Mannitol and Outcome in Intracerebral Hemorrhage

Propensity Score and Multivariable Intensive Blood Pressure Reduction

in Acute Cerebral Hemorrhage Trial 2 Results
Xia Wang, MMed; Hisatomi Arima, MD, PhD; Jie Yang, MD, PhD; Shihong Zhang, MD;
Guojun Wu, MD; Mark Woodward, PhD; Paula Muoz-Venturelli, MD;
Pablo M. Lavados, MD; Christian Stapf, MD; Thompson Robinson, MD; Emma Heeley, PhD;
Candice Delcourt, MD; Richard I. Lindley, MD; Mark Parsons, MD, PhD; John Chalmers, MD, PhD;
Craig S. Anderson, MD, PhD; for the INTERACT2 Investigators*

Downloaded from http://stroke.ahajournals.org/ by guest on November 15, 2016

Background and PurposeMannitol is often used to reduce cerebral edema in acute intracerebral hemorrhage but without
strong supporting evidence of benefit. We aimed to determine the impact of mannitol on outcome among participants of
the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2).
MethodsINTERACT2 was an international, open, blinded end point, randomized controlled trial of 2839 patients with
spontaneous intracerebral hemorrhage (<6 hours) and elevated systolic blood pressure allocated to intensive (target
systolic blood pressure, <140 mmHg within 1 hour) or guideline-recommended (target systolic blood pressure, <180
mmHg) blood pressurelowering treatment. Propensity score and multivariable analyses were performed to investigate
the relationship between mannitol treatment (within 7 days) and poor outcome, defined by death or major disability on
the modified Rankin Scale score (36) at 90 days.
ResultsThere was no significant difference in poor outcome between mannitol (n=1533) and nonmannitol (n=993)
groups: propensity scorematched odds ratio of 0.90 (95% confidence interval, 0.751.09; P=0.30) and multivariable
odds ratio of 0.87 (95% confidence interval, 0.711.07; P=0.18). Although a better outcome was suggested in patients
with larger (15 mL) than those with smaller (<15 mL) baseline hematomas who received mannitol (odds ratio, 0.52
[95% confidence interval, 0.350.78] versus odds ratio, 0.91 [95% confidence interval, 0.721.15]; P homogeneity <0.03
in propensity score analyses), the association was not consistent in analyses across other cutoff points (10 and 20 mL)
and for differing grades of neurological severity. Mannitol was not associated with excess serious adverse events.
ConclusionsMannitol seems safe but might not improve outcome in patients with acute intracerebral hemorrhage.
Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00716079.
(Stroke. 2015;46:2762-2767. DOI: 10.1161/STROKEAHA.115.009357.)
Key Words: blood pressure cerebral hemorrhage clinical trial mannitol propensity score

Mannitol also increases cardiac preload and cerebral perfusion pressure, which contributes to a decrease in intracranial
pressure through cerebral vasoreactivity. Although guidelines
recommend using mannitol where there is increased intracranial pressure in ICH,5 uncertainty exists over the magnitude of
potential benefit, with various observational studies,6,7 clinical

annitol is frequently used in the management of patients

with spontaneous intracerebral hemorrhage (ICH),1 particularly in China2 and India.3 It is an intravascular osmostic
agent that establishes an osmotic gradient between plasma
and neurons, thereby drawing water from the cerebral extracellular space into the vasculature to reduce cerebral edema.4

Received March 7, 2015; final revision received June 17, 2015; accepted July 10, 2015.
From The George Institute for Global Health, School of Public Health, the University of Sydney, Sydney, Australia (X.W., H.A., M.W., P.M.-V., E.H.,
C.D., R.I.L., J.C., C.S.A.); Neurology Department, Royal Prince Alfred Hospital, Sydney, Australia (C.D., C.S.A.); Department of Neurology, Nanjing
First Hospital, Nanjing Medical University, Nanjing, China (J.Y.); Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
(S.Z.); Department of Neurology, Hebei Yutian Hospital, Tangshan, China (G.W.); Servicio de Neurologa, Departamento de Medicina Clnica Alemana,
Universidad del Desarrollo, Santiago, Chile (P.M.-V., P.M.L.); Departamento de Ciencias Neurolgicas, Universidad de Chile, Santiago, Chile (P.M.L.);
Department of Neurology, APHP-Hpital Lariboisire and DHU NeuroVasc Paris-Sorbonne, Universit Paris Diderot-Sorbonne Paris Cit, Paris, France
(C.S.); Department of Cardiovascular Sciences and NIHR Biomedical Research Unit in Cardiovascular Disease, University of Leicester, Leicester, United
Kingdom (T.R.); Department of Medicine, Westmead Hospital Clinical School, Westmead, New South Wales, Australia (R.I.L.); and Department of
Neurology, John Hunter Hospital, and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia (M.P.).
*For a full list of INTERACT2 Investigators, see reference 11.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
115.009357/-/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@georgeinstitute.org.au
2015 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org

DOI: 10.1161/STROKEAHA.115.009357

2762

Wang et al Mannitol and Cerebral Hemorrhage 2763

trials,8,9 and a systematic review,10 unable to provide evidence
of a clear treatment effect of mannitol in acute ICH. The present analysis aimed to determine the impact of use of mannitol
on clinical outcome in patients with acute ICH who participated in the main phase Intensive Blood Pressure Reduction
in Acute Cerebral Hemorrhage Trial (INTERACT2). Our
hypothesis was that mannitol would improve outcome in
patients with more severe ICH.

Methods
Study Design

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Details of the INTERACT2 study have been described elsewhere.11,12

In summary, this was an international, multicenter, open, blinded
end point assessed, randomized controlled trial, that involved 2839
adult patients with computed tomography-confirmed spontaneous
ICH within 6 hours of onset and elevated systolic blood pressure
(SBP, 150220 mmHg) randomly assigned to receive intensive (SBP
<140 mmHg within 1 hour) or guideline-recommended (SBP <180
mmHg) BP-lowering therapy. Exclusion criteria included a clear indication for, or contraindication to intensive BP lowering; low likelihood of benefit because of severe illness, comorbid condition, or
high likelihood of death; and early planned surgical intervention. 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.

Procedures and Outcomes

Patients allocated to the intensive BP-lowering group commenced a
standardized treatment regime involving intravenous and later oral
agents, with the goal of achieving a SBP target of <140 mmHg within
1 hour and to maintain this level for 7 days in hospital. Specific
treatment protocols were developed for each participating region/site,
based on the availability of BP-lowering agents for routine use. For
patients allocated to the guideline group, BP-lowering treatment was
recommended to achieve a target SBP of 180 mmHg. Data on any
use of mannitol within 7 days of ICH were collected.
The primary outcome was death or major disability (defined as a
score of 36 on the modified Rankin Scale)13 at 90 days. Secondary
outcomes were major disability and death (modified Rankin Scale
scores of 35, and 6, respectively) at 90 days. The outcome assessment was undertaken by a site investigator, who was not involved in
the clinical management of the patient and blind to the randomized
treatment allocation.12

Statistical Analysis
Because of significant variability in baseline covariates between
patients treated with and without mannitol, we used propensity
scores (PS) analyses and multivariable models to reduce imbalance.
Predictors of mannitol treatment and the primary outcome among the
baseline characteristics of participants were determined by a 2 test
for binary measures, t test for approximately normally distributed
variables, and Wilcoxon signed-rank test for skewed continuous variables. A multivariable logistic regression model, including all univariate significant predictors of mannitol treatment and the primary
outcome, and other clinically important factors (sex and randomized
BP-lowering treatment), was constructed to produce estimates of the
treatment effect of mannitol (Tables I and II in the online-only Data
Supplement).14,15 On the basis of coefficients from this model, we
generated a PS14,16 for each patient. Only patients with complete data
were included in the analyses to maximize balancing of the PS analysis with the largest number of variables and to avoid the need to impute data. As the variable, China region (for patient recruitment) was
both associated with mannitol treatment and the primary outcome; it
was not included in the PS building model because it was so closely
matched with mannitol use as to be insensitive as a discriminator of
mannitol-related outcomes.

Various methods were used to account for the nonrandom allocation of mannitol to show consistency of the results. We used optimal matching 1:1 without replacement, with an initial caliper width
matching algorithm that equates to 0.19 (20% of the SD of the logit
of the PS).14 A smaller caliper of 0.1 was also used to potentially
provide better balancing of covariate imbalances. Generalized estimating equations were used to test the effect of mannitol on primary
and secondary outcomes, accounting for matching in the PS-matched
subpopulation.15 We next estimated the impact of mannitol using inverse probability of treatment weighting (IPTW). Stabilized weights
were used to reduce variance of the estimated effect of mannitol and
were incorporated into a logistic regression model that only included
the mannitol variable.17 We also conducted an analysis that was stratified across fifths of the PS. A summary estimate was calculated using
unadjusted logistic regression stratified by PS strata.17 Finally, PS was
used as a covariate in the logistic model to assess the impact of mannitol treatment. Effects of mannitol on outcomes were also estimated
in multivariable logistic regression models with the same covariates
as PS. The model was further adjusted by significant medical and
surgical treatment factors at 7 days (admission to an intensive care
unit, prophylactic treatment for deep venous thrombosis, hemostatic
therapy, and any surgical intervention) to reduce management bias.
Subgroup analyses were also undertaken by key demographic variables (age <65 versus 65 years; sex) and clinical severity
(defined by baseline hematoma volume <15 versus 15 mL; and
National Institutes of Health Stroke Scale [NIHSS] scores <15 versus
15 points). Consistency of any association of mannitol and outcome
according to severity of ICH was assessed in sensitivity analyses using lower (<10 versus 10 mL) and higher (<20 versus 20 mL) cutoff points for ICH volume and at lower (<10 versus 10) and higher
(<20 versus 20) NIHSS score thresholds for stroke severity. We assessed the heterogeneity of association in subgroups by adding an
interaction term in the models.
As it was not possible to adjust for China region in analyses because of manniol use in these participants, the data were stratified
by China and non-China region to assess the consistency of any association in these broadly different populations using the same PS
and multivariable modeling approaches. However, we were not able
to adjust for unaccounted bias, including differences in background
care. Thus, we used the modified ICH score,18 which has been shown
to provide high discrimination for 90-day poor outcome when compared with other popular prognostic scales,19 to help interpreting this
comparison. Data were presented with odds ratios (ORs) and 95%
confidence intervals (CI). A 2-sided P<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
After excluding patients with missing data on the outcome or
any covariates, 2526 (89%) patients were included in these
analyses. A total of 1678 patients (839 mannitol users and
839 nonmannitol users) were PS matched. Table1 shows the
baseline characteristics of patients according to mannitol use;
with all baseline variables included in the multivariable model
to generate PS. Table1 also shows improved balance in the
distribution of covariates by mannitol use in the PS-matched
and IPTW subpopulations. However, the 2 groups of patients
were treated differently over the first 7 days post randomization, and the medical and surgical treatment variables were
not evenly distributed in PS analyses. The distribution of PS is
shown in Figure I in the online-only Data Supplement.
Table2 shows significantly fewer serious adverse events
over 90 days in mannitol-treated patients. There were 775
(50.6%) patients in the mannitol treatment group than 566
(57%) of those in the nonmannitol treatment group, who were
dead or had major disability at 90 days (crude OR, 0.77; 95%

2764StrokeOctober 2015
Table 1. Distribution of Patient Characteristics by Mannitol Treatment in Overall, PS-Matched, and IPTW Populations
Overall
Nonmannitol
(n=993)

Mannitol (n=1533)

PS Matched
Nonmannitol
(n=839)

Mannitol (n=839)

IPTW*
Nonmannitol
(n=993)

Mannitol (n=1533)

Demographic
Age, y

67 (13)

66 (13)

64 (13)

63.0 (15)

64.0 (12)

Male

612 (62)

952 (62)

61 (12)*

520 (62)

504 (60)

791.4 (63)

786.1 (62)

NIHSS15

293 (30)

421 (28)

244 (29)

237 (28)

367.8 (29)

367.2 (29)

Time to randomization, h

3.6 (2.74.6)

3.8 (2.84.8)

3.6 (2.74.6)

3.8 (2.94.8)

Systolic BP, mmHg

179 (17)

179 (17)

179 (17)

179 (17)

65 (7)

134 (9)

61 (7)

71 (9)

99.3 (8)

96.0 (8)

Clinical features

Prior intracerebral hemorrhage

Prior ischemic/undifferentiated stroke

3.8 (2.84.7)
179.1 (19.1)

3.7 (2.94.7)
179.1 (15.2)

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89 (9)

197 (13)

76 (9)

77 (9)

144.9 (12)

143.0 (11)

Heart disease

160 (16)

114 (7)

86 (10)

79 (9)

137.1 (11)

145.3 (12)

Diabetes mellitus

153 (15)

121 (8)

105 (13)

80 (10)

134.1 (11)

158.2 (13)

Antihypertensive therapy

533 (54)

605 (40)

399 (48)

359 (43)

577.4 (46)

589.1 (47)

Use of warfarin anticoagulation/aspirin

224 (23)

85 (6)

97 (12)

76 (9)

152.5 (12)

178.9 (14)

Use of statin/other lipid-lowering agent

147 (15)

39 (3)

52 (6)

38 (5)

93.0 (7)

118.6 (9)

Deep location of hematoma

820 (83)

1295 (85)

690 (82)

697 (83)

1044.4 (83)

1045.7 (83)

Left hemisphere site of hematoma

493 (50)

779 (51)

424 (51)

414 (49)

629.7 (50)

651.2 (51)

Hematoma volume at baseline, mL

8.9 (4.317.1)

12.1 (6.719.9)

9.3 (4.517.9)

10.3 (5.818.0)

Intraventricular extension

274 (28)

422 (28)

234 (28)

244 (29)

357.7 (28)

353.5 (28)

Randomized intensive BP lowering

504 (51)

765 (50)

434 (52)

428 (51)

634.2 (50)

627.9 (50)

67 (7)

108 (7)

10.3 (5.420.5)

10.8 (5.918.7)

Medical and surgical treatment

Intubation

58 (7)

57 (7)

100.4 (8)

94.9 (8)

Admission to an intensive care unit

297 (30)

660 (43)

266 (32)

373 (45)

417.1 (33)

576.0 (45)

Thromboembolism prophylaxis

503 (51)

72 (5)

398 (47)

45 (5)

601.2 (48)

99.4 (8)

Hemostatic therapy

56 (6)

32 (2)

31 (4)

18 (2)

48.5 (4)

28.5 (2)

Any surgical intervention

37 (4)

105 (7)

31 (4)

55 (7)

51.6 (4)

84.3 (7)

Withdraw active care

58 (6)

53 (4)

45 (5)

31 (4)

60.6 (5)

47.4 (4)

Data are n (%), mean (SD), or median (interquartile range). BP indicates blood pressure; IPTW, inverse probability of treatment weighting; NIHSS, National Institutes
of Health stroke scale; and PS, propensity score.
*Synthetic n values derived from weights.
P<0.05.
Deep location refers to location in the basal ganglia or thalamus.
The use of fresh frozen plasma, vitamin K, and recombinant tissue factor VIIa.

CI, 0.660.91; P<0.01; Figure1). However, the association

was no longer significant after adjustment for baseline imbalances (OR, 0.87; 95% CI, 0.711.07; P=0.18), and further
with the addition of treatment imbalances (OR, 1.02; 95%
CI, 0.811.30; P=0.86). These neutral results were confirmed
by PS analyses: matching (OR, 0.90; 95% CI, 0.751.09;
P=0.30), IPTW (OR, 0.97; 95% CI, 0.831.14; P=0.72), summary stratified (OR, 0.91; 95% CI, 0.771.08; P=0.30), and
covariate adjustment using PS (OR, 0.92; 95% CI, 0.771.10;
P=0.35). The PS-matched analysis with the smaller caliper of
0.10 showed a similar result (OR, 0.89; 95% CI, 0.731.09;
P=0.26). There was no association with the separate outcomes
of death and major disability (data on request) and no heterogeneity according to sex and age (Figures II and III in the
online-only Data Supplement, respectively).
Our primary subgroup analysis by severity of ICH
showed an association of mannitol and reduced poor outcome in patients with larger (15 mL) when compared with

smaller (<15 mL) hematomas (OR, 0.52; 95% CI, 0.350.78

versus OR, 0.91; 95% CI, 0.721.15; P homogeneity 0.02
in PS-matched analysis; Figure2). The association was
also significant in IPTW, summary stratified, and covariate
adjustment using PS analyses, but not either in multivariable-adjusted analyses or in other sensitivity analyses of different cutoff points (10 and 20 mL; Tables III and IV in the
online-only Data Supplement, respectively), despite favorable
trends in the point estimates. Associations for mannitol use
by degree of neurological impairment were not consistent
across analyses: whereas a better outcome was seen for mannitol use in those with greater clinical severity (NIHSS15)
in PS-matched analysis, summary stratified, and covariate
adjustment using PS analyses (all P heterogeneity P<0.05), no
significant heterogeneity was evident in the adjusted models,
IPTW, and also in other sensitivity analyses of different cutoff
points (10 and 20; Figure3, Tables V and VI in the onlineonly Data Supplement, respectively). Moreover, subgroup

Wang et al Mannitol and Cerebral Hemorrhage 2765

Table 2. Safety Outcomes by Mannitol Treatment
Nonmannitol
(n=993)

Mannitol
(n=1533)

P Value

Neurological deterioration in first 24 h

161 (16)

216 (14)

0.12

Non-fatal serious adverse events*

312 (31)

295 (19)

<0.01

Direct effects of the primary ICH event

31 (3)

60 (4)

Cardiovascular disease

44 (4)

26 (2)

Recurrent ICH
Ischemic or undifferentiated stroke
Acute coronary event
Other cardiovascular disease
Noncardiovascular disease
Renal failure

2 (0.2)
10 (1)
4 (0.4)

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5 (0.5)

4 (0.4)

Discussion

This is the largest study to investigate the impact of mannitol

in patients with acute ICH. Overall, there was no significant
difference in frequency of the conventional poor outcome of
death or major disability at 90 days between mannitol and non
mannitol-treated patients independent of other prognostic factors assessed across a variety of analyses that took account of
significant imbalances in baseline and management covariates.
Although there was an apparent benefit of mannitol in patients
with larger hematomas (15 mL), this was not consistent in
analyses across other cutoff points (10 and 20 mL) and for
differing grades of neurological impairment (NIHSS score cut
points of 10, 15, and 20). Moreover, the impact of mannitol
was not consistent between Chinese and non-Chinese patients,
but this could be because of other diseases and management
factors because patients with similar predicted prognosis had
different outcomes between the 2 groups. Finally, there was
no evidence that mannitol use was associated with any clear
harms such as an increase in renal or cardiac complications,
or of neurological deterioration, that may have occurred from
rebound intracranial hypertension.2023
Few studies have investigated the effects of mannitol in
acute ICH. An observational study6 of 111 consecutive patients
within 72 hours of ICH found no association of mannitol on
survival. Similarly, 2 small randomized controlled trials of 21
ICH patients with medium- or small-sized hematomas,8 and

3 (0.3)

30 (3)

15 (1)

136 (14)

150 (10)

5 (0.5)

7 (1)

associations between Chinese and non-Chinese patients might

be explained by differences in characteristics, management,
and prognosis that were not fully accounted for in analyses
(Tables XIIIXV in the online-only Data Supplement), which
was supported by a lower proportion of poor outcome in
Chinese patients with the same baseline modified ICH score
as in non-Chinese patients (Table XVI in the online-only Data
Supplement).

Respiratory infections

53 (5)

48 (3)

Sepsis (includes other infections)

28 (3)

10 (1)

Nonvascular medical

44 (4)

17 (1)

Data are numbers (%). ICH indicates intracerebral hemorrhage.

*One patient could have >1 event.

analyses of patients with both large hematomas (15 mL) and

greater clinical severity (NIHSS15) and of younger patients
(age <65 years) with either large hematoma (volume 15 mL)
or more severe (NIHSS15) showed no clear association of
mannitol and outcome (Tables VIIIX in the online-only Data
Supplement, respectively).
Analysis of patients recruited from China (Table X in
the online-only Data Supplement) showed a similar neutral
association of mannitol and outcome as seen for the whole
population. However, use of mannitol was associated with
an increased risk of death or major disability in non-Chinese
patients (Table XI in the online-only Data Supplement). There
was no association in Chinese patients with larger ICH (Table
XII in the online-only Data Supplement). The disparities in

Figure 1. Association of mannitol treatment on death or major disability at 90 days. Solid boxes represent estimates of treatment effect
on the risk of outcomes. Centers of boxes are placed at the estimates of the effect; areas of the boxes are proportional to the reciprocal of the variance of the estimates. Horizontal lines represent 95% confidence intervals (CIs). Adjusted model 1: adjusted by age, sex,
National Institutes of Health Stroke Scale 15, time to randomization, systolic blood pressure (BP), prior intracerebral hemorrhage, prior
ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of statin or other lipid-lowering agent, deep location of hematoma, left hemisphere site of hematoma, log-transformed
baseline hematoma volume, intraventricular extension, and randomized BP-lowering treatment. Adjusted model 2: model 1+admission to
an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical intervention. IPTW indicates inverse probability of treatment weighting; and PS, propensity score.

2766StrokeOctober 2015

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Figure 2. Association of mannitol treatment on death or major disability at 90 days by baseline hematoma volume. Solid boxes represent
estimates of treatment effect on the risk of outcomes. Centers of boxes are placed at the estimates of the effect; areas of the boxes are
proportional to the reciprocal of the variance of the estimates. Horizontal lines represent 95% confidence intervals (CIs). Adjusted model
1: adjusted by age, sex, National Institutes of Health Stroke Scale 15, time to randomization, systolic blood pressure (BP), prior intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy,
use of warfarin anticoagulation or aspirin, use of statin or other lipid-lowering agent, deep location of hematoma, left hemisphere site of
hematoma, intraventricular extension, and randomized BP-lowering treatment. Adjusted model 2: model 1+admission to an intensive care
unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical intervention. ICH indicates intracerebral
hemorrhage; IPTW, inverse probability of treatment weighting; and PS, propensity score.

128 ICH patients within 6 days after onset,9 found no effect of

mannitol on early mortality. A Cochrane review of the topic
concluded with uncertainty over whether mannitol is beneficial in this clinical setting.10 The much larger data set of >2500
patients provided by the INTERACT2 study also indicates

that mannitol has no effect in this population of predominantly

mild to moderate severity of ICH.
Strengths of this study include the large heterogeneous
sample of patients recruited from a diverse range of hospitals and healthcare settings, who were assessed according to a

Figure 3. Association between mannitol treatment and death or major disability at 90 days by National Institutes of Health Stroke Scale
(NIHSS). Solid boxes represent estimates of treatment effect on the risk of outcomes. Centers of the boxes are placed at the estimates
of the effect; areas of the boxers are proportional to the reciprocal of the variance of the estimates. Horizontal lines represent 95% confidence intervals (CIs). Adjusted model 1: adjusted by sex, age, time to randomization, systolic blood pressure (BP), prior intracerebral
hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of
warfarin anticoagulation or aspirin, use of statin or other lipid-lowering agent, deep location of hematoma, left hemisphere site of hematoma, log-transformed baseline hematoma volume, intraventricular extension, and randomized BP-lowering treatment. Adjusted model 2:
model 1+admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical
intervention. IPTW indicates inverse probability of treatment weighting; and PS, propensity score.

Wang et al Mannitol and Cerebral Hemorrhage 2767

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standardized protocol and objective measures. We also undertook PS-matched analysis, which allowed us to mimic some
of the characteristics of a randomized controlled trial, and the
numerous subgroup and sensitivity analyses strengthen the
consistency of the findings. Although a benefit of mannitol
was suggested in larger hematomas (>15 mL), the absence
of a clear doseresponse relationship in smaller and larger
hematomas indicates that the former was likely to have been
a spurious finding. Furthermore, the worse outcome for mannitol use in non-Chinese participants seems to relate more to
background differences in prognosis between Chinese and
non-Chinese patients rather than from mannitol.
However, there are limitations to our analytic approaches,
where mannitol was administered according to the discretion of investigators, with variable doses and duration of
treatment that were not captured in this study. Furthermore,
mannitol was much more frequently used in China than for
the other countries, which could have introduced bias despite
our efforts to balance the baseline characteristics of patients.
Because these analyses were not prespecified, they are prone
to random error and incomplete adjustment for potential confounding, especially because we were unable to address all
potential management confounders in analyses. Finally, the
data are prone to selection bias by using a clinical trial population, where patients with a poor prognosis because of massive hematoma or deep coma, and those with early surgery,
being excluded. Thus, the study sample may have been too
small to adequately assess the effects of mannitol in patients
with large hematomas.
We conclude that the use of mannitol is safe but might not
improve outcome in patients with acute ICH. In the absence of
definitive evidence from future randomized controlled trials,
these data may serve as a guide in the management of patients.

Sources of Funding
The second Intensive Blood Pressure Reduction in Acute Cerebral
Hemorrhage Trial 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 reports membership of Advisory Boards for Pfizer and
The Medicines Company, and receiving travel reimbursement and
honorarium from Takeda China and Covidien. Dr Lavados reports
grants from the George Institute for Global Health as a national leader
of Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage
Trial (INTERACT) 2.

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Mannitol and Outcome in Intracerebral Hemorrhage: Propensity Score and Multivariable

Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 Results
Xia Wang, Hisatomi Arima, Jie Yang, Shihong Zhang, Guojun Wu, Mark Woodward, Paula
Muoz-Venturelli, Pablo M. Lavados, Christian Stapf, Thompson Robinson, Emma Heeley,
Candice Delcourt, Richard I. Lindley, Mark Parsons, John Chalmers and Craig S. Anderson
for the INTERACT2 Investigators
Stroke. 2015;46:2762-2767; originally published online August 11, 2015;
doi: 10.1161/STROKEAHA.115.009357
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2015 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/46/10/2762

Data Supplement (unedited) at:

http://stroke.ahajournals.org/content/suppl/2015/08/13/STROKEAHA.115.009357.DC1.html

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SUPPLEMENTAL MATERIAL
Mannitol and outcome in intracerebral hemorrhage: propensity score and multivariable
INTERACT2 results
Xia Wang MMed,1 Hisatomi Arima MD PhD,1 Jie Yang PhD,3 Shihong Zhang MD,4 Guojun
Wu MD,5 Mark Woodward PhD,1 Paula Muoz-Venturelli MD,1,6 Pablo M Lavados MD,6,7
Christian Stapf MD,8 Thompson Robinson MD,9 Emma Heeley PhD,1 Candice Delcourt
MD,1,2 Richard I Lindley MD,1,10 Mark Parsons MD PhD,11 John Chalmers MD,1 Craig S
Anderson MD PhD,1,2 for the INTERACT2 Investigators
1

The George Institute for Global Health, School of public health, the University of Sydney

Royal Prince Alfred Hospital, Sydney, Australia

Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing,

China
4

Department of Neurology, West China Hospital, Sichuan University, Chengdu, China

Department of Neurology, Hebei Yutian Hospital, Tangshan, China

Servicio de Neurologa, Departamento de Medicina Clnica Alemana, Universidad del

Desarrollo, Santiago, Chile
7

Universidad de Chile, Santiago, Chile

Department of Neurology, APHP - Hpital Lariboisire and DHU NeuroVasc Paris Sorbonne, Univ Paris Diderot - Sorbonne Paris Cit, Paris, France
9

Department of Cardiovascular Sciences and NIHR Biomedical Research Unit in

Cardiovascular Disease, University of Leicester, Leicester, UK
10

Westmead Hospital Clinical School, Westmead, NSW, Australia

11

Department of Neurology, John Hunter Hospital, University of Newcastle, Newcastle, New

South Wales, Australia

Author for correspondence:

Professor Craig 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@georgeinstitute.org.au

Supplemental Table I. Baseline characteristics by mannitol use

Variable
Age, yr
Male
Recruited from China
NIHSS
NIHSS 15
Time to randomization, hr
Systolic BP, mmHg,
Diastolic BP, mmHg,
History of hypertension
Prior intracerebral hemorrhage
Prior ischemic/undifferentiated stroke
Heart disease
Diabetes mellitus
Current use of antihypertensive therapy
Use of warfarin anticoagulation/aspirin
Use of insulin/oral hypoglycemic agents
Use of statin/other lipid lowering
Deep location of hematoma*
Left hemisphere site of hematoma
Hematoma volume at baseline, mL
Intraventricular extension
Randomized BP lowering treatment

Non-mannitol
(N=1037)
67 (13)
648 (63)
292 (28)
10 (6-16)
300 (29)
3.7 (2.8-4.6)
179 (17)
97 (16)
757 (73)
67 (7)
92 (9)
166 (16)
159 (15)
555 (54)
231 (22)
114 (11)
151 (15)
820 (83)
493 (50)
8.9 (4.3-17.1)
274 (28)
512 (49)

Mannitol
(N=1707)
61 (12)
165 (62)
1583 (93)
11 (6-15)
468 (27)
3.8 (2.9-4.8)
179 (17)
104 (13)
1229 (72)
152 (9)
221 (13)
124 (7)
136 (8)
684 (40)
93 (6)
65 (4)
42 (3)
1308 (85)
785 (51)
12.1 (6.6-19.9)
434 (28)
850 (50)

P value
<0.01
0.96
<0.01
0.50
0.39
0.03
0.41
<0.01
0.60
0.02
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
0.18
0.58
<0.01
0.79
0.83

Data are numbers (%), mean (SD) or median (IQR)

NIHSS, denotes National Institutes of Health (NIH) stroke scale; BP, blood pressure
*Deep location refers to location in the basal ganglia or thalamus

Supplemental Table II. Baseline characteristics and death or major disability at 90 days

Variable
Age, yr
Male
Recruited from China
NIHSS
NIHSS 15
Time to randomization, hr
Systolic BP, mmHg,
Dystolic BP, mmHg,
History of hypertension
Prior intracerebral hemorrhage
Prior ischemic/undifferentiated stroke
Heart disease
Diabetes mellitus
Current use of antihypertensive therapy
Use of warfarin anticoagulation or aspirin
Use of insulin/oral hypoglycemic agents
Use of statin/other lipid lowering
Deep location of hematoma*
Left hemisphere site of hematoma
Hematoma volume at baseline, mL
Intraventricular extension
Randomized BP lowering treatment

Death or major disability

No
Yes
(n=1290)
(n=1504)
60 (12)
67 (13)
822 (64)
931 (62)
999 (77)
911 (61)
7 (4-11)
18 (14-22)
135 (11)
665 (44)
3.8 (2.9-4.8)
3.6 (2.7-4.7)
178 (17)
180 (17)
102 (14)
100 (15)
942 (73)
1079 (72)
88 (7)
138 (9)
133 (10)
186 (12)
93 (7)
200 (13)
106 (8)
194 (13)
562 (44)
693 (46)
99 (8)
231 (15)
67 (5)
115 (8)
63 (5)
134 (9)
971 (82)
1189 (85)
569 (48)
728 (52)
8.3 (4.1-14.0)
14.1 (7.8-25.5)
249 (21)
481 (35)
663 (51)
719 (48)

P value
<0.01
0.32
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
0.50
0.02
0.09
<0.01
<0.01
0.17
<0.01
0.01
<0.01
0.01
0.03
<0.01
<0.01
0.06

Data are numbers (%), mean (SD) or median (IQR)

NIHSS, denotes NIH stroke scale; BP, blood pressure
*Deep location refers to location in the basal ganglia or thalamus

Supplemental Table III. Mannitol and death or major disability at 90 days by baseline hematoma volume 10mL
Baseline hematoma volume 10mL

Model
Adjusted

Mannitol

Events (%)

OR (95%CI)

P homogeneity

No

No
548
241 (44.0)
0.966
Yes
620
221 (35.7)
0.92 (0.69-1.22)
Yes
No
445
325 (73.0)
Yes
913
554 (63.0)
0.87 (0.65-1.16)
2
Adjusted
No
No
548
241 (44.0)
0.977
Yes
620
221 (35.7)
1.18 (0.85-1.64)
Yes
No
445
325 (73.0)
Yes
913
554 (63.0)
0.91 (0.64-1.30)
PS matched
No
No
455
183 (40.2)
0.554
Yes
455
169 (37.1)
0.88 (0.67-1.16)
Yes
No
381
268 (70.3)
Yes
381
247 (64.8)
0.78 (0.58-1.05)
IPTW
No
No
548
241 (44.0)
0.185
Yes
620
221 (35.7)
1.05 (0.83-1.33)
Yes
No
445
325 (73.0)
Yes
913
554 (63.0)
0.85 (0.68-1.06)
Summary stratified
No
No
548
241 (44.0)
0.190
Yes
620
221 (35.7)
0.91 (0.71-1.17)
Yes
No
445
325 (73.0)
Yes
913
554 (63.0)
0.77 (0.59-1.00)
Covariate adjustment No
No
548
241 (44.0)
0.174
Yes
620
221 (35.7)
0.94 (0.73-1.21)
Using the PS
Yes
No
445
325 (73.0)
Yes
913
554 (63.0)
0.80 (0.61-1.04)
CI denotes confidence interval; OR, odds ratio; PS, propensity score; IPTW, inverse probability of treatment weighting.
Adjusted model 1: Adjusted by age, sex, NIHSS 15, time to randomization, systolic BP, prior intracerebral hemorrhage, prior ischemic or
undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of

statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of hematoma, intraventricular extension, and randomized BP
lowering treatment
Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and
any surgical intervention

Supplemental Table IV. Mannitol and death or major disability at 90 days by greater (20mL) baseline hematoma volume
Model
Adjusted1

Baseline hematoma volume 20mL

No

Mannitol
N
Events (%)
OR(95%CI)
P homogeneity
No
783 393 (50.2)
0.638
Yes
1150 492 (42.8) 0.95 (0.77-1.18)
Yes
No
210 173 (82.4)
Yes
383 283 (73.9) 0.98 (0.60-1.61)
2
Adjusted
No
No
783 393 (50.2)
0.888
Yes
1150 492 (42.8) 1.19 (0.92-1.55)
Yes
No
210 173 (82.4)
Yes
383 283 (73.9) 0.96 (0.54-1.73)
PS matched
No
No
662 313 (47.3)
0.370
Yes
662 293 (44.3) 0.89 (0.71-1.10)
Yes
No
179 142 (79.3)
Yes
179 135 (75.4) 0.80 (0.49-1.30)
IPTW
No
No
783 393 (50.2)
0.690
Yes
1150 492 (42.8) 1.04 (0.87-1.24)
Yes
No
210 173 (82.4)
Yes
383 283 (73.9) 0.95 (0.65-1.39)
Summary stratified
No
No
783 393 (50.2)
0.311
Yes
1150 492 (42.8) 0.95 (0.78-1.16)
Yes
No
210 173 (82.4)
Yes
383 283(73.9)
0.90 (0.57-1.42)
Covariate adjustment
No
No
783 393 (50.2)
0.305
Using the PS
Yes
1150 492 (42.8) 0.97 (0.79-1.18)
Yes
No
210 173 (82.4)
Yes
383 283 (73.9) 0.96 (0.61-1.51)
CI denotes confidence interval; OR, odds ratio; PS, propensity score; IPTW, inverse probability of treatment weighting.
Adjusted model 1: Adjusted by age, sex, NIHSS 15, time to randomization, systolic BP, prior intracerebral hemorrhage, prior ischemic or
undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of
statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of hematoma, intraventricular extension, and randomized BP
lowering treatment
6

Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and
any surgical intervention

Supplemental Table V. Mannitol and death or major disability at 90 days by NIHSS

score 10
Model
PS matched

NIHSS 10
No
Yes

IPTW

No
Yes

Summary
stratified

No
Yes

Covariate
adjustment
Using the
PS

No
Yes

Mannitol
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes

N
389
389
445
445
458
670
533
853
389
389
445
445
389
389
445
445

Events (%)
115 (29.6)
87 (22.4)
343 (77.1)
327 (73.5)
148 (32.3)
162 (24.2)
418 (78.4)
608 (71.3)
115 (29.6)
87 (22.4)
343 (77.1)
327 (73.5)
115 (29.6)
87 (22.4)
343(77.1)
327(73.5)

OR (95%CI)

P homogeneity
0.406

0.69 (0.51-0.94)
0.82 (0.61-1.11)
0.567
0.86 (0.66-1.12)
0.96 (0.75-1.22)
0.984
0.79 (0.60-1.06)
0.89 (0.68-1.17)
0.973
0.82 (0.61-1.09)
0.88(0.67-1.16)

CI denotes confidence interval; OR, odds ratio; NIHSS, NIH stroke scale; PS, propensity
score; IPTW, inverse probability of treatment weighting

Supplemental Table VI. Mannitol and death or major disability at 90 days by NIHSS
score 20
Model
PS matched

IPTW

Summary
stratified

Covariate
adjustment
Using the
PS

NIHSS 20 Mannitol
No
No
Yes
Yes
No
Yes
No
No
Yes
Yes
No
Yes
No
No
Yes
Yes
No
Yes
No
No
Yes
Yes
No
Yes

N
738
738
95
95
881
1358
110
165
738
738
95
95
738
738
95
95

Events (%)
368 (49.9)
349 (47.3)
87 (91.6)
79 (83.2)
465 (52.8)
631 (46.5)
101 (91.8)
139 (84.2)
368 (49.9)
349 (47.3)
87 (91.6)
79 (83.2)
368 (49.9)
349 (47.3)
87 (91.6)
79 (83.2)

OR (95%CI)

P homogeneity
0.169

0.90 (0.74-1.10)
0.45 (0.17-1.18)
0.923
0.93 (0.79-1.10)
0.90 (0.45-1.78)
0.220
0.88 (0.73-1.06)
0.62 (0.27-1.43)
0.210
0.89 (0.74-1.08)
0.62 (0.27-1.42)

CI denotes confidence interval; OR, odds ratio; NIHSS, NIH stroke scale; PS, propensity
score; IPTW, inverse probability of treatment weighting

Supplemental Table VII. Mannitol and death or major disability at 90 days in patients
with both large (15mL) hematomas and greater clinical severity (NIHSS 15)
Model

Mannitol

Events (%)

Crude

No

175

157 (89.7)

Yes

262

217 (82.8)

OR (95%CI)

P value

0.55 (0.31-0.99)

0.047

0.90 (0.47-1.71)

0.737

Adjusted2

0.60 (0.25-1.48)

0.271

0.57 (0.31-1.03)

0.063

1.03 (0.61-1.73)

0.927

0.83 (0.45-1.51)

0.533

0.79 (0.43-1.46)

0.455

Adjusted

PS matched
IPTW
Summary stratified
Covariate adjustment
using the PS

No

148

130 (87.8)

Yes

148

119 (80.4)

No

175

157 (89.7)

Yes

262

217 (82.8)

No

175

157 (89.7)

Yes

262

217 (82.8)

No

175

157 (89.7)

Yes

262

217 (82.8)

CI denotes confidence interval; NIHSS, NIH stroke scale; OR, odds ratio; PS, propensity
score; IPTW, inverse probability of treatment weighting.
Adjusted model 1: Adjusted by age, sex, time to randomization, systolic BP, prior
intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes
mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin,
use of statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of
hematoma, intraventricular extension, and randomized BP lowering treatment
Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for
deep venous thrombosis, hemostatic therapy, and any surgical intervention

10

Supplemental Table VIII. Mannitol and death or major disability at 90 days in patients
who were aged <65 years with large hematomas (15mL)
Model
Crude

Mannitol
No
Yes
1

Adjusted
Adjusted2
PS matched

N
120
368

Events (%)
84 (70.0)
222 (60.3)

OR (95%CI)

P value

0.65 (0.42-1.02)
0.84 (0.51-1.37)
0.67 (0.37-1.22)

0.058
0.478
0.187

No
117
81 (69.2)
Yes
117
65 (55.6)
0.56 (0.32-0.96)
0.035
IPTW
No
120
84 (70.0)
Yes
368
222 (60.3)
0.70 (0.48-1.01)
0.059
Summary stratified
No
120
84 (70.0)
Yes
368
222 (60.3)
0.84 (0.52-1.35)
0.474
Covariate adjustment
No
120
84 (70.0)
Using the PS
Yes
368
222 (60.3)
0.86 (0.54-1.38)
0.534
CI denotes confidence interval; OR, odds ratio; PS, propensity score; IPTW, inverse
probability of treatment weighting.
Adjusted model 1: Adjusted by sex, NIHSS 15, time to randomization, systolic BP, prior
intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes
mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin,
use of statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of
hematoma, intraventricular extension, and randomized BP lowering treatment
Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for
deep venous thrombosis, hemostatic therapy, and any surgical intervention

11

Supplemental Table IX. Mannitol and death or major disability at 90 days in patients
who were aged <65 years with baseline NIHSS scores 15
Model
Crude

Mannitol
No
Yes
1

Adjusted
Adjusted2
PS matched

N
115
232

Events (%)
88 (76.5)
163 (70.3)

OR (95%CI)

P value

0.73 (0.43-1.21)
0.83 (0.48-1.44)
0.49 (0.22-1.07)

0.221
0.514
0.071

No
111
84 (75.7)
Yes
111
78 (70.3)
0.76 (0.42-1.38)
0.365
IPTW
No
115
88 (76.5)
Yes
232
163 (70.3)
0.95 (0.59-1.51)
0.817
Summary stratified
No
115
88 (76.5)
Yes
232
163 (70.3)
0.88 (0.52-1.50)
0.646
Covariate adjustment
No
115
88 (76.5)
Using the PS
Yes
232
163 (70.3)
0.88 (0.52-1.51)
0.643
CI denotes confidence interval; OR, odds ratio; PS, propensity score; IPTW, inverse
probability of treatment weighting.
Adjusted model 1: Adjusted by sex, time to randomization, systolic BP, prior intracerebral
hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current
use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of statin or
other lipid lowering agent, deep location of hematoma, left hemisphere site of hematoma, log
transformed baseline hematoma volume, intraventricular extension, and randomized BP
lowering treatment
Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for
deep venous thrombosis, hemostatic therapy, and any surgical intervention

12

Supplemental Table X. Mannitol and death or major disability at 90 days in patients

from China
Model
Crude

Mannitol
No
Yes
1

Adjusted
Adjusted2
PS matched

N
268
1421

Events (%)
93 (34.7)
687 (48.4)

OR (95%CI)

P value

1.76 (1.34-2.31)
1.11 (0.81-1.52)
1.10 (0.80-1.51)

<0.0001
0.507
0.557

No
268
93 (34.7)
Yes
268
110 (41.0)
1.31 (0.93-1.84)
0.119
IPTW
No
268
93 (34.7)
Yes
1421
687 (48.4)
1.16 (0.96-1.40)
0.137
Summary stratified
No
268
93 (34.7)
Yes
1421
687 (48.4)
1.14 (0.85-1.52)
0.394
Covariate adjustment No
268
93 (34.7)
Using the PS
Yes
1421
687 (48.4)
1.11 (0.82-1.49)
0.499
CI denotes confidence interval; OR, odds ratio; PS, propensity score; IPTW, inverse
probability of treatment weighting.
Adjusted model 1: Adjusted by age, sex, NIHSS 15, time to randomization, systolic BP,
prior intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease,
diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or
aspirin, use of statin or other lipid lowering agent, deep location of hematoma, left
hemisphere site of hematoma, log transformed baseline hematoma volume, intraventricular
extension, and randomized BP lowering treatment
Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for
deep venous thrombosis, hemostatic therapy, and any surgical intervention

13

Supplemental Table XI. Mannitol and death or major disability at 90 days in non-China
patients
Model
Crude

Mannitol
No
Yes
1

Adjusted
Adjusted2
PS matched

N
725
112

Events (%)
473 (65.2)
88 (78.6)

OR (95%CI)

P value

1.95 (1.21-3.15)
1.94 (1.10-3.43)
1.91 (1.05-3.48)

0.006
0.023
0.034

No
111
73 (65.8)
Yes
111
88 (79.3)
1.99 (1.09-3.64)
0.025
IPTW
No
725
473 (65.2)
Yes
112
88 (78.6)
1.67 (1.23-2.26)
0.001
Summary stratified
No
725
473 (65.2)
Yes
112
88 (78.6)
1.61 (0.99-2.62)
0.057
Covariate adjustment No
725
473 (65.2)
Using the PS
Yes
112
88 (78.6)
1.61 (0.98-2.64)
0.058
CI denotes confidence interval; OR, odds ratio; PS, propensity score; IPTW, inverse
probability of treatment weighting.
Adjusted model 1: Adjusted by age, sex, NIHSS 15, time to randomization, systolic BP,
prior intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease,
diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or
aspirin, use of statin or other lipid lowering agent, deep location of hematoma, left
hemisphere site of hematoma, log transformed baseline hematoma volume, intraventricular
extension, and randomized BP lowering treatment
Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for
deep venous thrombosis, hemostatic therapy, and any surgical intervention

14

Supplemental Table XII. Mannitol and death or major disability at 90 days by baseline hematoma volume in patients from China
Model
Adjusted1

Baseline hematoma volume 15mL

No

Mannitol
N
Events (%)
OR (95%CI)
P homogeneity
No
227
66 (29.1)
0.116
Yes
894
345 (38.6)
1.50 (1.06-2.14)
Yes
No
41
27 (65.9)
Yes
527
342 (64.9)
0.75 (0.36-1.57)
Adjusted2
No
No
227
66 (29.1)
0.141
Yes
894
345 (38.6)
1.45 (1.01-2.07)
Yes
No
41
27 (65.9)
Yes
527
342 (64.9)
0.77 (0.37-1.63)
PS matched
No
No
227
66 (29.1)
0.379
Yes
227
84 (37.0)
1.43 (0.96-2.14)
Yes
No
41
27 (65.9)
Yes
41
26 (63.4)
0.90 (0.35-2.34)
IPTW
No
No
227
66 (29.1)
0.676
Yes
894
345 (38.6)
1.23 (0.96-1.57)
Yes
No
41
27 (65.9)
Yes
527
342 (64.9)
1.13 (0.80-1.58)
Summary stratified
No
No
227
66 (29.1)
0.370
Yes
894
345 (38.6)
1.22 (0.88-1.70)
Yes
No
41
27 (65.9)
Yes
527
342 (64.9)
0.85 (0.43-1.68)
Covariate adjustment
No
No
227
66 (29.1)
0.505
Using the PS
Yes
894
345 (38.6)
1.19 (0.85-1.66)
Yes
No
41
27 (65.9)
Yes
527
342 (64.9)
0.83 (0.42-1.65)
CI denotes confidence interval; OR, odds ratio; PS, propensity score; IPTW, inverse probability of treatment weighting.
Adjusted model 1: Adjusted by age, sex, NIHSS 15, time to randomization, systolic BP, prior intracerebral hemorrhage, prior ischemic or
undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of

15

statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of hematoma, intraventricular extension, and randomized BP
lowering treatment
Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and
any surgical intervention

16

Supplemental Table XIII. Baseline characteristics of participants by region

Parameter
Time from onset of ICH to randomization, hr
Age, yr
Male
Systolic BP, mmHg
Diastolic BP, mmHg
NIHSS score*
GCS score
History of hypertension
Current use of antihypertensive drugs
Prior intracerebral hemorrhage
Prior ischemic or undifferentiated stroke
Prior acute coronary event
Diabetes mellitus
Use of warfarin anticoagulation
Use of aspirin or other antiplatelet agent
Baseline hematoma volume, mL
Deep location of hematoma
Left hemisphere site of hematoma
Intraventricular extension of hemorrhage

Non-China
(N=909)

China
(N=1920)

P value

3.6 (2.8-4.7)
6813
584 (64)
18017
9616
12 (7-17)
15 (13-15)
641/909 (71)
507/909 (56)
58/909 (6)
78/909 (9)
52/909 (6)
152/909 (17)
73/909 (8)
198/909 (22)
11 (6-23)
707/876 (81)
436/876 (50)
273/876 (31)

3.8 (2.9-4.7)
61.312
1196 (62)
17917
10413
10 (5-14)
14 (12-15)
1407/1917 (73)
767/1917 (40)
171/1917 (9)
245/1920 (13)
29/1917 (2)
153/1764 (8)
8/1917 (0)
67/1920 (4)
11 (6-18)
1475/1737 (85)
877/1737 (51)
467/1737 (27)

0.02
0.02
0.31
0.04
<0.01
<0.01
<0.01
0.11
<0.01
0.02
<0.01
<0.01
<0.01
<0.01
<0.01
0.40
0.01
0.73
0.02

Data are n (%), mean (SD), or median (IQR).

BP indicates blood pressure; NIHSS, National Institutes of Health stroke scale.
*Scores range from 0 (normal) to 42 (coma with quadriplegia).
Scores range from 15 (normal) to 3 (deep coma)
Location in the basal ganglia or thalamus

17

Supplemental Table XIV. Management of patients by region

Non-China
Parameter
(N=909)
Time from ICH to BP lowering treatment, hr
3.9 (2.8-5.3)
Time from randomisation to BP lowering treatment, hr 0.2 (0.0-0.6)
Any BP lowering treatment in first 24 hours
743 (82)
Intubation
112/894 (13)
Admission to an intensive care unit
304/894 (34)
Prophylactic treatment for deep venous thrombosis
596/894 (67)
Compression stockings used
283/894 (32)
Subcutaneous heparin administered
489/894 (55)
Use of intravenous mannitol
127/894 (14)
Hemostatic therapy*
70/894 (8)
Any surgical intervention
49/894 (6)
Evacuation or decompression of the hematoma
24/894 (3)
Insertion of a ventricular drain
29/894 (3)
Decision to withdraw active treatment and care
58/894 (7)

China
(N=1920)
4.1 (3.0-5.5)
0.1 (0.0-0.7)
1130 (59)
77/1885 (4)
757/1885 (40)
14/1885 (1)
10/1885 (1)
4/1885 (0)
1592/1885 (85)
27/1885 (1)
105/1885 (6)
57/1885 (3)
56/1885 (3)
63/1885 (3)

P value
0.01
0.04
<0.01
<0.01
<0.01

<0.01
<0.01
0.92
0.62
0.70
<0.01

ICH denotes intracerebral haemorrhage; BP, blood pressure

*Includes the use of fresh frozen plasma, vitamin K, and recombinant tissue Factor VIIa.

18

Supplemental Table XV. Death or major disability at 90 days by region

Outcome
Death or major disability

Non-China
(N=909)

China
(N=1920)

593/884 (67)

911/1910 (48)

OR (95% CI)
0.45 (0.38-0.53)

P value
<0.01

aOR (95% CI)*

0.66 (0.54-0.82)

P value
<0.01

OR denotes odds ratio; CI, confidence interval; aOR, adjusted OR

*adjusted by age, sex, prior ICH, antithrombotictherapy, national Institutes of Health stroke scale (NIHSS) score 15, baseline hematoma
volume, deep location of hematoma, and randomized treatment.

19

Table XVI. Modified intracerebral haemorrhage score and death or major disability by region
Death or major disability, n(%)
MICH score

China

Non-China

231(29.2)

202(51.9)

340(54.4)

200(75.8)

174(75.7)

102(83.6)

57(85.1)

59(92.2)

15(93.8)

13(100.0)

20

.8

.6

.4

.2

0
No

Yes

Mannitol treatment

Supplemental Figure I. Propensity score distribution stratified by mannitol treatment

21

Supplemental Figure II. Association between mannitol treatment and death or major
disability at 90 days, by gender
95% CI, 95% confidence interval; PS, propensity score; IPTW, inverse probability of
treatment weighting.
Solid boxes represent estimates of treatment effect on the risk of outcomes. Centers of the
boxes are placed at the estimates of the effect; areas of the boxers are proportional to the
reciprocal of the variance of the estimates. Horizontal lines represent 95% CIs.
Adjusted model 1: Adjusted by age, NIHSS 15, time to randomization, systolic BP, prior
intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes
mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin,
use of statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of
hematoma, log transformed baseline hematoma volume, intraventricular extension, and
randomized BP lowering treatment
Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for
deep venous thrombosis, hemostatic therapy, and any surgical intervention.

22

Supplemental Figure III. Association between mannitol treatment and death or major
disability at 90 days by age (yr)
95% CI, 95% confidence interval; PS, propensity score; IPTW, inverse probability of
treatment weighting.
Solid boxes represent estimates of treatment effect on the risk of outcomes. Centres of the
boxes are placed at the estimates of the effect; areas of the boxers are proportional to the
reciprocal of the variance of the estimates. Horizontal lines represent 95% CIs.
Adjusted model 1: Adjusted by sex, NIHSS 15, time to randomization, systolic BP, prior
intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes
mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin,
use of statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of
hematoma, log transformed baseline hematoma volume, intraventricular extension, and
randomized BP lowering treatment
Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for
deep venous thrombosis, hemostatic therapy, and any surgical intervention.

23