Prognostic Significance of Hyperglycemia in Acute

Intracerebral Hemorrhage
The INTERACT2 Study
Anubhav Saxena, MBBS, BSc (Adv); Craig S. Anderson, MD, PhD; Xia Wang, MMed;
Shoichiro Sato, MD, PhD; Hisatomi Arima, MD, PhD; Edward Chan, MBBS, BSc (Adv);
Paula Muoz-Venturelli, MD; Candice Delcourt, MD; Thompson Robinson, MD;
Christian Stapf, MD; Pablo M. Lavados, MD; Jiguang Wang, MD; Bruce Neal, MD, PhD;
John Chalmers, MD, PhD; Emma Heeley, PhD; for the INTERACT2 Investigators
Background and PurposeWe aimed to determine associations of baseline blood glucose and diabetes mellitus with clinical
outcomes in participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2).
MethodsINTERACT2 was an international prospective, open, blinded end point, randomized controlled trial of 2839
patients with spontaneous intracerebral hemorrhage (<6 hours) and elevated systolic blood pressure randomly assigned
to intensive (target systolic blood pressure <140 mmHg) or guideline-based (systolic blood pressure <180 mmHg) BP
management. Associations of hyperglycemia at presentation (>6.5 mmol/L) and combined and separate poor outcomes
of death and major disability (scores of 36, 35, and 6, respectively, on the modified Rankin scale) at 90 days were
determined in logistic regression models.
ResultsIn 2653 patients with available data, there were 1348 (61%) with hyperglycemia and 292 (11%) with diabetes
mellitus. Associations of baseline blood glucose and poor outcome were strong and near continuous. After adjustment
for baseline variables, the highest fourth (7.925.0 mmol/L) of blood glucose was significantly associated with combined
poor outcome (adjusted odds ratio 1.35, 95% confidence interval 1.011.80; P trend 0.015). Diabetes mellitus also
predicted poor outcome (adjusted odds ratio 1.46, 95% confidence interval 1.052.02; P=0.023), though more important
for residual disability than death on separate analysis.
ConclusionsHyperglycemia and diabetes mellitus are independent predictors of poor outcome in patients with
predominantly mild to moderate severity of intracerebral hemorrhage. These data support guideline recommendations
for good glycemic control in patients with intracerebral hemorrhage.
Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00716079.
(Stroke. 2016;47:682-688. DOI: 10.1161/STROKEAHA.115.011627.)
Key Words: clinical trial death diabetes mellitus disability hyperglycemia outcome prognosis

cute intracerebral hemorrhage (ICH) is the most serious and least treatable form of acute stroke1 for which
established prognostic factors include clinical severity and
location and volume of hematoma at presentation.2 Although
stress hyperglycemia is associated with adverse outcomes in
many medical conditions, including acute ischemic stroke,3,4
traumatic brain injury,5 and acute myocardial infarction,6

evidence specifically related to the critical condition of ICH

is varied and conflicting because of previous studies being
limited to small single-center series7,8 with short duration of
follow-up.9 Animal models have shown that elevated blood
pressure (BP) exacerbates cerebral injury after ICH10 and of
an association between hyperglycemia and cerebral edema.
There may be a supra-additive effect of hyperglycemia and

Received September 29, 2015; final revision received December 9, 2015; accepted December 18, 2015.
From the The George Institute for Global Health, Royal Prince Alfred Hospital, Sydney, NSW, Australia (A.S., C.S.A., X.W., S.S., H.A., E.C., P.M.-V.,
C.D., B.N., J.C., E.H.); Central Clinical School, University of Sydney, Sydney, Australia (A.S., C.S.A., X.W., E.C., P.M.-V., C.D., B.N., J.C., E.H.);
Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Japan (H.A.); Clnica Alemana de Santiago, Universidad del Desarrollo,
Chile (P.M.-V., P.M.L.); Department of Cardiovascular Sciences and NIHR Biomedical Research Unit in Cardiovascular Disease, University of Leicester,
Leicester, UK (T.R.); CRCHUM, Dpartement de Neurosciences, Universit de Montral, Montral, QC, Canada (C.S.); Departamento de Ciencias
Neurolgicas, Facultad de Medicina, Universidad de Chile (P.M.L.); and The Shanghai Institute of Hypertension, Rui Jin Hospital, Shanghai Jiaotong
University, Shanghai, China (J.W.).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
115.011627/-/DC1.
Correspondence to Craig S. Anderson, MD, PhD, The George Institute for Global Health, PO Box M201, Missenden Rd, NSW 2050, Australia. E-mail
canderson@george.org.au
2016 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org

DOI: 10.1161/STROKEAHA.115.011627

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682 by ROY LEMBONG on March 17, 2016

Saxena et al Hyperglycemia in Acute Intracerebral Hemorrhage 683

the hypertensive response in ICH on outcome. The purpose
of this study was to quantify risk associations of hyperglycemia and diabetes mellitus among participants of the Intensive
Blood Pressure Reduction in Acute Cerebral Hemorrhage
Trial (INTERACT2).11 Our hypothesis was that hyperglycemia is associated with poor outcome in ICH.

Materials and Methods

INTERACT2 was an international, multicenter, prospective, openlabel, assessor-blinded end point, randomized controlled trial, the details of which are described elsewhere.11 In brief, 2839 patients with
computed tomographyconfirmed spontaneous ICH within 6 hours
of onset and elevated systolic BP (150220 mmHg) were randomly
assigned to receive intensive (target systolic BP <140 mmHg within
1 hour) or guideline-recommended (target systolic BP <180 mmHg)
BP-lowering therapy using locally available agents according to standardized protocols. The study protocol was approved by the appropriate ethics committee at each participating site, and written informed
consent was obtained from the patient or an appropriate surrogate.
Demographic and clinical characteristics recorded at the time of
enrollment included a history of diabetes mellitus and level of blood
glucose. Stroke severity was measured using the Glasgow coma
scale and National Institutes of Health stroke scale at baseline, 24
hours, and at Day 7 (or on discharge from hospital if this occurred
earlier). For each computed tomography scan, uncompressed digital
images were sent to a central analysis laboratory in DICOM format
on a CD-ROM identified only with the patients unique study number.
Hematoma volumes with and without inclusion of any intraventricular hemorrhage component were calculated independently by trained
scientists who were blind to clinical data, treatment, and date and
sequence of scan. This calculation was done with computer-assisted
multislice planimetric and voxel threshold techniques in MIStar software (version 3.2; Apollo Medical Imaging Technology, Melbourne,
Australia). Inter-reader reliability was checked by periodic reanalysis
of the scans (15%) throughout the study to avoid drift (intraclass correlation coefficients 0.92).
The primary clinical outcome was death or major disability,
defined by scores 3 to 6 on the modified Rankin scale12 at 90 days.
Secondary outcomes were separately those of death and major disability (modified Rankin scale score of 6 and 35, respectively) and
serious adverse events, including early neurological deterioration (defined as an increase of 4 on the National Institutes of Health stroke
scale or a decline of 2 on the Glasgow coma scale from baseline to
24 hours postrandomization). Primary causes of death were classified into 3 categories: (1) direct effects of initial ICH, defined as any
death after the onset of the randomized ICH event in a patient who
had progressive neurological deterioration, and either the baseline or
follow-up brain scan showed hematoma with mass effect, midline
shift, or significant extension of initial hematoma in the absence of
a clear extracranial cause for the death; (2) recurrent cardiovascular
event, defined by clear clinical evidence of a recurrent stroke, coronary vascular event, or sudden death, according to standard definitions; (3) other causes, defined by clear evidence of death because of
a non-neurological cause that included pneumonia, sepsis, or injury.
Baseline characteristics were summarized as mean (standard deviation) or median (interquartile range) for continuous variables and
as number (%) for categorical variables. Collinearity and interactions
between variables were checked. Independent associations between
baseline characteristics and level of blood glucose, defined as normoglycemia (<6.5 mmol/L) or hyperglycemia (6.5 mmol/L), and with
a history of diabetes mellitus, were examined in multivariable logistic
regression models with all significant baseline variables. Curves of
predicted 90-day outcomes according to baseline glucose level were
constructed using predicted values and 95% confidence intervals (CI)
from the univariate logistic regression models. Multivariable logistic
regression models adjusted by all the significant and clinically important baseline variables, as well as significant interactions, were
also used to determine associations of baseline level of blood glucose,
both as continuous and categorical (fourths) variables, and clinical

outcomes, as well as the association between a history of diabetes

mellitus and clinical outcomes. Sensitivity analyses were conducted
to examine clinical outcomes based on diagnostic thresholds of blood
glucose for normoglycemia, pre-diabetes mellitus, and diabetes mellitus (<6.1, 6.17.0, >7.0 mmol/L, respectively). Cox proportional
hazard modeling was used to measure survival over 90 days post ICH.
The associations of hypergycemia on absolute increase in hematoma
and perihematoma edema volumes over 24 hours were assessed by an
analysis of covariance, including the same adjusted variables above.
Data are presented with odds ratios (OR) and 95% CI. A 2-sided P
value <0.05 was set as the level for statistical significance. All statistical analyses were performed using SAS version 9.3 (SAS institute,
Cary, NC).

Results
Of the 2829 ICH patients, 176 were excluded because of
missing baseline blood glucose measurements (Figure in the
online-only Data Supplement). Table1 shows the baseline
characteristics of the remaining 2653 patients, which included
1348 (51%) with hyperglycemia (>6.5 mmol/L) and 292
(11%) with diabetes mellitus. After adjusting for confounding
factors, hyperglycemic patients were significantly more often
female, from outside of China, had greater cortical hematomas, diabetes mellitus, higher systolic BP, greater clinical
severity of stroke, and larger hematomas with intraventricular
hemorrhage extension, whereas patients who presented with
a history of diabetes mellitus tended to be older, more often
from outside China, had lower diastolic BP, greater history
of hypertension, heart disease, and use of antihypertensive,
antiplatelet, and warfarin anticoagulation therapies, and with
lower hematoma volume than those patients without diabetes
mellitus (Table I in the online-only Data Supplement).
No collinearity was found between the baseline variables.
All significant interactions (ageNational Institutes of Health
stroke scale 15, Chinaintraventricular hemorrhage extension, baseline hematoma volumedeep location of hematoma,
and deep location of hematomaintraventricular hemorrhage
extension) were included in the multivariable analyses. There
was a strong and near continuous relationship between baseline blood glucose level and death or major disability (OR
1.29, 95% CI 1.191.40; P<0.0001) and death (OR 1.23,
95% CI 1.121.37; P<0.0001) at 90 days, and they were
still significant after adjusted by confounders and significant
interactions: adjusted OR [aOR] 1.11, 95% CI 1.00 to 1.24;
P<0.0001 and aOR 1.16, 95% CI 1.011.33; P=0.043 for
death or major disability and death, respectively (Figure1).
Table2 shows that the combined poor outcome of death or
major disability was significantly greatest for the highest
fourth of baseline blood glucose (aOR 1.35, 95% CI 1.01
1.80; P trend 0.015). Similar trends were evident for death (P
trend 0.062) and major disability (P trend 0.041). The trends
are also similar after removing the variable of randomized
lowering treatment from the multivariate model (Table II in
the online-only Data Supplement). A history of diabetes mellitus (Table III in the online-only Data Supplement) was significantly associated with death or major disability (aOR 1.46,
95% CI 1.052.02; P=0.023) and major disability (aOR 1.51,
95% CI 1.082.12; P=0.017), but not for death alone (aOR
0.96, 95% CI 0.621.51; P=0.871). For diagnostic thresholds
of blood glucose, significant trend was found for death or
major disability (P=0.01) and major disability (P=0.031). In

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684StrokeMarch 2016
Table 1. Patients Characteristics According to Baseline Blood Glucose Level
Baseline Glucose Level, mmol/L
Variable

2.605.59 (N=644)

5.606.49 (N=661)

6.507.90 (N=693)

7.9125.0 (N=655)

P Value

Age, y

62 (12)

63 (13)

65 (13)

65 (13)

<0.001

Male

436 (68)

427 (65)

411 (59)

381 (58)

0.001

Recruited from China

487 (76)

456 (69)

422 (61)

399 (61)

<0.001

Time to randomization, h

3.8 (2.84.7)

3.7 (2.94.6)

3.7 (2.84.8)

3.7 (2.84.7)

0.936

Level of consciousness, GCS score

15 (1315)

14 (1315)

14 (1215)

14 (1215)

<0.001

8 (413)

10 (615)

12 (716)

12 (717)

<0.001

Neurological impairment, NIHSS score

Systolic BP, mmHg

177 (17)

177 (17)

180 (17)

182 (17)

<0.001

Diastolic BP, mmHg

102 (14)

101 (14)

100 (15.3)

100 (15)

0.486

History of hypertension

454 (71)

468 (71)

494 (71.4)

512 (78)

0.004

Use of antihypertensive therapy

277 (43)

279 (42)

309 (44.7)

344 (53)

0.001

Heart disease

58 (9)

57 (9)

72 (10.4)

100 (15)

<0.001

Prior ICH

52 (8)

53 (8)

56 (8.1)

56 (9)

Prior ischemic/undifferentiated stroke

76 (12)

69 (10)

82 (11.9)

75 (12)

0.835

History of diabetes mellitus*

22 (3)

24 (4)

52 (7.5)

194 (30)

<0.001

Insulin or glucose-lowering treatment*

13 (2)

18 (3)

28 (4.1)

120 (18)

<0.001

Use of warfarin anticoagulation

10 (2)

21 (3)

19 (2.8)

27 (4)

0.049

Use of aspirin or other antiplatelet agent

46 (7)

49 (7)

77 (11.1)

88 (14)

<0.001

Deep location of hematoma

514 (85)

538 (88)

524 (81.0)

460 (78)

<0.001

IVH extension

120 (20)

144 (24)

209 (32.3)

212 (36)

<0.001

9.0 (4.616.1)

11.4 (6.218.7)

11.5 (6.420.8)

11.9 (6.022.8)

<0.001

10.2 (5.118.0)

13.3 (7.121.8)

14.2 (7.227.0)

15.3 (7.029.1)

<0.001

0.983

Hematoma volume, mL
ICH
Combined ICH+IVH

Data are n (%), mean (SD), or median (IQR). P values based on chi-squared, t test, or Wilcoxon rank-sum test. BP indicates blood pressure; GCS,
Glasgow coma scale; ICH, intracerebral hemorrhage; IVH, intraventricular hemorrhage; and NIHSS, National Institutes of Health stroke scale.
*As there was a strong collinearity between history of diabetes mellitus and insulin or glucose lowering treatment, only diabetes mellitus was included
in the multivariable analyses.
Deep location refers to location in the basal ganglia or thalamus.

patients with admission blood glucose >7.0 mmol/L, there

was significantly greater association with poor outcome
(aOR 1.36, 95% CI 1.081.71; Table IV in the online-only
Data Supplement). Adjusted Cox regression models indicate
increasing risks of death by increasing (fourths) levels of
baseline blood glucose (Figure2A), although this association
did not appear independent of diabetes mellitus (Figure2B).
In regard to reported serious adverse events (Table3), hyperglycemic patients had significantly greater frequency of early
neurological deterioration (16.5% versus 13.1%; P=0.014),
death (14.4% versus 8.9%; P<0.0001), and nonfatal adverse
events (25.5% versus 20.6%; P=0.003) in comparison with
normoglycemic patients. However, there was no apparent
difference in the frequencies of fatal and nonfatal ischemic,
cardiovascular, or infectious events between the 2 groups
of patients, but these numbers were small. Patients with a
history of diabetes mellitus experienced significantly more
nonfatal serious adverse events, particular of major cardiovascular events, during follow-up, but the frequency of early
neurological deterioration or deaths from the initial ICH was
similar to those without diabetes mellitus (Table V in the
online-only Data Supplement).
There was a trend toward higher glucose levels among
patients with higher baseline hematoma and perihematomal

edema volumes (Tables VI and VII, respectively, in the onlineonly Data Supplement). However, there was no significant
difference of increase in either hematoma or perihematomal
edema volumes between patients with admission glucose
<6.5 or 6.5 mmol/L.

Discussion
This study shows that elevated blood glucose levels and
diabetes mellitus both predict serious outcomes in patients
with predominantly mild to moderate severity of acute
ICH. Hyperglycemia seems to influence prognosis of the
acute event, increasing the risks of early neurological deterioration and death directly from the ICH, but without any
apparent effect on growth in either hematoma or perihematomal edema over 24 hours. Further, a near continuous
association was evident between the level of blood glucose
at presentation and the separate and combined outcomes
of death and major disability over the subsequent 90 days.
Moreover, the association was not affected by randomized
BP lowering treatment. Although diabetes mellitus was also
associated with poor outcome, this seems to relate more to
effects on residual disability and increased risks of future
cardiovascular events rather than through a direct effect on
the initial event.

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Saxena et al Hyperglycemia in Acute Intracerebral Hemorrhage 685

Figure 1. Predicted probabilities of outcome by baseline blood glucose level. Multivariate model adjusted for age, geographical region,
sex, history of heart disease, history of hypertension, history of diabetes mellitus, use of aspirin or warfarin, baseline hematoma volume
and location, intraventricular extension, baseline systolic blood pressure, admission National Institutes of Health stroke scale (score 15),
randomized treatment, ageNIHSS 15, chinaintraventricular extension, baseline hematoma volumedeep location of hematoma, and
deep location of hematomaintraventricular extension. aOR indicates adjusted odds ratio of outcome; 95% CI, 95% confidence interval;
NIHSS, National Institutes of Health stroke scale; and OR, odds ratio for outcome.

Our findings extend previous reports of elevated blood

glucose being a predictor of adverse outcomes in ICH8,9,13,14;
in particular, the finding of a trend toward greater mortality
from hyperglycemia that was observed in Korean multicenter
study9 of 1387 ICH patients, but not with that seen in a smaller
Finnish study.13 Sensitivity analysis of outcomes based on diagnostic thresholds (reference group <6.1 mmol/L) of blood glucose rather than fourths (reference group of 2.65.6 mmol/L)
potentially allowed more clinically relevant glucose levels to
be assessed. Specifically, the patient groups with admission

glucose levels <6.1 and 6.1 to 7.0 mmol/L had less adverse
outcomes than those with admission levels >7.0 mmol/L.
In contrast to previous studies that have defined critical prognostic thresholds of hyperglycemia, such as 815 or 10 mmol/L,7
for mortality, we have shown no threshold but rather a strong
continuous relationship between this exposure and poor outcome
in the INTERACT2 data set. The multivariable analyses indicate
that these associations are specific to hyperglycemia rather than
that of the pathophysiology of diabetes mellitus. In contrast to
previous studies showing that diabetes mellitus is an independent

Table 2. Fourths of Baseline Blood Glucose and 3-Month Outcomes After Acute Intracerebral Hemorrhage
Fourths of Glucose, mmol/L
Outcome

Category

Death or major disability

<5.6

Death

Major disability

Multivariate*

Events, n (%)

OR (95% CI)

P Trend

aOR (95% CI)

P Trend

637

268 (42)

1.0

<0.001

1.0

0.015

5.66.5

650

319 (49)

1.33 (1.071.65)

1.07 (0.821.39)

6.57.9

685

395 (58)

1.88 (1.512.33)

1.31 (1.011.71)

>7.9

647

399 (62)

2.22 (1.772.77)

<5.6

637

45 (7)

1.0

5.66.5

650

70 (11)

1.59 (1.072.35)

1.37 (0.882.12)

6.57.9

685

86 (13)

1.89 (1.292.76)

1.16 (0.761.79)

>7.9

647

107 (17)

2.61 (1.813.76)

<5.6

592

223 (38)

1.0

1.35 (1.011.80)
<0.01

1.0
0.062

1.63 (1.062.51)
<0.001

1.0

5.66.5

580

249 (43)

1.25 (0.991.57)

1.04 (0.791.37)

6.57.9

599

309 (52)

1.76 (1.402.22)

1.32 (1.001.74)

>7.9

540

292 (54)

1.95 (1.542.47)

1.27 (0.941.72)

0.041

aOR indicates adjusted odds ratio; CI, confidence interval; and OR, odds ratio.
*Adjusted for age, geographical region, sex, history of heart disease, history of hypertension, history of aspirin or warfarin use, history
of diabetes mellitus, baseline hematoma volume and location, intraventricular extension, baseline systolic blood pressure, National
Institute of Health stroke scale (NIHSS) score (15), randomized treatment, and ageNIHSS15, Chinaintraventricular extension,
baseline hematoma volumedeep location of hematoma, and deep location of hematomaintraventricular extension.

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686StrokeMarch 2016

Figure 2. A, Cox proportional hazards regression curves for fourths of baseline blood glucose and death. B, Cox proportional hazards
regression curves for death according to level of presence of hyperglycemia (>6.5 mmol/L) and history of diabetes mellitus (DM).

predictor of mortality after acute ischemic stroke,16 and for inhospital17 and 118 and 3 months1921 time points after ICH, we did
not find that diabetes mellitus predicted death after ICH.

The exact pathophysiological mechanisms underlying the

adverse effects of hyperglycemia in ICH are yet to be elucidated. Hyperglycemia has been shown to induce neuronal

Table 3. Serious Adverse Events, by Baseline Blood Glucose Level

Glucose Level
<6.5 mmol/L (N=1305)

6.5 mmol/L (N=1348)

P Value

Early neurological deterioration

168/1282 (13.1)

217/1313 (16.5)

0.014

Nonfatal serious adverse events

269/1305 (20.6)

344/1348 (25.5)

0.003

Initial ICH

26/1305 (2.0)

36/1348 (2.7)

Cardiovascular disease

27/1305 (2.1)

37/1348 (2.7)

Recurrent ICH

6/1305 (0.5)

2/1348 (0.1)

Ischemic/undifferentiated stroke

3/1305 (0.2)

7/1348 (0.5)

Acute coronary event

Other cardiovascular disease
Noncardiovascular disease
Severe hypotension
Fatal serious adverse events

3/1305 (0.2)

5/1348 (0.4)

15/1305 (1.1)

23/1348 (1.7)

101/1305 (7.7)

137/1348 (10.2)

4/1305 (0.3)

7/1348 (0.5)

115/1297 (8.9)

193/1343 (14.4)

<0.001

Initial ICH

66/1297 (5.1)

124/1343 (9.2)

<0.001

Cardiovascular disease

12/1297 (0.9)

16/1343 (1.2)

ICH

1/1297 (0.1)

1/1343 (0.1)

Ischemic/undifferentiated stroke

1/1297 (0.1)

0/1343

Acute coronary event

2/1297 (0.2)

2/1343 (0.1)

Other vascular disease

1/1297 (0.1)

3/1343 (0.2)

Other cardiac disease

7/1297 (0.5)

10/1343 (0.7)

37/1297 (2.9)

53/1343 (4.0)

1/1297 (0.1)

3/1343 (0.2)

12/1297 (0.9)

14/1343 (1.0)

Noncardiovascular disease
Renal failure
Respiratory infections
Sepsis (includes other infections)
Nonvascular medical

6/1297 (0.5)

4/1343 (0.3)

18/1297 (1.4)

32/1343 (2.4)

ICH denotes intracerebral hemorrhage.

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Saxena et al Hyperglycemia in Acute Intracerebral Hemorrhage 687

apoptosis in experimental ICH in adult SpragueDawley male
rats,22 but other reactions from inflammatory (interleukin-1
and tissue necrosis factor alpha)23,24 and toxic (cerebral lactate and lactate/pyruvate ratios)25 effects of oxygen-free radical generation26 may also be important. Recent studies have
also shown increased superoxide production, disruption of
the bloodbrain barrier,27,28 and enhanced cerebral edema29 in
hyperglycemic rat models. Moreover, the study of Parsons et
al30 in patients with ischemic stroke has shown an association
of hyperglycemia and brain lactate and penumbral damage,
quantified by magnetic resonance imaging with spectroscopy,
which suggests there could be a similar mechanistic pathway in ICH. Whatever the mechanism, our data lend support
guideline recommendations for good glycemic control in
ICH31 and suggest that a blood glucose level of <7.0 mmol/L
may be an optimal therapeutic target, despite the absence of
randomized evidence. In the United Kingdom Glucose Insulin
in Stroke Trial (GIST-UK),32 there was no effect ofglucose
potassiuminsulin compared with saline over the initial 24
hours on mortality in 933 patients with stroke (including 114
with ICH) when the trial was stopped early because of slow
enrollment. Moreover, a meta-analysis of randomized controlled trials comparing glycemic control by insulin with usual
care in patients with ischemic stroke also showed no benefit
regarding mortality or functional outcome and increased risk
of hypoglycemic events, suggesting the potential harmful
effects of intensive glycemic control to vulnerable ischemic
penumbra.33 However, there are still significant uncertainties
regarding optimal glucose levels and glycemic control methods in acute stroke, especially in ICH which has different
pathophysiological mechanisms from ischemic stroke.
Strengths of our study include the large and heterogeneous patient population which had rigorous prospective and
systematic evaluations early after the onset of acute ICH.
However, as these analyses were not prespecified, they are
open to chance or biased associations, and therefore, the findings require further validation. Another limitation is that they
are based on single measurements of blood glucose and thus
prone to regression dilution bias as well as some misclassification bias with respect to diabetes mellitus status because this
was based only on a history of the condition at presentation.
Although our study had a much lower frequency of diabetes
mellitus (11%) than has been reported in other studies (14%
to 23%),7,8,20 many of the participants were from China where
the frequency of obesity and diabetes mellitus is lower than in
the west. Finally, because the INTERACT studies excluded
patients with a high likelihood of early death and planned
surgical evacuation of hematoma, these findings may not be
applicable to patients with severe ICH.
In summary, our study has shown that hyperglycemia
has strong and continuous associations with poor outcomes
from predominantly mild to moderate severity of ICH.
Hyperglycemia seems to have a direct deleterious effect on the
initial ICH, whereas diabetes mellitus reduces the potential for
recovery and increases the risk of subsequent cardiovascular
events. In the absence of randomized evidence, these findings
support current guidelines recommending treatment of hyperglycemia in ICH.34

Acknowledgments
We thank the participants and investigators of the Intensive
Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial
(INTERACT2) study.

Sources of Funding
The INTERACT2 study was supported by Program (571281) and
Project (512402 and 1004170) grants from the National Health and
Medical Research Council of Australia. The study was designed, conducted, analyzed, and interpreted by the investigators independent of
sponsors.

Disclosures
Dr Anderson holds a Senior Principal Research Fellowship of
the National Health and Medical Research Council (NHMRC)
of Australia, has speaking engagements with Takeda China, and
is a member of Advisory Boards for Medtronic and Astra Zeneca.
Dr Arima has speaking engagements with Takeda China. Dr Lavados
reports research grants from the NHMRC of Australia. The other authors report no conflicts.

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Prognostic Significance of Hyperglycemia in Acute Intracerebral Hemorrhage: The

INTERACT2 Study
Anubhav Saxena, Craig S. Anderson, Xia Wang, Shoichiro Sato, Hisatomi Arima, Edward
Chan, Paula Muoz-Venturelli, Candice Delcourt, Thompson Robinson, Christian Stapf, Pablo
M. Lavados, Jiguang Wang, Bruce Neal, John Chalmers, Emma Heeley and for the
INTERACT2 Investigators
Stroke. 2016;47:682-688; originally published online January 26, 2016;
doi: 10.1161/STROKEAHA.115.011627
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2016 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

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World Wide Web at:
http://stroke.ahajournals.org/content/47/3/682

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http://stroke.ahajournals.org/content/suppl/2016/01/26/STROKEAHA.115.011627.DC1.html

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STROKE/2015/011627D, R1

Supplemental Material
Tables I, II, III, IV, V, VI and VII; and Figure I
Prognostic significance of hyperglycemia in acute intracerebral hemorrhage: the
INTERACT2 study
Anubhav Saxena BSc (Adv),1,2 Craig S. Anderson MD PhD,1,2 Xia Wang MMed,1,2 Shoichiro
Sato MD PhD,1 Hisatomi Arima MD,1,3 Edward Chan BSc (Adv),1,2 Paula Muoz-Venturelli
MD,1,4 Candice Delcourt MD,1,2 Thompson Robinson MD,5 Christian Stapf MD,6 Pablo M.
Lavados MD,3,7 Jiguang Wang MD,8 Bruce Neal MD PhD,1,2 John Chalmers MD PhD,1,2
Emma Heeley PhD,1,2 for the INTERACT2 Investigators
1

The George Institute for Global Health, Royal Prince Alfred Hospital, Sydney, NSW,
Australia
2

Central Clinical School, University of Sydney, Sydney, Australia

Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Japan

Clnica Alemana de Santiago, Universidad del Desarrollo, Chile

Department of Cardiovascular Sciences and NIHR Biomedical Research Unit in

Cardiovascular Disease, University of Leicester, Leicester, UK
6

Department of Neurology, APHP - Hpital Lariboisire and DHU NeuroVasc Paris Sorbonne, Univ Paris Diderot - Sorbonne Paris Cit, Paris, France
7

Departamento de Ciencias Neurolgicas, Facultad de Medicina, Universidad de Chile

The Shanghai Institute of Hypertension, Rui Jin Hospital, Shanghai Jiaotong University,
Shanghai, China
Author for correspondence:
Professor Craig S Anderson
The George Institute for Global Health
PO Box M201, Missenden Road, NSW 2050, AUSTRALIA
T:+61-2-9993-4500, F:+61-2-9993-4502, Email: canderson@george.org.au

STROKE/2015/011627D, R1

Table I: Baseline characteristics for ICH patients according to the presence of diabetes mellitus
All
(n=2826)
63 (54-74)
1777 (63)
1917 (68)
1.8 (1.2-2.7)
11 (6-15)
179 (17)
101 (15)
76 (68-86)
2048 (73)
1274 (45)
227 (8)
393 (14)
299 (11)
229 (8)
323 (11)
81 (3)
265 (9)
183 (7)
2180 (84)
1312 (50)
739 (28)

No diabetes mellitus
(n=2521)
63 (54-73)
1579 (63)
1764 (70)
1.8 (1.2-2.7)
10 (6-15)
179 (17)
102 (15)
76 (68-86)
1786 (71)
1069 (42)
178 (78)
319 (13)
238 (9)
201 (8)
273 (11)
63 (3)
198 (8)
12 (1)
1940 (83)
1170 (50)
647 (28)

Diabetes mellitus
(n=305)
67 (60-76)
107 (65)
153 (50)
1.8 (1.3-2.9)
12 (7-16)
180 (17)
97 (14)
78 (70-87)
262 (86)
205 (67)
49 (16)
74 (24)
61 (20)
28 (9)
50 (16)
18 (6)
67 (22)
171 (56)
240 (84)
142 (50)
92 (32)

P value

Age
<0.001
Male
0.436
Recruited from China
<0.001
Time to CT scan, hr
0.158
NIHSS score
0.120
Systolic BP, mmHg
0.320
Diastolic BP, mmHg
<0.001
Heart rate, beats/min
0.057
History of hypertension
<0.001
Antihypertensive therapy
<0.001
Beta-blocker
<0.001
Calcium-channel blocker
<0.001
History of heart disease
<0.001
Prior intracerebral hemorrhage
0.466
Prior ischemic or undifferentiated stroke
0.004
Use of warfarin anticoagulation
0.001
Use of aspirin or other antiplatelet agent
<0.001
Insulin therapy or glucose lowering treatment
Deep location of hematoma*
0.838
Left hemisphere site of hematoma
0.830
Intraventricular extension
0.124
Hematoma volume, mL
Hematoma alone
10.9 (5.8-19.5)
11.2 (5.9-19.7)
9.2 (4.7-16.7)
0.002
Combined with intraventricular hemorrhage
13.1 (6.5-23.8)
13.3 (6.6-23.9)
11.4 (5.6-22.8)
0.035
Data are n (%), mean (SD), or median (IQR). aOR indicates adjusted odds ratio; BP, blood pressure; CT, computed tomography; NIHSS,
National Institutes of Health Stroke Scale; and ICH, intracerebral hemorrhage. P values based on chi-squared, t-test or Wilcoxon rank sum test.
*Deep location refers to location in the basal ganglia or thalamus.

STROKE/2015/011627D, R1

Table II: Quartiles of baseline blood glucose and 90-day outcomes after acute intracerebral hemorrhage (not adjusted by randomized BP
lowering treatment)
Glucose (mmol/L)
Outcomes

Events

Multivariable

Category

n (%)

aOR (95% CI)

P trend

Death or major disability

<5.6
5.6-6.5
6.5-7.9
>7.9

637
650
685
647

268 (42)
319 (49)
395 (58)
399 (62)

1.0
1.06 (0.81-1.38)
1.31 (1.01-1.70)
1.35 (1.01-1.80)

0.016

Death

<5.6
5.6-6.5
6.5-7.9
>7.9

637
650
685
647

45 (7)
70 (11)
86 (13)
107 (17)

1.0
1.37 (0.88-2.12)
1.16 (0.76-1.79)
1.63 (1.06-2.51)

<5.6
5.6-6.5
6.5-7.9
>7.9

592
580
599
540

223 (38)
249 (43)
309 (52)
292 (54)

1.0
1.03 (0.78-1.36)
1.32 (1.00-1.73)
1.27 (0.94-1.72)

Major disability

0.062

0.043

OR indicates odds ratio; aOR, adjusted odds ratio; and CI, confidence interval.
*Adjusted for age, geographical region, sex, history of hypertension, heart disease, and diabetes, use of aspirin and/or warfarin use, baseline
hematoma volume and location, intraventricular extension, baseline systolic blood pressure, National Institute of Health Stroke Scale (NIHSS)
score (15), and age*NIHSS15, China*intraventricular extension, baseline hematoma volume*deep location of hematoma, and deep location
of hematoma*intraventricular extension.

STROKE/2015/011627D, R1

Table III: Outcomes from intracerebral hemorrhage, by diabetes mellitus status

Outcomes

n (%)

Death or major disability

No
2329
Yes
287

1192 (51)
186 (65)

OR

P value

aOR

P value

1.0
1.76 (1.36-2.27) <0.001

1.0
1.43 (1.03-2.00)

0.035

Death
No
Yes

2329
287

267 (12)
39 (14)

1.0
1.22 (0.85-1.74)

0.291

1.0
0.93 (0.59-1.46)

0.743

Major disability
No
Yes

2062
248

925 (45)
147 (59)

1.0
1.79 (1.37-2.34) <0.001

1.0
1.49 (1.06-2.10)

0.023

OR indicates odds ratio; aOR, adjusted odds ratio.

Models were adjusted for age, geographical region, sex, history of hypertension, diabetes, and heart disease, use of aspirin and/or warfarin, baseline
hematoma volume and location, intraventricular extension, baseline systolic blood pressure, National Institute of Health stroke scale (NIHSS) score (15),
randomized treatment, and age*NIHSS 15, China*intraventricular extension, baseline hematoma volume*deep location of hematoma, and deep location of
hematoma*intraventricular extension.

STROKE/2015/011627D, R1

Table IV Baseline blood glucose (mmol/L) by diagnostic thresholds for diabetes mellitus and 90-day outcomes after acute ICH
Glucose (mmol/L)
Events
Crude
Multivariable adjusted*
Outcomes
Category
n
n (%)
OR (95% CI)
P trend
aOR (95% CI)
P trend
Death or major disability
<6.1
996
443 (45)
1
<0.001
1
0.010
6.1-7.0
655
349 (53)
1.42 (1.17-1.74)
1.13 (0.88-1.43)
>7.0
968
589 (61)
1.94 (1.62-1.74)
1.36 (1.08-1.71)
Death
<6.1
996
85 (9)
1
<0.001
1
0.081
6.1-7.0
655
70 (11)
1.28 (0.92-1.79)
0.93 (0.63-1.36)
>7.0
968
153 (16)
2.01 (1.52-2.67)
1.34 (0.95-1.89)
Major disability
<6.1
911
358 (39)
1
<0.001
1
0.031
6.1-7.0
585
279 (48)
1.41 (1.14-1.74)
1.11 (0.87-1.43)
>7.0
815
436 (54)
1.78 (1.47-2.15)
1.30 (1.02-1.65)
OR indicates odds ratio; aOR, adjusted odds ratio; CI, confidence interval; ICH, intracerebral hemorrhage
*Adjusted for age, geographical region, sex, history of hypertension, diabetes, and heart disease, use of aspirin and/or warfarin, baseline
hematoma volume and location, intraventricular extension, baseline systolic blood pressure, National Institute of Health Stroke Scale (NIHSS)
score (15), randomized treatment, and age*NIHSS 15, China*intraventricular extension, baseline hematoma volume*deep location of
hematoma, and deep location of hematoma*intraventricular extension.

STROKE/2015/011627D, R1

Table V: Safety outcomes during 90-day follow-up after intracerebral hemorrhage, stratified by diabetes mellitus status at baseline

Early neurological deterioration

Non-fatal serious adverse events
Any neurological deterioration from intracerebral hemorrhage
Cardiovascular disease
Recurrent intracerebral hemorrhage
Ischemic or undifferentiated stroke
Acute coronary event
Other cardiovascular disease
Non-cardiovascular disease
Severe hypotension
Cause of death
Direct effects of primary intracerebral hemorrhage event
Cardiovascular disease
intracerebral hemorrhage
Ischaemic/undifferentiated stroke
Acute myocardial infarction/coronary event/other
Other vascular disease
Other cardiac disease
Non-cardiovascular disease
Renal failure
Respiratory infections
Sepsis (includes other infections)
Non-vascular medical

No diabetes mellitus
(n=2358)
345/2308 (15.0)
509/2358 (21.6)
81/2358 (3.4)
56/2358 (2.4)
7/2358 (0.3)
10/2358 (0.4)
9/2358 (0.4)
33/2358 (1.4)
242/2358 (10.3)
9/2358 (0.4)
267/2358 (11.3)
165/2358 (7.0)
21/2358 (0.9)
Feb-58
Jan-58
4/2358 (0.2)
4/2358 (0.2)
10/2358 (0.4)
81/2358 (3.4)
3/2358 (0.1)
23/2358 (1.0)
9/2358 (0.4)
46/2358 (2.0)

Diabetes mellitus
(n=295)
40/285 (14.0)
101/285 (34.6)
7/285 (2.5)
19/285 (6.7)
1/285 (0.4)
4/285 (1.4)
1/285 (0.4)
14/285 (4.9)
41/285 (14.4)
5/285 (1.8)
39/285 (13.4)
23/285 (7.9)
7/285 (2.4)
0
0
0
0
7/285 (2.4)
9/285 (3.1)
1/285 (0.3)
3/285 (1.0)
1/285 (0.3)
4/285 (1.4)

P value
0.683
<0.001
<0.001

<0.001
0.239
0.506

STROKE/2015/011627D, R1

Table VI: Hematoma growth over 24 hours post-randomization by glucose levels

Glucose <6.5 mmol/L(n=422)

Hematoma volume (mL), meanSD

Glucose 6.5 mmol/L(n=489)

Baseline

24 hours

Baseline

24 hours

13.413.3

17.722.9

16.916.6

20.421.1

P value

Hematoma growth
Absolute growth volume (mL), crude mean (95% CI)

4.3 (2.8-5.9)

3.4 (2.0-4.9)

0.395

Absolute growth volume (mL), adjusted mean* (95% CI)

6.9 (3.9-9.9)

5.4 (2.8-8.0)

0.189

SD indicates standard deviation; and CI, confidence interval.

*Adjusted for age, geographical region, sex, history of hypertension, diabetes, and heart disease , use of aspirin and/or warfarin, baseline
hematoma volume and location, intraventricular extension, baseline systolic blood pressure, randomized treatment, China*intraventricular
extension, baseline hematoma volume*deep location of hematoma, and hematoma location*intraventricular extension.

STROKE/2015/011627D, R1

Table VII: Growth of perihematomal edema over 24 hours post randomization by glucose levels
Glucose <6.5 mmol/L (n=376)

Perihematomal edema volume (mL), meanSD

Glucose 6.5 mmol/L (n=413)

Baseline

24 hours

Baseline

24 hours

2.83.6

5.57.8

3.54.8

6.18.2

P Value

Growth of perihematomal edema

Absolute growth volume (mL), crude mean (95% CI)

2.7 (2.1-3.3)

2.6 (2.0-3.1)

0.809

Absolute growth volume (mL), adjusted mean* (95% CI)

3.0 (1.9-4.1)
2.6 (1.6-3.5)
0.293
SD indicates standard deviation; and CI, confidence interval.
*Adjusted for age, geographical region, sex, history of hypertension, diabetes, and heart disease, use of aspirin and/or warfarin, baseline
hematoma volume and location, intraventricular extension, baseline systolic blood pressure, randomized treatment, China*intraventricular
extension, baseline hematoma volume*deep location of hematoma, and hematoma location*intraventricular extension.

STROKE/2015/011627D, R1

Supplemental Figure I: Patient flow