Curr Treat Options Neurol (2018) 20:39

DOI 10.1007/s11940-018-0523-4

Cerebrovascular Disorders (DG Jamieson, Section Editor)

Acute Blood Pressure

Management in Acute Ischemic
Stroke and Spontaneous
Cerebral Hemorrhage
Mollie McDermott, MD, MS*
Cemal B. Sozener, MD, MEng
Address
*
University of Michigan Stroke Program, Cardiovascular Center, 3rd Floor, Recep-
tion C, 1500 East Medical Center Drive, SPC 5855, Ann Arbor, MI, 48109-5855,
USA
Email: mcdermom@med.umich.edu

* Springer Science+Business Media, LLC, part of Springer Nature 2018

This article is part of the Topical Collection on Cerebrovascular Disorders

Keywords Acute ischemic stroke I Blood pressure I Hypertension I Cerebral hemorrhage

Abstract
Purpose of review We discuss the evidence and guidelines for acute blood pressure (BP)
management for patients presenting with acute ischemic stroke or spontaneous cerebral
hemorrhage.
Recent findings Observational data suggest that the extremes of BP should be avoided in
patients presenting with acute ischemic stroke. There is no convincing evidence that
active BP reduction results in improved outcomes for ischemic stroke patients. Current
guidelines recommend that BP be maintained ≤ 185/110 mmHg in patients who are
candidates for intravenous tissue plasminogen activator (IV tPA) or mechanical
thrombectomy and that BP be maintained ≤ 180/105 mmHg for at least 24 h in patients
who have received IV tPA or have undergone mechanical thrombectomy. Acute BP goals
for spontaneous cerebral hemorrhage remain unclear despite a number of randomized
controlled trials.
Summary Acute BP goals for patients with acute ischemic stroke largely depend on
candidacy for, and receipt of, IV tPA and mechanical thrombectomy. As thrombectomy
is now the standard of care for many patients with large vessel occlusion, we will see a
heightened interest in pre- and post-thrombectomy BP management. Future trials of
spontaneous cerebral hemorrhage may focus on hyperacute BP lowering (e.g., in the
prehospital setting).
39 Page 2 of 13 Curr Treat Options Neurol (2018) 20:39

Introduction
Given its moment-to-moment fluctuations, arterial
blood pressure (BP) is a difficult physiologic param-
eter to study. However, the established relationship
of BP to cerebral perfusion pressure (defined as
systemic mean arterial pressure minus intracranial
pressure)—and the ability to pharmacologically
control BP—makes BP manipulation an attractive
strategy to improve outcomes after acute ischemic
stroke and spontaneous cerebral hemorrhage. In this
article, we review the existing literature regarding
acute BP management in ischemic stroke and cere-
bral hemorrhage. We focus on spontaneous
intraparenchymal hemorrhage rather than post-
traumatic or subarachnoid hemorrhage as manage-
ment of the latter entities is beyond the scope of
this review.

Acute blood pressure management in ischemic stroke

Acute ischemic stroke patients commonly present with elevated arterial BP. An
analysis of 276,734 ischemic stroke patients included in the National Hospital
Ambulatory Medical Care Survey found that 76.5% of patients with ischemic
stroke presenting to the emergency department had a systolic BP ≥ 140 mmHg
[1]. In 17,398 patients with confirmed acute ischemic stroke enrolled in the
1997 International Stroke Trial, 81.6% of the patients had a systolic BP ≥
140 mmHg and 27.6% had a systolic BP ≥ 180 mmHg [2]. The mean systolic
BP at enrollment was 160.1 mmHg (± 27.5 mmHg). The cause of elevated BP in
acute ischemic stroke remains unclear. A commonly held belief is that elevated
BP represents a compensatory response aimed at improving perfusion to focal
areas of cerebral ischemia; however, the physiologic mechanisms underlying
such a response are unestablished.
The aforementioned analysis of 17,398 acute ischemic stroke patients in-
cluded in the International Stroke Trial examined the relationship between
prerandomization systolic BP and two primary outcomes: death at 14 days
and death or dependency at 6 months [2]. A U-shaped relationship was ob-
served, with the lowest risk of death or dependency observed in patients with a
baseline systolic BP of 140–170 mmHg. After adjustment for potential con-
founders, patients with a systolic BP ≤ 150 mmHg had, for every 10 mmHg
drop in systolic BP, an increased risk of death within 14 days of 16% (adjusted
odds ratio [aOR] 1.16; 95% confidence interval [CI], 1.10–1.22) and an in-
creased risk of death or dependency at 6 months of 5% (aOR 1.05; 95% CI,
1.01–1.10). After adjustment for potential confounders, patients with a systolic
BP ≥ 150 mmHg had, for every 10 mmHg increase in systolic BP, an increased
risk of death within 14 days of 5% (aOR 1.05; 95% CI, 1.01–1.08), and no
significant increased risk of death or dependency at 6 months (aOR 1.01; 95%
CI, 0.99–1.03). Similarly, a single-center prospective trial of 930 patients with
acute ischemic stroke found a U-shaped relationship between admission sys-
tolic BP and mortality at 12 months [3]. In unadjusted analysis, the 12-month
mortality rate for patients presenting with a systolic BP G 100 mmHg was 52.2%
(95% CI, 31.4–73.0%), 121–140 mmHg was 24.6% (95% CI, 14.2–35.0%),
and 9 220 mmHg was 47.0% (95% CI, 23.3–70.7%).
Most recently, an analysis of 309,611 acute ischemic stroke patients includ-
ed in the Get With the Guidelines-Stroke registry examined the relationships
between admission systolic BP and in-hospital death, discharge elsewhere than
Curr Treat Options Neurol (2018) 20:39 Page 3 of 13 39

home, and inability to ambulate independently at discharge [4]. A systolic

BP of 150 mmHg was used as the comparator. A U-shaped relationship
between admission systolic BP and in-hospital death was observed, such
that systolic BP 100 mmHg was associated with two thirds greater odds of
in-hospital death (aOR 1.67; 95% CI, 1.56–1.79), systolic BPs 110 and
210 mmHg were associated with an approximately one-third greater odds
of in-hospital death (aOR for systolic BP 110 mmHg 1.35; 95% CI, 1.28–
1.41 and aOR for systolic BP 210 mmHg 1.36; 95% CI, 1.29–1.44), and
systolic BP of 220 mmHg was associated with an approximately one half
greater odds of in-hospital death (aOR 1.53; 95% CI, 1.44–1.63). U-shaped
relationships were also observed between admission systolic BP and dis-
charge elsewhere than home and between admission systolic BP and inabil-
ity to ambulate independently at discharge.
These observational data suggest that the extremes of BP should be avoided
in patients presenting with acute ischemic stroke. The next section discusses the
treatment of elevated BP in patients with acute ischemic stroke. No prospective
studies have addressed treatment of hypotension in ischemic stroke patients.
Current American Heart Association/American Stroke Association (AHA/ASA)
guidelines recommend that hypotension be corrected to maintain systemic
perfusion necessary to support organ function (class of recommendation
[COR] I, level of evidence [LOE] C based on expert opinion) [5•].

Antihypertensive treatment in acute ischemic stroke

A 2015 meta-analysis by Lee et al. examined the effect of active BP lowering
versus control BP management across 13 randomized controlled trials enrolling
12,703 subjects [6]. All subjects had a diagnosis of ischemic stroke confirmed by
computed tomography (CT) or magnetic resonance imaging (MRI). The out-
come of interest was the risk of dependency or death at 3 months or at trial end
point. Across all studies, BP control was not associated with a lower risk of
dependency or death (RR 1.04; 95% CI, 0.96–1.13). Significant heterogeneity
was seen among the studies (I2 = 51%; p = 0.02), but there was no evidence of
publication bias. It should be noted that the median time from stroke onset to
randomization in the 2015 meta-analysis ranged from 11 to 58 h, leaving open
the possibility that earlier BP treatment may confer a greater benefit. The results
of the Lee meta-analysis are in keeping with two other 2015 meta-analyses that
found no association between antihypertensive treatment and death and de-
pendency in acute ischemic stroke patients [7, 8].
Several studies have examined the effects of BP reduction according to
time from stroke onset or randomization. In 2015, the Third International
Stroke Trial investigators performed a secondary analysis of 3035 patients
who were randomized to receive intravenous tissue plasminogen activator
(IV tPA) or standard care within 6 h of stroke onset [9]. In this secondary
analysis, subjects who received antihypertensives within 24 h of randomi-
zation had a lower risk of poor outcome on the Oxford Handicap Scale at
6 months compared to subjects who did not receive antihypertensives (OR
0.78; 95% CI, 0.65–0.93) [10]. This result was independent of receipt of IV
tPA (p value for interaction 9 0.05).
In 2016, the Scandinavian Candesartan Acute Stroke Trial (SCAST) investi-
gators performed a secondary analysis of their original trial, using ordinal
39 Page 4 of 13 Curr Treat Options Neurol (2018) 20:39

analysis [11]. SCAST, which was included in the aforementioned 2015 meta-
analysis by Lee et al., was a randomized, placebo-controlled trial that enrolled
1733 patients within 30 h of ischemic stroke symptom onset and randomly
assigned them to treatment with candesartan or placebo for 7 days [12]. Eligible
subjects had a systolic BP ≥ 140 mmHg at presentation. In the secondary
ordinal analysis, the outcome of interest was a vascular event, defined as
vascular death, non-fatal stroke, or non-fatal myocardial infarction. Across all
subjects with acute ischemic stroke, no difference was seen in vascular events
between the candesartan group and the control group (aOR 1.07; 95% CI,
0.80–1.44). However, subjects who were treated within 6 h of symptom onset
had a lower odds of a vascular event (aOR 0.28; 95% CI, 0.11–0.73). (No
difference was seen in subjects treated within 6–11, 12–23, or 9 24 h.) This
result should be interpreted with caution given that no improvement in func-
tional outcome was observed in the candesartan group in the original study.
Finally, in 2017, the China Antihypertensive Trial in Acute Ischemic Stroke
(CATIS) investigators examined the effects of BP reduction according to time
from stroke onset [13]. Like SCAST, CATIS was also included in the aforemen-
tioned 2015 meta-analysis by Lee et al. Subjects in CATIS had ischemic stroke
confirmed on CT or MRI, presented within 48 h of symptom onset, and had a
systolic BP between 140 and 220 mmHg. The prespecified subgroups of time
from symptom onset to antihypertensive treatment included G 12, 12–23, and
24–48 h. The outcome of interest was a combination of death and major
disability (modified Rankin scale [mRS] score 0–3) measured at 14 days or at
hospital discharge and at 3-month follow-up. At 14 days or hospital discharge,
no difference was observed in death or major disability in any of the subgroups.
At 3-month follow-up, subjects who received treatment between 24 and 48 h
had less death or major disability than the control subjects (OR 0.73; 95% CI,
0.55–0.96). However, after adjustment for National Institutes of Health Stroke
Scale (NIHSS), age, and sex, this result became non-significant (OR 0.75; 95%
CI, 0.54–1.04). No difference in 3-month death or major disability was ob-
served for subjects who received antihypertensive treatment within 12 h and
between 12 and 23 h in adjusted or unadjusted analysis.
At present, there is no convincing evidence that BP reduction results in
improved outcomes for patients with acute ischemic stroke. Subgroup
analyses have resulted in somewhat contradictory conclusions about spe-
cific time windows during which BP lowering may be beneficial. It remains
possible that hyperacute (G 6 h) BP lowering is beneficial, though a pro-
spective, randomized trial would be required to establish this benefit and
change management recommendations. Similarly, it remains possible that
different stroke subtypes (for example, large vessel occlusion versus small
vessel ischemia) or stroke location (anterior versus posterior circulation)
respond differently to acute BP lowering. A post-hoc analysis of SCAST
found a trend toward better functional outcome in patients with total
anterior circulation (versus partial anterior, posterior, or lacunar) stroke
who were treated with candesartan as compared to placebo in unadjusted
analysis (OR 0.47; 95% CI, 0.22–1.01), although this difference was no
longer significant after adjustment for potential confounders [14].
Current AHA/ASA guidelines state that, in patients with BP G 220/
120 mmHg who did not receive IV tPA or undergo mechanic thrombectomy
and have no comorbid condition requiring antihypertensive treatment (for
Curr Treat Options Neurol (2018) 20:39 Page 5 of 13 39

example, aortic dissection, acute coronary event, or acute heart failure), treat-
ment of hypertension within the first 48 to 72 h is not considered effective to
prevent death or dependency (COR III, LOE A) [5•]. For similar patients with
BP ≥ 220/120 mmHg, the benefit of antihypertensive treatment within the first
48 to 72 h remains uncertain (COR IIb, LOE C based on expert opinion) given
that acute ischemic stroke patients with severe hypertension were excluded from
clinical trials of acute BP lowering. The guidelines further state that, if treatment
of hypertension is required because of a comorbid condition, lowering BP
initially by 15% is probably safe (COR I, LOE C based on expert opinion).

Pre-thrombolysis blood pressure

The 1995 National Institute of Neurological Disorders and Stroke (NINDS) IV
tPA trial showed a benefit of IV tPA on 3-month functional outcomes for acute
ischemic stroke patients who could be treated within 3 h of symptom onset
[15]. To be enrolled in this trial, patients were required to have a systolic BP ≤
185 mmHg and diastolic BP ≤ 110 mmHg. Thirteen years later, the third
European Cooperative Acute Stroke Study (ECASS-III) trial showed a benefit
of IV tPA when given to a stricter subset of patients between 3 and 4.5 h after
acute ischemic stroke onset [16]. As in the NINDS trial, eligible patients had a
systolic BP ≤ 185 mmHg and diastolic BP ≤ 110 mmHg.
An analysis of 309,611 patients included in the Get With the Guidelines-
Stroke registry found that, compared to a reference systolic BP of 150 mmHg,
lower admission systolic BP was associated with a lower odds of complications
of thrombolytic therapy (for systolic BP 120 mmHg, aOR 0.89; 95% CI, 0.83–
0.97), whereas higher admission systolic BP was associated with a higher odds
of complications of thrombolytic therapy (for systolic BP 160 mmHg, aOR
1.05; 95% CI, 1.02–1.07 and for systolic BP 220 mmHg, aOR 1.25; 95% CI,
1.10–1.42) [4].
Based on the eligibility criteria of the NINDS and ECASS-III trials, current
AHA/ASA guidelines recommend that patients who have elevated BP and are
otherwise eligible for treatment with IV tPA should have their systolic BP
carefully lowered to G 185 mmHg and their diastolic BP to G 110 mmHg before
treatment (COR I, LOE B) [5•].
A post-hoc analysis of 224 patients included in two randomized controlled
stroke trials found that active BP lowering was associated with greater than four
times the odds of IV tPA treatment than conservative “watch and measure”
management (aOR 4.39; 95% CI, 2.05–9.41) [17]. There was no difference in
symptomatic hemorrhage rate in patients treated with active BP lowering
compared to those treated via the conservative strategy, regardless of receipt of
IV tPA. First-line options for the treatment of BP 9 185/110 mmHg prior to IV
tPA administration include intravenous labetalol, nicardipine infusion, or
clevidipine infusion [5•]. Our general practice is to aggressively pursue BP
control in IV tPA candidates by administering a nicardipine infusion shortly
after a first dose of labetalol has failed to lower the BP to G 185/110 mmHg.

Post-thrombolysis blood pressure

The most feared complication of elevated BP after IV tPA is symptomatic
cerebral hemorrhage. A single-center cohort study of 1868 consecutive acute
ischemic stroke patients treated with IV tPA found that patients with
39 Page 6 of 13 Curr Treat Options Neurol (2018) 20:39

symptomatic cerebral hemorrhage had significantly higher systolic BP at 2, 4,

12, and 48 h after IV tPA administration compared to patients without symp-
tomatic hemorrhage [18]. The odds ratio for symptomatic hemorrhage per each
10 mmHg increase in systolic BP was 1.14 at 2 h (95% CI, 1.03–1.25), 1.14 at
4 h (95% CI, 1.03–1.25), 1.12 at 12 h (95% CI, 1.01–1.23), and 1.12 at 48 h
(95% CI, 1.01–1.23).
Similarly, an analysis of 11,080 IV tPA-treated patients in the Safe Imple-
mentation of Thrombolysis in Stroke registry found that systolic BP was higher
at baseline, 2 h, and 24 h in patients with symptomatic intracerebral hemor-
rhage (ICH) compared to those without and in patients who were dead at
3 months compared to those who were not [19]. In this study, patients with a
history of hypertension treated with antihypertensives within 7 days after
thrombolysis had a lower rate of mortality at 3 months (13.9 versus 22.9%;
p G 0.0001), as did patients without a history of hypertension (8.1 versus
11.4%; p = 0.007).
Current AHA/ASA guidelines recommend that BP be maintained G 180/
105 mmHg for at least the first 24 h after IV tPA treatment (COR 1, LOE B) [5•].

Pre-thrombectomy blood pressure

In 2015 and 2016, six trials showed benefit of mechanical thrombectomy
for acute ischemic stroke patients with large vessel occlusion who could be
treated within 5 h [20], 6 h [21–24], or 8 h [25] from symptom onset or
randomization. More recently, the DEFUSE 3 trial showed efficacy of
thrombectomy for select patients in a 16-h treatment window [26], and
the DAWN trial showed efficacy for select patients in a 24-h treatment
window [27]. As thrombectomy is now the standard of care for many
patients with large vessel occlusion, there is heightened interest in pre-
and post-thrombectomy BP management.
A post-hoc analysis of the Multicenter Randomized Clinical Trial of
Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR
CLEAN) trial found no interaction between baseline systolic BP G 120 mmHg
and systolic BP ≥ 120 mmHg and mechanical thrombectomy on 90-day func-
tional outcome (p = 0.90), symptomatic intracranial hemorrhage (p = 0.80),
and death within 90 days (p = 0.18) [28]. A registry-based pooled analysis of
1332 acute ischemic stroke patients who underwent mechanical thrombectomy
found a J-shaped relationship between 90-day all-cause mortality and baseline
systolic BP, with the lowest all-cause mortality associated with a baseline
systolic BP value of 157 mmHg (95% CI, 143–170 mmHg) [29]. Compared
to a baseline systolic BP 150–160 mmHg, a baseline systolic BP of G 110 mmHg
was associated with an almost four-time odds of all-cause mortality (OR 3.78;
95% CI, 1.50–9.55) and a baseline systolic BP ≥ 180 mmHg was associated
with an almost two-time odds (OR 1.81; 95% CI, 1.01–3.36). A prospective
cohort study of 116 patients who underwent endovascular treatment at a single
center from 2011 to 2014 found that, after adjustment for potential con-
founders, each 10 mmHg increase in admission systolic BP was associated with
a 36% decreased odds of a good 3-month functional outcome (aOR 0.64; 95%
CI, 0.45–0.91) [30].
Based on inclusion criteria from the aforementioned mechanical
thrombectomy trials, current AHA/ASA guidelines recommend that BP be
Curr Treat Options Neurol (2018) 20:39 Page 7 of 13 39

maintained G 185/110 mmHg for patients who have not received IV tPA and for
whom intra-arterial therapy is planned (COR IIa, LOE B) [5•].

Intra- and post-thrombectomy blood pressure

A retrospective review of 147 patients who underwent intra-arterial therapy for
anterior circulation stroke found that maximum intraprocedural systolic BP was
inversely associated with good outcome (mRS ≤ 2) after adjustment for poten-
tial confounders (aOR 0.93; 95% CI, 0.89–0.96) [31]. Anecdotal evidence
suggests that BP may drop acutely after successful thrombectomy. In a retro-
spective study of 62 patients with documented ICA or MCA occlusion who
underwent intra-arterial therapy, patients who achieved successful recanaliza-
tion (thrombolysis in cerebral infarction [TICI] score 2b-3) had a drop in
systolic BP from 158.4 ± 24.6 to 142.2 ± 22.4 at the end of the procedure (p =
0.005) [32]. Patients who did not achieve successful recanalization had a drop
in systolic BP from 154.3 ± 23.8 to 138.3 ± 35 (p = 0.066). Despite the statistical
significance in the recanalized group, the magnitudes of the change in systolic
BP between the recanalized and non-recanalized group are similar.
General anesthesia is sometimes required for mechanical thrombectomy,
particularly in patients with airway compromise, left-sided neglect, or altered
mental status. General anesthesia can be associated with significant fluctuations
in BP. A small subgroup analysis of 60 patients from the MR CLEAN trial who
underwent mechanical thrombectomy under general anesthesia found that
each 1 unit decrease in mean arterial BP in millimeter of mercury during
intervention was associated with a 5% lower likelihood of a shift toward a
better outcome on the mRS (aOR 0.95; 95% CI, 0.92–0.99) [33]. A single-center
trial randomly assigned patients receiving mechanical thrombectomy to general
anesthesia (n = 73) versus conscious sedation (n = 77) [34]. No difference was
observed between the two groups in the primary outcome of early neurologic
improvement on NIHSS after 24 h or in the secondary outcomes of mortality
and mRS after 3 months. Current AHA/ASA guidelines recommend that
individualized patient risk factors, technical aspects of the procedure, and
other clinical characteristics guide the selection of anesthetic technique
(COR IIa, LOE B) [5•].
A prospective cohort study of 217 consecutive stroke patients with large
vessel occlusion treated with mechanical thrombectomy recorded hourly BPs
for 24 h following thrombectomy [35]. After adjustment for potential con-
founders, each 10 mmHg increment in maximum systolic BP was associated
with a lower odds of 3-month functional independence (aOR 0.70; 95% CI
0.56–0.87) and a higher odds of 3-month mortality (aOR 1.49; 95% CI 1.18–
1.88). Interestingly, no association was observed between symptomatic cerebral
hemorrhage and maximum systolic BP (p = 0.793) or maximum diastolic BP
(p = 0.129). An association between each 10 mmHg increment in maximum
systolic BP and worse 3-month functional status has been observed for patients
with non-recanalized large vessel occlusion [36].
Similarly, a retrospective cohort study of 228 patients with anterior circula-
tion thrombus who underwent mechanical thrombectomy found that maxi-
mum systolic BP within the first 24 h after thrombectomy was associated with
worse outcomes at 90 days (aOR for each 1-unit increase in systolic BP 1.02;
95% CI, 1.01–1.03) [37]. Maximum systolic BP was also associated with
39 Page 8 of 13 Curr Treat Options Neurol (2018) 20:39

hemorrhagic complications at 48 h (aOR 1.02; 95% CI, 1.01–1.04). Diastolic

BP and mean arterial pressure were not associated with 90-day mRS or hemor-
rhagic complications. In a study of 168 patients with successful endovascular
therapy, mean systolic BP over the subsequent 24 h was lower in subjects with a
favorable outcome (mRS ≤ 2 at discharge) compared to those without (127.2 ±
13.8 versus 131.9 ± 14.4, p = 0.035), as was maximum systolic BP (157.9 ± 20.7
versus 169.9 ± 18.1, p G 0.001) [38].
Observational data suggest a role for BP control after endovascular therapy.
The goal BP parameters will likely remain unclear until a prospective, random-
ized trial of different BP management strategies is conducted. Current AHA/ASA
guidelines state that, for patients who undergo mechanical thrombectomy, it is
reasonable to maintain BP ≤ 180/105 mmHg during and for 24 h after the
procedure (COR IIa, LOE B) [5•].

Acute blood pressure management in cerebral hemorrhage

Like acute ischemic stroke patients, patients with cerebral hemorrhage com-
monly present with elevated BP. This elevation may be due to baseline hyper-
tension, may represent a compensatory response to increased intracranial pres-
sure, or may be related to acute pain. An analysis of 45,330 patients with
cerebral hemorrhage presenting to a US emergency department included in
the National Hospital Ambulatory Medical Care Survey found that 75% of
patients had a systolic BP ≥ 140 mmHg [1]. Mean 24-h systolic BP [39] and
maximum 24-h systolic BP [40] in patients with cerebral hemorrhage have been
associated with hematoma expansion on CT in some studies but not in others
[41]. A study of 191 patients with cerebral hemorrhage found that, compared to
patients with systolic BP 141–160 mmHg, 1- and 12-month mortality rates
were higher in patients with systolic BP 9 220 mmHg (1-month mortality
69.2% [44.2–94.2] versus 32.3% [16.6–48.0], p G 0.05; 12-month mortality
76.9% [54.2–99.6] versus 41.2% [24.3–58.1], p G 0.05) [3].
A post-hoc analysis of the Field Administration of Stroke
Therapy—Magnesium (FAST-MAG) trial [42] evaluated the effect of BP
variability on outcome after spontaneous cerebral hemorrhage [43]. The
FAST-MAG trial enrolled patients with acute stroke presenting within 2 h
of last known normal with systolic BP between 90 and 220 mmHg. Of
1700 patients enrolled, 386 had spontaneous cerebral hemorrhage. Both
BP variabilities in the hyperacute period (0 to 4–6 h after onset) and in the
acute period (0 to 24–26 h after onset) were associated with poor 3-month
outcome (mRS 3–6) in unadjusted and adjusted analyses. The authors
suggested that blood pressure stabilization should serve as therapeutic
target for future ICH trials. A retrospective analysis of 672 patients with
spontaneous intracerebral hemorrhage found that patients who died dur-
ing their hospitalization had a higher pulse pressure compared to those
who did not die (68.5 ± 16.4 versus 65.4 ± 12.4 mmHg; p = 0.032) [44].

Antihypertensive treatment in cerebral hemorrhage

A 2017 meta-analysis investigated the effect of intensive BP lowering versus
standard BP lowering across five randomized controlled trials enrolling 4360
Curr Treat Options Neurol (2018) 20:39 Page 9 of 13 39

subjects [45]. The outcomes of interest were 3-month mortality and 3-month
death or dependency (mRS ≥ 3). Across all studies, intensive BP control was not
associated with lower 3-month mortality (OR 0.99; 95% CI, 0.82–1.20) or
lower 3-month death or dependency (OR 0.91; 95% CI, 0.81–1.03). Significant
heterogeneity was not observed among the studies, and there was no evidence
of publication bias.
The largest of the randomized controlled trials included in the aforemen-
tioned meta-analysis was the INTEnsive BP Reduction in Acute Cerebral hem-
orrhage Trial (INTERACT2) trial, which enrolled 2839 patients with spontane-
ous intracerebral hemorrhage within the prior 6 h with systolic BP 150–
220 mmHg [46]. Patients were randomized to intensive BP treatment to lower
their BP to G 140 mmHg within 1 h or to standard BP lowering with a goal of G
180 mmHg. The primary outcome was death or major disability (mRS 3–6) at
90 days. No difference was observed in the primary outcome between the
intensive and standard treatment groups (OR 0.87; 95% CI, 0.75–1.01) nor
in a number of safety outcomes including neurologic deterioration within the
first 24 h, recurrent ICH, and any neurologic deterioration attributed to ICH. An
ordinal analysis of individual mRS scores, which was a secondary end point,
showed lower mRS scores in those in the intensive treatment arm (OR for a
higher mRS, 0.87; 95% CI, 0.77–1.00, p = 0.04). There was no effect of treat-
ment arm on hematoma expansion.
The second largest of the randomized controlled trials included in the
aforementioned meta-analysis was the Antihypertensive Treatment of Acute
Cerebral Hemorrhage II (ATACH-2) trial, which enrolled 1000 patients with
spontaneous intracerebral hemorrhage and at least one systolic BP ≥ 180 mmHg
within an earlier time window than INTERACT2 [47•]. In ATACH-2, intensive
versus standard antihypertensive treatment was initiated within 4.5 h of symp-
tom onset and continued for the next 24 h. Patients were randomized to
intensive BP treatment to lower their BP to 110–139 mmHg or standard BP
lowering with a goal range of 140–179 mmHg. The primary outcome was
moderately severe or severe disability (mRS 4–6) at 90 days. As in INTERACT2,
no difference was observed in the primary outcome between the intensive and
standard treatment groups (aOR 1.04; 95% CI, 0.85–1.27), nor in a number of
safety outcomes including neurologic deterioration within the first 24 h, hema-
toma expansion, and any treatment-related serious adverse event within 72 h.
However, the rate of renal adverse events within 7 days of randomization was
more than two times higher in the intensive treatment than standard treatment
group (9.0 versus 4.0%; p − 0.002).
A post-hoc analysis of patients enrolled in the ATACH-2 trial investigated the
association between non-contrasted head CT markers of intracerebral hemor-
rhage expansion and patient outcomes [48]. Hematoma expansion was defined
as radiographic growth 9 33%. A number of CT signs predicted hemorrhage
expansion on multivariate analysis, including hypodensities, blend sign, irreg-
ular shape hematoma, and heterogeneous density of the hematoma. Blend sign,
irregular shape, and heterogeneous density also predicted poor 90-day outcome
(mRS 9 3) after adjustment. There was no effect of treatment on hemorrhage
expansion by CT sign.
Based on the INTERACT2 results, the 2015 AHA/ASA guidelines recom-
mend that for ICH patients presenting with systolic BP between 150 and
220 mmHg without contraindication to acute BP treatment, acute lowering of
39 Page 10 of 13 Curr Treat Options Neurol (2018) 20:39

systolic BP to 140 mmHg is safe (class I; LOE A) and can be effective for
improving functional outcomes (class IIa; LOE B) [49•]. The guidelines also
state that, for patients presenting with systolic BP 9 200 mmHg, it may be
reasonable to consider aggressive BP reduction with a continuous intravenous
infusion and frequent BP monitoring (class IIb; LOE C). The adverse renal
outcomes observed in ATACH-2 will likely lead to a revision of these recom-
mendations in future guideline statements.
The ICH ADAPT II trial, which is currently recruiting, will randomize
patients to intensive BP lowering (systolic BP reduced to G 140 mmHg
with treatment started within 6 h of randomization) versus standard BP
lowering (G 180 mmHg) [50]. The primary outcome is ischemic imaging
changes represented by magnetic resonance (MR) diffusion-weighted im-
aging lesion frequency at 48 h [50]. Future trials of spontaneous cerebral
hemorrhage may focus on even earlier BP lowering (e.g., in the prehospital
setting). The advent of prehospital telemedicine and mobile CT scanners
has made the ability to control BP before hospital presentation more
feasible across the USA and the world.

Conclusion
Observational data suggest that the extremes of BP should be avoided in
patients presenting with acute ischemic stroke. There is no convincing
evidence that active BP reduction results in improved outcomes for ische-
mic stroke patients. Acute BP goals for patients with acute ischemic stroke
depend on candidacy for, and receipt of, IV tPA and mechanical
thrombectomy. Current guidelines recommend that BP be maintained ≤
185/110 mmHg in patients who are candidates for IV tPA or mechanical
thrombectomy and that BP be maintained ≤ 180/105 mmHg for at least
24 h in patients who have received IV tPA or have undergone mechanical
thrombectomy. As thrombectomy becomes the standard of care for pa-
tients with stroke caused by large vessel occlusion, we will see a heightened
interest in pre- and post-thrombectomy BP management.
Acute BP goals for spontaneous cerebral hemorrhage remain unclear.
While the results of the INTERACT2 trial suggested that intensive BP
lowering was safe, the results of the ATACH-2 trial have raised safety
concerns related to adverse renal outcomes. Future trials of spontaneous
cerebral hemorrhage may focus on hyperacute BP lowering (e.g., in the
prehospital setting).

Compliance with Ethical Standards

Conflict of Interest
The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.
Curr Treat Options Neurol (2018) 20:39
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