Review

Complications of intracerebral haemorrhage

Joyce S Balami, Alastair M Buchan

Intracerebral haemorrhage (ICH) is the most devastating type of stroke and is a leading cause of disability and mortality. Lancet Neurol 2012; 11: 101–18
By contrast with advances in ischaemic stroke treatment, few evidence-based targeted treatments exist for ICH. Acute Stroke Programme,
Management of ICH is largely supportive, with strategies aimed at the limitation of further brain injury and the Department of Medicine and
Clinical Geratology
prevention of associated complications, which add further detrimental effects to an already lethal disease and jeopardise (J S Balami MRCP), and Acute
clinical outcomes. Complications of ICH include haematoma expansion, perihaematomal oedema with increased Vascular Imaging Centre,
intracranial pressure, intraventricular extension of haemorrhage with hydrocephalus, seizures, venous thrombotic University of Oxford
events, hyperglycaemia, increased blood pressure, fever, and infections. In view of the restricted number of therapeutic (Prof A M Buchan FMedSci),
Oxford University Hospitals
options for patients with ICH, improved surveillance is needed for the prevention of these complications, or, when this NHS Trust, Oxford, UK
is not possible, early detection and optimum management, which could be effective in the reduction of adverse effects Correspondence to:
early in the course of stroke and in the improvement of prognosis. Further studies are needed to enhance the evidence- Prof Alastair M Buchan,
based recommendations for the management of this important clinical problem. Biomedical Research Centre,
University of Oxford, Oxford
University Hospitals NHS
Introduction treatment for ICH, and whether or not surgical Trust, John Radcliffe,
Spontaneous or primary intracerebral haemorrhage approaches are beneficial remains controversial. Oxford, OX3 9DU, UK
(ICH) is a major cause of morbidity and mortality Additional therapeutic dilemmas can arise over the alastair.buchan@medsci.ox.
worldwide. It is the second most common form of stroke, safest and most effective approach to VTE prevention in ac.uk

accounting for 10–30% of first-ever strokes.1–3 The 30 day
mortality for ICH has been reported to be 30–55%,1–6 with
half the deaths occurring in the acute phase, especially in
the first 48 h.1,2,5 The complications of ICH are among the
major predictors of early mortality and poor outcome.
ICH complications include haematoma expansion
(HE), perihaematomal oedema (PHE), intraventricular
extension of haemorrhage (IVH) with hydrocephalus,
seizures, venous thromboembolic events (VTE), hyper-
glycaemia, increased blood pressure (BP), fever, and
infections. Complications such as HE,7,8 IVH with
obstructive hydrocephalus,9–11 and hyperglycaemia4,12,13
are major predictors of increased early mortality and
adverse outcome during the hyperacute phase of ICH.
Similarly, HE, hydrocephalus, and PHE have been
associated with early neurological deterioration (END)
and poor outcome.14 A prospective observational study
reported END in about 33% of patients with ICH within
48 h of onset, with an associated 30 day mortality of 47%
in those with END.14
The complications of ischaemic stroke (IS) and their
management have been reviewed extensively,15,16 with
little discussion of the complications of ICH. Despite its
seriousness, the treatment options for ICH are restricted
and few evidence-based data exist to guide the
management of ICH complications. By contrast with IS,
for which therapeutic advances have been made to
improve clinical outcome, the management of ICH is
generally supportive, but with poor prognosis because no
specific treatments have been shown to improve outcome
after ICH. For example, the management of HE is of
unproven value because all measures aimed at restricting
HE have so far not improved outcome in controlled trials.
Similarly, PHE management is mainly supportive and
measures aimed at decreasing intracranial pressure
(ICP) are also of unproven value. Also, insufficient
evidence exists with regard to the efficacy of surgical
patients with ICH because prophylaxis with anti-
coagulants can increase the risk of HE or further
bleeding. Perhaps a more difficult therapeutic dilemma
is how to manage patients with clinical thromboembolic
complications after ICH, balancing the risk of subsequent
life-threatening thromboembolism if untreated against
the risk of recurrence of ICH. A related issue is whether
or when to resume anticoagulation after ICH in patients
with cardiac disease associated with high embolism risk,
such as those who need mechanical valve prostheses or
those with atrial fibrillation.
In this review, we focus on the early complications of
ICH, discussing emerging therapies and relevant
preventative and management strategies based on
available evidence and guidelines. We draw attention to
the scarcity of evidence to guide the management of
many important and common complications of ICH.
Haematoma expansion
Clinical features
HE, defined as an increase in volume of 33–50% or an
absolute change in haematoma volume of 12·5–20 mL
(on repeat CT), is a common early and severe complication
of ICH.8,17–20 Although HE is one of the main pathophysio-
logical phases of ICH, it can also be a serious complication
subsequent to the acute phase—up to 40% of the
haematoma grows in the first few hours post ictus.
Various terms such as haematoma extension, expansion,
progression, growth, enlargement, and rebleeding have
been used to describe this subsequent increase in
haematoma volume after ICH.
The precise mechanism of early HE during the acute
phase is poorly understood. It is proposed to be a
heterogeneous process that includes dysregulation of
haemostasis via inflammatory cascade activation and
matrix metalloproteinase (MMP) overexpression, break-
down of the blood–brain barrier, a sudden increase in

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 Review
A B
Figure 1: CT angiogram showing contrast extravasation
Arrowheads indicate contrast extravasation. Spot-sign score 1 (A), 2 (B), 3(C), and 4 (D). Reproduced from Delgado Almandoz and colleagues,31 by permission of
Wolters Kluwer Health.
ICP leading to local tissue distortion and disruption, and
vascular engorgement due to reduced venous outflow.8
Early HE can also result from an increased plasma
concentration of cellular fibronectin (c-FN) and the in-
flammatory mediator interleukin-6 (IL-6).21 Pathological
studies have shown multiple microscopic and macro-
scopic bleeding points around the border of
haemorrhages, arising from ruptured arterioles or
venules that result from the stretching of surrounding
vessels after clot expansion.22
Several studies indicate that early HE occurs in 18–38%
of patients scanned within 3 h of ICH onset7,18,19 and more
than 70% develop at least some extent of HE within 24 h
of symptom onset,23 even in the absence of known
coagulopathy, suggesting an active bleeding process in
the hyperacute phase of ICH.22 In warfarin-associated
ICH, 27–54% of patients develop early HE and a delayed
expansion because of protracted bleeding,24–26 which is
associated with up to 70% increase in mortality.24,27
A prospective study showed 38% of patients had an
increase in haematoma volume (>33% increase compared
with admission CT) within 3 h of symptom onset. HE
was evident even within 1 h of the baseline scan in two-
thirds of those patients, whereas an additional 12%
developed growth within the next 21 h, which suggests
continued active bleeding.7 Subsequent prospective
studies have confirmed this finding, noting that 23–32%
of patients had an increase in haematoma volume (>33%
from baseline or 12·5 mL) in the first 24 h.8,20
CT angiographic studies that show contrast extra-
vasation (the so-called spot sign) into the haematoma28–30
have provided additional evidence of progressive bleeding
several hours after the onset of ICH. The spot sign is an
important predictor of haematoma growth and might be
useful in the prediction of HE with high specificity28–30
and as a predictor of mortality.28,30,31 In fact, the spot-sign
score (figure 1), which is used to grade the number of
spot signs and their maximum dimensions and
attenuation, is the strongest predictor of HE and is an
independent predictor of in-hospital mortality and poor
outcome in people with ICH.31
102
C D
Other important predictors of HE include large
haematoma volume on presentation,29,32 early presentation
(especially within 3 h of onset),17,19,29,32 heterogeneity of
haematoma density on admission CT,33 and prior use of
warfarin.17,24,25 Blood biomarkers such as increased IL-6,
MMP-9, c-FN, and tumour necrosis factor, reduced
platelet activity,21 reduced fibrinogen concentrations,19
and increased serum creatinine,32 have been suggested to
predict HE in patients with ICH. Conflicting results were
seen for increased D-dimers as a predictor of HE.34,35
Some studies have shown an association between systolic
BP (SBP) and HE,36,37 but others have not.7,19,32,38 Similarly,
some studies show an association between prior use of
antiplatelet drugs and HE,32,34,39 although others do not.40,41
Other risk factors include hyperglycaemia,4,12,36 previous
cerebral infarction, liver disease,36 a decreased level of
consciousness, and heavy alcohol intake.19
HE is often associated with END and is an independent
predictor of poor outcome and increased mortality.1,8,23,42
Findings from a meta-analysis of 218 patients with ICH
who had CT scans within 3 h of onset and follow-up
scans within 24 h23 showed that for every 10% increase in
ICH growth there was a 5% increased risk of death, a
16% increased risk of worsening outcome as measured
with the modified Rankin score (mRS), and an 18%
increased likelihood of being dependent or of a poor
outcome on the Barthel index.
Management
Interventions to restrict HE include haemostatic
therapy, cautious lowering of high BP, quick reversal of
prior anticoagulation, and surgical evacuation (table 1).
Clinical trials8,43 targeting HE in ICH and a meta-
analysis65 have shown that the use of recombinant factor
VII (rFVIIa) limits the extent of HE in patients with
non-coagulopathic ICH. However, there was an increase
in thromboembolic risk with no clear clinical benefit in
unselected patients. The SPOTLIGHT (Spot Sign
Selection of Intracerebral Hemorrhage to Guide
Hemostatic Therapy; ClinicalTrials.gov identifier
NCT01359202) and STOP-IT (Spot Sign for Predicting
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 Review

Description Level of
evidence*
Medical management
Haemostatic therapy with In a phase 2 trial in patients with ICH, rFVIIa (NovoSeven; Novo Nordisk Health Care, Bagsvaerd, Denmark) led to a reduction in HE (p=0·01) and Level 3A
rFVIIa improvement in neurological outcomes and mortality,8 but the phase 3 study (FAST trial), despite showing a statistically significant (p=0·009)
reduction in haematoma growth in rFVIIa-treated patients, did not show any functional or survival benefit;43 however, post-hoc analysis of the
FAST data suggests a potential benefit of rFVIIa in younger patients (<70 years) without known factors for poor outcome such as large haematoma
volume (<60 mL) or substantial IVH, if given within 2·5 h of the onset of symptoms44
AHA/ASA guidelines do not recommend rFVIIa for routine use in restricting HE in patients with ICH45
Blood pressure control In the INTERACT trial, the mean HE was 22·6% less at 24 h in the group that received intensive blood pressure control than it was in the Level 1B
guideline-based blood pressure control group (36·3%; p=0·04), but no statistically significant difference was recorded in functional outcome at
3 months between the two groups (median mRS score was 2 in both groups; p=0·66);20 a further subanalysis showed a beneficial effect of early
blood pressure reduction on HE, extending over 72 h46
In the ATACH phase 1 trial, in which patients were divided into tiers on the basis of blood pressure control (tier 1 being the highest level), HE was Level 1B
seen in 33% of patients in tier 1, 15% of patients in tier 2, and 22% of patients in tier 347
Surgery
Craniotomy A meta-analysis of ten trials of surgery for supratentorial ICH showed a benefit of surgery in primary supratentorial ICH on reduction of odds of an Level 1A
unfavourable outcome at follow-up; however, the authors noted that more trials were needed to make a definitive conclusion48
The STICH trial, which randomised 1033 ICH patients, showed no overall benefit of early surgery compared with initial conservative treatment for Level 1B
patients (26% vs 24% favourable outcome; p=0·41); however, a subgroup analysis showed that patients with haematoma within 1 cm of the
cortical surface benefited from early surgery, although this did not reach statistical significance (p=0·007)49
The AHA/ASA guidelines state the following:
(1) that evacuation of supratentorial ICH with standard craniotomy might be considered for patients presenting with lobar clots >30 mL and within Level 2b B
1 cm of the surface;45 and
(2) that surgical evacuation of infratentorial ICH is recommended as soon as possible for patients with cerebellar haemorrhage who are Level 1B
deteriorating neurologically or who have brainstem compression and/or hydrocephalus from ventricular obstruction2,45
Decompressive Evidence for the beneficial effect of decompressive surgery comes from small case series: in one series of 12 consecutive patients with a Level 2b B
craniectomy hypertensive ICH volume of >60 mL treated with decompressive craniectomy, 11 patients survived at discharge, of whom six had a good functional
outcome (mRS 0–3)50
In another case series of 23 patients with putaminal haematoma who underwent decompressive craniectomy, 13 patients had a good outcome and Level 2b B
10 had a poor outcome (including three deaths) at 90 days,51 suggesting that decompressive craniectomy might also have a role in the
management of patients
Minimally invasive surgery with stereotactic aspiration and thrombolysis
Alteplase The combination of frameless stereotactic aspiration and thrombolysis (FAST) in a phase 2 study of 28 patients with deep subcortical ICH showed Level 3B
the procedure to be safe and associated with reduction in ICH volume and early improvement on the NIHSS, with the potential to improve
outcome52
In another study of 15 patients who underwent frameless stereotactic aspiration and thrombolysis (FAST) of the clot, demonstrable ICH reduction ··
without perihaematoma enlargement was detected53
Urokinase Evidence for the potential beneficial effect of stereotactic infusion of urokinase on survival but not necessarily rebleeding has been provided by Level 2b B
randomised trials54–58
In a randomised controlled trial that compared 64 patients treated with MISPTT and 58 treated with conventional craniotomy, the MISPTT group Level 1B
had fewer complications and a trend towards improved short-term and long-term outcomes58
Image-guided Small randomised59,60 and non-randomised studies61–63 have shown the image-guided stereotactic endoscopic aspiration procedure to be effective Level 2b B
stereotactic endoscopic for immediate haematoma evacuation, with improved functional outcome and reduced mortality compared with best medical management61–63
aspiration In view of the uncertainty of the effectiveness of MIS for haematoma evacuation and the need for further research, the application of MIS with Level 2b B
either stereotactic or endoscopic aspiration with or without thrombolysis is not recommended for routine use2,45

AHA/ASA=American Heart Association/American Stroke Association. ATACH=Antihypertensive Treatment of Acute Cerebral Hemorrhage. FAST trial=Factor Seven for Acute Haemorrhagic Stroke trial.
HE=haematoma expansion. ICH=intracerebral haemorrhage. INTERACT=Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial. IVH=intraventricular extension of haemorrhage. MIS=minimally
invasive surgery. MISPTT=minimally invasive stereotactic puncture and thrombolysis therapy for acute intracerebral haemorrhage. mRS=modified Rankin score. NIHSS=National Institutes of Health Stroke Scale.
rFVIIa=recombinant factor VIIa. STICH=Surgical Trial in Intracerebral Haemorrhage. *The level of evidence is according to the Oxford Centre for Evidence-based Medicine (Level 1A being the highest level of evidence).64

Table 1: Management to restrict haematoma expansion

and Treating ICH Growth Study; NCT00810888) trials
that are underway use the CT angiography spot sign
to stratify patients most at risk of HE who might benefit
from therapy with rFVIIa. However, rFVIIa is not
recommended at present for routine use to
restrict HE.45
Evidence from the INTERACT (Intensive Blood
Pressure Reduction in Acute Cerebral Haemorrhage
Trial) and ATACH (Antihypertensive Treatment of Acute
Cerebral Hemorrhage) trials show that SBP reduction
might restrict HE in the hyperacute phase of ICH.20,46,47
Both INTERACT 2 (NCT00716079) and ATACH 2
(NCT01176565) are phase 2 trials underway to further
investigate the benefit of early BP reduction on HE and
clinical outcome in patients with ICH.
The role of surgical treatment for ICH is controversial.
Surgical procedures with varying amounts of supportive
evidence include conventional craniotomy,48,49 minimally
invasive surgery (MIS),52–63,66 and decompressive crani-
ectomy.50,51 Results from the STICH (Surgical Trial in
Intracerebral Haemorrhage) trial49 showed no overall
benefit of early surgical clot evacuation compared with

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 Review

Description Level of
evidence*
Reversal of The AHA/ASA recommend immediate reversal of anticoagulation;2,45 recommendations for reversal of anticoagulation in patients with ICH are as ··
anticoagulation follows:
Patients with a severe coagulation factor deficiency or severe thrombocytopenia should receive appropriate factor replacement therapy or platelets, Level 1C
respectively45
Patients with ICH whose INR is increased because of oral anticoagulants should have their warfarin treatment discontinued and receive therapy to Level 1C
replace vitamin K-dependent factors and to correct their INR45
Vitamin K (5–10 mg intravenously) remains an adjunct to initial therapy for OAC-associated haemorrhage because normalisation of INR can take up to Level 1C
24 h45
FFP (10–50 U/kg) is commonly used as an adjunct to vitamin K; it acts within a few h, but is associated with greater volume expansion, which might Level 2b B
precipitate heart failure, and requires much longer infusion times2
Prothrombin complex concentrates (10–50 U/kg), which act within a few min and have not shown improved outcome compared with FFP, might lead Level 2a B
to fewer complications than FFP and can be considered as an alternative to FFP45
rFVIIa (40–80 μg/kg), which acts within a few min, does not replace all clotting factors, and although the INR might be lowered, clotting might not be Level 3C
restored in vivo; rFVIIa is therefore not routinely recommended as a sole agent for OAC reversal in ICH45
The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is unclear and is considered investigational45 Level 2b B
Resumption of The decision as to whether to resume anticoagulation depends on analysis of the risk of recurrent haemorrhage balanced against the risk of ··
anticoagulation therapy thromboembolism because either complication can be associated with poor outcome and high mortality
after ICH The decision as to whether to resume anticoagulation should be based on underlying risk factors for recurrence: lobar location of the initial ICH, older Level 2a B
age (>65 years), ongoing anticoagulation, presence of the apolipoprotein ε2 or ε4 alleles, and greater number of microbleeds on MRI45
For nonvalvular AF, long-term anticoagulation should be avoided after spontaneous lobar ICH because of the high risk of recurrence, but antiplatelet Level 2a B
agents might be considered; antiplatelet treatment is probably safer than anticoagulation because it carries a substantially lower risk of bleeding2,40
Anticoagulation after non-lobar ICH might be considered depending on the indication2 Level 2a B
When to resume The optimum timing of the resumption of anticoagulation is a crucial issue with conflicting evidence:
anticoagulation A large retrospective study of 2869 patients with AF, mechanical heart valves, and additional risk factors for stroke with warfarin-related ICH suggests Level 2B
resumption of warfarin after about 10–30 weeks67
By contrast with reference 67, another systematic review of 492 patients concluded that anticoagulation might be resumed after 72 h68 Level 2A
A systematic review of six retrospective studies of 120 patients with mechanical heart valves and ICH concluded that resumption of warfarin within Level 2A
2 weeks is safe69
However, the AHA/ASA suggest that in patients with a very high risk of thromboembolism for whom restarting warfarin is considered, warfarin can be Level 2b B
restarted 7–10 days after ICH onset;2 the European Stroke Initiative recommends that warfarin can be restarted after 10–14 days70
Alternatives to warfarin Factor Xa and direct thrombin inhibitors are alternatives to warfarin, both of which might reduce the risk of thromboembolism with fewer bleeding ··
complications71
The direct thrombin inhibitor dabigatran (Pradaxa) has been shown to prevent ischaemic stroke to a similar extent as does warfarin, with reduced Level 1C
bleeding complications72

AF=atrial fibrillation. AHA/ASA=American Heart Association/American Stroke Association. ATACH=Antihypertensive Treatment of Acute Cerebral Hemorrhage. FFP=fresh frozen plasma. ICH=intracerebral
haemorrhage. INCH=International Normalized Ratio (INR) Normalization in Coumadin Associated Intracerebral Haemorrhage. OAC=oral anticoagulant. rFVIIa=recombinant factor VIIa. *The level of evidence is
according to the Oxford Centre for Evidence-based Medicine (Level 1A being the highest level of evidence).64

Table 2: Management of anticoagulant-associated intracerebral haemorrhage

initial conservative treatment in patients with ICH.
However, a subgroup analysis showed a potential benefit
for surgery in lobar ICH within 1 cm of the cortical
surface.49 Pending the results of the STICH phase 2 trial
(NCT00716079), craniotomy is currently recommended
in selected patients with lobar clots of more than 30 mL
and within 1 cm of the surface.2,45
MIS is a promising option with many advantages over
conventional craniotomy, such as shorter surgery time,
reduced tissue damage, and the fact that the procedure
can be done with local anaesthesia. The several methods
of MIS include stereotactic guidance with aspiration
and thrombolysis with alteplase52,53,66 or urokinase,54–58
and image-guided stereotactic endoscopic aspiration.59–63
The preliminary analysis of MISTIE (Minimally
Invasive Surgery Plus rtPA for Intracerebral
Hemorrhage Evacuation; NCT00224770), an ongoing
evacuation trial combining stereotactic clot aspiration
with different doses of alteplase, suggests that MIS plus
alteplase shows greater clot resolution than does con-
ventional medical management.66
Although decompressive hemicraniectomy is a life-
saving procedure for malignant middle cerebral artery
infarction, no randomised controlled trial has been done
in patients with ICH. The evidence for the potential
beneficial effect of decompressive craniectomy comes
from small case series.50,51 In the absence of further data,
both MIS and decompressive craniectomy are not
recommended for routine use in patients with ICH.2,45
In anticoagulant-associated ICH (AAICH) the goal of
treatment is to rapidly normalise the international
normalised ratio (INR) and correct clotting factors
immediately (table 2). AAICH should be reversed
immediately with vitamin K and fresh frozen plasma or
prothrombin complex concentrate.45 The INCH (INR
Normalization in Coumadin Associated Intracerebral
Haemorrhage; NCT00928915) trial comparing the use
of fresh frozen plasma with prothrombin complex
concentrate in patients with AAICH is underway.
Further studies are needed to confirm the efficacy of
platelet replacement or other interventions aimed at
preventing or treating antiplatelet-related ICH because

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Description Level of
evidence*
General Little evidence exists for the management of ICP in patients with ICH; data on the management principles for increased ICP in ··
considerations patients with ICH are based on guidelines for traumatic brain injury, which recommend maintenance of CPP at 50–70 mm Hg93
Reduction of increased ICP and maintenance at <20 mm Hg as well as maintenance of CPP at 50–70 mm Hg have become ··
therapeutic targets to prevent potentially life-threatening cerebral hypoperfusion45,93
Medical
Simple Simple non-interventional therapeutic manoeuvres for reduction of raised ICP include elevating the patient’s head to 30° and use Level 2a B
measures of analgesia and sedation2,45
Suggested drugs for analgesia and antitussive effect are morphine or alfentanil; propofol, etomidate, or midazolam are the ··
suggested drugs for sedation
Advanced More aggressive therapies for reducing ICP include osmotic diuretics (mannitol and hypertonic saline solution), drainage of CSF Level 2a B
measures through a ventricular catheter, neuromuscular blockade hyperventilation (with agents such as vecuronium or pancuronium),
and hypothermia2,45
Despite the beneficial effect of corticosteroids on vasogenic oedema (stabilisation of the capillary endothelial junction and Level 3B
reduction of cerebrovascular permeability), corticosteroids are contraindicated because randomised controlled trials showed
no efficacy in the treatment of oedema after ICH for lowering ICP and improving neurological deficit2
Concomitant monitoring of ICP and blood pressure to maintain CPP at >70 mm Hg is recommended when aggressive Level 2a B
measures are being used2
AHA/ASA guidelines recommend the consideration of ICP monitoring and treatment for patients with a Glasgow Coma Scale Level 2b C
score of 8 or less, those with clinical evidence of transtentorial herniation, or those with substantial IVH or hydrocephalus to
maintain CPP at 50–70 mm Hg, depending on the status of cerebral autoregulation45
Hypothermia A small pilot study of 12 patients with large ICH with mild endovascular hypothermia (35°C) for 10 days showed the following: Level 3C
hypothermia is safe and feasible in this patient group; hypothermia prevented the increase of PHE as compared with the matched
historical controls, in whom PHE volume doubled within 2 weeks; no rebound effect was recorded after rewarming, and all patients
survived during the 90 day follow-up period, unlike the historical control group, in which about 25% died because of an increase in
oedema and herniation within the first week of treatment;94 complications such as pneumonia, shivering, and bradycardia did not
seriously affect clinical course during the study
Neurosurgery Definitive neurosurgical interventions include craniotomy or ventriculostomy2 Level 2a B

AHA/ASA=American Heart Association/American Stroke Association. CPP=cerebral perfusion pressure. ICH=intracerebral haemorrhage. ICP=intracranial pressure.
IVH=intraventricular extension of haemorrhage. PHE=perihaematomal oedema. *The level of evidence is according to the Oxford Centre for Evidence-based Medicine
(Level 1A being the highest level of evidence).64

Table 3: Management of perihaematomal oedema and increased intracranial pressure after intracerebral haemorrhage

the usefulness of platelet transfusion in this group of
patients is unclear.45 The decision as to whether or when
to restart anticoagulation therapy after ICH will depend
on the risk of subsequent arterial or venous thrombo-
embolism, the risk of recurrent ICH, and the clinical
state of the patient.
Although guidelines from the American Heart
Association and American Stroke Association (AHA/
ASA)2 suggest restarting warfarin 7–10 days after ICH
onset in patients with a very high risk of thrombo-
embolism, the European Stroke Initiative (EUSI) recom-
mends starting warfarin after 10–14 days.70
Perihaematomal oedema
Clinical features
PHE, which is present in most patients with ICH, can
be associated with increased mass effect and END14,73
and is a predictor of poor functional outcome and
mortality.1,73–75 PHE develops early in the hyperacute
phase (increasing in volume by 75% in the first 24 h),75
evolves over many days, and increases strongly during
the first week 74 before it reaches its maximum during
the second week after bleeding.1,14,76
Although the mechanisms of oedema formation after
ICH are not fully understood, several potential
mechanisms have been postulated for the different
stages of PHE formation after ICH. Whereas early PHE
is caused by the vasogenic effect of pro-osmotic
substances (protein, electrolytes) from the clot, starting
immediately after bleeding and peaking at 4–5 days,76
delayed PHE arises from a combination of vasogenic
and cytotoxic effects and lasts for 2–4 weeks.77 Within
the hyperacute first phase (a few hours post ictus) the
development of hydrostatic pressure during haematoma
formation and clot retraction leads to leakage of serum
proteins from the clot into the surrounding tissue,
resulting in vasogenic oedema.78 A second phase (which
begins a few days post ictus) results from activation of
the coagulation cascade and thrombin production.79 The
third, delayed phase (which begins days to weeks post
ictus) is related to erythrocyte lysis and haemoglobin-
mediated toxic effects caused by the iron-catalysed
production of reactive oxygen species.80,81
Thrombin-induced activation of the inflammatory
cascade and overexpression of MMPs is another
potential mechanism that leads to blood–brain barrier
breakdown and PHE formation after ICH.79,82 MMPs
probably act by enhancing extracellular matrix
proteolysis, damaging the basal lamina, and degrading
c-Fn, a glycoprotein that is essential for haemostasis.83
Radiological evidence of PHE formation after ICH
has been provided by various studies.73–75,84–86 In the

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A B C Management
Figure 2: CT scans showing intraventricular extension of haemorrhage
A non-contrast CT showing left thalamic haematoma with extension of haemorrhage into the third ventricle
(A), a conventional contrast-enhanced CT showing two foci of active contrast extravasations (B), and follow-up
non-contrast CT 12 h later showing pronounced haematoma growth with haemorrhage in both lateral
ventricles and severe hydrocephalus (C). Reproduced from Kim and colleagues,30 by permission of the American
Journal of Neuroradiology.
INTERACT study of patients with CT-confirmed ICH
who were assessed within 6 h of onset, PHE volume
increased within 72 h of the initial CT.84 In an MRI
study, PHE volume increased most rapidly in the first
2 days after symptom onset and peaked towards the end
of the second week.86
Other factors that have been proposed to affect PHE
volume include hyperglycaemia, coagulation factors,
and use of statins.86,87 Likewise, increased serum
concentrations of MMP-988,89 and persistently increased
SBP90 are associated with an increased PHE volume.
Although the possible presence of an ischaemic
penumbra around the area of the ICH—leading to
secondary neuronal injury and cytotoxic oedema—was
previously a concern, evidence against a peri-
haemorrhagic penumbra has since been provided by
MRI and perfusion CT studies, which have linked
perihaematoma hypoperfusion to reduced metabolic
demand rather than tissue ischaemia.91,92
The oedema volume can exceed that of the original
haematoma, leading to substantial additional mass
effect with tissue shifts, and might contribute to further
neuronal injury and poor outcome after ICH.14,73,74,80
Also, rapidly developing PHE could lead to increased
ICP or obstructive hydrocephalus and subsequent
herniation.80 The increased ICP resulting from
surrounding PHE can contribute to brain injury and
END, and to reduced cerebral perfusion pressure.45
Evidence for an effect of PHE on clinical outcome and
mortality after ICH is unclear: although some obser-
vational studies have recorded an association between
PHE and poor outcome,73,74,80 another study detected no
clear association.75 Also, in another study, absolute
oedema volume growth was correlated with a decrease
in neurological status at 48 h after ICH, but not with
3 month functional outcome.86
In the INTERACT trial, both absolute and relative
growth in PHE volume were associated with mortality
or dependency at 90 days after adjustment for age, sex,
and randomised treatment, but not when further
adjusted for baseline haematoma volume.84
106
The goal of therapy for PHE that occurs as a complication
of ICH is to prevent secondary brain insults, reduce ICP,
maintain blood supply and oxygen delivery, and optimise
cerebral metabolism. The treatment options for PHE and
increased ICP complicating ICH are mostly supportive
(table 3). Elevation of the head to 20–30° and avoidance of
pain and fever could minimise any rise in ICP. Medical
measures such as hyperventilation and the use of
analgesia, sedatives, and osmotic diuretics are designed
to lower ICP before placement of an ICP monitor or any
definitive neurosurgical intervention such as craniotomy
or ventriculostomy.2 Placement of an ICP monitor is
recommended, especially in patients with a Glasgow
Coma Scale (GCS) score of less than 8 and those with
transtentorial herniation.45
Intraventricular extension of haemorrhage and
hydrocephalus
Clinical features of IVH
IVH is common after ICH, occurring in 30–50% of
patients, and is a major additional predictor of poor
prognosis (figure 2).9–11,95–97 A relation exists between the
location and volume of ICH and the presence of IVH.11,95
A subanalysis of the activated rFVIIa phase 2 trial showed
a relation between thalamic ICH and increased frequency
of IVH.11 This was attributable to the anatomical closeness
of the thalamus to the third ventricle and the
predisposition for blood to spread medially.11,95
Hallevi and colleagues95 calculated a decompression
range for each location of ICH, the range of ICH volume
within which IVH is more likely to occur during the
acute phase of ICH as the haematoma enlarges and
below which ICH is unlikely to be complicated by IVH.
They noted a narrow decompression range for thalamic
and pontine haemorrhages, a wide range for lobar ICH,
and a non-measurable decompression range for caudate
haemorrhage.95
Several studies have shown that IVH in patients with
ICH is an independent predictor of poor functional
outcome and higher mortality,9–11,43,49,75,95,98 with a reported
overall mortality rate of 50–75%.75,99–101 The 30 day mortality
rate was shown to be 43% in ICH patients with IVH
compared with 9% in those without.9 In the rFVIIa trial,
although 38% of 375 patients with ICH had IVH at
baseline, 45% had developed IVH by 24 h after presentation.
A good functional outcome (mRS 0–3) was achieved by
43% of the patients without IVH at presentation compared
with only 20% of those with IVH at baseline. Similarly, out
of the group that had IVH growth in the first 24 h, only 7%
had a good functional outcome (mRS 0–3) at 90 days.11 A
mean arterial pressure (MAP) of greater than 120 mm Hg
at baseline, a large baseline ICH volume, and the presence
of IVH at presentation were identified as risk factors for
IVH growth.11 Both the presence of IVH at any time and
IVH growth increased the likelihood of death or severe
disability at 90 days.11
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In the subanalysis of the STICH trial, only 15% of the
377 patients with IVH had good (normal, good, or
moderate recovery) Glasgow Outcome Scale functional
outcomes, compared with 31% of the 375 ICH patients
without IVH.10
Proposed mechanisms for the deleterious effects of
IVH on mortality and morbidity include damage to
periventricular brain structures, especially the brainstem,
complications of acute obstructive hydrocephalus, and
IVH-induced inflammatory response, possibly due to
blood and its breakdown products.10,102,103
The volume of IVH affects morbidity and mortality at
30 days.11,98,104 A review of 47 patients with ICH by Young
and colleagues98 identified a lethal volume of 20 mL,
above which patients had a poor outcome. Similarly,
early expansion of IVH worsens clinical outcome and
increases mortality to 50–75%.9
Although IVH volume in itself is associated with poor
outcome, an even stronger association exists between the
total (ICH plus IVH) volume and adverse outcomes.1,10,95,98,104
Another study identified a 40 mL total volume as a cutoff
value, above which patients were 41 times more likely to
have a poor prognosis, and 50 mL as a poor outcome
threshold, above which 100% of patients would have an
unfavourable outcome.104
Clinical features of hydrocephalus
Extension of haemorrhage into the ventricles can impede
normal CSF flow and, with direct mass effects of
ventricular blood, lead to acute obstructive hydrocephalus
(AOH). AOH can be a life-threatening disorder, especially
if the third and fourth ventricles are affected.9–11 Up to
50% of patients with IVH secondary to ICH can develop
hydrocephalus caused by obstruction of the third and
fourth ventricles by ventricular clots.105
Many studies have shown involvement of the third and
fourth ventricles in patients with IVH after ICH to be
predictive of adverse outcome and high mortality.9–11,105 In
a subanalysis of CT images from the STICH trial, the
presence of hydrocephalus reduced the likelihood of
positive outcome from 15·1% to 11·5%.10
Acute hydrocephalus is more common in patients with
high IVH volume (Graeb score ≥6) than it is in patients
with low to moderate IVH volume (Graeb score ≤6).101
Hydrocephalus occurs more with thalamic than with
putaminal haemorrhages and is almost absent in the
case of lobar haemorrhages, probably because small
thalamic haemorrhages can easily compress the cerebral
aqueduct leading to obstruction to normal CSF flow and
subsequent hydrocephalus, whereas small ganglionic
haemorrhages rarely have any effect on ventricular
size.98,105 Communicating hydrocephalus can develop with
impairment of the Pacchioni granulations by ventricular
haemorrhage.97,106,107 Increased ICP can result from large
volume ICH, especially in the presence of IVH with
hydrocephalus, leading to further clinical deterioration
and poor outcome.9–11
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Review
Management
The aim of treatment in ICH patients with IVH and
hydrocephalus is to evacuate the intraventricular
haematoma, thus relieving the obstruction to CSF flow,
reversing ventricular dilatation, and restoring normal
intracerebral pressure (table 4). Insertion of external
ventricular drainage (EVD) can be a life-saving procedure,
relieving acute hydrocephalus and subsequent herniation
in ICH patients with severe IVH and AOH.97,100,108 EVD is
recommended for the treatment of hydrocephalus in
patients with decreased consciousness.45
Because EVD is often occluded by blood clots, leading
to inadequate CSF drainage, thrombolytics can be
instilled into the ventricles to maintain EVD functionality
and promote fast clearance of the ventricles.106,109–117
Findings from the CLEAR IVH (Clot Lysis: Evaluating
Accelerated Resolution of Intraventricular Hemorrhage)
phase 2 trial117 suggest that low-dose alteplase can be safe
and might increase the lysis rate. However, pending the
results of the ongoing CLEAR phase 3 trial (NCT00784134),
routine clinical use of intraventricular fibrinolysis is not
recommended.45 Other treatment options include
endoscopic surgical evacuation of the haemorrhage118–120
and the less-invasive lumbar drainage.97,107,122
Seizures and epilepsy
Clinical features
Seizures are a frequent complication of ICH and can
even be the presenting symptom.123 Seizures most
commonly occur at the onset of ICH, but can be delayed.
About 50–70% of seizures occur within the first 24 h, and
90% in the first 3 days,124–127 with an overall 30 day risk of
seizures of about 8%.123
Early seizures are defined as those occurring within
2 weeks of initial ictus, late seizures occurring there-
after.124,125 Whereas early seizures are thought to be caused
by structural disruption and cellular biochemical
dysfunction, late seizures are attributed to gliosis and the
development of meningocerebral cicatrices.124,125 Early
seizures can be predictive of epilepsy development.128
The incidence of seizures after ICH varies widely
depending on study design, diagnostic criteria, duration
of follow-up, and the population studied. Similarly, the
true incidence of seizures might be underestimated,
because subclinical seizures can be detected with use of
continuous EEG (cEEG) monitoring only. Overall
incidence after ICH is 4·2–20%123,124,127,129,130 for clinical
seizures and 29–31% for subclinical seizures.125,126,131 In a
series of 63 patients with ICH in an intensive care unit
(ICU) who had cEEG monitoring within 72 h of
admission, non-convulsive seizures were detected in
28%, four times the incidence of observable seizures.
The presence of seizures was independently associated
with increased midline brain shift on 48–72 h follow-up
head CT scans, with neurological deterioration.126
In a retrospective review125 of 102 patients with ICH
with cEEG monitoring, 19% had convulsive seizures,
107
 Review

Description Level of evidence*

External EVD insertion has been suggested as a life-saving procedure in patients with ICH with severe IVH and AOH through reduction of ICP and subsequent Level 2b C
ventricular herniation;97,100,108 however, the complications of EVD include occlusion by blood clots leading to inadequate CSF drainage,97,100 infections leading to frequent
drainage EVD exchange,96,107,109 and CH caused by impairment of the Pacchioni granulations by IVH107
AHA/ASA guidelines recommend that:
Patients with a GCS score of 8, those with clinical evidence of transtentorial herniation, or those with substantial IVH or hydrocephalus should be considered Level 2b C
for ICP monitoring and treatment; treatment should aim to maintain a CPP of 50–70 mm Hg, depending on the status of cerebral autoregulation45
Ventricular drainage as treatment for hydrocephalus should be considered in patients with a decreased level of consciousness45 Level 2a B
Intraventricular Compared with ventriculostomy alone, IVF with either urokinase106,109 or alteplase110–112 has been shown to promote early and effective clearance of blood in Level 2b B
fibrinolysis the ventricles, maintain EVD functionality, and reduce the need for permanent shunts as well as improve clinical outcome and reduce mortality;
the benefits of IVF might be offset by complications such as secondary haemorrhage and EVD infection111,113,114
IVF can reduce the mortality rate from a range of 60–90% to only 5%;112 two systematic reviews of clinical studies recorded a 30–50% reduction in mortality Level 2a B
after IVF115,116
Improved short-term outcome in patients with EVD and IVF can improve 30 day106 and 90 day outcome,111 but not long-term outcome after 12 months110 Level 2B
In the CLEAR IVH phase 2 trial, designed to assess the safety of open-label doses of intraventricular alteplase in 52 patients with IVH, one dose of 1 mg Level 3B
alteplase and a dosing interval of 8 h was shown to be the most appropriate dosing for IVH,117 suggesting that low-dose alteplase can be safely given to treat
stable intraventricular clots and can increase the lysis rates; symptomatic bleeding occurred in 4% and bacterial ventriculitis in 2% of patients with a 30 day
mortality rate of 17%117
AHA/ASA guidelines do not recommended the routine use of IVF in clinical practice45 Level 2bB
Endoscopic Evidence for the potential beneficial effect of neuroendoscopic surgical removal of IVH comes from observational studies:118–121 in one study, 24 of 25 patients Level 3B
surgical who had ESE of IVH and obstructive hydrocephalus had resolution of hydrocephalus;120 similarly, in another study of 17 patients with IVH and hydrocephalus
evacuation treated with ESE, all patients had successful resolution of hydrocephalus with good outcomes;121 and in a non-randomised comparison study, patients treated
with ESE of IVH had a higher rate of good recovery at 2 months than did those treated with EVD119
Lumbar LD is an alternative option for extracorporeal CSF drainage in patients with CH and has been shown to be a simple, safe, and less invasive procedure; it avoids ··
drainage the need for EVD exchange and can substantially reduce the incidence of permanent hydrocephalus and the need for shunt surgery; it also has a lower
complication profile than does EVD97,107,122
In a prospective case series of three patients, the combination of IVF and LD was shown to be a simple and promising alternative for the treatment of CH after Level 1C
ICH and IVH122
In a retrospective analysis of 16 patients with persisting CH after secondary IVH who received an EVD and concurrent LD compared with 39 historical patients Level 2b C
treated with EVD alone, LD replaced the need for repeated EVD exchanges, extending the duration of extracorporeal CSF drainage (16 days EVD vs 21 days
EVD plus LD) and eventually reducing the need for a permanent ventriculoperitoneal shunt (18·75% vs 33%; p<0·03) in LD-treated patients107
In a prospective study, 32 patients with ICH and severe IVH with AOH received an EVD (n=32), and of the 28 patients who developed CH, early LD replaced the Level 1C
need for EVD, with one patient requiring a shunt; the additional treatment with either IVF or LD reduced the incidence of EVD exchange (to 32% and 40%,
respectively) and shunt surgery (to 18%)97

AHA/ASA=American Heart Association/American Stroke Association. AOH=acute obstructive hydrocephalus. CH=communicating hydrocephalus. CLEAR IVH=Clot Lysis: Evaluating Accelerated Resolution of
Intraventricular Hemorrhage. CPP=cerebral perfusion pressure. ESE=endoscopic surgical evacuation. EVD=external ventricular drainage. GCS=Glasgow Coma Scale. ICH=intracerebral haemorrhage.
ICP=intracranial pressure. IVF=intraventricular fibrinolysis. IVH=intraventricular extension of haemorrhage. LD=lumbar drainage. *The level of evidence is according to the Oxford Centre for Evidence-based
Medicine (Level 1A being the highest level of evidence).64

Table 4: Management of ventricular extension of haemorrhage and hydrocephalus

13% had electrographic seizures, and 5% had both, with
94% of the seizures detected in the first 72 h. Subclinical
seizures were associated with expanding haemorrhages,
especially if they expanded by more than 30% in the
first 24 h or if they reached the cortex, and were also
associated with a poor outcome. Electrographic seizures
were twice as common (31% vs 14%) in patients with
expanding haemorrhages.125
The reported frequency of status epilepticus is
0·3–21·4%.130,132,133 In an earlier study of 1402 patients with
ICH, status epilepticus occurred in 11 of 65 patients with
seizures and was the initial presentation of ICH in six of
these 65 patients.130 Epilepsy (recurrent seizures) has
been reported to develop in 2·5–4% of patients,124,130 but
Passero and colleagues123 reported the risk of late seizures
or epilepsy in survivors of ICH to be 5–27%. Recurrent
seizures occurred in four of 14 patients in one study,
despite the provision of antiepileptic treatment.133
Although the cause of seizures in patients with ICH is
unclear, the combination of sudden development of a
space-occupying lesion with mass effect, focal ischaemia,
and blood breakdown products has been postulated to
account for seizures early in ICH.124 Early-onset seizures
are thought to be directly related to the insult of ICH to
the brain.127
Identified predisposing factors include haemorrhagic
size, the presence of hydrocephalus, intracranial midline
shift, low GCS, and severe neurological deficit.124 Lobar
location is an independent predictor of early seizures.123
Non-occipital lobar haemorrhages,125–127,133 as well as
subcortical haemorrhages,126 are commonly associated
with seizures.
Conflicting results on the association of seizures after
ICH with clinical outcome and mortality have been
reported. In one study,134 the in-hospital mortality rate
was 37·9% in patients with both acute ICH and IS with
seizures within 48 h of symptom onset compared with
14·4% for patients without seizures. Another study128 of
ICH and IS showed an increased risk of mortality within
30 days if seizures developed within the first 24 h after
stroke (32·1% vs 13·3%). Although mortality rates were
higher in patients with seizures, seizures were not an
independent predictor of mortality at 30 days or of poor
outcome post stroke after adjusting for other factors,

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 Review

Description Level of evidence*

General No randomised controlled trials have been done to guide decisions on seizure prophylaxis or treatment in patients with ICH; however, AHA/ASA guidelines45 ··
considerations recommend the following:
Patients with clinical seizures should be treated with AEDs Level 1A
Patients with a change in mental status who have electrographic seizures on EEG should be treated with AEDs Level 1C
EEG monitoring is indicated in ICH patients with depressed mental status that is out of proportion with the extent of brain injury Level 2a B
Antiepileptic The choice of initial AED depends on individual circumstance and contraindications; the AEDs to be considered for the acute treatment of ··
drugs post-haemorrhagic stroke seizures include intravenous lorazepam (0·05–0·10 mg/kg) followed by a loading dose of phenytoin or fosphenytoin
(15–20 mg/kg), valproic acid (15–45 mg/kg), levetiracetam (500–1500 mg), or phenobarbital (15–20 mg/kg)
Prophylaxis The benefit of seizure prophylaxis after ICH is controversial: some investigators have advocated the use of prophylaxis in most patients126 and previous ··
guidelines2,70 have recommended a 30 day course of prophylactic AEDs in patients with lobar haemorrhage or those who have had seizures, on the basis
of risk reduction of seizures in patients with lobar haemorrhage reported in observational studies123
However, two observational studies have since shown prophylactic therapy with AEDs to be associated with poor outcome:136,137 in a prospective study of Level 3B
98 patients with ICH, prophylactic phenytoin was associated with higher fever and worse outcome at 14 days or at discharge, and worse functional
outcome at 14 day, 28 day, and 3 month follow-up;136 similarly, in another trial, an association was recorded between AED use and worse 3 month
functional outcome137
In the absence of data for patients with ICH showing a benefit of seizure prophylaxis, the most up-to-date AHA/ASA guidelines recommend against Level 3B
prophylactic use of AEDs45

AEDs=antiepileptic drugs. AHA/ASA=American Heart Association/American Stroke Association. ICH=intracerebral haemorrhage. *The level of evidence is according to the Oxford Centre for Evidence-based
Medicine (Level 1A being the highest level of evidence).64

Table 5: Clinical management of seizures and epilepsy after intracerebral haemorrhage

although the risk in patients with ICH was not
independently determined.128
Findings from one study126 showed that post-ICH
seizures are associated with worsening neurological
function as measured with the NIHSS (National
Institutes of Health Stroke Scale), and recorded a trend
towards increased poor outcome, with a mortality rate of
27·8% compared with 15% in those without seizures.126
However, other studies have recorded no substantial
difference in mortality between patients with or without
seizures after stroke,124 and, surprisingly, there was an
association with better outcomes after stroke as measured
with Scandinavian stroke scales.135
Management
No randomised controlled trials (RCTs) have been done
to guide decisions on seizure prophylaxis or treatment
in patients with ICH. Similarly, no definitive evidence
or clear guidelines exist for the choice of treatment or
duration of treatment for patients with one or more
seizures or status epilepticus (table 5). However,
available guidelines recommend that patients with
clinical seizures should be treated with antiepileptic
drugs (AEDs).45 The choice of initial AED is dependent
on the individual characteristics of each patient,
including medical comorbidities, concurrent drugs, and
contraindications. The benefit of seizure prophylaxis
after ICH is controversial. Whereas previous studies
have advocated the use of prophylaxis in most
patients,123,136 two observational studies have since shown
prophylactic therapy with AEDs to be associated with
poor outcome.136,137 Whereas previous guidelines2,64 have
recommended a 30 day course of prophylactic AED in
patients with lobar haemorrhage or those who have had
seizures, the most up-to-date guideline recommends
against prophylactic use.45
Venous thromboembolic events
Clinical features
VTE are a common and potentially fatal complication in
patients with ICH that can manifest as either deep-vein
thrombosis (DVT) or pulmonary embolism (PE).138,139 The
reported rate of clinically symptomatic VTE is 3–7%.138,140,141
Overall, studies have estimated the short-term post-ICH
risk of PE to be 1–2% and of DVT to be 1–4%.138 Subclinical
DVT is more common than is clinically apparent DVT,
with asymptomatic DVT rates occurring in up to 17% of
patients with ICH.142 In a small prospective study of
52 patients with acute ICH, DVT was detected in 40% of
patients within 2 weeks, with one case of PE recorded.143
The high rate was attributed to the extent of paralysis due
to severe stroke. In the rFVIIa trial,8 about 2% of patients
in both the placebo and treatment groups developed
DVT, and about 2% developed PE.8
DVT is a risk factor for PE. PE generally arises from
venous thrombi that develop in a paralysed lower leg or
pelvis.144 However, about 30% of patients diagnosed with
acute PE show no evidence of DVT in their lower legs,
implying that a negative venous duplex ultrasound does
not exclude the diagnosis of acute PE.145
Independent risk factors associated with the
development of VTE in patients with ICH include severe
stroke, lengthy immobilisation, advanced age, and
increased prothrombotic activity.143,146 Discontinuation of
antithrombotic agents after ICH could also accelerate the
formation of DVT.143
Although a high D-dimer value is a useful predictor of
DVT formation in patients with ICH, this value could
also be increased because of the presence of infection or
hyperfibrinolysis caused by the cessation of anti-
coagulation.143
In a retrospective study of symptomatic VTE in patients
with ICH, the most commonly identified risk factors were

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 Review
age (>40 years), immobility due to paresis or restrictions
for mechanical ventilation, presumed infection, and the
presence of an indwelling central venous catheter.141
A systematic review detected racial disparity in the
incidence of VTE after ICH, with a higher rate of DVT in
black patients than in white patients after adjusting for
differences in the risk factors for ICH.147 A sex difference
also exists, with women being at greater risk of VTE.139,148
VTE is associated with a 30 day mortality rate
of 35–52%.2 In the Oxford Community Stroke Project,
5% of patients with ICH died of PE within the first
30 days.3 Both DVT and PE can slow down rehabilitation
and recovery, and extend the duration of hospital stay.144
Management
A clinical dilemma can arise as to the best possible
approach to VTE prevention in patients with ICH, because
anticoagulants can increase the risk of HE or rebleeding.
Although this decision is often made on the basis of a risk–
benefit analysis in the context of the individual patient,
prophylaxis for VTE in patients with ICH has been
addressed in some guidelines.2,149 Options for reducing the
risk of VTE after ICH include intermittent pneumatic
compression, low-dose subcutaneous low-molecular-
weight heparin or unfractionated heparin (table 6).2,45
An even greater clinical therapeutic dilemma is the
management of patients with ICH who subsequently
develop VTE. If untreated, the risk of recurrent fatal PE is
increased and, if treated, patients are at increased risk of
bleeding. Anticoagulation has been estimated to double
the risk of recurrent ICH compared with the overall
recurrence risk of ICH, and the mortality rate associated
with recurrent ICH can be as high as 50%.160 The risk of
recurrent ICH can depend on factors such as the patient’s
age and the location of ICH. Patients with lobar
haemorrhages are at higher risk of rebleeding, probably
due to suspected amyloid angiopathy.161
Insertion of a vena cava filter is recommended in
patients with ICH who develop an acute proximal venous
thrombosis. The decision to start antithrombotic
treatment several weeks after the vena cava filter should
be made on the basis of a risk–benefit analysis of the
potential for rebleeding as well as the patient’s co-
morbidities and mobility.2
Fever
Clinical features
Fever occurs in up to 40% of patients after ICH,162,163 and is
independently associated with a poor outcome and
increased mortality.163–167 The incidence of fever
(temperature >38·3°C) is high in basal ganglionic and
lobar ICH, especially in patients with IVH.45,162,163 The cause
of high temperature after stroke is not always apparent,
although increased body temperature might be a direct
consequence of brain damage caused by stroke or
accompanying infections.164,168 Increased body temperature
could result from damage to the thermostatic centre after
110
hypothalamic stroke164—patients with IVH are thought to
have more of a neurogenic or central fever.166
A high body temperature after ICH is associated with
HE, cerebral oedema, increased ICP, and END.45,169 Fever
after ICH is associated with longer ICU and hospital
stays, poor functional outcome, and increased mortality.167
A prospective study of 390 mixed ischaemic and
intracerebral haemorrhagic stroke patients (9% with
ICH) admitted within 6 h of stroke onset showed that the
relative risk of poor outcome increased by 2·2 times and
that mortality increased by a factor of 1·8 for each 1°C
increase in baseline body temperature.166
In a subanalysis of data from the PAIS (Paracetamol
[Acetaminophen] In Stroke) trial168 of 1332 IS and ICH
patients admitted within 12 h of stroke onset, 10% of
163 ICH patients had admission body temperatures of
more than 37·5°C. An early rise in body temperature
rather than high body temperature on admission was the
greatest risk factor for adverse outcome.164
In a study of 251 cases of ICH, initial body temperature
was not an independent prognostic factor, but an increase
in body temperature during the first 72 h, which occurred
in 91% of patients, was associated with poor clinical
outcome. Also, for those patients surviving the first 72 h
after hospital admission, a longer duration of fever was
associated with a worse outcome.163
In a retrospective study of 330 patients with acute IS
and ICH, of the 37·6% of 330 patients who had fever,
22·7% had a documented infection and 14·8% had fever
without a documented infection.170 Reith and colleagues166
detected infection in a fifth of the 25% of mixed IS and
ICH pyrexial patients (body temperature >37·5°C on
admission within 6 h of stroke onset). Pulmonary and
urinary infections are the main causes of infectious fever
in patients with stroke.162,163,168,171 In the PAIS study, most
infectious fevers were due to pneumonia and urinary
tract infections (UTIs).168 In the review with only ICH
patients, pulmonary infection was diagnosed within the
first 72 h in 84 patients (43% of 196 patients) and UTI was
diagnosed within the same time in 69 patients (35% of
196 patients).163
Management
ICH patients with a high temperature should be
physically examined and investigated to establish the
cause of fever and possibly the source of infection.
Generally, treatment with antipyretics and cooling
blankets is used169 for patients with a sustained fever of
more than 38·3°C (panel). Although new adhesive
surface-cooling systems and endovascular heat-exchange
catheters might prove more effective,171,173 they have not
been systematically investigated in patients with ICH. No
evidence is available from RCTs linking fever treatment
with improved clinical outcome or reduced mortality. A
Cochrane review showed no statistically significant effect
of pharmacological or physical temperature-lowering
therapy in reducing the risk of death or dependency.172 In
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 Review

Description Level of evidence*

Prevention
Non- On the basis of findings from a randomised controlled trial that showed intermittent pneumatic compression combined with elastic stockings to be Level 1B
pharmacological better than elastic stockings alone in the reduction of the rate of asymptomatic DVT after ICH (4·7% vs 15·9%)142 and the finding that graduated
approaches compression stockings alone are ineffective in preventing DVT,150 AHA/ASA guidelines recommend that patients with ICH should have intermittent Level 1B
pneumatic compression for prevention of venous thromboembolism in addition to elastic stockings2,45
Pharmacological Randomised trials,144,151 a non-randomised study,152 and a retrospective study140 have shown pharmacological prophylaxis with LMWH for DVT and PE Level 2b B
approaches prevention 24–48 h after ICH to be safe with no increased risk of haematoma expansion or further bleeding, although LMWH has not been shown to
be better than elastic stockings
On the basis of these studies, AHA/ASA guidelines suggest that after cessation of bleeding, low-dose subcutaneous LMWH or unfractionated heparin can Level 2b B
be considered for prevention of venous thromboembolism in patients who are immobile after 1–4 days from onset of ICH45
Treatment
IVC filters Insertion of an IVC filter is an option for patients who cannot receive therapeutic anticoagulation or for those who have to wait for several weeks ··
before starting anticoagulation;153–156 IVC filters prevent PE by trapping most of the large emboli originating from the deep veins of the pelvis and
feet,157 but the benefits can by counterbalanced by complications such as venous thromboembolism and caval occlusion, with no difference in
mortality153–156
A retrospective review of 371 mixed stroke patients (105 [28%] with ICH) who received an IVC filter recorded a 16% incidence of symptomatic Level 2b C
post-filter DVT, a 0·8% incidence of post-filter fatal PE, and a 5·1% incidence of caval occlusion; other filter-related complications included fracture of
filter, penetration of caval wall, and filter migration156
No randomised controlled trial has compared vena cava filters with anticoagulation in patients with ICH or ischaemic stroke; nonetheless, in the Level 1B
PREPIC randomised controlled trial of 400 patients with documented proximal DVT or PE who received concurrent anticoagulation, IVC filters
reduced the risk of PE, even after 8 years, although there was an associated long-term risk of recurrent DVT but no statistically significant reduction in
mortality, probably because of the older study population, and most deaths were due to cancer or cardiovascular diseases158
Similarly, an earlier randomised study comparing the effectiveness of a combination of anticoagulation and IVC filters versus anticoagulation alone in Level 1B
patients with proximal DVT showed a statistically significant decrease in the incidence of PE in the filter group (1·1% vs 4·8%); there was, however, a
subsequent excess of recurrent DVT, without any difference in mortality153
The AHA/ASA and international guidelines recommend that patients with ICH who develop an acute proximal DVT, particularly those with clinical or Level 2b C
subclinical PE, should be considered for acute placement of a vena cava filter2,149
Anticoagulation The AHA/ASA guidelines recommend that the decision to start antithrombotic therapy several weeks after the placement of a vena cava filter must be Level 2b B
made on the basis of a risk–benefit analysis of the potential for recurrent bleeding (amyloid-related ICH has higher risk of recurrent ICH than does
hypertension-related ICH), as well as associated disorders with increased arterial thrombotic risk (eg, atrial fibrillation), and the overall health and
mobility of the patient2
Surgical The evidence for the benefit of surgical embolectomy as a life-saving procedure for PE as a complication of ICH comes from case series: in one series of Level 3C
embolectomy three consecutive cases of pulmonary embolectomy in patients with ICH with massive PE, the interval between the onset of intracranial bleeding and
emergency surgical embolectomy was 7–16 days, and all three patients survived without any neurological exacerbation;159 however, the problem
associated with surgical embolectomy is the possible exacerbation of intracranial bleeding from systemic heparinisation

AHA/ASA=American Heart Association/American Stroke Association. DVT=deep-vein thrombosis. ICH=intracerebral haemorrhage. IVC=inferior vena cava. LMWH=low-molecular-weight heparin.
PE=pulmonary embolism. PREPIC=Prévention du Risque d’Embolie Pulmonaire par Interruption Cave. *The level of evidence is according to the Oxford Centre for Evidence-based Medicine (Level 1A being
the highest level of evidence).64

Table 6: Prevention and clinical management of venous thromboembolic events after intracerebral haemorrhage

the PAIS RCT,168 no difference was seen between the
placebo group and the group treated with paracetamol in
patients with IS and ICH within 12 h of symptom onset.
However a post-hoc analysis of patients with a baseline
body temperature of 37–39°C who were treated with
paracetamol showed improved outcome. Sources of
infectious fever should be treated with appropriate
antibiotics, and antipyretics should be given to lower
temperature in ICH patients with fever.2
Hyperglycaemia
Clinical features
A high proportion of patients (about 60%) might develop
hyperglycaemia even in the absence of a previous history
of diabetes after ICH.174 Increased blood glucose in the
acute setting of ICH is probably a response to stress and
severity of ICH13 and can persist for up to 72 h after
ICH.174
Many studies have shown that increased serum glucose
on admission is associated with larger haematoma size,
HE, PHE, cell death, and increased risk of poor
outcome,12,32,174–176 and that it is a potent predictor of 30 day
mortality in both diabetic and non-diabetic patients with
ICH13 as well as an independent predictor of early
mortality and worse functional outcome in non-diabetic
patients with ICH.175,176
In the post-hoc analysis of the ATACH trial of
60 patients, the risk of poor outcome (mRS 4–6) in
patients with persistent or increasing serum glucose
concentrations was more than twice that of patients with
a reduction in serum glucose concentrations (relative
risk [RR]=2·64, 95% CI 1·03–6·75). Also, the RRs were
2·59 (1·27–5·30) for HE of more than 33%, and 1·25
(0·73–2·13) for a relative oedema expansion of more
than 40%.177
Management
Poor outcomes associated with hyperglycaemia could be
avoided or minimised through monitoring glucose and
maintaining normoglycaemia (table 7). Control of
hyperglycaemia in the acute setting of ICH decreases the
likelihood of HE, PHE, ICP, and seizures, and improve

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 Review

multifactorial process that includes activation of the

Panel: Clinical management of fever and infection after intracerebral haemorrhage neuroendocrine systems (sympathetic nervous system,
The goal should be to maintain normothermia and treat infections in patients with glucocorticoid system, or the renin–angiotensin axis),
ICH. Patients with ICH and sustained fever in excess of 38·3°C should be treated with increased cardiac output, and stress response to
antipyretics and cooling blankets163,169 (Level 1C). However, there is no evidence from conditions such as increased ICP, headache, and
randomised controlled trials to link fever treatment with improved clinical outcome or urinary retention.45,180,182
reduced mortality. A Cochrane review of five pharmacological temperature-lowering Many studies have shown an association between
trials and three physical cooling trials with 423 participants recorded no statistically increased BP in the acute phase of ICH and HE, PHE,
significant effect of pharmacological or physical temperature-lowering therapy in and rebleeding.19,36,37,90 Increased BP in the acute setting of
reducing the risk of dependency (odds ratio 0·9, 95% CI 0·6–1·4) or death (0·9, ICH is associated with worse outcome and increased
0·5–1·5)172 (Level 1C). Equally, an updated meta-analysis of a Cochrane review with six mortality.180,182,183 In a large study of 3930 mixed stroke
pharmacological temperature-lowering therapies did not show any statistically patients (1760 with ICH), the in-hospital case-fatality rate
significant difference between the treated and placebo groups in the proportion of was 5·9% for patients with ICH. Also, both SBP and
patients who were alive and independent (modified Rankin score ≤2) at final follow-up diastolic BP were associated with odds of death or
(1·1, 0·9–1·3)168 (Level 1C). In PAIS, a randomised controlled trial, treatment with disability in such patients.183
high-dose acetaminophen (6 g daily) in 1400 patients with ischaemic stroke and ICH However, the effect of BP levels on mortality seems to
within 12 h of symptom onset was associated with a 0·26°C (95% CI 0·18–0·31) conform to a U-shaped distribution after ICH, as poorer
reduction in mean body temperature measured 24 h after admission; the trial did not outcomes have also been seen at very low SBP
provide sufficient evidence to lend support to routine use of high-dose paracetamol in (<120 mm Hg) and at very high (>220 mm Hg) SBP
patients with acute stroke. However, in a post-hoc analysis of patients with a baseline values.184
body temperature of 37–39°C treated with paracetamol, a 9% absolute increase was
recorded in the number of patients with improved outcome, with a number needed to Management
treat of 11; serious adverse events occurred in 8% of the paracetamol group versus 10% The poor outcome associated with increased BP after
of the placebo group (Level 1B). Although no evidence from randomised controlled ICH could be minimised with BP monitoring and
trials is available to lend support to the routine use of physical or pharmacological treatment aimed at maximisation of cerebral perfusion
strategies to reduce temperature in patients with acute stroke, the AHA/ASA guidelines while minimising ongoing bleeding (table 8). The
recommend that the sources of fever should be treated with appropriate antibiotics rationale for lowering BP after ICH is because SBP
and that antipyretic drugs should be given to lower temperature in febrile patients reduction can reduce the rate of HE and possibly improve
with ICH (Level 1C).2 clinical outcome.
The INTERACT trial showed that a reduction of SBP to
AHA/ASA=American Heart Association/American Stroke Association. ICH=intracerebral haemorrhage. PAIS=Paracetamol
140 mm Hg is safe and might reduce the risk of HE in
(Acetaminophen) In Stroke. The level of evidence is according to the Oxford Centre for Evidence-based Medicine (Level 1A
being the highest level of evidence).64 patients treated within 6 h of onset of ICH, but had no
effect on outcome.20,46 In ATACH, aggressive SBP
reduction to 110–140 mm Hg in the first 24 h was well
outcomes,12,177 although the optimum glucose target and tolerated, with a low risk of HE, neurological deterioration,
duration of glucose control in patients with ICH are and in-hospital mortality.47
unclear. However, studies have suggested targeting a The results of both INTERACT 2 and ATACH 2 are
glucose concentration of 150 mg/dL in the acute setting of awaited, and might further answer the question of
ICH,12,174 and the avoidance of hyperglycaemia during the whether there are other benefits of early SBP reduction
first 72 h after symptom onset, possibly because admission in patients with ICH, and provide clearer evidence for
hyperglycaemia can persist for at least 72 h post ictus.174,177 the target BP and the choice of drugs. Pending these
Although large RCTs are needed to define the optimum results, the AHA/ASA guidelines recommend BP
glucose target and duration of treatment that can improve lowering if SBP is 150–220 mm Hg or MAP is higher
clinical outcomes in patients with ICH, an increased than 150 mm Hg, and that acute lowering of SBP to
serum glucose of more than 140 mg/dL (>7·8 mmol/L) 140 mm Hg is probably safe.45 Meanwhile, the EUSI
should be treated with insulin.2,45 recommends a target of 160/100 mm Hg or a MAP of
125 mm Hg in patients with a history of hypertension
Increased blood pressure and 150/90 mm Hg or a MAP of 110 mm Hg in those
Clinical features without a history of hypertension.64
Increased BP (≥140/90 mm Hg) is common in the acute
phase of ICH, occurring in more than 70% of patients on Conclusions
presentation.180,181 Increased BP in the acute setting of Complications occurring during the acute phase of ICH
ICH occurs even in the absence of a previous history of add further detrimental effects to an already potentially
hypertension and is independently associated with poor fatal disorder and substantially affect the clinical
outcome.180,182 outcome. In view of the small number of therapeutic
The mechanism for the acute increase of BP after options available for ICH, a need exists to provide the
ICH is unknown. However, it is proposed to be a best evidence-based supportive care. Patients should be

112 www.thelancet.com/neurology Vol 11 January 2012

 Review

managed in a neuroscience ICU or a similar setting
during the acute phase of ICH, with continuous
monitoring of vital signs and frequent neurological
assessment. Improved surveillance is needed for the
early detection of complications, which should be
managed on the basis of current recommendations and
guidelines, especially when little evidence exists or
when trials are still in progress. Once patients are
stabilised, early rehabilitation is needed to prevent or
reduce the risk of further complications. The

Description Level of evidence*

General Data from the post-hoc analysis of the ATACH trial has linked a decrease in serum glucose concentration to a Level 1B
considerations reduction in haematoma expansion and improved clinical outcome177
Optimum The optimum glucose target is unclear and various glucose concentrations from 127 mg/dL to 180 mg/dL have been Level 1B
glucose target suggested; some prospective studies have suggested a target glucose concentration of 150 mg/dL in the acute
setting of ICH12,174
In the Oxfordshire Community Stroke Project, in 645 patients (86%) with ischaemic stroke and 105 (14%) with Level 2B
haemorrhagic stroke, a plasma glucose concentration higher than 144 mg/dL (>8 mmol/L) was associated with
increased mortality, particularly in the first month after stroke178
In the Acute Brain Bleeding Analysis, a prospective study of 1387 patients with ICH, an admission glucose Level 1B
concentration of >167 mg/dL was shown to be an independent risk factor for early mortality176
Optimum The optimum duration of glucose control is unclear, although studies have suggested the avoidance of hyperglycaemia ··
duration of during the first 72 h of symptom onset, possibly because admission hyperglycaemia can persist for up to 72 h post ictus174,177
glucose control In a post-hoc analysis of the ATACH trial, patients who had serum glucose reduction during the first 72 h after ICH had Level 1B
a lower relative risk of death or disability at 3 months177
In a prospective observational study of 295 patients, individuals with a serum glucose concentration maintained Level 1B
within 60–150 mg/dL during the first 72 h after ICH did better than those with a persistently high serum glucose
concentration174
In GIST-UK, which had a shorter duration than did ATACH, 24 h of intensive glucose control did not reduce mortality Level 2B
or improve functional outcome in the treatment group,179 although the trial had a small number of patients with ICH
(114 of the total 933) randomly allocated to treatment within 24 h of stroke onset; no separate analysis for patients
with ICH was reported
AHA/ASA guidelines suggest that serum glucose concentrations of >140 mg/dL (>7·8 mmol/L) should be treated Level 2a C
with insulin2,45

AHA/ASA=American Heart Association/American Stroke Association. ATACH=Antihypertensive Treatment of Acute Cerebral Hemorrhage. GIST-UK=UK Glucose Insulin in Stroke
Trial. ICH=intracerebral haemorrhage. *The level of evidence is according to the Oxford Centre for Evidence-based Medicine (Level 1A being the highest level of evidence).64

Table 7: Clinical management of hyperglycaemia after intracerebral haemorrhage

Description Level of evidence*

Blood pressure control The INTERACT pilot trial that compared intensive (target SBP 140 mm Hg) with guideline-based (target SBP 180 mm Hg) BP control showed the Level 1B
feasibility and safety of early intensive BP reduction within the first 6 h of onset of supratentorial ICH; however, no statistically significant
difference was recorded in functional outcome at 3 months between the two groups (median mRS score was 2 in both groups; p=0·66)20
In the ATACH phase 1 trial, patients with a SBP of >170 mm Hg were treated with intravenous nicardipine within 6 h of onset of lobar Level 1B
supratentorial ICH to reduce BP in three escalating target BP tiers: tier 1 (170–200 mm Hg; n=18), tier 2 (140–170 mm Hg; n=20), and tier 3
(110–140 mm Hg; n=22); BP reduction was safe and feasible in all three tiers 47

AHA/ASA guidelines recommend that in patients presenting with a SBP of 150–220 mm Hg, acute lowering of SBP to 140 mm Hg is Level 2a B
probably safe45
Target blood pressure The following target BP should be considered in various situations:2,45
If SBP is >200 mm Hg or MAP is >150 mm Hg, aggressive reduction of BP could be considered with continuous intravenous infusion, with Level 2b C
frequent BP monitoring every 5 min
If SBP is >180 mm Hg or MAP is >130 mm Hg and there is the possibility of increased ICP, then consider monitoring ICP and reducing BP using
intermittent or continuous intravenous drugs while maintaining a cerebral perfusion pressure of 60 mm Hg
If SBP is >180 mm Hg or MAP is >130 mm Hg and there is no evidence of increased ICP, then consider a slight reduction of BP (eg, MAP of
110 mm Hg or target BP of 160/90 mm Hg), using intermittent or continuous intravenous drugs to control BP, and clinically re-examine the
patient every 15 min
If SBP exceeds 180 mm Hg or MAP exceeds 130 mm Hg, management should involve either bolus or continuous infusion of drugs to a target Level 2b C
MAP of 110 mm Hg or less or a goal BP of 160/90 mm Hg
Antihypertensive Suitable antihypertensive drugs include labetalol, esmolol, or nicardipine (drugs with a cerebral vasodilation effect should be avoided)2 Level 2bC
drugs recommended Labetalol: 5–20 mg (intermittent boluses) every 15 min or 2 mg/min in continuous infusion (drip)
in AHA/ASA guidelines Esmolol: 250 mcg/kg (loading dose), then 25–300 mcg/kg per min (maintenance)
Nicardipine: 5–15 mg/h
Hydralazine: 5–20 mg (intermittent boluses)
Nitroprusside: 0·1–10 mcg/kg per min

AHA/ASA=American Heart Association/American Stroke Association. ATACH=Antihypertensive Treatment of Acute Cerebral Haemorrhage. BP=blood pressure. ICH=intracerebral haemorrhage. ICP=intracranial
pressure. INTERACT=Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial. MAP=mean arterial pressure. mRS=modified Rankin score. SBP=systolic blood pressure. *The level of evidence is
according to the Oxford Centre for Evidence-based Medicine (Level 1A being the highest level of evidence).64

Table 8: Clinical management of raised blood pressure after intracerebral haemorrhage

www.thelancet.com/neurology Vol 11 January 2012 113

 Review
Search strategy and selection criteria
We searched Medline and the Cochrane Library, reference lists
of retrieved articles, and main journal contents pages, and we
also did cross referencing. Search terms included
“h(a)emorrhagic stroke”, “cerebral h(a)emorrhage”,
“intracerebral h(a)emorrhage”, “primary intracerebral h(a)
emorrhage”, “spontaneous intracerebral h(a)emorrhage”,
“complications”, “neurological complications”, “medical
complications”, “management”, “treatment”, and “outcome”.
The search included both human and animal studies, and was
restricted to studies published in English before November,
2011. Studies were selected on the basis of relevance to the
topics covered in the Review. Guidelines for the management
of acute ischaemic stroke and intracerebral haemorrhage
from the American Heart Association and the European
Stroke Organisation were also reviewed.
implementation of appropriate preventative and thera-
peutic interventions could minimise the morbidity and
mortality associated with this devastating type of
stroke. A clear need exists for further research into the
prevention and treatment of ICH complications to
improve the level of evidence available, because most
guidelines and recommendations are based on
empirical data.
Contributors
JSB searched the literature, reviewed available studies, and wrote the
paper. AMB reviewed and made critical revisions of the paper.
Conflicts of interest
We declare that we have no conflicts of interest.
Acknowledgments
We are grateful for funding received from the Biomedical Research
Centre, the Fondation Leducq, the Dunhill Medical Trust, the Henry
Smith Charity, and the Oxford University Hospitals NHS Trust, UK.
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