Original Contribution

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 Muñoz-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*

Background and Purpose—Mannitol 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).
Methods—INTERACT2 was an international, open, blinded end point, randomized controlled trial of 2839 patients with
Downloaded from http://stroke.ahajournals.org/ by guest on January 2, 2018

spontaneous intracerebral hemorrhage (<6 hours) and elevated systolic blood pressure allocated to intensive (target
systolic blood pressure, <140 mm Hg within 1 hour) or guideline-recommended (target systolic blood pressure, <180
mm Hg) blood pressure–lowering 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 (3–6) at 90 days.
Results—There was no significant difference in poor outcome between mannitol (n=1533) and nonmannitol (n=993)
groups: propensity score–matched odds ratio of 0.90 (95% confidence interval, 0.75–1.09; P=0.30) and multivariable
odds ratio of 0.87 (95% confidence interval, 0.71–1.07; 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, 0.35–0.78] versus odds ratio, 0.91 [95% confidence interval, 0.72–1.15]; 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.
Conclusions—Mannitol seems safe but might not improve outcome in patients with acute intracerebral hemorrhage.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00716079.   
(Stroke. 2015;46:00-00. DOI: 10.1161/STROKEAHA.115.009357.)
Key Words: blood pressure ◼ cerebral hemorrhage ◼ clinical trial ◼ mannitol ◼ propensity score

M annitol is frequently used in the management of patients

with spontaneous intracerebral hemorrhage (ICH),1 par-
ticularly 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 extra-
cellular space into the vasculature to reduce cerebral edema.4
Mannitol also increases cardiac preload and cerebral perfu-
sion pressure, which contributes to a decrease in intracranial
pressure through cerebral vasoreactivity. Although guidelines
recommend using mannitol where there is increased intracra-
nial pressure in ICH,5 uncertainty exists over the magnitude of
potential benefit, with various observational studies,6,7 clinical

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 Neurología, Departamento de Medicina Clínica Alemana,
Universidad del Desarrollo, Santiago, Chile (P.M.-V., P.M.L.); Departamento de Ciencias Neurológicas, Universidad de Chile, Santiago, Chile (P.M.L.);
Department of Neurology, APHP-Hôpital Lariboisière and DHU NeuroVasc Paris-Sorbonne, Université Paris Diderot-Sorbonne Paris Cité, 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

1
 2  Stroke  October 2015
trials,8,9 and a systematic review,10 unable to provide evidence
of a clear treatment effect of mannitol in acute ICH. The pres-
ent analysis aimed to determine the impact of use of mannitol
on clinical outcome in patients with acute ICH who partici-
pated 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
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, 150–220 mm Hg) randomly assigned to receive intensive (SBP
<140 mm Hg within 1 hour) or guideline-recommended (SBP <180
mm Hg) BP-lowering therapy. Exclusion criteria included a clear in-
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dication for, or contraindication to intensive BP lowering; low like-
lihood 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 mm Hg 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 mm Hg. 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 3–6 on the modified Rankin Scale)13 at 90 days. Secondary
outcomes were major disability and death (modified Rankin Scale
scores of 3–5, and 6, respectively) at 90 days. The outcome assess-
ment 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 χ2 test
for binary measures, t test for approximately normally distributed
variables, and Wilcoxon signed-rank test for skewed continuous vari-
ables. A multivariable logistic regression model, including all uni-
variate 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 analy-
sis with the largest number of variables and to avoid the need to im-
pute 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 alloca-
tion of mannitol to show consistency of the results. We used opti-
mal 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 esti-
mating 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 in-
verse 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 strati-
fied 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 man-
nitol 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 demograph-
ic 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 us-
ing lower (<10 versus ≥10 mL) and higher (<20 versus ≥20 mL) cut-
off points for ICH volume and at lower (<10 versus ≥10) and higher
(<20 versus ≥20) NIHSS score thresholds for stroke severity. We as-
sessed 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 be-
cause of manniol use in these participants, the data were stratified
by China and non-China region to assess the consistency of any as-
sociation 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 com-
pared 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. Table 1 shows the
baseline characteristics of patients according to mannitol use;
with all baseline variables included in the multivariable model
to generate PS. Table 1 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 randomiza-
tion, 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.
Table 2 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%
 Wang et al   Mannitol and Cerebral Hemorrhage    3

Table 1.  Distribution of Patient Characteristics by Mannitol Treatment in Overall, PS-Matched, and IPTW Populations
Overall PS Matched IPTW*
Nonmannitol Nonmannitol Nonmannitol
(n=993) Mannitol (n=1533) (n=839) Mannitol (n=839) (n=993) Mannitol (n=1533)
Demographic
 Age, y 67 (13) 61 (12)* 66 (13) 64 (13) 63.0 (15) 64.0 (12)
 Male 612 (62) 952 (62) 520 (62) 504 (60) 791.4 (63) 786.1 (62)
Clinical features
 NIHSS≥15 293 (30) 421 (28) 244 (29) 237 (28) 367.8 (29) 367.2 (29)
 Time to randomization, h 3.6 (2.7–4.6) 3.8 (2.8–4.8) 3.6 (2.7–4.6) 3.8 (2.9–4.8) 3.8 (2.8–4.7) 3.7 (2.9–4.7)
 Systolic BP, mm Hg 179 (17) 179 (17) 179 (17) 179 (17) 179.1 (19.1) 179.1 (15.2)
 Prior intracerebral hemorrhage 65 (7) 134 (9)† 61 (7) 71 (9) 99.3 (8) 96.0 (8)
 Prior ischemic/undifferentiated stroke 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)
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 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 (4.3–17.1) 12.1 (6.7–19.9)† 9.3 (4.5–17.9) 10.3 (5.8–18.0) 10.3 (5.4–20.5) 10.8 (5.9–18.7)
 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)
Medical and surgical treatment
 Intubation 67 (7) 108 (7) 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, 0.66–0.91; P<0.01; Figure 1). However, the association
was no longer significant after adjustment for baseline imbal-
ances (OR, 0.87; 95% CI, 0.71–1.07; P=0.18), and further
with the addition of treatment imbalances (OR, 1.02; 95%
CI, 0.81–1.30; P=0.86). These neutral results were confirmed
by PS analyses: matching (OR, 0.90; 95% CI, 0.75–1.09;
P=0.30), IPTW (OR, 0.97; 95% CI, 0.83–1.14; P=0.72), sum-
mary stratified (OR, 0.91; 95% CI, 0.77–1.08; P=0.30), and
covariate adjustment using PS (OR, 0.92; 95% CI, 0.77–1.10;
P=0.35). The PS-matched analysis with the smaller caliper of
0.10 showed a similar result (OR, 0.89; 95% CI, 0.73–1.09;
P=0.26). There was no association with the separate outcomes
of death and major disability (data on request) and no het-
erogeneity 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 out-
come in patients with larger (≥15 mL) when compared with
smaller (<15 mL) hematomas (OR, 0.52; 95% CI, 0.35–0.78
versus OR, 0.91; 95% CI, 0.72–1.15; P homogeneity 0.02
in PS-matched analysis; Figure 2). The association was
also significant in IPTW, summary stratified, and covariate
adjustment using PS analyses, but not either in multivari-
able-adjusted analyses or in other sensitivity analyses of dif-
ferent 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 man-
nitol use in those with greater clinical severity (NIHSS≥15)
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; Figure 3, Tables V and VI in the online-
only Data Supplement, respectively). Moreover, subgroup
 4  Stroke  October 2015

Table 2.  Safety Outcomes by Mannitol Treatment associations between Chinese and non-Chinese patients might
be explained by differences in characteristics, management,
Nonmannitol Mannitol
(n=993) (n=1533) P Value and prognosis that were not fully accounted for in analyses
(Tables XIII–XV in the online-only Data Supplement), which
Neurological deterioration in first 24 h 161 (16) 216 (14) 0.12
was supported by a lower proportion of poor outcome in
Non-fatal serious adverse events* 312 (31) 295 (19) <0.01
Chinese patients with the same baseline modified ICH score
Direct effects of the primary ICH event 31 (3) 60 (4) … as in non-Chinese patients (Table XVI in the online-only Data
 Cardiovascular disease 44 (4) 26 (2) … Supplement)
 Recurrent ICH 2 (0.2) 5 (0.5) …
 Ischemic or undifferentiated stroke 10 (1) 4 (0.4) … Discussion
 Acute coronary event 4 (0.4) 3 (0.3) … This is the largest study to investigate the impact of mannitol
 Other cardiovascular disease 30 (3) 15 (1) … in patients with acute ICH. Overall, there was no significant
 Noncardiovascular disease 136 (14) 150 (10) …
difference in frequency of the conventional poor outcome of
death or major disability at 90 days between mannitol and non–
 Renal failure 7 (1) 5 (0.5) …
mannitol-treated patients independent of other prognostic fac-
 Respiratory infections 53 (5) 48 (3) …
tors assessed across a variety of analyses that took account of
 Sepsis (includes other infections) 28 (3) 10 (1) … significant imbalances in baseline and management covariates.
 Nonvascular medical 44 (4) 17 (1) … Although there was an apparent benefit of mannitol in patients
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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 (NIHSS≥15) and of younger patients
(age <65 years) with either large hematoma (volume ≥15 mL)
or more severe (NIHSS≥15) showed no clear association of
mannitol and outcome (Tables VII–IX 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
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.20–23
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

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 recipro-
cal 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 anticoagula-
tion 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 indi-
cates inverse probability of treatment weighting; and PS, propensity score.
 Wang et al   Mannitol and Cerebral Hemorrhage    5

Figure 2. Association of mannitol treatment on death or major disability at 90 days by baseline hematoma volume. Solid boxes represent
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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 intra-
cerebral 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 benefi-
cial 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 hospi-
tals 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% con-
fidence 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 hema-
toma, 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.
 6  Stroke  October 2015
standardized protocol and objective measures. We also under-
took 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 dose–response relationship in smaller and larger
hematomas indicates that the former was likely to have been
a spurious finding. Furthermore, the worse outcome for man-
nitol 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 discre-
tion 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
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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 con-
founding, 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 popu-
lation, where patients with a poor prognosis because of mas-
sive 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, con-
ducted, 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
Muñoz-Venturelli, Pablo M. Lavados, Christian Stapf, Thompson Robinson, Emma Heeley,
Candice Delcourt, Richard I. Lindley, Mark Parsons, John Chalmers and Craig S. Anderson
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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 Muñoz-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
2
Royal Prince Alfred Hospital, Sydney, Australia
3
Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing,
China
4
Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
5
Department of Neurology, Hebei Yutian Hospital, Tangshan, China
6
Servicio de Neurología, Departamento de Medicina Clínica Alemana, Universidad del
Desarrollo, Santiago, Chile
7
Universidad de Chile, Santiago, Chile
8
Department of Neurology, APHP - Hôpital Lariboisière and DHU NeuroVasc Paris -
Sorbonne, Univ Paris Diderot - Sorbonne Paris Cité, 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

1
 Supplemental Table I. Baseline characteristics by mannitol use

Non-mannitol Mannitol
Variable (N=1037) (N=1707) P value
Age, yr 67 (13) 61 (12) <0.01
Male 648 (63) 165 (62) 0.96
Recruited from China 292 (28) 1583 (93) <0.01
NIHSS 10 (6-16) 11 (6-15) 0.50
NIHSS ≥15 300 (29) 468 (27) 0.39
Time to randomization, hr 3.7 (2.8-4.6) 3.8 (2.9-4.8) 0.03
Systolic BP, mmHg, 179 (17) 179 (17) 0.41
Diastolic BP, mmHg, 97 (16) 104 (13) <0.01
History of hypertension 757 (73) 1229 (72) 0.60
Prior intracerebral hemorrhage 67 (7) 152 (9) 0.02
Prior ischemic/undifferentiated stroke 92 (9) 221 (13) <0.01
Heart disease 166 (16) 124 (7) <0.01
Diabetes mellitus 159 (15) 136 (8) <0.01
Current use of antihypertensive therapy 555 (54) 684 (40) <0.01
Use of warfarin anticoagulation/aspirin 231 (22) 93 (6) <0.01
Use of insulin/oral hypoglycemic agents 114 (11) 65 (4) <0.01
Use of statin/other lipid lowering 151 (15) 42 (3) <0.01
Deep location of hematoma* 820 (83) 1308 (85) 0.18
Left hemisphere site of hematoma 493 (50) 785 (51) 0.58
Hematoma volume at baseline, mL 8.9 (4.3-17.1) 12.1 (6.6-19.9) <0.01
Intraventricular extension 274 (28) 434 (28) 0.79
Randomized BP lowering treatment 512 (49) 850 (50) 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

2
Supplemental Table II. Baseline characteristics and death or major disability at 90 days

Death or major disability

No Yes
Variable (n=1290) (n=1504) P value
Age, yr 60 (12) 67 (13) <0.01
Male 822 (64) 931 (62) 0.32
Recruited from China 999 (77) 911 (61) <0.01
NIHSS 7 (4-11) 18 (14-22) <0.01
NIHSS ≥15 135 (11) 665 (44) <0.01
Time to randomization, hr 3.8 (2.9-4.8) 3.6 (2.7-4.7) <0.01
Systolic BP, mmHg, 178 (17) 180 (17) <0.01
Dystolic BP, mmHg, 102 (14) 100 (15) <0.01
History of hypertension 942 (73) 1079 (72) 0.50
Prior intracerebral hemorrhage 88 (7) 138 (9) 0.02
Prior ischemic/undifferentiated stroke 133 (10) 186 (12) 0.09
Heart disease 93 (7) 200 (13) <0.01
Diabetes mellitus 106 (8) 194 (13) <0.01
Current use of antihypertensive therapy 562 (44) 693 (46) 0.17
Use of warfarin anticoagulation or aspirin 99 (8) 231 (15) <0.01
Use of insulin/oral hypoglycemic agents 67 (5) 115 (8) 0.01
Use of statin/other lipid lowering 63 (5) 134 (9) <0.01
Deep location of hematoma* 971 (82) 1189 (85) 0.01
Left hemisphere site of hematoma 569 (48) 728 (52) 0.03
Hematoma volume at baseline, mL 8.3 (4.1-14.0) 14.1 (7.8-25.5) <0.01
Intraventricular extension 249 (21) 481 (35) <0.01
Randomized BP lowering treatment 663 (51) 719 (48) 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

3
Supplemental Table III. Mannitol and death or major disability at 90 days by baseline hematoma volume ≥10mL
Model Baseline hematoma volume ≥10mL Mannitol N Events (%) OR (95%CI) P homogeneity
1
Adjusted 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
Using the PS Yes 620 221 (35.7) 0.94 (0.73-1.21)
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

4
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

5
Supplemental Table IV. Mannitol and death or major disability at 90 days by greater (≥20mL) baseline hematoma volume
Model Baseline hematoma volume ≥20mL Mannitol N Events (%) OR(95%CI) P homogeneity
Adjusted1 No 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

7
 Supplemental Table V. Mannitol and death or major disability at 90 days by NIHSS
score ≥10

Model NIHSS ≥10 Mannitol N Events (%) OR (95%CI) P homogeneity

PS matched No No 389 115 (29.6) 0.406
Yes 389 87 (22.4) 0.69 (0.51-0.94)
Yes No 445 343 (77.1)
Yes 445 327 (73.5) 0.82 (0.61-1.11)
IPTW No No 458 148 (32.3) 0.567
Yes 670 162 (24.2) 0.86 (0.66-1.12)
Yes No 533 418 (78.4)
Yes 853 608 (71.3) 0.96 (0.75-1.22)
Summary No No 389 115 (29.6) 0.984
stratified Yes 389 87 (22.4) 0.79 (0.60-1.06)
Yes No 445 343 (77.1)
Yes 445 327 (73.5) 0.89 (0.68-1.17)
Covariate No No 389 115 (29.6) 0.973
adjustment Yes 389 87 (22.4) 0.82 (0.61-1.09)
Using the Yes No 445 343(77.1)
PS Yes 445 327(73.5) 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

8
 Supplemental Table VI. Mannitol and death or major disability at 90 days by NIHSS
score ≥20

Model NIHSS ≥20 Mannitol N Events (%) OR (95%CI) P homogeneity

PS matched No No 738 368 (49.9) 0.169
Yes 738 349 (47.3) 0.90 (0.74-1.10)
Yes No 95 87 (91.6)
Yes 95 79 (83.2) 0.45 (0.17-1.18)
IPTW No No 881 465 (52.8) 0.923
Yes 1358 631 (46.5) 0.93 (0.79-1.10)
Yes No 110 101 (91.8)
Yes 165 139 (84.2) 0.90 (0.45-1.78)
Summary No No 738 368 (49.9) 0.220
stratified Yes 738 349 (47.3) 0.88 (0.73-1.06)
Yes No 95 87 (91.6)
Yes 95 79 (83.2) 0.62 (0.27-1.43)
Covariate No No 738 368 (49.9) 0.210
adjustment Yes 738 349 (47.3) 0.89 (0.74-1.08)
Using the Yes No 95 87 (91.6)
PS Yes 95 79 (83.2) 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

9
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 N Events (%) OR (95%CI) P value

Crude No 175 157 (89.7)
Yes 262 217 (82.8) 0.55 (0.31-0.99) 0.047
1
Adjusted 0.90 (0.47-1.71) 0.737
Adjusted2 0.60 (0.25-1.48) 0.271
PS matched No 148 130 (87.8)
Yes 148 119 (80.4) 0.57 (0.31-1.03) 0.063
IPTW No 175 157 (89.7)
Yes 262 217 (82.8) 1.03 (0.61-1.73) 0.927
Summary stratified No 175 157 (89.7)
Yes 262 217 (82.8) 0.83 (0.45-1.51) 0.533
Covariate adjustment No 175 157 (89.7)
using the PS Yes 262 217 (82.8) 0.79 (0.43-1.46) 0.455
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 Mannitol N Events (%) OR (95%CI) P value

Crude No 120 84 (70.0)
Yes 368 222 (60.3) 0.65 (0.42-1.02) 0.058
1
Adjusted 0.84 (0.51-1.37) 0.478
Adjusted2 0.67 (0.37-1.22) 0.187
PS matched 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 Mannitol N Events (%) OR (95%CI) P value

Crude No 115 88 (76.5)
Yes 232 163 (70.3) 0.73 (0.43-1.21) 0.221
1
Adjusted 0.83 (0.48-1.44) 0.514
Adjusted2 0.49 (0.22-1.07) 0.071
PS matched 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 Mannitol N Events (%) OR (95%CI) P value

Crude No 268 93 (34.7)
Yes 1421 687 (48.4) 1.76 (1.34-2.31) <0.0001
1
Adjusted 1.11 (0.81-1.52) 0.507
Adjusted2 1.10 (0.80-1.51) 0.557
PS matched 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 Mannitol N Events (%) OR (95%CI) P value

Crude No 725 473 (65.2)
Yes 112 88 (78.6) 1.95 (1.21-3.15) 0.006
1
Adjusted 1.94 (1.10-3.43) 0.023
Adjusted2 1.91 (1.05-3.48) 0.034
PS matched 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 Baseline hematoma volume ≥15mL Mannitol N Events (%) OR (95%CI) P homogeneity
Adjusted1 No 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
Non-China China P value
Parameter (N=909) (N=1920)
Time from onset of ICH to randomization, hr 3.6 (2.8-4.7) 3.8 (2.9-4.7) 0.02
Age, yr 68±13 61.3±12 0.02
Male 584 (64) 1196 (62) 0.31
Systolic BP, mmHg 180±17 179±17 0.04
Diastolic BP, mmHg 96±16 104±13 <0.01
NIHSS score* 12 (7-17) 10 (5-14) <0.01
GCS score† 15 (13-15) 14 (12-15) <0.01
History of hypertension 641/909 (71) 1407/1917 (73) 0.11
Current use of antihypertensive drugs 507/909 (56) 767/1917 (40) <0.01
Prior intracerebral hemorrhage 58/909 (6) 171/1917 (9) 0.02
Prior ischemic or undifferentiated stroke 78/909 (9) 245/1920 (13) <0.01
Prior acute coronary event 52/909 (6) 29/1917 (2) <0.01
Diabetes mellitus 152/909 (17) 153/1764 (8) <0.01
Use of warfarin anticoagulation 73/909 (8) 8/1917 (0) <0.01
Use of aspirin or other antiplatelet agent 198/909 (22) 67/1920 (4) <0.01
Baseline hematoma volume, mL 11 (6-23) 11 (6-18) 0.40
Deep location of hematoma‡ 707/876 (81) 1475/1737 (85) 0.01
Left hemisphere site of hematoma 436/876 (50) 877/1737 (51) 0.73
Intraventricular extension of hemorrhage 273/876 (31) 467/1737 (27) 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 China
Parameter (N=909) (N=1920) P value
Time from ICH to BP lowering treatment, hr 3.9 (2.8-5.3) 4.1 (3.0-5.5) 0.01
Time from randomisation to BP lowering treatment, hr 0.2 (0.0-0.6) 0.1 (0.0-0.7) 0.04
Any BP lowering treatment in first 24 hours 743 (82) 1130 (59) <0.01
Intubation 112/894 (13) 77/1885 (4) <0.01
Admission to an intensive care unit 304/894 (34) 757/1885 (40) <0.01
Prophylactic treatment for deep venous thrombosis 596/894 (67) 14/1885 (1)
Compression stockings used 283/894 (32) 10/1885 (1)
Subcutaneous heparin administered 489/894 (55) 4/1885 (0)
Use of intravenous mannitol 127/894 (14) 1592/1885 (85) <0.01
Hemostatic therapy* 70/894 (8) 27/1885 (1) <0.01
Any surgical intervention 49/894 (6) 105/1885 (6) 0.92
Evacuation or decompression of the hematoma 24/894 (3) 57/1885 (3) 0.62
Insertion of a ventricular drain 29/894 (3) 56/1885 (3) 0.70
Decision to withdraw active treatment and care 58/894 (7) 63/1885 (3) <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
Non-China China OR (95% CI) P value aOR (95% CI)* P value
Outcome (N=909) (N=1920)
Death or major disability 593/884 (67) 911/1910 (48) 0.45 (0.38-0.53) <0.01 0.66 (0.54-0.82) <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
0 231(29.2) 202(51.9)
1 340(54.4) 200(75.8)
2 174(75.7) 102(83.6)
3 57(85.1) 59(92.2)
4 15(93.8) 13(100.0)

20
 1

.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
 25

Abstract 1

뇌내출혈에서 만니톨과 결과
성향점수와 다변수 INTERACT2
(Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2) 결과

Mannitol and Outcome in Intracerebral Hemorrhage

Propensity Score and Multivariable Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 Results
Wang et al Mannitol and Cerebral Hemorrhage 2765
Xia Wang, MMed; Hisatomi Arima, MD, PhD; Jie Yang, MD, PhD; Shihong Zhang, MD; Guojun Wu, MD; Mark Woodward, PhD; Paula Munoz-Venturelli, MD;
2. Pablo Treatment
Safety Outcomes by Mannitol M. Lavados, MD; Christian Stapf, MD;
associations Thompson
between Robinson,
Chinese MD; Emma
and non-Chinese Heeley,
patients might PhD; Candice Delcourt, MD; Richard I. Lindley, MD;
be explained by differences in characteristics, management,
Mark Parsons, MD, PhD; John Chalmers, MD, PhD; Craig S. Anderson, MD, PhD; for the INTERACT2 Investigators
Nonmannitol Mannitol
(n=993) (n=1533) P Value and prognosis that were not fully accounted for in analyses
ogical deterioration in first 24 h 161 (16) 216 (14) 0.12 (Stroke. 2015;46:2762-2767.)
(Tables XIII–XV in the online-only Data Supplement), which
was supported by a lower proportion of poor outcome in
al serious adverse events* 312 (31) 295 (19) <0.01
Key Words: blood
Chinese pressure
patients with■the
cerebral hemorrhage
same baseline ■ clinical
modified trial ■ mannitol ■ propensity score
ICH score
effects of the primary ICH event 31 (3) 60 (4) … as in non-Chinese patients (Table XVI in the online-only Data
iovascular disease 44 (4) 26 (2) … Supplement).
urrent ICH 2 (0.2) 5 (0.5) …
emic or undifferentiated stroke
배경과 목적 10 (1) 4 (0.4) … Discussion 결과
e coronary event 4 (0.4) 3 (0.3) … This is the largest study to investigate the impact of mannitol
만니톨은
r cardiovascular disease
급성뇌내출혈에서
30 (3) 15 (1) …
뇌부종을 in 줄이기
patients 위해
with acute 종종
ICH. 사용되
Overall, there was 만니톨군(n=1533)과
no significant 비만니톨군(n=993) 사이에 나쁜 결과의 유
difference in frequency of the conventional poor outcome of
cardiovascular disease 지만 그 효과의 136 (14) 강력한 150 (10) 근거는 … 없다. 이 연구는 급성뇌출혈에서 의한 차이는 없었다: 성향점수-짝지음 교차비 0.90 (95% CI,
death or major disability at 90 days between mannitol and non–
al failure
Intensive 7Blood (1) 5 (0.5)
Pressure …
Reduction in Acute
mannitol-treated patients Cerebral 0.75–1.09;
independent of other prognostic fac- P=0.30) 및 다변수 교차비 0.87 (95% CI, 0.71–
piratory infections 53 (5) 48 (3) …
tors assessed across a variety of analyses that took account of
Hemorrhage
sis (includes other infections) 28 (3) Trial102(1)(INTERACT2)
… 참가자들에서 만니톨의 효 1.07;
significant imbalances in baseline and management covariates.
P =0.18). 비록 더 큰(≥15 mL) 초기 혈종을 가진 환자에서
vascular medical 과를 확인하고자 44 (4) 하였다.
17 (1) … Although there was an apparent benefit of mannitol 더 in작은(＜15
patients mL) 혈종을 가진 환자보다 만니톨 투여의 더 나은
are numbers (%). ICH indicates intracerebral hemorrhage. with larger hematomas (≥15 mL), this was not consistent in
e patient could have >1 event. 결과가
analyses across other cutoff points (≥10 and ≥20 mL) and for 예상되었지만(OR, 0.52 [95% CI, 0.35–0.78] vs. OR
방법 differing grades of neurological impairment (NIHSS score cut
0.91 [95% CI, 0.72–1.15]; 성향점수분석에서의 P homogeneity
ses of patients with both large hematomas (≥15 mL) and points of 10, 15, and 20). Moreover, the impact of mannitol
er clinical severity INTERACT2는
(NIHSS≥15) and of수축기 younger 혈압상승을
patients 동반한 자발성뇌내출혈(6시
was not consistent between Chinese and non-Chinese (균질성)＜0.03),
patients, 이러한 관련성은 다른 기준점(cutoff point, ≥
<65 years) with either 간 이내) large hematoma
환자 2839명을 (volume ≥15 집중적(1시간
mL) but this 이내
could be목표 because of other diseases and 10
수축기혈압 management
및 ≥20 mL)을 통한 분석 및 신경학적 중증도의 정도에 따라
ore severe (NIHSS≥15) showed no clear association of factors because patients with similar predicted prognosis had
itol and outcome＜140 mmHg)
(Tables VII–IX in the또는 가이드라인-권장(목표
online-only Data 수축기혈압
different outcomes between the＜180 구분하면
2 groups. Finally, there was동일하게 나타나지 않았다. 만니톨은 중대한 이상반응
ement, respectively). no evidence that mannitol use was associated with any clear 관련이 없었다.
mmHg) 혈압강하 치료를 비교한 국제, 공개, 눈가림 종결점, 무 의 증가와
nalysis of patients recruited from China (Table X in harms such as an increase in renal or cardiac complications,
nline-only Data 작위 배정 showed
Supplement) 대조군a similar연구였다. neutral만니톨 or of치료(7일
neurological이내)와 90일째
deterioration, that may have occurred from
iation of mannitol and outcome as seen for the whole rebound intracranial hypertension.20–23
mRS 3-6점의 사망
ation. However, use of mannitol was associated with
또는 주요 장애로 정의된 나쁜 결과 사이의 결론
Few studies have investigated the effects of mannitol in
creased risk of death 관계를 조사하기
or major disability위해 성향점수 및 다변수분석이
in non-Chinese 시행되었다.
acute ICH. An observational 만니톨은
study6 of 111 consecutive patients급성뇌내출혈 환자에서 안전해 보이나 결과를 개선시
nts (Table XI in the online-only Data Supplement). There within 72 hours of ICH found no association of mannitol on
o association in Chinese patients with larger ICH (Table
키지는 않는 것 같다.
survival. Similarly, 2 small randomized controlled trials of 21
n the online-only Data Supplement). The disparities in ICH patients with medium- or small-sized hematomas,8 and

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