Minimally Invasive Surgery Plus Recombinant Tissue-type Plasminogen Activator for Intracerebral Hemorrhage Evacuation Decreases Perihematomal Edema

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DOI: 10.1161/STROKEAHA.111.000411 · Source: PubMed
Abstract
Background and purpose: Perihematomal edema (PHE) can worsen outcomes after intracerebral hemorrhage (ICH). Reports suggest that blood degradation products lead to PHE. We hypothesized that hematoma evacuation will reduce PHE volume and that treatment with recombinant tissue-type plasminogen activator (rt-PA) will not exacerbate it. Methods: Minimally invasive surgery and rt-PA in ICH evacuation (MISTIE) phase II tested safety and efficacy of hematoma evacuation after ICH. We conducted a semiautomated, computerized volumetric analysis on computed tomography to assess impact of hematoma removal on PHE and effects of rt-PA on PHE. Volumetric analyses were performed on baseline stability and end of treatment scans. Results: Seventy-nine surgical and 39 medical patients from minimally invasive surgery and rt-PA in ICH evacuation phase II (MISTIE II) were analyzed. Mean hematoma volume at end of treatment was 19.6±14.5 cm(3) for the surgical cohort and 40.7±13.9 cm(3) for the medical cohort (P<0.001). Edema volume at end of treatment was lower for the surgical cohort: 27.7±13.3 cm(3) than medical cohort: 41.7±14.6 cm(3) (P<0.001). Graded effect of clot removal on PHE was observed when patients with >65%, 20% to 65%, and <20% ICH removed were analyzed (P<0.001). Positive correlation between PHE reduction and percent of ICH removed was identified (ρ=0.658; P<0.001). In the surgical cohort, 69 patients underwent surgical aspiration and rt-PA, whereas 10 underwent surgical aspiration only. Both cohorts achieved similar clot reduction: surgical aspiration and rt-PA, 18.9±14.5 cm(3); and surgical aspiration only, 24.5±14.0 cm(3) (P=0.26). Edema at end of treatment in surgical aspiration and rt-PA was 28.1±13.8 cm(3) and 24.4±8.6 cm(3) in surgical aspiration only (P=0.41). Conclusions: Hematoma evacuation is associated with significant reduction in PHE. Furthermore, PHE does not seem to be exacerbated by rt-PA, making such neurotoxic effects unlikely when the drug is delivered to intracranial clot.
for the MISTIE Investigators
Issam Awad, Mario Zuccarello and Daniel F. Hanley
Nichol A. McBee, Amanda J. Bistran-Hall, Natalie L. Ullman, Paul Vespa, Neil A. Martin,
W. Andrew Mould, J. Ricardo Carhuapoma, John Muschelli, Karen Lane, Timothy C. Morgan,
Intracerebral Hemorrhage Evacuation Decreases Perihematomal Edema
Minimally Invasive Surgery Plus Recombinant Tissue-type Plasminogen Activator for
Print ISSN: 0039-2499. Online ISSN: 1524-4628
Copyright © 2013 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Stroke
doi: 10.1161/STROKEAHA.111.000411
2013;44:627-634; originally published online February 7, 2013;Stroke.
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627
I
ntracerebral hemorrhage (ICH) remains a devastating form
of stroke. The initial injury induced by the mechanical
effect of the hematoma on surrounding brain tissue as well as
the subsequent cascade of processes, such as perihematomal
edema (PHE), account for the high 30-day mortality and poor
neurological outcome in the surviving victims. Attempts at
clot removal via craniotomy and hematoma evacuation with
operative hemostasis have failed to provide an effective
treatment alternative for most ICH patients.
1–3
The advent
and refinement of minimally invasive surgery (MIS) in recent
years has allowed testing of new modalities of clot evacuation.
Concomitant use of direct aspiration, endoscopic removal, or
ultrasound-enhanced thrombolysis of intraparenchymal clots
have been reported, suggesting positive results regarding
the safety and efficacy of such techniques.
4,5
In particular,
the administration of recombinant tissue-type plasminogen
activator (rt-PA) using MIS has been reported by several
groups in the last decade showing important results favoring
Background and Purpose—Perihematomal edema (PHE) can worsen outcomes after intracerebral hemorrhage (ICH).
Reports suggest that blood degradation products lead to PHE. We hypothesized that hematoma evacuation will reduce
PHE volume and that treatment with recombinant tissue-type plasminogen activator (rt-PA) will not exacerbate it.
Methods—Minimally invasive surgery and rt-PA in ICH evacuation (MISTIE) phase II tested safety and efficacy of hematoma
evacuation after ICH. We conducted a semiautomated, computerized volumetric analysis on computed tomography to
assess impact of hematoma removal on PHE and effects of rt-PA on PHE. Volumetric analyses were performed on
baseline stability and end of treatment scans.
Results—Seventy-nine surgical and 39 medical patients from minimally invasive surgery and rt-PA in ICH evacuation phase
II (MISTIE II) were analyzed. Mean hematoma volume at end of treatment was 19.6±14.5 cm
3
for the surgical cohort and
40.7±13.9 cm
3
for the medical cohort (P<0.001). Edema volume at end of treatment was lower for the surgical cohort:
27.7±13.3 cm
3
than medical cohort: 41.7±14.6 cm
3
(P<0.001). Graded effect of clot removal on PHE was observed when
patients with >65%, 20% to 65%, and <20% ICH removed were analyzed (P<0.001). Positive correlation between PHE
reduction and percent of ICH removed was identified (ρ=0.658; P<0.001). In the surgical cohort, 69 patients underwent
surgical aspiration and rt-PA, whereas 10 underwent surgical aspiration only. Both cohorts achieved similar clot reduction:
surgical aspiration and rt-PA, 18.9±14.5 cm
3
; and surgical aspiration only, 24.5±14.0 cm
3
(P=0.26). Edema at end of
treatment in surgical aspiration and rt-PA was 28.1±13.8 cm
3
and 24.4±8.6 cm
3
in surgical aspiration only (P=0.41).
Conclusions—Hematoma evacuation is associated with significant reduction in PHE. Furthermore, PHE does not seem to be
exacerbated by rt-PA, making such neurotoxic effects unlikely when the drug is delivered to intracranial clot. (Stroke.
2013;44:627-634.)
Key Words: brain edema clot aspiration intracerebral hemorrhage minimally invasive surgery
MISTIE rt-PA thrombolysis
Minimally Invasive Surgery Plus Recombinant Tissue-
type Plasminogen Activator for Intracerebral Hemorrhage
Evacuation Decreases Perihematomal Edema
W. Andrew Mould, BA*; J. Ricardo Carhuapoma, MD*; John Muschelli, ScM; Karen Lane, CCRP;
Timothy C. Morgan, MPH; Nichol A. McBee, MPH; Amanda J. Bistran-Hall, BS;
Natalie L. Ullman, BS; Paul Vespa, MD; Neil A. Martin, MD; Issam Awad, MD;
Mario Zuccarello, MD; Daniel F. Hanley, MD; for the MISTIE Investigators
Received December 10, 2012; first revision received December 24, 2012; accepted December 27, 2012.
From the Department of Neurology, Division of Brain Injury Outcomes (W.A.M., K.L., T.C.M., N.A.M., A.J.B-H., N.L.U., D.F.H.), Departments
of Neurology, Neurosurgery and Anesthesiology/Critical Care Medicine (J.R.C.), Johns Hopkins Medical Institutions, Baltimore, MD; Department of
Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (J.M.); Departments of Neurology and Neurosurgery, UCLA School of
Medicine, Los Angeles, CA (P.V., N.A.M.); Department of Neurosurgery, University of Chicago Medicine and Biological Sciences, Chicago, IL (I.A.); and
Department of Neurosurgery, University of Cincinnati, Cincinnati, OH (M.Z.).
*W.A. Mould, BA, and Dr Carhuapoma contributed equally to this work.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
111.000411/-/DC1.
Correspondence to J. Ricardo Carhuapoma, MD, The Johns Hopkins Hospital, 600 N Wolfe St, Meyer 8–140, Baltimore, MD 21287. E-mail jcarhua1@
jhmi.edu
© 2013 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.111.000411
2013
58,73,43
Nancy.I
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628 Stroke March 2013
accelerated clot thrombolysis with an acceptable safety
profile.
6–8
As a result of this, the minimally invasive surgery
and rt-PA in ICH evacuation phase II (MISTIE II) was
designed and conducted in 2 stages, dose finding and safety,
from 2005 to 2012 to determine the safety and efficacy of
using MIS combined with rt-PA administration.
9
Interest in the physiopathology of PHE has gained signifi-
cant momentum in recent years. The role of inflammation and
blood–brain barrier breakdown in the genesis of this form of
edema has been known for some time. Thrombin, iron, microg-
lia, neutrophils, matrix metalloproteinases, and cytokines have
been identified as playing key roles in the process of edema
formation.
10–12
Experimental studies have shown promise in
ameliorating the cascade of secondary neuronal injury leading
to PHE by modifying the process of inflammation involved in
this response.
13
In humans, knowledge of the natural history of
this form of edema and its independent impact on neurologi-
cal outcome is still incomplete. Early clinical studies seem to
suggest delayed worsening of mass effect owing to cerebral
edema.
14
Wijman et al
15,16
have better defined the natural his-
tory of PHE using magnetic resonance imaging techniques.
Fainardi et al
17
have also identified the longitudinal changes
of apparent diffusion coefficient in the perihematoma regions
that evolve from elevated apparent diffusion coefficient (vaso-
genic edema) to reduced apparent diffusion coefficient (cyto-
toxic edema). Staykov et al
18
using computerized tomographic
(CT) studies reported that PHE can double the original hema-
toma volume from 7 to 11 days after the ictus. Unlike cerebral
edema after ischemic stroke, however, the relation of this form
of edema to treatment, tissue injury, and neurological outcome
after ICH remains poorly understood.
19,20
Therefore, improved
knowledge of PHE in patients with ICH is necessary.
MISTIE II enrollment was completed in 2012. We tested
the hypothesis that hematoma removal in patients treated with
MIS and rt-PA would lead to concomitant reduction of edema
volume at the end of treatment (EOT) as compared with ICH
patients treated with medical management. As part of this
analysis, we also tested the hypothesis that MISTIE II patients
treated with intraclot rt-PA do not develop PHE exacerba-
tion in the process of thrombolysis as compared with patients
treated with the clot aspiration only.
Subjects and Methods
Subjects
MISTIE II (R01NS046309) was a multicenter, randomized, prospec-
tive trial testing image-guided catheter-based removal of blood clot in
subjects with hypertensive ICH. Patients were recruited by 27 sites.
This 2-stage trial included a dose finding and a safety phase. Eighty-
one patients were assigned to MIS and 42 patients to standard medi-
cal care (either as pilot or randomized subjects). Five patients were
excluded, 3 medical, and 2 surgical, because of previous craniotomy
or poor image quality. In the surgical arm, 69 patients received surgi-
cal aspiration and rt-PA (S + rt-PA) (Alteplase, Genentech, Inc, South
San Francisco, CA), , whereas 10 patients received surgical aspiration
only (SO). A list of inclusion/exclusion criteria as well as an outline of
the surgical technique is provided in the online-only Data Supplement.
Thrombolysis Protocol
After the postoperative CT scan, intraclot rt-PA administration fol-
lowed by a sterile flush was initiated. After each assigned dose, the
system was closed for 1 hour to allow drug clot interaction. After 1
hour, the system was opened for gravitational drainage. Subsequent
doses of 0.3 mL (18 patients) or 1.0 mL (51 patients) were given ev-
ery 8 hours, up to 9 doses, or until an end point was reached. Clinical
endpoints included reduction of clot to 20% of original size, or clot
size is reduced to 10 cm
3
. Additional end points include any clini-
cally significant rebleeding event or any new hemorrhage (treatment
failures). CT scans were obtained every 24 hours to evaluate drainage
or as clinically indicated.
Medical Treatment Protocol
The medical management of these patients followed the MISTIE II
protocol, which followed the American Heart Recommendations for
the treatment of Spontaneous ICH.
21
Volumetric Analysis of Hematoma and PHE
Independent and adjudicated volumetric measurements of all intra-
parenchymal clot and edema volumes were performed by W.A.M.
and J.R.C. using an open source DICOM viewer software program
for MAC (Osirix v. 4.1, Pixmeo; Geneva, Switzerland). Generous
regions were drawn by hand to include areas of ICH and PHE sus-
ceptible to the computerized analysis, as determined by the reader.
A semiautomated threshold-based approach using a Hounsfield unit
range of 5 to 33 HU was then used to identify regions of PHE, as
previously reported by Volbers et al.
22
Using such range, a fixed lower
value of 5 HU was set. The upper limit and absolute maximum of 33
HU was adjusted to obtain the best delineation of edema and avoid ar-
tifact introduced by leukoaraiosis. Once these HU limits were deter-
mined, Osirix created edema regions and produced a volume in cubic
centimeters (cm
3
) by computing region of interest and slice thickness.
Volumes were calculated using a similar threshold-based segmenta-
tion on well-definable boundaries of blood on CT (Figure 1).
For the purpose of this study, we identified the baseline stability
(BLS) scan as the closest gradable scan before randomization. An
EOT scan was defined as the scan performed 24 hours (±12) post last
dose for S+rt-PA or post operative treatment for SO. A homologous
time window was then ascribed to the medical cohort to perform the
statistical analysis (closest scan to 3.9 days post onset).
Statistical Analysis
t Tests were done to test differences in means for continuous vari-
ables. ANOVA was used to determine differences across groups.
Wilcoxon rank-sum tests and a Kruskal–Wallis test also determined
that inferences were not different at a probability value of 0.05 using
these nonparametric tests. Fisher exact tests were done to determine
differences in the distributions of categorical variables across groups.
locally weighted scatterplot smoothing smoothing was used to de-
termine the relationship between variables.
23
Spearman ρ was used
to determine the association between variables when the relationship
seemed monotonic but not necessarily linear. We choose direct com-
parisons of pretreatment and posttreatment edema volume as the most
specific primary analysis of data to support or reject our hypothesis.
We performed multivariate linear models to assess factors with the
possibility to affect edema reduction.
Results
MISTIE II was composed of 2 stages: (1) dose finding (2005–
2009) and (2) safety (2009–2012). One hundred and twenty-
three patients were prospectively enrolled into 1 of 2 treatment
groups, MIS plus rt-PA (surgery) or best medical management
(medical), as shown in Table 1. Eighty-one patients were
randomized to receive MIS, whereas 42 were randomized to
medical management. Imaging of 5 patients (3 medical, 2 sur-
gical) was not graded owing to instance of prior craniotomy
creating image artifact and therefore poor image quality. The
data of 118 patients are reported in this communication.
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Mould et al Perihematomal Edema Following MISTIE 629
Demographic and Clinical Data
The surgical and medical cohorts were similar in age, sex,
race, hematoma location, and admission Glasgow Coma Scale
(Table 1). It is important to note that instance of symptomatic
hemorrhage and central nervous system infection, within the
analysis window (BLS-EOT), was low. Three symptomatic
hemorrhages occurred in the surgical cohort (P=0.30), and 2
instances of central nervous system infection compared with 1
in the medical cohort (P=1.00).
Neuroradiologic Features
Data on 118 patients were analyzed; time from ictus to BLS,
ictus to EOT, and number of patients with intraventricular
involvement were similar for the surgical and medical cohorts
(Table 2).
ICH and edema volumes at BLS for surgical patients
were similar compared with the medical cohort: surgi-
cal ICH, 43.8±17.2 cm
3
, PHE, 33.3±19.5 cm
3
; medical
ICH 42.2±14.8 cm
3
, PHE, 30.3±12.0 cm
3
. Neither of these
Figure 1. Computed tomography scan at EOT for a medical patient with (right) and without (left) the semiautomated threshold-based
segmentation of perihematomal edema. EOT indicates end of treatment scan.
Table 1. Demographic and Clinical Characteristics of the Study Patients
Surgical (n=79) Medical (n=39) P Value SO (n=10) S+rt-PA (n=69) P Value
Symptom onset age, y 60.6 (11.5) 61.0 (12.4) 0.87 68.9 (9.2) 59.4 (11.4) 0.01
Enrollment GCS 10.1 (2.9) 10.4 (3.8) 0.67 11.5 (2.8) 9.8 (2.9) 0.09
% Male 53 (67.1%) 26 (66.7%) 1.00 6 (60.0%) 47 (68.1%) 0.72
Race 0.60 0.81
White 44 (55.7%) 21 (53.8%) 7 (70.0%) 37 (53.6%)
Black 25 (31.6%) 10 (25.6%) 2 (20.0%) 23 (33.3%)
Hispanic 9 (11.4%) 5 (12.8%) 1 (10.0%) 8 (11.6%)
Asian or Pacific Islander 1 (1.3%) 2 (5.1%) 0 (0.0%) 1 (1.4%)
Unknown 0 (0.0%) 1 (2.6%) 0 (0.0%) 0 (0.0%)
Clot location 0.22 0.10
Thalamus 4 (5.1%) 1 (2.6%) 0 (0.0%) 4 (5.8%)
Putamen 46 (58.2%) 24 (61.5%) 3 (30.0%) 43 (62.3%)
Lobar 22 (27.8%) 14 (35.9%) 6 (60.0%) 16 (23.2%)
Globus pallidus 7 (8.9%) 0 (0.0%) 1 (10.0%) 6 (8.7%)
CNS infection* 2 (2.5%) 1 (2.6%) 1.00 0 (0.0%) 2 (2.9%) 1.00
Symptomatic bleed* 3 (3.8%) 0 (0.0%) 0.55 0 (0.0%) 3 (4.3%) 1.00
Emergent ICP therapy† 14 (17.7%) 10 (25.6%) 0.34 1 (10.0%) 13 (18.8%) 0.68
Emergent osmotherapy 10 (12.7%) 9 (23.1%) 0.18 1 (10.0%) 9 (13.0%) 1
CNS indicates central nervous system; GCS, Glasgow Coma Scale; ICP, intracranial pressure; SO, surgery only; and S+tPA, surgery + rt-PA.
*Within analysis window of BLS to EOT; † ICP therapy included osmotherapy, aggressive hyperventilation, and surgical decompression.
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630 Stroke March 2013
comparisons was statistically significant (Table 2). Surgical
patients had lower EOT ICH volume, 19.6±14.5 cm
3
, as
compared with their medical counterparts, 40.7±13.9 cm
3
(P<0.001). EOT edema volume was lower in surgical patients,
27.7±13.3 cm
3
, when compared with medical patients,
41.7±14.6 cm
3
(P<0.001) as shown in Figure 2.
When patients were subdivided into roughly equally sized
tertiles respecting the trial goal of clot removal of >65%
(n=32), 20% to 65% (n=39), and <20% (n=8) clot removal
from BLS to EOT, surgical patients with >65% clot removal
demonstrated PHE reduction of 10.7±13.9 cm
3
, whereas
medical patients, all with <20% resolution by EOT, showed
an increase in PHE of 11.4±9.6 cm
3
(P<0.001), as depicted
in Figure 3. A significant graded effect of clot removal on
PHE was observed overall (ANOVA P<0.001). Furthermore,
a positive correlation between PHE reduction and percent of
ICH removed was identified (Spearman ρ=0.66; P<0.001)
as represented in Figure 3. In multivariate analyses, this
relation was unaltered by dose of rt-PA, osmotherapy, or
intracranial pressure therapy.
In the surgical arm, 69 patients received S+rt-PA, whereas
10 patients received SO. Both treatment subgroups were com-
parable for enrollment Glasgow Coma Scale, intraventricu-
lar involvement, time from symptom onset to BLS or EOT,
baseline ICH volume, and baseline PHE volume but differed
for age: SO, 68.9±9.2 years old and S+rt-PA, 59.4±11.4 years
old (P=0.01). Both treatment cohorts achieved similar blood
clot reduction: S+rt-PA, 18.9±14.5 cm
3
and SO, 24.5±14.0
cm
3
(P=0.26). Mean edema at EOT in patients treated with
S+rt-PA was 28.1±13.8 cm
3
, while in patients treated with SO
was 24.4±8.6 cm
3
(P=0.41). Edema levels for both arms of the
surgical cohort, S+rt-PA and SO, at BLS and EOT are shown
in Figure 4.
Conclusions
We report on the effect of hematoma removal using MIS and
rt-PA on PHE formation in ICH patients. We identified a sig-
nificant PHE reduction in patients who underwent successful
clot evacuation after the MISTIE procedure. Furthermore,
administration of rt-PA for clot lysis in addition to initial
Table 2. Radiological and Volumetric Data of the Study Patients
Surgical (n=79) Medical (n=39) P Value SO (n=10) S+rt-PA (n=69) P Value
Symptom onset to EOT scan, days 3.9 (1.1) 3.7 (0.5) 0.23 3.6 (0.7) 4.0 (1.1) 0.27
Patients w/ IVH extension 48 (60.8%) 25 (64.1%) 0.84 5 (50.0%) 43 (62.3%) 0.50
BLS ICH volume, mL 43.8 (17.2) 42.2 (14.8) 0.61 40.1 (15.7) 44.4 (17.4) 0.46
EOT ICH volume, mL 19.6 (14.5) 40.7 (13.9) <0.001 24.5 (14.0) 18.9 (14.5) 0.26
BLS edema volume, mL 33.3 (19.5) 30.3 (12.0) 0.37 6.4 (12.9) 34.3 (20.1) 0.24
EOT edema volume, mL 27.7 (13.3) 41.7 (14.6) <0.001 24.4 (8.6) 28.1 (13.8) 0.41
Reduction in edema (BLS-EOT) 5.6 (15.1) 11.4 (9.6) <0.001 2.1 (10.6) 6.2 (15.7) 0.43
Relative PHE stability 0.8 (0.3) 0.7 (0.3) 0.66 0.7 (0.2) 0.8 (0.4) 0.24
Reduction in edema/stability ICH* 0.1 (0.3) 0.3 (0.3) <0.001 -0.0 (0.3) 0.1 (0.3) 0.31
BLS indicates baseline stability scan; EOT, end of treatment scan; ICH, intracerebral hemorrhage; IVH, intraventricular hemorrhage; PHE, perihematomal edema; SO,
surgery only; and S + rt-PA, surgery + rt-PA.
*Relative PHE difference, edema reduction divided by BLS ICH.
Figure 2. BLS and EOT edema volumes for the
surgical (S+rt-PA and SO) and medical cohorts.
BLS indicates baseline stability scan; EOT, end of
treatment scan; SO, surgery only; and S + rt-PA,
surgery + rt-PA.
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Mould et al Perihematomal Edema Following MISTIE 631
aspiration did not enhance edema formation in relation to
patients treated with clot aspiration only.
PHE is an almost universal occurrence after ICH.
Early interpretations of perihematomal events included
cerebral ischemia, which found some support in animal
experiments.
24–31
Subsequent human studies using surrogates
of cerebral ischemia, such as single photon emission CT and
perfusion weighted magnetic resonance imaging, corroborated
the presence of hypoperfused tissue surrounding parenchymal
clots.
32–34
Only when studies measuring cerebral metabolism
were performed did it become clear that hypoperfusion was
likely the result of hypometabolism.
35
This metabolic state
of hibernation is hypothesized to be associated to vasogenic
cerebral edema. Attempts to indirectly quantify blood–
brain barrier disruption using diffusion weighted magnetic
resonance imaging have suggested a cause-effect or dose-
response association between the volume of ICH, intensity of
apparent diffusion coefficient elevation PHE volume.
36–38
The clinical significance of PHE remains unclear.
Volumetric analyses of PHE using CT and magnetic reso-
nance imaging studies have repeatedly demonstrated edema
volumes reaching 2- to 3-fold the original hematoma vol-
ume.
38
Delayed neurological deterioration as late as 2 to 3
weeks after the ictus, likely the result of PHE, has also been
described. However, the independent impact of these events
on long-term neurological outcome remains unknown. Gebel
et al
39,40
reported on the paradoxical improved functional
outcome predicted by relative PHE in the initial 24 hours.
Using data from the Intensive Blood Pressure Reduction in
Acute Cerebral Hemorrhage (INTERACT) trial, Arima et al
20
reported differently. These investigators found PHE to be sig-
nificantly associated to the underlying hematoma volume but
lacking independent effect on the outcome of ICH patients.
These studies and ours are limited by difficulty completely
blinding the edema analysis of surgical subjects and our still
limited knowledge of factors that provoke and mitigate edema.
Figure 3. A, BLS and EOT edema volumes for patients separated by treatment group (medical, surgical aspiration only, and surgery plus
rt-PA) and trichotimized by order of percent intracerebral hemorrhage (ICH) removed. BLS indicates baseline stability scan; EOT, end of
treatment scan. B, Percent of ICH removed as calculated by ([BLS ICH volumeEOT ICH volume]/BLS volume) in a continuous fashion vs
reduction in edema (BLS edema volumeEOT edema volume) for patients receiving medical management (blue) and MIS (red). S + rt-PA
indicates surgery plus rt-PA; and SO, surgical aspiration only. *denotes statistical significance.
Figure 4. Relationship between BLS and EOT
edema volumes for patients separated by treat-
ment group (medical, surgical aspiration only, and
surgery plus rt-PA). BLS indicates baseline stability
scan; EOT, end of treatment scan; and rtPA, recom-
binant tissue-type plasminogen activator.
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632 Stroke March 2013
Targeted therapies for this form of edema for ICH are lack-
ing; thus the differential impact of PHE modification on neu-
rological outcome is largely unknown. Therapeutic trials for
ICH have concentrated primarily on clot evacuation.
2,3
Several
early clinical trials comparing best medical therapy alone ver-
sus best medical therapy and surgical evacuation of the hema-
toma have been completed. Minimally invasive neurosurgical
procedures seem to minimize trauma to viable brain tissue.
Studies using MIS and clot aspiration, thrombolysis, and endo-
scopic evacuation have reported on their safety and potential
for efficacy when used in selected ICH patients. These studies
not only suggest that hematoma evacuation is safe but that
a parallel response between hematoma volume reduction and
PHE volume exists.
41–43
Our results confirm such observations
in this prospectively recruited cohort of patients. The com-
bined effect of this form of hematoma evacuation and edema
volume attenuation on neurological recovery after ICH awaits
testing in a properly powered prospective clinical trial.
rt-PA has been used in several paradigms of brain injury, more
conspicuously as the thrombolytic agent for acute recanalization
during acute ischemic stroke. The safety and efficacy profiles
of rt-PA in this setting have been evaluated in several studies
before its recommendation as thrombolytic agent for the treat-
ment of acute cerebral ischemia using the intravenous adminis-
tration route. The experimental use of rt-PA in the treatment of
intraventricular and ICH, however, has opened 2 new modali-
ties of drug delivery that have not been previously tested. After
completing proof of concept and dose escalation studies, Clot
Lysis: Evaluating Accelerated Resolution of Hemorrhage with
rt-PA Intraventricular Hemorrhage (CLEAR IVH) and MISTIE
II have reported on the efficient and safe clot evacuation from
the intraventricular and intraparenchymal compartments using
rt-PA. Concerns of toxicity produced from the direct exposure
of the drug to neuronal tissue have, however, been raised by
some investigators.
44,45
Early reports of retinal toxicity when
tissue plasminogen activator and L-arginine when used in the
treatment of vitreal hemorrhage exist.
46–48
Furthermore, first in a
pig model and more recently in a clinical study, rt-PA has been
postulated to worsen vasogenic edema when used in the treat-
ment of intraventricular hemorrhage and ICH.
49,50
Nonetheless,
no evidence for this toxicity was noted when histological
assessments in large animal intracranial and retinal hemorrhage
models were performed.
51–55
Additionally, recent mouse tissue
plasminogen activator knockout studies suggest amelioration
of blood-clot-related neuronal and glial tissue injury by rt-PA.
56
Finally, no signs of human neuronal rt-PA toxicity have been
noted in the current treatment of ischemic stroke, despite admin-
istration under conditions of blood–brain barrier disruption.
57
Our study is the first a priori investigation that uses a semi-
automated volumetric analysis for prospectively obtained
group of patients treated with clot aspiration alone versus clot
aspiration and thrombolytic therapy with rt-PA. Both groups
achieved similar clot volume reduction without experiencing
differences in PHE volumes, confirming the overall positive
impact of hematoma removal using rt-PA on PHE volumes,
reported by our group as well as others.
Our analysis of 118 patients enrolled in the MISTIE II trial
is consistent with the hypothesis that successful hematoma
evacuation leads to significant edema volume reduction. In
2008, we did report on such association after the retrospective
analysis of a convenience cohort of ICH patients treated using
a similar approach with MIS and thrombolysis. This is the
first time such an observation is confirmed in a prospectively
obtained cohort of ICH patients. Hematoma evacuation and
its impact on vasogenic edema formation leading to improved
neurological outcomes after ICH remains under investigation.
MISTIE III offers to test for such association. In the mean-
time, our results demonstrate that efficient hematoma evacua-
tion using a combined approach of MIS and aspiration with or
without rt-PA leads to a significant reduction in PHE.
Acknowledgments
We thank the patients and families who volunteered for this study,
Genentech Inc for the donation of study drug (Alteplase), and the
following people for their support in assisting data collection, Lucas
First, Saman Nekoovaght-Tak, Johanna Block.
List of PIs and Surgeons for MISTIE II
Allegheny General Hospital, Pittsburgh, PA, Khaled Aziz, MD, PI;
Bronson Methodist Hospital, Kalamazoo, MI, Jeffrey Fletcher, MD,
PI, Bratislav Velimirovic, MD, Coinvestigator, Daryl Warder, MD,
Coinvestigator; Duke University Medical Center, Durham, NC, Gavin
Britz, MBBCh, MPH, Coinvestigator, Carmelo Graffagnino, MD, PI;
Hartford Hospital, Hartford, CT, Inam Kureshi, MD, PI; Johns Hopkins
Medical Institutions, Baltimore, MD, Judy Huang, MD, PI; Medical
University of South Carolina, Charleston, NC, Byron Bailey, MD,
PI, Dilantha Ellegala, MD, PI, Angela Hays, MD, PI, Marc LaPointe,
PharmD, PI; Montreal Neurological Institute at McGill University,
Montreal, QC, Canada, David Sinclair, MD, PI; Mount Sinai Medical
Center, New York, NY, Joshua B Bederson, MD, PI, Henry Moyle,
MD, PI; Newcastle University, Newcastle on Tyne, United Kingdom,
Professor A David Mendelow, PI, Prokopios Panaretos, Coinvestigator;
New Jersey Neuroscience Institute at JFK Medical Center, Edison, NJ,
Martin Gizzi, MD, PhD, PI, Thomas Steineke, MD, PhD, Coinvestigator;
Rush University, Chicago, IL, Lorenzo Munoz, MD, Coinvestigator,
Shaun T O’Leary, MD, Coinvestigator, Richard E Temes, MD, PI;
Stanford University School of Medicine, Palo Alto, CA, Robert Dodd,
MD, Coinvestigator, Cristanne Wijman, MD, PhD, PI; St. Luke’s
Hospital, Kansas City, MO, Paul Camarata, MD, PI; Temple University,
Philadelphia, PA, Jack Jallo, MD, PhD, PI, Christopher Loftus, MD,
PI, Michael Weaver, MD, Coinvestigator; University of Alabama at
Birmingham, Birmingham, AL, Mark Harrigan, MD, PI; University of
California, Los Angeles, Los Angeles, CA, Neil Martin, MD, PI, Paul
Vespa, MD, PI; University of California, San Diego, San Diego, CA,
Bob Carter, MD, PhD, PI; University of Chicago, Chicago, IL, Issam
Awad, MD, PI, Fernando Goldenberg, MD, PI; University of Cincinnati,
Cincinnati, OH, Andrew Ringer, MD, Coinvestigator, Mario Zuccarello,
MD, PI; University of Maryland, Baltimore, MD, E. Francois Aldrich,
MD, PI; University of Texas, Houston, Houston, TX, William Ashley,
MD, Coinvestigator, Peng Roc Chen, MD, Coinvestigator, George Lopez,
MD, PI; University of Texas, San Antonio, San Antonio, TX, Jean-Louis
Caron, MD, PI; Universitätsklinikum Heidelberg, Heidelberg, Germany,
Dr. med. Daniel Haux, Coinvestigator, Berk Orakcioglu, Coinvestigator,
Dr. med. Sven Poli, PI, Thorsten Steiner, MD, PhD, PI; Virginia
Commonwealth University, Richmond, VA, William C Broaddus, MD,
PhD, PI, R. Scott Graham, MD, Coinvestigator.
Sources of Funding
National Institute of Health/National Institute of Neurological
Disorders and Stroke supported this research with grants number
R01Ns046309 and 5U01NS062851.
Disclosures
Dr Daniel F. Hanley was awarded significant research support of grants
number R01Ns046309 and 5U01NS062851. Johns Hopkins University
holds a use patent for intraventricular tissue plasminogen activator.
at WELCH MED LIBR-JHU-MEYER SERIA on April 16, 2013http://stroke.ahajournals.org/Downloaded from
Mould et al Perihematomal Edema Following MISTIE 633
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    • "Currently, clinical treatment for ICH mainly involves selective surgery or non-operative treatment, as indicated by the size of the hematoma and the overall condition of the patient. Most surgeries for removal of the hematoma are minimally invasive [10] [11]. Non-operative treatments include lowering blood pressure, stopping bleeding, maintaining the internal environment, and symptomatic therapy and support. "
    Full-text · Article · Jan 2016
    • "As a result, MIS to remove ICH followed by medications to prevent secondary brain damage might be another optimal choice [18, 19]. MIS plus a recombinant tissue-type plasminogen activator has achieved favorable results by reducing perihematomal edema [20]. Initial ICH is always followed by secondary brain damage , which is associated with a range of inflammatory factors, including matrix metalloproteinase-9 (MMP-9), a member of matrix metalloproteinase family (MMPs). "
    [Show abstract] [Hide abstract] ABSTRACT: The objective of this study was to investigate the effects of Rosiglitazone (RSG) infusion therapy following minimally invasive surgery (MIS) for intracerebral hemorrhage(ICH) evacuation on perihematomal secondary brain damage as assessed by MMP-9 levels, blood-brain barrier (BBB) permeability and neurological function. A total of 40 male rabbits (2.8-3.4 kg) were randomly assigned to a normal control group (NC group; 10 rabbits), a model control group (MC group; 10 rabbits), a minimally invasive treatment group (MIS group; 10 rabbits) or a combined MIS and RSG group (MIS + RSG group; 10 rabbits). ICH was induced in all the animals, except for the NC group. MIS was performed to evacuate ICH 6 hours after the successful preparation of the ICH model in the MIS and MIS + RSG groups. The animals in the MC group underwent the same procedures for ICH evacuation but without hematoma aspiration, and the NC group was subject to sham surgical procedures. The neurological deficit scores (Purdy score) and ICH volumes were determined on days 1, 3 and 7. All of the animals were sacrificed on day 7, and the perihematomal brain tissue was removed to determine the levels of PPARγ, MMP-9, BBB permeability and brain water content (BWC). The Purdy score, perihematomal PPARγ levels, BBB permeability, and BWC were all significantly increased in the MC group compared to the NC group. After performing the MIS for evacuating the ICH, the Purdy score and the ICH volume were decreased on days 1, 3 and 7 compared to the MC group. A remarkable decrease in perihematomal levels of PPARγ, MMP-9, BBB permeability and BWC were observed. The MIS + RSG group displayed a remarkable increase in PPARγ as well as significant decrease in MMP-9, BBB permeability and BWC compared with the MIS group. RSG infusion therapy following MIS for ICH treatment might be more efficacious for reducing the levels of MMP-9 and secondary brain damage than MIS therapy alone.
    Full-text · Article · Dec 2015
    • "An example is the current phase III Minimally Invasive Surgery plus rtPA for Intracerebral Hemorrhage Evacuation (MISTIE) trial which uses t-PA to aid in clot removal [141] . This has recently been reported to reduce perihematomal edema which may suggest reduced BBB per- meability [142]. A potential concern of such trials is that surgery or surgery plus tPA might cause the release of factors from the hematoma (e.g. "
    [Show abstract] [Hide abstract] ABSTRACT: This article reviews current knowledge of the mechanisms underlying the initial hemorrhage and secondary blood-brain barrier (BBB) dysfunction in primary spontaneous intracerebral hemorrhage (ICH) in adults. Multiple etiologies are associated with ICH, for example, hypertension, Alzheimer's disease, vascular malformations and coagulopathies (genetic or drug-induced). After the initial bleed, there can be continued bleeding over the first 24 hours, so-called hematoma expansion, which is associated with adverse outcomes. A number of clinical trials are focused on trying to limit such expansion. Significant progress has been made on the causes of BBB dysfunction after ICH at the molecular and cell signaling level. Blood components (e.g. thrombin, hemoglobin, iron) and the inflammatory response to those components play a large role in ICH-induced BBB dysfunction. There are current clinical trials of minimally invasive hematoma removal and iron chelation which may limit such dysfunction. Understanding the mechanisms underlying the initial hemorrhage and secondary BBB dysfunction in ICH is vital for developing methods to prevent and treat this devastating form of stroke.
    Full-text · Article · Aug 2014
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