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com
JNNP Online First, published on November 16, 2016 as 10.1136/jnnp-2016-314386
1
Department of Neurology,
Donders Institute for Brain,
Cognition and Behaviour,
Radboud University Medical
Centre, Nijmegen,
The Netherlands
2
Department of
Cerebrovascular Medicine,
National Cerebral and
Cardiovascular Center, Osaka,
Japan
3
Neurological and Mental
Health Division, The George
Institute for Global Health
Australia, Sydney, New South
Wales, Australia
4
Department of Neurology and
Neurosurgery, Brain Center
Rudolf Magnus, University
Medical Center, Utrecht,
The Netherlands
5
The George Institute for
Global Health China, Peking
University Health Science
Center, Beijing, China
6
Central Clinical School,
University of Sydney, Sydney,
Australia
7
Neurology Department, Royal
Prince Alfred Hospital, Sydney,
New South Wales, Australia
Correspondence to
Professor Craig Anderson,
The George Institute for Global
Health, Peking University
Health Science Center,
Beijing, 100088, PR China;
canderson@georgeinstitute.
org.cn
Received 21 August 2016
Revised 14 October 2016
Accepted 25 October 2016
To cite: Schreuder FHBM,
Sato S, Klijn CJM, et al. J
Neurol Neurosurg Psychiatry
Published Online First:
[please include Day Month
Year] doi:10.1136/jnnp-
2016-314386
Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd under licence.
Cerebrovascular disease
REVIEW
Medical management of intracerebral haemorrhage
Floris H B M Schreuder,1 Shoichiro Sato,2,3 Catharina J M Klijn,1,4
Craig S Anderson3,5,6,7
ABSTRACT
The global burden of intracerebral haemorrhage (ICH) is
enormous. Developing evidence-based management
strategies for ICH has been hampered by its diverse
aetiology, high case fatality and variable cooperative
organisation of medical and surgical care. Progress is
being made through the conduct of collaborative
multicentre studies with the large sample sizes necessary
to evaluate therapies with realistically modest treatment
effects. This narrative review describes the major
consequences of ICH and provides evidence-based
recommendations to support decision-making in medical
management.
INTRODUCTION
Acute non-traumatic intracerebral haemorrhage
(ICH) is not only complex and aetiologically
diverse, but also the most serious, least treatable
and more variable in incidence and management
compared to other stroke subtypes.1 2 Although
accounting for about one-fifth of the 16.8 million
new strokes that occur in the world each year,2 it is
more common in developing countries, particularly
in Asia,1 3 where populations have high prevalence
of elevated blood pressure (BP) and less-well-
defined predisposing genetic and environmental
(eg, high-salt diet) risk factors.4 5 Most importantly,
its consequence in terms of ‘loss-of-productive-life-
years’ is disproportionately greater on a global scale
than acute ischaemic stroke, because ICH is serious
and tends to affect people at earlier (working)
ages.2
Despite improved management of hypertension,
there has been no apparent decline in the incidence
of ICH, possibly because adherence to antihyper-
tensive therapy remains poor, continued population
ageing and increasing use of antithrombotic drugs
for various cardiovascular conditions. ICH has a
1 month case death rate of around 40%, and half
of the deaths occur in the first few days after onset;
an outlook that has similarly remained unchanged
in recent decades.1
These gloomy statistics continue to create clinical
nihilism in the management of patients with ICH.
However, new evidence has emerged supporting
the benefits of an active care approach and specific
therapies with potential to improve the outcome.
The role of decompressive surgery varies around
the world depending the availability and organisa-
tion of services, and acceptance of the evidence,
which has not clearly defined patients with
characteristics who have the most to gain from
such intervention. The medical management of
ICH is, therefore, primarily supportive, directed at
Schreuder FHBM, et al. J Neurol Neurosurg Psychiatry 2016;0:1–9. doi:10.1136/jnnp-2016-314386
providing a systematic clinical assessment that
includes ensuring there is no underlying treatable
structural lesion; good control of BP and other
physiological parameters; management of compli-
cations; early rehabilitation to promote recovery;
and effective secondary prevention. This narrative
review describes the major consequences of ICH
and provides expert recommendations that are
based on the available evidence to support
decision-making in medical management (table 1).
ORGANISATION OF CARE
As for acute ischaemic stroke, ICH is a medical
emergency that requires rapid assessment after con-
firmation of the diagnosis on brain imaging, as
patients are often unstable and can rapidly deterior-
ate. Loss of consciousness is a prominent feature of
ICH, which complicates the use of scales that assess
neurological impairment, such as the National
Institutes of Health Stroke Scale. The use of the
Glasgow Coma Scale, together with key imaging
prognostic features (the site, volume and presence
of intraventricular haemorrhage (IVH) extension)
of the haematoma in relation to time of presenta-
tion,6 is useful in triaging patients. Numerous
scales exist for grading the severity of ICH, the
ICH Score7 being the most widely known and vali-
dated; they all have comparable ‘fair to good’ pre-
dictive ability and clinical utility.8
As it is often difficult to reliably predict the
outcome of patients at the time they present with
ICH, and evidence indicates that the premature use
of ‘do-not-resuscitate’ or ‘withdrawal of care’ orders
independently predicts mortality,9 10 initiation of an
active management plan is recommended unless
there are particular clinical (eg, massive ICH with
deep coma), comorbid (eg, advanced dementia or
malignancy) or social (eg, advanced directives) cir-
cumstances. This also allows time for a patient’s
condition to stabilise, potential complicating factors
(eg, seizures and dehydration) to resolve and for
counselling family members in the context of their
cultural, religious and personal beliefs. Active care
includes monitoring and timely intervention for
neurological deterioration and adverse events, and
this is ideally organised in an intensive care or high
dependency unit, which provide high nurse:patient
ratio of care and expertise. Well organised acute
stroke unit care benefits ICH patients (number
needed to treat (NNT) 18)11 by directing effective
management according to the type and severity of
neurological impairment.
Non-contrast brain CT is the most appropriate
initial investigation to confirm the presence of
ICH, but it is less useful in establishing any
1
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Cerebrovascular disease
Table 1 Key recommendations for ICH management
Quality of
Recommendation evidence*
Admit to a designated stroke unit for initial High
active management
Use cerebrovascular imaging to exclude a Moderate‡
vascular anomaly
Intensively control BP (systolic target Moderate
<140 mm Hg within 1 hour of presentation)
as it is safe and improves functional
recovery
Provide feeding (enteral if necessary) within Low
48 hours of onset
Control elevated glucose Low
Rapidly treatment fever Low
Control seizures with an antiepileptic drug Moderate
Avoid prophylactic use of antiepileptic drugs Low
In immobile patients, avoid graduated High
compression stockings and use intermittent
pneumatic compression to reduce DVT risk
If there is elevated ICP, use simple measures Low
(eg, head elevation, analgesia, antiemetics)
and assisted ventilation when severe
Avoid activated recombinant factor VII Moderate
Avoid platelet transfusion in antithrombotic Moderate
related ICH
Rapidly reverse anticoagulation with Moderate
intravenous vitamin K and PCC in vitamin
K-associated ICH
Rapidly reverse anticoagulation with PCC Low
and/or selective antidotes in
DOAC-associated ICH
Reduce risk of recurrent ICH and other Moderate
serious vascular events through strict
long-term control of BP (systolic target
<140 mm Hg)
Resume antithrombotic drugs after ICH Low
*Grading of evidence:93 high—consistent data from multiple randomised controlled
trials; moderate—insufficient data from single large or multiple small randomised
trials; weak—data derived mainly observational studies.
†Grading of recommendation:93 strong—there are clear benefits; moderate—there
are probable benefits that out way potential harms; weak—there is uncertainty over
the balance of benefits and harms.
‡Based on data from good-quality observational studies.
BP, blood pressure; DOAC, direct oral anticoagulant; DVT, deep venous thrombosis;
ICH, intracerebral haemorrhage; ICP, intracranial pressure; iv, intravenous; PCC,
prothrombin concentrate complex.
underlying structural cause. A secondary cause of an ICH
should be suspected if it has an atypical deep or lobar location
with a disproportionate amount of subarachnoid haemorrhage
or perihaematomal oedema, and in younger patients without a
history of hypertension or illicit drug use as predisposing
factors. Recent attention has focused on particular features of
morphology of the haematoma (eg, swirl, irregularity and fluid
level) and the ‘spot-sign’ (ie, extravasation of contrast on CT
producing a spot or blush within or at the edge of the haema-
toma) that signify ongoing bleeding, greater haematoma growth
and poor outcome.12 While the former features are simple to
apply in routine practice, the utility of the spot-sign appears
limited outside of well-resourced specialist centres.
CT or MRI angiography is the next step towards a diagnosis
of any underlying vascular anomaly,13 such as intracranial aneur-
ysm, arteriovenous malformation (AVM), dural arteriovenous
fistula, cavernoma and cerebral venous sinus thrombosis. This
can be organised at the time of presentation or in the early
follow-up period, depending of clinical features, available
2 Schreuder FHBM, et al. J Neurol Neurosurg Psychiatry 2016;0:1–9. doi:10.1136/jnnp-2016-314386
resources and organisation of services. However, a small vascu-
lar anomaly may be missed in patients with large haematomas
Strength of (figure 1).
recommendation† A previously well, 48-year-old woman presented with sudden
Strong
left hemiparesis during fitness exercise. CT showed right frontal
lobar haemorrhage, volume 12 mL (image A). Early CT angiog-
Strong raphy and MRI with venous contrast excluded any vascular
anomalies and cortical vein or cerebral venous sinus thrombosis.
Moderate Digital subtraction angiography 1 month later showed a small
AVM in the right precentral gyrus, with an identified small
irregular vessel fed by a distal branch of the right middle cere-
bral artery (arrow, image B) without a clear nidus. During the
Weak
capillary phase, premature venous drainage to the superior sagit-
Weak tal sinus and Sylvian vein (arrowheads, image C) was observed.
Weak Subsequent surgical resection of the AVM was undertaken.
Moderate Thus, where there is a high suspicion of an underlying vascular
Weak anomaly with negative imaging findings in the acute phase,
Strong patients should be re-examined 1–3 months after ICH, when the
haematoma has been resorbed. The relevance of cerebral micro-
bleeds detected on MRI in guiding treatment options is currently
Weak unknown. Conventional cerebral angiography is usually required
in cases where there is a high likelihood of a vascular anomaly
and interventional treatment is being considered.13
Strong
Although early mobilisation is likely beneficial for patients,
Moderate
care should be taken in the early mobilisation of patients where
Moderate
potential resultant adverse impact on BP variability and ortho-
static hypotension may have harmful effects.14
Recommendations: After confirmation of ICH by a non-
Weak contrast brain CT, patients should be admitted to a designated
stroke unit with an active treatment plan. Diagnosis of ICH
should trigger additional cerebrovascular imaging to exclude
Strong
underlying vascular anomalies.
CONTROL OF BP AND OTHER PHYSIOLOGICAL VARIABLES
Weak Hypertension
Elevated BP or hypertension, defined by systolic BP
≥140 mm Hg, is very common after ICH and independently
predicts haematoma growth, perihaematomal oedema and sub-
sequent neurological worsening and poor outcome, including
death and disability.15 The association between elevated BP at
ICH presentation and haematoma expansion is strongest for sys-
tolic BP >175 mm Hg.16 There has been long-standing concern
that early lowering of BP after ICH can cause cerebral ischaemia
by reducing cerebral perfusion pressure, particularly if there is
altered cerebral autoregulation from long-standing hypertension
or from brain injury. However, advanced imaging has not been
able to show any significant relationship between BP lowering
and perihaematomal cerebral blood flow in patients with acute
ICH.17 The main phase, Intensive Blood Pressure Reduction in
Acute Cerebral Haemorrhage Trial (INTERACT2)18 evaluated
the effect of target-driven, early intensive BP lowering treatment
(systolic BP <140 mm Hg within 1 hour and continued for
7 days) compared to contemporaneous standard management
(systolic BP of <180 mm Hg) in 2839 ICH patients who pre-
sented within 6 hours of onset with elevated systolic BP (150–
220 mm Hg). The frequency of the primary outcome, death or
disability (modified Rankin scale (mRS) score of 3–6) was 52%
in the intensive and 56% standard BP lowering groups (OR
0.87, 95% CI 0.75 to 1.01; p=0.06; NNT 28). Moreover, ana-
lyses on the pre-specified key secondary outcome, an ordinal
shift analysis of the full range of score on the mRS, showed that
the intensive BP lowering group had significantly better func-
tional recovery at 90 days (OR for greater disability 0.87, 95%
CI 0.77 to 1.00; p=0.04). Although a nested imaging substudy
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Figure 1 Example of an intracerebral
haemorrhage.
demonstrated only a modest and non-significant trend towards a
reduction in haematoma growth over 24 hours from intensive
BP lowering, the effect on this most plausible mechanistic surro-
gate end point became significant in a meta-analysis of four ran-
domised controlled trials that included INTERACT2.19
The more recent, second Antihypertensive Treatment for
Acute Cerebral Hemorrhage (ATACH-II) study20 compared
‘very early’ (<4.5 hours of onset) and ‘very rapid and intensive’
(systolic BP <140 mm Hg with intravenous nicardipine for
24 hours) BP lowering with standard BP management (systolic
BP of 140–180 mm Hg). Death or disability (mRS score 4–6;
the primary outcome) at 90 days was 38.7% in the very inten-
sive and 37.7% in the standard BP lowering groups (adjusted
relative risk (RR) 1.04, 95% CI 0.85 to 1.27; p=0.72). While
there was no overall significant difference in treatment related
serious adverse events within 72 hours, significantly more renal
adverse events emerged over the initial 7 days (9.0% vs 4.0%;
p=0.002) and borderline more serious adverse events during
90 days in the very intensive group (adjusted RR 1.30, 95% CI
1.00 to 1.69; p=0.05). Interestingly, the percentage of patients
with haematoma growth (defined as >33% increase in ICH
volume over the initial 24 hours) was 18.9% in the very inten-
sive group and 24.4% in the standard treatment group (adjusted
RR 0.78, 95% CI 0.58 to 1.03; p=0.08).
The discrepancy in results between INTERACT2 and
ATACH-II may temper enthusiasm for early BP lowering in
ICH, but there are important differences between the two trials.
To begin with, all patients enrolled in ATACH-II had elevated
systolic BP of >180 mm Hg at presentation (mean 200 mm Hg)
for which most received initial treatment, while only approxi-
mately half of INTERACT2 participants had this same level of
systolic BP at the time of randomisation. Furthermore,
INTERACT2 participants received a wide variety of intravenous
and oral BP-lowering agents (eg, α-adrenergic antagonist (urapi-
dil), calcium-channel blocker (nicardipine or nimodipine), com-
bined α blocker and β blocker (labetalol), nitroglycerin,
diuretics (furosemide), nitroprusside, hydralazine, and others)
based on cost and local availability, according to pre-specified
protocols; whereas most ATACH-II participants were
Schreuder FHBM, et al. J Neurol Neurosurg Psychiatry 2016;0:1–9. doi:10.1136/jnnp-2016-314386
Cerebrovascular disease
administered intravenous nicardipine. Another difference is that
the achieved mean minimum systolic BP of patients in the inten-
sive treatment group in ATACH-II was <130 mm Hg
(129 mm Hg at 0–2 hours and 122 mm Hg at 2–24-hours), due
to the protocol-defined level of BP-lowering intensity and the
BP level for cessation of intravenous BP being lower in
ATACH-II (<110 mm Hg) than in INTERACT2
(<130 mm Hg). A subanalysis of INTERACT2 showed that
achieved post randomisation mean systolic BP of 130–
139 mm Hg during the initial 24 hours was associated with the
best outcome for ICH patients; but a modest increase in poor
outcome was suggested for levels <130 mm Hg.21 These differ-
ences would imply that very rapid and intensive BP lowering to
treatment targets <130 mm Hg in patients with very high BP
could refute any potential treatment benefit. With these differ-
ences in mind, and since ATACH-II and INTERACT2 included
predominantly ICH of mild-moderate severity, individual
patient data meta-analyses of these and other trials could
provide further valuable information regarding BP control (eg,
regimens, starting and stopping limits for BP treatment) and in
subgroups (eg, large haematoma, pre- and postdecompressive
surgery) of ICH patients.22
Hyperglycaemia
Early (enteral) feeding (ie, within 48 hours) should be consid-
ered in ICH patients as it is associated with reduced risk of
pneumonia and improved survival.23 High blood glucose in the
acute phase of ICH shows a continuous relation with early
deterioration, poor functional outcome and higher mortality
regardless of diabetic status.24 However, the UK Glucose Insulin
in Stroke Trial (GIST-UK)25 showed no benefit for the use of
standard glucose–potassium–insulin therapy during the initial
24 hours on mortality in 933 patients with stroke (including
12% with ICH) when it was stopped early due to slow enrol-
ment. Although underpowered, a possible explanation for this
finding is that hyperglycaemia is a hyperacute stress reaction,
merely reflecting stroke severity. A meta-analysis of eight rando-
mised controlled trials suggests similar magnitude of benefits of
stroke unit care, including management of hyperglycaemia for
3
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Cerebrovascular disease

ICH and acute ischaemic stroke,11 while the Quality in Acute
Stroke Care (QASC) study, a cluster randomised trial, showed
improved functional outcome from a multidisciplinary interven-
tion involving early control of fever, hyperglycaemia and swal-
lowing in patients with stroke (including 5% of ICH).26 Yet,
there is uncertainty over the optimal glucose level and control-
ling methods specifically in patients with ICH. At this stage,
intensive insulin treatment in patients with moderate to high
levels of hyperglycaemia with attention to avoiding hypogly-
caemia seem reasonable.27
Fever
Fever, often defined as a temperature of >38°C, is relatively
common and an independent prognostic factor of poor
outcome after acute ICH.28 Although often related to sepsis,
fever can also relate to an inflammatory reaction around the

Table 2 Ongoing clinical trials on medical management of ICH

Trial name/ Study
identifier Period Centres phase Mechanism Inclusion Intervention Primary outcome

SPOTLIGHT 2011–2017 15 centres Phase II Haemostatic N=110 Single injection of rFVIIa 80 mg/kg or ICH expansion at
NCT01359202 Canada therapy ICH <6 hours onset placebo 24 hours
Spot-sign+
STOP-IT 2010–2016 13 centres Phase II Haemostatic N=184 Single injection of rFVIIa 80 mg/kg or ICH expansion at
NCT00810888 2 countries therapy ICH <5 hours onset placebo 24 hours
Spot-sign+
NCT00699621 2009–2016 3 centres Phase II Haemostatic N=100 Platelet transfusion or no therapy ICH expansion at
Finland therapy ICH <6 hours onset 24 hours
Antiplatelet use
STOP-AUST 2012–2017 11 centres Phase II Haemostatic N=100 Intravenous tranexamic acid: 1 g loading ICH expansion at
NCT01702636 2 countries therapy ICH<4.5 hours dose over 10 min, followed by another 1 g 24 hours
onset over 8 hours or placebo
Spot-sign+
TRAIGE 2015–2018 11 centres Phase II Haemostatic N=240 intravenous tranexamic acid: 1 g loading ICH expansion at
NCT02625948 China therapy ICH <6 hours onset dose over 10 min, followed by another 1 g 24 hours
Spot-sign+ over 8 hours or placebo
TICH-DOAC 2016–2019 1 centre Phase II Haemostatic N=109 intravenous tranexamic acid: 1 g loading ICH expansion at
Switzerland therapy ICH <12 hours dose over 10 min, followed by another 1 g 24 hours
onset over 8 hours or placebo
DOAC use
TICH-2 2013–2018 95 centres Phase III Haemostatic N=2000 intravenous tranexamic acid: 1 g loading Ordinal shift on mRS
ISRCTN93732214 7 countries therapy ICH <8 hours onset dose over 10 min, followed by another 1 g at 90 days
over 8 hours or placebo
ICH-ADAPT II 2012–2017 2 centres Phase II BP control N=270 Aggressive BP therapy (<140 mm Hg) or DWI lesions at
NCT02281838 Canada ICH <6 hours onset regular BP therapy (<180 mm Hg) 48 hours
HI-DEF 2013–2017 29 centres Phase II Iron chelation N=324 Intravenous deferoxamine 62 mg/kg/day for mRS at 3 months
NCT01662895 2 countries ICH <24 hours 5 days or placebo
onset
iDEF 2014–2018 32 centres Phase II Iron chelation N=294 Intravenous deferoxamine 32 mg/kg/day for mRS at 3 months
NCT02175225 2 countries ICH <24 hours 3 days or placebo
onset
TTM-ICH 2013–2016 1 centre Phase II Cytoprotection N=50 Hypothermia (32–34C) for 72 hours or Safety at 15 days
NCT01607151 US ICH <18 hours normothermia
onset
MACH 2013–2017 1 centre Phase II Cytoprotection N=24 Intravenous minocycline 400 mg for 5 days mRS at 3 months
NCT01805895 US ICH <12 hours or placebo
onset
ChiCTR-PRC- 2012–2016 1 centre Phase IV Management of N=258 Valproate prophylaxis (500 mg daily for Seizure occurrence at
11001294 China complications ICH <72 hours 7 days) or placebo 3 months
onset
PEACH 2016–2019 1 centre Phase III Management of N=104 Levetiracetam prophylaxis (500 mg two Clinical or electrical
NCT02631759 France complications ICH <24 hours times per day for 45 days) or placebo seizure (48 hours
onset EEG)
APACHE-AF 2014–2018 15 centres Phase II Secondary N=100 Apixaban 5 mg two times per day or Combined vascular
NCT02565693 Netherlands prevention ICH 7–90 days antiplatelet therapy or no therapy outcome at 1 year
VKA use
RESTART 2013–2018 106 centres Phase III Secondary N=720 Antiplatelet drugs or avoid antiplatelet Recurrent
ISRCTN71907627 UK prevention ICH >24 hours drugs symptomatic ICH at
onset 2 years
Antithrombotic use
TRIDENT 2016–2022 To be Phase IV Secondary N=4200 Fixed low-dose combination BP lowering pill Recurrent stroke at
NCT02699645 determined prevention ICH up to 6 months (20 mg telmisartan, 2.5 mg amlodipine and 3 years
after onset 1.25 mg indapamide) or placebo
Trials labelled as scheduled or actively recruiting patients were identified at http://www.clinicaltrials.gov, http://www.isrctn.com and http://www.strokecenter.org/trials/ as of 9 October
2016.
BP, blood pressure; DOAC, direct oral anticoagulant; DWI, diffusion weighted image; ICH, intracerebral haemorrhage; mRS, modified Rankin scale; rFVIIa, activated recombinant factor
VII; VKA, vitamin K antagonist.

4 Schreuder FHBM, et al. J Neurol Neurosurg Psychiatry 2016;0:1–9. doi:10.1136/jnnp-2016-314386

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haematoma, as well as associated IVH or subarachnoid exten-
sion of the ICH.29 Animal studies suggest that induced hypo-
thermia mitigates perihaematomal oedema by reducing several
mediators of secondary brain injury, such as thrombin and the
proinflammatory cytokines;30 preliminary clinical studies
further support this action on perihaematomal oedema,31 an
independent prognostic factor in ICH.32 It seems reasonable,
therefore, that early treatment of fever should be safe and
provide benefits to patients, but the results of several ongoing
phase II trials, such as the Targeted Temperature Management
after Intracerebral Hemorrhage (TTM-ICH)33 and Paracetamol
(Acetaminophen) In Stroke 2 (PAIS 2)34 are awaited (table 2).
Recommendations: Patients with ICH and a systolic BP
>160 mm Hg should receive urgent BP lowering therapy. The
approach should allow safe and easy titration of dose, but no
advice can be made on a preferred antihypertensive agent. The
optimal systolic BP target level appears to be 130–139 mm Hg
in the first 24 hours and continued during the next several days.
ICH patients with moderate to severe hyperglycaemia should be
treated with insulin. Early enteral feeding and rapid treatment of
fever should be considered.
MANAGEMENT OF COMMON COMPLICATIONS
Seizures
The frequency of early seizures (within 7 days of ICH onset)
varies considerably (1–14%) across studies, and is even higher if
subclinical seizure activity is considered; these rates are greater
than those for acute ischaemic stroke.35–40 Early seizures are
thought to arise from acute disruption of brain integrity and
biochemical disturbances (eg, release of excitatory neurotrans-
mitters, direct toxic effects of blood degradation products), and
cortical involvement appears to be a key risk factor.37 41
Prolonged or single severe seizures should be treated with ben-
zodiazepines or a loading dose of an antiepileptic drug. In
patients with otherwise unexplained altered mental status, a trial
of antiepilepsy drug treatment should be considered; the use of
continuous EEG monitoring to determine subclinical seizures is
possible but is often complicated by the use of sedation, brain
injury and recording interference.40 42 Early seizures do not
appear to influence prognosis with respect to mortality or func-
tional outcome, but may increase the risk of long-term recurrent
seizures.37 43
Late seizures (beyond 7 days of ICH onset) occur in 1–10%
of patients and are thought to result from gliotic scarring and
neuronal reorganisation.36 The risk of late seizures can be esti-
mated using the CAVE score,44 which provides one point for
each of the four factors—cortical (C) involvement, young age
((A) <65 years), haematoma volume (V) >10 mL and early sei-
zures (E)—with the risk of late seizures increasing from 0.6%
for a score of 0% to 46.2% for a score of 4. Late seizures are
associated with poor long-term functional outcome and have a
high rate of recurrence.37 Antiepilepsy drugs are recommended
in guidelines of the American Heart Association (AHA)/
American Stroke Association (ASA)27 and European Stroke
Organisation.45
Primary prevention of seizures after ICH by means of prophy-
lactic use of antiepileptic drugs is a still a matter of debate and
is not recommended by current guidelines.27 45 In a small
placebo-controlled trial of sodium valproate in 72 patients for
1 month, the active group had a lower risk of early seizures and
better functional outcomes at 12 months, despite similar rates of
seizures between the groups.46 Sodium valproate should be used
cautiously in patients with ICH as it can occasionally cause coa-
gulopathy.47 48 The results of a large clinical trial investigating
Schreuder FHBM, et al. J Neurol Neurosurg Psychiatry 2016;0:1–9. doi:10.1136/jnnp-2016-314386
Cerebrovascular disease
the effect of 7-day prophylaxis with sodium valproate on early
and late seizures up to 12 months are expected shortly (http://
www.chictr.org.cn; ChiCTR-PRC-11001294; table 2).49
Venous thromboembolism
Venous thromboembolism (VTE) occurs in up to one-fifth of
patients with ICH, most often asymptomatic or as deep vein
thrombosis (DVT),50–52 which can lead to life-threatening pul-
monary embolism (PE) in 1–2%.53 Preventive measures for VTE
can consist of low-dose anticoagulation with (unfractionated or
low-molecular-weight) heparin, graduated compression stock-
ings, and intermittent pneumatic compression. A meta-analysis
of four small studies (all with methodological shortcomings)
showed that heparin was associated with a significant reduction
in PE (RR 0.37, 95% CI 0.17 to 0.80; NNT 86) and trend
towards lower mortality (RR 0.76, 95% CI 0.57 to 1.03), and
importantly without any significant increase in haematoma
enlargement (RR 1.42, 95% CI 0.57 to 3.53).54 However, post
hoc propensity-score matched analysis of the INTERACT2
study indicates that heparin-treated ICH patients were more
likely to have death or major disability at follow-up (OR 2.06,
95% CI 1.53 to 2.77; number needed to harm (NNH) 6) com-
pared to other patients.55 The 2015 AHA/ASA guideline recom-
mends initiation of heparin after 1–4 days of ICH in those
patients with persistent immobility and where there is radio-
logical confirmation of stable haematoma size.27 Graduated
compression stockings should be avoided as they are ineffective
and lead to complications.50 51 A large clinical trial has demon-
strated that intermittent pneumatic compression decreases the
risk of VTE in ICH patients (OR 0.36, 95% CI 0.17 to 0.75;
NNT 10).52
Inferior vena cava filter can be considered as an alternative to
systemic full-dose therapeutic anticoagulation, taking into
account the patient’s individual risks of VTE (ie, risk factors for
VTE, clinical condition), potential for haematoma enlargement
(time from ICH onset, size and stability of haematoma, and lobar
vs deep location), and the potential harms of interventions.27 56
Elevated intracranial pressure
Management of raised intracranial pressure (ICP) in ICH is
based on the experience of managing patients with traumatic
brain injury. If ICP approaches mean arterial pressure (MAP),
cerebral perfusion becomes compromised, leading to secondary
ischaemic injury.57 In particular, younger patients and those
with large volume haematomas, extensive perihaematoma
oedema, IVH and emerging concurrent hydrocephalus are at
high risk of raised ICP.58 The AHA/ASA guideline suggests a
stepwise approach, with considering less invasive methods first
and, if unsuccessful, initiating of more invasive measures.27
Patients with (suspected) elevated ICP should have the head of
the bed elevated to 30° and a neutral head position to ensure
optimal jugular venous drainage. The use of analgesia or sed-
ation to reduce ICP has not been clearly defined. Additionally,
BP should theoretically be controlled to ensure cerebral perfu-
sion pressure of 50–70 mm Hg, but in the absence of any clear
alternative data, those provided by INTERACT2 (aim for a sys-
tolic target <140 mm Hg) seems reasonable. Clear treatment
thresholds for ICP have not been identified, but one study
showed that an ICP >30 mm Hg is associated with poor
outcome.59 Osmolar therapy (eg, mannitol) is commonly
applied to patients with raised ICP, particularly in Asia, but a
Cochrane review60 and post hoc propensity-score matched ana-
lysis of the INTERACT2 study have shown no benefit of such
treatment.61
5
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Cerebrovascular disease
Other therapeutic options for raised ICP are limited.
Intravenous glycerol has shown no clear effect.62 A new phase
III clinical trial of dexamethasone will start soon (Klijn, personal
communication) as previous studies have showed no benefit due
to being under powered and with other methodological short-
comings.63 Other approaches to decrease ICP (ie, hypertonic
saline, neuromuscular blockage, forced hyperventilation, thera-
peutic hypothermia and barbiturate coma) have not been
studied systematically. The effect of surgical treatment, including
cerebrospinal fluid drainage through an external ventricular
drain, hemicraniectomy and evacuation of the haematoma, are
beyond the scope of this review.
Recommendations: Patients with ICH with prolonged or
severe seizures should be treated. Prophylactic use of antiepileptic
drugs should be avoided. Intermittent pneumatic compression or
prophylactic dose heparin/heparinoid therapy should be used to
prevent VTE in all immobile patients. Raised ICP should be
treated with non-invasive methods before invasive monitoring
and decompressive surgery is considered.
CORRECTIVE THERAPY FOR ANTITHROMBOTIC
ASSOCIATED ICH
Haemostatic therapy
Early haemostatic therapy may benefit ICH patients, as 20–40%
of haematomas expand from active bleeding, and that this pre-
dicts poor outcome.64 In one of the largest clinical trials showed
that recombinant tissue factor VII (rFVIIa) could restrict haema-
toma growth but this failed to improve clinical outcome and
increased risks of arterial thromboembolic events.65 Two
ongoing phase-II trials (NCT00810888 and NCT01359202;
table 2) are evaluating rFVIIa in highly selected patients with
increased risk of haematoma enlargement on the basis of a CT
angiography-identified spot-sign. Tranexamic acid, which
showed positive results in patients with trauma, is also being
investigated in a phase II study (NCT01702636; table 2) of
spot-sign-positive patients, and in a large phase III trial
(ISRCTN93732214; table 2) with a broad range of patients.66
Platelet transfusion
Antiplatelet therapy-associated ICH was shown in a review of
25 published and unpublished cohort studies to increase the risk
of death but not of worse functional outcome.67 In patients
who experience an ICH while on an antiplatelet agent, a plate-
let transfusion is often used to replace non-functional thrombo-
cytes to reduce the risk of further haemorrhage and improve
outcome if decompressive surgery is planned. However, the
recent PlAtelet Transfusion in Cerebral Haemorrhage (PATCH)
trial showed that platelet transfusion was associated with an
increased risk of poor outcome after ICH (OR 2.05, 95% CI
1.18 to 3.56; NNH 7),68 and results of a second trial of platelet
transfusion (NCT00699621; table 2) are expected shortly.
Reversal of anticoagulation
Vitamin K antagonists, mainly warfarin, have a 7–10-fold
increased risk of ICH,69 and the resulting haematoma has a
larger volume, a greater and more protracted expansion, and
results in a higher case death (up to 50%) than for other types
of ICH.70 71 Thus, rapid replenishment (avoiding delays for
coagulation test results72) of the vitamin K-dependent coagula-
tion factors (II, VII, IX and X) is considered essential to reverse
the anticoagulant effects, but the benefit of this approach has
never been demonstrated. The rapid reversal international nor-
malised ratio (INR) to <1.3, achieved within 4 hours, was asso-
ciated with a low rate of haematoma expansion in a large
6 Schreuder FHBM, et al. J Neurol Neurosurg Psychiatry 2016;0:1–9. doi:10.1136/jnnp-2016-314386
German retrospective cohort study.73 Other treatment options
include the use of fresh frozen plasma (FFP) or prothrombin
complex concentrate (PCC). Advantages of PCC include the
small infusion volume (lower risk of congestive heart failure)
and rapid infusion speed enabling rapid reversal, whereas FFP
requires thawing before infusion (as it is kept frozen), thus
delaying INR normalisation. Moreover, 30 mg/kg 4-factor PCC
has been shown superior over 20 mL/kg FFP in reversing antic-
oagulation within 3 hours after the start of treatment (OR 30.6,
95% CI 4.7 to 197.9) with higher odds of significant haema-
toma expansion in the FFP group (OR 3.8%, 95% CI 1.1 to
16.0).74 A large multinational pooled analysis of 16 stroke
centres suggests that the combination of FFP and PCC might
further improve the outcome compared to PCC alone.75 Besides
repletion of coagulation factors, 5–10 mg of vitamin K should
also be administered intravenously to restore the production of
vitamin K-dependent coagulation factors.27 INR should be
checked at regular intervals because of the long half-life of
warfarin.
Reversal strategies for new oral anticoagulants
Direct acting, new oral anticoagulants (DOACs, apixaban, dabi-
gatran, edoxaban and rivaroxaban) have been associated with
lower rates of ICH in comparison to warfarin.76 The enthusiasm
for DOACs was initially tempered by the fear that they would
be associated with larger haematomas and worse outcome due
to their lack of an antidote, but this has not been corroborated
by recent reports.77–79 Emergency reversal of DOACs in case
of bleeding complications is largely expert-based and includes
the intravenous administration of 30–50 U/kg 4-factor PCC,
90 U/kg activated 4-factor PCC (FEIBA) and/or 90 mg/kg
rFVIIa.80 Based on in vitro studies and animal experiments, it
has been suggested that FEIBA or rFVIIa may be more potent to
reverse dabigatran, whereas other PCCs may be better for the
Factor-Xa inhibitors. If ICH occurs within 2–3 hours after the
last dose, administration of activated charcoal (all DOACs) or
haemodialysis (in case of dabigatran) may be considered.
Administration of vitamin K is not useful.81 Recently, prelimin-
ary data of a phase-II trial testing a single dose of 5 mg idaruci-
zumab intravenously as an antidote for dabigatran showed a
complete, immediate and sustained reversal of the anticoagula-
tion effect in the majority of patients, of whom 18 had ICH.82
Although efficacy on clinical outcome remains to be proved, the
antidote has been approved by a number of drug regulatory
authorities.83 Antidotes for Factor-Xa inhibitors (andexanet α
and arapazine/ciraparantag (PER977)) are currently being tested
in phase-II and phase III trials for the reversal of apixaban,
edoxaban and rivaroxaban.84 85
Recommendations: Haemostatic agents or platelet transfusion
should be avoided in anticoagulation-free ICH patients. Patients
with vitamin K-associated ICH should receive urgent reversal
therapy combining PCC and intravenous vitamin K. In case of
DOAC use, consideration should be given for urgent reversal
therapy with selective antidotes where available.
Secondary prevention in ICH survivors
Patients who survive ICH are at high risk for new vascular
events. The annual risk of recurrent ICH lies between 1.3% and
7.4%, but it is higher in lobar compared to non-lobar ICH. The
5-year survival rate is 29% (95% CI 26% to 33%).86 Effective
long-term BP lowering is the single most significant intervention
for the secondary prevention of serious vascular events after
ICH,87 yet the optimal magnitude of BP drop or regimens to
achieve BP control are uncertain. Poor BP control increases the
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risk of recurrent ICH regardless of subtype (ie, lobar vs non-
lobar).88 89 A single-centre study involving 1145 ICH patients
with a median follow-up of 37 months showed that the risk of
ICH recurrence gradually increases from mean systolic BP of
110–119 mm Hg and mean diastolic BP of 70–79 mm Hg, for
lobar and non-lobar ICH. The risk of recurrence steeply
increases with BP above 140/90 mm Hg.89 In the Perindopril
Protection Against Recurrent Stroke Study (PROGRESS) trial,
of 660 participants with a history of ICH at baseline, a massive
49% (95% CI 20% to 67%) relative risk reduction was
observed on recurrent stroke; and there was a near-continuous
relationship between lower BP and lower risk.90 Similar effects
of BP lowering for the prevention of ICH were also seen in the
Secondary Prevention of Small Subcortical Strokes (SPS3)
trial,91 where there was 63% relative risk reduction on ICH but
insignificant reductions in recurrent total and ischaemic strokes.
These data suggest that much stricter BP control than is cur-
rently recommended in guidelines could provide larger benefits
in terms of prevention of recurrent major cardiovascular events.
However, it is recognised that intensive long-term BP control is
often difficult to achieve in clinical practice and there are
ongoing concerns that the potential harms (eg, falls, fatigue,
renal failure) out way any benefits. Most patients with hyperten-
sion require two or more antihypertensive agents to achieve
adequate BP control,92 but multiple tablets negatively impact on
adherence and attendance to scheduled visits. Electronic remin-
ders and simpler, more tolerable treatment regimens could
achieve better BP control from improved adherence in this high-
risk patient group. The ongoing Triple therapy prevention of
Recurrent Intracerebral Disease EveNts Trial (TRIDENT,
NCT02699645; table 2), a double-blind, placebo-controlled
trial, has been initiated to determine the effectiveness of more
intensive chronic BP lowering using a fixed low-dose combin-
ation of BP lowering agents (telmisartan, amlodipine and inda-
pamide—Triple Pill strategy) on top of standard of care, on
recurrent stroke in 4200 patients with ICH.
Some other important questions for ICH survivors that
remain unanswered are whether to resume oral anticoagulant or
antiplatelet therapy (which will be studied in the APACHE-AF
(NCT02565693) and RESTART trials (ISRCTN71907627);
table 2), whether lipid lowering therapy is beneficial or harmful,
and if the intensity of secondary prevention should differ
between patients with lobar and non-lobar ICH.
Recommendation: Patients who survive an ICH should have
strict BP-lowering therapy.
SUMMARY
ICH is a major health burden, particularly in developing
countries where there is much hypertension. Apart from early
control of elevated BP and possibly hyperglycaemia, there are
no proven medical therapeutic options. Management is based
on well-organised active care with close neurological monitor-
ing by trained staff, and early detection and management of
complications. This is largely based on empirical guidelines in
the absence of clinical end point, randomised controlled
trials. Once patients are stable, early rehabilitation is likely to
reduce the risk of further complications and promote recov-
ery and return to usual activities. Good long-term control of
BP is the single most important strategy to reduce the likeli-
hood of recurrent ICH and other serious cardiovascular
events.
Contributors CSA outlined the review process and contributed particular sections.
FHBMS and SS wrote first drafts of particular sections. CJMK wrote particular
Schreuder FHBM, et al. J Neurol Neurosurg Psychiatry 2016;0:1–9. doi:10.1136/jnnp-2016-314386
Cerebrovascular disease
sections. All authors made comments on the final manuscript and approved
submission.
Funding CJMK is supported by a clinical established investigator grant of the Dutch
Heart Foundation (grant number 2012 T077), and an Aspasia grant from The
Netherlands Organisation for Health Research and Development, ZonMw
(015008048). CSA holds a Senior Principle Research Fellowship of the National
Health and Medical Research Council (NHMRC) of Australia.
Competing interests SS reports receiving speaker fees from Otsuka
Pharmaceutical and Boehringer Ingelheim. CJMK reports receiving speaker fees from
Boehringer Ingelheim and Penumbra, which were paid to the hospital research fund
and not to a personal account; and has been site Principal Investigator for a
Pfizer-sponsored clinical stroke trial. CSA reports receiving travel reimbursement and
speaker fees from Boehringer Ingelheim and Takeda, and Advisory Board sitting fees
from AstraZeneca and Medtronic.
Provenance and peer review Commissioned; externally peer reviewed.
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Schreuder FHBM, et al. J Neurol Neurosurg Psychiatry 2016;0:1–9. doi:10.1136/jnnp-2016-314386 9

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Medical management of intracerebral

haemorrhage
Floris H B M Schreuder, Shoichiro Sato, Catharina J M Klijn and Craig S
Anderson

J Neurol Neurosurg Psychiatry published online November 16, 2016

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