Original Article

Original Article
The Intracerebral Hemorrhage Acutely Decreasing
Arterial Pressure Trial
Kenneth S. Butcher, MD, PhD; Thomas Jeerakathil, MSc, MD; Michael Hill, MD, MSc;
Andrew M. Demchuk, MD; Dariush Dowlatshahi MD, PhD; Shelagh B. Coutts, MD;
Bronwen Gould, BSc; Rebecca McCourt; Negar Asdaghi, MD, MSc; J. Max Findlay, MD, PhD;
Derek Emery, MD, MSc; Ashfaq Shuaib, MD; for the ICH ADAPT Investigators
Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2016
Background and Purpose—Acute blood pressure (BP) reduction aimed at attenuation of intracerebral hemorrhage (ICH)
expansion might also compromise cerebral blood flow (CBF). We tested the hypothesis that CBF in acute ICH patients
is unaffected by BP reduction.
Methods—Patients with spontaneous ICH <24 hours after onset and systolic BP > 150 mm Hg were randomly assigned to an
intravenous antihypertensive treatment protocol targeting a systolic BP of <150 mm Hg (n=39) or <180 mm Hg (n=36).
Patients underwent computed tomography perfusion imaging 2 hours postrandomization. The primary end point was
perihematoma relative (relative CBF).
Results—Treatment groups were balanced with respect to baseline systolic BP: 182±20 mm Hg (<150 mm Hg target group)
versus 184±25 mm Hg (<180 mmHg target group; P=0.60), and for hematoma volume: 25.6±30.8 versus 26.9±25.2 mL
(P=0.66). Mean systolic BP 2 hours after randomization was significantly lower in the <150 mm Hg target group (140±19
vs 162±12 mm Hg; P<0.001). Perihematoma CBF (38.7±11.9 mL/100 g per minute) was lower than in contralateral
homologous regions (44.1±11.1 mL/100 g per minute; P<0.001) in all patients. The primary end point of perihematoma
relative CBF in the <150 mm Hg target group (0.86±0.12) was not significantly lower than that in the <180 mm Hg group
(0.89±0.09; P=0.19; absolute difference, 0.03; 95% confidence interval −0.018 to 0.078). There was no relationship
between the magnitude of BP change and perihematoma relative CBF in the <150 mm Hg (R=0.00005; 95% confidence
interval, −0.001 to 0.001) or <180 mm Hg target groups (R=0.000; 95% confidence interval, −0.001 to 0.001).
Conclusions—Rapid BP lowering after a moderate volume of ICH does not reduce perihematoma CBF. These physiological
data indicate that acute BP reduction does not precipitate cerebral ischemia in ICH patients.
Clinical Trial Registration Information—ClinicalTrials.gov, NCT00963976. (Stroke. 2013;44:620-626.)
Key Words: cerebral blood flow
■
computed tomography perfusion
A
cutely elevated blood pressure (BP) is associated with
early mortality and poor clinical outcome in intracerebral hemorrhage (ICH),1,2 and this effect may be mediated by
hematoma expansion.3,4 Early BP treatment may, therefore,
be beneficial after ICH, and this hypothesis is being tested in
ongoing trials.5,6 In contrast, an association between very low
admission BPs (systolic BP [SBP] <120 mm Hg) and poor
outcome has also been reported.7 It has been postulated that
elevated BP is a homeostatic response to elevated intracranial
pressure serving to maintain cerebral blood flow (CBF)8 and
that there is a zone of ischemia surrounding the hematoma
referred to as the perihematoma penumbra.9,10
Reduced CBF in the perihematoma region has been
demonstrated,11–14 but the effect of rapid BP reduction on
■
hypertension
perihematoma and hemispheric flow remains unknown. The
potential for precipitation of ischemic injury is the primary
rationale underlying guideline statements recommending
caution with respect to early BP treatment.15,16 We aimed to
address the competing treatment rationales by measuring CBF
in acute ICH patients randomized to different BP management strategies. Our a priori hypothesis was that early acute
BP reduction would not result in significantly lower perihematoma CBF than that in patients managed conservatively.
Methods
Patients
The Intracerebral Haemorrhage Acutely Decreasing Arterial Pressure
Trial was a multicenter, prospective, randomized, open-label, with
Received November 20, 2012; final revision received December 13, 2012; accepted December 19, 2012.
From the Division of Neurology (K.S.B., T.J., B.G., R.M., A.S.), Department of Diagnostic Imaging (D.E.), and Division of Neurosurgery (J.M.F.),
University of Alberta, Edmonton, Canada; Department of Clinical Neurosciences, University of Calgary, Calgary, Canada (M.H., A.M.D., S.B.C.); Division
of Neurology, University of Ottawa, Ottawa, Canada (D.D.); and Division of Neurology, University of British Columbia, Vancouver, Canada (N.A.).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
111.000188/-/DC1.
Correspondence to Ken Butcher, MD, PhD, 2E3.27 WMC Health Sciences Center, 8440 112th St, Edmonton, Alberta T6G 2B7, Canada. E-mail ken.
[email protected]
© 2013 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.111.000188
620
Butcher et al ICH ADAPT Final Results 621
blinded evaluation study (ClinicalTrials.gov registration number
NCT00963976). The protocol has been published previously.17
Eligible patients were ≥18 years of age, with spontaneous ICH
diagnosed on noncontrast computed tomography (CT) <24 hours
after onset. SBP was ≥150 mm Hg (≥2 readings ≥5 minutes apart).
Patients with evidence of secondary ICH (eg, vascular malformation),
planned surgical resection, or contraindications to CT perfusion (CTP;
eg, contrast allergy or renal impairment) were excluded. Informed
consent was provided by the patient or surrogate decision maker. The
protocol was approved by local human research ethics committees.
Procedures
Randomization and BP Management Protocols
Patients were randomized to an SBP target of <150 mm Hg or <180
mm Hg to be achieved within 1 hour of randomization. A block randomization design (6 patients/block), stratified by onset to treatment
time (≤6 and 6–24 hours), was used. Acute BP was treated according
to a protocol (Table I in online-only Data Supplement).17 Noninvasive
BP and heart rate monitoring were continued for 24 hours.
Statistical Analysis
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Power calculations indicated that 31 evaluable patients were required
to detect a 15% difference in perihematoma relative CBF (rCBF) between treatment groups (90% power; 2-tailed α=0.05).17 We planned
to test the primary end point of perihematoma rCBF using ANCOVA,
adjusting for baseline hematoma volume11 and time to randomization. Initial data exploration revealed the assumptions of ANCOVA
were violated because the slopes of the relationship between volume
and CBF across time strata were different. Therefore, we tested the
primary hypothesis with a generalized linear model adjusting for
baseline ICH volume and time to randomization. BP differences between treatment groups at each time point were considered different
when the 95% confidence intervals (CIs) of the means did not overlap. The frequency of risk factors at baseline, mortality, and clinical
deterioration were compared using Pearson and Fisher exact χ2 tests.
Absolute differences in perfusion parameters between ipsilateral and
contralateral regions within patients were assessed with paired t tests.
Intergroup comparisons of normally and non-normally distributed
variables were assessed with unpaired t tests and Wilcoxon tests, respectively. The relationship between absolute BP change and perihematoma rCBF was explored using linear regression.
Imaging Procedures
Two hours after randomization, all patients underwent standard
noncontrast CT (5 mm slices [120 kvp, 300 mA/slice]) through the
entire brain (l8–20 slices; 512×512 matrix). A 38- to 80-mm thick
CTP section was centered on the slice, where the hematoma had the
greatest diameter. The CTP slab thickness and acquisition protocol
varied with scanner capabilities, which ranged from 64 to 320 slices
at the trial sites, reflecting a pragmatic approach to perfusion acquisition. CTP images were acquired with intravenous iodinated contrast
(40–50 mL via 18 g antecubital vein angiocatheter at 4–7 mL/s), with
CT images acquired every second for 50 seconds (80 kvp; 200 mA/
image). A repeat noncontrast CT scan was obtained 24±3 hours after
randomization.
Clinical Assessments
A National Institutes of Health Stroke Scale (NIHSS) score was
assessed by trained personnel blinded to treatment group allocation
immediately after the CTP scan, 2±1 hours, 24±3 hours, 30±5 days,
and 90±5 days after randomization. Functional outcome was assessed
with Barthel Index and modified Rankin Scale at 24 hours, day 30,
and day 90 by assessors blinded to BP treatment.
Image Analysis
Images were postprocessed and measured centrally by readers (B.G. and R.M.) blinded to clinical outcome and treatment
group. Hematoma, intraventricular hemorrhage, and total ICH
(hematoma+intraventricular hemorrhage) volumes were calculated
using planimetric techniques. Raw CTP source images were transferred to a computer workstation and analyzed using the PerfScape
analysis package (Olea Medical, Marseilles). CTP maps were derived
from tissue time–density curves, based on the change in x-ray film
attenuation, which is linearly related to contrast concentration, over
time. Errors introduced by delay and dispersion of the contrast bolus
before arrival in the cerebral circulation were corrected with singular
value deconvolution and quantitative CBF, and cerebral blood volume
(CBV) maps were generated on a voxelwise basis.18 Perfusion maps
were transferred to the Analyze 11.0 software package (Biomedical
Imaging Resource, Mayo Clinic) for region of interest analysis. The perimeter of the hematoma was determined on the precontrast CT source
image using an intensity threshold technique. A region of interest was
drawn 1 cm from the perimeter of the hematoma, excluding intraventricular and subarachnoid spaces.11 Voxels containing blood vessels
were removed from the regions of interest using an intensity threshold
(CBF >100 mL/100 g per minute or CBV >8 mL/100 g).18 The magnitude of flow changes in the perihematoma region was calculated as
the mean CBF or CBV of all voxels. To assess global changes, mean
perfusion indices were also measured in the entire hemisphere ipsilateral and contralateral to the hematoma. After calculation of absolute
values, all perfusion parameters were standardized as changes relative (r) to unaffected contralateral homologous regions.
Results
A total of 456 patients were screened between January 28,
2007, and December 6, 2011, and 75 patients were randomized. The most common reasons for not enrolling patients were
evidence of secondary ICH, including trauma, inability to randomize within 24 hours, and a presenting SBP <150 mm Hg
(Figure 1).
Baseline Characteristics
The treatment groups were balanced with respect to baseline
demographics, including a history of hypertension, treatment
with antihypertensives, BP, time to enrollment, and hematoma
location (Table 1).
BP Management
All patients in the <150 mm Hg target group were treated
with intravenous antihypertensive agents, and the mean
dose of all drugs was significantly higher than that used in
the <180 mm Hg target group (Table II in the online-only Data
Supplement). Patients in the latter group were treated with
intravenous antihypertensive drugs in 44% of cases. Mean
SBP was significantly lower in the <150 mm Hg target group
within 30 minutes of randomization (Figure 2). Mean SBP
and diastolic BP in the <150 mm Hg target group were both
significantly lower than that in the <180 mm Hg target group
immediately before CTP acquisition (Table II in the onlineonly Data Supplement). The mean SBP at the time of the CTP
scan was 140±19 mm Hg and 162±12 mm Hg in the <150
and <180 mm Hg target groups, respectively. The target BP
was achieved in 79% and 100% of patients at the time of
the CTP scan in the <150 and <180 mm Hg target groups,
respectively (P=0.005).
Cerebral Perfusion and BP
Focal decreases in CBF and CBV within the perihematoma
region were evident in all patients (Figure 3). Mean absolute
CBF was 38.7±11.9 mL/100 g per minute in the perihematoma
region and 44.1±11.1 mL/100 g per minute in the contralateral homologous region (absolute difference, 5.4±4.6 mL/100
622 Stroke March 2013
Figure 1. Intracerebral Hemorrhage Acutely
Decreasing Arterial Pressure Trial (ICH ADAPT) profile. BP indicates blood pressure; CTP, computed
tomography perfusion; and IVH, intraventricular
hemorrhage.
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g per minute; P<0.001). This corresponded to a perihematoma rCBF of 0.87±0.01 in all patients, irrespective of BP
treatment. There was a modest inverse relationship between
baseline ICH volume and perihematoma rCBF (β=−0.20;
P=0.09). Mean absolute CBV within the perihematoma region
(3.65±0.70 mL/100 g) was also lower than that in contralateral
regions (4.21±1.53 mL/100 g; P=0.001).
Primary Outcome
After adjustment for baseline intraparenchymal hematoma
volume and time to randomization, perihematoma rCBF was
not significantly lower in patients randomized to a target SBP
of <150 mm Hg (0.86±0.12) than in those in the <180 mm Hg
target group (0.89±0.09; P=0.18; absolute difference,0.03;
95% CI, −0.018 to 0.078). The actual sample size allows us
to reject the hypothesis that rCBF differs between treatment
groups by >15% (absolute difference of 0.135) with 99%
power. The results of an unadjusted analysis were nearly
identical (Table 2). Linear regression indicated no relationship between perihematoma rCBF and the absolute change
in SBP in the <150 mm Hg target group (R=0.00005; 95%
CI, −0.001 to 0.001) or <180 mm Hg target group (R=0.000;
95% CI, −0.001 to 0.001; Figure 4). Perihematoma rCBV was
also similar between the 2 treatment groups (0.90±0.14 vs
0.91±0.15; P=0.73).
The interval between symptom onset and BP treatment did
not affect cerebral perfusion or the response to BP treatment.
There were no overall differences in perihematoma rCBF
between patients randomized within 6 hours (0.86±0.11)
relative to those treated 6 to 24 hours after onset (0.89±0.10;
P=0.20). BP treatment did not affect rCBF in patients treated
within 6 hours (0.78±0.22 in the <150 mm Hg group and
0.88±0.10 in the <180 mm Hg group; P=0.08; absolute difference, 0.10; 95% CI, −0.020 to 0.22) or in those treated 6
to 24 hours after onset (0.85±0.21 in the <150 mm Hg group
and 0.89±0.10 in the <180 mm Hg group; P=0.46; absolute
difference, 0.04; 95% CI, −0.07 to 0.15). There was no significant interaction between time to randomization and treatment group with respect to rCBF (P=0.25 for interaction).
Similarly, among patients with large ICH volumes (>30
mL), perihematoma rCBF was not affected by treatment:
0.88±0.10 mL/100 g per minute in the <150 mm Hg target
group (n=10) and 0.87±0.09 mL/100 g per minute in the <180
mm Hg target group (n=12; P=0.82). There was no significant
interaction between volume and treatment group (P=0.73 for
interaction).
Hemispheric CBF, Hematoma Expansion, and
Clinical Outcome
Ipsilateral hemispheric rCBF (a prespecified secondary end
point) was lower in patients randomized to the <150 mm Hg
target group (0.95±0.05), relative to those in the <180 mm Hg
target group (0.99±0.05; P=0.0013). Absolute hemispheric
CBF in the <150 mm Hg group was only 2.07±2.40 mL/100
g per minute lower than that in the contralateral hemisphere
(P<0.0001). Absolute ipsilateral hemispheric CBF in the <150
mm Hg group (42.42±12.05 mL/100 g per minute) was not
different than that in the <180 mm Hg group (41.79±8.68;
P=0.80). Finally, the observed reduction in ipsilateral
hemispheric rCBF was not associated with a decrease in
hemispheric rCBV (Table 2).
Total ICH volume growth between the baseline noncontrast CT and the CTP scan was similar between the 2
treatment groups (Table 2). Mortality and neurological
and functional disability scale scores between 2 hours and
90 days postrandomization were all comparable between
treatment groups. Neurological deterioration, defined as
an increase in the NIHSS score of ≥4 points, occurred in
Butcher et al ICH ADAPT Final Results 623
Table 1. Baseline Characteristics of Randomized Patients
<150 mm Hg
Target (n=39)
<180 mm Hg
Target (n=36)
P
Value
Age (mean±SD)
70.7±12.5
68.7±11.1
0.46
Male
26 (67%)
28 (78%)
0.28
Symptom onset to
randomization (median, IQR)
7.83 (3.25–16.75) 8.54 (3.80–15.75) 0.94
Randomized <6 h
18 (46%)
17 (42%)
0.93
Hypertension
26 (67%)
27 (75%)
0.43
Previous ICH
4 (11%)
1 (3%)
0.19
Ischemic stroke
6 (16%)
2 (6%)
0.17
18 (46%)
15 (42%)
4 (10%)
4 (11%)
Past medical history
Medication history
Antihypertensive use
Antithrombotic use
0.55
1.0
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Clinical characteristics
Systolic BP, mm Hg
(mean±SD)
182±20
184±25
0.60
Diastolic BP, mm Hg
93±19
97±23
0.42
122±17
126±22
0.44
76±15
79±18
0.53
15 (4–15)
15 (6–15)
0.77
Mean arterial pressure, mm Hg
Heart rate, bpm (mean±SD)
Glasgow Coma Scale
(median, IQR)
Glasgow Coma Scale <9
2 (5%)
NIHSS Score (median, IQR)
10 (6–18)
1 (3%)
1.0
11 (5.5–15.5) 0.94
Hematoma location/volume
Basal ganglia
Lobar
Brain stem
29 (74%)
27 (75%)
9 (23%)
8 (22%)
0.99
1 (3%)
1 (3%)
23.90±28.30
22.61±21.35
0.94
Intraventricular extension
13 (33%)
16 (44%)
0.35
Intraventricular volume,
mL, (mean±SD)
2.09±6.12
4.25±8.78
0.23
25.98±30.84
26.86±25.24
0.66
Intraparenchymal hematoma
volume, mL (mean±SD)
Total ICH volume, mL
(mean±SD)
Figure 2. Temporal profile of systolic blood pressure (BP) in
the <150 mm Hg and <180 mm Hg treatment groups. Error bars
are standard error of the mean. Mean systolic BP was considered
significantly different at time points, where the 95% confidence
intervals did not overlap (*).
BP indicates blood pressure; ICH, intracerebral hemorrhage; IQR, interquartile
range; and NIHSS, National Institutes of Health Stroke Scale.
3 patients (8%) in the <150 mm Hg group and 2 (6%) in the
<180 mm Hg group (P=0.54).
Discussion
In this trial, early BP treatment had no effect on perihematoma
CBF and was associated with a modest reduction in ipsilateral
hemispheric rCBF. These results do not support the hypothesis that a treatment-related ischemic penumbra within the
perihematoma region exists.
Relative perihematoma hypoperfusion in acute/subacute ICH patients has been described previously.11–14
A single study evaluated the effects of BP reduction on
CBF.19 Fourteen ICH patients were treated 6 to 22 hours
after onset, and CBF was measured with positron emission
tomography. Consistent with our own findings, a reduction target of 15% from baseline was not associated with
significant perihematoma or global CBF decreases. In addition, our results suggest that a more aggressive absolute target
of <150 mm Hg did not reduce CBF, relative to conservatively
managed patients, even when treatment was initiated earlier
and in those with larger hematoma volumes. We also found no
consistent relationship between the magnitude of the BP drop
and perihematoma CBF.
There are 2 other prospective studies of the clinical safety of
acute BP reduction in ICH patients. A nonrandomized trial of
60 ICH patients treated with nicardipine (SBP lowered to target
tiers between 110 and 200 mm Hg) demonstrated no adverse
events.20 The only randomized investigation of BP reduction
in ICH is the INTensive Reduction of Acute BP in Cerebral
Hemorrhage Trial (INTERACT).21 Acute ICH patients were
randomized to <140 mm Hg versus <180 mm Hg SBP target
groups within 6 hours of onset. Clinical deterioration was
not more common after intensive antihypertensive therapy,
which was also associated with a trend to lower rates of ICH
expansion (15% in the <140 mm Hg vs 23% in <180 mm Hg
group). Our data support the safety of this absolute SBP target
approach, rather than a fractional treatment reduction based on
the presenting pressure. As in our trial, BP in conservatively
managed INTERACT patients gradually declined in the first
hours after onset.21 Despite this natural history, it is clear that
rapid reduction is not easily achieved (77% <150 mm Hg
in our study and 42% <140 mm Hg in INTERACT)21 and
requires intensive monitoring/treatment.
The perihematoma region has been studied with diffusionweighted MRI (DWI). The DWI characteristics within the
perihematoma region are consistent with vasogenic edema,11
and possibly inflammatory/mechanical cellular injury,12 rather
624 Stroke March 2013
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Figure 3. Examples of cerebral blood flow (CBF) and cerebral blood volume (CBV) maps and corresponding computed tomography
(CT) images in patients after acute blood pressure reduction to <150 mm Hg (top) and <180 mm Hg (bottom). Hematoma (red) and perihematoma (white) regions of interest are demonstrated on all slices. Reductions in CBF are evident in the perihematoma region of both
patients.
than ischemic changes. A more recent MRI study demonstrated
small areas of discrete diffusion restriction, consistent with
ischemic injury, distinct from the perihematoma region in one
third of acute ICH patients.22 Although there was an association
with BP reduction, this observation was retrospective. Whereas
it is possible that the modest reduction in ipsilateral hemispheric rCBF in the <150 mm Hg target group in our trial is
linked mechanistically to DWI lesion development, this appears
unlikely for several reasons. The absolute reduction in CBF is
minute, does not reach ischemic thresholds,18 and is not associated with a fall in CBV (an indicator of ischemic tissue injury).
In addition, DWI lesions were reported with equal frequency
in both the ipsilateral and contralateral hemispheres,22 and we
observed no differences in CBF associated with BP reduction in
the latter. Nonetheless, a randomized study of acute BP reduction followed by DWI assessment will be required to definitively address any link between BP and these lesions.
We did not observe differences in ICH expansion rates or
clinical outcomes in this trial, which was underpowered to
assess these events. These were secondary end points included
for hypothesis generation only because larger studies, such as
the ongoing INTERACT II5 and Antihypertensive Treatment
of Acute Cerebral Hemorrhage II66 trials, will be required
to demonstrate differences in these outcomes. Our results
support the safety of these trials.
Patients with contraindications to CTP were excluded from
this study, particularly those with renal failure. Thus, many
patients with advanced small vessel changes secondary to
hypertension/diabetes mellitus were not assessed. In addition,
patients who were too medically unstable to undergo CTP were
excluded, which likely limited the number of very large hematomas in our study. We had planned to analyze patients with
ICH volumes >50 mL separately, but revised this to >30 mL
based on actual volumes in our study. Thus, it remains possible
that patients with very large ICH volumes will exhibit worsening of CBF in response to BP reduction. Difficulty assessing
outcomes in large ICH, beyond early mortality, is not unique
to this study, given the poor prognosis.15 A technical limitation
is the multiple CT scanners used to acquire perfusion images,
necessitated by the multicenter design. Central analysis of
all raw CTP data by blinded raters ensured postprocessing
techniques were uniform, but the possibility of differences in
acquisition protocols affecting our data cannot be excluded.
These effects will have been minimized with respect to the
primary outcome because it was a relative measure of CBF,
resulting in data standardization. A further limitation of our
study is the relatively small number of patients randomized <3
hours from onset, the time at which BP reduction is most likely
to attenuate ICH expansion.21 Nonetheless, we found no relationship between time to randomization and CBF, both when
time was included in our generalized linear model and when
results were analyzed separately by randomization strata (0–6
vs 6–24 hours). Inclusion of only hyperacute patients may also
have minimized the confounding effects of spontaneous BP
decreases with time. This would have limited recruitment to
a very small number of patients. In addition, the effects of BP
reduction on CBF remain relevant at later time points.
We find no evidence that cerebral ischemia is precipitated
by rapid BP reduction with intravenous antihypertensive
agents in acute ICH patients, with moderate hematoma volumes. These results support the safety of randomized trials of
BP reduction after ICH.
Acknowledgments
The Intracerebral Haemorrhage Acutely Decreasing Arterial
Pressure Trial (ICH ADAPT) Investigators gratefully acknowledge
the contributions of Dr M. Sharma and M. Bussiere (Data Safety
Committee). ICH ADAPT Sites and Investigators (Site, Investigator,
Butcher et al ICH ADAPT Final Results 625
Table 2. Effects of Blood Pressure Treatment on Cerebral Perfusion, Hemorrhage Growth, and Clinical
Outcome
<150 mm Hg Target (n=37)
<180 mm Hg Target (n=36) P Value
Relative perfusion measures (mean±SD)
Perihematoma rCBF
0.86±0.12
0.89±0.09
0.18
Ipsilateral hemispheric rCBF
0.95±0.05
0.99±0.05
0.001
Perihematoma rCBV
0.90±0.14
0.91±0.15
0.73
Ipsilateral hemispheric rCBV
0.98±0.05
0.99±0.06
0.59
Perihematoma absolute CBF, mL/100 g per min
38.88±12.98
38.56±10.81
0.91
Ipsilateral hemispheric absolute CBF, mL/100 g per min
42.42±12.05
41.79±8.68
0.80
Contralateral hemispheric absolute CBF, mL/100 g per min
44.49±12.22
42.18±8.40
0.35
Perihematoma absolute CBV, mL/100 g
3.81±0.65
3.48±0.72
0.05
Ipsilateral hemispheric absolute CBV, mL/100 g
3.99±0.58
3.67±0.65
0.03
Contralateral hemispheric absolute CBV, mL/100 g
4.07±0.58
3.71±0.65
0.02
(n=39)
(n=36)
0.67 (−0.08–3.75)
0.71 (−0.04–2.91)
0.53
Growth >6 mL
8 (21%)
8 (22%)
0.86
Growth >1/3
9 (24%)
4 (11%)
0.17
GCS Score (2 h)
15 (11–15)
15 (13–15)
0.50
NIHSS Score (2 h)
11 (6–17)
13 (5–17)
0.75
GCS Score (24 h)
15 (10.75–15)
14 (13–15)
0.64
NIHSS Score (24 h)
10 (5–19)
12 (6–20)
0.85
Absolute perfusion measures (mean±SD)
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ICH volume change (2 h post randomization)
Absolute growth (median, IQR)
Clinical outcomes (median, IQR)
30-day mortality
7 (17.9%)
4 (11.1%)
0.40
90-day Barthel Index
95 (70–100)
95 (40–100)
0.51
90-day mRS
2.5 (1–5.75)
4 (2–5)
0.65
CBF indicates cerebral blood flow; CBV, cerebral blood volume; GCS, Glasgow Coma Scale; ICH, intracerebral hemorrhage; IQR, inter
quartile range; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; rCBF, relative CBF; and rCBV, relative CBV.
Perfusion measures were calculated in 73 evaluable patients. Perihematoma rCBF P value (0.18) is unadjusted for ICH volume or
time to randomization (P=0.19 after adjustment).
number of patients): University of Alberta, K. Butcher (64),
University of Calgary, A. Demchuk (10), University of Ottawa, D.
Dowlatshahi (1)
Sources of Funding
This trial was funded by grant-in-aid support from Alberta Innovates
Health Solutions (G513000128) and the Heart and Stroke Foundation
Figure 4. Linear regression indicated no relationship between the absolute change in systolic blood
pressure (BP) and perihematoma relative cerebral
blood flow (rCBF) in the <150 mm Hg (R=0.00005;
95% CI, −0.001 to 0.001) or <180 mm Hg target
groups (R=0.000; 95% CI, −0.001 to 0.001). Confidence intervals removed for clarity.
626 Stroke March 2013
of Canada (G220170180). Dr Butcher holds a Canada Research Chair
in Cerebrovascular Disease, a Heart and Stroke Foundation of Alberta
(HSFA) Professorship in Stroke Medicine and a New Investigator
Award from Alberta Innovates Health Solutions (AIHS). Dr Hill
holds an HSFA Professorship in Stroke Medicine. Dr Demchuk holds
a Chair in Stroke Medicine (HSFA). Dr Coutts holds an AIHS New
Investigator award. B. Gould and R. McCourt were supported by
AIHS studentships.
Disclosures
None.
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The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial
Kenneth S. Butcher, Thomas Jeerakathil, Michael Hill, Andrew M. Demchuk, Dariush
Dowlatshahi, Shelagh B. Coutts, Bronwen Gould, Rebecca McCourt, Negar Asdaghi, J. Max
Findlay, Derek Emery, Ashfaq Shuaib and for the ICH ADAPT Investigators
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Abstract
27
Abstract
ICH ADAPT 試験：脳内出血急性期患者における降圧治療に
関する試験
The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial
Kenneth S. Butcher, MD, PhD1; Thomas Jeerakathil, MSc, MD1; Michael Hill, MD, MSc4; Andrew M.
Demchuk, MD4; Dariush Dowlatshahi MD, PhD5; Shelagh B. Coutts, MD4; Bronwen Gould, BSc1; Rebecca
McCourt1; Negar Asdaghi, MD, MSc6; J. Max Findlay, MD, PhD3; Derek Emery, MD, MSc2; Ashfaq Shuaib,
MD1; for the ICH ADAPT Investigators
1
Division of Neurology, 2 Department of Diagnostic Imaging, and 3 Division of Neurosurgery, University of Alberta, Edmonton, Canada;
Department of Clinical Neurosciences, University of Calgary, Calgary, Canada; 5 Division of Neurology, University of Ottawa, Ottawa, Canada;
and 6 Division of Neurology, University of British Columbia, Vancouver, Canada
4
背景および目的：脳内出血（ ICH ）拡大を抑制する目的で行
われる急性期の降圧治療は，頭蓋内血流（ CBF ）を損なう
可能性もある。本研究では，ICH 急性期患者の CBF は降
圧治療の影響を受けないという仮説を立てて調べた。
方法：特発性 ICH 発症 24 時間未満の収縮期血圧
（BP）＞ 150 mmHg の患者を，収縮期 BP 目標値を＜ 150
mmHg（ n ＝ 39 ）
もしくは＜ 180 mmHg（ n ＝ 36 ）
とする降
圧剤静脈内投与プロトコルに無作為に割り付けた。無作為
化の 2 時間後に患者にコンピュータ断層灌流画像法を行っ
た。主要評価項目を血腫周囲の相対的 CBF とした。
結果：＜ 150 mmHg 目標群と＜ 180 mmHg 目標群にお
いて，ベースライン時の収縮期 BP（ 182 ± 20 対 184 ±
25 mmHg，p ＝ 0.60 ）
および血腫量（ 25.6 ± 30.8 対 26.9
± 25.2 mL，p ＝ 0.66 ）はバランスが取れていた。無作為
化 2 時間後の平均収縮期 BP は，＜ 150 mmHg 目標群の
方が＜ 180 mmHg 目標群よりも有意に低かった（ 140 ±
19 対 162 ± 12 mmHg，p ＜ 0.001 ）
。血腫周囲の CBF
（ 38.7 ± 11.9 mL/100 g/ 分）は全患者において対側の
同じ領域の方が少なかった（ 44.1 ± 11.1 mL/100 g/ 分，
p ＜ 0.001 ）。主要評価項目である血腫周囲の相対的 CBF
は，＜ 150 mmHg 目標群（ 0.86 ± 0.12 ）の方が＜ 180
mmHg 目標群（ 0.89 ± 0.09 ）よりも低かったが，有意差
はなかった［p ＝ 0.19，絶対差＝ 0.03，95 ％信頼区間
（ CI ）
：－ 0.018 〜 0.078 ］
。BP の変化の大きさおよび血
腫周囲の相対的 CBF との関係は，＜ 150 mmHg 目標群
（ R ＝ 0.00005，95％ CI：－ 0.001 〜 0.001 ）でも＜ 180
mmHg 目標群（R ＝ 0.000，95％ CI：－ 0.001 〜 0.001）
で
も認められなかった。
結論：中等度の体積の ICH を発症後は，迅速に降圧治療
を行っても，血腫周囲の CBF は減少しない。上記の生理
学的なデータは，ICH 患者では急性期に降圧治療を行って
も脳虚血を惹起する可能性がないことを示している。
臨床試験登録情報：URL : http://crinicartrials.gov。固有
の識別番号： NCT00963976。
Stroke 2013; 44: 620-626
CBV
患者1
＜ 150 mmHg
0
mL/100g/分
100
患者2
＜ 180 mmHg
0
mL/100g/分
100
10
mL/100g
CBF
0
10
mL/100g
CT
0
急性期の血圧を＜ 150 mmHg（上）と＜ 180 mmHg（下）に低下した後の頭蓋内血流（ CBF ）と脳血液量（ CBV ）のマップおよびコ
図 3 ンピュータ断層撮影像の例。全てのスライスで関連する血腫（赤）と血腫周囲（白）領域を示す。両患者において CBF の減少が血腫周
囲領域で明らかである。

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