Hypothermia Reduces Perihemorrhagic Edema After

Intracerebral Hemorrhage
Rainer Kollmar, MD*; Dimitre Staykov, MD*; Arnd Dörfler, MD; Peter D. Schellinger, MD;
Stefan Schwab, MD; Jürgen Bardutzky, MD

Background and Purpose—The prognosis of spontaneous intracerebral hemorrhage (sICH) is poor because of the mass
effect arising from the hematoma and the associated peri-hemorrhagic edema, leading to increased intracranial pressure.
Because the efficacy of surgical and anti-edematous treatment strategies is limited, we investigated the effects of mild
induced hypothermia in patients with large sICH.
Methods—Twelve patients with supratentorial sICH ⬎25 mL were treated by hypothermia of 35°C for 10 days. Evolution
of hematoma volume and perifocal edema was measured by cranial CT. Functional outcome was assessed after 90 days.
These patients were compared to patients (n⫽25; inclusion criteria: sICH volume ⬎25 mL, no acute restriction of
medical therapy on admission) from the local hemorrhage data bank (n⫽312). Side effects of hypothermia were
analyzed.
Results—All patients from both groups needed mechanical ventilation and were treated in a neurocritical care unit. All
hypothermic patients (mean age, 60⫾10 years) survived until day 90, whereas 7 patients died in the control group (mean
age, 67⫾7 years). Absolute hematoma size on admission was 58⫾29 mL (hypothermia) compared to 57⫾31 mL
(control). In the hypothermia group, edema volume remained stable during 14 days (day 1, 53⫾43 mL; day 14, 57⫾45
mL), whereas edema significantly increased in the control group from 40⫾28 mL (day 1) to 88⫾47 mL (day 14). ICH
continuously dissolved in both groups. Pneumonia rate was 100% in the hypothermia group and 76% in controls
(P⫽0.08). No significant side effects of hypothermia were observed.
Conclusions—Hypothermia prevented the increase of peri-hemorrhagic edema in patients with large sICH. (Stroke. 2010;
41:1684-1689.)
Key Words: edema 䡲 hypothermia 䡲 intracerebral hemorrhage 䡲 intracranial pressure
Downloaded from http://ahajournals.org by on December 28, 2019

I ntracerebral hemorrhage (ICH) causes 10% to 15% of first-

ever strokes and is usually associated with a poor outcome.
The 30-day mortality rate accounts up to 52%.1,2 Major
factors contributing to the unfavorable prognosis during the
acute phase of spontaneous intracerebral hemorrhage (sICH)
are the size of hematoma,3 rebleeding or hematoma expan-
sion,4 and intraventricular hemorrhage.5 After the acute
phase, high morbidity and mortality are essentially caused by
the evolution of a peri-hemorrhagic, space-occupying edema
associated with gradually increasing intracranial pressure
(ICP).6,7 Although the natural course of edema formation is
still not fully understood, edema commonly increases
strongly during the first week and reaches its maximum
during the second week after bleeding onset.8
To date, there is no effective therapy for spontaneous ICH.2
Large randomized trials targeting the intracerebral blood clot
failed to demonstrate benefits, including hematoma evacua-
tion9 or factor VIIa treatment.10 Similarly, there is no proven
therapy of peri-hemorrhagic edema.2
However, experimental and clinical data indicate that
induced hypothermia is useful for neuroprotection11,12 and the
treatment of cerebral edema11,13 after acute brain injury, such
as ischemic stroke, brain trauma, and global cerebral ische-
mia after cardiac arrest.
Recent experimental studies suggest that hypothermia also
has neuroprotective effects after ICH and can considerably
reduce edema formation by various mechanisms.14 –16 How-
ever, substantial clinical data on the use of therapeutic
hypothermia for ICH are lacking.
Therefore, we investigated the effects of mild hypothermia
(35°C) over a period of 10 days in patients who require
intensive care treatment because of large (⬎25 mL) supra-
tentorial sICH.
Subjects and Methods
Patient Selection
The cooling management protocol of this prospective pilot study was
approved by the local ethics committee. Because a hematoma size of

Received April 16, 2010; accepted May 13, 2010.

From Neurology Department (R.K., D.S., P.D.S., S.S., J.B.) and Department of Neuroradiology (A.D.), University of Erlangen, Erlangen, Germany.
*R.K. and D.S. contributed equally to this work.
Correspondence to Rainer Kollmar, MD, Department of Neurology, University of Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany. E-mail
rainer.kollmar@uk-erlangen.de
© 2010 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.110.587758

1684
 Kollmar et al
⬇30 mL is considered as the crucial value for high morbidity and
mortality,3 all patients with a supratentorial intracerebral hematoma
⬎25 mL who required intensive care were included. Exclusion
criteria were international normalized ratio ⬎1.4, known coagulopa-
thy; ICH caused by trauma, intracerebral tumor, or vascular malfor-
mation; infratentorial ICH; enrollment ⬎12 hours after symptom
onset; and age younger than 18 years. A total of 12 consecutive
patients were treated by mild hypothermia.
Patients with sICH in the control group were identified from our
prospectively organized ICH database (since 2007; n⫽312). To
minimize matching bias, inclusion criteria were supratentorial ICH
with a hematoma size on the cranial CT at admission of ⬎25 mL and
no acute decision on admission to stop further medical treatment. Of
a total of 312 patients, 255 were excluded because of a hematoma
size of ⬍25 mL. From the remaining 57 patients, 3 patients were
ruled out because of infratentorial ICH, and 7 patients were ruled out
because of early (⬍36 hours) surgical hematoma evacuation. In a last
step, 22 of the remaining 47 patients with early orders for limitation
of care were excluded. Hence, 25 patients remained in the control
group.
Basic Management
All patients included in the historical control group received standard
medical treatment according to the European Stroke Initiative
guidelines for monitoring and treatment of ICH.17 All patients were
mechanically ventilated because of poor level of consciousness or
need for airway protection; midazolam was used for sedation and
sufentanil was used for analgesia. Pethidine was used for treatment
of shivering and Cisatracurium was used for neuromuscular blockade
when necessary. According to our institutional standards of neuro-
critical care, ICP was recorded hourly using an external ventricular
catheter. ICP increase (⬎20 mm Hg for ⬎15 minutes) was treated
with 125 to 250 mL of 20% Mannitol or 100 mL of 10% saline. Body
core temperature was measured continuously with a Foley temper-
Downloaded from http://ahajournals.org by on December 28, 2019
ature bladder catheter.
Endovascular Hypothermia
A 9.3-Fr, 38-cm catheter central line (ICY, IC-3893; Alsius) and a
temperature management device (CoolGard 3000; Alsius) were used
in this study, as described previously.18 Mild hypothermia was
induced within 12 hours after symptom onset and continued for 10
days. However, patients were not treated by hypothermia within the
first 3 hours after symptom onset. At a minimum time of 3 hours
from symptom onset, target temperature was 35°C (bladder temper-
ature). The standard rewarming rate was 0.5°C per 24 hours. No
antipyretics were used during hypothermia.
Management of Temperature in Controls
In the control group, tympanic temperature was measured every 6
hours and temperatures ⬎37.5°C were treated with acetaminophen
and metamizol.
Imaging and Data Collection
According to our institutional protocol, all sICH patients requiring
intensive care received cranial CT controls on days 1 to 3, day 6, day
11, day 14, and before discharge.
CT scans were performed on a fourth-generation CT scanner
(Somatom; Siemens). Each CT scan consisted of 10 to 12 slices of
4.8-mm thickness for the scull base and 10 to 12 slices of 7.2-mm
thickness for the cerebrum. Measurements of blood and edema
volumes were performed using the Siemens Leonardo V semiauto-
matic software for volumetry. For this purpose, a region of interest
was set by generously tracing the hemorrhage, including the perifo-
cal hypodense area on each slice. The software then reconstructed a
3-dimensional dataset and added up all voxels within a threshold
range set between 5 and 33 Hounsfield units for perifocal edema and
Hypothermia in Intracerebral Hemorrhage 1685
Table. Baseline Characteristics on Admission
Hypothermia (n⫽12) Control (n⫽25) P
Age, y 60⫾10 67⫾7 0.08
GCS 5 (3–10) 8 (3–10) 0.12
ICH volume, mL 58⫾29 59⫾31 0.98
Edema volume, mL 53⫾43 40⫾28 0.26
IVH present 8/12 14/25 0.72
Values are represented as mean⫾standard deviation or median and range
when appropriate.
GCS indicates Glasgow Coma Scale; ICH, intracerebral hemorrhage; IVH,
intraventricular hemorrhage.
between 44 to 100 Hounsfield units for blood. Measurements were
performed by 1 observer blinded to clinical data. The absolute
volume (mL) of ICH and the peri-hemorrhagic edema returned by
the software were recorded for each time point. Relative edema was
calculated as a unitless ratio by dividing absolute edema volume by
initial hematoma volume.19,20
Statistical Analysis
Statistical tests were performed with the SPSS 16.0 software pack-
age. Data are given as mean⫾standard deviation, if not indicated
differently. Normality of distribution was tested using the Shapiro-
Wilk and Kolmogorov-Smirnov tests. Absolute edema values were
not distributed normally. Accordingly, single comparisons of abso-
lute edema between the 2 groups at different time points were
performed using the nonparametric Mann–Whitney U test. All other
data, including relative edema values at all time points, were
distributed normally. The unpaired t test was used for single
comparisons of relative edema and ICH values between the 2 groups.
A multifactorial analysis of variance (general linear model for
variance analysis) was performed for between-group and within-
group comparisons of the time course of relative edema in the
hypothermia and match group. Frequency distributions were ana-
lyzed using the Fisher exact and ␹2 tests. P⬍0.05 was considered
significant.
Results
Patient Characteristics
Twelve patients (7 male, 5 female) with a mean age of 60⫾10
years were treated with mild hypothermia. On admission,
median Glasgow coma scale score was 5 (range, 3–10) and
mean parenchymal hematoma volume was 58⫾29 mL. A
total of 25 patients (15 male, 10 female) meeting the inclusion
criteria of the control group were identified from the data
bank. As shown in the Table, baseline characteristics on
admission did not differ significantly between the hypother-
mia group and the historical control group.
Additional intraventricular hemorrhage was present in 8
patients of the hypothermia group and 14 patients of the
control group (Table). Intraventricular hemorrhage was com-
plicated by hydrocephalus in 1 patient of the hypothermia
group and 4 patients of the control group (P⫽1.0, Fisher
exact test). Hydrocephalus was treated with external ventric-
ular drainage and intraventricular fibrinolysis consisting of
administration of single doses of 4 mg recombinant tissue
plasminogen activator up to a maximum of 20 mg, or until
clearance of the third and fourth ventricles on CT was
achieved.
 1686 Stroke August 2010
Figure 1. Temperature course measured in the urinary bladder
over a period of 14 days after intracerebral hemorrhage. Values
are given as means⫾SD. In the hypothermia group, a mean
temperature of 35.3°C⫾0.2°C was achieved by endovascular
cooling 12 hours after admission.
Course of Temperature and ICP
The course of body temperature for both groups is illustrated
in Figure 1. The temperature in the hypothermia group was
35.3°C⫾0.2°C compared to 37.3°C⫾1°C 12 hours after
symptom onset. A target temperature of 35°C could be
maintained for the entire time period of 10 days without
significant changes.
An ICP increase (⬎20 mm Hg for ⬎15 minutes) was not
observed in any of the hypothermia patients during the
14-days period. In contrast, 11 (44%) of 25 control patients
had ICP crises.
Downloaded from http://ahajournals.org by on December 28, 2019
In-Hospital Mortality
In the control group, 6 patients (24%) died because of
space-occupying edema and subsequent cerebral herniation
during hospital treatment in the intensive care unit. One
patient died in the rehabilitation hospital. None of the
hypothermia-treated patients died during the hospital stay
(Fisher exact test, 2-sided P⫽0.07).
Volume of the Hemorrhage
The mean volume of ICH on admission was 58⫾29 mL (range,
27–103 mL) in the hypothermia group and 57⫾31 mL (range,
26 –129 mL) in the control group (P⫽0.98). A plot of the initial
ICH volumes in both groups is shown in the Supplemental
Figure available online at http://stroke.ahajournals.org. ICH
volume gradually decreased over the next 14 days in both groups
and showed no significant difference at the investigated days
(Figure 2).
Volume of Peri-Hemorrhagic Edema
The course of edema evolution is shown in Figures 2, 3, and
to 4. The peri-hemorrhagic edema volume on admission was
comparable between the 2 groups (hypothermia group 53⫾43
mL vs control group 40⫾28 mL; P⫽0.26). In hypothermia
patients, the peri-hemorrhagic edema remained essentially
identical during the entire 14-days observation period
(within-group comparison, analysis of variance, P⫽0.9). In
contrast, in the control group, edema increased markedly
Figure 2. Volume of intracerebral hemorrhage and edema
(mean⫾SE; mL) for hypothermia patients and controls. *P⬍0.05.
already within the first 48 hours after sICH onset, and the
within-group comparison (analysis of variance) showed a
significant difference between relative edema at admission
and all following time points (days 2–14: F⫽83.8, P⬍0.001).
The between-group comparison of the time course of relative
edema in the hypothermia and control groups revealed a
statistically significant difference (analysis of variance,
F⫽4.93, P⫽0.035).
Single comparisons at corresponding time points revealed
a significantly larger absolute and relative edema volume in
the control group as compared to the hypothermia group
starting at day 3 and persisting on days 6, 11, and 14 (Figures
2 and 4).
Complications During Hypothermia
Respirator-associated pneumonia developed in all patients
during hypothermia; severe pneumonia with the need for a
fraction of inspired oxygen ⬎0.5 occurred in 2 hypothermia
patients. All patients could be sufficiently treated with anti-
biotics. In the control group, pneumonia was observed in 19
patients (76%; Fisher exact test, 2-sided P⫽0.08). Other
complications during hypothermia were asymptomatic
thrombocytopenia ⬍100 000/uL in 4 patients, hypokaliemia
in 2 patients, and shivering in 6 patients. No coagulopathy
was observed as measured by international normalized ratio
and partial thromboplastin time. Self-limited bradycardia
episodes of ⬍40 beats per minute occurred in 3 patients
without the need for intervention. No local complications
were observed during the use of catheters for endovascular
cooling, and no catheter exchange attributable to catheter
malfunction or infection was necessary.
Mortality and Outcome at Day 90
Although no patient in the hypothermia group died until day
90, 7 patients in the control group died (modified Rankin
Scale [mRS] score, 6).
Out of the surviving patients (n⫽12) in the hypothermia
group, 2 patients (16%) had mRS score of 3, 6 patients (50%)
had mRS score of 4, and 4 patients (33%) had mRS score of 5.
Out of the surviving patients (n⫽18) in the control group,
2 patients (11%) had mRS score of 2, 2 patients (11%) had
 Kollmar et al
mRS score of 3, 3 patients (17%) had mRS score of 4, and 11
patients (61%) had mRS score of 5.
Discussion
Downloaded from http://ahajournals.org by on December 28, 2019
We report on the effects of mild therapeutic hypothermia in
patients with large supratentorial sICH. The cooling regimen
we used, namely endovascular cooling for 10 days with a
target temperature of 35°C, was chosen for several reasons.
With the mild level of hypothermia (35°C), we intended to
minimize side effects of lowering body temperature. The
period of 10 days was chosen to span the duration of
treatment over the known critical phase of development of
peri-hemorrhagic edema. Finally, endovascular cooling was
superior to other approaches regarding maintenance of a
constant body temperature over this relatively long period of
time. Two major aspects emerge from our pilot study.
Figure 4. Relative edema is indicated by a ratio of absolute
edema volume and initial hematoma volume. *P⬍0.05;
**P⬍0.01.
Hypothermia in Intracerebral Hemorrhage 1687
Figure 3. Representative CT scans for a
patient in the control group (A) and in the
hypothermia group (B) at days 1, 3, and
11. The yellow line surrounds the region
of interest for volume calculation. Blue
areas represent peri-hemorrhagic edema
on a threshold base algorithm.
First, prolonged hypothermia for 10 days initiated within
12 hours after ICH onset was feasible and relatively safe, as
compared to that in a historical control group. The type of
complications observed in the present study were comparable
to those described in previous studies on induced hypother-
mia in ischemic stroke patients,18,21–23 with pneumonia rep-
resenting the most common side effect. However, pneumonia
also was a frequent complication in the control group (76%).
The high incidence most likely contributes to severe disease,
including previously described central immunodeficiency
syndrome24 and ventilator-associated pneumonia. However,
pneumonia could be sufficiently treated in all patients.
Importantly, prolonged hypothermia had no effect on coagu-
lation parameters, such as international normalized ratio,
partial thromboplastin time, or thrombocyte counts, and did
not lead to hematoma expansion in any patient.
Second, hypothermia essentially stopped the progression of
peri-hemorrhagic brain edema. This finding is of high signif-
icance. Although the mass effect of the initial hematoma is
the major determent for high morbidity in the acute phase of
sICH, the progressive evolution of peri-hemorrhagic edema
represents the main factor for clinical deterioration in the
subacute phase, and the growth of edema is strongly related to
the size of underlying hematoma in sICH.19 Thus, in the
present study, only patients with large hematoma (⬎25 mL)
were included because these patients were expected to likely
have critical extent of peri-hemorrhagic edema in the course
of the disease.
Because the natural evolution of edema is usually charac-
terized by a marked increase during the first week, with the
maximum occurring during the second week,6,8,19 hypother-
mia was induced early, within 12 hours, after bleeding onset
and maintained for 10 days in all patients. Importantly, the
effects of hypothermia on the peri-hemorrhagic brain edema
 1688 Stroke August 2010
were permanent and not transient. This finding is remarkable
because rewarming of the patients could have led to a delayed
increase of edema and associated increase of ICP, as seen in
large cerebral infarcts.25,26
Using this regimen, hypothermia was a highly effective
anti-edematous therapy. Because the edema essentially
stopped growing, no patient had episodes of critical ICP
increase during the 14-day observation period. These effects
were associated with excellent survival rate during the first 90
days after ICH. Notably, at this time, 8 of 12 patients (66%)
reached a mRS score of 3 or 4.
In contrast, 44% in the control group with essentially
identical baseline hematoma size had at least 1 episode of
critical ICP increase and 6 patients died during intensive care
unit stay because of the space-occupying edema progression,
despite maximal medical treatment.
The presented clinical data are in accordance with exper-
imental studies in which hypothermia decreased edema dur-
ing the first 72 hours after experimental ICH.14 –16 Because of
the small study group and short observational time of 90 days,
there is no clear evidence whether prolonged mild hypother-
mia also has neuroprotective effects, as have been observed
after cardiac arrest and perinatal asphyxia.12
Certainly, this study has limitations, mainly because of its
pilot character. Only a small number of patients were treated
by hypothermia, and outcome parameters were assessed after
a relatively short interval of 90 days after ICH. In addition,
we compared these patients to a historical control group from
an ICH database.
Downloaded from http://ahajournals.org by on December 28, 2019
However, the study was a pilot study to evaluate a novel
treatment approach. Thus, it was designed as a feasibility and
safety trial and not as a controlled randomized study to
investigate efficacy on outcome. The comparison to a histor-
ical control group has clear limitations and does not allow
definite interpretation and generalization of the observed
data. However, to minimize bias by the matching procedure,
we used simple inclusion criteria including hematoma vol-
ume and decision to treat the patient. In addition, 2 other
major predictors for outcome in sICH patients, age and initial
Glasgow coma scale score, were comparable between the
groups. It can be argued that hypothermia would have been
even more effective on outcome when started as soon as
possible after symptom onset. Because even mild hypother-
mia might impair coagulation and therefore increase the
hematoma size, we avoided treating patients by therapeutic
hypothermia within the first 3 hours after symptom onset.
Still, the most important clinical finding was that all treated
patients survived. In contrast, 28% of historical controls had
died after 90 days. These findings are promising because the
overall prognosis of patients with this size of hematoma is
poor.3,5
Conclusion
In conclusion, mild hypothermia was feasible and safe in
patients with severe supratentorial sICH, and it stopped
edema growth without a rebound phenomenon during re-
warming. Further clinical studies are needed to answer the
question of whether mild hypothermia has anti-edematous
effects after sICH and if it leads to improved functional
outcome.
Acknowledgment
Rainer Kollmar, Dimitre Staykov, Peter Schellinger, and Jürgen
Bardutzky were responsible for study design, treatment of patients,
and preparation of the manuscript. Stefan Schwab was responsible
for treatment of patients, in-hospital support, and preparation of the
manuscript. Arnd Dörfler was responsible for neuroradiological
investigations and preparation of the manuscript.
Sources of Funding
Nonspecific support was given for this study from industrial partners.
Disclosure
None.
References
1. Broderick JP, Brott T, Tomsick T, Miller R, Huster G. Intracerebral
hemorrhage more than twice as common as subarachnoid hemorrhage.
J Neurosurg. 1993;78:188 –191.
2. Broderick J, Connolly S, Feldmann E, Hanley D, Kase C, Krieger D,
Mayberg M, Morgenstern L, Ogilvy CS, Vespa P, Zuccarello M;
American Heart Association; American Stroke Association Stroke
Council; High Blood Pressure Research Council; Quality of Care and
Outcomes in Research Interdisciplinary Working Group. Guidelines for
the management of spontaneous intracerebral hemorrhage in adults: 2007
update: a guideline from the American Heart Association/American
Stroke Association Stroke Council, High Blood Pressure Research
Council, and the Quality of Care and Outcomes in Research Interdisci-
plinary Working Group. Stroke. 2007;38:2001–2023.
3. Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of
intracerebral hemorrhage: a powerful and easy-to-use predictor of 30-day
mortality. Stroke. 1993;24:987–993.
4. Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, Sauerbeck L,
Spilker J, Duldner J, Khoury J. Early hemorrhage growth in patients with
intracerebral hemorrhage. Stroke. 1997;28:1–5.
5. Daverat P, Castel JP, Dartigues JF, Orgogozo JM. Death and functional
outcome after spontaneous intracerebral hemorrhage: A prospective study
of 166 cases using multivariate analysis. Stroke. 1991;22:1– 6.
6. Zazulia AR, Diringer MN, Derdeyn CP, Powers WJ. Progression of mass
effect after intracerebral hemorrhage. Stroke. 1999;30:1167–1173.
7. Fernandes HM, Siddique S, Banister K, Chambers I, Wooldridge T,
Gregson B, Mendelow AD. Continuous monitoring of ICP and CPP
following ICH and its relationship to clinical, radiological and surgical
parameters. Acta Neurochir Suppl. 2000;76:463– 466.
8. Inaji M, Tomita H, Tone O, Tamaki M, Suzuki R, Ohno K. Chronological
changes of perihematomal edema of human intracerebral hematoma. Acta
Neurochir Suppl. 2003;86:445– 448.
9. Mendelow AD, Gregson BA, Fernandes HM, Murray GD, Teasdale GM,
Hope DT, Karimi A, Shaw MD, Barer DH. STICH investigators. Early
surgery versus initial conservative treatment in patients with spontaneous
supratentorial intracerebral haematomas in the International Surgical
Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet.
2005;365:387–397.
10. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN,
Skolnick BE, Steiner T. FAST Trial Investigators. Efficacy and safety of
recombinant activated factor VII for acute intracerebral hemorrhage.
N Engl J Med. 2008;358:2127–2137.
11. Kollmar R, Schwab S. Hypothermia in focal ischemia: implications of
experiments and experience. J Neurotrauma. 2009;26:377–386.
12. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypo-
thermia to improve the neurologic outcome after cardiacarrest. N Engl
J Med. 2002;346:549 –556. Erratum in N Engl J Med. 2002;346:1756.
13. Polderman KH. Induced hypothermia and fever control for prevention
and treatment of neurological injuries. Lancet. 2008;371:1955–1969.
14. Fingas M, Clark DL, Colbourne F. The effects of selective brain hypo-
thermia on intracerebral hemorrhage in rats. Exp Neurol. 2007;208:
277–284.
 Kollmar et al
15. MacLellan CL, Davies LM, Fingas MS, Colbourne F. The influence of
hypothermia on outcome after intracerebral hemorrhage in rats. Stroke.
2006;37:1266 –1270.
16. Kawanishi M, Kawai N, Nakamura T, Luo C, Tamiya T, Nagao S. Effect
of delayed mild brain hypothermia on edema formation after intracerebral
hemorrhage in rats. J Stroke Cerebrovasc Dis. 2008;17:187–195.
17. Steiner T, Kaste M, Forsting M, Mendelow D, Kwiecinski H, Szikora I,
Juvela S, Marchel A, Chapot R, Cognard C, Unterberg A, Hacke W.
Recommendations for the management of intracranial haemorrhage—part
I: spontaneous intracerebral haemorrhage. The European Stroke Initiative
Writing Committee and the Writing Committee for the EUSI Executive
Committee. Cerebrovasc Dis. 2006;22:294 –316.
18. Georgiadis D, Schwarz S, Kollmar R, Schwab S. Endovascular cooling
for moderate hypothermia in patients with acute stroke: first results of a
novel approach. Stroke. 2001;32:2550 –2553.
19. Arima H, Wang JG, Huang Y, Heeley E, Skulina C, Parsons MW, Peng
B, Li Q, Su S, Tao QL, Li YC, Jiang JD, Tai LW, Zhang JL, Xu E, Cheng
Y, Morgenstern LB, Chalmers J, Anderson CS. INTERACT Investiga-
tors.Significance of perihematomal edema in acute intracerebral hemor-
rhage: the INTERACT trial. Neurology. 2009;73:1963–1968.
20. Gebel JM Jr, Jauch EC, Brott TG, Khoury J, Sauerbeck L, Salisbury S,
Spilker J, Tomsick TA, Duldner J, Broderick JP. Relative edema volume
Downloaded from http://ahajournals.org by on December 28, 2019
Hypothermia in Intracerebral Hemorrhage 1689
is a predictor of outcome in patients with hyperacute spontaneous intra-
cerebral hemorrhage. Stroke. 2002;33:2636 –2641.
21. Georgiadis D, Schwab S. Hypothermia in acute stroke. Curr Treat
Options Neurol. 2005;7:119 –127.
22. De Georgia MA, Krieger DW, Abou-Chebl A, Devlin TG, Jauss M, Davis
SM, Koroshetz WJ, Rordorf G, Warach S. Cooling for Acute Ischemic
Brain Damage (COOL AID): a feasibility trial of endovascular cooling.
Neurology. 2004 27;63:312–317.
23. Krieger DW, De Georgia MA, Abou-Chebl A, Andrefsky JC, Sila CA,
Katzan IL, Mayberg MR, Furlan AJ. Cooling for acute ischemic brain
damage (cool aid): an open pilot study of induced hypothermia in acute
ischemic stroke. Stroke. 2001;32:1847–1854.
24. Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U. Central nervous
system injury-induced immunedeficiency syndrome. Nat Rev Neurosci.
2005;6:775–786.
25. Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W.
Moderate hypothermia in the treatment of patients with severe middle
cerebral artery infarction. Stroke. 1998;29:2461–2466.
26. Steiner T, Friede T, Aschoff A, Schellinger PD, Schwab S, Hacke W.
Effect and feasibility of controlled rewarming after moderate hypo-
thermia in stroke patients with malignant infarction of the middle cerebral
artery. Stroke. 2001;32:2833–2835.