Significance of Perihematomal Edema in Acute Intracerebral Hemorrhage by MikeJenny


									                          EUROPEAN NEUROLOGICAL JOURNAL                                                                      REVIEW ARTICLE

Significance of Perihematomal Edema in Acute
Intracerebral Hemorrhage
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:

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
                                                                                                                        the midbrain
       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-
      Component                                           Points
                                                                               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                                                    123                                      ENJ 2010; 2:(2). August 2010
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                                                 125                                        ENJ 2010; 2:(2). August 2010
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
                                          activator (tPA)
                                        Local brain hypothermia                                  Reduction of interleukin-1β gene expression and
                                                                                                   formation of vasogenic edema34
                                      Rat models
                                        Early administration (<24 hours after ICH) of            Inhibition of free and bound thrombin57
                                           high-dose argatroban
                                        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
                                                                                                   C9 expression62
                                        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
   outcome unknown
                                        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                                                                     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
Institute for International Health and as a Senior Principal Research                  JH. Oxyhemoglobin-induced apoptosis in cultured endothelial cells. J
Fellow of the National Health and Medical Research Council of                          Neurosurg. 1999;91(3):459–465.
Australia.                                                                         22. Regan RF, Guo Y. Toxic effect of hemoglobin on spinal cord neurons in
     Disclosure: The authors declare no competing interests.                           culture. J Neurotrauma. 1998;15(8):645–653.
                                                                                   23. Willmore LJ, Rubin JJ. Formation of malonaldehyde and focal brain
                                                                                       edema induced by subpial injection of FeCl2 into rat isocortex. Brain Res.
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