ORIGINAL ARTICLE

Debate – does a reversible penumbra exist in intracerebralhaemorrhage?

MATTHEW ANTHONY KIRKMAN

Brain Injury Research Group, The University of Manchester, UK

AbstractIntracerebral haemorrhage is a devastating condition lacking effective therapies, with an uncertain role for surgery in many.Early research described an ischaemic penumbra around the haematoma, representing an area of potential therapeuticintervention. This article discusses the evidence for and against the existence of an ischaemic penumbra in ICH, withparticular reference to recent imaging studies.

Key words: Intracerebral haemorrhage, ischaemic penumbra, perihaematomal hypoperfusion, metabolic derangement,imaging, microdialysis.

Introduction

Spontaneous supratentorial intracerebral haemor-

rhage (ICH) is a significant cause of morbidity and

mortality affecting 25 per 100,000 people annually,

and less than 40% of ICH survivors regain indepen-

dence.1 Despite extensive evidence from human and

animal studies on the deleterious role of thrombin,

iron, as well as immune and inflammatory responses

following ICH,2 effective pharmacological therapies

are currently lacking. There is continuing uncertainty

regarding the optimal management of ICH, and

whether surgery or conservative management offers

the best prognosis.3

One contentious issue affecting the management

of ICH is the existence, extent and effect of a

penumbra; that is, an area of functionally impaired

but potentially viable tissue surrounding a haemato-

ma. The concept of an ischaemic penumbra has

historically been characterised as perihaematomal

hypoperfusion following ICH associated with (i)

compression of the brain parenchyma around the

haematoma and its microcirculation by the expand-

ing haematoma (mass effect) and (ii) the release of

vasoactive substances from the extravasated blood

resulting in vasoconstriction.4 The resulting hypo-

perfusion would in theory lead to ischaemic damage

and necrosis to the perihaematomal tissues, and thus

to neurological dysfunction. Whilst elements of both

mass effect and the release of vasoactive substances

could co-exist in many ICH,4 significant mass effect

suggests a strong role for early surgery, perhaps in the

same timeframe as that employed by thrombolysis

strategies for ischaemic stroke. On the other hand, if

the ICH was not causing mass effect but releasing

vasoactive and other detrimental substances, the

window of opportunity for therapeutic intervention

may in fact be more prolonged. Raised intracranial

pressure and reduced cerebral perfusion pressure are

associated with a poor prognosis in ICH, lending

support to early surgery, and simulated removal of

the mass lesion in experimental ICH has been shown

to improve perfusion in the surrounding tissue.5,6

Since this early experimental work, rapid advances in

neuroimaging and invasive monitoring techniques

have helped elucidate on this penumbra.

Investigating the penumbra

More recently, findings from imaging and regional

blood flow studies in both animals and humans7–13

have questioned the existence of an ischaemic

penumbra in ICH. Perfusion computed tomography

studies have suggested reduced perfusion and oede-

ma in ICH have a common cause rather than

presupposing one another.7,8 Diffusion-weighted

imaging (DWI) and perfusion-weighted imaging

(PWI) studies have also found evidence against a

reversible ischaemic penumbra surrounding the

Correspondence: Matthew Anthony Kirkman, Brain Injury Research Group, Salford Royal NHS Foundation Trust, Clinical Sciences Building, Salford

M6 8HD, UK. Tel: þ44(0)7886608978. E-mail: matthew.kirkman@doctors.org.uk

Received for publication 4 January 2011. Accepted 3 April 2011.

British Journal of Neurosurgery, August 2011; 25(4): 523–525

ISSN 0268-8697 print/ISSN 1360-046X online ª 2011 The Neurosurgical Foundation

DOI: 10.3109/02688697.2011.578773

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haematoma in ICH.9 DWI assesses alterations in

water diffusibility, regarded as a measure of tissue

bioenergetic compromise. PWI, on the other hand,

provides a measure of relative cerebral perfusion.

DWI and PWI studies in rat10 have corroborated this

opinion, although the model used to induce ICH has

been criticised for not accurately replicating the

clinical condition. Human imaging studies utilising

single photon emission computed tomography

(SPECT) found reduced blood flow in the perihae-

matomal region in the first 24 h following ICH, with

normalisation of blood flow within 72 h.11 Xenon

computed tomography studies have shown that an

ischaemic penumbra as defined by generally accepted

cerebral blood flow thresholds does not exist in most

ICH patients.12 However, the parameters for identi-

fying ischaemic damage in most ICH imaging studies

have been drawn from studies of ischaemic stroke;

important to note, since the pathophysiological

processes underlying ischaemic stroke and ICH are

different. An experimental study in dogs found

prominent increases in intracranial pressure and

mean arterial pressure, but no changes in regional

blood flow or metabolism in the first 5 h following

ICH.13

An important observation is that most human

studies incorporate patients with smaller haemato-

mas (520 ml). It is possible that unwell patients with

larger haematomas are more likely to demonstrate an

ischaemic penumbra through mass effect of the

haematoma compressing surrounding tissue (as

described earlier). To corroborate this, a PWI study

with a larger mean haematoma volume (56 ml)

found perihaematomal hypoperfusion in acute ICH,

although this resolved completely by day 7 post-

ictus.14 Further, a CT perfusion study found

perihaematomal cerebral blood flow to be increased

in patients with smaller haematomas (�20 ml)

compared to larger haematomas (420 ml).15

Differentiating reduced blood flow from ischaemia

Of note, in most cases of ICH a small slit-like scar is

all that remains on CT scanning – not consistent with

major ischaemic damage in the perihaematomal

region.9 Do reductions in blood flow therefore

necessarily reflect true ischaemia? The most convin-

cing evidence against this comes from positron

emission tomography (PET) studies. Ischaemia is

defined as the deprivation of oxygen to tissue,

resulting in an increased oxygen extraction fraction

(OEF), acidosis in the local tissues and eventually

cell death. A PET study of 19 ICH patients

(haematoma size range: 4–99 ml) 5–22 h after

haemorrhage onset demonstrated that perihaemato-

mal tissue does not exhibit classical ischaemia

according to OEF criteria.16 Instead, reductions in

oxidative metabolism and hence oxygen utilisation

are probably a result of mitochondrial dysfunction –

confirmed by tissue sampling of perihaematomal

tissue during surgery for ICH.17 The result is a non-

ischaemic metabolic crisis, similar to that identified

in patients with traumatic brain injury.18 A recent

PET study confirmed increased glucose uptake

(hyperglycolysis) in the perihaematomal tissue in

the first week following ICH,19 but unfortunately no

concurrent EEG measurements were taken. Con-

vulsive and non-convulsive seizures recorded using

continuous EEG monitoring,20,21 and direct current

spreading depression recorded using electrocortigra-

phy in regions adjacent to surgically evacuated

haematomas,22 have both been postulated as con-

tributors to the hyperglycolysis in ICH patients. So,

too, have glutamate-induced cytotoxic injury and

regional inflammation. Of note, seizures occurring 2–

4 days following ICH onset are associated with more

dramatic increases in intracranial pressure, increased

midline shift worsening mass effect, and a trend

towards worse outcome compared to ICH patients

without electrographic evidence of seizure activity.20

Whether hyperglycolysis itself correlated with worse

clinical outcomes was not assessed in the PET study

by Zazulia et al.19, although only thirteen subjects

were included. Further work on the relationship

between perihaematomal hyperglycolysis, seizure

activity and outcomes is required. Nevertheless,

microdialysis studies have confirmed ongoing dis-

rupted metabolism in the perihaematomal tissue,

with elevated glutamate, lactate, glycerol and lactate/

pyruvate ratios in this region.23 Such ongoing injury

may therefore represent an important therapeutic

target.

Implications of a non-ischaemic penumbra

This accumulated evidence has led us away from the

idea of an ischaemic penumbra in ICH, at least in the

majority of patients. If ultimately correct, this

suggests intensive blood pressure lowering may help

reduce ongoing haematoma growth without compro-

mising a non-existent ischaemic penumbra; impor-

tant as severe hypertension is common in the acute

stages of ICH, and haematoma expansion occurs in

almost three-quarters of ICH patients in the first 3 h

following symptom onset.24 Of note, small reduc-

tions in blood pressure have no significant effect on

global or perihaematomal cerebral blood flow.25 The

evidence presented here also moves the focus away

from early surgery to salvage an ischaemic penumbra;

although of course patients with superficial/lobar

haemorrhages and worsening conscious level/neuro-

logical deficit are more likely to be operated on.

However, since including patients with larger hae-

matomas who are generally more unwell in clinical

research studies is difficult, we cannot be sure that an

ischaemic penumbra that would benefit from surgical

intervention is not present in these individuals. Even

in the absence of an ischaemic penumbra a favour-

able role for surgical evacuation of ICH may exist,

since biochemical derangements (raised glutamate,

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lactate, glycerol, and lactate/pyruvate ratios) in the

perihaematomal region have been shown to normal-

ise within 24–48 hours of clot evacuation23; however,

no comparison was made to the biochemical profile

over time of perihaematomal regions in patients who

did not undergo surgical evacuation. Further, corre-

lation of these biochemical derangements with

clinical outcomes is vital to ascertain their clinical

significance.

Conclusion

The perihaematomal region in most ICH appears

to be a site of ongoing neuronal injury due to a

metabolic crisis rather than ischaemia. With continual

advances in our understanding of the pathophysiolo-

gical basis of ICH, and – for example – the role of

inflammation, there may be an extended window

of opportunity for therapeutic intervention. Further

studies in ICH utilising latest imaging techniques

and multimodality as well as invasive monitoring

techniques are required to further define the

characteristics of the perihaematomal region, its

amenability to therapeutic intervention and its effect

on prognosis. Through suppressing ongoing neuronal

injury, there is exciting potential to improve outcomes

for this devastating condition.

Declaration of interest: The author reports no

conflicts of interest. The author alone was respon-

sible for the content and writing of the paper.

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