R e c e n t A d v a n c e s in t h e

Acute M anagement o f
I n tra c e rebr al Hemo r r h age
Joseph D. Burns, MDa,*, Jennifer L. Fisher, MSN, ANCP-BCa,
Anna M. Cervantes-Arslanian, MDb

KEYWORDS
 Intracerebral hemorrhage  Hypertension  Prothrombin complex concentrate
 Minimally invasive surgery

KEY POINTS
 Aggressive antihypertensive treatment in acute intracerebral hemorrhage (ICH) is not associated
with better outcomes than more moderate control and may be associated with increased rates
of acute renal dysfunction. Therefore, a reasonable systolic blood pressure goal may be 140 to
160 mm Hg.
 Prothrombin complex concentrate is recommended over fresh frozen plasma for reversal of vitamin
K antagonists in ICH.
 Platelet transfusion appears harmful in nonsurgical antiplatelet-associated ICH.
 Minimally invasive surgery has shown promising results in early-phase trials and multiple studies
are ongoing.

INTRODUCTION ANTIHYPERTENSIVE TREATMENT

Primary intracerebral hemorrhage (ICH) is a com-
mon, devastating disease that lacks an effective
specific treatment. Mortality is high, functional
outcomes are poor, and these have not substan-
tially changed for decades.1,2 There is, therefore,
considerable opportunity for advancement in the
management of ICH. A significant amount of
research has recently begun to address this
gap. This article is aimed at updating neurologists
on the most clinically relevant contemporary
research. Comprehensive reviews of and guide-
lines for the management of ICH are outside
the scope of this review and can be found
elsewhere.3
Acute hypertension is common after ICH4 and is
associated with larger hematoma volumes and
worse outcomes.5–7 Three recently published ran-
domized control trials (RCTs) investigated the
hypothesis that aggressive control of acute hyper-
tension, as compared with moderate control,
would lead to decreased hematoma expansion,
lower mortality, and improved functional out-
comes (Table 1).8–10 The phase 2 trial INTERACT
produced neutral, albeit somewhat equivocal,
results regarding the effect of aggressive hyper-
tension control on hematoma expansion.9 The re-
sults of the phase 3 INTERACT2 on clinical
outcomes were similarly equivocal. Although there
neurosurgery.theclinics.com

This article originally appeared in Neurologic Clinics, Volume 35, Issue 4, November 2017.
Disclosure Statement: The authors have nothing to disclose.
a
Neurocritical Care, Department of Neurology, Lahey Hospital and Medical Center, 41 Mall Road, Burlington,
MA 01805, USA; b Neurocritical Care, Department of Neurology, Boston Medical Center, Boston University
School of Medicine, Collamore Building, C-3, 72 East Concord Street, Boston, MA 02118, USA
* Corresponding author.
E-mail address: joseph.d.burns@lahey.org

Neurosurg Clin N Am 29 (2018) 263–272

https://doi.org/10.1016/j.nec.2017.11.005
1042-3680/18/Ó 2017 Elsevier Inc. All rights reserved.
264 Burns et al

Table 1
Comparison of key elements of clinical trials of antihypertensive treatment in intracerebral
hemorrhage

Variable INTERACT9 INTERACT 28 ATACH210

Number of subjects 404 2839 1000a
Selected inclusion criteria
Time from symptom 6 6 4.5b
onset to
randomization, h
SBP, mm Hg 150–220 150–220 180–240
SBP treatment goals
Intensive, mm Hg <140 <140 120–139
Guideline/Standard, mm <180 <180 140–179
Hg
Medication regimen Protocol based on Protocol based on local Nicardipine
local availability availability (urapidil
(urapidil most most common)
common)
Blood pressure separation 146 vs 157, mean 150 vs 164, 1st hour; 139 vs 129 vs 141, mean
(intensive vs guideline, of hours 1–24 153, 6th hour minimum for
time frame) first 2 h
Primary outcome (results, Proportional Proportion of subjects Proportion of subjects
guideline/standard vs hematoma with 90-d mRS 3–6 (55.6 with 90-d mRS 4–6
intensive) growth over vs 52%, P 5 .06, (37.7% standard vs
1st 24 h (16.2 vs adjusted P 5 .12) 38.7% intensive,
6.2%, P 5 .06) P 5 .72)
Adverse event rates No difference No difference Adverse renal events
higher in intensive
group (9% vs 4%,
P 5 .002)

Abbreviations: ATACH, Antihypertensive Treatment of Acute Cerebral Hemorrhage; INTERACT, Intensive Blood Pressure
Reduction in Acute Cerebral Haemorrhage trial; mRS, modified Rankin scale; SBP, systolic blood pressure.
a
Planned sample size n 5 1280, but trial stopped for futility at n 5 1000 after second preplanned interim analysis.
b
Originally 3.0 h, extended to 4.5 h midtrial.

was no difference in the dichotomized modified
Rankin score (mRS) primary outcome, a second-
ary ordinal analysis demonstrated a possible shift
in favor of the intensive group (odds ratio 0.87 for
shift to higher mRS, 95% confidence interval
0.77–1.00, P 5 .04, adjusted P 5 .10). In the
one-third of patients who had sufficient radio-
graphic data, there was no difference between
groups in relative or absolute hematoma growth.
ATACH 2 was more definitively negative, showing
no beneficial effect of intensive antihypertensive
treatment in any clinical or radiographic outcomes
reported. Additionally, a higher rate of renal
adverse events within 7 days of randomization in
the intensive group was detected in post hoc
analysis.
The main caveat in applying results of these
trials at the bedside is the unexpectedly small sys-
tolic blood pressure (SBP) difference between
treatment groups, driven by SBP control to the
low end of the specified rage in the standard treat-
ment groups acting as controls. Considered
together, then, these trials indicate that SBP con-
trol to 120 to 140 mm Hg does not lead to
improved outcomes compared with 140 to
160 mm Hg, and may be associated with an
increased risk of acute renal dysfunction, support-
ing an SBP goal of 140 to 160 mm Hg in acute ICH.
COAGULOPATHY CORRECTION
Vitamin K Antagonists
Vitamin K antagonists (VKAs) considerably in-
crease the frequency and severity of ICH,11–14
making rapid reversal of VKA coagulopathy in pa-
tients with ICH crucial (Box 1). In a recent large,
multicenter, retrospective cohort study, patients
who had the international normalized ratio (INR)
corrected to less than 1.3 within 4 hours of admis-
sion had lower rates of significant hematoma
 Acute Management of Intracerebral Hemorrhage
Box 1
Summary of Neurocritical Care Society
guidelines for reversal of select
antithrombotics in intracranial hemorrhage
 Vitamin K antagonists (international normal-
ized ratio [INR] 1.4)
 Vitamin K 10 mg intravenous (IV) AND
 Prothrombin complex concentrates (PCC)
(dose based on type, weight, and INR) or
 If PCC not available or contraindicated:
fresh frozen plasma 10 to 15 mL/kg
 Dabigatran
 Activated charcoal (50 g) within 2 hours of
ingestion AND
 Idarucizumab 5 g IV (given as 2 doses of
2.5 g/50 mL)
 Consider hemodialysis or idarucizumab re-
dosing for recurrent/refractory bleeding
 Direct FXa inhibitors
 Activated charcoal (50 g) within 2 hours of
ingestion AND
 Activated PCC (factor 8 inhibitor bypassing
activity) 50 units/kg IV or 4-factor PCC
50 units/kg IV
 Antiplatelet agents
 Desmopressin 0.4 mg/kg IV  1
 If surgery planned: transfuse platelets
(1 apheresis unit)
Data from Frontera JA, Lewin JJ 3rd, Rabinstein AA,
et al. Guideline for reversal of antithrombotics in
intracranial hemorrhage: a statement for healthcare
professionals from the Neurocritical Care Society and
Society of Critical Care Medicine. Neurocrit Care
2016;24(1):6–46.
expansion than the rest of the cohort.13 Fresh
frozen plasma (FFP) is suboptimal for VKA reversal
because of prolonged times to INR correction, the
risk of volume overload, and transfusion reac-
tions.15,16 These shortcomings are overcome by
the use of prothrombin complex concentrates
(PCCs) without evidence of increased thromboem-
bolic events (TEs).15,17,18 The prospective, ran-
domized INCH trial compared PCC and FFP in
50 patients with VKA-associated intracranial hem-
orrhage.19 Median time to INR correction was
much faster with PCC (40 vs 1482 minutes,
P 5 .05), significant hematoma expansion or death
at 24 hours was twice as common in the FFP
group, and there was no significant difference in
TE rates. Because PCCs have not been well-
studied in patients with TEs within the preceding
265
30 days,17,19,20 they should be used with caution
in such patients.
Novel Oral Anticoagulants
Although ICH occurs approximately half as
frequently in patients taking novel oral anticoagu-
lants (NOACs) compared with patients taking
warfarin,21 the prevalence of NOAC use is
increasing.22,23 Additionally, NOAC-associated
ICH is as severe as warfarin-associated ICH.24–27
Safe and effective methods for rapid reversal of
NOAC coagulopathy are therefore essential.
Idarucizumab is a monoclonal antibody frag-
ment that neutralizes dabigatran.28 In a recent
interim analysis of a phase 3 prospective cohort
study, it rapidly and effectively corrected anticoa-
gulation induced by dabigatran among patients
with life-threatening bleeding or need for urgent
invasive procedure. Its administration was safe,
without excessive TEs. There was evidence of
rebound coagulopathy beginning 12 hours after
idarucizumab administration. The final results of
the study have not yet been published.29
No specific reversal agent for FXa inhibitors is
currently available, but some investigational drugs
are in late stages of development. Andexanet alfa
is an investigational recombinant version of FXa
modified to bind and inhibit direct and indirect
FXa inhibitors without causing direct effects on
coagulation.30 In healthy volunteers taking apixa-
ban or rivaroxaban, andexanet nearly completely
reversed FXa inhibition and restored thrombin
generation to normal in more than 95% of
subjects.31 Rebound coagulopathy was evident
2 hours after administration. There were no signif-
icant adverse events. Ciraparantag is an investiga-
tional synthetic molecule that binds to and inhibits
direct and indirect FXa inhibitors, unfractionated
heparin, and dabigatran.32 It completely reversed
edoxaban and enoxaparin coagulopathy in healthy
volunteers without serious adverse events.33–35
Antiplatelet Agents
Approximately 25% of patients with ICH are on an-
tiplatelet therapy (APT),36 which might increase the
risk of hematoma expansion, poor functional
outcome,37 and mortality,38 although contradic-
tory data exist.39,40 The utility of treatments to
counteract platelet inhibition is unclear. In the
phase 3 PATCH trial, 190 patients on APT with pri-
mary supratentorial ICH were randomized to
platelet transfusion versus standard care within
6 hours of symptom onset.41 Patients with planned
surgery within 24 hours of admission, including
external ventricular drain placement, were
excluded. Approximately 80% of subjects were
266 Burns et al
on aspirin monotherapy. Platelet transfusion was
harmful, associated with a shift toward higher
mRS scores, higher odds of severe disability or
death, no benefit in terms of hematoma expansion,
and a numerically higher rate of ICH-related
serious adverse events, such as cerebral edema.
Accordingly, there is presently no indication for
platelet transfusion in APT-associated ICH when
surgery is not planned. Although PATCH data are
not directly applicable to patients on APT other
than aspirin, unless contradictory results are found
in future trials, the harm associated with platelet
transfusion argues against its routine clinical use
in all nonsurgical patients with APT-associated
ICH.15
Platelet transfusion in 366 aspirin-taking pa-
tients undergoing emergency craniotomy for basal
ganglia ICH was investigated in a prospective, ran-
domized trial at a single Chinese academic hospi-
tal.42 Postoperative hemorrhage recurrence rates
and volumes, mortality, and functional outcome
were all better in aspirin responders (determined
by preoperative platelet function testing) who
received platelets than in aspirin responders who
were not transfused.
In 2 small prospective pilot studies of patients
with ICH, intravenous desmopressin led to
improved platelet function, lasting for approximately
3 hours, without significant adverse effects.43,44
Desmopressin has not been meaningfully evaluated
for effects on clinical outcomes.
NEUROPROTECTION
Elucidation of secondary injury mechanisms in ICH
has provided numerous targets for neuroprotec-
tion, although none has yet proven effective.45
This actively expanding line of research has been
reviewed in detail elsewhere.45,46 What follows is
an update on the most clinically relevant recent
research.
Statins
Effects of statins on ICH are complex and incom-
pletely understood. Multiple recent studies
suggest they are beneficial in acute ICH. Two
retrospective cohort studies and a meta-analysis
showed that in patients with ICH, short-term out-
comes were better in (1) statin users whose statin
was continued in the acute period compared with
nonusers, and (2) statin nonusers compared with
pre-ICH statin users whose statin was discontin-
ued in the acute period.47–49 Nonetheless, there
are no high-quality data to support de novo statin
introduction in acute ICH. Additionally, how to
reconcile the possible acute benefit with the
possible increased risk of recurrent hemorrhage
in the long-term50–52 when making decisions
about statin continuation after the acute post-
ICH period is not clear.3
Deferoxamine
Deferoxamine is an iron chelator that decreases
the ability of free iron in brain tissue to cause
oxidative injury, an important secondary injury
mechanism.53 A phase I study of deferoxamine
mesylate (DFO) in patients with ICH demonstrated
tolerability of doses up to 62 mg/kg per day to a
maximum of 6000 mg/d for 5 days without major
safety concerns.54 In a similar pilot trial of DFO at
the same dosage for 3 days, perihematomal
edema (PHE) growth was lower in DFO-treated
patients compared with controls.55 However,
recruitment for a phase 2 trial of DFO at this
dose was stopped due to increased occurrence
of acute respiratory distress syndrome.56 Recruit-
ment is ongoing in the lower-dose phase 2 iDEF
trial.57
Targeted Temperature Management
Although targeted temperature management
(TTM) is well-studied in other forms of brain injury
and fever is common and deleterious in ICH, clin-
ical data on TTM in ICH are sparse.45,58–61
Compared with historical controls, consecutive
patients with ICH (n 5 25) treated with therapeutic
hypothermia (TH) to 35 C for 8 to 10 days had
less PHE growth, lower mortality, and possibly
improved functional outcomes in one study.62
However, acute complications, including shiv-
ering, neuromuscular blockade, pneumonia,
sepsis, TEs, and thrombocytopenia, were all
more frequent in the TH group. Interestingly, TH
had a temporally limited effect, substantially atten-
uating PHE in the first 3 days but having effect
thereafter.63 A retrospective study of 40 patients
treated to maintain normothermia (goal 37 C) for
persistent fever using a surface TTM device (Arctic
Sun; CR Bard, Inc, Covington, GA) found no differ-
ence in functional outcome or mortality compared
with historical controls despite significant reduc-
tion in fever burden. Maintenance of strict normo-
thermia was also associated with more days of
sedation, mechanical ventilation, longer intensive
care unit (ICU) length of stay, and a higher rate of
tracheostomy.64 Therefore, whether TTM with
physical cooling in ICH provides net benefit,
harm, or neither remains unanswered. Results
from 2 ongoing phase 2 trials of TH in
ICH, CINCH65 and TTM-ICH,66 and a recently
completed pilot trial67 targeting normothermia
will hopefully provide more guidance.
 Acute Management of Intracerebral Hemorrhage
SURGERY
The role of surgery for supratentorial ICH remains
disputed despite the theoretic benefits of
decreasing mass effect and limiting damage
caused by secondary injury pathways driven by
the extravasated blood.68 Interest in minimally
invasive surgery (MIS) is increasing, as large trials
of medical and traditional surgical treatments have
failed to show benefit,8–10,69–71 whereas meta-
analyses of MIS studies have shown it to be asso-
ciated with improved outcomes compared with
medical therapy and traditional surgery.72,73
Traditional Surgery
The large, prospective, multicenter STICH trials
dominate our knowledge about standard crani-
otomy and corticotomy for ICH evacuation. In
STICH I, early surgery and initial medical therapy
produced equivalent rates of good neurologic out-
comes (26% vs 24%, P 5 .141).70 Subgroup anal-
ysis suggested that patients with superficial
hematomas 1 cm from the cortical surface might
benefit from surgery. Hence, in STICH II, such pa-
tients were randomized to early surgery or initial
medical management.71 The rate of favorable out-
comes at 6 months was again equivalent (41% vs
38%, P 5 .367). Importantly, 26% of patients
assigned to initial medical management in STICH
I and 21% in STICH II ultimately underwent surgery
for delayed neurologic deterioration (DND).70,71 A
strategy of never operating was not tested.
Accordingly, a reasonable interpretation of these
trials is that a uniform policy of early surgery pro-
duces equivalent outcomes to a strategy of initial
medical management in which surgery is reserved
for significant DND due to mass effect.
The role of decompressive craniectomy (DC)
in ICH is unclear. It might improve decompression
compared with hematoma evacuation alone when
used adjunctively74–78 and allow for decompres-
sion without violation of eloquent brain when
used alone.79,80 Data from several small, non-
randomized, retrospective, single-center studies
suggest the possibility of improved survival
without beneficial effect on function in high-grade
patients.74–76,79,80 Two RCTs (SWITCH and CAR-
ICH) are ongoing.81,82
Minimally Invasive Surgery
In MIS, imaging guidance is used to in-
troduce catheters or other suction-irrigation
conduits  endoscopes into the hematoma for
evacuation, sometimes also using intrahemato-
mal thrombolytics. The rationale is to gain the
potential benefit of hematoma evacuation while
267
minimizing injury to adjacent brain.68,83 Two
meta-analyses, each including thousands of
patients, found MIS was associated with
a decreased risk of death or dependence
compared with conventional surgery or medical
management.72,73 Building on these earlier trials,
several early-phase studies of MIS have recently
been published.
MISTIE II investigated computed tomography–
guided catheter-based hematoma aspiration com-
bined with local recombinant tissue plasminogen
activator (tPA) to facilitate the aspiration84
Ninety-six adults with supratentorial ICH were ran-
domized to MIS 1 tPA or standard medical care.
There were no significant differences in the
primary outcomes of mortality, symptomatic
bleeding, or brain infections. Asymptomatic hem-
orrhages were more common in the treatment
group (22% vs 7%, P 5 .051). Hematoma volume
reduction was substantially improved with
MIS 1 tPA compared with medical therapy (57%
vs 5%) and this was associated with improved
functional outcomes. MISTIE-III, a phase 3 trial
testing the same treatment protocol but using
functional outcome as the primary endpoint, is
ongoing.85
Several other MIS techniques are being investi-
gated that, compared with the MISTIE technique,
might allow for more rapid clot evacuation and
better ability to control surgical bleeding. In the
phase 1 MISTIE-ICES, hematoma evacuation
using MISTIE’s navigation approach combined
with endoscopic aspiration and irrigation was
compared with standard medical care.86 The pro-
cedure was safe and effective at reducing hema-
toma volume and showed a trend toward
increased likelihood of good functional outcome.
A multicenter retrospective case series of hema-
toma evacuation using the Penumbra Apollo
aspiration-irrigation system (Penumbra, Inc,
Alameda, CA) with neuronavigation  endoscopy
also showed efficacy in clot volume reduction.87
A phase 2 randomized trial (INVEST) is planned.88
Results of minimally invasive subcortical parafas-
cicular access for clot evacuation (MISPACE)
were reported in a retrospective case series.89
MISPACE uses an atraumatic transsulcal cannula-
tion system (NICO device; NICO Corp, Indianapo-
lis, IN) to access the hematoma via trajectories
planned to minimize injury to eloquent white mat-
ter tracts, guided by dynamic neuronavigation.
The hematoma is evacuated through the cannula
under direct visualization via an extracorporeal
telescope. Clot evacuation results were again
promising without major safety concerns. The
MiSPACE registry90 and the ENRICH RCT,91 are
ongoing.
268 Burns et al
MIS thus has been shown to safely and effectively
evacuate hematomas, and has potential to improve
functional outcomes. Yet many questions remain
about timing, technique, patient selection, and,
crucially, efficacy in terms of functional outcomes.
Nevertheless, the results of MISTIE II and other
MIS trials provide reason for cautious optimism.
SYSTEMS OF CARE
Management of patients with ICH within systems
of organized neurocritical care has a beneficial ef-
fect on outcomes. Adjusted hospital mortality was
threefold higher in 772 patients with ICH from 40
non-neurologic ICUs compared with 266 patients
from 2 neurologic ICUs.92 A more recent study of
more than 10,000 patients with ICH showed the
odds of in-hospital mortality were 20% to 40%
higher for those admitted to general ICUs
compared with neurologic ICUs.93 This mortality
benefit does not appear to come at the expense
of worse functional outcomes in survivors, and,
in fact, the contrary may be true.94,95 Mechanisms
by which these benefits are achieved are not
known. Possibilities include more effective man-
agement of disease-specific problems and risks,
improved adherence to established clinical guide-
lines, more careful monitoring, more aggressive
intervention95–97 and, as implied by the consis-
tently longer ICU length of stay for patients with
ICH cared for in neuroscience ICUs,92,93 less early
withdrawal of life support.
SUMMARY
Despite its substantial burden on worldwide public
health,1,2 a specific treatment for ICH that leads to
improved functional outcomes remains elusive. A
considerable amount of research is addressing
this problem, providing reason for hope. Recently
published research indicates that the optimal
goal SBP is probably 140 to 160 mm Hg in the first
few hours after ICH, PCC is superior to FFP for
correction of coagulopathy in VKA-associated
ICH, idarucizumab is the preferred agent for
reversal of dabigatran, platelet transfusions for
APT-associated ICH appear harmful in nonsur-
gical patients and might be helpful in surgical pa-
tients, and patients with ICH benefit from
organized neurocritical care. Ongoing work in
NOAC antidote development, neuroprotection,
and particularly MIS provide reason for cautious
optimism about the future.
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