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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
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Qureshi
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.
178
Circulation
July 8, 2008
Ischemic
stroke
Intracerebral
hemorrhage
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
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
179
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)
BP reduction and
case fatality
218
Comments
Randomized trial
Hemispheric stroke
presenting within 48 h
of symptom onset
Neurological
assessment at
entry, day 8, and
1 and 6 mo
302
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
Functional status
assessed by
mRS and Barthel
Index and
mortality rates
after 3 mo
339
Nitroglycerin for
acute stroke57
Meta-analysis
(2 studies)
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)
Poor outcome,
defined as death
or dependency in
activities of daily
living
7521
NINDS rt-PA
Stroke Trial42
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
Controlling
Hypertension
and Hypotension
Immediately
Post-Stroke Trial
(CHHIPS)59
Prospective,
multicenter,
randomized,
double-blind,
titrated-dose trial
(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 )
Qureshi
Table 1.
181
Continued
No. of
Patients
Comments
Mortality rate
and mRS at
3 mo
5000
Ongoing
Death or
disability at 6
mo; combination
of vascular
death,
myocardial
infarction, or
stroke during
first 6 mo
2500
Ongoing
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
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
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
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
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
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
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.
182
Circulation
July 8, 2008
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.
Qureshi
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
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.
184
Circulation
July 8, 2008
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.
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KEY WORDS: stroke hypertension blood pressure cerebral
infarction cerebral ischemia hemorrhage thrombolysis
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