intracerebral hemorrage

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Intracerebral haemorrhage

Adnan I Qureshi, A David Mendelow, Daniel F Hanley

Intracerebral haemorrhage is an important public health problem leading to high rates of death and disability in adults.Although the number of hospital admissions for intracerebral haemorrhage has increased worldwide in the past10 years, mortality has not fallen. Results of clinical trials and observational studies suggest that coordinated primaryand specialty care is associated with lower mortality than is typical community practice. Development of treatment goalsfor critical care, and new sequences of care and specialty practice can improve outcome after intracerebral haemorrhage.Specific treatment approaches include early diagnosis and haemostasis, aggressive management of blood pressure,open surgical and minimally invasive surgical techniques to remove clot, techniques to remove intraventricularblood, and management of intracranial pressure. These approaches improve clinical management of patientswith intracerebral haemorrhage and promise to reduce mortality and increase functional survival.

IntroductionNon-traumatic intracerebral haemorrhage results from

rupture of blood vessels in the brain. It is a major publichealth problem1with an annual incidence of 1030 per100 000 population,1,2accounting for 2 million (1015%)3of about 15 million strokes worldwide each year.4Hospital admissions for intracerebral haemorrhagehave increased by 18% in the past 10 years, 5probablybecause of increases in the number of elderly people,6many of whom lack adequate blood-pressure control,and the increasing use of anticoagulants, thrombolytics,and antiplatelet agents. Mexican Americans, LatinAmericans, African Americans, Native Americans,Japanese people, and Chinese people have higherincidences than do white Americans.2,79 Thesedifferences are mostly seen in the incidence of deep

intracerebral haemorrhage and are most prominent inyoung and middle-aged people. Incidence might havedecreased in some populations with improved access tomedical care and blood-pressure control.810

Primary and secondary (anticoagulant-induced) intra-cerebral haemorrhage have similar underlying patho-logical changes.11Intracerebral haemorrhage commonlyaffects cerebral lobes, the basal ganglia, the thalamus,the brainstem (predominantly the pons), and the

cerebellum as a result of ruptured vessels affected byhypertension-related degenerative changes or cerebral

amyloid angiopathy.1

Most bleeding in hypertension-related intracerebral haemorrhage is at or near thebifurcation of smallpenetrating arteries that originatefrom basilar arteries orthe anterior, middle, or posteriorcerebral arteries.12Small artery branches of 50700 min diameter often have multiple sites of rupture; someare associated with layers of platelet and fibrin aggre-gates. These lesions are characterised by breakage ofelastic lamina, atrophy and fragmentation of smoothmuscle, dissections, and granular or vesicular cellulardegeneration.12,13Severe atherosclerosis including lipiddeposition can affect elderly patients in particular.Fibrinoid necrosis of the subendothelium with sub-sequent focal dilatations (microaneurysms) leads to

rupture in a small proportion of patients.12

Cerebral amyloid angiopathy is characterised by thedeposition of amyloid- peptide and degenerative

changes (microaneurysm formation, concentricsplitting, chronic inflammatory infiltrates, and fibrinoidnecrosis) in the capillaries, arterioles, and small andmedium sized arteries of the cerebral cortex,leptomeninges, and cerebellum.14 Cerebral amyloidangiopathy leads to sporadic intracerebral haemorrhagein elderly people, commonly associated with variationsin the gene encoding apolipoprotein E, and a familialsyndrome in young patients, typically associated withmutations in the gene encoding amyloid precursorprotein.15 White-matter abnormalities (eg, leukoariosis)

seem to increase the risk of both sporadic and familialintracerebral haemorrhage, suggesting a shared vascularpathogenesis.16,17

Intracerebral haemorrhage associated with the takingof oral anticoagulants typically affects patients withvasculopathies related to either chronic hypertension orcerebral amyloid angiopathy, which might representexacerbation of an existing risk of clinical and subclinicaldisease.16

PathophysiologyThe regions surrounding haematomas are characterised

by oedema, apoptosis and necrosis, and inflammatory

Lancet2009; 373: 163244

Zeenat Qureshi Stroke Research

Center, Department of

Neurology and Neurosurgery,

University of Minnesota, MN,

Minnesota, USA

(A I Qureshi MD); Department

of Neurosurgery, University of

Newcastle, Newcastle, UK

(A D Mendelow FRCS); and

Division of Brain Injury

Outcomes, Johns Hopkins

Medical Institutions,

Baltimore, MD, USA

(D F Hanley MD)

Correspondence to:Dr Adnan I Qureshi, Department

of Neurology, University of

Minnesota, 12-100 PWB,

516 Delaware St SE, Minneapolis,

MN 55455, USA

[email protected]

Search strategy and selection criteria

We based our review on personal knowledge of the subject

supplemented by data derived from multicentre randomised

trials, and selected non-randomised or observational clinicalstudies. The information was identified with multiple

searches on Medline from 2002 to the present by cross

referencing the following keywords: cerebral haemorrhage,

intracerebral hemorrhage, neuroimaging, clinical

studies, randomised trials, cytotoxicity, oedema,

haemostatic treatment, factor VII, acute hypertension,

surgery, endoscopic evacuation, stereotactic surgery,

intraventricular catheter, hydrocephalus, and oral

anticoagulants. Other pertinent articles were identified

through review of bibliography from selected articles. We

also reviewed abstracts from pertinent scientific meetings.


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060 min

04 h

4 h to 7 days

TFNK-

Cytochrome C

Neuronal and glial

mechanical disruption,oligaemia or ischaemia

Thrombin,ferrous iron,

haemin,halotransferrin

release

Neuronal and

glial mechanicalstretch

Calcium influx,

mitochondrial failure

Increased BBB

permeability,vasogenic oedema

Recruitment of PMNsand macrophages

Sodium accumulation,

cytotoxic oedema,necrosis

Caspase activation,apoptosis in neurons

and glia

AQ-4 expression inastrocytes, breakdown

of connective tissuein BBB, expression of

adhesion molecules

Haematoma

Glutamaterelease

Microglialactivation

Oxygen freeradicals

MMP

Complementfactors

TNFInterleukin 1

Figure :Cascade of neural injury initiated by intracerebral haemorrhage

The steps in the first 4 h are related to the direct effect of the haematoma, later steps to the products released from the haematoma. BBB=bloodbrain barrier.

MMP=matrix metallopeptidase. TNF=tumour necrosis factor. PMN=polymorphonuclear cells.

A

E F J

B C D

G H I

Figure :Progression of haemotoma and oedema on CT

Top: hyperacute expansion of haematoma in a patient with intracerebral haemorrhage on serial CT scans. Small haematoma detected in the basal ganglia and

thalamus (A). Expansion of haematoma after 151 min (B). Continued progression of haematoma after another 82 min (C). Stabilisation of haematoma after another

76 min (D). Bottom: progression of haematoma and perihaematomal oedema in a patient with intracerebral haemorrhage on serial CT scans. The first scan (E) was

acquired before the intracerebral haemorrhage. Perihaematoma oedema is highlighted in green to facilitate recognition of progression of oedema. At 4 h after

symptom onset there is a small haematoma in the basal ganglia (F). Expansion of haematoma with extension into the lateral ventricle and new mass-effect and

midline shift at 14 h (G). Worsening hydrocephalus and early perihaematomal oedema at 28 h (H). Continued mass-effect with prominent perihaematomal oedema

at 73 h (I). Resolving haematoma with more prominent perihaematomal oedema at 7 days (J).


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cells.18Haematomas induce injury (figure 1) by mech-anical disruption of the neurons and glia, 1followed bymechanical deformation causing oligaemia, neuro-transmitter release, mitochondrial dysfunction, andmembrane depolarisation.1921Dependent on the severityof mitochondrial dysfunction, the results of injuryrange from temporary metabolic suppression(hibernation phase) to cellular swelling and necrosis. Asecondary cascade of injury is started by products ofcoagulation and haemoglobin breakdown, in particularthrombin, which activate of microglia by 4 h afterinjury.2225 Activated microglia26 release products thatinduce breakdown of the bloodbrain barrier, vasogenicoedema, and apoptosis in neurons and glia.2732

Haemostasis is initiated by local activation ofhaemostatic pathways and mechanical tamponade.33,34

However, about 73% of patients assessed within 3 h ofsymptom onset have some degree of haematomaenlargement35and up to 35% have clinically prominentenlargement35(figure 2). Most haematoma enlargementoccurs within 3 h, although enlargement can occur up to12 h after onset.36,37Perihaematomal oedema increases involumeby about 75% in the first 24 h after intracerebralhaemorrhage,38peaks around 56 days,39and lasts up to14 days.40 Early large oedema volume relative tohaematoma volume makes the greatest contribution tooutcome.41 However, oedema that is small initially canincrease in volume in the first 24 h after haemorrhage.38An acute hypometabolic and hypoperfusion (hibernation)phase,42,43with mitochondrial dysfunction44and metabolic

failure,45

has been reported in the region surroundingthe haematoma (figure 3). Regional hypoperfusion inclinical46,47 and experimental studies48,49 does not alwaysseem severe enough to induce ischaemia and might besecondary to hypometabolism. In the presence of veryhigh intracranial pressure and low cerebral perfusionpressure, the risk of global ischaemia is high. A variablereperfusion phase lasts from 2 days to 14 days, and anormalisation phase develops after 14 days, withre-establishment of normal cerebral blood flow in allviable regions.

Diagnosis, clinical features, and outcomesAlthough CT scanning is the first-line diagnostic

approach, MRI with gradient echo can detect hyperacuteintracerebral haemorrhage with equal sensitivity andoverall accuracy50,51and is more accurate for the detectionof microhaemorrhages (figure 4). Perihaematomal extra-vasation of intravenous contrast on CT scan can detectongoing bleeding.52,53Cerebralangiography is needed todiagnose secondary causes of intracerebral haemorrhage,

such as aneurysms, arteriovenous malformations, duralvenous thromboses, and vasculitis1,34,54,55 (figure 5). MRIand magnetic-resonance angiography can also identifysecondary causes of intracerebral haemorrhage such ascavernous malformations,55 although their sensitivity isnot well established.

T2 Pre B0

Post B0

Lactate

TTP

Figure :Advanced MRI of lobar intracerebral haemorrhage

Left: before craniotomy. Middle: after craniotomy for treatment of mass-effect and removal of haematoma.

Sequential T2, lactate magnetic resonance spectroscopy, and perfusion studies showed qualitative decreases of

perihaematomal oedema and perihaematomal lactate and increased occipital regional perfusion measured as time to

peak of bolus injectate (TTP) after removal of clot; TTP is represented by intensity and distribution of green colour.

Right: magnetic susceptibility images show paramagnetic influence before surgery and limited susceptibility after

removal of the iron-containing blood clot by craniotomy. Figures provided by J Ricardo Carhuapoma (Johns Hopkins

Medical Institution, Baltimore, MD, USA).

Figure :Detection of microhaemorrhages with MRI and CT scans

Left: asymptomatic pontine microbleed (arrow) in a patient with ischaemic stroke shown as focal hypointensity

on gradient echo MRI. Right: microbleed not detected on CT scan. Figures are provided by David S Liebeskind

(University of California at Los Angeles, CA, USA).


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Classic presentations, such as rapid-onset focal neuro-logical deficits, decreased consciousness, and signs ofbrainstem dysfunction, are related to the size and

location of haematoma.1

Neurological deterioration iscommon before56and during57hospital admission and isrelated to early haematoma enlargement or lateworsening of oedema.58 Several descriptors of diseaseseverity are predictive of early death, including age,initial score on the Glasgow coma scale (GCS),haematoma volume, ventricular blood volume,59 andhaematoma enlargement.35

Mortality at 3 months was 34% in a review of586 patients with intracerebral haemorrhage from30 centres.60In other studies it was 31% at 7 days, 59% at1 year, 82% at 10 years, and more than 90% at 16 years.61,62Subsequent risk of other cardiovascular events was

4% for all stroke, 2% for intracerebral haemorrhage, and1% for ischaemic stroke per patient-year.63Patients with alobar haemorrhage had a high rate of recurrence (4% per

patient-year). Asymptomatic disease progression isparticularly common when microbleeds and whitematter abnormalities are taken into account.64Effects ofrecurrent bleeding can be changed by antihypertensivetreatment;65whether progressive functional impairmentsare equally treatable is unknown.66

ManagementOverall principlesIn a review of 1421 patients with intracerebral haemor-rhage, care limitations or withdrawal of life-sustaininginterventions was the most common (in 68%) cause ofdeath.67A state-wide survey in the USA68showed that the

24 h Days 17 Days 814 Post dischargeEmergency departmentEvents

Lobar haemorrhages

Cerebellar haemorrhage

Basal ganglionic, thalamic,

or pontine haemorrhage

Conservative management; cerebral angiography in

normotensive patients age 45 years

Consider external ventricular drainage; cerebral angiography

in patients with isolated intraventricular haemorrhage

Intraventricular

haemorrhage/hydrocephalus

Consider Intravenous insulin infusion

Oral paracetamol

Oral hypoglycaemic drugs or subcutaneous insulin if required

Prophylaxis

Clinical orelectroencephalographic

seizures

Clinically significant

intracranial mass-effect ortranstentorial herniation

Neurological, respiratory,and haemodynamicmonitoring

Impaired consciousness

(initial Glasgow comascale score


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odds of dying in hospital were associated with thefrequency of use of do-not-resuscitate orders. In anotherstudy, in-hospital mortality was lower in patients treatedin an intensive-care neurology unit.69 These studiesprovide indirect evidence that aggressive medicalmanagement and specialist care can improve the overalloutcome in patients with intracerebral haemorrhage. Inthe USA, admissions for haemorrhage to urban teachinghospitals increased from 30% in 199091 to 49%in 200001.5 Mortality was decreased substantially forpatients admitted to urban teaching hospitals but noturban non-teaching hospitals and rural hospitals,suggesting that changing trends in admissions might bebeneficial.5 Trials addressing a single severity factor(haemorrhage volume70 or haematoma enlargement71)have been physiologically successful but without clinical

benefit. These results emphasise that a single treatmentapproach might accomplish its physiological goal but beinsuffi cient to produce clinical benefit, thus opening thepossibility that well organised, multimodal therapyaddressing each of the modifiable factorshaematomavolume, ventricular blood, and haematoma enlarge-mentmight be needed.72

Early assessment and managementAirway support,1 blood-pressure control,73 intracranialpressure treatment,74and anticoagulation reversal75arecommonly started in emergency departments, whichare also the site of many first neurosurgical con-sultations for patients with intracerebral haemorrhage.1

Observational studies show that about 30% of patientswith supratentorial haemorrhage and almost allpatients with brainstem or cerebellar haemorrhagehave either decreased consciousnessor bulbar muscledysfunction necessitating intubation.76 Rapiddeterioration, clinical evidence of transtentorial

herniation, or mass-effect or obstructive hydrocephaluson neuroimaging should mandate an emergentneurosurgical consultation for possible intraventricularcatheter placement or surgical evacuation andconcomitant use of hyperventilation and intravenousmannitol7779 (figure 5). The risk of neurologicaldeterioration and cardiovascular instability is greatestin the first 24 h after symptom onset,80 and frequent

assessment of patients neurological status andhaemodynamic variables in dedicated intensive-careunits is needed.

Acute haemostatic treatmentActivated recombinant factor VII (fVIIa) promoteshaemostasis at sites of vascular injury and limits haema-toma enlargement after intracerebral haemorrhage. Arandomised, double-blind, placebo-controlled phase IItrial81 treated 399 patients within 3 h of onset withplacebo or 40 m/kg, 80 m/kg, or 160 g/kg of fVIIa.Overall, the mean increase in haematoma volume was29% in the placebo group, compared with 1116% in

the groups given fVIIa. Mortality at 90 days was 29% forpatients who received placebo and 18% for those whoreceived fVIIa. The phase III fVIIa for AcuteHemorrhagic Stroke Treatment (FAST) trial 71assessedthe effi cacy of fVIIa in patients with intracerebralhaemorrhage who presented within 3 h of symptomonset. Of 821 patients, 263 received placebo, 265 received20 g/kg, and 293 received 80 g/kg of fVIIa. The abilityof fVIIa to limit expansion was similar to the initial trialfor both the 20 g/kg and 80 g/kg doses. However, at3 months, 24% given placebo had died or had disabilitycompared with 26% and 29% of patients given20 g/kg and 80 g/kg of fVIIa, respectively; mortalitywas not different between the groups. The rate ofarterial thrombosis was higher in patients treated with80 g/kg of fVIIa (10%) than in those treated with

placebo (5%) or 20 g/kg of fVIIa (6%). Thus, thispivotal trial of fVIIa did not confirm better functionaloutcomes despite producing a significant reduction inrate of haematoma expansion. The absence of majorbenefit for fVIIa, despite its ability to stabilise bleeding,suggests that additional treatments, such as surgicalevacuation after stabilisation might be needed tochange the natural history of intracerebralhaemorrhage. The FAST trial subgroup analysis82suggested potential benefit for patients younger than70 years, with baseline haematoma volume less than60 mL, baseline intraventricular haemorrhage volumeless than 5 mL, and time fromonset less than or equalto 25 h.

Management of mass-effects causing intracranialhypertensionMass-effects resulting from haematomas, oedematoustissue surrounding haematomas, and obstructive hydro-cephaluswith subsequent herniation are a major causeof death in the first few days after intracerebral haemor-rhage. Monitoring of intracranial pressure mightidentify the risk of neurological deterioration83 inpatients with impaired consciousness.55 Intensive careleading to controlled cerebral perfusion pressure of5070 mm Hg might improve outcome.83

Two randomised trials showed no benefit on regionalcerebral blood flow, neurological improvement, mor-

tality, and functional outcomes from regular use ofintravenous mannitol boluses.8487 Therefore, onlyshort-term use of mannitol in patients with intra-cerebral haemorrhage under special circumstances,such as transtentorial herniation or acute neurologicaldeterioration associated with high intracranial pressureor mass-effect, should be considered. A single-centreobservational study suggested that aggressive, timelyreversal of transtentorial herniation through the useofhyperventilation and osmotic drugs improved thelong-termoutcome.74

The American Stroke Association (ASA) StrokeCouncil88 recognises the absence of definitive clinical


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trial evidence in this specialty but recommendsmonitoring of intracranial pressure in patients treatedwith osmotic diuretics, cerebrospinal fluid drainage viaventricular catheter, neuromuscular blockade, andhyperventilation. The European Stroke Initiative (EUSI)guidelines 54 recommend monitoring of intracranialpressure for patients who need mechanical ventilationand recommend treatment in patients who haveneurological deterioration related to increasing cerebraloedema on neuroimaging or high intracranial pressure.Both guidelines recommend selective use of mannitol,hypertonic saline, and short-term hyperventilation tomaintain cerebral perfusion pressure greater than70 mm Hg.

Management of blood pressure

The acute hypertensive response in intracerebralhaemorrhage is characterised by its high prevalence,self-limiting nature, and prognostic significance.89In ananalysis of 45 330 patients with intracerebral haemor-rhage, 75% had systolic blood pressure greater than140 mm Hg and 20% greater than 180 mm Hg atpresentation.90 The high blood pressure might besecondary to uncontrolled chronic hypertension, withdisruption of central autonomic pathways by intra-cerebral haemorrhage.89 High blood pressure isassociated with haematoma enlargement and pooroutcome;37however, an exact cause and effect relation isnot proven.34 The 1999 ASA guidelines55 are based onexpert opinion and recommend lowering of blood

pressure to keep mean arterial pressure at less than130 mm Hg in patients with a history of hypertension.Patients with intracerebral haemorrhage treated withintravenous infusion of calcium channel blockersconsistent with 1999 ASA guidelines within 24 h ofsymptom onset tolerated treatment well and had lowrates of neurological deterioration and haematomaexpansion.36 Comparisons suggest that intravenous-bolus-based regimens produce more variable blood-pressure control than do infusion-based regimens ofantihypertensive treatment.73

The current ASA Stroke Council88 guidelines recom-mend until ongoing clinical trials of blood pressureintervention for intracerebral haemorrhage are com-

pleted, physicians must manage blood pressure on thebasis of the present incomplete evidence by main-taining systolic blood pressure less than 180 mm Hg inthe acute period with short half-life intravenous anti-hypertensive drugs. Both guidelines consider moreaggressive systolic blood-pressure lowering in theabsence of clinical signs of high intracranial pressure88or chronic hypertension.54Recent data suggest a greatertherapeutic benefit with more aggressive lowering ofblood pressure.91In one observational study, haematomasenlarged in 9% of patients with systolic blood pressuremaintained below 150 mm Hg and in 30% of those withsystolic blood pressure maintained at less than

160 mm Hg or a higher threshold.91The AntihypertensiveTreatment of Acute Cerebral Hemorrhage (ATACH)trial92 and the Intensive Blood Pressure Reduction inAcute Cerebral Haemorrhage (INTERACT) trial reportedthat aggressive reduction of blood pressure to less than140 mm Hg probably decreases the rate of substantialhaematoma enlargement93 without increasing adverseevents.94In subgroup analyses from INTERACT,93patientsrecruited within 3 h and those with an initial systolicblood pressure of 181 mm Hg or more seemed to have thegreatest benefit with aggressive lowering of blood pressure.No difference in rates of death and disability at 3 monthswere seen between patients treated with aggressive andconservative lowering of blood pressure in ATACH orINTERACT studies, although the analyses were limitedby small sample sizes. Because the effect on clinical

outcome has not been fully assessed, the moreconservative targets set in the ASA Stroke Council 88andthe EUSI guidelines54should be followed. Great caution isadvised about lowering blood pressure too aggressivelywithout concomitant management of cerebral perfusionpressure.

Management of intraventricular haemorrhage andhydrocephalusTwo clinical trials70,81 confirmed that intraventricularhaemorrhage and hydrocephalus are independent pre-dictors of poor outcome in spontaneous intracerebralhaemorrhage.95 Impaired flow of cerebrospinal fluidand direct mass-effects of ventricular blood lead to

obstructive hydrocephalus. External drainage ofcerebrospinal fluid through ventricular cathetersreduces intracranial pressure,96but clots in the catheterand infections prevent sustained beneficial effects onhydrocephalus and neurological status in manypatients.79,97Shortening the length of external ventriculardrainage with early ventriculoperitoneal shunt place-ment98 or lumbar drainage for communicatinghydrocephalus99 might lower the rate of infections.Substitution of lumbar drainage for external ventriculardrainage in patients with communicating hydrocephalusmight also lessen the need to change temporaryventricular catheters and to use ventriculoperitonealshunts.99

Intraventricular haemorrhage is a dynamic processthat follows intracerebral haemorrhage. In a recentstudy of fVIIa, 45% of 374 patients with intracerebralhaemorrhage had intraventricular haemorrhage by24 h after presentation.100Growth of the intraventricularhaemorrhages occurred in 17% of placebo-treatedpatients and 10% of those given fVIIa. Risk factors forgrowth included a baseline mean arterial pressure ofmore than 120 mm Hg, large baseline volume ofintracerebral haemorrhage, presence of intraventricularhaemorrhage at baseline, shorter time from symptomonset to first CT scan, and lack of treatment with fVIIa.Presence of intraventricular haemorrhage at any time


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and growth of this haemorrhage increased the likelihoodof death or severe disability by 90 days.To facilitate early and effective clearance of blood in

the ventricles, recent efforts have focused onintraventricular use of thrombolytic drugs in patientswho have intraventricular haemorrhage in associationwith spontaneous intracerebral haemorrhage.77,78,101 In arandomised, double-blind, controlled trial,79 intra-ventricular thrombolytics given every 12 h led to fasterresolution of intraventricular haemorrhage than didtreatment with ventricular drainage alone. Twosystematic reviews of clinical studies102,103 found a3050% reduction in mortality associated withthrombolytic treatment for intraventricular haemor-

rhage. Clinical trials have not clearly shown improvedneurological outcome in survivors of intraventricularhaemorrhage. The Clot Lysis: Evaluating AcceleratedResolution of IVH (CLEAR-IVH) trial is investigatingthis issue.104

Observational studies showed encouraging results forendoscopic removal of intraventricular haemor-rhage.105107 In one study, 24 of 25 patients with intra-ventricular haemorrhage and obstructive hydrocephalushad resolution of hydrocephalus after endoscopicevacuation.107In a single-centre, non-randomised com-parison study,105endoscopic removal of intraventricularhaemorrhage resulted in a higher rate of good recoveryat 2 months than did external ventricular drainage

alone.

Surgical evacuationSurgical evacuation may prevent expansion, decreasemass-effects, block the release of neuropathic productsfrom haematomas, and thus prevent initiation ofpathological processes.The Surgical Trial in IntracerebralHaemorrhage (STICH) trial70 compared early surgery(median time of 20 h from presentation to surgery) withmedical treatment. 1033 patients were randomly assignedto early surgery or initial conservative treatment. At6 months, early surgery had no benefit compared withinitial conservative treatment: 24% versus 26% had good

recovery or moderate disability after treatment.70 Thebenefits of surgery via open craniotomy can be out-weighed by neural damage incurred and recurrence ofbleeding, especially in deep lesions. In a subgroupanalysisof the STICH trial, surgical treatment of lobarhaematomas and haematomas within 1 cm of thecortical surface were most likely to benefit70,108110(figure 6). The STICH II trial has started, and willprospectively test for benefits of surgery in lobarintracerebral haemorrhage when clots extend to within1 cm of the cortical surface but remain intraparenchymalwithout spread to the ventricular system.108 Anotherpotential indication for surgery is acute neurologicalworsening. One report111 suggested that emergentsurgical evacuation could result in functionalindependence in a quarter of patients if they had not

lost upper brainstem reflexes and did not show extensorposturing. Another prospective randomised study112suggested that the benefit of early surgery is limited topatients presenting with initial Glasgow coma scalescores of 8 or more or intracerebral haemorrhagevolumes of 80 mL or less.

To limit neural damage and the risk of recurrentbleeding associated with open craniotomy, studies arenow focusing on less invasive stereotactic andendoscopic evacuation with the use of thrombolyticdrugs.113 A randomised trial114 showed that stereotacticevacuation of putaminal haematoma was associatedwith lower mortality and better recovery to functionalindependence in patients with mildly reduced

consciousness. Another trial109

randomly assigned36 patients to stereotactic aspiration after liquefactionwith urokinase and 35 to conservative management.Surgery showed a greater haematoma reduction (18 mLcompared with 7 mL with conservative management),but no clinical improvement. The ongoing MinimallyInvasive Surgery plus Tissue Plasminogen Activator forIntracerebral Hemorrhage Evacuation (MISTIE)108 trialis designed to find the best dose of thrombolytics capableof removing 80% of intracerebral haemorrhage volumeby use of stereotactic aspiration followed bycatheter-based removal irrigation of intracerebralhaemorrhage with thromboytics.

The ASA Stroke Council88 and EUSI guidelines54 do

not recommend routine evacuation of supratentorialhaemorrhage by standard craniotomy within 96 h ofictus. Both guidelines recommend surgery for patientspresenting with lobar haemorrhage within 1 cm of thesurface, particularly for those with good neurologicalstatus who are deteriorating clinically. Guidelinesacknowledge that operative removal within 12 h, parti-cularly with minimally-invasive methods, has the mostevidence for beneficial effect and could be consideredfor deep haemorrhages in the presence of mass-effect.54However, guidelines note that very early craniotomymight be associated with an increased risk of recurrentbleeding.115

15/217/971/113

143

036 (011116)086 (013563)062 (036105)

058 (036092)

11/2412/1656/110

150

Auer (1989)Teernstra (2001)Mendelow (2004)

Total (95% CI)

Total events: 79 (surgery), 93 (control)Test for heterogeneity: 2=087, df=2 (p=065), l2=0%

Test for overall effect:Z=230 (p=002)

01 02 05 1 2 5 10Favours treatment Favours control

Surgeryn/N

Controln/N

Peto OR95% CI

Peto OR95% CI

Figure :Odds ratio for death or disability in patients with lobar intracerebral haemorrhage treated

surgically or conservatively

Boxes are Petos odds ratio (OR), lines are 95% CI. Adapted with permission from Lippincott Williams

and Wilkins.108

For CLEAR-IVHsee http://

clearivh.com/default.aspx

For the STICH II trialsee http://

www.ncl.ac.uk/stich/

For the MISTIE trial see http://

mistietrial.com/


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Posterior fossa surgeryTimely decompression in cerebellar haematomas canlower morbidity andmortality related to compression ofthe brainstem. In an analysis of the data from a nationalstroke registry,116 patients treated surgically had sig-nificantly greater improvement in neurological scoresthan did those treated medically, independent of ageand initial severity of deficits. In most institutions,evidence of neurological deterioration is an indicationfor surgical evacuation;117although surgical interventionbefore neurological deterioration might be morebeneficial if there is severe fourth ventricularcompression.118The best functional results are seen withearly craniotomy in patients with a cerebellarhaemorrhage who had an initial Glasgow coma scalescore of less than 14 or large haemorrhages (40 mL). 1

Endoscopic removal of cerebellar haemorrhage119

canalso effectively remove the haematoma with lowerprocedure time and a shorter period of cerebrospinalfluid drainage than with craniectomy.

The ASA Stroke Council88 and EUSI guidelines54recommend urgent surgery for patients with cerebellarhaemorrhages with a relatively good neurological statusor haematoma larger than 3 cm who are deterioratingclinically, or who have brainstem compression or hydro-cephalus from ventricular obstruction. Cerebellarhaemorrhage is commonly complicated by obstructivehydrocephalus120 with delayed but rapidly risingintracranial pressure, which can be treated successfullywith external ventricular drainage.121The consequences

of longlasting intracranial hypertension with delayeddrainage should be avoided by careful monitoring ofintracranial pressure and neurological status and useof serial CT scans.

Neuroprotective and seizure treatmentNXY-059, a free-radical-trapping neuroprotectant,122wasinvestigated in a randomised trial of 607 patients withintracerebral haemorrhage within 6 h of symptomonset.123 Although the use of NXY-059 was associatedwith slightly less haematoma growth than use ofplacebo (mean change of 45 mL vs 67 mL), oncomparison of baseline scans to those 72 h aftertreatment onset, the drug had no effect on mortality at

3 months, disability, or neurological deficit scores.8% of patient with intracerebral haemorrhage have

clinical seizures124 within 1 month of symptom onset,associated with lobar location or haematoma enlarge-ment. However, continuous electroencephalographicmonitoring in an observational study125 showed that28% of patients with intracerebral haemorrhage had(predominantly subclinical) seizures within the first72 h of admission. Seizures were associated withneurological worsening, an increase in midline shift,and poorer outcomes. In another study of 45 patientswith intracerebral haemorrhage,126subclinical seizuresand non-convulsive status epilepticus were detected

in 13% and 9% of the patients, respectively. Therefore, alow threshold for obtaining electroencephalographicstudies and use of anticonvulsants in patients withintracerebral haemorrhage might be advisable. On thebasis of risk reduction reported in observationalstudies,124 a 30-day course of prophylactic anti-convulsants is recommended in patients with lobarhaemorrhage or those who develop seizures.54,88Patientswho have a seizure more than 2 weeks after intracerebralhaemorrhage onset are at greater risk of recurrentseizures than those who do not and might need long-term prophylactictreatment with anticonvulsants.

Management of medical complicationsAbout 30% of patients with intracerebral haemorrhagehave gastric haemorrhages. Prophylactic H2 blockers or

drugs that can protect the mucosa lower the numbers ofsuch events.127 In a randomised trial,127 gastrichaemorrhages occurred in 23%, 11%, and 14% ofpatients treated with placebo, ranitidine, and sucralfate,respectively; in-hospital mortality was 28%, 11%,and 25%.

In the first 2 weeks, deep-venous thrombosis can bedetected by ultrasonography in 40% of patients. 128Patients with severe neurological deficits and highd-dimer concentrations are at highest risk.128The rate ofclinical deep-venous thrombosis was 4% and pulmonaryembolism 1% within 3 months, in a combined analysisof placebo-treated patients in fVIIa trials. 129 A ran-domised study130 showed that intermittent pneumatic

compression decreased the occurrence of asymptomaticdeep-venous thromboembolism compared with elasticstockings alone and should be used in all patients. Theseventh American College of Chest Physicians panelrecommends that a low-dose regimen of subcutaneousheparin or low-molecular-weight heparin can be startedon the second day after onset of intracerebralhaemorrhage in neurologically stable patients.131 Asmall study showed a low incidence of pulmonaryembolism without an incremental rate of newintracerebral haemorrhage if low-dose heparin wasstarted on the second day after onset (compared withlater intervals).132Once a deep-venous thromboembolismdevelops, treatment should be given to patients at high

risk of pulmonary embolism. Inferior vena-cava filtersor a 510-day course of full-dose low-molecular-weightheparin followed by 3 months of lower-dose low-molecular-weight heparin are possible alternatives towarfarin.133

10% of intensively treated patients with intracerebralhaemorrhage need tracheostomies, and early usemight reduce the risk of aspiration and long-termmechanical ventilation.134 Recent guidelines haveplaced emphasis on control of hyperthermia andhyperglycaemia with antipyretic medication andpossibly insulin infusion in the acute period ofintracerebral haemorrhage.54,88


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Intracerebral haemorrhage related to use oforal anticoagulantsA population based study135 reported that intracerebralhaemorrhage associated with oral anticoagulant usecomprised 5% of all intracerebral haemorrhages in 1988,9% in 199394, and 17% in 1999, with the observedincrease presumably due to increasing prevalence ofatrial fibrillation and higher rates of warfarin use. 11Although most cases associated with oral anticoagulantuse occur when international normalised ratios arewithin the therapeutic range, higher ratios increase therisk.136 Advancing age and cerebral amyloid angiopathyare also important contributory factors to intracerebralhaemorrhage associated with oral anticoagulant use.11,137In a multicentre study, a progressive neurologicaldeterioration during the first 2448 h was seen in almost

half of patients with intracerebral haemorrhageassociated with oral anticoagulant use and a highmortality (64%) by 6 months.138 The high mortality inthese patients was mediated by a high rate of early anddelayed haematoma enlargement139 which wascommonly associated with persistently high inter-national normalised ratio after admission.140,141

Rapid reversal of systemic anticoagulation with acombination of intravenous vitamin K, prothrombincomplex concentrates, or fresh frozen plasma and fVIIais recommended preferably within 2 h of onset.11,142,143Prothrombin complex concentrates or fVIIa can achieverapid reversal although the international normalisedratio might increase in subsequent hours owing to the

short half-lives of these drugs requiring follow-upmonitoring. In a single-centre review,141 haematomasenlarged in 19% of patients given prothrombin complexconcentrates, 33% given fresh frozen plasma, and50% given vitamin K. An early reversal of internationalnormalised ratio (within 2 h) was achieved in 84% withprothrombin complex concentrates, 39% with freshfrozen plasma, and 0% with vitamin K. Internationalnormalised ratio reversal to less than 14 within 2 h wasassociated with low rates of haematoma enlargement. Aretrospective study144 compared the outcomes ofneurosurgical patients with intracranial haemorrhagetreated with fresh frozen plasma and fVIIa and thosemanaged with fresh frozen plasma alone. International

normalised ratios returned to normal over a meanperiod of 7 h in those given fVIIa and 47 h in those whowere not. More patients treated with fVIIa had goodfunctional outcome than did those who received onlyfresh frozen plasma. Rapid reversal of internationalnormalised ratios also enables urgent surgicalevacuations in patients who are deterioratingneurologically with intracerebral haemorrhage relatedto oral anticoagulant use. One study 145reported a highrate (65%) of favourable outcomes in patients withprominent midline shift (with or without uncalherniation) who had emergent surgical evacuation afterreversal.

The clinical issue regarding reinstitution of anti-coagulation is controversial. Two studies concluded thatantithrombotic drugs should be avoided where possiblein patients with acute intracerebral haemorrhage.146,147Asubgroup at high risk of thromboembolic stroke andlow risk of recurrence might benefit from long-termanticoagulation or aspirin. Both the ASA StrokeCouncil88 and the EUSI guidelines54 recommend thatwarfarin can be started again in patients at a very highrisk of thromboembolism at 714 days after onset of theoriginal intracerebral haemorrhage.148,149

Future directionsClinical evidence suggests the importance of threemanagement tasks in intracerebral haemorrhage:stopping the bleeding,81 removing the clot,70 and con-

trolling cerebral perfusion pressure.92

The precisionneeded to achieve these goals and the degree of benefitattributable to each clinical goal would be preciselydefined when the results of trials in progress becomeavailable. An NIH workshop150identified the importanceof animal models of intracerebral haemorrhage and ofhuman pathology studies. Use of real-time, high-fieldMRI with three-dimensional imaging and high-resolution tissue probes is another priority. Trials ofacute blood-pressure treatment and coagulopathyreversal are also medical priorities. And trials ofminimally invasive surgical techniques includingmechanical and pharmacological adjuncts are surgicalpriorities. The STICH II trial should determine the

benefit of craniotomy for lobar haemorrhage. A betterunderstanding of methodological challenges, includingestablishment of research networks and multispecialtyapproaches, is also needed.150 New information createdin each of these areas should add substantially to ourknowledge about the effi cacy of treatment forintracerebral haemorrhage.

Contributors

All authors contributed equally to the preparation of this Seminar.

Conflicts of interest

AIQ has received funding from National Institutes of HealthRO-1-NS44976-01A2 (medication provided by ESP Pharma), AmericanHeart Association Established Investigator Award 0840053N, andMinnesota Medical Foundation (Minneapolis, MN, USA). ADM is thedirector of the Newcastle Neurosurgery Foundation, and has received

honoraria for attending Advisory Committee Meetings for Codman andfor Novo Nordisk. DFH receives funding through the US Food andDrug Administration orphan-drugs programme grant 5RO1-FD 001693,National Institute of Neurological Disorders and Stroke (NINDS)planning grant, 1R34-NS056638, MISITIE: NINDS, 1R01-NS 046309,Jeffrey and Harriet Legum professorship, Genentech, sponsoredresearch agreement; he also has disavowed interest in this patent(Johns Hopkins University use patent application # 10/509,694) andhas received an honorarium from Novo Nordisk.

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