EUROPEAN NEUROLOGICAL JOURNAL REVIEW ARTICLE
Signiﬁcance of Perihematomal Edema in Acute
Jade W Wei, Hisatomi Arima and Craig S Anderson
Afﬁliation : The George Institute for Global Health and Department of Neurology, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia
A B S T R A C T
Intracerebral hemorrhage (ICH) is the most serious form of stroke, with more than two-thirds of the patients either dying or left perma-
nently disabled from the condition. Despite considerable research effort, there is still no treatment of proven efﬁcacy for ICH and the chances
of surviving an ICH has failed to improve in recent decades. The brain damage from the initial hematoma is considered largely irreversible,
which is because of the early time window of opportunity for treatment beneﬁt and the modest potential effects of any medical therapy that
limits hematoma growth. Knowledge has accumulated regarding the nature of secondary effects of the perihematomal edema in ICH, making
it an attractive therapeutic target. The pathophysiology of ICH-related perihematomal edema is complex: a number of different mechanisms
are involved from the initial hydrostatic pressure of the hematoma to the subsequent toxic effects of breakdown products resulting from
coagulation cascade activation and erythrocyte lysis as part of the natural process of hematoma resolution. Although perihematomal edema
and hematoma volumes are strongly correlated, there is less and conclusive evidence regarding the independent prognostic role of perihe-
matomal edema per se. Patient management is primarily supportive and aimed at reducing resulting increases in intracranial pressure. No
therapies have been shown to deﬁnitely inﬂuence outcome, and all are associated with some hazard. Further studies are required to clarify the
relationship between perihematomal edema and outcome in ICH, and to translate the positive results of therapies identiﬁed in the laboratory
into the clinical domain.
Keywords: perihematomal edema, intracerebral hemorrhage, stroke, treatment
Correspondence: Craig S Anderson, The George Institute for Global Health, P.O. Box M201, Missenden Rd, Camperdown, NSW 2050, Australia.
Tel: +61-2-9993-4521; Fax: +61-2-9993-4502; e-mail: firstname.lastname@example.org
INTRODUCTION in cerebral perfusion pressure (CPP) from mass effect and
raised intracranial pressure (ICP); (iv) brain herniation; and
Of the various pathological stroke types, intracerebral hem-
ﬁnally, (v) in those who survive, residual brain atrophy from
orrhage (ICH) is the most devastating and least treatable, caus-
the original lesion.4,5 Along with hematoma expansion, perihe-
ing death, disability, and long-term suffering in most of those
matomal edema is implicated in many of the fundamental pro-
affected.1 Despite considerable research effort, there is still a
cesses driving the neuronal damage in ICH (Figure 1), although
paucity of evidence regarding the efﬁcacy of pharmacological
the prognostic signiﬁcance of perihematomal edema on its
and surgical interventions for ICH, and the chances of surviv-
own remains uncertain.6,7 However, while it is widely accepted
ing ICH does not appear to have improved in recent decades.1,2
that hematoma-induced brain damage is irreversible, the
Although ICH constitutes about 10–15% of strokes in Western
injury arising from perihematomal edema may be reversible,
populations, its impact in terms of acute and long-term med-
and thereby presents a potential therapeutic target for
ical care costs as well as productivity loss is high, estimated
at US$6 billion annually in the United States alone.3 In Asian
populations, where rates of ICH are higher and people tend This review examines ICH-related perihematomal edema:
to be affected at younger ages, the impact of ICH is likely pathophysiology and the factors inﬂuencing growth; its contri-
to be enormous. The heavy burden of ICH, coupled with the bution to neurological deﬁcits; and what potential therapeutic
lack of proven therapies, underpins the need to develop novel measures are currently available to limit its growth and enhance
strategies to improve outcomes. A better understanding of the its resolution.
underlying pathophysiological and pathochemical sequelae of
ICH should aid in this endeavor.
GENERAL CONSIDERATIONS ABOUT THE
The following processes have been shown to occur in ICH:
(i) early hematoma expansion and secondary edema-induced CLINICAL MANIFESTATIONS OF ICH
brain compression and consequent neuronal death; (ii) cyto- In the majority of cases, ICH presents as an abrupt onset
toxic (intracellular) and vasogenic (extracellular) edema result- of clinical manifestations whilst a person is awake and active,
ing from disruption of the blood–brain barrier; (iii) reductions resulting in the need to seek medical attention because of the
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European Neurological Journal
Certain clinical features may help direct attention toward the
possibility of ICH and need for early brain imaging, generally
by CT, in order to establish the diagnosis and potential early
intervention, as outlined in Table 1. However, there are certain
confounding situations that may complicate the assessment
of the patients with ICH. It is important to note the relatively
high frequency (5–10%) of co-occurring seizures in ICH, so
that a patient’s reduced consciousness may be due to a post-
ictal state (ie, where the generalized tonic–clonic convulsion
was not witnessed) or from ongoing seizures that are min-
imally or deﬁnitely nonconvulsive, rather than being due to
any mass effect of the ICH. Another issue worth remember-
ing is the possibility of a secondary cause of the ICH, as this
will determine other management strategies than for primary
spontaneous ICH. Decisions about whether and how to use
radiological investigations other than CT to establish the cause
of ICH are generally based on three principal factors—patient
age, ICH location, and existence of pre-stroke hypertension—
although there are few systematic investigations of the most
parsimonious strategies for the investigation of such patients,
particularly in low resource settings where access to MRI and
angiography is more limited.8 Certain features should raise the
Figure 1. Hemorrhage with perihematomal edema.
likelihood of an underlying structural lesion (ie, arteriovenous
malformation [AVM], cerebral aneurysm, dural arteriovenous
ﬁstula, cavernous malformation, cerebral venous thrombosis,
cerebral arteritis, or tumor): clinical—young age (<40 years), no
persistence of, or deterioration in, their condition. The clinical history of hypertension, potential for illicit drug use, or infec-
manifestations of ICH can be divided into those who relate to tions; and radiological—perihematomal edema that is dispro-
(i) the speciﬁc location of the lesion resulting from the hemor- portionately large relative to the size of the hematoma (suggestive
rhage (eg, paresis, hemianopia, ataxia) and (ii) the secondary of malignancy), the lobar location is atypical (eg, temporal lobe),
mass effect and elevations in ICP (eg, headache, vomiting, the morphology (ie, irregular pattern, multiple hemorrhages),
reduced level of consciousness). As the severity of ICH may be and the presence of vascular enhancement (with or without
becoming less marked in recent years because of the improved contrast).
detection and control of hypertension, and the increasing fre-
quency of lobar ICH related to warfarin anticoagulation and
cerebral amyloid angiopathy in aging populations, the differ- PROGNOSTIC ASSESSMENT IN ICH
entiation of ICH from ischemic stroke is often difﬁcult to be Accurate information on the patterns of recovery from stroke
made at the bedside and can only be established reliably by is important for patients who wish to know how much better
early computerized tomography (CT) or magnetic resonance they will get and how fast, and for doctors who have to decide
imaging (MRI) of the brain. on the proper course of action. In light of these needs, there has
Table 1. Key clinical features indicative of underlying pathologies
Clinical feature Indicative of –
Alteration in consciousness that is disproportionate to the severity and/or Mass effect and raised ICP
distribution of focal neurological deﬁcits, ie, paresis, dysphasia
Rapid reduction in the level of consciousness Hematoma expansion with mass
effect and raised ICP
Evidence of meningism Presence of intraventricular
Behavioral and perceptual disturbance with grasp reﬂex and/or other ICH within the frontal lobe
frontal lobe release signs
Severe hemicranial or global headache Mass effect
Characteristic ocular disturbance:
Forced medial and downward gaze Thalamic ICH with extension into
Vertical gaze paresis Midbrain compression and mass
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Signiﬁcance of perihematomal edema in acute intracerebral hemorrhage
long been interest in identifying factors early after stroke that the initial event but risk secondary effects from perihematomal
might inﬂuence or predict the degree of long-term recovery. edema and inﬂammation from hemoglobin-breakdown
Knowledge of the natural history and prognosis for recovery products.
help doctors and other health professionals manage patients
more efﬁciently by directing appropriate action and avoiding
unnecessary treatment. PATHOPHYSIOLOGY OF PERIHEMATOMAL
An accurate prognostic assessment is ﬁrst relevant at the EDEMA—ANIMAL STUDIES
time of presentation in ICH, when clinicians and families Several mechanisms underlie the formation of ICH-related
are often confronted with the decision whether early decom- perihematomal edema (Figure 2). First, in the ﬁrst few hours
pressive surgery and/or other invasive procedure should be after onset, there is the development of hydrostatic pressure
undertaken, and whether there is a need for monitoring to be associated with growth in the hematoma, which increases
undertaken in an intensive care unit. Later on, decisions need blood–brain barrier permeability to cause an inﬂux of protein
to be made regarding potential withdrawal of care if the con- molecules into the extracellular space and subsequent creation
dition is considered fatal or associated with a poor prognosis of an osmotic pressure gradient that drives the movement of
for “good” recovery, and in directing medical care, rehabilita- water from the blood into the brain, thereby producing vaso-
tion, and community services according to the likely pattern of genic edema.13 A second phase (the next 24–48 hours) involves
recovery. the clot retraction and activation of the coagulation cascade
Several prognostic variables have been identiﬁed and scor- that results in the production of thrombin, which further dis-
ing tools developed to help clinicians predict mortality and rupts the integrity of the blood–brain barrier to enhance the
functional outcome in ICH. However, many are complicated by formation of edema.14,15 A third phase results from comple-
selection bias, confounding from the high rates of withdrawal ment cascade activation that leads to the formation of mem-
of care (a self-fulﬁlling prophecy), and a failure to validate brane attack complex,16 and erythrocyte lysis, with toxicity to
a system in an independent sample, thereby limiting their neurons from hemoglobin and hemoglobin-breakdown prod-
clinical utility.9–12 Two of the most widely known and validated ucts such as oxyhemoglobin, iron, and bilirubin oxidation
predictor scales are the ICH score for mortality12 and the FUNC products (BOXes), which results in cytotoxic edema.16–19 In
score for functional outcome,11 the latter of which is outlined cell culture, hemoglobin activates lipid peroxidation, oxyhe-
in Table 2. Among the various parameters in ICH, hamatoma moglobin causes apoptosis,20–22 and iron is associated with
volume is a key determinant of outcome:10 volumes >15 mL lipid peroxidation and hydroxyl-free radical formation;23 all
invariably result in death from direct trauma and mass effect in have toxic effects on neurons, whereas BOXes contribute to
the brain, whereas patients with smaller volumes may survive cerebral vasospasm.19
Other molecules have been implicated in the processes
of inﬂammation and injury that arise from perihematomal
Table 2. Components of the FUNC score in primary intracerebral edema. These include the excitatory neurotransmitter gluta-
hemorrhage (ICH)11 mate, which has been found to occur at high levels in the
perihematomal region of ICH,24 as well as activation of both N-
methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-
ICH volume (cm3 ) 4-isoxazolepropionic acid glutamate receptors.25 An increase
<30 4 in the excitatory glutamate signaling increases release of glu-
30–60 2 tamate from damaged neurons and blood, and decreases glu-
>60 0 tamate uptake by astrocytes, resulting in oxidative stress and
Age (years) death to astrocytes.25,26 Recent attention has also centered
<70 2 on aquaporins, a highly selectively water transporter,27 where
70–79 1 animals deﬁcient in aquaporin-4 have signiﬁcantly greater
≥80 0 brain water content and higher ICP compared with wild-type
ICH location controls.28 Other notable effects of endogenous molecules
Lobar 2 include inducible nitric oxide synthase (iNOS), where knock-
Deep 1 out mice show higher brain content than controls despite
Infratentorial 0 similar hematoma volumes;29 poly(ADP-ribose) polymerase
Glasgow Coma Scale score activation following hemoglobin infusion, which is associated
≥9 2 with brain edema;30 tissue-type transglutaminase, potentially
≤8 0 important in neurodegeneration, which shows high concen-
Pre-ICH cognitive impairment trations after experimental ICH;31 and inhibition of microglia,
No 1 which reduces edema formation and improves neurological
Yes 0 outcomes.32 Various inﬂammatory processes are also activated
Total score 0–11 in ICH: tumor necrosis factor (TNF)-α levels are increased,
Note: Scores 0–7 = <20% chance of functional independence at
possibly by thrombin,33 and TNF-α knockout animals have
90 days. less brain edema than their wild-type counterparts;33 and
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European Neurological Journal
Figure 2. Schematic of the pathophysiology of perihematomal edema.
interleukin-1β, a proinﬂammatory cytokine linked to blood– a pathophysiological process of endothelial membrane dissolu-
brain barrier opening, is upregulated.34 tion, is again different from the processes that occur in human
Knowledge generated from early in vitro and in vivo stud- ICH.5
ies has been enhanced by a recent genomics studies in rats,
where it has been revealed that ICH upregulates urinary plas-
minogen activator receptor and annexin II (a plasminogen PATHOPHYSIOLOGY OF PERIHEMATOMAL
receptor that can regulate cell surface plasmin) and increases EDEMA—HUMAN STUDIES
the expression of hemeoxygenase (HO)-1, which metabolizes In humans, perihematomal edema increases rapidly in the
heme.35 Moreover, interleukin-1β, iNOS, and chemokine gro ﬁrst 48–72 hours after ICH, with corresponding neurolog-
and chemokine (C-X-C motif ) ligand 2 (Cxcl2) genes, are all ical deterioration in accordance with initial stroke sever-
markedly induced by ICH.35 Furthermore, there are increases ity. Perihematomal edema continues to increase, albeit at a
in the expression of several other immunomodulatory genes slower rate, until about 1–2 weeks, after which it gradually
(eg, caspase-1, interleukin-18), and immune response genes subsides.36–38 In general, peri-lesional blood ﬂow normalizes
(eg, glycoprotein CD44, CD48 antigen, complement compo- after an initial reduction in levels over the ﬁrst 72 hours post-
nent 1, and complement component C3), which implicates a ICH, with the resulting edema correlating with the volume of
role for the immune system in the development of ICH-related reperfused tissue, implicating reperfusion injury in the patho-
cerebral edema.35 Finally, there is also an increased expres- physiology of perihematomal edema.38 Increased rates of water
sion of matrix metalloproteinases (MMP)-3 and MMP-9 that diffusion in the perihematomal region has also been shown to
can disrupt the blood–brain barrier, and in atrium natriuretic be an independent predictor of edema volume, indicating that
polypeptide after ICH, the latter suggesting an endogenous there is early movement of plasma (ie, vasogenic edema).39 No
anti-edema response.35 major differences in edema volume between deep (eg, hyperten-
All animal models have intrinsic limitations that fail to repro- sive) and lobar (eg, cerebral amyloid angiopathy-related) ICH
duce precisely processes of human disease. Although rats and have been identiﬁed.40 However, consistent with animal stud-
mice are commonly used as an experimental model of ICH, ies that emphasize the importance of the coagulation cascade
they lack white matter (compared with higher species), have and erythrocyte lysis in the development of edema, patients
different cerebral blood volumes, pressure, and ﬂow patterns, with spontaneous ICH have signiﬁcantly larger perihematomal
and there is difﬁculty in accounting for aging effects, thereby edema volumes than patients with thrombolysis-related ICHs,14
limiting the relevance of such data to humans. The pig brain, and accordingly, non-coagulopathic ICH is associated with
which has a greater amount of white matter, is more optimally more early relative edema than warfarin-related ICH.41 In addi-
placed for the study of ICH-induced injury,5 but such exper- tion, a signiﬁcant positive correlation between the levels of
iments are expensive and complex. The typical simulation of serum ferritin and perihematomal edema on days 3–4 after
hemorrhage through the direct injection of autologous blood ICH has also been noted.42 Moreover, there is evidence to sug-
into the brain,5 whilst mimicking a mass effect, does not have gest that MMP-9 concentration is positively correlated, and its
a ruptured vessel as the cause of injury as in ICH in man. An tissue inhibitor (TIMP-1) negatively associated, with perihe-
alternative model that involves the injection of collagenase into matomal edema volume; and MMP-3 is positively related to
animals, which is toxic to brain parenchymal cells and produces mortality.37 The effect of MMPs has been postulated to involve
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Signiﬁcance of perihematomal edema in acute intracerebral hemorrhage
nuclear factor κB, which is known to induce several MMPs associated with absolute increases in perihematomal edema
including MMP-9 and MMP-3, and laminin degradation, which volume (Figure 3), whereas history of hypertension, baseline
leads to neuronal death in animal models.43,44 Multivariate anal- hematoma volume, and earlier time from onset to CT were
yses have also showed that TNF-α concentration is strongly associated with relative increase in edema volume.6 However,
correlated (r = 0.83, p < 0.0001) with perihematomal edema the treatment of early intensive BP lowering does not appear
volume.45 Furthermore, human leukocyte antigen-G molecules to have any appreciable effects on perihematomal edema.81
in soluble form have been found to be positively correlated Nevertheless, it has been postulated that the acute hyperten-
with perihematomal edema volume at 24 and 48 hours, thereby sion and BP instability because of autonomic dysfunction may
implicating sHLA-G1 in the inﬂammatory processes of ICH,46 be detrimental after ICH. Indeed, decreased baroreﬂex sensitiv-
and presence of soluble Fas, an inhibitor of apoptosis induced ity is an independent predictor for relative edema in humans.82
by the interaction between Fas and its ligand (Fas-L), has also In a retrospective study of ICH patients, prior use of statins
been observed to be lower in ICH patients than controls and (3-hydroxy-3-methyl-glutaryl [HMG]-CoA reductase inhibitor)
to be inversely correlated with perihematomal edema growth.47 was associated with a reduced early absolute perihematomal
All these data provide good support for the hypothesized patho- edema compared with those without prior statins, a differ-
physiological and pathochemical processes generated in exper- ence that remained signiﬁcant after adjusting for other poten-
imental animal studies to apply to ICH in man. tial confounders, possibly because of the anti-inﬂammatory,
angiogenic, and neurogenic properties of statins.83 Recently,
the severity of obstructive sleep apnea has been found to cor-
FACTORS UNDER INVESTIGATION THAT relate with the development of the perihematomal edema in
INFLUENCE THE FORMATION OF patients with hypertensive ICH,84 possibly because of oxida-
PERIHEMATOMAL EDEMA tive stress, inﬂammation, coagulation cascade activation, and
impaired endothelial function arising as a result of the episodes
Factors found to aggravate perihematomal edema include
of hypoxia/reoxygenation during the momentary cessation of
(i) age—compared with young rats, larger perihematomal
breathing that occurs in these patients. These deleterious pro-
edema, greater neurological deﬁcits, and more prolonged
cesses could theoretically be reversed through the use of con-
recovery occurs in aged rats,48 suggesting greater complement
tinuous positive airway pressure therapy.85
activation,49 microglial activation,50 thrombin production,
and erythrocyte fragility with increasing age in humans;51,52
(ii) hyperglycemia—contributes to acidosis, release of excita-
tory amino acids, and greater blood–brain barrier injury in rat
models;53 (iii) isotonic or slightly hypotonic solutions (ie, that con- EFFECT OF PERIHEMATOMAL EDEMA ON
tain “free water,” eg, 0.45% saline, 5% dextrose, or Ringer’s CLINICAL OUTCOME
lactate) have been shown to exacerbate edema and increase ICP
It seems plausible that perihematomal edema would have
after brain injury in dogs.54,55 Various factors found to attenu-
a similarly detrimental effect on the neurological outcome:
ate edema formation are summarized in Table 3. In addition,
there is a modest but signiﬁcant correlation (r = 0.393,
in vitro models have shown no impact of calcium channel
p = 0.0002) between baseline absolute perihematomal edema
blockers on oxyhemoglobin-induced apoptosis,76 but use of
and hematoma volumes;86 ICH volume is an independent pre-
the non-competitive NMDA receptor antagonist MK-801 results
dictor of absolute perihematomal volume;6 and hematoma vol-
in reduced delayed edema volume and inﬂammatory response
ume is considered a powerful predictor of outcome following
when given as an adjuvant to tissue plasminogen activator
ICH.87 This hypothesis is further supported by the presumed
(rtPA) in a porcine model.77 Conversely, amantadine, another
pathophysiology, whereby ICP increases with increasing edema
NMDA receptor antagonist, does not have any apparent effect
growth, leading to midline shift and/or uncal herniation and
on brain edema in a rat model.78 Moreover, with regard to the
death. Yet, relative edema at presentation has been found to
antioxidants, which could theoretically limit oxidative stress
independently predict early neurological deterioration in ICH
and thus injury in the perihematomal area, melatonin has not
(odds ratio [OR] 22.6, p = 0.009),82 while baseline relative
been shown to affect either the extent of edema or the neuro-
edema (<20 hours of onset) has been found to be strongly asso-
logical deﬁcits in rats,79 and superoxide dismutase and catalase,
ciated with improved functional outcome (OR 0.79 per 10%
two enzymes involved in the decomposition of the reactive oxy-
increase; p = 0.02) but not mortality.88 This conﬂicting result
gen species superoxide and hydrogen peroxide, have also failed
has been suggested to reﬂect successful hematoma clotting and
to reduce brain edema associated with ICH in rat models.80
hematoma retraction in the very early phase of brain edema
formation.82,88 In addition, it has been found that relative edema
Effects of Blood Pressure Levels, Statins, and Sleep at 48 hours does not differ between patients with and without
Apnea on Perihematomal Edema early neurologic deterioration.89 However, in another study of a
Secondary analysis of the Intensive Blood Pressure Reduction larger series of ICH patients, Arima et al. reported that although
in Acute Cerebral Hemorrhage Trial (INTERACT), an open, signiﬁcant associations were found between both absolute and
randomized controlled trial of rapid early blood pressure (BP) relative perihematomal edema growth and death/dependency
reduction in 404 patients with ICH, showed that lower systolic at 90 days,6 these relationships became nonsigniﬁcant when
BP, and baseline hematoma volume were each independently the statistical models were additionally adjusted for baseline
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European Neurological Journal
Table 3. Factors that attenuate perihematomal edema formation
Effect Factor Potential mechanism
Reduced edema formation Porcine models
Hematoma aspiration after tissue plasminogen Prevention of vasogenic edema56
Local brain hypothermia Reduction of interleukin-1β gene expression and
formation of vasogenic edema34
Early administration (<24 hours after ICH) of Inhibition of free and bound thrombin57
Administration of TIMP-2 Protection of the blood–brain barrier58
Administration of dexamethasone Regulation of aquaporin-4 in different brain regions59
Preconditioning with hyperbaric oxygen Induction of brain tolerance through activation of
p44/42 MAP kinase60
Preconditioning with low-dose thrombin HSP-27 induction and tolerance effect61
Administration of batroxobin Down-regulation of ICAM-1 and complement C3d and
Administration of cobra venom factor Reduction of TNF-α production63
Reduced edema formation, Rat models
reduced neuronal death, and
improved functional outcome
Administration of geranylgeranylacetone Induction of HSP-7064
Administration of cystamine Competitive inhibition of transglutaminase31
Administration of deferoxamine Chelation of free iron (effects independent of age)65–68
Administration of granulocyte colony-stimulating Reduction of blood–brain barrier permeability69
Administration of erythropoetin Tissue protection in toxic and inﬂammatory injuries,
possibly through activation of eNOS70
Administration of minocycline Reduction of microglial activation (in rat models),
reduction of thrombin-induced upregulation of
TNF-α and interleukin-1β (in vitro)71
Administration of telmisartan Induction of eNOS and PPAR-γ , reduction of oxidative
stress, apoptotic signaling, and decreased
expression of TNF-α and COX-272
Administration of celecoxib COX-2 inhibition with resultant reduction in
prostaglandin E2 production59
Administration of tacrolimus Immunosuppression73
Reduced edema formation, and Rat models
neuronal death but effect on
Administration of metallothionein (MT) 1 Reduction of iron-induced cell death and edema
Administration of bortezomib Inﬂammatory response regulation - reduced expression
of TNF-α, interleukin-6, iNOS, and COX-2,
decreased inﬂammatory inﬁltrates, and cell death in
the perihematomal regions75
COX, cyclooxygenase; HSP, heat shock protein; ICAM, inﬂammatory molecule intercellular adhesion molecule; MAP, mitogen-activated protein; eNOS,
endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; PPAR, peroxisome proliferator-activated receptor; TIMP, tissue inhibitor of
metalloproteinase; TNF, tumor necrosis factor.
hematoma volume.6 These data indicate that hematoma volume optimize cerebral metabolism.90 However, the primary strategy
(and growth) are the principal drivers of prognosis after ICH. is supportive care, with interventions undertaken in a graded
stepwise approach starting with relatively simple measures,
such as 30◦ elevation of the head of the bed and simple analge-
sia, followed by stronger sedation using agents such as intra-
CURRENT MANAGEMENT OF PERIHEMATOMAL venous propofol, midazolam, morphine or alfentanil,91 and
EDEMA assisted ventilation, best undertaken in a monitored setting.
There is a limited evidence base on which to make ﬁrm rec- As patients with ICH are frequently medically and neu-
ommendations regarding speciﬁc therapeutic interventions in rologically unstable, particularly within the ﬁrst 72 hours,
ICH. The ultimate goal of therapy is to reduce brain edema and careful monitoring of the vital signs and the early signs of
thus ICP, to maintain blood supply and oxygen delivery, and to increased ICP, either because of direct mass effect or indirectly
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Signiﬁcance of perihematomal edema in acute intracerebral hemorrhage
e. Hyperventilation and positive end-expiratory pressure is
often used to improve oxygenation by preventing atelectasis,
Perihematomal edema volume (cm3)
increasing the pulmonary residual capacity, and reducing
pulmonary shunting, but is compounded by concomitant
effects on reducing cerebral blood ﬂow and the transient
nature of its effect.91
f. Corticosteroids, namely, dexamethasone, have traditionally
been used for the treatment of cerebral edema, as they are
purportedly beneﬁcial in extracellular (vasogenic) edema
through the inhibition of inﬂammatory mediator release,
which limits blood–brain barrier permeability and sup-
presses the extracellular buildup of ﬂuid.27 The approach has
been regarded as predominantly preventative and thereby
0 20 40 60 80 100 more efﬁcacious in the early stages of edema formation.27
Total hematoma volume (cm³) Nevertheless, any potential beneﬁt of steroid use in ICH
must be counterbalanced by the potential detrimental effects
Figure 3. Association between hematoma and perihematomal edema of hyperglycemia and associated immunodeﬁciency. Indeed,
volumes at baseline. Linear regression line was estimated using a simple lin-
ear regression model of the raw data. Edema volume (cm3 ) = 3.853 + 0.392
a Cochrane review has shown that any potential ben-
× hematoma volume (cm3 ). r2 = 0.33. eﬁt of steroids fails to translate into clinical efﬁcacy,94
whereas current international guidelines such as from the
American Heart Association/American Stroke Association
recommend that steroids should generally be avoided in the
hydrocephalus, is required. This is best undertaken in a ded- management of ICP.95
icated (neuroscience) intensive care unit, where the chances g. Surgical decompression—whilst still a controversial area,
of survival after ICH should be increased because of92 (i) use most clinicians would accept that decompressive surgery
of structured protocols to provide (ii) frequent checks of (and for cerebellar ICH with signiﬁcant mass effect is beneﬁcial,
appropriate responses to) vital signs and for (iii) neurologic although there have not been any randomized trials. Surgery
assessments to be undertaken; and the availability of (iv) for hemispheric ICH may limit the mechanical compression
continuous cardiopulmonary monitoring including the use of of brain and the toxic effects of blood products but is offset
a cycled automated BP cuff, (v) electrocardiographic (EKG) by risks related to bleeding, infection, and in all but the most
telemetry, and (vi) use of an O2 saturation probe. Continuous superﬁcial hemorrhages, injury because of cutting through
intra-arterial BP monitoring should be considered in patients uninjured brain. Trials of surgery for ICH, to date, have been
receiving intravenous vasoactive medications to control BP and limited by the exclusion of young and middle-aged patients
other physiological variables. More aggressive medical man- who are at a greatest risk of herniation from large ICHs; rec-
agement may be initiated as clinically indicated, but any poten- ommendations regarding such intervention in these patients
tial beneﬁts may be offset by an increased risk of adverse are therefore uncertain.
effects. h. Minimally invasive surgical approaches, including endo-
Various popular interventions for ICH, each with speciﬁc pros scopic surgical evacuation and ventriculostomy, intraven-
and cons, are outlined below: tricular rtPA, ventriculoperitoneal shunting, or lumbar
drainage for hydrocephalus, all appear to be promising
treatments but few randomized data exist to date to sup-
a. Mannitol is often used to reduce ICP but there is no ran- port the routine use of these strategies, and they should
domized evidence of efﬁcacy and it is complicated by renal be considered experimental. Drainage of cerebrospinal ﬂuid
failure, rebound ICP, and volume depletion because of its through ventriculostomy can relieve high ICP but is associ-
effects on both intracellular (cytotoxic) and extracellular ated with infection and secondary hemorrhage in 1–2% of
edema in drawing excess ﬂuid from the parenchyma into the cases.
b. Induced neuromuscular paralysis can reduce agitation and
restlessness and allows use of assisted ventilation, but Thus, treatment of the ICP resulting from perihematomal
increases the risk of complications such as pneumonia and edema is primarily directed at the underlying cause, especially
sepsis, and can obscure the degree of neurological deﬁcit if there is hydrocephalus or mass effect from the hematoma.
and any underlying seizure activity. Because of limited data regarding ICP in ICH, management
c. Barbiturate coma can result in respiratory and cardiovascu- principles for elevated ICP are borrowed from traumatic brain
lar depression.91 injury guidelines that emphasize maintaining a CPP of 50–70
d. Systemic hypothermia is potentially neuroprotective, often mmHg depending on the status of cerebral autoregulation.96
used following global anoxic brain damage after cardiac ICH patients with a Glasgow Coma Scale (GCS) score of 8
arrest, but is associated with a relatively high risk of cardiac, or less, those with clinical evidence of transtentorial herni-
immunologic, hematologic, and metabolic complications.93 ation, or those with signiﬁcant intraventricular hemorrhage
www.slm-neurology.com 127 ENJ 2010; 2:(2). August 2010
European Neurological Journal
or hydrocephalus may be considered for ICP monitoring and 13. Wagner KR, Xi G, Hua Y, et al. Lobar intracerebral hemorrhage model
treatment. in pigs: rapid edema development in perihematomal white matter. Stroke.
14. Gebel JM, Brott TG, Sila CA, et al. Decreased perihematomal edema in
thrombolysis-related intracerebral hemorrhage compared with sponta-
FUTURE DIRECTIONS neous intracerebral hemorrhage. Stroke. 2000;31(3):596–600.
15. Xi G, Wagner KR, Keep RF, et al. Role of blood clot formation on early
In summary, ICH-related perihematomal edema growth is a
edema development after experimental intracerebral hemorrhage. Stroke.
progressive process, with multiple mechanisms implicated in 1998;29(12):2580–2586.
its pathophysiology encompassing the hematologic, immuno- 16. Hua Y, Xi G, Keep RF, Hoff JT. Complement activation in the brain
logic, and inﬂammatory pathways. Although the signiﬁcance of after experimental intracerebral hemorrhage. J Neurosurg. 2000;92(6):
perihematomal edema as a prognostic indicator per se is as yet 1016–1022.
17. Xi G, Hua Y, Bhasin RR, Ennis SR, Keep RF, Hoff JT. Mechanisms of
uncertain, its secondary effects on ICP are clear and emphasize
edema formation after intracerebral hemorrhage: effects of extravasated
the consideration of treatment options that are largely support- red blood cells on blood ﬂow and blood-brain barrier integrity. Stroke.
ive and aimed at reducing ICP and associated complications, 2001;32(12):2932–2938.
most notably of brain herniation-related death. Further studies 18. Huang FP, Xi G, Keep RF, Hua Y, Nemoianu A, Hoff JT. Brain edema after
are therefore required to elucidate the prognostic signiﬁcance experimental intracerebral hemorrhage: role of hemoglobin degradation
products. J Neurosurg. 2002;96(2):287–293.
of perihematomal edema in ICH and to translate the results
19. Clark JF, Loftspring M, Wurster WL, Beiler S, Beiler C, Wagner KR,
the considerable experimental animal research into the clinical Pyne-Geithman GJ. Bilirubin oxidation products, oxidative stress, and
domain. intracerebral hemorrhage. Acta Neurochir Suppl. 2008;105:7–12.
Acknowledgments: JWW was a recipient of an Australian Post- 20. Gutteridge JMC. The antioxidant activity of haptoglobin towards
haemoglobin-stimulated lipid peroxidation. Biochimica et Biophysica Acta
graduate Award. HA received Post Doctoral Research Fellowship from
(BBA)—Lipids and Lipid Metabolism. 1987;917(2):219–223.
the University of Sydney. CSA received salary support from The George 21. Ogihara K, Zubkov AY, Bernanke DH, Lewis AI, Parent AD, Zhang
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