Hemorrhagic Stroke

Surgical Trials in Intracerebral Hemorrhage

Paul M. Vespa, MD; Neil Martin, MD; Mario Zuccarello, MD; Issam Awad, MD; Daniel F. Hanley, MD

Pathophysiology of powered sample size, incomplete evacuation, primary dam-

Intracerebral Hemorrhage
Intracerebral hemorrhage (ICH) is crucially important neu-
rological emergency with high societal impact of >1 million
deaths worldwide each year.1–3 The pathophysiology of intra-
cerebral hemorrhage can be considered to occur in ≤2 con-
ceptual phases. In the first phase, there is immediate cellular
injury in the hemorrhage core because of the acute bleed and
early hemorrhagic expansion. The final hemorrhagic volume
after the period of hemorrhagic expansion and the location are
of hemorrhage are strong predictors of outcome.4,5 Prevention
of hemorrhagic expansion can be achieved,6 but doing so does
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age of the hemorrhage, recurrent bleeding in the immediate
postoperative period, persistent intraventricular hemorrhage.
However, the type of surgical technique and the damage
induced by the operative procedure itself has not been ade-
quately investigated.
The Surgical Trial in Intracererbral Hemorrhage (STICH)
trial has offered promise for the effect of limited surgery on the
basis of the observation that evacuation of surface hematomas
seems to result in improved outcome. However, conventional
open evacuation surgery did not improve outcome in the over-
all STICH cohort. STICH II is a randomized controlled trial

not improve outcome. The second conceptual phase of brain
hemorrhage is the persistent hematoma phase characterized
by progressive damage to perihematomal tissue caused by
mass effect, excitotoxic edema, and progressive neurotoxic-
ity resulting from iron, thrombin, blood breakdown products,
free radical formation, protease activation and inflammation,
and hyperglycolysis.7–12 The evolutionary damage to the peri-
hematomal tissue is complex and involves multiple mecha-
nisms that are presumed to be linked to the presence of the
mass of collected blood and progressive edema. Animal mod-
els demonstrate that persistence of the hematoma in brain tis-
sue results in progressive brain edema, metabolic distress, and
potentially other mechanisms, which result in long-term dis-
ability. We hypothesize that in humans, early removal of the
hemorrhage from the parenchyma will result in avoidance or
mitigation of these secondary insults and result in substan-
tially enhanced neurological recovery.
Surgery for ICH
The effectiveness of craniotomy in the treatment of ICH
remains controversial, despite having been evaluated during from the open craniotomy in which a large bone flap is created;
the past 4 decades. To date, ≤7 randomized trials of surgi-
cal intervention have been completed and published in the
English language (Table).13–19 Results of individual trials have
generally failed to demonstrate improvement in outcome in
surgically treated patients.
Interestingly, the 1 positive trial used a minimally invasive
surgical approach. A variety of factors have been addressed
that may explain the lack of greater efficacy for invasive
surgical evacuation of ICH in prior trials, including late tim-
ing of surgery beyond a therapeutic window, inadequately
of 600 patients that was designed as an open craniotomy trial
for lobar hematomas that are based or near the cortex with no
intraventricular component. Thus, it tests a form of less inva-
sive craniotomy. STICH II data are expected in the spring of
2013. Many questions were raised by STICH I and II, includ-
ing whether open surgery creates new traumatic brain injury,
if open surgery results in near-complete hematoma evacuation,
and whether recurrent bleeding after surgery negates the poten-
tial benefits of hematoma volume reduction. Comparison of
STICH I and II will provide some of these answers. However,
these questions are best answered through the use of minimally
invasive surgery performed in a prospective fashion with serial
imaging to determine the adequacy of hematoma evacuation,
surgical induced injury, and recurrence of bleeding.16
Minimally Invasive Neurosurgery
for Hemorrhage Evacuation
Minimally invasive surgery generally refers to the concept of
creating minimal trauma to normal appearing tissue during the
process of removing the hematoma. This stands in distinction
the brain is exposed, retracted, and manipulated to inspect the
site of bleeding and suction blood from multiple areas. Two
main types of minimally invasive surgery have been attempted
for hematoma removal. The first is endoscopic evacuation of
the hematoma. In endoscopic evacuation, a small burr hole is
created, and an endoscope measuring from 5 to 8 mm diameter
is inserted through normal brain tissue into the hematoma.
Suction and irrigation are applied to remove the hematoma.
The brain is then visualized via the endoscope to determine
the site of bleeding and to determine the amount of ICH

Received March 20, 2013; accepted April 10, 2013.

From the Departments of Neurology and Neurosurgery (P.M.V.) and Department of Neurosurgery (N.M.), David Geffen School of Medicine at UCLA,
CA; Department of Neurosurgery, University of Cincinnati, Cincinnati, OH (M.Z.); Department of Neurosurgery, University of Chicago, Chicago, IL
(I.A.); and Department of Neurology, John Hopkins University, Baltimore, MD (D.F.H.).
Correspondence to Paul M. Vespa, MD, FCCM, FAAN, David Geffen School of Medicine at UCLA, 757 Westwood Blvd, Room 6236A, Los Angeles,
CA 90095. E-mail PVespa@mednet.ucla.edu
(Stroke. 2013;44[suppl 1]:S79-S82.)
© 2013 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.113.001494

S79
 S80  Stroke  June 2013
Table. Randomized Surgical Trials for Intracerebral Hemorrhage
Author Intervention Year
McKissock et al 13
Craniotomy 1961
Juvela et al14 Craniotomy 1989
Batjer et al15 Craniotomy 1990
Morgenstern et al16 Craniotomy 1998
Auer et al 17
Endoscopic 1989
Zuccarello et al18 Crani/Stereo 1999
Mendelow et al19 Craniotomy 2005
evacuated. Auer et al17 reported the first randomized trial of
endoscopic-guided hemorrhage evacuation. This trial of 100
patients demonstrated a trend toward decreased morbidity and
mortality in the surgical arm, particularly in younger patients
with subcortical hematomas. Patients were randomized to
stereotactic-guided endoscopic evacuation or medical therapy
within 24 hours of symptom onset. The investigators found
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that, at 6 months, 40% of surgically treated patients had no
or minimal disability compared with 25% of patients in
the medically treated group (P<0.01). This encouraging
predecessor trial using first-generation endoscopic technology
without the aid of computed tomography guidance indicates
that endoscopic surgical evacuation offers promise as a means
to maximize hematoma evacuation while minimizing damage
to normal tissue. A preliminary single-center randomized
controlled study of frameless stereotactically guided endoscopic
evacuation trial was performed, which demonstrated the safety
of early hematoma evacuation with resultant reduction in
hematoma volume by 80%12 in comparison to a 78% growth in
hematoma by 48 hours.
The second main type of minimally invasive surgery for
brain hemorrhage is stereotactic aspiration and thrombolysis.
This technique involves using image guidance to place a cath-
eter into the main body of the hematoma and aspirate blood.
A catheter is left in the body of the hematoma, and during the
course of several days, repeated small doses of thrombolytics
(recombinant tissue-type plasminogen activator) are instilled
via the catheter into the brain to clear the blood slowly dur-
ing the course of 72 to 96 hours. Several studies demonstrate
the feasibility of this approach.12,16,18,20–26 In these studies,
hematoma evacuation seems to occur slowly, and result in
reduction in hematoma volume, brain edema, and midline
shift. However, these studies have been nonrandomized and
questions on safety of thrombolysis, chemical toxicity of
recombinant tissue-type plasminogen activator, and effects on
outcome remain at this time.
Randomized Controlled Trials in Minimally
Invasive Surgery for ICH
The National Institutes of Neurological Disorders and Stroke
has funded 2 randomized controlled studies of minimally
invasive surgery for ICH. The first is entitled the Minimally
Invasive Surgery Thrombolysis Plus Recombinant Tissue-type
Plasminogen Activator for ICH Evacuation (MISTIE)27 and
the second is entitled Intraoperative Computed Tomography–
guided Endoscopic Surgery (ICES) for ICH. The studies are
coordinated through an executive committee and designed
N, Surgery N, Medical Timing, h Effect
89 91 72 None
26 26 48 None
8 9 24 None
17 17 12 None
50 50 48 Positive
9 11 24 None
503 530 24 Neutral
to be cooperative in nature and make use of identical inclu-
sion and exclusion criteria, timing of surgery, and medical
treatment protocols. A total of 35 centers are participating
in MISTIE and an additional nonoverlapping 8 centers are
participating in ICES. The main data coordinating center for
both studies in Johns Hopkins Brain Injury Outcomes Center
and the 2 surgical coordinating centers are the University of
Cincinnati (MISTIE) and the University of California, Los
Angeles (ICES). The studies are designed to demonstrate
safety of early minimally invasive surgical evacuation of ICH
within 48 hours of hemorrhage onset as compared with best
medical management. The surgical entry window, stereotactic
approach, and fundamental presurgical safety imaging (com-
puted tomography angiography) are the same in both stud-
ies (Figure). Novel surgical, such as the eyebrow approach,
is being used to create novel surgical trajectories that theo-
retically try to avoid creating new damage by traversing the
corticospinal tracts.28 The studies are jointly monitored by a
Data Safety Monitoring Board. The outcome measures are
exactly the same and consist of 90, 180, 365 days assessment
of modified Rankin Outcome. The safety end points include
mortality, surgical mortality, surgical-related repeat bleeding,
and surgical-related infection.
For both the MISTIE and the ICES studies, the inclusion
and exclusion criteria are summarized below: inclusion crite-
ria: spontaneous, supratentorial, primary ICH within 48 hours
from onset, men or women, aged 18 to 89 years, inclusive,
written informed consent ICH volume >20 cc, Glasgow Coma
Score >5, National Institutes of Health Stroke Scale score
>5. The exclusion criteria are: ICH secondary to: cervico-
cephalic aneurysm, intracranial arteriovenous malformation,
intracranial tumor, trauma, hemorrhagic transformation of
an ischemic infarction, isolated intraventricular hemorrhage,
Glasgow Coma Score <5, nonreversible coagulopathy, signifi-
cant prior disability (premorbid modified Rankin Scale, ≥2),
known allergy to MR contrast agent, participation in any clini-
cal treatment trial within prior 30 days. The medical manage-
ment is uniform in both studies.
To date, both studies have reached completion of enroll-
ment of subjects but are in the follow-up phase.
Open Questions about Surgical
Evacuation of ICH
There are many open questions about the process of surgical
evacuation of ICH. (1) The optimal timing of hematoma
evacuation remains unclear. We have chosen a time window
of 48 hours to optimize the safety of the procedures and to
 Vespa et al   ICH Surgical Trials   S81
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Figure. The minimally invasive surgical approach for minimally invasive surgery thrombolysis plus recombinant tissue-type plasminogen
activator for intracerebral hemorrhage evacuation (MISTIE) and intraoperative computed tomography (CT)–guided endoscopic surgery
(ICES). Top, The preoperative screening, imaging, and intraoperative image guidance is similar in both studies. The trajectory along the
longest axis of the hematoma is shown, in this case the supraorbital approach. Middle, Highlights of the MISTIE and ICES procedures.
Note that MISTIE uses repeat doses of recombinant tissue-type plasminogen activator (rt-PA) through a catheter that is left in place,
whereas ICES does not. Bottom, CT images of postoperative appearance in MISTIE (hematoma remains with catheter in center) followed
by gradual resolution of the ICH. CT image of postoperative appearance in ICES showing >80% hematoma removal.

permit stability of the hematoma. In this way, the hemorrhagic
expansion process has stabilized, and we avoid confounding
the potential benefits of surgery with the negative effects
of recurrent bleeding.6,16 Testing ultra early surgery would
require prothrombotic hemostatic agents or ultra early blood
pressure control. (2) The optimal time to maximum clot
removal remains unclear. The MISTIE procedure is a gradual
process of hematoma volume reduction >72 hours, whereas
the ICES procedure is a rapid process of hematoma volume
reduction >1 hour. It is unclear if 1 approach is superior.
(3) The optimal hematoma location for surgery remains
unclear, but may be better after bleeding has stopped in the
24- to 72-hour time window.16,29 There may be brain regions
that are better adaptable to 1 minimally invasive technique.
(4) Selection of candidates who are likely to respond to
minimally invasive surgery remains unclear. The predictors of
poor outcome without surgery include hemorrhage location,
but it is not clear that these predictors hold true once surgery
has been performed (as is suggested by preliminary ICES and
MISITE data). Preliminary reports of these studies suggest
that 180-day prognosis is associated with residual size of the
postsurgical hematoma.16,27
Conclusions
ICH is a devastating illness for which preliminary data from
surgical trials indicate that surgery may be helpful. To date, this
premise remains unproven. Ongoing trials, including STICH
II, MISTIE, and ICES, are attempting to determine the poten-
tial for surgical efficacy for limited craniotomy and image
guide minimally invasive surgical removal using thrombolysis
or endoscopic evacuation. Preliminary results seem promising.
Acknowledgements
We acknowledge the clinical trial expertise of Karen Lane, Amanda
Bistran-Hall, Courtney Real, and the entire Brain Injury Outcomes
center.
Disclosures
Drs Vespa, Martin, Awad, Zuccarrelo, and Hanley have received
funding from the National Institutes of Health Stroke Scale. Dr Vespa
is consultant for Edge Pharmaceutical. Dr Martin is a consultant for
Zoll. Dr Hanley receives medical legal consultation fees.
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Key Words: cerebral edema ◼ coma ◼ endoscopy ◼ intracerebral
hemorrhage ◼ surgery ◼ thrombolysis
 Surgical Trials in Intracerebral Hemorrhage
Paul M. Vespa, Neil Martin, Mario Zuccarello, Issam Awad and Daniel F. Hanley

Stroke. 2013;44:S79-S82
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doi: 10.1161/STROKEAHA.113.001494
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