Review Article To Look Beyond Vasospasm in Aneurysmal Subarachnoid Haemorrhage - Hindawi

15 Pages·2015·1.71 MB·English

Hindawi Publishing Corporation
BioMed Research International
Volume 2014, Article ID 628597, 14 pages
http://dx.doi.org/10.1155/2014/628597
Review Article
To Look Beyond Vasospasm in
Aneurysmal Subarachnoid Haemorrhage
GiuliaCossu,1MahmoudMesserer,1MauroOddo,2 andRoyThomasDaniel1
1DepartmentofNeurosurgery,CentreHospitalierUniversitaireVaudois,FacultyofHumanMedicineandBiology,
LausanneUniversity,rueduBugnon46,1011Lausanne,Switzerland
2DepartmentofIntensiveCareMedicine,CentreHospitalierUniversitaireVaudois,FacultyofHumanMedicineandBiology,
LausanneUniversity,rueduBugnon46,1011Lausanne,Switzerland
CorrespondenceshouldbeaddressedtoGiuliaCossu;[email protected]
Received11March2014;Accepted7May2014;Published19May2014
AcademicEditor:AaronS.Dumont
Copyright©2014GiuliaCossuetal.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Delayedcerebralvasospasmhasclassicallybeenconsideredthemostimportantandtreatablecauseofmortalityandmorbidity
inpatients with aneurysmal subarachnoidhemorrhage (aSAH). Secondary ischemia (ordelayed ischemic neurological deficit,
DIND)hasbeenshowntobetheleadingdeterminantofpoorclinicaloutcomeinpatientswithaSAHsurvivingtheearlyphaseand
cerebralvasospasmhasbeenattributedtobeingprimarilyresponsible.Recently,variousclinicaltrialsaimedattreatingvasospasm
have produced disappointing results. DIND seems to have a multifactorial etiology and vasospasm may simply represent one
contributingfactorandnotthemajordeterminant.Increasingevidenceshowsthataseriesofearlysecondarycerebralinsults
mayoccurfollowinganeurysmrupture(theso-calledearlybraininjury).Thisfurtheraggravatestheinitialinsultandactually
determinesthefunctionaloutcome.Abetterunderstandingofthesemechanismsandtheirpreventionintheveryearlyphaseis
neededtoimprovetheprognosis.Theaimofthisreviewistosummarizetheexistingliteratureonthistopicandsotoillustratehow
thepresenceofcerebralvasospasmmaynotnecessarilybeaprerequisiteforDINDdevelopment.Thevariousfactorsdetermining
DINDthatworsenfunctionaloutcomeandprognosisarethendiscussed.
1.Introduction but classically it has been attributed to cerebral vasospasm
[5].
SAH accounts for only 5% of all strokes, with an incidence During the last century there was a wide consensus
of nine per 100,000 person years [1]. Half the patients are that cerebral vasospasm was the most important determi-
younger than 55 years and therefore SAH has a severe nant of poor prognosis in patients with aSAH [6]. Re-
economic and social impact [2]. One in six patients die search was mainly directed to control and prevent delayed
duringthesuddenonsetofbleedingandthosewhosurvive vasospasm, often with disappointing results. Indeed radio-
maydieordeteriorateowingtoearlyaneurysmalrebleeding, logicalimprovementofvasospasmdoesnotcorrelateclearly
secondarydelayedcerebralischemia(DCI),hydrocephalus, with changes in functional outcome [7, 8]. Over the last
ormedicalcomplications.Approximately70%ofpatientsdie decade, growing experimental and clinical evidence has
orsubsequentlyneedhelpwiththeordinaryactivitiesofdaily demonstratedthatthepresenceofdelayedvasospasmofthe
life[3]. majorcerebralvesselsmayindeedbeacontributingfactorbut
Secondary DCI occurs in c. 30% of all patients [4] and notnecessarilytheprincipaldeterminantofDCIandDIND.
results in poor outcome in half of these [3]. The high risk Indeed, cerebral infarction can also occur when vasospasm
period for DIND is between 4 and 10 days after aneurysm is not angiographically detected in the territorial artery [9]
rupture[4];thepathogenesisisstillincompletelyunderstood, andpooroutcomeinaSAHseemstobedirectlydependent
2 BioMedResearchInternational
on infarction but independent of vasospasm [10]. There is hyponatremic patients have a risk of developing delayed
increasing evidence that other coexisting factors may be ischemic injury three times higher than normonatremic
involved in the development of DIND and their character- patients[22].Riskfactorsforhyponatremiaincludeahistory
isation and treatment could improve the consistently poor of diabetes, chronic heart, hepatic failure, adrenal insuffi-
clinicaloutcomeinpatientswithaSAH. ciency,andNSAIDsordiureticuse[23].
The aim of this review is to discuss the various mech- Cellular calcium homeostasis is impaired in neuronal,
anisms contributing to the poor prognosis in patients with cerebral endothelial, and smooth muscle cells; the intra-
SAHandtoredefinetheroleofdelayedcerebralvasospasm cellular elevation is due to N-methyl-D-aspartate (NMDA)
inDIND. glutamatereceptoractivationandderegulationofadenosine
triphosphatase (ATPase) dependent channels. Pathological
riseinintracellularcalciummayresultinpersistentcontrac-
2.EarlyBrainInjury
tionofsmoothmusclecellsincerebralarteries,alsocausing
glutamaterelease and activationof apoptoticpathways [24]
The term early brain injury (EBI) was first coined in 2004
(Figure1).
to explain the acute pathophysiological events occurring
Approximately40%ofpatientsadmittedwithin48hours
within 72 hours of aSAH that begin minutes after bleeding
after SAH have abnormally low serum magnesium [25].
commences[11,12].Theseeventsincludecerebralautoregula-
Magnesium decrease contributes to the rise in intracellular
tionandblood-brainbarrier(BBB)disruption,activationof
calcium by blocking NMDA receptors in an activated state
inflammatory pathways, excitotoxicity, oxidative stress, and
and this provokes vasoconstriction, platelet aggregation,
activation of apoptosis [13]. These are direct effects of the
release of excitatory aminoacids,and increased synthesis of
presence of blood in the subarachnoid space and also of
endothelin-1(ET-1)[26].
transient cerebral ischemia. Brain injury is not limited to
A high level of serum potassium has been detected
the primary site of haemorrhage; many of the mechanisms
after SAH [27], probably owing to decreased activity in
occurringwithEBIcontributetothepathogenesisofdelayed
the potassium-sodium pump mechanism. Subarachnoid
ischemic injury and are thus responsible for subsequent
haemoglobincombinedwithahighconcentrationofpotas-
poor outcome. Hence early detection of EBI may make
siummaycausewidespreadconstrictionofcerebralarteries
it possible to predict patient outcome; logically, therefore,
andapathologicaldecreaseinCBF.
early intervention that inhibits such changes may decrease
mortalityandimproveoveralloutcome.
2.3. Excitotoxicity. The increased interstitial glutamate con-
2.1. Mechanical Injury and Cerebral Autoregulation Disrup- centration after SAH is linked to cellular leakage, altered
tion. Immediately after an aSAH a reactive constriction of synaptic transmission, BBB disruption, and decreased glu-
the artery supplying the ruptured aneurysm occurs, thus tamateuptake[28].Inanimalexperimentsanexcitotoxicity
producing a mechanical injury [14]. The consequence is an from excessive activation of ionotropic and metabotropic
acute global ischemia leading to BBB disruption through glutamate NMDA receptors [29] was observed, leading
endothelial cell death [15, 16]. Furthermore,both vasogenic to excessive intracellular calcium influx and activation of
and cytotoxic brain oedema may contribute by elevating apoptotic pathways [30]. The NMDA receptor-antagonist,
intracranialpressure(ICP)andimpairingcerebralbloodflow felbamate,improvedneurologicalperformanceinratmodels,
(CBF). limiting BBB disruption [31] and development of delayed
EarlyelevationofICPvaluesiscommonafterSAH.Two vasospasm [32]. Similarly blood glutamate scavengers have
patterns of ICP elevation, namely, transitory and sustained, been shown to improve neurological outcome in animal
are described. The extent of rise in ICP is often used to models, but the blockade of NMDA receptors may actually
predictoutcomeinSAH[17]andsustainedICPelevationis hinder neuronal survival [33]. In clinical studies glutamate
associated with higher mortality [18]. This phenomenon is elevation in cerebral interstitial fluid detected with micro-
associatedwithaseverereductioninCBF,cerebralperfusion dialysis was predictive of ischemia [34] and the release of
pressure (CPP), and impaired cerebral autoregulation [19, excitatory amino acid after SAH measured in interstitial
20],thusincreasingmortalityrates.Bedersonetal.observed and cerebrospinal fluid (CSF) correlated strongly with ICP
that CBF reduction to less than 40% of baseline in the first elevation,secondarybraininjury,andpooroutcome[35].
hourafterSAHpredicted100%mortality,independentofICP
andCPPvalues[11].
2.4.NitricOxideAlterationsandEndothelin-1Increase. Alter-
ations in nitric oxide (NO) pathways are described in the
2.2. Electrolyte Disturbances. Electrolyte disturbances are early period after aSAH both in animals and humans. [36,
oftenobservedwithinthefirsthoursafterSAHandtheymay 37] NO is produced by nitric oxide synthase (NOS) which
beresponsibleforseveralmechanismsofEBI.Hyponatremia canbedistinguishedbetweenendothelial(eNOS),neuronal
develops within 1-2 days from the initial bleed [21] and it (nNOS),andinducibleNOS(iNOS).NOplaysanimportant
occursin10%–30%ofpatientsatadmission;itiscausedbya role in regulating vascular hemodynamic activity; it dilates
cerebral salt-wasting syndrome and inappropriate secretion vessels by blocking intracellular calcium release from the
of antidiuretic hormone. The treatment of hyponatremia is sarcoplasmicreticuluminsmoothmusclecellsanditinhibits
not easy and clinical signs may mimic DIND. Furthermore plateletaggregationandleucocyteadhesiontotheendothelial
BioMedResearchInternational 3
↑ICP
↓CBF ↓Seric Na
Autoregulation loss ↑Seric K
ATP stores depletion
↓Seric Mg Vasospasm
↑Intracellular
calcium
↑NMDA
activation
Synaptic dysfunction
and increased
glutamate release
Apoptosis
Figure1
layer. Its alteration may disrupt autoregulation homeostasis SAHresultinginhaemoglobinautooxidationandlipidper-
andmayberelatedtothepathogenesisofdelayedvasospasm oxidationandaconsequentrapidconsumptionofenzymatic
[37]. Animal studies demonstrate that cerebral NO level and nonenzymatic antioxidant defence systems [47]. Such
decreases within 10min of aSAH [36] and it increases oxidativestressmaybethetriggerforanumberofdeleterious
excessivelyafter24hours[38].Thedecreasedavailabilityof pathophysiological changes including structural alterations
NOmaybeattributedtonNOSdestructionandinhibitionof inendothelialcells,endothelialdysfunctionandproliferation
eNOSthroughthepresenceofsubarachnoidhaemoglobin.A of smooth muscle cells [48], disruption of BBB, activation
downregulationofeNOSandlossofnNOSinspasticarteries of the inflammatory cascade, and production of powerful
afterSAHhaveindeedbeendemonstrated[39]. localvasoconstrictors(e.g.,leukotrieneC4andprostaglandin
Inclinicalstudies,increasedcerebralNOlevelsarefound D2). [47]. The vasodilator effect of bradykinin in cerebral
24 hours after aSAH and this indicates a poor prognosis vesselsthroughaninhibitionbyROSfurthersupportssuch
[37, 40]. Inflammation activates iNOS and NO production a hypothesis [49]. The treatment of oxidative stress during
may act as a vasodilator, in the form of peroxynitrite or as theshorteffectivetherapeuticwindowthatexistsisdifficult;
freeradicalitself,causinganoxidativestressinthevascular injurycausedbyfreeradicalsmaywelloccurbeforeapatient
wallatthecriticalmoment[41]. canreceiveeffectivetreatment[50].
Endothelin-1(ET-1)isthemostpotentendogenousacti-
vatorofvasoconstriction,throughtheactivationofcalcium-
2.6. Inflammatory Pathways. The correlation between
dependent and independent mechanisms. The level of ET-1
inflammationandthepresenceofbloodinthesubarachnoid
increasesinserumandplasmawithinminutesafterSAHwith
space was established over fifty years ago. In 1955 Walton
apeak3-4daysafterinjury[42];itisphysiologicallyproduced
demonstrated that febrile patients with SAH have a worse
bytheendothelium,butinSAHthereisanexcessiverelease
final outcome than afebrile patients [51]. SAH triggers an
by astrocytes during the period of initial ischemia [43].
inflammatorycascade:asystemicleucocytosisiscommonly
An upregulation of its receptors is equally observed in
observed [52] and white cells can directly promote free
the delayed phase; ET receptor in particular is expressed
A radicalformation,releasecytokinesandchemotacticfactors
predominantly on smooth muscle cells and is crucial in
to propagate the immunological response, and produce
vasoconstriction and cell proliferation. ET-1 can produce
ET-1 and leukotrienes [53] and consume NO. Furthermore
long lasting vasoconstriction directly [44] and can induce
Spallone et al. have shown how leucocyte concentrations
morphologicalchangessuchasfibrosisorhyperplasiainthe
are more elevated in the CSF of patients with SAH-related
vascular wall [45]. Furthermore, a disequilibrium between
ischemia when compared to controls [52]. By analogy
NOandET-1levelleadstounopposedvasoconstrictionand
elevated serum C-reactive protein levels on admission are
promotesvasospasmdevelopment[46].
knowntoberelatedtopoorprognosisandtheoccurrenceof
delayedvasospasm[54].
2.5. Oxidative Stress. Reactive oxygen species (ROS), prin- Subarachnoid blood is a stimulant for nuclear fac-
cipally oxygen free radicals, and reactive nitrogen species tor 𝜅-light-chain-enhancer of activated B cells (NF-𝜅B),
(RNS)arebothlinkedtoanumberofvasculardiseasestates. which mediates the transcription of multiple components
Oxidative stress plays a significant role in EBI. Animal and oftheinflammatorycascade,includingadhesionmolecules,
human studies indicate that ROS are generated early after cytokines,andcomplement[55].
4 BioMedResearchInternational
Tumor necrosis factor-alpha (TNF𝛼) may also have a 2.8. Small Vessel Spasm. Vascular spasm on angiographic
critical role in determining EBI. According to Starke et imagingisrestrictedmostlytoproximallargevesselsandit
al., TNF𝛼 contributes to the formation and rupture of the occurs 3–7 days after SAH. However evidence from exper-
aneurysmandinhibitorsofTNF𝛼maythereforebebeneficial imental studies shows that the constriction effect seen on
notonlyinpreventinganeurysmalprogressionandrupture parenchymalsmallvesselswithinthefirstminutesafterSAH
[56], but also in limiting the inflammatory process after is greater than on large proximal vessels [11, 69]. Technical
subarachnoidbleeding. reasons limit the data on SAH-induced microcirculatory
Cytokines and chemokines may be implicated in the changestoanimalstudies.Theydemonstratethepresenceof
developmentandmaintenanceofneurovascularinjurywith abnormalpialmicrocirculationwithspasmofthemicrovas-
anearlyincreaseatsixhoursandalatepeakbetween48and culatures, decreased blood flow and agglutination of red
72 hours. Their elevation in serum, CSF, and microdialysis blood cells [70]. In the majority of patients, aSAH induces
fluid is related to early and delayed ischemia and poor multiplevasospasmofarterioleswithoutangiographicsigns
outcome[44,57]. ofvasospasmorincreasesinbloodflowonevaluationwith
In particular, as shown by Muroi et al., higher serum transcranialDoppler.
interleukin-6(IL-6)levelsareassociatedwithworseclinical Uhl et al. confirmed constriction of small vessels in
outcome and DIND. Thus it is feasible that IL-6 levels may patientsundergoingsurgerywithinthefirst72hafteraSAH
alsobeusedasamarkertomonitorclinicalprogression[58]. [71] and they proposed that SAH is associated with a
The serum and CSF levels of endothelial adhesion microvascular spasm primarily involving arterioles, with
molecules (in particular E-selectin, ICAM, and VCAM-1),
constriction in pial vessels and decrease in capillary den-
which are vital to the capture, rolling, transmigration, and
sity. Pennings later confirmed this finding [72]. In animal
diapedesis of leucocytes to the site of inflammation, are
and postmortem pathological studies a disruption of the
significantlyelevatedafteraSAH[59].Theirincreasewithin
basalmembraneandtheendotheliallayerwasdemonstrated
the first three days of haemorrhage is associated with poor
[73], with morphological changes being more evident on
outcome[60].
parenchymal vessels compared to large vessels [74]. These
Aquantitativecorrelationbetweenthedegreeofinflam-
may contribute to early clinical signs and may influence
matoryresponseandtheprognosisinpatientswithSAHmay
thepostoperativecourse[71].Inparticularendothelialdys-
thereforebepossible.
function is considered to be one of the key factors initi-
ating early vasoconstriction, keeping in with a decreased
2.7. Blood Breakdown Products. Haemoglobin may cause response to vasodilators(such as acethilcoline,bradikinine,
vasoconstriction by direct oxidative stress (as oxy-Hb or or thrombin) which require a functional endothelium [75].
as bilirubin oxidation products (BOXes)) [61] and also by Basementmembranedegradationseemstobemorerelated
altering the balance between NO and ET-1. Oxy-Hb is a todestabilizationofmicrocirculationandincreaseinvascular
strongspasmogenicsubstance;itcausesprolongedcontrac- permeability and interstitial oedema [76]. Whether these
tionofsmoothmusclecellswhenappliedtocerebralarteries earlychangesinmicrocirculationcanbeusedasaprognostic
in vivo and antagonists seem to prevent the occurrence of factor for the development of delayed proximal vasospasm
vasospasm[62].Itcancatalysethegenerationofsuperoxide remaintobeproven.
and hydrogen peroxide, resulting in subsequent lipid per-
oxidation. Furthermore haemoglobin may scavenge nitric
oxide,destroynNOS,andaltereNOSfunctionalityanditmay 2.9. Cortical Spreading Depolarization. Cortical spreading
indeedstimulateET-1production[63]. depolarization (CSD) is a wave of almost complete depo-
larization of the neuronal and glial cells that occurs in
Bilirubinformationismaximalduringthethirdorfourth
day after SAH and BOXes reach a maximal concentration differentneurologicaldiseases[77].Itisobservedwithinthe
during the major vasospasm period (4–11 days). However, first 72 hours of SAH and it occurs probably as a result of
BOXes seem to be potentiators rather than initiators of the irritating activity of subarachnoid haemoglobin and an
vasospasm[64]. elevated extracellular potassium, glutamate, and ET-1 [78].
This results in a breakdown of ion gradients characterized
The role of iron in early brain injury after SAH was
by a change in the negative potential with an amplitude
investigatedbyLeeetal.[65];theyshowedhowironchelator
desferroxamine halved mortality, attenuated DNA damage, between−10and−30mVandadurationofaboutoneminute.
and lessened induction of iron-handling proteins in exper- The histological result is neuronal oedema and dendritic
imental models [66]. Treatment was efficacious as early as distortion.ThecombinationofdecreasedCBFandincreased
the first day and by improving all outcomes significantly, energyrequirementsimposedbyCSDmayworsenneuronal
supporting the contention that toxic blood metabolites are injury[79].Clusteredspreadingdepolarisationsarerelatedto
significantinearlybraininjury[66].Bothferrousandferric metabolicchangessuggestiveofongoingsecondarydamage
iron are prooxidant molecules and ROS may promote the primarily in nonischemic brain tissue [80]. Experimentally,
transcription of NF-𝜅B and activator protein-1 [67], thus spreadingdepolarizationleadstomassiveincreaseingluta-
activatinginflammatorypathways.ROSproductioncatalyzed mate,decreaseinglucose,andincreaseinlactatelevels[81].
byfreeironmayalsocausevasogenicoedemaandincrease Underpathologicstatesofhypoperfusion,corticalspreading
ICPbydisruptingBBB[68]. depolarizationmayproduceoxidativestress,worsenhypoxia,
BioMedResearchInternational 5
(DBI) describes critical events arising in the late phase of
↑Subaracnoid Hb ↑Seric K aSAH(3–14days)resultingfromtheinteractionofmultiple
pathological pathways as a direct consequence of EBI and
leadingtodelayedcerebralischemia(DCI)[93].DCIcauses
↑Glutamate Cortical spreading ↑ET-1 pooroutcomeordeathinupto30%ofpatientswhosurvive
depolarization theinitialimpactofSAHafterhavingtheiraneurysmtreated
effectively[94].DCIisactuallythoughttobecausedbythe
combined effects of delayed vasospasm, arteriolar constric-
tion, thrombosis and dysfunction in microcirculation, and
corticalspreadingischemia,allprocessestriggeredbyEBI.
Mismatch btw
metabolic ↓ATP
↓Glucose needs and CBF ↑intracellular Ca
3.1.DelayedCerebralVasospasm. Historicallydelayedspasm
↑lactate
incerebralproximalvesselswasthoughttobetheprincipal
Oxidative factor responsible for tissue infarction and clinical deterio-
Hypoxia
stress ration and its monitoring was considered a reliable marker
in the followup of aSAH patients. Several studies found
a correlation between radiologically confirmed vasospasm
Neuronal death and cortical spreading ischemia and clinical symptoms of DCI [95]. In the acute phase it is
considered the result of a prolonged contraction of smooth
Figure2 muscle cells, with an abnormal endothelial hypertrophy
arising from inflammatory changes and gene expression
modification [96]. An increase in inflammatory cells in the
and induce neuronal death [16]. Elevated intracellular cal- adventitiaisobservedwithanecrosisinthemuscularlayer.
cium is possibly the predominant mediator of neuronal Inthechronicphase,aproliferationofsmoothmusclecellsis
deathfromischemia[82](Figure2).Clinicalstudiesconfirm characteristic,probablymediatedbyET-1[97],finallyleading
howthenumberofspreadingdepolarisationsrecordedwith to cerebral ischemia. Vasospasm begins on the third day
a subdural electrode strip correlates significantly with the after the onset of SAH with a peak at 6–8 days, eventually
development of DCI and showed it to be a more reliable lasting2-3weeks[98].Clinicalpredictorsarevolume,density,
markerthanvasospasmseenonangiograms[83,84]. and prolonged presence of SAH (Fisher classification) [99]
andtheincidenceincreaseswithageandcigarettesmoking,
2.10. Cell Death. Secondary brain injury in particular is preexistinghypertension,andhypovolemia.
mediated by apoptosis, while a minor role is exercised by Asignificantrelationshipbetweenseverityofvasospasm
necrosisandautophagy.Celldeathstartswithin24hoursof and the proportion of patients with infarction was shown
SAH, secondary to an early decrease in CPP and CBF with by Crowley et al. [100] analyzing the CONSCIOUS-1 data;
the consequent activation of hypoxia-induced factors and a strong association was demonstrated between vasospasm
cysteine-asparticproteases(caspases)[85]. seenonangiogramsandnewcerebralinfarctions[101].
Serum levels of neuron specific enolase, a marker of Thephysiopathologyofdelayedcerebralvasospasmisstill
neuronal injury, show a trend related to the amount of poorly understood but many mechanisms are shared with
subarachnoidblood,whichcorrelateswithpoorneurological EBI, with activation of inflammatory pathways, oxidative
statusonadmission[86].Apoptosisistriggeredbyelevated stress, electrolyte changes, and apoptosis activation playing
ICP,ischemia,reperfusion,andacutevasospasmandbythe animportantrole.Vasospasmmaycriticallyinfactbealate
neurotoxicityofbloodbreakdowncomponentsandoxidative signofEBI[102](Figure3).
stress [11, 44]. It involves neuronal, glial [87], and smooth
muscle and endothelial cells, causing BBB disruption [88] 3.2. Microcirculation Dysfunction and Vasospasm. Micro-
andpromotingvasospasmdevelopment.Apathologicalele- circulatory dysfunction is a process distinct from proxi-
vation of intracellular calcium activates caspase-dependent malvesselspasm.Normallyautoregulationcompensatesfor
apoptotic pathways [89] and beneficial effects have been decreased CPP with a proportional vasodilatation [103].
observed upon inhibition of caspase activity [90] in terms SAH causes failure of the microcirculation, decrease in
of improvement of cerebral vasospasm in animal models themassdensityofcapillariesandspasm,vasoconstriction,
[91].Furthermoreafteraninteractionbetweenapoptosisand and pathologic changes in small vessels that may lead to
autophagy was demonstrated, rapamycin and simvastatin infarction.Arteriolardiameterisphysiologicallytheprimary
were shown to inhibit apoptosis by activating post-SAH determinantforCBFandDINDislikelytobestronglyrelated
autophagy[92]. tomicrocirculatorychanges[9].
Furthermore after aSAH, the coagulation cascade is
3.DelayedBrainInjury stronglyactivatedwithadiffuseformationofmicrothrombi.
The concentrations of fibrinopeptide A, tissue factor, and
Many patients survive EBI but deteriorate a few days later thrombin-antithrombincomplexesaresignificantlyelevated
after the hemorrhagic onset. The term delayed brain injury in patients who developed DCI [104]. The pathological
6 BioMedResearchInternational
Ionic alterations
↑Intracellular ∙↓Seric Mg
calcium in ∙↑Seric K Endothelial
dysfunction and
smooth muscle
apoptosis
cells
Platelets
activation and ↓NO
release of
vasoconstrictor ↑ET-1
substances
Oxidative stress
Inflammatory blood
Vasospasm
cells breakdown
products
Figure3
formation of microthrombi blocking the possibility of col- showed how moderate perfusion pressure, with a CPP of
lateral revascularisaton or causing a persistent “no-reflow” 80–120mmHg in a normovolemic hemodiluted patient, is
phenomenon may represent an alternative explanation for an effective method of improving cerebral autoregulation
CBF reduction and DIND, independent of CPP alteration and is associated with a lower complication rate compared
[74]. withhypervolemiaoraggressivehypertensiontherapy[110].
Usingtheindexofbraintissueoxygenpressurereactivity Similarly, Muench et al. showed in experimental models
(ORx, a variable correlation coefficient between cerebral how triple-H therapy failed to improve regional blood flow
perfusion pressure and partial pressure of brain tissue oxy- more than maintaining hypertension alone. They showed
gen),Jaegeretal.showedhowimpairedautoregulationwas thatthetriple-Htherapywascharacterizedbyadetrimental
associated with an unfavourable outcome in patients with effectofhypervolemiaand/orhemodilutionwhichreversed
SAH, measured according to their Glasgow Coma Score the positive effect of induced hypertension on brain tissue
[105]. Disrupted autoregulation may predict which patients oxygenation[111].Inconclusion,hypervolemiaandhemod-
willfinallydevelopdelayedinfarction[106]. ilutionarenotbeneficialonCBFandarenotrecommended
nowadays[112].
3.3.CorticalSpreadingIschemia. Corticalspreadingischemia
4.2.CalciumChannelBlockers. CurrentSAHtreatmentpro-
is a direct consequence of neuronal/glial depolarization
tocols include, besides neurointensive care and hyperdy-
(cerebral spreading depolarization), normally occurring 72
namictherapy,theprophylacticadministrationofnimodip-
hours after initial haemorrhage. The direct consequence of
ine. The rationale for the use of calcium antagonists for
CSD is consumption of ATP stores, electrolyte imbalance,
prevention of secondary ischemia was initially based on
cerebral oedema, and neuronal death, as a result of a
the blocking of the dihydropyridine-type calcium channel,
prolongeddisproportionbetweenincreasedmetabolicneeds
thereby preventing the influx of calcium into the vascu-
and decreased CBF, thus ultimately producing widespread
lar smooth-muscle cells and decreasing the rate of cere-
corticalnecrosis[107].
bral vasospasm [113]. After their introduction into clinical
practice it was discovered that calcium-channel blockers
4.TherapeuticStrategies have neuroprotective properties and they seem to provide
beneficial effects without angiographic evidence of cerebral
Therapeutic strategies in aSAH are currently designed to
vasodilatation [113]. Nimodipine, an L-type Ca channel
treatvasospasmwiththeultimategoalofpreventingdelayed
blocker, is currently the only pharmacologic agent showing
ischemicinjuryandimprovingclinicaloutcome.
an improvement in neurological outcome when used for
a period of 21 days after aneurysmal rupture. This occurs
4.1. Triple-H Therapy. Triple-H therapy (hypertension, hy- without a real effect on cerebral vasospasm [114]. Calcium
pervolemia, and hemodilution) was routinely used for pro- blockersseemusefultherapeuticagentsoutsideofanyeffect
phylaxisandtreatmentofcerebralvasospasm.Hyperdynamic onvasospasm[114].
therapy by increasing blood pressure and, if necessary, car-
diac output is considered the best available medical option 4.3. Magnesium Sulphate. Magnesium sulphate acts as a
for treatment of cerebral vasospasm [108, 109]. Raabe et al. noncompetitive antagonist of voltage-dependent calcium
BioMedResearchInternational 7
channels and as a NMDA-receptor antagonist and has 4.6. Nitric Oxide Donors. NO donors were investigated in
neuroprotective and vasodilator properties [26]. Further- experimentalstudies(sodiumnitrate,sodiumnitroprusside,
moremagnesiumtherapyseemstoreducetheinflammatory andnitrite)andtheyseemtopreventcerebralvasospasmin
burden in treated patients [115]. Intravenous magnesium aprimatemodel[126].However,theclinicalutilityofNOis
sulphate was shown by van den Bergh et al. to reduce limitedbyitsshorthalf-lifeanditspotentialtoxicity[127].
cerebral vasospasm and infarct volume after experimental
SAH [25]. However, MacDonald et al. [116] and Veyna et 4.7.Antioxidants. Antioxidantssuchasmethylprednisolone
al. [117] failed to show prevention or clinical improvement (also an anti-inflammatory agent) and tirilazad mesylate (a
incerebralvasospasmwithmagnesiumtherapy.Ithasbeen freeradicalscavenger)maypreventoxidativestressandEBI
considered a promising agent [114] but clinical trials failed damage[128],thoughapparentlywithlimitedefficacyrelated
todemonstrateaclearbenefit[118].Nonetheless,theriskof toaone-yearfunctionaloutcome[50,129,130].Furthermore,
adverse effects is minimal and some practitioners prefer to free radical scavengers seem to be associated with a lower
maintain high serum levels of magnesium in patients with incidenceofdelayedischemicinjury[131].
aSAH. Recently Zhang et al. [132] published a study of the use
ofastaxanthin(ATX),oneofthemostcommoncarotenoids
with potent antioxidant properties, on experimental SAH.
4.4. ET-1 Receptor Antagonists. Disappointing results were
The authors showed how ATX (by intracerebroventricular
observed in two randomized double blind phase II and
injectionororaladministration)couldsignificantlyalleviate
III trials using an ET-1 receptor antagonist (clazosentan)
EBIinratmodelsbyreducingbrainoedema,BBBdisruption,
[119, 120]: ET-1 seems to have a key role in vasospasm but
neural cells apoptosis, and neurological dysfunction. ATX
inhibition of its action seems to reduce cerebral vasospasm
mayhavepleiotropiceffectsthroughinhibitionofglutamate
without improving final functional outcome or mortality release [133] by blocking inflammatory pathways (NF-𝜅B)
[8]. Only a small reduction was observed in the number of
[134],bylimitingapoptosisandbyplateletsaggregation[135].
patientsexhibitingDINDandtherewasnobeneficialeffect
NosideeffectswerereportedfollowingATXuse[136]andit
ontheGlasgowOutcomeScale(GOS)at3months’followup.
mayrepresentanewpromisingtherapeuticoption.
However the sample size estimates for CONSCIOUS-1 trial
were not intended to demonstrate an effect on functional
4.8. Nonsteroidal Anti-Inflammatory Agents. Different anti-
outcomeandthestudywasunderpoweredtodetectchanges
inflammatory treatments have been studied in cerebral
inmortality[119].
vasospasmwithcontrastingresults.Thismaybeexplainedby
The CONSCIOUS-2 trial was designed to investigate
theheterogeneityofinflammatorypatternsactivatedduring
whether clazosentan reduced vasospasm-related morbidity
aSAH[53].Currentlyanti-inflammatoryagentsarenotused
andall-causemortality.Ithowevershowednoclinicalbenefit
as standard treatment in patients with SAH. However the
(includingfunctionaloutcome)andsystemiccomplications
useofnonsteroidalanti-inflammatorydrugsmayproducea
weremorefrequentinpatientstreatedwiththisdrug[120].
reductionintheinflammatoryresponseandreducetheodds
forunfavourableoutcomes[137].
4.5. Vasodilators. Among vasodilator agents, milrinone has
theaddedeffectofbeinganinotrope.Itisaphosphodiesterase 4.9.AntiplateletAgentsandInhibitorsofThrombusFormation.
III inhibitor that increases the level of cyclic adenosine Clinical studies using antiplatelet agents show contrasting
monophosphate(cAMP);itwasfirstusedintheshort-term outcomes;onestudyshowedareducedriskofcerebralinfarc-
therapy for chronic heart failure and its first use in the tioninpatientsusingaspirin[138]andanotherstudyshowed
treatmentofcerebralvasospasmafterruptureofanintracra- an increased haemorrhagic volume in patients habitually
nial aneurysm was reported in 2001 [121]. Furthermore it usingcyclooxygenaseinhibitors[139].
has a supposed anti-inflammatory effect [122]. However, in Cerebrovascularmicrothrombosiswasalsothetargetof
ordertoobtainadirecteffectonEBI,vasodilatorsshouldbe therapeutic research; ADAMTS-13 inhibits physiologically
introducedimmediatelyonhospitaladmission. thrombus formation and thus inflammatory responses. Its
Recent attention was drawn to the vasodilator effects systemicadministrationinexperimentalmodelsdiminished
of oestrogen therapy. Ding et al. showed recently how the microthrombotic process and improved neurological
17 beta-estradiol (E2) is a potent vasodilator [123]. They performances probably by limiting neuronal inflammation,
demonstrated in vivo an attenuated cerebral vasospasm on withouteffectsonvasospasm[140].
angiography,whichisprobablyrelatedtoadecreasediNOS
expression, a normal eNOS expression, and diminished 4.10. Statins. The debate is open for the use of statins as a
ET-1 production [124]. Furthermore, E2 may have direct therapeuticoptionintheacuteperiodafterSAH.Statinsare
antioxidant effects by scavenging ROS and it may decrease hydroxymethylglutaryl- (HMG-) CoA reductase inhibitors
TNF𝛼 expression through a reduction of JNK signalling with pleiotropic effects; they may decrease the inflamma-
activity [125] and of inflammatory pathways. E2 may also tory burden und upregulate the production of vasodilator
inhibit apoptosis by neuroglobin and ERK pathway activa- substances(NO)bymodulatingeNOSexpression[141,142].
tion. However, it must be noted that known adverse effects Furthermore statins may reduce the excitotoxicity of glu-
ofoestrogentreatmentarenotnegligible. tamate, inhibit platelet aggregation, and prevent apoptosis
8 BioMedResearchInternational
Early brain injury
∙Mechanical injury ∙Oxidative stress
∙Autoregulation ∙Inflammatory
impairment cascade
∙Ionic disturbances ∙Small vessel
vasospasm
∙Cortical spreading ∙↓NO↑ET-1
depolarization ∙Cell death ∙Platelets activation
∙Excitotoxicity
72hours
Delayed brain injury
∙Delayed vasospasm ∙Cortical spreading
in proximal vessels ischemia
∙Microcirculatory
spasm and
dysfunction
Figure4
[143].Somestudiesshowedadecreasedincidenceofcerebral vasospasmintheterritorialartery[152]andothereffectssuch
vasospasm and of mortality rate in patients treated with asmicrothrombusformationorspasmanddysfunctioninthe
statins [144, 145]. One meta-analysis showed how statin microcirculationmaymakeasignificantcontribution[153].
use decreases the overall incidence of delayed vasospasm, Therapeutic strategies in SAH patients are currently
ischemic injury, and mortality [146], while another meta- still designed to treat vasospasm with the ultimate goal of
analysisshowednodifferencesinoutcome[147]. preventing delayed ischemic injury and improving clinical
outcome.Thesetherapiesresulteitherinareducedincidence
of radiologically evident vasospasm without improvement
5.Discussion
in delayed ischemic injury or in quality of life (as in the
Delayedcerebralvasospasmofproximalcerebralvesselshas case of ET-1 receptor antagonists) or in clinical benefit
classically been considered the primary marker to monitor withoutevidentangiographicresponseintermsofdecreased
patients’progression[148]andthemostimportantandtreat- vasospasm(asinthecaseofcalciumblockers).
ablecauseofmortalityandmorbidityinSAH[149].Inthelast Different reasons may be put forward to explain these
fewyears,thekeyroleofdelayedcerebralvasospasmhasbeen results; bias in the construction of studies could play a role
questioned; DIND, the principal prognostic determinant in (e.g., sample populations being not big enough to show a
patients surviving the acute phase, has been shown to be real clinical benefit or low sensibility of scores chosen to
a multifactorial process. Multiple mechanisms other than evaluateclinicaloutcomes).Furthermoredifferentpatholog-
vasospasm may contribute to long-term outcome and the ical pathways may be implicated in the final outcome in
role of events occurring during the immediate hours after patientssufferingfromaSAH,independentofanyvasospasm
bleedinghasrecentlybeenemphasized(Figure4). demonstratedangiographically.
Accordingtotheliterature,21%ofaSAHsurvivors,who Theroleofvasospasmhasprobablybeenmisinterpreted;
donotdevelopvasospasm,developdelayedischemicinjury treating vasospasm alone probably targets the wrong focus
andonly20%–30%ofthosewhodevelopdelayedvasospasm and may not lead to improvement in functional outcome.
sufferfromdelayedischemicinjury[150].Thecerebralblood The events occurring early after haemorrhage are clearly
flowdiminutionobservedinpatientswithmoderateandeven responsible for the development of delayed ischemia; the
severe vasospasm seems, in fact, not a sufficient cause for massivebraindamageobservedatautopsyinpatientsdying
cerebralinfarction[9].Someauthorsclaimthatmanyfactors within the first 72 hours of haemorrhage confirms the
determinewhetherinfarctiondevelopsaftervasospasmcon- importanceofEBI[154].Acuteintracranialcirculatoryarrest
firmedangiographically,includingthedurationandseverity [18] promotes metabolic deregulation and impairment of
of ischemia, the presence and length of stenosis, and the vascularreactivityresultinginanalteredautoregulationand
presenceofcollateralpathways[151].Insomecases,however, CO2responsiveness[155].Corticalspreadingdepolarization,
infarctionoccursimmediatelyafterSAHwithoutdetectable inflammation,andoxidativestressmaycontributefurtherto
BioMedResearchInternational 9
smallvesseldysfunction,microthrombosis,andearlyischem- ConflictofInterests
icsigns[156].
Understanding, monitoring, and treating the various The authors declare that there is no conflict of interests
mechanismsattherootofearlybraininjurywillbethekey regardingthepublicationofthispaper.
to improve the prognosis in SAH. Whilst human data are
actuallyscant,preclinicalstudiesdemonstratethattreatment Acknowledgments
ofEBIimprovesfunctionaloutcome.
Examining what happens early on in aSAH is usually ForhelpwitheditinginEnglish,andothervaluableadvices,
monitored in the neurological ICU by a multimodal neu- theauthorsthankDr.MichaelCottonoftheCentreHospital-
romonitoring[157]. Data existing strongly suggest that bio- ierUniversitaireVaudois,Lausanne,Switzerland.
chemical changes detected with cerebral microdialysis may
precede the onset of secondary neurological deterioration
References
followingSAH[158].Microdialysismaythereforebeauseful
tooltooptimizeneuroreanimationactivitiesbasedonmea- [1] N. K. de Rooij, F. H. H. Linn, J. A. van der Plas, A. Algra,
suresofbrainmetabolitesinextracellularfluid,excitotoxicity andG.J.E.Rinkel,“Incidenceofsubarachnoidhaemorrhage:
and oxidative stress [40] in a the very early phase of SAH. asystematicreviewwithemphasisonregion,age,genderand
EquallyPbtO2monitoringcouldhelpinguidingtherapeutic timetrends,”JournalofNeurology,NeurosurgeryandPsychiatry,
decisionsandinpredictingtheprognosis. vol.78,no.12,pp.1365–1372,2007.
PharmacologicalagentsabletodiminishEBImayinclude [2] M. Venti, “Subarachnoid and intraventricular hemorrhage,”
vasodilators (calcium blockers, magnesium sulphate, ET-1 Frontiers of Neurology and Neuroscience, vol. 30, pp. 149–153,
antagonists,NOdonors,milrinone,andoestrogentherapy), 2012.
antioxidants, anti-inflammatory, or antiplatelet agents [13] [3] J.W.Hop,G.J.Rinkel,A.Algra,andJ.vanGijn,“Case-fatality
and iron binding molecules. A combination of these thera- ratesandfunctionaloutcomeaftersubarachnoidhemorrhage:
peuticoptionsmaybenecessarytoobtainasynergiceffect. asystematicreview,”Stroke,vol.28,no.3,pp.660–664,1997.
New promising strategies include using pleiotropic [4] E.H.Brilstra,G.J.E.Rinkel,A.Algra,andJ.Gijn,“Rebleeding,
molecules with vasodilator properties (such as 17𝛽–estra- secondaryischemia,andtimingofoperationinpatientswith
diol), anti-inflammatory and antioxidative drugs, such as subarachnoidhemorrhage,”Neurology,vol.55,no.11,pp.1656–
astaxanthineorTNF𝛼inhibitors,andmoleculeslimitingmi- 1660,2000.
crothrombusformation,suchasADAMTS-13.Theseshowed [5] B. Ljunggren, L. Brandt, and H. Saveland, “Outcome in 60
encouragingresultsinpreclinicalstudiesanditisnowevident consecutivepatientstreatedwithearlyaneurysmoperationand
thatfocusingonvasospasmtreatmentalonecannotachieve intravenousnimodipine,”JournalofNeurosurgery,vol.61,no.5,
pp.864–873,1984.
improvement in functional outcome. Promoting strategies
to treat early brain injury will prevent many of the tragic [6] N.F.Kassell,J.C.Torner,E.C.HaleyJr.,J.A.Jane,H.P.Adams,
consequences of SAH and new therapeutic options should andG.L.Kongable,“TheInternationalCooperativeStudyon
theTimingofAneurysmSurgery.Part1:overallmanagement
concentratefurtherresearchintoEBIandconsequentlyDBI
results,”JournalofNeurosurgery,vol.73,no.1,pp.18–36,1990.
determinants[88].
[7] R.L.Macdonald,“Clazosentan:anendothelinreceptorantag-
onist for treatment of vasospasm after subarachnoid hemor-
rhage,”ExpertOpiniononInvestigationalDrugs,vol.17,no.11,
6.Conclusions
pp.1761–1767,2008.
[8] A. Kramer and J. Fletcher, “Do endothelin-receptor antago-
Delayedischemicinjuryisacomplexprocess,resultingfrom
nistspreventdelayedneurologicaldeficitsandpooroutcomes
the contribution of different pathological pathways and it
afteraneurysmalsubarachnoidhemorrhage?:ameta-analysis,”
is the leading determinant of poor functional outcome in
Stroke,vol.40,no.10,pp.3403–3406,2009.
patientssurvivingtheinitialhemorrhagicinsultofaSAH.The
[9] J.W.Dankbaar,M.Rijsdijk,I.C.vanderSchaaf,B.K.Velthuis,
role of vasospasm has long been overemphasized. Delayed
M. J. H. Wermer, and G. J. E. Rinkel, “Relationship between
vasospasm is not a necessary prerequisite for DIND devel-
vasospasm,cerebralperfusion,anddelayedcerebralischemia
opment. Vasospasm alone should not be used to monitor
after aneurysmal subarachnoid hemorrhage,” Neuroradiology,
theefficacyoftherapeuticinterventionsnorusedasaprog- vol.51,no.12,pp.813–819,2009.
nostic marker. Indeed, its reversal alone is inadequate as a
[10] M.D.I.Vergouwen,D.Ilodigwe,andR.L.MacDonald,“Cere-
therapeutic target. Many other mechanisms may underlie
bral infarction after subarachnoid hemorrhage contributes to
prognosisandacontemporarytherapeuticapproachreacting poor outcome by vasospasm-dependent and -independent
to multiple pathological pathways evident in early brain effects,”Stroke,vol.42,no.4,pp.924–929,2011.
injury should be sought. Despite extensive research and
[11] J.B.Bederson,A.L.Levy,W.H.Dingetal.,“Acutevasoconstric-
aggressivemanagementofcerebralvasospasm(bothmedical tionaftersubarachnoidhemorrhage,”Neurosurgery,vol.42,no.
and endovascular), SAH prognosis remains poor. Invasive 2,pp.352–362,1998.
neuromonitoringtodetectpathologicalalterationsoccurring
[12] G. Kusaka, M. Ishikawa, A. Nanda, D. N. Granger, and J.
inearlybraininjurymaypermitpreventionofDIND;such H. Zhang, “Signaling pathways for early brain injury after
therapeuticinterventionsneedtobeundertakenwithinthe subarachnoidhemorrhage,”JournalofCerebralBloodFlowand
firsthoursafteraSAH. Metabolism,vol.24,no.8,pp.916–925,2004.
10 BioMedResearchInternational
[13] F.A.Sehba,R.M.Pluta,andJ.H.Zhang,“Metamorphosisof [30] J. Owens, D. J. Wyper, J. Patterson et al., “First SPET images
subarachnoidhemorrhageresearch:fromdelayedvasospasmto of glutamate (NMDA) receptor activation in vivo in cerebral
earlybraininjury,”MolecularNeurobiology,vol.43,no.1,pp.27– ischaemia,”NuclearMedicineCommunications,vol.18,no.2,pp.
40,2011. 149–158,1997.
[14] F. A. Simeone, K. G. Ryan, and J. R. Cotter, “Prolonged [31] A. Germano`, M. Caffo, F. F. Angileri et al., “NMDAreceptor
experimentalcerebralvasospasm,”JournalofNeurosurgery,vol. antagonist felbamate reduces behavioral deficits and blood-
29,no.4,pp.357–366,1968. brain barrier permeability changes after experimental sub-
[15] W. J. Cahill, J. H. Calvert, and J. H. Zhang, “Mechanisms of arachnoidhemorrhageintherat,”JournalofNeurotrauma,vol.
earlybraininjuryaftersubarachnoidhemorrhage,”Journalof 24,no.4,pp.732–744,2007.
CerebralBloodFlowandMetabolism,vol.26,no.11,pp.1341– [32] M. Zuccarello, A. I. Lewis, S. Upputuri, J. B. Farmer, and D.
1353,2006. K. Anderson, “Effect of remacemide hydrochloride on sub-
[16] J. Hansen-Schwartz, P. Vajkoczy, R. L. Macdonald, R. M. arachnoidhemorrhage-inducedvasospasminrabbits,”Journal
Pluta,andJ.H.Zhang,“Cerebralvasospasm:lookingbeyond ofNeurotrauma,vol.11,no.6,pp.691–698,1994.
vasoconstriction,”TrendsinPharmacologicalSciences,vol.28, [33] C. Ikonomidou and L. Turski, “Why did NMDA receptor
no.6,pp.252–256,2007. antagonists fail clinical trials for stroke and traumatic brain
[17] A. Y. Schwartz, A. Masago, F. A. Sehba, and J. B. Bederson, injury?”TheLancetNeurology,vol.1,no.6,pp.383–386,2002.
“Experimentalmodelsofsubarachnoidhemorrhageintherat:
[34] A. Sarrafzadeh, D. Huax, O. Sakowtz et al., “Acute focal
a refinement of the endovascular filament model,” Journal of
neurologicaldeficitsinaneurysmalsubarachnoidhemorrhage:
NeuroscienceMethods,vol.96,no.2,pp.161–167,2000.
relationofclinicalcourse,CTfindings,andmetaboliteabnor-
[18] H. Nornes, “The role of intracranial pressure in the arrest of malitiesmonitoredwithbedsidemicrodialysis,”Stroke,vol.34,
hemorrhageinpatientswithrupturedintracranialaneurysm,” no.6,pp.1382–1388,2003.
JournalofNeurosurgery,vol.39,no.2,pp.226–234,1973.
[35] R.Bullock,A.Zauner,J.J.Woodwardetal.,“Factorsaffecting
[19] E.W.Lang,R.R.Diehl,andH.M.Mehdorn,“Cerebralautoreg-
excitatory amino acid release following severe human head
ulationtestingafteraneurysmalsubarachnoidhemorrhage:the
injury,”JournalofNeurosurgery,vol.89,no.4,pp.507–518,1998.
phaserelationshipbetweenarterialbloodpressureandcerebral
[36] F.A.Sehba,A.Y.Schwartz,I.Chereshnev,andJ.B.Bederson,
bloodflowvelocity,”CriticalCareMedicine,vol.29,no.1,pp.
“Acutedecreaseincerebralnitricoxidelevelsaftersubarachnoid
158–163,2001.
hemorrhage,”JournalofCerebralBloodFlowandMetabolism,
[20] A.LosinieckiandM.Zuccarello,“Subarachnoidhemorrhage:
vol.20,no.3,pp.604–611,2000.
effectoncerebralbloodflowandcerebralmetabolism,”Frontiers
[37] W. H. Ng, S. Moochhala, T. T. Yeo, P. L. Ong, and P. Y. Ng,
inBioscience,vol.13,no.5,pp.1845–1856,2008.
“Nitricoxideandsubarachnoidhemorrhage:elevatedlevelsin
[21] E. Berendes, M. Walter, P. Cullen et al., “Secretion of brain
cerebrospinal fluid and their implications,” Neurosurgery, vol.
natriureticpeptideinpatientswithaneurysmalsubarachnoid
49,no.3,pp.622–627,2001.
haemorrhage,”TheLancet,vol.349,no.9047,pp.245–249,1997.
[38] H.Yatsushige,J.W.Calvert,J.Cahill,andJ.H.Zhang,“Limited
[22] E.F.M.Wijdicks,M.Vermeulen,andJ.A.T.Haaf,“Volume
role of inducible nitric oxide synthase in blood-brain barrier
depletionandnatriuresisinpatientswitharupturedintracra-
functionafterexperimentalsubarachnoidhemorrhage,”Journal
nialaneurysm,”AnnalsofNeurology,vol.18,no.2,pp.211–216,
ofNeurotrauma,vol.23,no.12,pp.1874–1882,2006.
1985.
[39] R.M.Pluta,“Dysfunctionofnitricoxidesynthasesasacause
[23] R. E. Harbaugh, “Aneurysmal subarachnoid hemorrhage and
and therapeutic target in delayed cerebral vasospasm after
hyponatremia,” Contemporary Neurosurgery, vol. 15, pp. 1–5,
SAH,”inCerebralVasospasm,vol.104ofActaNeurochirurgica
1993.
Supplementum,pp.139–147,2008.
[24] T. Meguro, C. P. R. Klett, B. Chen, A. D. Parent, and J. H.
Zhang,“Roleofcalciumchannelsinoxyhemoglobin-induced [40] L. Hillered, P. M. Vespa, and D. A. Hovda, “Translational
apoptosisinendothelialcells,”JournalofNeurosurgery,vol.93, neurochemical research in acute human brain injury: the
no.4,pp.640–646,2000. currentstatusandpotentialfutureforcerebralmicrodialysis,”
JournalofNeurotrauma,vol.22,no.1,pp.3–41,2005.
[25] W. M. van den Bergh, A. Algra, J. W. B. van der Sprenkel et
al.,“Hypomagnesemiaafteraneurysmalsubarachnoidhemor- [41] J. S. Beckman, T. W. Beckman, J. Chen, P. A. Marshall, and
rhage,”Neurosurgery,vol.52,no.2,pp.276–282,2003. B. A. Freeman, “Apparent hydroxyl radical production by
[26] W.M.vandenBergh,R.M.Dijkhuizen,andG.J.E.Rinkel, peroxynitrite: implications for endothelial injury from nitric
“Potentialsofmagnesiumtreatmentinsubarachnoidhaemor- oxideandsuperoxide,”ProceedingsoftheNationalAcademyof
rhage,”MagnesiumResearch,vol.17,no.4,pp.301–313,2004. SciencesoftheUnitedStatesofAmerica,vol.87,no.4,pp.1620–
1624,1990.
[27] S. Fukui, H. Katoh, N. Tsuzuki et al., “Gender disparities
in serum electrolytes levels after subarachnoid hemorrhage,” [42] B. P. Thampatty, P. R. Sherwood, M. J. Gallek et al., “Role of
JournalofClinicalNeuroscience,vol.11,no.6,pp.606–609,2004. endothelin-1inhumananeurysmalsubarachnoidhemorrhage:
associations with vasospasm and delayed cerebral ischemia,”
[28] P. Enblad, J. Valtysson, J. Andersson et al., “Simultaneous
NeurocriticalCare,vol.15,no.1,pp.19–27,2011.
intracerebralmicrodialysisandpositronemissiontomography
in the detection of ischemia in patients with subarachnoid [43] R.M.Pluta,R.J.Boock,J.K.Afsharetal.,“Sourceandcauseof
hemorrhage,”JournalofCerebralBloodFlowandMetabolism, endothelin-1releaseintocerebrospinalfluidaftersubarachnoid
vol.16,no.4,pp.637–644,1996. hemorrhage,”JournalofNeurosurgery,vol.87,no.2,pp.287–293,
[29] J. Puyal, V. Ginet, and P. G. Clarke, “Multiple interacting 1997.
cell death mechanisms in the mediation of excitotoxicity [44] A. Gruber, K. Roessler, A. Georgopoulos, A. Missbichler,
andischemicbraindamage:achallengeforneuroprotection,” R. Bonelli, and B. Richling, “Evaluation of big endothelin-1
ProgressinNeurobiology,vol.105,pp.24–48,2013. concentrations in serum and ventricular cerebrospinal fluid