mentioned ascertainment criteria and rationale are not valid. The executive
summary of the ISH statement8 on management of BP in
acute stroke stated that high BP (140/90 mm Hg) is very
common early after ischemic stroke (occurring in 75% of
cases) and intracerebral hemorrhage (ICH; 80%) and is
independently associated with a poor functional outcome. To
maintain consistency with the ISH statement, acute hypertensive response is defined as systolic BP 140 mm Hg or
diastolic BP of 90 mm Hg demonstrated on 2 recordings
taken 5 minutes apart within 24 hours of symptom onset.
This definition predominantly serves to provide a uniform
standard for measuring prevalence and not for setting treatment thresholds for antihypertensive treatment, which may
vary depending on stroke subtype and other considerations.

Prevalence of Acute Hypertensive Response


The reported prevalence of the acute hypertensive response
depends on patient selection, study design, referral patterns,
and the definition used. In a systematic review of 18 studies,9
52% of patients with stroke were reported to have an acute
hypertensive response at the time of admission. The criteria
used to define high BP varied considerably: Systolic BP
criteria ranged from 150 to 200 mm Hg and diastolic BP
criteria from 90 to 115 mm Hg. In one of the largest studies
in the United States using the National Hospital Ambulatory
Medical Care Survey,1 systolic BP 140 mm Hg was observed in 63% of the 563 704 adult stroke patients, diastolic
BP 90 mm Hg in 28%, and mean arterial pressure (MAP)
107 mm Hg in 38%. In the International Stroke Trial,10
17 398 patients were randomized within 48 hours of stroke
onset (median time 20 hours) from 467 hospitals in 36
countries. Mean systolic BP at enrollment was 160.1 mm Hg,
and 82% of patients had high BP based on the WHO
definition of hypertension (systolic BP 140 mm Hg).

From the Zeenat Qureshi Stroke Research Center, University of Minnesota, Minneapolis.
Correspondence to Adnan I. Qureshi, MD, University of Minnesota, MMC 295, 420 Delaware St SE, Minneapolis, MN 55455.
(Circulation. 2008;118:176-187.)
2008 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org

DOI: 10.1161/CIRCULATIONAHA.107.723874

176
Downloaded from http://circ.ahajournals.org/
by guest on February 27, 2014

Qureshi

Characteristics of Acute Hypertensive Response


The acute hypertensive response in stroke is characterized by
its high prevalence, self-limiting nature, and prognostic significance. With the definition of hypertension provided by the
WHO6 and JNC 7,7 the age-, sex-, and ethnicity-adjusted rates
were 61% among stroke patients and 14% in the US population in 1999 to 2000.1,11 New-onset high BP in patients
without a previous history of hypertension has been observed
in 20% of patients with stroke12 and 8% of the general
population.11 A crude comparison suggests that these proportions are higher than expected on the basis of premorbid
hypertension among stroke patients. There is also spontaneous reduction of BP (by an average of 20/10 mm Hg) within
10 days after the acute event without any specific antihypertensive therapy.13 Among the 1455 patients from the Glycine
Antagonist in Neuroprotection International Trial14 evaluated
within 6 hours of symptom onset, MAP declined gradually
over the next 60 hours regardless of initial MAP value, with
a prominent reduction observed within 10 hours of the first
measurement. The prognostic significance is highlighted in a
systematic review of 18 studies9 that demonstrated that
patients with stroke and high initial BP were at a 1.5- to
5.0-fold increased risk of death or dependency and clinical
deterioration.

Underlying Causes of Acute


Hypertensive Response
In at least a portion of these patients, the acute hypertensive
response is merely a reflection of inadequately treated or
undetected chronic hypertension15; however, spontaneous
reduction in the initial BP over the next few days in most
patients13,14 supports the role of other transient and strokespecific mechanisms. Spontaneous reduction of BP after
vessel recanalization in patients with ischemic stroke also
implies stroke-specific mechanisms.16 Stroke involves transient or permanent damage to the areas involved in the brain
regulation of cardiovascular functioning, including BP. The
parasympathetic and sympathetic nervous systems are lateralized to the left and right cerebral hemispheres, respectively.17 Prefrontal18 and insular19 cortices provide inhibitory and
excitatory input, respectively, through pathways that connect
to the nuclei in the brainstem, particularly in nucleus tractus
solitarius and ventrolateral medulla.20 Further modulation is
provided by cingulated cortex, amygdala, and hypothalamus.
Because of the widespread distribution of these areas, most
stroke lesions involve these areas to a varied extent.
Increased sympathoadrenal tone21 with subsequent release
of renin and vasoconstriction of arterioles results from (1)
direct injury to inhibitory or modulatory brain regions or (2)
indirect effects of reduced parasympathetic activity,22 which
leads to impaired cardiac baroreceptor sensitivity in patients
with stroke.23 Although direct injury is the most likely
explanation, an indirect effect of muscle paralysis24 or the
release of neurotransmitters such as nitric oxide25 during
ischemia may be contributing factors to altered activity of
these nuclei. Other stress responses to hospitalization, headache, urinary retention, or concomitant infection26 may lead
to abnormal autonomic activity and raised levels of circulating catecholamines27 and inflammatory cytokines12 and sub-

Acute Hypertensive Response in Stroke Patients

177

sequently may contribute to the hypertensive response. Presumably, these abnormal autonomic responses normalize
over a few hours owing to spontaneous or therapeutic
recanalization and resolution of the ischemia and perhaps
because of other neural compensatory mechanisms.28
An increase in systemic BP associated with increased
intracranial pressure (ICP), particularly in the presence of
brainstem compression,29 31 has particular relevance for patients with intracerebral and subarachnoid hemorrhages. Elevated ICP can result in a systemic BP increase32; however,
the elevation in systemic BP does not appear to demonstrate
a clear relationship to the presence of cerebral ischemia,32,33
ICP values, transtentorial herniation,32,33 or response to hyperosmotic treatment.32,33 This suggests that the primary
cause of the acute hypertensive response is damage or
compression of specific regions in the brain that mediate
autonomic control. Hypertensive responses to other factors
mentioned above are exaggerated and additive because of
impaired parasympathetic activity and baroreceptor
sensitivity.

Cerebrovascular Physiology and Implications


for Treatment
Under normal circumstances, changes in precapillary arteriolar diameter (400 m) maintain constant cerebral blood
flow in the capillary bed between MAPs of 60 and
150 mm Hg.34 A fast dynamic response to changes in pressure pulsations is followed by a slow static response that
restores cerebral blood flow after the initial dynamic response
has settled35 by myogenic (mechanogenic) and metabolic
(chemogenic) mechanisms.36 With decreasing BP, there is
vasodilation of arterioles until maximal vasodilation occurs,
and subsequently, there is reduction of blood flow. With
increasing BP, there is progressive vasoconstriction of arterioles until the BP exceeds the upper limit of autoregulation,
followed by breakthrough vasodilation, increase in cerebral
blood flow,36 blood-brain barrier dysfunction, and cerebral
edema.
In chronic hypertension, the lower end of the autoregulation curve is shifted toward high pressure,37 presumably
because vessel wall thickening and luminal narrowing limit
the capacity of the resistance vessels for dilation. In acute
stroke, autoregulation may be impaired in regions surrounding an acute lesion and even in the hemisphere contralateral
to the lesion because of dilation of cerebral resistance vessels
in an attempt to increase blood flow in response to tissue
ischemia and acidosis.38 More recently, it has been shown
that autoregulation is impaired for rapid changes (dynamic
autoregulation) in systemic BP even when it is preserved for
controlled changes.39 Other conditions, such as cerebral
vasospasm in subarachnoid hemorrhage,40 also cause arteriolar constriction, which shifts the autoregulatory range toward
higher values.
In the presence of elevated ICP, MAPs 60 mm Hg may
not be adequate to maintain constant cerebral blood flow in
the capillary bed. Ascertainment of the difference between
MAP and ICP is recommended as an index of cerebral
perfusion pressure. The standard, global measure of cerebral
perfusion pressure can underestimate the localized pressure

Downloaded from http://circ.ahajournals.org/ by guest on February 27, 2014

178

Circulation

July 8, 2008

Clinical diagnosis of acute stroke

Reduce BP if >185/110 mm Hg using short acting IV medication*

Ischemic
stroke

Emergent computed tomographic scan

Intracerebral
hemorrhage

Candidate for
thrombolysis

Not a candidate for


thrombolysis

Suspect
high ICP

Do not suspect
high ICP

Reduce BP if
>185/110 mm Hg
using short acting
IV medication.

Reduce BP if
>220/120 mm Hg
using short acting
IV medication.
Avoid and treat
hypotension
(<100/70 mm Hg).

Reduce BP if
SBP >180 mm Hg
or MAP >130 mm Hg
using short acting
IV medication;
ICP monitoring
recommended to
maintain
CPP >60 mm Hg.

Reduce BP if
SBP >180 mm Hg
or MAP >130 mm Hg
using short acting
IV medication.
Monitor neurological
examination every
15 minutes.

Treat with
thrombolysis.

Maintain BP
<180/105 mm Hg
using short acting
IV medication or
infusions for 24 h.

Oral antihypertensive agents may be considered after 24 hours; BP goal 160/110 mm Hg.
Titrate to more aggressive goals after neurological stability is achieved.

Figure. Algorithm for treatment of acute hypertensive response among patients with stroke and stroke subtypes. IV indicates intravenous; SBP, systolic BP; DBP, diastolic BP; and CPP, cerebral perfusion pressure. *Based on the NINDS rtPA prethrombolytic protocol42 for patients with acute ischemic stroke, for short-term BP management by Emergency Medical Services without delaying early
diagnosis and differentiation. The Emergency Medical Services BP management practices vary considerably in the absence of distinction between ischemic stroke and ICH.43 Based on recommendations of the ASA, Stroke Council,44,46 and/or European Stroke Initiative.45 The recommended BP treatment threshold is similar to the existing ASA and European Stroke Initiative recommendations for
patients with ICH.44,45 Based on recommendations of JNC 77 and the ACCESS protocol.47

and perfusion changes in focal stroke lesions but is still useful


in the absence of another, more sensitive measure. The Brain
Trauma Foundation41 recommends maintenance of a cerebral
perfusion pressure 70 mm Hg to enhance perfusion to
ischemic regions of the brain after severe traumatic injury. In
stroke, such treatment thresholds have been extrapolated from
global cerebral perfusion data derived from traumatic brain
injury patients in the absence of any other pertinent data.

Management of Acute Hypertensive Response


in Stroke Subtypes
Despite the high prevalence of acute hypertensive responses
observed in all stroke subtypes, differences in underlying
pathophysiology mandate different management strategies
(Figure).7,42 47 BP responses can be categorized as (1) spontaneous decline without medication; (2) no clear decline, or
even an elevation, despite administration of antihypertensive
medication; (3) modest decline with antihypertensive medication (10% to 15% from baseline value); and (4) intense
decline with antihypertensive medication (20% from baseline value). The studies presented below are confounded by
overlap of the 4 categories of responses in varying proportions and require interpretation with this understanding.
Another important issue in management is the identification
of intravascular volume depletion (dehydration)48 in these
patients, which may result in a natural hypertensive or

hypotensive response or an exaggerated hypotensive response


to antihypertensive medication.49,50 Early identification and
appropriate fluid repletion before pharmacological intervention ensures a controlled response to treatment.

Patients With Acute Ischemic Stroke


Ischemic stroke results from occlusion of an artery with
subsequent reduction in regional cerebral blood flow, demarcated into regions of severe reduction (core) and moderate
reduction (penumbra).51 The penumbra remains viable for
hours because some degree of blood flow is sustained through
collateral supply; however, it is theoretically vulnerable to
further ischemic injury with systemic BP reduction52 because
of impaired regional autoregulation,38 particularly during
rapid BP reduction. Conversely, in an experimental model of
focal cerebral ischemia and reperfusion, BP reduction reduced infarct size and deficits.53 Therefore, a period of
vulnerability to progression of ischemic deficits may exist
after which there may be benefit from BP reduction. A higher
rate of death or dependency was observed in patients with
initially high or low systolic BP (U-shaped relationship)
among 17 398 ischemic stroke patients randomized in the
International Stroke Trial.10 The relationship appeared to be
mediated in part by increased rates of early recurrence and
death that resulted from presumed cerebral edema in patients
with high BP and increased coronary heart disease events in

Downloaded from http://circ.ahajournals.org/ by guest on February 27, 2014

Qureshi
those with low BP. Recent data suggest that wide fluctuations
(not initial values) of BP in the first few hours in patients with
acute ischemic stroke may be associated with an increased
risk of death at 90 days.14,54
The Low Dose Beta Blockade in Acute Stroke (BEST)
study55 (Table 142,47,55 60) revealed greater mortality among
patients in whom -blocker therapy was begun within 48
hours of symptom onset. An analysis of data from the Intravenous Nimodipine West European Stroke Trial (INWEST)
found a significant correlation between diastolic BP reduction
with nimodipine and worsening of neurological status (within
24 hours of symptom onset).61 Patients with a diastolic BP
reduction 20% or a diastolic BP drop to 60 mm Hg had a
significantly higher risk of death or dependency at 21 days. A
subsequent meta-analysis58 evaluating the use of oral or
intravenous calcium channel blockers initiated at 6 hours to 5
days after symptom onset in acute ischemic stroke patients
found that intravenous administration, higher doses, and
administration within 12 hours of symptom onset were
associated with an increased risk of poor outcomes. The
effect may be mediated in part by alterations of regional
cerebral blood flow.62 This susceptibility varies with stroke
subtype and evolution stage, showing higher tolerance to
BP lowering in patients with total anterior circulation
infarction63 and in those treated after 12 hours of symptom
onset.58
New data suggest that the increased risk of poor outcomes is probably limited to patients treated very aggressively or to specific antihypertensive agents (Table 1). The
Acute Candesartan Cilexetil Evaluation in Stroke Survivors
(ACCESS)47 trial initiated treatment with either the angiotensin receptor antagonist candesartan or placebo in patients
with ischemic stroke and a BP measurement 200/
100 mm Hg 6 to 24 hours after admission or 180/
105 mm Hg at 24 to 36 hours. The target reduction in BP was
10% to 15% within 24 hours. If patients in the candesartan
group displayed a hypertensive profile on day 7 (mean
daytime BP 135/85 mm Hg), candesartan was increased or
an additional antihypertensive drug was added. In placebotreated patients with a hypertensive profile on day 7, candesartan was begun. Both the cumulative 12-month mortality
rate (2.9% versus 7.2%) and the incidence of vascular events
(9.8% versus 18.7%) were lower in the candesartan-treated
group; however, the primary outcome of disability measured
by Barthel index at 3 months was not different between the 2
treatment groups.
A post hoc analysis of hypertensive patients in the National
Institutes of Neurological Disorders and Stroke (NINDS)
recombinant tissue plasminogen (rtPA) trial42 who received
antihypertensive therapy (intravenous labetalol and/or nitroprusside in selected patients) but no rtPA therapy within 24
hours of randomization showed no difference in rates of
deterioration or death at 24 hours or in rates of favorable
outcome at 3 months compared with hypertensive patients
who received neither antihypertensive medication nor rtPA.
The results from various studies suggest somewhat contradictory consequences of antihypertensive treatment in
acute ischemic stroke: INWEST showed a detrimental
effect; ACCESS, a favorable effect; and post hoc analysis of

Acute Hypertensive Response in Stroke Patients

179

NINDS rtPA study showed no effect. The mean systolic BP


in the ACCESS trial was higher than in INWEST (196
versus 162 mm Hg), and the mean value during the first 2
days was also higher (150 versus 145 mm Hg). The
average maximum MAP in the NINDS placebo group (those
not given rtPA) who received antihypertensive medication
(133 mm Hg) and the average lowest value during the first 24
hours (110 mm Hg) also appear higher than those observed
in INWEST. The difference in aggressiveness of BP reduction between the studies was also evident from the 60%
incidence of diastolic BP values of 60 mm Hg during
nimodipine treatment in INWEST. These differences stress
the importance of BP thresholds and treatment targets in
determining tolerability of antihypertensive treatment in
acute ischemic stroke.
Another aspect that requires further consideration is the
potential for differential benefit or harm between classes of
antihypertensive medication. The differences in results between trials such as the BEST, INWEST, ACCESS, and
NINDS rtPA studies may be related to the properties of the
antihypertensive medication used. A systematic review64 of 7
randomized, controlled trials involving patients with prior
stroke or transient ischemic attack demonstrated heterogeneity in outcomes that were related in part to the class of
antihypertensive drugs used. Angiotensin-converting enzyme
inhibitors and diuretics, separately and in combination, but
not -blockers, reduced vascular events. Another estimate of
stroke reduction with different antihypertensive medications
(angiotensin-converting enzyme inhibitors, calcium antagonists, angiotensin receptor blockers, and diuretics or
-blockers) using data from 29 randomized trials65 directed
toward primary prevention suggested that the greatest
reduction was observed with angiotensin receptor blockers, with small (borderline significance) differences between the other different classes of antihypertensive medication. Conclusive evidence for differential effects of
different antihypertensive medications in the acute period
is not available.
The management of high BP in acute ischemic stroke is
highly controversial because of a lack of reliable evidence
from randomized, controlled trials. The current recommendations regarding BP management in acute ischemic stroke46
are based on 2 observations. BP reduction is associated with
an increased risk of neurological deterioration and worse
outcome in patients with ischemic stroke in some studies,59,66
although a causal relationship has not been demonstrated
conclusively. The benefit of acute BP lowering (unlike
chronic treatment) in patients with ischemic stroke remains
unclear.46 There may be a reduction of cardiovascular events
with early institution of angiotensin receptor antagonists;
however, the benefit is not conclusively related to BP
reduction.47 Therefore, in the absence of definitive benefit,
both the ASA and the European Stroke Initiative are consistent in not recommending routine lowering of BP unless it is
repeatedly exceeds 200 to 220 mm Hg systolic or 120 mm Hg
diastolic in the acute period.46,67,68 However, with the anticipated completion of several large clinical trials42,47,55 60 in
the next 5 years (Table 1), these recommendations may be
modified.

Downloaded from http://circ.ahajournals.org/ by guest on February 27, 2014

180

Circulation

July 8, 2008

Table 1. Summary of Completed and Ongoing Prospective Clinical Trials That Evaluated or Are Evaluating Various Aspects of
Antihypertensive Treatment in the Acute Period of Stroke
Trial(s)

No. of
Patients

Design

Patients Included

Intervention

Primary Outcome

Interventions for
deliberately
altering BP in
acute stroke56

Meta-analysis
(5 trials)

Any stroke within 2 wk


of symptom onset

Nimodipine (n66), nicardipine


(n5), captopril (n3),
clonidine (n2), nitroglycerin
(n16), perindopril (n14), and
placebo/control (n92)

BP reduction and
case fatality

218

Oral calcium channel blockers


reduced SBP (weighted mean
difference 10.9 mm Hg) at 48
h, ACEI reduced SBP
(weighted mean difference
15.0 mm Hg) at 24 h;
Nitroglycerin showed a
nonsignificant reduction in BP
at 24 h

Comments

Low Dose Beta


Blockade in
Acute Stroke
(BEST)55

Randomized trial

Hemispheric stroke
presenting within 48 h
of symptom onset

Atenolol (50 mg/d), slow-release


propranolol (80 mg/d), or
matching placebo capsules for 3
wk or until discharge

Neurological
assessment at
entry, day 8, and
1 and 6 mo

302

Deaths more common among


patients taking -blockers.
Neurological recovery and
functional outcome at 6 mo
did not differ

Acute
Candesartan
Cilexetil
Evaluation in
Stroke Survivors
(ACCESS)47

Double-blind,
randomized
multicenter trial

Initial BP
200/110 mm Hg,
acute cerebral
ischemia and motor
paresis

Candesartan or placebo for 7 d


initiated over a mean period of
30 h after symptom onset

Functional status
assessed by
mRS and Barthel
Index and
mortality rates
after 3 mo

339

Total mortality, cerebral


complications, and
cardiovascular complications
reduced by 47.5% with
candesartan initiated within
24 h of admission

Nitroglycerin for
acute stroke57

Meta-analysis
(2 studies)

Any stroke within 4 d


of symptom onset

Nitroglycerin (510 mg/d) by


transdermal patch

BP change on
day 1

127

No clear effect on
end-of-treatment death,
combined death or
deterioration, or end-of-trial
death, combined death, or
dependency

Calcium
antagonists for
acute ischemic
stroke58

Meta-analysis
(28 trials)

Any stroke 6 h to 5 d
after symptom onset
(ischemic stroke only
in 23 trials)

IV isradipine (1 trial); oral


nimodipine (16 trials); IV
nimodipine (5 trials); IV
flunarizine (3 trials); oral
PY108-608 (1 trial); and IV and
oral nimodipine (2 trials)

Poor outcome,
defined as death
or dependency in
activities of daily
living

7521

No overall effect on outcome


at the end of follow-up. IV
administration, higher doses,
and administration within 12
h of symptom onset were
associated with an increased
rate of poor outcome

NINDS rt-PA
Stroke Trial42

Post hoc analysis


of randomized
trial

Ischemic stroke within


3 h of symptom onset
and BP
180/105 mm Hg
after receiving IV rt-PA
or placebo

IV labetalol or nitroprusside
infusion if DBP 140 mm Hg or
inadequate response to
labetalol; treatment for 24 h;
80/195 placebo-treated patients
and 65/177 rtPA-treated
patients received
antihypertensive treatment

Neurological
deterioration,
ICH, and good
outcome
(multiple scales
at 3 mo)

372

All outcome measures similar


for those patients who
received postrandomization
antihypertensive therapy and
those who did not among
placebo-treated patients;
among rtPA patients, those
who received antihypertensive
therapy had worse outcomes
than those who did not

Controlling
Hypertension
and Hypotension
Immediately
Post-Stroke Trial
(CHHIPS)59

Prospective,
multicenter,
randomized,
double-blind,
titrated-dose trial

(1) Hypotensive (SBP


140 mm Hg)
nonhemorrhagic stroke
patients treated within
12 h of symptom
onset; (2) Hypertensive
(SBP 160 mm Hg),
nondysphagic within
36 h of stroke onset;
(3) Hypertensive,
dysphagic within 36 h
of stroke onset

(1) IV phenylephrine at 80
g/min titrated to target SBP
150 mm Hg or 15 mm Hg
increase above baseline;
(2) oral lisinopril 5 mg or
labetalol 50 mg to target SBP
150 mm Hg or 15 mm Hg
reduction from baseline; (3)
sublingual lisinopril 5 mg and/or
IV labetalol 50 mg to target SBP
150 mm Hg or 15 mm Hg
reduction from baseline

Death or
dependency
(mRS 3) at
14 d

2050

Ongoing

(Continued )

Downloaded from http://circ.ahajournals.org/ by guest on February 27, 2014

Qureshi
Table 1.

Acute Hypertensive Response in Stroke Patients

181

Continued
No. of
Patients

Comments

Mortality rate
and mRS at
3 mo

5000

Ongoing

Candesartan (dose increasing


from 4 to 16 mg/d) or placebo
for 7 d

Death or
disability at 6
mo; combination
of vascular
death,
myocardial
infarction, or
stroke during
first 6 mo

2500

Ongoing

Any stroke within 24 h


of symptom onset

Patients will receive


antihypertensive therapy for a
2-wk period

Death or
disability (mRS
2) at 14 d
after stroke

2900

Ongoing

Prospective,
open-label,
multicenter
safety and
tolerability study

Supratentorial ICH
within 6 h of symptom
onset and SBP
200 mm Hg

Stepwise, interventional design


to test 3 tiers of SBP reduction:
170200 mm Hg,
140170 mm Hg and
110140 mm Hg with
IV nicardipine

Ability to achieve
and maintain
treatment goals
(SBP range for
the 1824-h
period) and any
neurological
deterioration

60

Recruitment complete; no
safety concerns

Intensive Blood
Pressure
Reduction in
Acute Cerebral
Hemorrhage
(INTERACT) Pilot
Study59

Randomized,
open-label,
active-control,
parallelassignment,
safety/efficacy
study

ICH within 6 h of
symptom onset and
SBP 150 mm Hg and
200 mm Hg

Intensive SBP lowering; control


group receives ASA
guideline-based BP
management

Mortality and
dependency
(mRS of 3 to 5)
at 3 mo

400

Recruitment complete; no
safety concerns

Intracerebral
Hemorrhage
Acutely
Decreasing
Arterial Pressure
Trial (ICH
ADAPT)59

Multicenter,
randomized,
open-label,
blinded-point
trial

Primary ICH and SBP


150 mm Hg

IV labetalol to reduce SBP to


150 mm Hg within 1 h of
treatment; control group
receives ASA guideline-based
BP management

Perihematomal
rCBF measured
with CT scan
perfusion 2 h
after treatment

82

Ongoing

Nicardipine for
the Treatment
of Hypertension
in Patients with
Ischemic Stroke,
Intracerebral
Hemorrhage or
Subarachnoid
Hemorrhage
(CARING)59

Phase IV,
prospective,
open-label study

Ischemic stroke, ICH,


or SAH patients who
require BP control

25 Patients will receive


double-concentrate dose; 25 will
receive triple-concentrate dose

Rate of
peripheral IV
phlebitis, time,
and dosage
adjustment
needed to reach
target BP range

50

Double-concentrated IV
nicardipine can be given
safely

Trial(s)

Design

Patients Included

Intervention

Primary Outcome

Efficacy of Nitric
Oxide in Stroke
Trial (ENOS)59

Prospective,
international,
multicenter,
randomized,
parallel-group,
double-blind,
placebocontrolled trial

Any stroke treated


within 48 h

Transdermal nitroglycerin or
placebo for 7 d. Patients taking
antihypertensive drugs will be
randomized to continue or
discontinue their medication
for 7 d

Scandinavian
Candesartan
Acute Stroke
Trial (SCAST)59

Randomized,
controlled
multicenter trial

Acute stroke within 30


h and SBP
140 mm Hg

Continue Or
Stop post-Stroke
Antihypertensives
Collaborative
Study
(COSSACS)59

Multicenter,
prospective,
randomized,
open, blinded
end-point
ascertainment
study

Antihypertensive
Treatment in
Acute Cerebral
Hemorrhage
(ATACH)60

SBP indicates systolic BP; ACEI, ACE inhibitor; mRS, modified Rankin scale; DBP, diastolic BP; ASA, American Stroke Association; rCBF, regional cerebral blood flow;
and SAH, subarachnoid hemorrhage.

Downloaded from http://circ.ahajournals.org/ by guest on February 27, 2014

182

Circulation

July 8, 2008

Patients With Acute Ischemic Stroke


Receiving Thrombolysis
The acute hypertensive response among patients with ischemic stroke receiving thrombolysis is frequently transient69
and resolves after recanalization70; however, elevated BP
before receipt of thrombolysis has been associated with an
increased risk of ICH. In the Australian Streptokinase Trial,71
baseline systolic BP 165 mm Hg resulted in a 25% increased risk of major ICHs among patients with ischemic
stroke treated with streptokinase. In a multicenter retrospective and prospective investigation72 of individual data from
1205 patients treated in routine clinical practice with intravenous rtPA within 3 hours of stroke symptom onset, elevated pretreatment MAP was associated with an increased
rate of ICH. In a large audit of practices and outcomes in 29
hospitals in the Cleveland, Ohio, area,73 BP parameters
recommended by the NINDS rtPA trial were not followed in
52% of the 70 patients treated with intravenous thrombolysis.
The result was a 16% rate of symptomatic ICHs. A qualityimprovement program in 9 of these hospitals74 decreased the
rate of noncompliance to BP recommendations to 6% in 47
patients subsequently treated with rtPA. The rate of symptomatic ICH dropped to 6%, which indirectly supports the
beneficial value of BP control in reducing rtPA-related ICHs.
Both the ASA and European Stroke Initiative guidelines
recommend the reduction of BP according to the eligibility
thresholds for inclusion in the NINDS rtPA efficacy trial42
(Figure7,42 47) before thrombolytics are administered.46,67,68
In the NINDS rtPA efficacy trial,42 patients were not eligible
if they required aggressive antihypertensive therapy, defined
as use of intravenous nitroprusside or repeated intravenous
infusions of other medications. A post hoc analysis reported
the frequency, course, and treatment of hypertension (185/
110 mm Hg before randomization or 180/105 mm Hg
within the first 24 hours after randomization).42 Antihypertensive treatment before and after treatment with rtPA was
used in 9% and 24%, respectively, of the patients treated with
rtPA. Prethrombolysis use of antihypertensive treatment did
not adversely affect the rate of favorable outcomes at 3
months. Postthrombolysis hypertension and use of antihypertensive treatment correlated with a lower rate of favorable
outcome at 3 months. It remains unclear whether this adverse
effect was related to more severe ischemic injury, persistent
vascular occlusion, or pronounced reduction in BP. Patients
treated with thrombolytics and antihypertensive therapy were
more likely to have an abrupt decline in BP than those who
were not treated. The higher susceptibility to hypotension
associated with antihypertensive treatment after thrombolytic
use (not seen in the placebo group) may be related to
recanalization or reperfusion; however, the rate of ICH
among patients with acute hypertension with appropriate
control was similar to that observed in nonhypertensive
patients. Another study75 reported that postthrombolytic acute
hypertension occurred predominantly within 6 hours of receipt of thrombolysis, and if treated adequately, is not
associated with an increased risk of ICH. Therefore, early BP
reduction with rapidly acting antihypertensive treatment appears paramount for safe and beneficial thrombolysis among
patients with acute ischemic stroke. Frequent BP monitoring

and titration with short-acting intravenous agents are preferable to avoid uncontrolled decline in BP. The data about
treating the acute hypertensive response after thrombolytic
use are limited, because most studies excluded patients with
difficult-to-control BP and did not use some of the newer
antihypertensive agents. With the increasing use of
thrombolytics and other endovascular treatment in acute
ischemic stroke, new studies are required to address these
issues.

Patients With ICH


One third of subjects presenting with ICH continue to
demonstrate hematoma expansion (with subsequent deterioration and death) in the first few hours after onset.76 An initial
systolic BP 200 mm Hg is associated with hematoma
expansion77 and increased mortality78 among patients with
ICH. Persistently higher systolic BP is also associated with
perihematoma brain edema formation.79 Reducing BP may
reduce the rate of hematoma expansion, although conclusive
evidence of this is not available.29 Recent studies suggest that
reduction of BP may be tolerated because of reduced metabolism (hibernation)80 and preserved autoregulation in the
perihematoma region.81
A multicenter prospective observational study82 reported
the use of intravenous labetalol, hydralazine, and/or nitroprusside for maintaining BP 160/90 mm Hg within 24
hours of symptom onset among patients with ICH. Low rates
of neurological deterioration and hematoma expansion were
observed in treated patients. Patients treated within 6 hours of
symptom onset were more likely to be functionally independent at 1 month than patients who were treated between 6 and
24 hours. Another study83 evaluated the tolerability and safety
of intravenous nicardipine infusion within 24 hours of symptom onset to reduce and maintain MAP 130 mm Hg,
consistent with previous ASA guidelines. The primary outcome of tolerability was achieved in 86% of the patients. Low
rates of neurological deterioration and hematoma expansion
were observed among treated patients. Indirect comparisons
suggest that intermittent intravenous bolus regimens of antihypertensive agents have greater variability in BP control
than continous infusion regimens.83
The current ASA44 and European Stroke Initiative45 guidelines recommend lowering BP in patients with an ICH to
maintain systolic BP below 180 mm Hg. Both guidelines
acknowledge that there may be a subset of patients who can
tolerate more aggressive BP reduction, such as those with
good neurological status or those without chronic hypertension. A recent observational study suggested that more
aggressive BP reduction may have greater benefit in reducing
the rate of hematoma expansion. One study assessed the
results of lowering systolic BP below targets of 140, 150, or
160 mm Hg.84 The rate of hematoma expansion was 9% in
patients with systolic BP 150 mm Hg and 30% among
patients treated to maintain systolic BP 160 mm Hg or a
higher threshold. Several ongoing trials (Table 1) are prospectively evaluating whether more aggressive BP lowering
is safe and reduces the rate of hematoma expansion. The
NINDS-funded Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)60 trial is presently determining

Downloaded from http://circ.ahajournals.org/ by guest on February 27, 2014

Qureshi

Acute Hypertensive Response in Stroke Patients

183

Table 2. Pharmacological Characteristics of Antihypertensive Agents Recommended in the Stroke Council, American Heart
Associations Statements for Healthcare Professionals
Mechanism of
Action

Agent
Labetalol

Hydralazine

- and
-Adrenergic
blocker

CBF

ICP

Autoregulation

Platelet
Activity

Cardiac
Contractility

Dose

Onset of
Action

Half-Life

Ischemic
Stroke

ICH

Direct relaxation of
arteriolar smooth
muscle

520-mg bolus
every 15 min

1020
min

14 h

SS, ES53

SS, CS82

SS,
CS,42
ES90

SS, CS82

520-mg bolus
every 15 min up
to 300 mg

510
min

36 h

SS,
CS,42
ES87

SS, CS,82,88
ES89

Nitroprusside

Releases nitric
oxide

Infusion of 0.2 to
10
g kg1 min1

Within
seconds

25 min

Nitroglycerine

Releases nitric
oxide

20 to 400
g/min

12 min

35 min

Nitropaste

Releases nitric
oxide

0.20.4 mg/h up
to 0.8 mg/h

12 min

35 min

SS, CS92

SS, CS92

Nicardipine

Calcium channel
blocker

515 mg/h

510
min

0.54 h

SS, CS58

SS, CS81,83

Esmolol

-Adrenergic
blocker

250 g/kg bolus


followed by 25
to 300
g kg1 min1

5 min

9 min

Enalapril*

ACE inhibitor

1.255 mg every
6h

15 min

14 h

SS, CS91

SS

CS,93
ES53

SS, ES94

CBF indicates cerebral blood flow; SS, scientific statement; CS, clinical study; ES, experimental study; ACE, angiotensin-converting enzyme; , increase or favorable
effects; , substantial increase or favorable effects; , decrease or negative effects; and . . . , no documented direct effect.
No conclusive evidence is present at this point to avoid any particular class of antihypertensive medication (including -blockers95). In general, medications with
slow onset of action, long half-lives, or those known to cause precipitous BP reduction (sublingual nifedipine96) should be avoided in the first 24 hours because they
cannot be titrated to ensure controlled BP reduction.
*Data predominantly derived from other ACE inhibitors; limited data available; not derived from studies performed in acute stroke settings and unclear direct
relevance.

the exact threshold of BP lowering (systolic BP


140 mm Hg, 170 mm Hg, or 200 mm Hg) for patients
with ICH within 6 hours of symptom onset. Another pilot
randomized study, Intensive Blood Pressure Reduction in
Acute Cerebral Hemorrhage (INTERACT), is comparing
clinical outcomes in patients treated with intensive BP lowering (systolic BP 140 mm Hg) versus those treated according to ASA guidelines within 6 hours of symptom onset. Both
trials recently reported preliminary results that suggested that
aggressive BP reduction to a target of 140 mm Hg probably
decreases the rate of substantial hematoma enlargement84a
without increasing adverse events.84b
A new consideration is the combination of intravenous
hemostatic treatment and aggressive BP control. In an exploratory analysis from a study of recombinant activated factor
VII85 in ICH, initial systolic BP 170 mm Hg was associated
with a trend toward lower hematoma expansion rates. In
another study,86 a total of 188 patients admitted within 24
hours of symptom onset were treated with a combination of
rapidly administered antifibrinolytic agents and systolic BP
maintained 150 mm Hg. Hematoma enlargement was observed in only 4.3% of patients, which supports further
evaluation of this approach.

Antihypertensive Agents and Regimens


The agents that are recommended by the ASA for acute
hypertensive response are either intravenous or transdermal

agents with rapid onset and short duration of action to allow


precise titration (Table 242,53,58,81 83,8796). BP can be monitored adequately with an inflatable cuff in most patients with
acute hypertensive response, whereas intra-arterial monitoring should be considered in patients who require frequent
titration with intravenous antihypertensive agents and in
patients whose neurological status is deteriorating. ICP monitoring may be necessary in patients with a suspected increased ICP, to measure and preserve cerebral perfusion
pressure during systemic BP lowering. Patients with a poor
level of consciousness, midline shift, or compression of basal
cisterns on computed tomographic scan may be considered
for ICP monitoring when being treated with antihypertensive
agents. Of note, cerebral perfusion pressure may overestimate
regional perfusion because of its inability to measure regional
pressure and autoregulatory disturbances.

Management of Chronic Hypertension in the


Immediate Poststroke Period
Approximately 50% of patients are admitted with stroke
while taking regular antihypertensive therapy.8 The abrupt
discontinuation of antihypertensive medication may lead to
enhanced sympathetic activity, rebound hypertension, and a
consequent increase in cardiovascular events97,98 in patients
with coronary artery disease using -adrenergic blockers or
those using high doses of centrally acting antiadrenergic
drugs. In studies conducted in nonstroke patients, a slow

Downloaded from http://circ.ahajournals.org/ by guest on February 27, 2014

184

Circulation

July 8, 2008

increase in systemic BP99 and a low rate of cardiovascular


events100 follows discontinuation of antihypertensive treatment. A small randomized trial101 was unable to demonstrate
any difference in the rate of death or disability after discontinuation of antihypertensive treatment in patients with ischemic stroke within 72 hours of symptom onset. New multicenter trials are addressing this question (Table 1). In the
interim, the decision to continue or discontinue antihypertensive agents must be made on a case-by-case basis with the
intent to avoid hypotension, excessive hypertension, and
myocardial ischemia. Reduction of the dose of the current
agent or a change to a short-acting intravenous antihypertensive agent may be considered.
Another issue is the timing of initiation or aggressive
titration of oral antihypertensive treatment in patients with
stroke who have chronic hypertension or undetected hypertension. In the California Acute Stroke Prototype Registry,102
great variability in practices between hospitals and considerable room for improvement was noted among two thirds of
patients with acute ischemic cerebrovascular events discharged from the hospital who were given 1 or more
antihypertensive medications. The heterogeneity in practice
despite the definitive benefit demonstrated in clinical trials103105 is concerning. Theoretically, oral hypertensive
agents can be initiated at 24 to 48 hours after symptom onset,
because most of the acute processes, such as ischemic
penumbra and hematoma expansion, are uncommon after the
first 24 hours. In the ACCESS trial47 (discussed above),
treatment was started with daily candesartan or placebo on
day 1. On day 2, the dosage was increased 2- or 4-fold if BP
was 160/100 mm Hg. If patients in the candesartan group
showed a hypertensive profile on day 7 (mean daytime BP
135/85 mm Hg), candesartan was increased or an additional
antihypertensive drug was added. The results support early
initiation of antihypertensive treatment with gradual titration
to more aggressive BP treatment targets.
The JNC 7 report7 recommends that BP be maintained at
intermediate levels (around 160/100 mm Hg) until neurological stability is achieved. Special circumstances such as
elevated ICP, progressive cerebral edema, ongoing cerebral
ischemia due to occlusive vessel disease or symptomatic
cerebral vasospasm, and postoperative cerebral changes require individualized management. After the first week, or
when neurological stability is achieved, a more aggressive
treatment can be initiated for secondary prevention of recurrent stroke.7,106 The ASA107 recommends that antihypertensive therapy be considered for all patients with ischemic
stroke or transient ischemic attack, because benefit is seen in
persons with and without a history of hypertension. Special
consideration may be necessary for patients with bilateral
severe carotid stenoses,108 who may bear a high risk of stroke
with aggressive BP lowering until carotid revascularization is
performed.

Conclusions
Different strategies are required to manage the acute hypertensive response in different subtypes of stroke. Therefore,
early diagnosis and differentiation are critically important for
timely institution of the appropriate strategy. The manage-

ment of high BP in acute ischemic stroke is highly controversial because of a lack of reliable evidence from randomized, controlled trials. Aggressive BP reduction is currently
not recommended in patients with ischemic stroke in the
acute phase because of potentially deleterious effects observed in some observational studies and absence of a
documented benefit of acute BP lowering. A reduction in BP
before administration of thrombolytics in patients with ischemic stroke is important to reduce the risk of secondary ICHs.
Reduction of BP in patients with ICH requires further
evaluation for efficacy given recent studies that have documented clinical tolerability due to reduced metabolism (hibernation) with preserved autoregulation in the perihematoma
region.
Further studies are required to demonstrate the clinical
benefits of treating the acute hypertensive response in patients with stroke and to determine whether these benefits are
agent specific. Imaging modalities need to be developed that
allow bedside measurement of regional cerebral blood flow
and metabolism so that titration of antihypertensive treatment
can be based on critical variables. Most recommendations are
based on expert opinions and general principles defined by
observational studies and small clinical trials. With the
anticipated completion of several large clinical trials in the
next 5 years, these recommendations can be established on
the basis of superior levels of scientific evidence.

Acknowledgment
The author wishes to thank Donald Quick, PhD, for his careful
review of the manuscript and helpful comments.

Sources of Funding
Dr Qureshi was supported in part by the National Institute of
Neurological Diseases and Stroke, National Institutes of Health, as
Principal Investigator of the Antihypertensive Treatment in Acute
Cerebral Hemorrhage (ATACH; R01-NS44976-01A2), medication
for which was provided by Protein Design Labs. Dr Qureshi is also
the recipient of an Established Investigator Award from the American Heart Association as principal investigator of Innovative Strategies for Treating Cerebral Hemorrhage (American Heart Association grant No. 0840053N).

Disclosures
Dr Qureshi was the recipient of an honorarium from the Emergency
Medicine Cardiac Research Education Group.

References
1. Qureshi AI, Ezzeddine MA, Nasar A, Suri MF, Kirmani JF, Hussein
HM, Divani AA, Reddi AS. Prevalence of elevated blood pressure in
563704 adult patients with stroke presenting to the ED in the United
States. Am J Emerg Med. 2007;25:3238.
2. Qureshi AI, Suri MFK, Nasar A, Kirmani JF, Ezzeddine MA, Divani
AA, Giles WH. Changes in cost and outcome among US patients with
stroke hospitalized in 1990 to 1991 and those hospitalized in 2000 to
2001. Stroke. 2007;38:2180 2184.
3. International cardiovascular disease statistics (2007 update).
Available at: www.americanheart . org / downloadable / heart/
1140811583642InternationalCVD.pdf. Accessed November 21, 2007.
4. Lindenauer PK, Mathew MC, Ntuli TS, Pekow PS, Fitzgerald J,
Benjamin EM. Use of antihypertensive agents in the management of
patients with acute ischemic stroke. Neurology. 2004;63:318 323.
5. Lakshminarayan K, Anderson DC, Borbas C, Duval S, Luepker RV.
Blood pressure management in acute ischemic stroke. J Clin Hypertens
(Greenwich). 2007;9:444 453.

Downloaded from http://circ.ahajournals.org/ by guest on February 27, 2014

Qureshi
6. Whitworth JA. 2003 World Health Organization (WHO)/International
Society of Hypertension (ISH) statement on management of hypertension. J Hypertens. 2003;21:19831992.
7. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo
JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. The
seventh report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure: the JNC
7 report. JAMA. 2003;289:2560 2572.
8. Bath P, Chalmers J, Powers W, Beilin L, Davis S, Lenfant C, Mancia G,
Neal B, Whitworth J, Zanchetti A; International Society of Hypertension
Writing Group. International Society of Hypertension (ISH): statement
on the management of blood pressure in acute stroke. J Hypertens.
2003;21:665 672.
9. Willmot M, Leonardi-Bee J, Bath PM. High blood pressure in acute
stroke and subsequent outcome: a systematic review. Hypertension.
2004;43:18 24.
10. Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock PA. Blood pressure
and clinical outcomes in the International Stroke Trial. Stroke. 2002;33:
13151320.
11. Qureshi AI, Suri MF, Kirmani JF, Divani AA. Prevalence and trends of
prehypertension and hypertension in United States: National Health and
Nutrition Examination Surveys 1976 to 2000. Med Sci Monit. 2005;11:
CR403CR409.
12. Rodriguez-Yanez M, Castellanos M, Blanco M, Garcia MM, Nombela
F, Serena J, Leira R, Lizasoain I, Davalos A, Castillo J. New-onset
hypertension and inflammatory response/poor outcome in acute ischemic stroke. Neurology. 2006;67:19731978.
13. Wallace JD, Levy LL. Blood pressure after stroke. JAMA. 1981;246:
21772180.
14. 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:
2420 2425.
15. Arboix A, Roig H, Rossich R, Martinez EM, Garcia-Eroles L. Differences between hypertensive and non-hypertensive ischemic stroke.
Eur J Neurol. 2004;11:687 692.
16. Mattle HP, Kappeler L, Arnold M, Fischer U, Nedeltchev K, Remonda
L, Jakob SM, Schroth G. Blood pressure and vessel recanalization in the
first hours after ischemic stroke. Stroke. 2005;36:264 268.
17. Resstel LB, Correa FM. Involvement of the medial prefrontal cortex in
central cardiovascular modulation in the rat. Auton Neurosci. 2006;
126 127:130 138.
18. Hilz MJ, Devinsky O, Szczepanska H, Borod JC, Marthol H, Tutaj M.
Right ventromedial prefrontal lesions result in paradoxical cardiovascular activation with emotional stimuli. Brain. 2006;129:33433355.
19. Meyer S, Strittmatter M, Fischer C, Georg T, Schmitz B. Lateralization
in autonomic dysfunction in ischemic stroke involving the insular
cortex. Neuroreport. 2004;15:357361.
20. Nason MW Jr, Mason P. Modulation of sympathetic and somatomotor
function by the ventromedial medulla. J Neurophysiol. 2004;92:
510 522.
21. Barron SA, Rogovski Z, Hemli J. Autonomic consequences of cerebral
hemisphere infarction. Stroke. 1994;25:113116.
22. Robinson TG, James M, Youde J, Panerai R, Potter J. Cardiac baroreceptor sensitivity is impaired after acute stroke. Stroke. 1997;28:
16711676.
23. Oppenheimer S. The anatomy and physiology of cortical mechanisms of
cardiac control. Stroke. 1993;24:I3I5.
24. Ichiyama RM, Waldrop TG, Iwamoto GA. Neurons in and near insular
cortex are responsive to muscular contraction and have sympathetic
and/or cardiac-related discharge. Brain Res. 2004;1008:273277.
25. Resstel LBM, Correa FMA. Medial prefrontal cortex NMDA receptors
and nitric oxide modulate the parasympathetic component of the
baroreflex. Eur J Neurosci. 2006;23:481 488.
26. Murros K, Fogelholm R, Kettunen S, Vuorela AL. Serum cortisol and
outcome of ischemic brain infarction. J Neurol Sci. 1993;116:1217.
27. Chamorro A, Amaro S, Vargas M, Obach V, Cervera A, Gomez-Choco
M, Torres F, Planas AM. Catecholamines, infection, and death in acute
ischemic stroke. J Neurol Sci. 2007;252:29 35.
28. Qureshi AI, Luft AR, Sharma M, Janardhan V, Lopes DK, Khan J,
Guterman LR, Hopkins LN. Frequency and determinants of postprocedural hemodynamic instability after carotid angioplasty and stenting.
Stroke. 1999;30:2086 2093.

Acute Hypertensive Response in Stroke Patients

185

29. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF.
Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:
1450 1460.
30. Qureshi AI, Geocadin RG, Suarez JI, Ulatowski JA. Long-term outcome
after medical reversal of transtentorial herniation in patients with supratentorial mass lesions. Crit Care Med. 2000;28:1556 1564.
31. Qureshi AI, Wilson DA, Traystman RJ. Treatment of transtentorial
herniation unresponsive to hyperventilation using hypertonic saline in
dogs: effect on cerebral blood flow and metabolism. J Neurosurg Anesthesiol. 2002;14:2230.
32. Qureshi AI, Suri MFK, Ringer AJ, Guterman LR, Hopkins LN. Regional
intraparenchymal pressure differences in experimental intracerebral
hemorrhage: effect of hypertonic saline. Crit Care Med. 2002;30:
435 441.
33. Qureshi AI, Wilson DA, Traystman RJ. Treatment of elevated intracranial pressure in experimental intracerebral hemorrhage: comparison
between mannitol and hypertonic saline. Neurosurgery. 1999;44:
10551063.
34. Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation.
Cerebrovasc Brain Metab Rev. 1990;2:161192.
35. Aaslid R, Lindegaard KF, Sorteberg W, Nornes H. Cerebral autoregulation dynamics in humans. Stroke. 1989;20:4552.
36. Symon L, Held K, Dorsch NW. A study of regional autoregulation in the
cerebral circulation to increased perfusion pressure in normocapnia and
hypercapnia. Stroke. 1973;4:139 147.
37. 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;53:720 727.
38. Olsen TS, Larsen B, Herning M, Skriver EB, Lassen NA. Blood flow
and vascular reactivity in collaterally perfused brain tissue: evidence of
an ischemic penumbra in patients with acute stroke. Stroke. 1983;14:
332341.
39. Dawson SL, Panerai RB, Potter JF. Serial changes in static and dynamic
cerebral autoregulation after acute ischaemic stroke. Cerebrovasc Dis.
2003;16:69 75.
40. Yamamoto S, Nishizawa S, Tsukada H, Kakiuchi T, Yokoyama T, Ryu
H, Uemura K. Cerebral blood flow autoregulation following subarachnoid hemorrhage in rats: chronic vasospasm shifts the upper and lower
limits of the autoregulatory range toward higher blood pressures. Brain
Research. 1998;782:194 201.
41. The Brain Trauma Foundation, The American Association of Neurological Surgeons, The Joint Section on Neurotrauma and Critical Care.
Guidelines for cerebral perfusion pressure. J Neurotrauma. 2000;17:
507511.
42. Brott T, Lu M, Kothari R, Fagan SC, Frankel M, Grotta JC, Broderick
J, Kwiatkowski T, Lewandowski C, Haley EC, Marler JR, Tilley BC.
Hypertension and its treatment in the NINDS rt-PA stroke trial. Stroke.
1998;29:1504 1509.
43. Moon JS, Janjua N, Ahmed S, Kirmani JF, Harris-Lane P, Jacob M,
Ezzeddine MA, Qureshi AI. Prehospital neurologic deterioration in
patients with intraparenchymal hemorrhage. Crit Care Med. 2008;36:
172175.
44. Broderick J, Connolly S, Feldmann E, Hanley D, Kase C, Krieger D,
Mayberg M, Morgenstern L, Ogilvy CS, Vespa P, Zuccarello M.
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 Council, and the Quality of Care and Outcomes in
Research Interdisciplinary Working Group. Stroke. 2007;38:20012023.
45. Steiner T, Kaste M, Forsting M, Mendelow D, Kwiecinski H, Szikora I,
Juvela S, Marchel A, Chapot R, Cognard C, Unterberg A, Hacke W.
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 [published correction appears in Cerebrovasc Dis. 2006;
22:461]. Cerebrovasc Dis. 2006;22:294 316.
46. Adams HP Jr, Del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan AJ,
Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden P, Morgenstern
L, Qureshi AI, Rosenwasser RH, Scott P, Wijdicks EF. Guidelines for
the early management of patients with ischemic stroke. Circulation.
2007;115:e478 534.
47. Schrader J, Luders S, Kulschewski A, Berger J, Zidek W, Treib J,
Einhaupl K, Diener HC, Dominiak P. The ACCESS Study: evaluation of

Downloaded from http://circ.ahajournals.org/ by guest on February 27, 2014

186

48.
49.

50.

51.
52.

53.

54.

55.

56.

57.

58.
59.

60.
61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

Circulation

July 8, 2008

acute candesartan cilexetil therapy in stroke survivors. Stroke. 2003;34:


1699 1703.
McGee S, Abernethy WB III, Simel DL. The rational clinical examination: is this patient hypovolemic? JAMA. 1999;281:10221029.
Jivraj S, Mazer CD, Baker AJ, Choi M, Hare GMT. Case report:
profound hypotension associated with labetalol therapy in a patient with
cerebral aneurysms and subarachnoid hemorrhage. Can J Anaesth. 2006;
53:678 683.
McLaren GD, Danta G. Cerebral infarction due to presumed haemodynamic factors in ambulant hypertensive patients. Clin Exp Neurol.
1987;23:55 66.
Janardhan V, Qureshi AI. Mechanisms of ischemic brain injury. Curr
Cardiol Rep. 2004;6:117123.
Astrup J, Symon L, Branston NM, Lassen NA. Cortical evoked potential
and extracellular K and H at critical levels of brain ischemia. Stroke.
1977;8:5157.
Elewa HF, Kozak A, Johnson MH, Ergul A, Fagan SC. Blood pressure
lowering after experimental cerebral ischemia provides neurovascular
protection. J Hypertens. 2007;25:855 859.
Stead LG, Gilmore RM, Vedula KC, Weaver AL, Decker WW, Brown
RD Jr. Impact of acute blood pressure variability on ischemic stroke
outcome. Neurology. 2006;66:1878 1881.
Barer DH, Cruickshank JM, Ebrahim SB, Mitchell JR. Low dose beta
blockade in acute stroke (Best Trial): an evaluation. BMJ. 1988;296:
737741.
Blood pressure in Acute Stroke Collaboration (BASC). Interventions for
deliberately altering blood pressure in acute stroke. Cochrane Database
Syst Rev. 2001:CD000039.
Bath PM, Willmot M, Leonardi-Bee J, Bath FJ. Nitric oxide donors
(nitrates), L-arginine, or nitric oxide synthase inhibitors for acute stroke.
Cochrane Database Syst Rev. 2002;(4):CD000398.
Horn J, Limburg M. Calcium antagonists for acute ischemic stroke.
Cochrane Database Syst Rev. 2000;(2):CD001928.
Oliveira-Filho J, Silva SCS, Trabuco CC, Pedreira BB, Sousa EU,
Bacellar A. Detrimental effect of blood pressure reduction in the first 24
hours of acute stroke onset. Neurology. 2003;61:10471051.
Qureshi AI. Antihypertensive treatment of acute cerebral hemorrhage
(ATACH): rationale and design. Neurocrit Care. 2007;6:56 66.
Ahmed N, Nasman P, Wahlgren NG. Effect of intravenous nimodipine
on blood pressure and outcome after acute stroke. Stroke. 2000;31:
1250 1255.
Lisk DR, Grotta JC, Lamki LM, Tran HD, Taylor JW, Molony DA,
Barron BJ. Should hypertension be treated after acute stroke? A randomized controlled trial using single photon emission computed
tomography. Arch Neurol. 1993;50:855 862.
Ahmed N, Wahlgren NG. Effects of blood pressure lowering in the acute
phase of total anterior circulation infarcts and other stroke subtypes.
Cerebrovasc Dis. 2003;15:235243.
Rashid P, Leonardi-Bee J, Bath P. Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic
review. Stroke. 2003;34:27412748.
Turnbull F; Blood Pressure Lowering Treatment Trialists Collaboration. Effects of different blood-pressure-lowering regimens on major
cardiovascular events: results of prospectively-designed overviews of
randomised trials. Lancet. 2003;362:15271535.
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;35:520 526.
Hacke W, Kaste M, Skyhoj Olsen T, Bogousslavsky J, Orgogozo JM.
Acute treatment of ischemic stroke: European Stroke Initiative (EUSI).
Cerebrovasc Dis. 2000;10(suppl 3):2233.
Klijn CJM, Hankey GJ; American Stroke Association and European
Stroke Initiative. Management of acute ischaemic stroke: new guidelines
from the American Stroke Association and European Stroke Initiative.
Lancet Neurol. 2003;2:698 701.
Broderick J, Brott T, Barsan W, Haley EC, Levy D, Marler J, Sheppard
G, Blum C. Blood pressure during the first minutes of focal cerebral
ischemia. Ann Emerg Med. 1993;22:1438 1443.
Mattle HP, Kappeler L, Arnold M, Fischer U, Nedeltchev K, Remonda
L, Jakob SM, Schroth G. Blood pressure and vessel recanalization in the
first hours after ischemic stroke. Stroke. 2005;36:264 268.
Gilligan AK, Markus R, Read S, Srikanth V, Hirano T, Fitt G, Arends
M, Chambers BR, Davis SM, Donnan GA. Baseline blood pressure but
not early computed tomography changes predicts major hemorrhage

after streptokinase in acute ischemic stroke. Stroke. 2002;33:


2236 2242.
72. Tanne D, Kasner SE, Demchuk AM, Koren-Morag N, Hanson S, Grond
M, Levine SR. Markers of increased risk of intracerebral hemorrhage
after intravenous recombinant tissue plasminogen activator therapy for
acute ischemic stroke in clinical practice: the multicenter rt-PA stroke
survey. Circulation. 2002;105:1679 1685.
73. Katzan IL, Furlan AJ, Lloyd LE, Frank JI, Harper DL, Hinchey JA,
Hammel JP, Qu A, Sila CA. Use of tissue-type plasminogen activator for
acute ischemic stroke: the Cleveland area experience. JAMA. 2000;283:
11511158.
74. Katzan IL, Hammer MD, Furlan AJ, Hixson ED, Nadzam DM;
Cleveland Clinic Health System Stroke Quality Improvement Team.
Quality improvement and tissue-type plasminogen activator for acute
ischemic stroke: a Cleveland update. Stroke. 2003;34:799 800.
75. Aiyagari V, Gujjar A, Zazulia AR, Diringer MN. Hourly blood pressure
monitoring after intravenous tissue plasminogen activator for ischemic
stroke: does everyone need it? Stroke. 2004;35:2326 2330.
76. Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN, Mayer
SA, Begtrup K, Steiner T. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology.
2006;66:11751181.
77. Kazui S, Minematsu K, Yamamoto H, Sawada T, Yamaguchi T. Predisposing factors to enlargement of spontaneous intracerebral
hematoma. Stroke. 1997;28:2370 2375.
78. Dandapani BK, Suzuki S, Kelley RE, Reyes-Iglesias Y, Duncan RC.
Relation between blood pressure and outcome in intracerebral hemorrhage. Stroke. 1995;26:2124.
79. Vemmos KN, Tsivgoulis G, Spengos K, Zakopoulos N, Synetos A,
Kotsis V, Vassilopoulos D, Mavrikakis M. Association between 24-h
blood pressure monitoring variables and brain oedema in patients with
hyperacute stroke. J Hypertens. 2003;21:21672173.
80. Kim-Han JS, Kopp SJ, Dugan LL, Diringer MN. Perihematomal mitochondrial dysfunction after intracerebral hemorrhage. Stroke. 2006;37:
24572462.
81. Powers WJ, Zazulia AR, Videen TO, Adams RE, Yundt KD, Aiyagari
V, Grubb RL Jr, Diringer MN. Autoregulation of cerebral blood flow
surrounding acute (6 to 22 hours) intracerebral hemorrhage. Neurology.
2001;57:18 24.
82. Qureshi AI, Mohammad YM, Yahia AM, Suarez JI, Siddiqui AM,
Kirmani JF, Suri MF, Kolb J, Zaidat OO. 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;20:34 42.
83. Qureshi AI, Harris-Lane P, Kirmani JF, Ahmed S, Jacob M, Zada Y,
Divani AA. Treatment of acute hypertension in patients with intracerebral hemorrhage using American Heart Association guidelines. Crit
Care Med. 2006;34:19751980.
84. Ohwaki K, Yano E, Nagashima H, Hirata M, Nakagomi T, Tamura A.
Blood pressure management in acute intracerebral hemorrhage: relationship between elevated blood pressure and hematoma enlargement.
Stroke. 2004;35:1364 1367.
84a. Anderson C, Huang Y, Wang J, Jin R, Arima H, Neal B, Peng B, Heeley
E, Skulina C, Parsons M, Kim JS, Heritier S, Morgenstern L, Chalmers
J. The Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage (INTERACT) trial: results of the vanguard phase. Paper presented
at: International Stroke Conference 2008; February 20 22, 2008; New
Orleans, La.
84b. Qureshi AI. Antihypertensive Treatment of Acute Cerebral Hemorrhage
(ATACH) trial. Paper presented at: International Stroke Conference
2008; February 20 22, 2008; New Orleans, La.
85. Broderick JP, Diringer MN, Hill MD, Brun NC, Mayer SA, Steiner T,
Skolnick BE, Davis SM. Determinants of intracerebral hemorrhage
growth: an exploratory analysis. Stroke. 2007;38:10721075.
86. Sorimachi T, Fujii Y, Morita K, Tanaka R. Predictors of hematoma
enlargement in patients with intracerebral hemorrhage treated with rapid
administration of antifibrinolytic agents and strict blood pressure
control. J Neurosurg. 2007;106:250 254.
87. 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;150:153158.
88. Patel RV, Kertland HR, Jahns BE, Zarowitz BJ, Mlynarek ME, Fagan
SC. Labetalol: response and safety in critically ill hemorrhagic stroke
patients. Ann Pharmacother. 1993;27:180 181.

Downloaded from http://circ.ahajournals.org/ by guest on February 27, 2014

Qureshi
89. Qureshi AI, Wilson DA, Hanley DF, Traystman RJ. Pharmacologic
reduction of mean arterial pressure does not adversely affect regional
cerebral blood flow and intracranial pressure in experimental intracerebral hemorrhage. Crit Care Med. 1999;27:965971.
90. Zhang F, Iadecola C. Nitroprusside improves blood flow and reduces
brain damage after focal ischemia. Neuroreport. 1993;4:559 562.
91. Kuroda K, Kuwata N, Sato N, Funayama M, Yabuta A, Taguchi S,
Suzuki M, Takahashi A, Ogawa A. Changes in cerebral blood flow
accompanied with reduction of blood pressure treatment in patients with
hypertensive intracerebral hemorrhages. Neurol Res. 1997;19:169 173.
92. Willmot M, Ghadami A, Whysall B, Clarke W, Wardlaw J, Bath PMW.
Transdermal glyceryl trinitrate lowers blood pressure and maintains
cerebral blood flow in recent stroke. Hypertension. 2006;47:1209 1215.
93. Waldemar G, Vorstrup S, Andersen AR, Pedersen H, Paulson OB.
Angiotensin-converting enzyme inhibition and regional cerebral blood
flow in acute stroke. J Cardiovasc Pharmacol. 1989;14:722729.
94. Smeda J, Vasdev S, King SR. Effect of poststroke captopril treatment on
mortality associated with hemorrhagic stroke in stroke-prone rats.
J Pharmacol Exp Ther. 1999;291:569 575.
95. Dziedzic T, Slowik A, Pera J, Szczudlik A. Beta-blockers reduce the risk
of early death in ischemic stroke. J Neurol Sci. 2007;252:5356.
96. Rehman F, Mansoor GA, White WB. Inappropriate physician habits in
prescribing oral nifedipine capsules in hospitalized patients.
Am J Hypertens. 1996;9:10351039.
97. Houston MC. Abrupt discontinuation of antihypertensive therapy. South
Med J. 1981;74:11121123.
98. Houston MC. Abrupt cessation of treatment in hypertension: consideration of clinical features, mechanisms, prevention and management of
the discontinuation syndrome. Am Heart J. 1981;102:415 430.
99. Sieg-Dobrescu D, Burnier M, Hayoz D, Brunner HR, Waeber B. The
return of increased blood pressure after discontinuation of antihypertensive treatment is associated with an impaired post-ischemic skin blood
flow response. J Hypertens. 2001;19:13871392.
100. Kostis JB, Espeland MA, Appel L, Johnson KC, Pierce J, Wofford JL.
Does withdrawal of antihypertensive medication increase the risk of
cardiovascular events? Trial of Nonpharmacologic Interventions in the
Elderly (TONE) Cooperative Research Group. Am J Cardiol. 1998;82:
15011508.
101. Popa G, Voiculescu V, Popa C, Stnescu A, Nistorescu A, Jipescu I.
Stroke and hypertension: antihypertensive therapy withdrawal. Rom
J Neurol Psychiatry. 1995;33:29 35.

Acute Hypertensive Response in Stroke Patients

187

102. Ovbiagele B, Hills NK, Saver JL, Johnston SC. Antihypertensive medications prescribed at discharge after an acute ischemic cerebrovascular
event. Stroke. 2005;36:1944 1947.
103. Gueyffier F, Boissel JP, Boutitie F, Pocock S, Coope J, Cutler J, Ekbom
T, Fagard R, Friedman L, Kerlikowske K, Perry M, Prineas R, Schron
E. Effect of antihypertensive treatment in patients having already
suffered from stroke: gathering the evidence: the INDANA (Individual
Data Analysis of Antihypertensive Intervention Trials) Project Collaborators. Stroke. 1997;28:25572562.
104. Rezaiefar P, Pottie K. Blood pressure and secondary prevention of
strokes: how low should we go? Randomised trial of a perindopril-based
blood-pressure-lowering regimen among 6,105 individuals with
previous stroke or transient ischaemic attack. Can Fam Physician. 2002;
48:16251629.
105. Arima H, Chalmers J, Woodward M, Anderson C, Rodgers A, Davis S,
Macmahon S, Neal B, Group PC. Lower target blood pressures are safe
and effective for the prevention of recurrent stroke: the PROGRESS
trial. J Hypertens. 2006;24:12011208.
106. Chalmers J, Todd A, Chapman N, Beilin L, Davis S, Donnan G,
Frommer M, Huxley R, Lenfant C, MacMahon S, Mancia G, Mendis S,
Whitworth J, Zanchetti A; International Society of Hypertension Writing
Group. International Society of Hypertension (ISH): statement on blood
pressure lowering and stroke prevention. J Hypertens. 2003;21:
651 663.
107. Sacco RL, Adams R, Albers G, Alberts MJ, Benavente O, Furie K,
Goldstein LB, Gorelick P, Halperin J, Harbaugh R, Johnston SC, Katzan
I, Kelly-Hayes M, Kenton EJ, Marks M, Schwamm LH, Tomsick T;
American Heart Association/American Stroke Association Council on
Stroke, Council on Cardiovascular Radiology and Intervention,
American Academy of Neurology. Guidelines for prevention of stroke in
patients with ischemic stroke or transient ischemic attack: a statement
for healthcare professionals from the American Heart Association/
American Stroke Association Council on Stroke: co-sponsored by the
Council on Cardiovascular Radiology and Intervention: the American
Academy of Neurology affirms the value of this guideline. Circulation.
2006;113:e409 e449.
108. Rothwell PM, Howard SC, Spence JD; Carotid Endarterectomy Trialists Collaboration. Relationship between blood pressure and stroke
risk in patients with symptomatic carotid occlusive disease. Stroke.
2003;34:25832590.
KEY WORDS: stroke hypertension blood pressure cerebral
infarction cerebral ischemia hemorrhage thrombolysis

Downloaded from http://circ.ahajournals.org/ by guest on February 27, 2014