Intracerebral Hemorrhage

Intracerebral
Hemorrhage
By Wendy C. Ziai, MD, MPH, FAHA, FNCS, FESO;
J. Ricardo Carhuapoma, MD, FAHA
ABSTRACT
PURPOSE OF REVIEW:This article describes the advances in the management of
spontaneous intracerebral hemorrhage in adults.
RECENT FINDINGS: Therapeutic intervention in intracerebral hemorrhage has
continued to focus on arresting hemorrhage expansion, with large
randomized controlled trials addressing the effectiveness of rapidly
lowering blood pressure, hemostatic therapy with platelet transfusion,
and other clotting complexes and clot volume reduction both of
intraventricular and parenchymal hematomas using minimally invasive
techniques. Smaller studies targeting perihematomal edema and
inflammation may also show promise.
SUMMARY: The management of spontaneous intracerebral hemorrhage,
long relegated to the management and prevention of complications, is
undergoing a recent evolution in large part owing to stereotactically guided
clot evacuation techniques that have been shown to be safe and that
may potentially improve outcomes.
INTRODUCTION
I ntracerebral hemorrhage (ICH) remains a cause of significant morbidity and
mortality and is associated with severe long-term disability. Furthermore, it comprises

10% to 15% of all strokes, with an incidence of 24.6 per 100,000 person-years and with
a growing incidence related to the use of anticoagulation, antiplatelet drugs, and an
aging population.1 Despite this,
ICH is the last form of stroke without specific therapy. The financial impact of
ICH is, in part, owing to its high mortality, with up to one-half of patients dying
30 days after experiencing ICH, often despite extensive stays in the intensive
care unit.2 Moreover, those who survive are left with a high degree of disability.1
Treatment of ICH ranges from best medical therapy to approaches involving
several different surgical techniques, most of which are at different levels of
experimental state.1,3 A lack of definitive evidence-based recommendations to
guide the care of patients with ICH has led to significant heterogeneity in current
clinical practice.1,3–5
PATHOPHYSIOLOGY
ICH occurs after a parenchymal arteriole in the brain ruptures. Common
processes leading to ICH include amyloid angiopathy, tumors, hemorrhagic
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2018;24(6, NEUROCRITICAL CARE):
1603–1622.
Address correspondence to
Dr J. Ricardo Carhuapoma, Johns
Hopkins Hospital, 1800 Orleans
St, Phipps 455, Baltimore, MD
21287, jcarhua1@jhmi.edu.
RELATIONSHIP DISCLOSURE:
Dr Ziai serves as an associate
editor for Neurocritical Care, on
an advisory board for C.R. Bard
Inc, and has received personal
compensation as a consultant
for and research/grant support
from HeadSense Medical Ltd.
Dr Ziai has received grant
support from the Johns Hopkins
Anesthesiology and Critical Care
Medicine (ACCM) Stimulating
and Advancing ACCM Research
(StAAR) program and from the
National Institutes of Health
(5U01NS062851, 1U01NS08082).
Dr Carhuapoma reports no
disclosure.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Drs Ziai and Carhuapoma discuss
the unlabeled/investigational
use of alteplase for the
treatment of intracerebral
hemorrhage and discuss the use
of several devices, including
ultrasound microcatheters,
sonothrombolysis for minimally
invasive subcortical
parafascicular transsulcal
access for clot evacuation
(MiSPACE), and the stereotactic
mechanical (suction/vibration/
aspiration) thrombolytic
technique for minimally invasive
evacuation of intracerebral
hemorrhage.
© 2018 American Academy
of Neurology.
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
transformation of an ischemic stroke, cerebral venous thrombosis, vasculitis, and

vascular malformations such as cavernous malformations, arteriovenous
malformations, and ruptured saccular aneurysms. In the case of spontaneous
ICH, where preexisting hypertension is ubiquitous, Charcot-Bouchard
aneurysms, believed to result from lipohyalinosis of small arterioles, are often
blamed for the rupture of small penetrating blood vessels implicated in ICH
involving the cerebellum, pons, thalamus, and basal ganglia.6
The primary nature of ICH is determined as a diagnosis of exclusion based on a
thorough investigation for secondary structural causes of ICH. Advanced age,
deep location (basal ganglia, thalami, or posterior fossa), or history of
hypertension are often interpreted as surrogates of primary ICH, although
cerebral angiography studies suggest that these imaging and clinical features are
not always reliable indicators, and patients with these features may have
coexisting vascular abnormalities.7,8
MEDICAL MANAGEMENT
Medical management is aimed at treating intracranial pressure (ICP), controlling
systemic hypertension, and preventing hematoma expansion. With the
exception of early blood pressure control, no successful phase 3 trials have been
conducted at the time of this writing that have proven to improve survival or
neurologic outcomes after ICH.9 Surgical management is focused on clot
extraction, removal of intraventricular blood products, and managing
intracranial hypertension.
Initial management should focus on standard principles of critical care such
as the stabilization of the patient’s airway, breathing, and circulation.10 Hourly
or more frequent neurologic examinations should be scheduled immediately
thereafter. Neuroimaging recommended by the American Heart Association
includes CT with CT angiography to look for a spot sign (associated with
increased risk of ICH expansion; see below) and to assess for structural vessel
pathology and MRI to rule out other etiologies of ICH.10 Characteristics that
increase the likelihood of finding a vascular abnormality include female sex,
younger than 65 years of age with lobar ICH, primary intraventricular
hemorrhage (IVH), and an absent history of hypertension, smoking, or
coagulopathy.11 In properly selected cases, catheter cerebral angiography can
confirm if an underlying vascular lesion is present.11 If cerebral venous
thrombosis is suspected, CT venography or magnetic resonance venography
(MRV) should be performed.12
ICH grading scales are routinely used to assess initial neurologic severity,
facilitate communication between providers, and frame expectations of family
members. However, they should not be used in isolation when prognosticating
survival and functional outcomes after ICH. Overreliance on grading scales can
lead to self-fulfilling prophecies in which patients with predicted poor outcomes
can have subsequent limitations in the level of care provided to them.13,14 The
ICH Score allows rapid outcome stratification of patients with ICH and has been
widely adopted since several studies have validated its feasibility.5 It includes
five independent risk factors for 30-day mortality that are assigned weights to
derive a score from 0 to 6 (TABLE 2-1 and FIGURE 2-1). The Glasgow Coma Scale
(GCS) has more utility when evaluated after clinical stabilization than on initial
assessment.16 Another useful score for clinical decision making and potential
patient selection for clinical trials is the Functional Outcome in Patients With
KEY POINTS
● Treatment for
intracerebral hemorrhage
revolves around acute
management of blood
pressure, intracranial
pressure, and cerebral
edema.
● Although the majority
of intracerebral hemorrhage
is attributed to hypertensive
small penetrating vessel
arteriopathy, vascular
imaging (CT angiography,
magnetic resonance
angiography, or catheter
angiography) and MRI are
essential to rule out other
etiologies of intracerebral
hemorrhage.
● The Intracerebral
Hemorrhage Score and the
Functional Outcome in
Patients With Primary
Intracerebral Hemorrhage
score allow rapid outcome
stratification of patients
with intracerebral
hemorrhage. Nevertheless,
they should not be used
independently to guide
goals of care discussions of
patients with intracerebral
hemorrhage.
● A spot sign, defined by
the presence of contrast
within the hematoma
visualized on CT
angiography or contrastenhanced CT, is associated
with a high risk of early

expansion.
INTRACEREBRAL HEMORRHAGE
1604 DECEMBER 2018

Primary Intracerebral Hemorrhage (FUNC) score, which estimates the likelihood

of functional independence at 90 days. (TABLE 2-2 and TABLE 2-3).17
HEMATOMA EXPANSION
Hematoma expansion is a common cause of secondary neurologic deterioration
and is a leading modifier of survival and functional outcomes in up to one-third
of patients after ICH occurs. Hematoma expansion generally occurs within
24 hours, although delayed expansion has been described (FIGURE 2-2).16 The
strong prognostic impact of hematoma expansion on ICH outcomes is
predominantly owing to its effect on midline shift and cerebral herniation,
although even relatively small expansions can cause neurologic deterioration.18,19
Extravasation of contrast within the hematoma, called the spot sign (FIGURE 2-3),20
can be visualized on CT angiography source images or contrast-enhanced CT and
Determination of the Intracerebral Hemorrhage Scorea,b TABLE 2-1
Component
Intracerebral Hemorrhage
Score Points
Glasgow Coma Scale score
3–4 2
5–12 1
13–15
0
Intracerebral hemorrhage volume, cm3
1
≥30
<30
0
Intraventricular hemorrhage
Yes 1
No 0
Infratentorial origin of intracerebral hemorrhage
Yes 1
No 0
Age in years
1
≥80
<80 0
Total intracerebral hemorrhage score 0–6
a Reprinted with permission from Hemphill JC 3rd, et al, Stroke. 5 © 2001 American Heart Association.
b Glasgow Coma Scale score indicates score on initial presentation (or after resuscitation); intracerebral
hemorrhage volume indicates volume on initial CT calculated using the ABC/2 method (the ABC/2 method is
the mathematical formula using the greatest three-dimensional diameters [A = length, B = width, and
C = thickness] of the intracerebral hemorrhage, that provides an accurate representation of the hematoma
volume)15; and intraventricular hemorrhage indicates the presence of any intraventricular hemorrhage on
initial CT. The total score is used to stratify 30-day mortality.
is an independent predictor of
early hematoma growth.21
Although such predictive value
has been repeatedly and
independently validated, the
current utility of this information
is not well defined in the absence
of therapies specifically targeted
to prevent this feared
complication. In the PREDICT
(Prediction of Hematoma
score on 30-day mortality. Hemphill and
Growth and Outcome in Patients
colleagues5 reported on the association between
With Intracerebral Hemorrhage
mortality and the ICH score studied in a cohort
Using the CT Angiography Spot
of 152 participants. Thirty-day mortality increases
Sign) trial, patients with the spot

sign had significantly higher
of 5 died. No patient in the University of California,
mortality at 3 months (43.4%) as
San Francisco ICH cohort had an ICH score of 6,
compared to patients who were
although this would be expected to be associated
spot sign negative (19.6%).22

Ongoing bleeding during
hematoma evacuation was also
Stroke.5 © 2001 American Heart Association.
predicted by the spot sign, and a
retrospective study found that
among patients with ICH who are spot sign positive, surgical treatment was
associated with lower mortality than conservative management.23,24
Several trials have attempted to arrest hematoma expansion by acutely
controlling hypertension or by supplementing clotting factors. INTERACT 1
(Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 1)
was a feasibility study that demonstrated the safety and feasibility of intensive
blood pressure reduction in acute cerebral hemorrhage.18 The follow-up study,
INTERACT 2, randomly assigned 2839 patients to receive either intensive
treatment of systolic blood pressure to less than 140 mm Hg or treatment of
systolic blood pressure to less than 180 mm Hg as recommended by the American
Heart Association guidelines.18 The primary outcome was death or major
disability at 90 days, as assessed by the modified Rankin Scale (mRS), and was
not statistically different between subjects in the intensive treatment group
compared to the group treated according to the American Heart Association
guidelines (52% versus 55.6%, respectively), and mortality was also similar
(11.9% versus 12.0%). No significant reduction in hematoma growth was found
in the intensive treatment group, although several secondary outcomes,
including ordinal analysis of the mRS score, did show a significant favorable shift
for intensive blood pressure lowering versus guideline management. ATACH-2
(Antihypertensive Treatment of Acute Cerebral Hemorrhage II), another large
randomized trial of acute blood pressure reduction, randomly assigned 1000
subjects with an ICH volume of <60 mL and a GCS score of ≥5 to either a systolic
blood pressure goal of 110 mm Hg to 139 mm Hg or to a standard treatment goal
of 140 mm Hg to 179 mm Hg.19 All subjects received IV nicardipine. This trial
again failed to show a significant difference in the primary outcome: death or
disability at 3 months (38.7% in the intensive group versus 37.7% of the
standard group).
KEY POINT
● Although hematoma
expansion is a complication
that negatively modifies
mortality and functional
outcome after intracerebral
hemorrhage, it lacks
specific interventions aimed
at ameliorating its impact.
FIGURE 2-1
Impact of the Intracerebral Hemorrhage (ICH)

as the ICH score increases. No patient with an
ICH score of 0 died. All patients with an ICH score
with mortality.
Reprinted with permission from Hemphill JC 3rd, et al,
1606 DECEMBER 2018

The FAST (Factor Seven for Acute Hemorrhagic Stroke) trial targeted ICH
expansion using recombinant activated factor VII, which enhances local hemostasis
after binding to exposed tissue factor, facilitating conversion of prothrombin to
thrombin.25 Preliminary studies had suggested that the administration of
recombinant activated factor VII within 4 hours of ICH onset could reduce
mortality and could be associated with improved functional outcomes after
3 months.26 The phase 3 multicenter trial randomly assigned 841 patients with ICH
within 4 hours after onset to placebo, 20 mcg/kg of recombinant activated factor
VII, or 80 mcg/kg of recombinant activated factor VII. The primary outcome,
death or severe disability at 90 days, was not different between the groups
(placebo: 24%; low-dose recombinant activated factor VII: 26%; high-dose
Determinants of the Functional Outcome in Patients With Primary TABLE 2-2
Intracerebral Hemorrhage Scorea
Component
Functional Outcome in
Patients With Primary Intracerebral
Hemorrhage (FUNC) Score Points
Intracerebral hemorrhage volume, cm3
<30 4
30–60 2
>60
0
Age in years
2
<70
70–79 1
≥80
0
Intracerebral hemorrhage location
Lobar 2
Deep 1
Infratentorial 0
Glasgow Coma Scale score

2
≥9
≤8
Pre–intracerebral hemorrhage
0
cognitive impairment
No
Yes 0
Total FUNC score 0–11
a Reprinted with permission from Rost NS, et al, Stroke. 17 © 2008 American Heart Association.
recombinant activated factor VII: 29%). The absolute reduction in ICH growth
relative to the placebo group was statistically significant but clinically minor
(2.6 mL in the low-dose group and 3.8 mL in the high-dose group). Therefore, the
use of recombinant activated factor VII in acute ICH did not find clinical benefit
in a phase 3 trial and was associated with more arterial thrombotic events.
A different approach using the antifibrinolytic agent tranexamic acid is currently
nearing completion of a multicenter phase 3 randomized trial (TICH-2
[Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage]), testing
the hypothesis that IV tranexamic acid reduces death and disability when given
within 8hours of ICH.27
Patients with abnormalities of primary or secondary hemostasis or who are
taking oral anticoagulants (up to 20% of patients with ICH) have an increased
likelihood of ICH expansion because of their inability to form stable clots.28
Recommended therapy is emergent replacement of deficient factors and includes
vitamin K for those on vitamin K antagonists. Additionally, such patients benefit
from prothrombin complex concentrate since this corrects the international
TABLE 2-3 Proportion of Patients Who Achieve Functional Independence at 90 Days
Stratified by Functional Outcome in Patients With Primary Intracerebral

Hemorrhage Scorea
Functionally Independent at 90 Days, n/N (%)
Functional Outcome in Patients
With Primary Intracerebral
Hemorrhage (FUNC) Score
Development
Subset (n = 418)b
Validation Subset
(n = 211)b
0 0/1 (0) 0/0 (0)
1 0/12 (0) 0/2 (0)
2 0/15 (0) 0/8 (0)
3 0/37 (0) 0/17 (0)
4 0/28 (0) 0/13 (0)
5 2/48 (4) 2/19 (10)
6 4/36 (11) 0/16 (0)
7 14/77 (18) 10/46 (22)
8 20/51 (39) 14/30 (47)
9 60/87 (69) 24/40 (60)
10 9/12 (75) 6/12 (50)
11 12/14 (86) 6/8 (75)

n/N = proportion of subjects functionally independent at 90 days.
a Reprinted with permission from Rost NS, et al, Stroke. 17 © 2008 American Heart Association.
b The development subset represents the cohort of patients used to construct the logistic regression
analysis leading to the prognostication model. The validation subset represents the group of patients used
to test the prognostication model.
1608 DECEMBER 2018

normalized ratio (INR) rapidly and completely, although with a small

prothrombotic risk, but overall safety is superior to fresh frozen plasma (FFP).29,30
Direct oral anticoagulants, which include direct thrombin inhibitors and factor
Xa inhibitors, are used increasingly over warfarin because of more stable
pharmacokinetics. Currently, only dabigatran (direct thrombin inhibitor) has a
reversal agent (idarucizumab, a humanized monoclonal antibody fragment
against dabigatran). For the remaining agents in this group, current
anticoagulation reversal options include prothrombin complex concentrate,
antifibrinolytic agents, and prohemostatic therapies such as desmopressin;
dialysis is not useful because of low renal excretion of the factor Xa inhibitors.
Specific reversal agents such as andexanet alfa for factor Xa inhibitors and
aripazine (which also targets direct thrombin inhibitors, and unfractionated and
low-molecular-weight heparin) are expected to be available soon. Reversal of
factor Xa inhibitors is typically managed with prothrombin complex
concentrates at this time, although randomized prospective data in humans to
support this approach is lacking.31,32
In clinical practice, considerable controversy exists surrounding the best care
of patients on antiplatelet agents who develop ICH. In the recent past, several
reports described worse clinical outcomes and increased hematoma expansion in
this subset of patients with ICH.26,28 Recent studies show that rates of hematoma
expansion and clinical outcomes are independent of antiplatelet use.29,30 Despite
a number of small observational studies suggesting clinical benefit for platelet
FIGURE 2-2
Head CT of patient with left basal ganglia intracerebral hemorrhage. Images show initial
head CT (A) and follow-up head CT (B) 6 hours later after clinical deterioration, demonstrating
hematoma expansion with intraventricular hemorrhage.
transfusion after ICH, a single randomized phase 3 trial (PATCH [Platelet

Transfusion Versus Standard Care After Acute Stroke Due to Spontaneous
Cerebral Haemorrhage Associated With Antiplatelet Therapy]) did not confirm
clinical benefit and raised the possibility of additional harm from platelet
transfusion.33 This small trial enrolled 190 patients with ICH within 6 hours of
symptom onset who were on antiplatelet therapy; patients were randomly
assigned to platelet transfusion within 90 minutes of diagnostic imaging
compared to standard care. The primary end point, a shift in ordinal mRS scores
at 3 months, demonstrated worse outcomes in subjects who received platelet
transfusion compared to those who did not (odds ratio of 2.5; 95% confidence
interval, 1.18–3.56; P=.01). Median ICH growth at 24 hours was not different
between groups, and serious adverse events were more frequent in the
transfused versus standard care group (42% versus 29%, respectively). Platelet
transfusion is therefore not currently indicated in conservatively managed
patients with ICH but should be considered in patients who undergo
neurosurgical intervention.34,35
CEREBRAL EDEMA
Perihematomal edema evolves during the first 2 weeks after ICH and most
rapidly evolves over the first 48 to 72 hours.36 It is associated with activation of
inflammatory pathways by the toxic biochemical and metabolic effects of clot
products.37 Although the association between perihematomal edema and ICH
outcomes has conflicting results in the literature, perihematomal edema growth
appears to be a biomarker for secondary injury, and a number of clinical early
phase studies have evaluated pharmacologic agents targeting inflammatory
responses with edema reduction as a clinical end point. These agents include
fingolimod, which significantly reduced perihematomal edema volume in a small
proof-of-concept study in 23 patients with ICH treated within 72 hours of
symptom onset,38 and the iron chelator deferoxamine mesylate, studied in a
multicenter, randomized, placebo-controlled, phase 2 clinical trial to determine
whether deferoxamine reduces perihematomal edema and improves outcomes
when administered within 24 hours of ICH.39 There is currently no proven clinical
therapy that both reduces perihematomal edema and improves outcomes.
KEY POINTS
● Currently, no proven
benefit has been shown
from recombinant activated
factor VII in spontaneous or
anticoagulation-associated
intracerebral hemorrhage.
● In patients with
with disorders of primary or
secondary hemostasis, rapid
reversal of coagulopathy is
indicated in an attempt to
improve neurologic outcomes
and survival.
● In patients with
with a history of recent use
of antiplatelet agents,
routine use of platelet
transfusions is not indicated.
The only exception for this
recommendation is if
surgical interventions are
anticipated in the
emergency care of these
patients.
● Perihematomal edema,
which contributes to early
neurologic deterioration and
poor outcome, develops
rapidly following
intracerebral hemorrhage,
reaching maximal volume by
2 weeks. There is currently
no proven clinical therapy
that both reduces
perihematomal edema and
improves outcomes.
● The routine use of
antiepileptic drugs following
intracerebral hemorrhage is
currently not recommended.
There should be, however,
a high degree of suspicion of
electrographic seizures or
status epilepticus in patients
with intracerebral
hemorrhage with decreased
level of consciousness.
FIGURE 2-3
Spot sign demonstrating extravasation and hematoma expansion. A, Unenhanced CT
demonstrates left posterior putaminal and internal capsule hematoma with mild surrounding
edema. An old parietooccipital infarct is seen posterior to this. B, A small focus of
enhancement is seen peripherally on CT angiography, consistent with the spot sign (yellow
arrow). C, Postcontrast CT demonstrates enlargement of the spot sign, consistent with
extravasation (white arrow). D, Unenhanced CT 1 day after presentation reveals hematoma
enlargement and intraventricular hemorrhage.

Reprinted with permission from Wada R, et al, Stroke.20 © 2007 Wolters Kluwer.
1610 DECEMBER 2018

SEIZURES
During the first 7 days after the ICH, up to 16% of patients experience clinical
seizures and up to 31% develop electrographic seizures.40–42 Seizures are the
product of cortical irritation and are most likely to occur in patients with cortical
extension of the ICH.43,44 However, while a large single-center study has shown
that prophylaxis decreases seizure risk, prospective and population-based studies
have not shown an association between clinical seizures and mortality and
outcome. Seizure prophylaxis in ICH is therefore not recommended in current
guidelines. Moreover, antiepileptic agents such as phenytoin have been
associated with worse neurologic outcomes and increased mortality,45,46 while
levetiracetam, which is increasingly used for prophylaxis, has significantly
less data regarding impact on outcomes.47 This is a point well demonstrated
by CASE 2-1.
INTRAVENTRICULAR HEMORRHAGE
IVH complicates ICH in approximately 40% of cases and is a well-established
independent predictor of increased mortality, with estimates ranging from 50%
to 80%.34,35,49–51 The surgical management of IVH has also received considerable
attention over the past few years, although it is likely that external ventricular
drains (EVDs), for treatment of obstructive hydrocephalus and to reduce the
neurotoxic effects of intraventricular blood, remain underutilized, and the
clinical and radiographic threshold for EVD insertion after IVH varies
considerably.35,52–55 The American Heart Association guidelines currently state
A 61-year-old woman presented to the emergency department for CASE 2-1
evaluation of acute-onset right-sided weakness. She had a history of
hypertension. Head CT without contrast revealed a 32 cc left basal
ganglia hemorrhage.
The following day in the neurointensive care unit, the patient
developed speech difficulties and altered level of consciousness. A
repeat head CT was unchanged. An initial spot EEG did not reveal
significant abnormalities. The patient developed a short-lasting clinical
seizure that manifested as generalized tonic-clonic convulsions and loss
of consciousness, and she remained somnolent while on an antiepileptic
drug. Continuous EEG monitoring revealed electrographic status
epilepticus. The patient required dual antiepileptic drug therapy and
benzodiazepine IV infusion to control electrographic seizure activity.
As described by Vespa and colleagues,48 the occurrence of electrographic COMMENT
seizure activity can occur in up to 28% of patients with intracerebral
hemorrhage. Although prophylactic antiepileptic drug administration
following intracerebral hemorrhage is discouraged, demonstration of ictal
activity requires a high degree of suspicion and the use of continuous EEG
to best guide the medical therapy of status epilepticus after intracerebral
hemorrhage.
that an EVD is reasonable in the management of ICH and IVH, especially in

patients with decreased level of consciousness and obstructive hydrocephalus
(Class IIa/level of evidence B).10
The brief history of intraventricular thrombolysis originates from
experimental models (canine and porcine) demonstrating that thrombolysis of
blood injected into the ventricles accelerates the resolution of the intraventricular
clot, promotes rapid return of consciousness, and improves neurologic outcome,56,57
and as a result of clinical observations that EVD placement does not immediately
clear the ventricular clot and is often complicated by obstruction from blood
clots and debris, requiring replacement. Building on the underlying biological
premise that thrombolytic therapy can decrease white blood cell infiltrates, reduce
periventricular and generalized edema,45–47,58–60 and reverse or prevent ventricular
enlargement, herniation, and coma, a large number of small clinical trials and
retrospective studies have been reported, and several systematic reviews and
meta-analyses have been performed.61–65 These reports have consistently
demonstrated mortality reduction with intraventricular thrombolysis by nearly half
(compared to EVD alone), increased the odds of good functional outcome, and
decreased the rate of shunt dependence. Ventriculitis and rehemorrhage rates were
not increased with intraventricular thrombolysis.
The CLEAR IVH (Clot Lysis: Evaluating Accelerated Resolution of
Intraventricular Hemorrhage) trials represent a multiphase clinical trial program
that sought to establish the effectiveness of intraventricular alteplase for the
treatment of obstructive IVH.66,67 These trials targeted subjects with a
spontaneous ICH volume of <30 mL, obstruction of the third or fourth ventricles
with IVH, who presented within 24 hours of symptom onset, and who
demonstrated stability of ICH, IVH, and any EVD tract hemorrhage prior to
72 hours from diagnostic CT scan.59,63
The CLEAR III trial randomly assigned patients to receive up to 12 doses of
alteplase or 0.9% saline every 8 hours via a pragmatically placed EVD until the
third and fourth ventricles were radiographically open.66 The primary outcome,
defined by mRS at 6 months (dichotomized at scores of 0 to 3 versus scores of
4 to 6), showed no statistically significant difference in good functional status
between the groups treated with saline or alteplase (saline group at 45% versus
the alteplase group at 48%, a difference of 3.5% [P=.42] after adjustment for IVH
volume and thalamic ICH location). A significant decrease in mortality occurred
at 180 days for the experimental group (18% versus 29% in the saline group;
hazard ratio of 0.60 [95% confidence interval, 0.41–0.86], P=.006), which
appeared to come at the expense of a significantly greater proportion of patients
with an mRS score of 5 (indicating patients with severe disability who are
bedridden, incontinent, and require constant nursing care and attention)
compared to the saline group (17% versus 9%; P=.007). No difference was
observed, however, in the proportion of patients in a vegetative state as
measured by the extended Glasgow Outcome Scale (3% in both groups), nor any
difference in survival in a long-term facility (alteplase 14% versus saline 12%;
P=.48). Safety events, including symptomatic hemorrhage and 30-day mortality,
were not significantly different between treatment groups, and the rate of
bacterial ventriculitis was significantly lower compared to intraventricular saline.
A significant decrease in neurologic, respiratory, and sudden deaths in the
alteplase group suggested that intraventricular alteplase may correct lifethreatening
ventricular obstruction.
1612 DECEMBER 2018

In planned post hoc analyses, patients with initial IVH volumes of >20 mL and
those with >85% IVH removal during the active treatment phase demonstrated
statistically significant increases in good functional outcome (mRS scores of 0 to
3) at 180 days after adjustment for confounders. Because of a relatively small
proportion (33%) of the alteplase group reaching the treatment end point of 80%
IVH clot removal, a large number of subjects with small (<20 mL) IVH, and an
unexpectedly high proportion of patients treated with saline achieving good
outcomes (45%), the trial was inadequately powered to resolve narrow differences
between the group treated with alteplase and the group treated with saline.66
Further investigations are planned to evaluate a targeted approach to IVH clot
reduction with thrombolytic agents in both efficacy and effectiveness trials. Two
recent meta-analyses of thrombolytic therapy for IVH include the CLEAR III
data and largely reflect the results of the largest clinical trial. The first, with 17
studies, found a meaningful mortality benefit and possible functional outcome
benefits with different effect sizes depending on the functional outcome scale
used (mRS or Glasgow Outcome Scale).68 The second, with six studies, reported
that intraventricular thrombolysis reduced death from any cause by the end of
follow-up, but not the composite end point of death and poor functional
outcome, again suggesting an increased number of survivors with moderately
severe to severe disability.69
Intraventricular thrombolysis was deemed to be safe, neither increasing
ventriculitis nor rebleeding, but was not found to reduce the need for shunt
placement. The current status of intraventricular thrombolysis is unlikely to
significantly change the American Heart Association guidelines, which state
that intraventricular thrombolysis appears safe, while acknowledging that the
efficacy and safety of this treatment strategy remain uncertain (Class IIb/level
of evidence B).10
As with parenchymal hematoma reduction strategies, the next challenge will
be to test the hypothesis that greater ventricular clot reduction maximizes
functional outcomes consistent with reducing the biochemical effect of
ventricular blood on outcomes through reduction of hemoglobin toxicity and
inflammation, improving ventricular dilatation, and control of ICP.70,71 To this
end, newer minimally invasive approaches to IVH include endoscopic removal of
the ventricular clot and controlled lumbar drainage.72–75 The latter hypothesizes
that more rapid clearance of blood from the ventricles and removal of
inflammatory mediators using a lumbar drain may improve hydrocephalus and
CSF flow and absorption.
A randomized trial of combined intraventricular thrombolysis with lumbar
drainage versus intraventricular thrombolysis alone for prevention of permanent
shunt dependency after ICH with severe ventricular involvement was stopped
after treating 30 patients following interim analysis because of significant
efficacy of intraventricular thrombolysis plus lumbar drainage. Lumbar drainage
started after radiologic opening of the lower ventricular system was found to
be safe, avoided EVD exchange, and significantly reduced the need for
shunt surgery.74
Experience with minimally invasive endoscopic surgery for thalamic
hemorrhages with IVH and hydrocephalus in a small cohort (n = 48)
demonstrated shorter length of stay and reduced the need for shunt placement,
although without benefit in mortality or functional outcomes at 30 and 90 days.72
An earlier trial randomly assigned 42 patients with IVH to management with
KEY POINT
● Use of an external
ventricular drain is
recommended in cases of
with intraventricular
extension and obstructive
hydrocephalus. External
ventricular drains can
facilitate relief of
obstructive hydrocephalus
as well as reduce the
neurotoxic effects of
intraventricular blood.

EVD with intraventricular thrombolysis or to endoscopic evacuation. A
significant improvement in functional outcome was reported at 2 months in the
neuroendoscopy group.75
A meta-analysis comparing neuroendoscopic surgery combined with EVD for
IVH versus combination EVD plus intraventricular thrombolysis in 680 patients
observed significant benefits in mortality, good functional outcome, hematoma
evacuation rate, and reduced need for chronic ventriculoperitoneal CSF
diversion in favor of EVD plus intraventricular thrombolysis.73 This analysis
included small cohort studies, without protocolization of intraventricular
thrombolysis or safety event monitoring. These promising techniques will
require large-scale validation with evaluation of clot reduction, ICP control in the
acute phase, and prevention of chronic hydrocephalus.
SURGICAL MANAGEMENT
The allure of surgical reduction of hematoma volume is theoretically plausible
with advantages of correcting parenchymal displacement, decreasing ICP, and
potentially mitigating neurotoxic and inflammatory cascades.75 Although most
neurosurgeons operate on lobar or cerebellar hematomas larger than 3 cm in
patients who deteriorate clinically, as supported by current guidelines,76
uncertainty remains regarding deep hemorrhages where the parenchymal injury
required to access the hematoma appears to have been a limiting factor.54,77,78
The role of surgery for acute ICH is likely to increase significantly in the next
decade. Previously a relatively infrequent occurrence, with about one in
10 patients undergoing surgery for ICH in North America, new devices and a
focus on minimally invasive techniques are undergoing rigorous
investigation.3,54,79,80 These are intended to redefine surgical decision making
(patient selection, procedure selection, and timing) with evidence-based
models and will hopefully rescue these procedures from their most common
intended indication as a life-saving resort. Such thinking is largely influenced
and inspired by a small number of clinical trials that showed no overall benefit
for early craniotomy, ultra-early craniotomy, ultra-early treatment of bleeding,
or early neuroprotection.9 A description of the evolution of these surgical
studies follows.
In a Cochrane Review of traditional surgical evacuation utilizing standard
craniotomy compared to conservative treatment with medical care alone, 10
applicable randomized controlled trials, including 2059 participants, demonstrated
an odds ratio of 0.74 in favor of standard craniotomy for patients with ICH for
mortality and an odds ratio of 0.71 for odds of being dead or dependent at final
follow-up.81 This large meta-analysis was dominated by the STICH (Surgical Trial
in Intracerebral Haemorrhage) trial, making generalization difficult, but offered
some support for the use of craniotomy in the typical patient included in these
studies (ie, adults an average of 60 years of age with a GCS score between
5 and 15, with altered consciousness or severe neurologic deficit, and presenting
within 24 hours of onset). No evidence supports surgery after 72 hours, nor did
trials deal specifically with the deteriorating patient.54,78
In STICH I, which included 1033 patients (503 randomly assigned to surgery
and 530 randomly assigned to conservative medical therapy), it should be noted
that patients with spontaneous supratentorial ICH showed no overall benefit
from early surgery compared with initial conservative treatment.54 At 6 months,
26% of the patients who underwent surgery had a favorable outcome compared
1614 DECEMBER 2018

with 24% of those randomly assigned to conservative medical treatment (odds

ratio of 0.89 [95% confidence interval, 0.66–1.19], P=.41).
To further clarify potential subgroups that may benefit from open surgery, a
follow-up per patient, meta-analysis of eight prospective randomized controlled
trials of surgical treatment for spontaneous supratentorial ICH (2186 cases)
demonstrated improved outcomes with surgery for the following groups:
(1) patients who were randomly assigned within 8 hours of hemorrhage (actual
surgery times were unavailable), (2) patients with a hematoma volume between
20 mL and 50 mL, (3) patients with GCS scores of 9 to 12, and (4) patients
between the ages of 50 and 69 years.77 Including only patients with lobar
hematomas who did not have IVH demonstrated a nonsignificant trend toward
a benefit of surgery.
The apparent benefit of surgery for superficial (≤1 cm below the cortical
surface) lobar hematoma locations without IVH54,82 and with moderate a GCS
score8–14,16,17 was investigated in STICH II, which tested the hypothesis that
surgery within 12 hours in this select cohort of patients with ICH could produce
a 12% benefit of improved functional outcome.78 The concept that superficial
corticotomy would limit the damage to normal brain tissue while providing
the benefit of clot volume reduction was certainly plausible, but the results of
STICH II suggested otherwise. Early surgery in conscious patients with lobar
hemorrhage did not decrease the rate of death or disability at 6 months compared
with best medical treatment. Median hematoma volume was 36 mL (23.0 mL
to 55.5 mL), and at 6 months 59% of the surgery group (n = 307) had an
unfavorable outcome versus 62% in the initial conservative group (n = 294).
Again, a high crossover rate of 21% from initial conservative to surgical treatment
was reported. Although noninferiority of surgery may be one interpretation,
the approach of standard bulk resection using open craniotomy in a pragmatic
trial did not demonstrate the hypothesized clinical improvement.
A more recent meta-analysis of 15 trials of surgery for ICH including STICH I
and II with individual patient data reported an odds ratio for death or disability of
0.74 (95% confidence interval, 0.64–0.86; P<.0001), showing a significant
advantage for surgery, although the heterogeneity score was highly significant
owing to different types of patients and surgical procedures.78 Analysis of the
subgroup with lobar ICH and no IVH demonstrated no significant benefit from
surgery, whereas inspection of point estimates from the full cohort for only
minimally invasive surgery trials suggests that minimal access techniques might
be more beneficial, especially for deeper clots.
A further meta-analysis of randomized controlled trials comparing
stereotactic puncture or endoscopic drainage versus other treatments included
12 trials with 1855 patients and reported significant reduction in end points of
both death and dependence at the end of study follow-up in favor of minimally
invasive techniques.83 Although the meta-analysis may be critiqued for
including both conservative management and craniotomy in the “other treatment”
group, the literature on minimally invasive surgery is beginning to sway the
equipoise regarding volume-reduction therapy.47,52,57 This meta-analysis also
determined that patients with smaller hemorrhages (25 mL to 40 mL) and a good
presenting GCS score (>8) were most likely to benefit from minimally
invasive surgery.
Auer and colleagues84 performed an early randomized study of endoscopic
evacuation versus medical treatment in 100 patients with ICH within 48 hours
KEY POINTS
● Minimally invasive
endoscopic surgery for
intraventricular hemorrhage
volume reduction is
considered experimental at
this time and awaits
large-scale studies to
evaluate safety and
efficacy.
● After several randomized

clinical trials and
contemporary metaanalyses, no clear
recommendation for open
craniotomy and surgical
evacuation of supratentorial
hypertensive hematomas
can be made at this point.
and reported significant mortality benefit at 6 months although mostly in

patients who were noncomatose with subcortical (versus deep) ICH.
Independent but parallel work by investigators in North America and Asia has
refined a variety of procedures that now include image-guided cannulation of
the hematoma with or without use of thrombolytic drugs, mechanical clot
disruption, and endoscopic removal including with continuous focal ultrasound
delivered directly into the ICH.85–94
Data from Asia have been studied in a meta-analysis of four randomized
controlled trials including 2996 participants and compared stereotactic aspiration
to craniotomy.95 Both the odds of death or dependence at final follow-up (odds
ratio of 0.80; 95% confidence interval, 0.69–0.93; P=.004) and the risk of
intracerebral rebleeding (odds ratio of 0.44; 95% confidence interval, 0.26–0.74;
P=.002) were significantly lower in subjects treated with minimally invasive
techniques versus conventional craniotomy.
The MISTIE II (Minimally Invasive Surgery Plus Recombinant Tissue-Type
Plasminogen Activator for ICH Evacuation) study was a prospective randomized
phase 2 clinical trial designed to determine if minimally invasive surgery using
aspiration with an image-guided catheter followed by intrahematomal delivery
of alteplase over 3 days is safe and could reduce clot burden.96 At presentation,
96 subjects had a mean ICH clot size of 35 mL, the median GCS score was 11, and
the median National Institutes of Health Stroke Scale score was 24. In 54 surgical
subjects, ICH volume was significantly reduced at the end of treatment
compared with the medically treated group (average of 19.6 mL versus 40.7 mL,
P<.001) (FIGURE 2-4).97 The trial results also reported significantly decreased
cerebral edema and potential improvement in clinical outcomes in surgically
treated patients (10% improved function at the 0 to 3 mRS cut point compared to
the control arm). The finding of reduction in perihematomal edema volume in
FIGURE 2-4
Patient with right basal ganglia intracerebral hemorrhage (A) treated with minimally invasive
clot aspiration after the intraclot administration of recombinant tissue plasminogen
activator, showing near complete resolution of intracerebral hemorrhage 13 days later (B).
Reprinted with permission from Barrett RJ, et al, Neurocrit Care. 97 © 2005 Humana Press.
1616 DECEMBER 2018

the surgical arm (22 ± 35%) versus an increase in edema volume of 47 ± 46%
in the medical arm (P<.001)98 is consistent with the reduction of toxic metabolic
injury seen in animal models87,92 and inconsistent with a small number of prior
“convenience samples” and clinical reports demonstrating an increase in edema
after exposure to recombinant tissue plasminogen activator.99 No significant
differences were found between groups in primary safety outcomes including
mortality, symptomatic hemorrhage, and infection.
Parallel efforts to the MISTIE trials have included endoscopic evacuation
without thrombolysis and minimally invasive surgery with focused ultrasound.100
The phase 1 multisite surgical trial ICES (Intraoperative Stereotactic CT-guided
Endoscopic Surgery) demonstrated in 20 subjects that CT-guided endoscopic
evacuation without thrombolysis can achieve rapid removal of clot (71.2%
reduction in ICH volume) and similar safety results to the MISTIE phase 2 data.100
The SLEUTH (Minimally Invasive Evacuation of Spontaneous Intracerebral
Hemorrhage Using Sonothrombolysis) study combined mechanical and
thrombolytic approaches to ICH and IVH using a standard EVD catheter with a
small ultrasound-emitting probe inserted in the catheter tip fenestration.101 The
distal catheter tip emitted ultrasound (2 MHz and 0.45 W) for 24 hours in nine
subjects (six subjects with ICH and three subjects with EVD) and demonstrated
clot lysis rates of 54.1% per day in ICH, faster than was observed in the MISTIE and
CLEAR IVH studies. No rebleeding was reported.
These successes have initiated investigation and refinement of several
device-based approaches currently undergoing testing in clinical trials. The
ENRICH (Early MiNimally Invasive Removal of Intracerebral Hemorrhage) trial
is a phase 3 study investigating the procedure described as minimally invasive
subcortical parafascicular transsulcal access for clot evacuation (Mi SPACE) for
ICH.102 This approach involves a small craniotomy (2 cm to 3 cm in length)
overlying the sulcus of interest and introduction of an image-guided 13.5 mm
sheath followed by clot removal performed with standard microsurgical
techniques.103 A multicenter feasibility study including 39 subjects with an
average ICH volume of 36 mL demonstrated safety with a relatively high
rate of clot evacuation and functional independence.103 The ongoing clinical
trial has inclusion criteria similar to MISTIE III except for the exclusion of a
GCS score of <5, an upper limit of 80 mL for ICH size, and surgery within
24 hours of symptom onset. The primary end point is utility-weighted mRS at
180 days.
Another device, the Penumbra Apollo vibration/suction system (Almeda,
California), initially approved for endoscopic intraventricular neurosurgery (510[k]
device approval) utilizes a 2.6 mm aspiration wand containing a vibrational
wire, an irrigation system, and a vacuum pump used within an endoscope,
which is currently being investigated for evacuation of intracerebral hematomas.104
Use of a specific image guidance protocol is not described for the Penumbra
Apollo device and does not appear to be standardized. A retrospective review
of clinical cases (no set entry criteria or standardized technique) included
29 patients from four centers with an initial mean ICH volume of 45.4 mL.105 The
mean postoperative volume was 21.8 mL. The mortality rate was 13.8%. Further
studies of this device are ongoing. Ultimately, the goal of these and other
minimally invasive surgical approaches is to determine whether hematoma
evacuation removes the toxic effects of the blood clot and whether early and
sufficient removal translates into better clinical outcomes.
KEY POINT
● Several new devices
placed via stereotactic
imaging enable enhanced
drainage of parenchymal
clots and await
demonstration of whether
successful volumetric
clot reduction is matched
with improvement in
functional outcomes.
CONCLUSION
The management of ICH continues to evolve. Recent progress has been made in
the understanding of the best management practices of coagulopathy, blood
pressure control, cerebral edema, and outcome prognostication during the care
of patients with ICH. However, specific treatments for the underlying
pathophysiologic process(es) triggered by the exposure of viable brain
parenchyma to blood and its degradation products are lacking.
The surgical management of ICH is undergoing rapid evolution with the early
successes of minimally invasive surgical techniques. The path forward will
require phase 3 randomized controlled trials to determine individual device
efficacy, best approaches, and the populations of patients with ICH most likely
to benefit from surgery.
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Intracerebral Hemorrhage

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Intracerebral Hemorrhage

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Intracerebral

I ntracerebral hemorrhage (ICH) remains a cause of significant morbidity and

mortality and is associated with severe long-term disability. Furthermore, it comprises

CONTINUUM (MINNEAP MINN)

2018;24(6, NEUROCRITICAL CARE):

Dr J. Ricardo Carhuapoma, Johns

Hopkins Hospital, 1800 Orleans

St, Phipps 455, Baltimore, MD

Dr Ziai serves as an associate

editor for Neurocritical Care, on

an advisory board for C.R. Bard

Inc, and has received personal

for and research/grant support

from HeadSense Medical Ltd.

Dr Ziai has received grant

support from the Johns Hopkins

Anesthesiology and Critical Care

Medicine (ACCM) Stimulating

and Advancing ACCM Research

(StAAR) program and from the

National Institutes of Health

Drs Ziai and Carhuapoma discuss

use of alteplase for the

hemorrhage and discuss the use

of several devices, including

sonothrombolysis for minimally

access for clot evacuation

(MiSPACE), and the stereotactic

technique for minimally invasive

© 2018 American Academy

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

transformation of an ischemic stroke, cerebral venous thrombosis, vasculitis, and

pressure, and cerebral

● Although the majority

small penetrating vessel

imaging (CT angiography,

angiography) and MRI are

essential to rule out other

Hemorrhage Score and the

Patients With Primary

score allow rapid outcome

they should not be used

goals of care discussions of

patients with intracerebral

● A spot sign, defined by

the presence of contrast

within the hematoma

angiography or contrastenhanced CT, is associated

with a high risk of early

1604 DECEMBER 2018

Primary Intracerebral Hemorrhage (FUNC) score, which estimates the likelihood

Glasgow Coma Scale score

Infratentorial origin of intracerebral hemorrhage

Total intracerebral hemorrhage score 0–6

initial CT. The total score is used to stratify 30-day mortality.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Sign) trial, patients with the spot

spot sign negative (19.6%).22

that negatively modifies

mortality and functional

outcome after intracerebral

specific interventions aimed

at ameliorating its impact.