Review ArticleVasospasm in Cerebral Inflammation
Michael Eisenhut
Luton and Dunstable University Hospital NHS Foundation Trust Lewsey Road Luton LU4ODZ UK
Correspondence should be addressed to Michael Eisenhut michael eisenhutyahoocom
Received 13 September 2014 Accepted 8 December 2014 Published 29 December 2014
Academic Editor Jean-Marc Cavaillon
Copyright copy 2014 Michael Eisenhut This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
All forms of cerebral inflammation as found in bacterial meningitis cerebral malaria brain injury and subarachnoid haemorrhagehave been associated with vasospasm of cerebral arteries and arterioles Vasospasm has been associated with permanentneurological deficits and death in subarachnoid haemorrhage and bacterial meningitis Increased levels of interleukin-1 maybe involved in vasospasm through calcium dependent and independent activation of the myosin light chain kinase andrelease of the vasoconstrictor endothelin-1 Another key factor in the pathogenesis of cerebral arterial vasospasm may be thereduced bioavailability of the vasodilator nitric oxide Therapeutic trials in vasospasm related to inflammation in subarachnoidhaemorrhage in humans showed a reduction of vasospasm through calcium antagonists endothelin receptor antagonists statinsand plasminogen activators Combination of therapeutic modalities addressing calcium dependent and independent vasospasmthe underlying inflammation and depletion of nitric oxide simultaneously merit further study in all conditions with cerebralinflammation in double blind randomised placebo controlled trials Auxiliary treatment with these agents may be able to reduceischemic brain injury associated with neurological deficits and increased mortality
1 Introduction
Cerebral vasospasm has been defined as ldquothe reversiblereduction in calibre of the lumen of a conducting artery inthe subarachnoid spacerdquo [1] The reduction in calibre refersto the appearance of cerebral arteries on an angiographSmall diameter cerebral arteries play important roles in theautoregulation of cerebral blood flow matching local bloodsupply in the brain to neuronal activity Although angiogra-phy which can assess arteries gt1mm in diameter has longbeen the standard to diagnose vasospasm constriction ofsmaller cerebral arteriesmay also contribute to ischaemia andremain undetectable by angiography Lindegaard developedblood velocity measurements using the noninvasive methodof transcranial Doppler ultrasound for definition of cerebralvasospasm [2] An inverse relation between vessel diameteron angiography and cerebral blood flow velocity (CBFV) ontranscranial Doppler sonography has been found and thereis considerable evidence that these alterations reflect changesin calibre of the insonated vessels as a result of transient orpersistent narrowing A ratio of gt3 in middle cerebral artery
flow to extracranial internal carotid artery flow was foundto be diagnostic of vasospasm [3] Transcranial Dopplerultrasound was determined in a meta-analysis as beingapproximately 67 sensitive formiddle cerebral artery spasmand 42 sensitive for anterior cerebral artery spasm [4] Ifsevere enough vasospasm can lead to cessation of distal bloodflow and if present for a sufficient duration and extent itcan cause cerebral infarction Positron emission tomographicstudies showed that ischemic deficits from vasospasm wereassociated with regions of reduced blood flow [5] Noneof the methods mentioned may however yield features ofvasospasm if this affects transiently precapillary sphinctersonly
The risk of infarction depends on adequacy of collateralblood supply cardiac output blood pressure and intracranialpressure In the context of cerebral inflammation manydifferent factors influence cerebral blood flow They includeinflammatory hyperaemia increased intracranial pressurearterial CO
2 body temperature mean arterial pressure the
use of mechanical ventilation and whether patients aresedated during procedures [6] Physiological regulation of
Hindawi Publishing CorporationInternational Journal of InflammationVolume 2014 Article ID 509707 14 pageshttpdxdoiorg1011552014509707
2 International Journal of Inflammation
cerebral perfusion is dominated by pressures of CO2and
O2in the cerebral circulation Cerebral vasodilatation in
response to hypercapnia is dependent on formation of nitricoxide a mediator released in inflammation [7] After releaseby endothelium NO stimulates soluble guanylate cyclase invascular muscle resulting in an increase in the intracellu-lar concentration of guanosine 3101584051015840-cyclic monophosphate(cGMP) resulting in relaxation NO is generated from L-arginine by NO synthase It is the endothelial NO synthasewhich regulates cerebral blood vessel tone under basal con-ditions [7]
This review includes studies investigating outcomes likeradiological or clinical evidence for focal cerebral ischaemiaand infarction Cerebral vasospasm is a potentially pre-ventable and treatable cause of ischemic cerebral damageA current lack of established treatment options was themotivation for this review of cerebral vasospasm in condi-tions with inflammation of the brain The objective was toinvestigate whether there is evidence of cerebral vasospasmin all conditions associated with cerebral inflammation andwhether there are common pathways to vasospasm in allconditions with cerebral inflammation pointing to commontherapeutic options which may have been explored in onetype of cerebral inflammation but should be evaluated inall others with the aim of preventing irreversible cerebraldamage thus reducing morbidity and mortality
2 Methods
The literature search for this review used the databasePubMed (search from beginning of database until 31 July2014) entering search terms ldquocerebral vasospasmrdquo ldquoinflam-mationrdquo ldquomeningitisrdquo ldquobrain injuryrdquo ldquocerebral malariardquo ldquosub-arachnoid haemorrhagerdquo ldquo tumor necrosis factorrdquo ldquoendothe-linrdquo ldquonitric oxiderdquo ldquoarachidonic acidrdquo ldquorho-kinaserdquo ldquofasudilrdquoldquoerythropoietinrdquo ldquocalcium channel blockersrdquo ldquostatinsrdquo ldquotiri-lazadrdquo and ldquomagnesiumrdquo References of articles were screenedfor relevance and included where appropriate
3 Vasospasm in Cerebral Infection
31 Bacterial Meningitis Tuberculous meningitis is the formof cerebral inflammation in which vasculopathy has been thesubject of most detailed studies starting in the 19th century[8] Radiologically identifiable cerebral infarctions are com-mon in tuberculous meningitis and are present in 20 atinitial assessment and in a further 10 they occur after startof treatment [9]Threemain pathologies have been proposedvasculitis most prominent in vessels passing through thebasilar exudate proliferative changes with intimal thickeningwith resultant stenosis or occlusion and necrotizing vascularlesions The fibrinoid necrosis in supplied tissue found in theabsence of blood vessel wall infiltration raised the possibilityof vasospasm as an additional feature of the vasculopathyIn some instances infarction was found to have occurredwithout vasculitic changes or thrombosis compatible withvasospasm
Supportive of an important role for vasospasm in thepathology of tuberculous meningitis was also the poor corre-lation between angiographic findings and infarction [10 11]Thefirst direct evidence for vasospasm in bacterialmeningitiswas established in a case ofHaemophilus influenzaemeningi-tis [12] A prospective investigation of 22 adults with bacterialmeningitis by transcranial Doppler sonography related thedegree of arterial narrowing to outcome Low Glasgow comascales (lt7) on admission focal cerebral ischaemic deficitsand seizures were more frequent in patients with cerebralblood flow velocity gt210 cms compatible with vasospasmFatal outcome was only found with this high velocityPatients with minor or no vascular involvement had lessprominent initial impairment of consciousness [13] Otherinvestigations confirmed features of cerebral vasospasm inbacterial meningitis [14] Patients with features of vasospasmhad significantly increased concentrations of IL-1 and IL-6 but not endothelin-1 (ET-1) or thromboxane levels in theCSF Underlying mechanisms have been explored in a ratmodel where cerebral blood flow as measured by injectionand recovery ofmicrospheres from the brain tissuewas foundto be reduced in pneumococcal meningitis The cerebralblood flow could be restored by the endothelin-1 antagonistbosentan with a reduction in cortical cerebral injury [15]Strong evidence of a protective role of nitric oxide againstvasospasm in bacterial meningitis was derived from ananimal model of neonatal meningitis where inhibition ofNO synthase worsened outcome in some models of bacterialmeningitis leading to local cerebral ischaemia [16]
32 Cerebral Malaria There is accumulating evidence fordisseminated vasospasm triggered by inflammatory medi-ators produced locally in the vascular bed in response tothe sequestered infected red blood cells in cerebral malaria(CM) Reversible vasospasm could explain the rapid onsetbut also often rapid and complete resolution of symptoms ofCM Vascular obstruction by clumps of infected blood cellsplatelets and uninfected red blood cells tightly adhering toendothelium is less likely to be rapidly reversible withoutleaving irreversible neurological damage which occurs in aminority of patients with CM
In a seminal study of the morphology of arterioles in thebrain of patients who died of cerebral malaria Polder et aldemonstrated as early as 1990 that there is evidence of spasticcontraction of arterioles with folding of the whole vessel walland of the astrocytic plasma membrane and glial basementmembrane with total occlusion of the lumen [17] There waslight microscopic interruption of the flow at the arterio-lar level resulting in irregular perfusion of the capillariesNumerous cerebral capillaries were entirely empty Recent invivo studies on retinas in 34 patients with CM by fluoresceinangiography showed the abrupt pruning of larger arterioleswith normal perfusion right up to the point of nonperfusionsuggesting an arterial vasospasm Normal angiograms in sixpatients including two with neurological sequelae indicateda lack of longstanding vasoocclusion This observation wascompatible with a transient vasospasm [18] Evidence for atemporary vasoocclusion as seen in a vasospasm was also the
International Journal of Inflammation 3
macular retinal whitening which occurredwithoutmatchingzones of capillary nonperfusion at the time of the angiogramin 734 patients including four for whom the angiogram wasdelayed gt24 hours after admission
Therewas no evidence for a reduced global cerebral bloodflow on extracranial basal artery Doppler measurementsHigh CBFVwas recorded in 30 of children with CMduringadmission [19] This suggested that ischemic events hadpassed by the time the angiography was performed as wouldbe seen in a transient vasospasm In CM cerebral arteriolarvasospasmmay be mediated by tumor necrosis factor (TNF)The degree of TNF elevation in the cerebrospinal fluid ofchildren with CM has been associated with risk of neurologicdeficits [20] Gambian children homozygote for the TNF2allele a variant of the TNF-alpha gene promoter region has arelative risk of 7 for death or severe neurological sequelae dueto CM [21] A subsequent study confirmed the association ofthe TNF-308 A allele of the TNF promoter with CM [22]Release of TNFmay be triggered by the local deposition of IgEcontaining immune complexes (IC) through cross-linkingof CD23 on monocytesmacrophages in cerebral capillaries[23]
Increased levels of serum ICrsquos have previously beenassociated with vasospasm in subarachnoid haemorrhages[24] IC levels are increased in CM and this may be related toreduced clearance because of interleukin-4 mediated down-regulation of Fc-receptors [25] An erythrocyte complementreceptor type 1 (E-CR1) promoter allele associated withhigher E-CR1 expression and hence enhanced clearance ofICrsquos conferred protection against CM [26]
An interesting recent study found evidence of cerebralarteriolar vasospasm in the murine Plasmodium bergheiANKAmodel of CMwith retinal features of vascular collapsevery similar to the angiographic findings in humanswithCMThe researchers increased survival of mice with CM by useof nimodipine a blocker of the vasoconstriction mediatingL-type voltage-gated calcium channel which is used toprevent and treat vasospasm associated with perivascularinflammation in subarachnoid haemorrhage [27] Furthersupport for a role of cerebral arteriolar vasospasm in CM isprovided by the fact that in murine and human CM there isa low bioavailability of nitric oxide which is an importantvasodilator [28]
Haemolysis inmalaria also leads to consumption of nitricoxide which is bound to free haemoglobin and haemolysisreleases erythrocyte arginase an enzyme that metabolizesarginine This reduces the amount of arginine available forproduction of NO [29] Investigation of the association ofthe single nucleotide polymorphism in the neuronal nitricoxide synthase (nNOS) gene with cerebral malaria revealedthat the polymorphism associated with low basal transcrip-tional activity (-84 G- -rarrA and 276C- -rarrT) was associatedwith an increased risk of cerebral malaria [30] The singlenucleotide polymorphism -1173C-rarrT in the nitric oxidesynthase 2 promoter was associated with increased fastingurine and plasma nitric oxide metabolite concentrationsin Tanzanian children and was associated with protectionagainst cerebral malaria [31] In the P berghei ANKAmurinemodel NO supplementation in the form of a NO donor
prevented vasoconstriction and improved blood flow in pialvessels [32] Nitric oxide production is partially downreg-ulated by IL-12 and polymorphisms in the gene encodingthe IL-12 p40 subunit associated with increased IL-12 levelsled in homozygous form to decreased production of nitricoxide and increased mortality in Tanzanian children withCM but not with severe anaemia in Kenyan children [33]High levels of erythropoietin which has been shown toupregulate endothelial nitric oxide synthase were associatedwith protection against neurological sequelae in Africanchildren with CM [34]
33 Neurocysticercosis Infection of the central nervous sys-tem with the larval stage of Taenia solium (neurocysticerco-sis) is the most common helminthic infection of the CNSand a cause of stroke in areas where cysticercosis is endemicOver 50 of patients with subarachnoid involvement havehereby features of vasculitis Antiparasitic treatment has beenassociated with enhanced subarachnoid inflammation anddelayed cerebral infarcts The focal cerebral lesions found inthe absence of changes on conventional angiograms and withnormal transcranial Doppler ultrasound point to vasospasmin their aetiology [35]
4 Brain Injury
Evidence of traumatic cerebral vasospasm (TCV) has beendetected in military personnel with blast injuries to the headPatients with TCV were also likely to have an intracranialbleed traumatic aneurysm or significant cerebral lobarinjury As indicator of cerebral vasospasm they had elevatedcerebral blood flow velocities for approximately 14 days in onestudy and TCV was associated with increased mortality [36]
A link between inflammation and TCV provided a studyinvestigating risk factors for cerebral vasospasm in 46 adultsand children with TCV fever on admission was an indepen-dently strongly predictive risk factor for the development ofTCV (OR 222 95 CI 19 to 2568) Importantly patientswith hypothermia on admission did not develop TCV [37]Underlying mechanisms were explored in the newbornand juvenile pig model of brain injury which showed thatcerebrospinal fluid concentration of ET-1 was increased andNMDA receptor mediated vasodilation decreased and moreso in the immature brain [38] In humans investigatorsobserved that the loss of nitric oxide bioavailability anddecreased sensitivity to NO after traumatic brain injurywere found to be contributory to impaired cerebral vascularautoregulation
5 Subarachnoid Haemorrhage
Since the demonstration of arterial narrowing in the syn-drome of cerebral vasospasm of subarachnoid haemorrhage(SAH) in 1951 and the further emphasis in 1978 byWeir et alit has been proven that SAH gives rise to arterial narrowingand in turn ischaemia causing infarction and poor outcomeMost research into delayed deterioration after SAH has been
4 International Journal of Inflammation
conducted in concordance with this axiom with the goal ofinterrupting this perceived chain of events [39]
Autopsy studies in nonoperated SAH patients reportedthat 80 of fatal cases showed widely scattered trian-gular round or laminar ischemic lesions in the cortexAn ongoing clinical multicenter study reported that in 18post-SAH patients the occurrence of spreading depolar-ization with cortical spreading ischaemia was associatedwith delayed infarcts in brain computed tomography andmagnetic resonance imaging These findings indicate a newSAH-related mechanism of acute brain injury involving therelease of oxyhaemoglobin and ET-1 and NO deprivationall of which are found in SAH and can cause corticalspreading depression and ischaemia in experimental models[40] Endothelium-dependent dilation hereby seems to bereduced partly because of reduced expression of guanylatecyclase [41] Experimentally neurogenic and endothelium-dependent vasodilatation have been shown to be alteredby the presence of haemoglobin (Hb) in the bath [42] Amore complete review of this mechanism can be foundelsewhere [43] Cerebral vasomotor disturbances have beendemonstrated in humans after SAH inmeasurements of cere-bral blood flow by 133-xenon tomography One of the mostimportant functional consequences of SAH is the relativeloss of cerebrovascular dilatory capacity after acetazolamideinjection [44]The sources of NO in the cerebral arteries [45]are such that it has been supposed that Hb scavenging of NOcould induce vasospasm (VS) The prolonged presence of aperivascular clot seems necessary to maintain VS since clotremoval up to 3 days after haemorrhage reduces VS but after5 days it has little influence [46]
Prostaglandin E2 (PGE2) is the eicosanoid moleculepresent in the highest concentration in the CSF after SAHThe concentration increases by more than 25 times soonafter the haemorrhage and remains high for several days[47] This rise probably explains the fever usually found inSAH The production of PGE2 is induced by cyclooxygenase2 induction by inflammatory mediators including TNF inplatelets and microvessel endothelial cells [48 49] There isevidence of early increased TNF-concentration in the CSF ofpatients with SAH [47 50] PGE2 has been shown to inducecontraction in large cerebral arteries [51]
6 The Role of Inflammatory Mediators inGeneration of Vasospasm
The Interaction of Inflammatory Mediators with CerebralVasculature To enable an understanding of the pathomech-anisms involved in inflammation related cerebral vasospasmand resulting brain ischaemia it is important to analyse theinteraction of inflammatory mediators with each other andthe cerebral vasculature Amediator whichwas found to be ofkey importance in reduction of the risk of cerebral vasospasmin bacterial meningitis cerebral malaria brain injury andsubarachnoid haemorrhage is nitric oxide (NO)
NO can be inactivated by reaction with the superoxideanion resulting in the formation of peroxynitrite Inactivationof NO by superoxide anion may contribute to impaired
NO-mediated dilatation of cerebral blood vessels underconditions inwhich reactive oxygen species are produced likebrain injury and meningitis
Production of superoxide anions has also been reportedto occur in brain in response to seizures fluid-percussioninjury perivascular blood and ischaemia with reperfusionEndothelial NO synthase is downregulated by TNF and NOby a negative-feedback mechanism [52 53] In addition toinflammatory mediators sensory fibres originating in thetrigeminal ganglion modulate constrictor responses in thecerebral microcirculation in conditions like meningitis [7]
The most important factor leading to vasoconstrictionin cerebral blood vessels is ET-1 a 21 amino acid peptidewith three isopeptides produced by separate genes Only ET-1 is produced in cerebral endothelium and mediates cerebralvasoconstriction via endothelin-A (ETA) receptors ETA islocalized in vascular smooth muscle cells and stimulationleads to increase in intracellular calcium concentrationsleading to vasoconstriction ET-1 expression is enhanced bytransforming growth factor-beta haemoglobin interleukin-1 and TNF and can be inhibited by NO nitric oxide donordrugs and dilator prostanoids via an increase in cellularcGMP and natriuretic peptides via an increase in cAMPlevels NO can produce relaxation of some blood vessels fromsome species via activation of potassium channels [7]
Cerebral blood vessels can produce 20-hydroxyeicosate-traenoic acid from arachidonic acid via a P-450 enzymeThissubstance is a potent vasoconstrictor whichmay produce thiseffect by inhibition of activity of potassium channels [7]
A further potential mechanism involved in cerebralvasospasm in cerebral inflammation is inhibition of potas-sium channels Nicorandil which produces relaxation ofcerebral vessels by activation of potassium channels partiallyreverses vasospasm in an experimental model of subarach-noid haemorrhage
The effectiveness of other synthetic activators of potas-sium channels like aprikalim and cromakalim and CGRPindicate that activators of potassium channels in vascularmuscle may help in cerebral vasospasm in cerebral inflam-mation [7]
The etiological role of specific cytokines in vasospasm inbacterial meningitis in vivo was highlighted by a study whichdocumented a significant increase in IL-1-beta and IL-6 con-centrations in patients with elevated cerebrovascular bloodflow indicative of vasospasm in humans [14 54] A similareffect on vasospasm of IL-1 and IL-6 was suggested by a studyof cerebral blood flow in subarachnoid haemorrhage whereincreased cerebral blood flow velocities were associated withsignificantly increased CSF concentrations of IL-1 IL-6 andTNF High concentrations of these immunomediators incerebrospinal fluid (CSF) may exert vasoactive effects forexample IL-1 (MW 17 000Da) or IL-6 (MW 26 000Da)could easily get access to the walls of contiguous basalarteries from their adventitial side as even larger molecules(eg horseradish peroxidase MW 40 000Da) pass from thecisternamagna through the vessel wall to the basalmembranewithin minutes This is possible because by contrast withother arteries the surface of the major cerebral arteries is not
International Journal of Inflammation 5
confined by collagen or fibroblasts but is in direct contactwiththe CSF
An investigation in patients with SAH showed that levelsof IL-1-beta but not TNF-alpha were increased and correlatedwith the later development of vasospasm IL-1 acts throughG-protein coupled receptors in three ways which causecontraction of vascular smooth muscle (see Figure 1)
(1) Activation of phospholipase C generated phosphat-idylinositol trisphosphate causes calcium releasewhich leads to myosin light chain kinase activationleading to myosin light chain activation and calciumdependent vasospasm Phosphorylation of myosinlight chain (MLC) by MLC kinase is one of themost important steps for vascular smooth musclecontraction
(2) Activation of protein kinase C (PKC) through phos-pholipase C generated diacylglycerol (from phos-phatidylinositol (45) bisphosphate) can act throughphosphorylation and hence activation of the myosinlight chain kinase Prolonged contraction in cerebralvasospasm for up to two weeks can be mediated bythis mechanism
(3) PKC activation regulates MLC phosphorylation thro-ugh activation of rho-kinase and the myosin-bindingsubunit (MBS) of MLC phosphatase (MLCPh) Rho-kinase hereby phosphorylates MBS which results inthe inhibition of MLCPh [55] The reduced MLCPhactivity leads to increased phosphorylation and hencecontractility of the MLC resulting in calcium inde-pendent vasospasm Investigations in a porcinemodelrevealed that hydroxyfasudil a specific rho-kinaseinhibitor exerted an inhibitory effect on vasospasmboth in vitro and in vivo Western blot analysisshowed that during serotonin-induced contractionsthe extent of phosphorylation of the MBS was sig-nificantly greater in the spastic than in the controlsegment There was a highly significant correlationbetween the extent of MBS phosphorylation andcontractions [55]
Another key mechanism whereby IL-1 mediates vasosp-asm may be through platelet derived growth factor Thereceptors for this growth factor are also known to havetyrosine kinase activity and inhibition of tyrosine kinase isknown to reduce vasospasm in a swine model [56 57] Thisaction influences vascular reactivity to different agonists andmight be crucial for the regulation of cerebral artery toneduring vasospasm [58]
Calcium independent vasospasm may also be inducibleby haemoglobin released in trauma or subarachnoid haem-orrhage
Haemoglobin might cause contraction of major cerebralarteries by scavenging nitric oxide reducing neuronal nitricoxide synthase (NOS) in the adventitia of the cerebral arter-ies and evoking dysfunction of endothelial NO synthase Adecrease in nitric oxide availability might produce prolongedpathological contraction regardless of the concentration ofintracellular calcium Much of the work investigating the
genetic predisposition to cerebral vasospasm focused on theendothelial isoform of nitric oxide synthase Hemoglobinalso stimulates the production of endothelins and the imbal-ance of nitric oxide and endothelin could be an importantcause of pathological arterial contraction In gene transferexperiments eNOS overexpression in animal and humanintracranial arteries is vasoprotective after aneurysmal SAH[59] Several investigations confirmed the association of theT-786C genotype of eNOS with vasospasm For a summaryof key mediators in cerebral vasospasm their function anddisease studied see Table 1
7 Therapeutic Approaches toPrevention and Correction of VasospasmAssociated with Cerebral InflammationTested in Clinical Trials in Humans
The most extensive experience with treatment approachesto vasospasm in cerebral inflammation has been gatheredin the context of management of SAH Clinical trials inhumans have been reported for endothelin-1 antagonists cal-cium channel blockers including the cisternal placement ofcontrolled-release nicardipine intravenous magnesium sul-phate oral statins rho-kinase inhibitors tissue plasminogenactivator tirilazad erythropoietin and methylprednisoloneThe evidence from controlled trials has been summarized inTable 2
71 Endothelin-1A Receptor Antagonists The selective endo-thelin-1A receptor antagonist clazosentan was assessed ina randomized placebo controlled trial (CONSCIOUS-1)and led to a significant reduction of angiographic cerebralvasospasm in SAH but without reduction in the numberof cerebral ischaemia events Subsequent phase II trials(CONSCIOUS-2 and CONSCIOUS-3) in SAH did notdemonstrate any effect on morbidity or mortality A meta-analysis of 4 RCTswith 2024 participants confirmed this find-ing but showed a reduction in delayed ischemic neurologicaldeficit with the endothelin-1A receptor antagonist [67]
72 Calcium Channel Blockers Calcium antagonists have thepotential to prevent the occurrence of calcium dependentvasospasm and delayed ischemic neurological deficit byreducing calcium release (see Figure 1) They have beenapplied directly to the subarachnoid space [74] Intraopera-tive implantation of nicardipine prolonged-release implantsso-called pellets into the basal cistern in close contact to theproximal cerebral vasculature has been reported to reducethe occurrence of cerebral vasospasm and cerebral infarctionand lead to an improvement in clinical outcome in SAH [75]Themagnesium ion is an antagonistic competitor for calciumbinding sites thus having the potential to reduce calciumdependent vasospasm and has been used in the form ofintravenous magnesium sulphate in a number of trials (seeTable 2)
6 International Journal of Inflammation
GPCR
Macrophage
Interleukin-1
Lipopolysaccharide
Plasmodium falciparum antigens
Stimulation of interleukin-1 release
MLCK
PKC
MLCMLCK-P
Rho-kinase MBSMBS-P
MLCPh
Intracellular autoantigens (fromtissue injury)
PLC ≫ IP3 ≫ calcium releaseminusRho-kinase-P
Figure 1 Mechanism for induction of cerebral vasospasm by interleukin-1 (GPCR = G-protein coupled receptor PKC = protein kinase CMLCK = myosin light chain kinase MLC = myosin light chain MBS = myosin-binding subunit of myosin light chain phosphatase MLCPh=myosin light chain phosphatase -P indicates phosphorylated state PLC = phospholipase C and IP3 = phosphatidylinositol trisphosphate)
Table 1 Inflammatory mediators and their role in cerebral vasospasm
Mediator Function of mediator Disease model where role hasbeen established References
(i) Nitric oxide(i) Vasodilator(ii) Inhibitor of endothelin-1expression
(i) Cerebral malaria(ii) Bacterial meningitis(iii) Subarachnoid haemorrhage
[1 7 16 28 32 41 45]
(i) Endothelin-1 (i) Vasoconstrictor (i) Bacterial meningitis(ii) Subarachnoid haemorrhage [7 15]
(i) Interleukin-1(ii) Interferon gamma(iii) Tumor necrosis factor
(i) Activators of protein kinase C(ii) Stimulators of release ofendothelin-1
(i) Bacterial meningitis(ii) Cerebral malaria(iii) Subarachnoid haemorrhage
[7 14 56]
73 Tissue Plasminogen Activator A recent meta-analysis offive randomized controlled trials (465 patients) of tissue plas-minogen activator (tPA) or urokinase applied intrathecallyreduced development of poor outcome and delayed cerebralischaemia and vasospasm [70]Themechanism proposed forthis effect is probably not related to thrombolysis but to adirect effect of tPA on vascular tone It is clear that the effectof tPA is endothelial cell dependent and more specificallyNO synthase dependent tPA seems to bind to a receptorpresent in endothelial cells that mediates the stimulation ofNO synthase activity and thus inhibits the vasoconstrictiveeffect of phenylephrine [76]
74 Statins Statins can reduce vasospasm by upregulatingendothelial NO synthase expression A threefold increasein endothelial NO synthase mRNA protein and enzymatic
activity has been demonstrated following statin treatmentresulting in an increase in cerebral blood flow Statintreatment has attenuated cerebral vasospasm and preventeddelayed ischemic deficits in amurine SAHmodel [77] A pre-vious systematic review of 4 studies with a total of 190 patientsshowed no statistically significant effect on vasospasm ontranscranial Doppler studies delayed cerebral ischaemia ormortality [78] but a more recent review demonstrated areduction in mortality and delayed ischemic neurologicaldeficits [66]
75 Rho-Kinase Inhibitor The specific rho-kinase inhibitorfasudil hydrochloride was in a recent systematic review of8 studies (843 patients) shown to reduce the occurrenceof cerebral vasospasm and cerebral infarction significantlyand led to an improvement in clinical outcome [71] The
International Journal of Inflammation 7
Table2Medicationfortreatmento
fcerebralvasospasm
the
evidence
from
controlledtrialsin
humans
Interventio
nTy
peof
study
Patholog
yRe
sultsodd
sratio
(OR)
orrelativer
isk(RR)
foro
ccurrencein
interventio
ngrou
pcomparedto
grou
pwith
outintervention
Reference
Calcium
channel
blockers
Syste
maticreview
(SR)
(sixrand
omized
controlledtrials
(RCT
s))
Acuteb
rain
injury
DeathO
R091
[95
070ndash117
]Death
andsevere
disabilityOR085
[95
068
to10
7]In
thes
ubgrou
pof
traumaticsubarachno
idhaem
orrhagep
atients
pooled
odds
ratio
was
059
[95
CI037ndash0
94]three
RCTs
repo
rtingdeathandsevere
disabilityas
anou
tcom
einthis
subgroup
OR067
[95
CI046
ndash098]
[60]
Calcium
channel
blockers
SR(16RC
Ts)
Aneurysmal
subarachno
idhaem
orrhage(aSAH)
Overallcalcium
antagonists
redu
cedther
iskof
poor
outcom
ethe
relativer
isk(RR)
was
081
[95
CI072
to092]thec
orrespon
ding
numbero
fpatientsn
eededto
treatwas
19[95
CI1to51]foro
ral
nimod
ipinea
lone
theR
Rwas
067
[95
CI055
to081]foro
ther
calcium
antagonists
orintravenou
sadm
inistratio
nof
nimod
ipine
ther
esultsweren
otsta
tistic
allysig
nificantcalcium
antagonists
redu
cedtheo
ccurrenceo
fsecon
dary
ischaem
iaandshow
eda
favourabletre
ndforc
asefatality
for
magnesiu
minadditio
nto
standard
treatmentw
ithnimod
ipinetheR
Rwas
075
[95
CI057
to10
0]fora
poor
outcom
eand
066
[95
CI045
to096]for
clinicalsigns
ofsecond
aryisc
haem
ia
[61]
Nicardipine
SR(five
controlled
trials)
aSAH
Risk
ofpo
orou
tcom
e(deathvegetativ
estateord
ependency)
OR
058
(95
CI037ndash0
9)
Mortalityod
dsratio
045[95
CI015
to12
9][62]
Magnesiu
msulfate
Prospective
rand
omise
dstu
dyEclampsia
Sign
ificant
redu
ctionof
pulsa
tility
index(119875=0002)a
ndmeanflo
wvelocityin
middlec
erebralartery(119875=002)
[63]
Prop
hylactic
magnesiu
msulfate
SRof
tenrand
omized
parallelgroup
controlledtrials
aSAH
Glasgow
outcom
escaleandmod
ified
Rank
inscaleR
R093
(95
CI082
to10
6)m
ortality095
(95
CI076ndash117
)delay
edcerebral
ischaem
iaRR
054(95
CI038
to075)delay
edisc
hemic
neurologicaldeficit(D
IND)RR
of093
[95
CI062ndash139
]transcranialDop
pler
vasospasmR
R072
[95
CI051ndash103]
[64]
Indu
ced
hyperm
agnesaem
iaRC
TaSAH
Vasospasm
ondigitalsub
tractio
nangiograph
yOR
051[95CI
026
to10
2]neurologicalrecoveryORforw
orse
outcom
e071
[95
CI039
to13
2][65]
Statins
SR(sixRC
Ts)
aSAH
Incidenceo
fvasospasm
RR080[95
CI054ndash
117]poo
rneurologicalou
tcom
eRR
094[95
CI077to
116]
MortalityRR
030[95
CI014
ndash064]
DIN
DR
R058
[95
CI037
ndash092]
[66]
Endo
thelin
receptor
antagonists
SR(fo
urRC
Ts)
aSAH
Incidenceo
fDIN
Drela
tiver
isk08[95
CI067ndash0
95]
angiograph
icvasospasm
RR062[95CI
052
to072]
unfavourableou
tcom
eRR
087[95
CI074ndash102]m
ortalityRR
105[95
CI077
to14
5]
[67]
8 International Journal of Inflammation
Table2Con
tinued
Interventio
nTy
peof
study
Patholog
yRe
sultsodd
sratio
(OR)
orrelativer
isk(RR)
foro
ccurrencein
interventio
ngrou
pcomparedto
grou
pwith
outintervention
Reference
Endo
thelin-1Areceptor
antagonistClazosentan
SR(fo
urRC
Ts)
aSAH
Relativer
iskforincidence
ofDIN
Ds076
(95
CI062ndash0
92)
delay
edcerebralinfarctio
n079
[95
CI063ndash100]G
lasgow
outcom
escaleextend
edRR
112
[95
CI096ndash130]m
ortalityRR
10
2[95
CI070ndash149]
[68]
Intravenou
smethylpredn
isolone
RCT
aSAH
Symptom
aticvasospasm
265in
interventio
ngrou
pcompared
with
26in
placebogrou
pfunctio
naloutcomes
caleredu
cedin
the
methylpredn
isolone
grou
pwith
riskdifference193
[95
CI05ndash379]ou
tcom
epoo
rin15of
patie
ntsinthe
methylpredn
isolone
grou
pversus
34in
thep
lacebo
grou
p
[69]
Tissue
plasminogen
activ
ator
SR(five
RCTs)
aSAH
Overalluseo
fintrathecalthrombo
lytic
swas
associated
with
significantreductio
nsin
thed
evelo
pmento
fpoo
routcomes
(OR
052034ndash
078119875lt001)DIN
Ds(OR054034ndash
087119875=001)
andangiograph
icvasospasm
(OR032015
ndash070119875lt001)
[70]
Rho-kinase
inhibitor
SR(8
controlledtrials)
aSAH
Absenceo
fsym
ptom
aticvasospasmoccurrenceo
flow
density
areas
associated
with
vasospasm
onCT
and
occurrence
ofadversee
vents
weres
imilarb
etweenthetwogrou
psthe
clinicaloutcomes
were
morefavorablein
thefasud
ilgrou
pthan
inthen
imod
ipineg
roup
(119875=004)
[71]
Tirilazad
SR(five
RCTs)
aSAH
Therew
asno
significantd
ifference
betweenthetwogrou
psatthe
endof
follo
w-upforthe
prim
aryou
tcom
edeathOR
089[95CI
074
to10
6]orinpo
orou
tcom
e(deathvegetativ
estateorsevere
disability)
OR10
4[95
CI090
to12
1]few
erpatie
ntsd
evelop
eddelay
edcerebralisc
haem
iain
thetirilazadgrou
pthan
inthec
ontro
lgrou
pOR080
[95
CI069
to093]subgroup
analyses
didno
tdemon
stratea
nysig
nificantd
ifference
ineffectsof
tirilazadon
clinicaloutcomes
[72]
Erythrop
oietin
RCT
aSAH
Nodifferences
wered
emon
strated
intheincidence
ofvasospasm
andadversee
ventspatie
ntsreceiving
EPOhadad
ecreased
incidenceo
fseverev
asospasm
from
275to
75(119875=0037)
redu
cedDID
swith
newcerebralinfarctsfro
m40
0to
75
(119875=0001)as
hortened
duratio
nof
impaire
dautoregu
latio
n(ip
silateralsid
e119875lt0001)andmorefavorableou
tcom
eat
discharge(favorableG
lasgow
outcom
escalescore119875=0039)
amon
gthe7
1survivorsthe
EPOgrou
phadfewer
deficits
measured
with
NationalInstitutes
ofHealth
Stroke
Scale(medianscore2
versus
6119875=0008)
[73]
International Journal of Inflammation 9
mechanism is apart from a contribution to inhibition ofcalcium independent vasospasm (see above) probably alsoan increase of endothelial nitric oxide synthase (eNOS)expression by stabilizing eNOSmRNA which can contributeto an increase of NO level to enhance vasodilatation
76 Other Treatments Steroid treatment can inhibit cytokineexpression and has thus the potential to reduce cytokinemediated calcium dependent and independent vasospasmIn tuberculous meningitis adjuvant treatment with corticos-teroids has been indirectly associatedwith features of reducedvasculopathy which may include vasospasm
A large randomised controlled trial showed improvedmortality in tuberculous meningitis with adjuvant corti-costeroids but did not show a reduction in severe disabil-ity however an observational MRI study did suggest areduction in strokes in patients treated with corticosteroids[79 80] An open-label study of aspirin in the preventionof stroke and mortality in tuberculous meningitis found anonsignificant reduction in stroke and a significant reductionin mortality with a possible synergism with corticosteroids[81] Mechanisms responsible for a potential effect may bea reduction of the vasoconstricting effect of PGE2 The 21-aminosteroid tirilazad is a lipid peroxidation inhibitor whichinhibits free radical-induced lipid peroxidation (LP) by acombination of lipid peroxide scavenging and a membrane-stabilizing action that limits the propagation of LP reactionsbetween a lipid peroxide and an adjacent polyunsaturatedfatty acid There has been no consistent evidence of benefitin animal or human studies Erythropoietin may act throughincrease in expression of endothelial nitric oxide synthasethus increasing NO bioavailability
8 Conclusions and Perspectives forFuture Developments
There is evidence for common pathways leading tovasospasm in all forms of cerebral inflammation involvinginterleukin-1 tumor necrosis factor endothelin-1 andnitric oxide Treatments addressing the pathophysiologyof vasospasm in one form of cerebral inflammation maytherefore apply to all others Treatment of cerebral vasospasmhas been mainly investigated in aneurysmal SAH Agentsfor which there is likely to be clinical benefit are calciumantagonists statins and intrathecal plasminogen activators(see Table 2) The fact that there is calcium dependent andindependent vasospasm in inflammation (see Figure 1)shows that a combination of calcium antagonists with agentsinterfering with calcium independent vasospasm includingagents improving the bioavailability of nitric oxide is theway forward Future trials need to investigate their effectsin patients with all forms of cerebral inflammation leadingto neurological deficits attributable to vasospasm In vivocorrelates for reduction of vasospasm in the peripheralcirculation could be explored as a surrogate for reduction ofvasospasm in the cerebral (micro) vasculature
Strategies to improve microvascular recruitment whichhave been explored in models of septicaemia could poten-tially be applied to cerebral vasospasm Distributive shockwhich occurs during sepsis and septic shock is associatedwith an abnormal distribution of microvascular blood flowVasospasm of part of the arterioles supplying the capillary isa mechanism involved in this maldistribution The clinicalintroduction of new microcirculatory imaging techniquessuch as orthogonal polarization spectral and side-streamdark-field imaging (OPSSDF) has allowed direct obser-vation of the microcirculation at the bedside Images ofthe sublingual microcirculation during septic shock andresuscitation have revealed that the distributive defect ofblood flow occurs at the capillary level [82]
In rat models of cecal ligation and puncture investiga-tors have used intravital video microscopy to demonstratethat sepsis is characterized by decreased microcirculatoryflow velocity an abundance of stopped-flow microvesselsincreased heterogeneity of microcirculatory flow and lowdensity of perfused capillaries As thesemicrocirculatory flowalterations can occur in the absence of global hemodynamicderangements (eg absence of arterial hypotension) micro-circulatory dysfunction largely reflects intrinsic events occur-ring in the microvessels like localized vasospasm [83] Appli-cation ofmicrocirculatory recruitmentmaneuver procedureshas been shown to be effective in promotingmicrocirculatoryblood flow in clinical studies using OPSSDF imaging [84ndash87] Fluid resuscitation in combination with the nitric oxidedonor nitroglycerine was shown to recruit disturbed micro-circulation following pressure guided resuscitation in septicshock patients
It is important to note that application of colloids inpatients with SAH was associated with worse outcomescompared to matched controls in a subgroup analysis of theCONSCIOUS-1 prospective randomized trial of clazosentanfor the prevention of angiographic vasospasm [88] Futureresearch needs to investigate whether colloids can bind nitricoxide and make this vasodilator less available by binding it
Regarding future therapeutic interventions increasingnitric oxide bioavailability erythropoietin and L-argininewhich increased bioavailability of nitric oxide in patients withmalaria [89] need to be explored as adjunctive treatmentin children with cerebral malaria in randomised controlledtrials In vitro the availability of L-arginine does not appearto be a rate limiting step for the activity of the NO synthasebecause its half-saturating concentration is less than 3of theplasma and endothelial concentration of this substrate
The nitric oxide donor intravenous sodium nitrite hasbeen shown to prevent and reverse cerebrovascular spasmin primates and has been demonstrated to be safe foradministration in humans [90]
Support of pump function by dobutamine therapy hasbeen shown to improvemicrocirculatory flow independent ofimprovement of global hemodynamic parameters [91] Fluidapplication nitric oxide donors and dobutamine therapyneed to be explored in isolation but also as combinationof interventions to improve cerebral perfusion in cerebralinflammation associated with vasospasm
10 International Journal of Inflammation
A potential role of nonsteroidal anti-inflammatory drugswas revealed by landmark experiments on dog basilararteries Arachidonic acid induced sustained contractionsand these responses were markedly inhibited (95) bymeclofenamate and similarly by indomethacin but aspirinhad no such effect [92] In the rabbit basilar artery model ofcerebral vasospasm local intracranial delivery of ibuprofenaccomplished using controlled-release polymers preventedvasospasm when administered within 6 hours but notat either 12 or 24 hours [93] Delivery of ibuprofen viacontrolled-release polymers into the subarachnoid space ofmonkeys with subarachnoid haemorrhage prevented angio-graphic vasospasm after SAH as evident from patency of themiddle cerebral artery [94]
Piroxicam was more effective than the above-mentioneddrugs in the SAH dog model after angiographic analysisand analysis of behavioural changes [95] Early studiesusing prostacyclin found that isolated canine basilar arteriescontraction induced by prostaglandin E2 hemoglobin orserum was relaxed by prostacyclin but not indomethacin[96] In isolated human pial arteries prostacyclin relaxedhuman pial arteries contracted by either PGF2 alpha nora-drenaline serotonin or haemorrhagic CSF [97] In an animalstudy meloxicam reduced ultrastructural and morphometricvasospastic changes in rats with subarachnoid haemorrhage[98] Investigation comparing rate of subsequent permanentdisability from vasospasm and angiographic and delayedcerebral ischaemia in patients with SAH with and withoutaspirin intake found no association with poor outcome [99100]
There are new areas of pathophysiology research wherethe role of vasospasm needs to be explored thoroughly inorder to find avenues for therapeutic interventions Investi-gations could evaluate whether intraventricular haemorrhageoccurring commonly in the neonatal period in pretermneonates is associated with vasospasm increasing mor-bidity Case reports of intraventricular haemorrhage fromAV malformations and aneurysms in adults demonstratedvasospasm [101 102]
Future research needs to explore the usefulness of a num-ber of agents which have been demonstrated to reduce vaso-spasm in animal models including L-citrulline [103] januskinase-2 [104] endothelin converting enzyme inhibitors[105] caspase inhibitor Z-VAD-FMK [106] anti-E selectinmonoclonal antibodies [107] trehalose [108] and curcuminwhich was demonstrated to protect against the developmentof cerebral vasospasm and secondary cerebral infarctionafter subarachnoid haemorrhage in mice by its broad anti-inflammatory activity including limitation of superoxidegeneration and influence on inducible nitric oxide synthaseexpression [109]
Aggressive maintenance of normothermia or mildhypothermia in patients with military blast injury resultedin a dramatic reduction in the incidence of posttraumaticvasospasm from 475 to 5 Future studies need to confirmthis finding and investigate whether hypothermia can reducecerebral inflammation related ischemic damage to the brainin other conditions like bacterial meningitis or cerebralmalaria [37]
Conflict of Interests
The author declares that there is no conflict of interestsregarding the publication of this paper
References
[1] B Weir ldquoThe pathophysiology of cerebral vasospasmrdquo BritishJournal of Neurosurgery vol 9 no 3 pp 375ndash390 1995
[2] H Bode and A Harders ldquoTransient stenoses and occlusionsof main cerebral arteries in childrenmdashdiagnosis and control oftherapy by transcranial Doppler sonographyrdquo European Journalof Pediatrics vol 148 no 5 pp 406ndash411 1989
[3] K-F Lindegaard H Nornes S J Bakke W Sorteberg and PNakstad ldquoCerebral vasospasm diagnosis by means of angiogra-phy and blood velocity measurementsrdquo Acta Neurochirurgicavol 100 no 1-2 pp 12ndash24 1989
[4] C Lysakowski B Walder M C Costanza and M R TramerldquoTranscranial Doppler versus angiography in patients withvasospasm due to a ruptured cerebral aneurysm a systematicreviewrdquo Stroke vol 32 no 10 pp 2292ndash2298 2001
[5] R L Grubb Jr M E Raichle J O Eichling and M HGado ldquoEffects of subarachnoid hemorrhage on cerebral bloodvolume blood flow and oxygen utilization in humansrdquo Journalof Neurosurgery vol 46 no 4 pp 446ndash452 1977
[6] C-H Lu H-W Chang C-C Lui C-R Huang and W-NChang ldquoCerebral haemodynamics in acute bacterial meningitisin adultsrdquoQuaterly Journal of Medicine vol 99 no 12 pp 863ndash869 2006
[7] F Faraci and D D Heistad ldquoRegulation of the cerebralcirculation role of endothelium and potassium channelsrdquoPhysiological Reviews vol 78 no 1 pp 53ndash97 1998
[8] L Hektoen ldquoThe vascular changes in tuberculous meningitisespecially in tuberculous endarteritisrdquo Journal of ExperimentalMedicine vol 1 pp 112ndash163 1896
[9] G Thwaites ldquoTuberculosis of the central nervous systemrdquo inClinical Tuberculosis P D O Davies S B Gordon and GDavies Eds pp 151ndash165 CRC Press 5th edition 2014
[10] P M Dalal ldquoObservations on the involvement of cerebral ves-sels in tuberculousmeningitis in adultsrdquoAdvances in Neurologyvol 25 pp 149ndash159 1979
[11] L A Rojas-Echeverri J L Soto-Hernandez S Garza et alldquoPredictive value of digital subtraction angiography in patientswith tuberculous meningitisrdquo Neuroradiology vol 38 no 1 pp20ndash24 1996
[12] E L Lyons and N E Leeds ldquoThe angiographic demonstrationof arterial vascular disease in purulent meningitis report of acaserdquo Radiology vol 88 no 5 pp 935ndash938 1967
[13] S Ries U Schminke K Fassbender M Daffertshofer WSteinke andMHennerici ldquoCerebrovascular involvement in theacute phase of bacterial meningitisrdquo Journal of Neurology vol244 no 1 pp 51ndash55 1997
[14] K Fassbender S Ries U Schminke S Schneider and M Hen-nerici ldquoInflammatory cytokines in CSF in bacterial meningitisassociation with altered blood flow velocities in basal cerebralarteriesrdquo Journal of Neurology Neurosurgery amp Psychiatry vol61 no 1 pp 57ndash61 1996
[15] L A Pfister J H Tureen S Shaw et al ldquoEndothelin inhibitionimproves cerebral blood flow and is neuroprotective in pneu-mococcal meningitisrdquoAnnals of Neurology vol 47 pp 329ndash3352000
International Journal of Inflammation 11
[16] S L Leib Y S Kim S M Black J H Tureen and M GTauber ldquoInducible nitric oxide synthase and the effect of amin-oguanidine in experimental neonatal meningitisrdquo The Journalof Infectious Diseases vol 177 no 3 pp 692ndash700 1998
[17] T W Polder C R Jerusalem andW M C Eling ldquoMorpholog-ical characteristics of intracerebral arterioles in clinical (Plas-modium falciparum) and experimental (Plasmodium berghei)cerebral malariardquo Journal of the Neurological Sciences vol 101no 1 pp 35ndash46 1991
[18] N A V Beare S P Harding T E Taylor S Lewallen and MEMolyneux ldquoPerfusion abnormalities in childrenwith cerebralmalaria andmalarial retinopathyrdquo Journal of Infectious Diseasesvol 199 no 2 pp 263ndash271 2009
[19] C R J C Newton K Marsh N Peshu and F J KirkhamldquoPerturbations of cerebral hemodynamics in Kenyans withcerebral malariardquo Pediatric Neurology vol 15 no 1 pp 41ndash491996
[20] C C John A Panoskaltsis-Mortari R O Opoka et alldquoCerebrospinal fluid cytokine levels and cognitive impairmentin cerebral malariardquo American Journal of Tropical Medicine andHygiene vol 78 no 2 pp 198ndash205 2008
[21] W McGuire A V S Hill C E M Allsopp B M Greenwoodand D Kwiatkowski ldquoVariation in the TNF-120572 promoter regionassociated with susceptibility to cerebral malariardquo Nature vol371 no 6497 pp 508ndash510 1994
[22] W McGuire J C Knight A V S Hill C E M Allsopp B MGreenwood and D Kwiatkowski ldquoSevere malarial anemia andcerebral malaria are associated with different tumor necrosisfactor promoter allelesrdquo Journal of Infectious Diseases vol 179no 1 pp 287ndash290 1999
[23] B Dugas M D Mossalayi C Damais and J-P Kolb ldquoNitricoxide production by human monocytes Evidence for a role ofCD23rdquo Immunology Today vol 16 no 12 pp 574ndash580 1995
[24] L Pellettieri B Nilsson C-A Carlsson andU Nilsson ldquoSerumimmunocomplexes in patients with subarachnoid hemorrhagerdquoNeurosurgery vol 19 no 5 pp 767ndash771 1986
[25] M Eisenhut ldquoCauses of reduced immune complex clearance incerebralmalariardquoParasite Immunology vol 31 no 2 p 59 2009
[26] P Teeranaipong J Ohashi J Patarapotikul et al ldquoA functionalsingle-nucleotide polymorphism in the CR1 promoter regioncontributes to protection against cerebral malariardquo Journal ofInfectious Diseases vol 198 no 12 pp 1880ndash1891 2008
[27] P Cabrales G M Zanini D Meays J A Frangos and LJ M Carvalho ldquoMurine cerebral malaria is associated witha vasospasm-like microcirculatory dysfunction and survivalupon rescue treatment is markedly increased by nimodipinerdquoTheAmerican Journal of Pathology vol 176 no 3 pp 1306ndash13152010
[28] I Gramaglia P Sobolewski D Meays et al ldquoLow nitricoxide bioavailability contributes to the genesis of experimentalcerebral malariardquoNature Medicine vol 12 no 12 pp 1417ndash14222006
[29] T W Yeo D A Lampah E Tjitra et al ldquoRelationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavail-ability and perfusion in severe falciparum malariardquo Journal ofInfectious Diseases vol 200 no 10 pp 1522ndash1529 2009
[30] G Dhangadamajhi B N Mohapatra S K Kar and M RanjitldquoGenetic variation in neuronal nitric oxide synthase (nNOS)gene and susceptibility to cerebral malaria in Indian adultsrdquoInfection Genetics and Evolution vol 9 no 5 pp 908ndash911 2009
[31] M R Hobbs V Udhayakumar M C Levesque et al ldquoAnew NOS2 promoter polymorphism associated with increased
nitric oxide production and protection from severe malaria inTanzanian and Kenyan childrenrdquoThe Lancet vol 360 no 9344pp 1468ndash1475 2002
[32] P Cabrales G M Zanini D Meays J A Frangos and L JM Carvalho ldquoNitric oxide protection against murine cerebralmalaria is associated with improved cerebral microcirculatoryphysiologyrdquo The Journal of Infectious Diseases vol 203 no 10pp 1454ndash1463 2011
[33] G Morahan C S Boutlis D Huang et al ldquoA promoterpolymorphism in the gene encoding interleukin-12 p40 (IL12B)is associated with mortality from cerebral malaria and withreduced nitric oxide productionrdquo Genes amp Immunity vol 3 no7 pp 414ndash418 2002
[34] C Casals-Pascual R Idro N Gicheru et al ldquoHigh levels of ery-thropoietin are associated with protection against neurologicalsequelae in African children with cerebral malariardquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 105 no 7 pp 2634ndash2639 2008
[35] F C Chow C M Marra and T A Cho ldquoCerebrovasculardisease in central nervous system infectionsrdquo Seminars inNeurology vol 31 no 3 pp 286ndash306 2011
[36] R A Armonda R S Bell A H Vo et al ldquoWartime traumaticcerebral vasospasm recent review of combat casualtiesrdquoNeuro-surgery vol 59 no 6 pp 1215ndash1225 2006
[37] K Shahlaie K Keachie I M Hutchins et al ldquoRisk factorsfor posttraumatic vasospasm clinical articlerdquo Journal of Neu-rosurgery vol 115 no 3 pp 602ndash611 2011
[38] Y Udomphorn W M Armstead and M S Vavilala ldquoCerebralblood flow and autoregulation after pediatric traumatic braininjuryrdquo Pediatric Neurology vol 38 no 4 pp 225ndash234 2008
[39] R M Pluta J Hansen-Schwartz J Dreier et al ldquoCerebralvasospasm following subarachnoid hemorrhage time for a newworld of thoughtrdquo Neurological Research vol 31 no 2 pp 151ndash158 2009
[40] J Hansen-Schwartz P Vajkoczy R L Macdonald R MPluta and J H Zhang ldquoCerebral vasospasm looking beyondvasoconstrictionrdquo Trends in Pharmacological Sciences vol 28no 6 pp 252ndash256 2007
[41] H Kasuya B K A Weir M Nakane et al ldquoNitric oxidesynthase and guanylate cyclase levels in canine basilar arteryafter subarachnoid hemorrhagerdquo Journal of Neurosurgery vol82 no 2 pp 250ndash255 1995
[42] M D Linnik and T J F Lee ldquoEffect of hemoglobin on neuro-genic responses and cholinergic parameters in porcine cerebralarteriesrdquo Journal of Cerebral Blood Flow and Metabolism vol 9no 2 pp 219ndash225 1989
[43] CG Sobey and FM Faraci ldquoSubarachnoid haemorrhage whathappens to the cerebral arteriesrdquo Clinical and ExperimentalPharmacology and Physiology vol 25 no 11 pp 867ndash876 1998
[44] Y R T Dinh G Lot R Benrabah O Baroudy J Cophignonand J Seylaz ldquoAbnormal cerebral vasodilation in aneurys-mal subarachnoid hemorrhage use of serial 133Xe cerebralblood flow measurement plus acetazolamide to assess cerebralvasospasmrdquo Journal of Neurosurgery vol 79 no 4 pp 490ndash4931993
[45] T J F Lee ldquoNitric oxide and the cerebral vascular functionrdquoJournal of Biomedical Science vol 7 no 1 pp 16ndash26 2000
[46] M Stoodley R L Macdonald B Weir et al ldquoSubarachnoidhemorrhage as a cause of an adaptive response in cerebralarteriesrdquo Journal of Neurosurgery vol 93 no 3 pp 463ndash4702000
12 International Journal of Inflammation
[47] Y R Tran Dinh A Jomaa J Callebert et al ldquoOverexpressionof cyclooxygenase-2 in rabbit basilar artery endothelial cellsafter subarachnoid hemorrhagerdquo Neurosurgery vol 48 no 3pp 626ndash635 2001
[48] A Gecse B Kis Z Mezei and G Telegdy ldquoEffects of inflam-matory neuropeptides on the arachidonate cascade of plateletsrdquoInternational Archives of Allergy and Immunology vol 118 no2ndash4 pp 166ndash170 1999
[49] K S Mark W J Trickler and D W Miller ldquoTumornecrosis factor-120572 induces cyclooxygenase-2 expression andprostaglandin release in brain microvessel endothelial cellsrdquoJournal of Pharmacology and Experimental Therapeutics vol297 no 3 pp 1051ndash1058 2001
[50] T Tanazawa Y Suzuki M Anzai S Tsugane M Takayasu andM Shibuya ldquoVasodilation by intrathecal lipopolysaccharide ofthe cerebral arteries after subarachnoid haemorrhage in dogsrdquoActa Neurochirurgica vol 138 no 3 pp 330ndash337 1996
[51] N Toda M Kawakami and K Yoshida ldquoConstrictor action ofoxyhemoglobin in monkey and dog basilar arteries in vivo andin vitrordquo American Journal of Physiology Heart and CirculatoryPhysiology vol 260 no 2 pp H420ndashH425 1991
[52] M Yoshizumi M A Perrella J C Burnett Jr and M-E LeeldquoTumor necrosis factor downregulates an endothelial nitricoxide synthase mRNA by shortening its half-liferdquo CirculationResearch vol 73 no 1 pp 205ndash209 1993
[53] A Rengasamy and R A Johns ldquoRegulation of nitric oxidesynthase by nitric oxiderdquo Molecular Pharmacology vol 44 no1 pp 124ndash128 1993
[54] A L de Souza A C P de Oliveira C C Romano J SztajnbokA J S Duarte and A C Seguro ldquoInterleukin-6 activation inischemic stroke caused by Neisseria meningitidis serogroup CrdquoInternational Journal of Cardiology vol 127 no 3 pp e160ndashe1632008
[55] T Kandabashi H Shimokawa K Miyata et al ldquoInhibition ofmyosin phosphatase by upregulated Rho-kinase plays a key rolefor coronary artery spasm in a porcine model with interleukin-1120573rdquo Circulation vol 101 no 11 pp 1319ndash1323 2000
[56] D-H Nam J-S Kim S-C Hong et al ldquoExpression ofinterleukin-1120573 in lipopolysaccharide stimulated monocytesderived from patients with aneurysmal subarachnoid hem-orrhage is correlated with cerebral vasospasmrdquo NeuroscienceLetters vol 312 no 1 pp 41ndash44 2001
[57] A Ito H Shimokawa T Kadokami et al ldquoTyrosine kinaseinhibitor suppresses coronary arteriosclerotic changes andvasospastic responses induced by chronic treatment withinterleukin-1120573 in pigs in vivordquo Journal of Clinical Investigationvol 96 no 3 pp 1288ndash1294 1995
[58] H Yanamoto H Kataoka Y Nakajo and K Iihara ldquoThe roleof the host defense system in the development of cerebralvasospasm analogies between atherosclerosis and subarach-noid hemorrhagerdquo European Neurology vol 68 no 6 pp 329ndash343 2012
[59] A F Ducruet P R Gigante Z L Hickman et al ldquoGeneticdeterminants of cerebral vasospasm delayed cerebral ischemiaand outcome after aneurysmal subarachnoid hemorrhagerdquoJournal of Cerebral Blood Flow amp Metabolism vol 30 no 4 pp676ndash688 2010
[60] J Langham C Goldfrad G Teasdale D Shaw and KRowan ldquoCalcium channel blockers for acute traumatic braininjuryrdquoCochrane Database Systematic Reviews no 4 Article IDCD000565 2000
[61] S M Dorhout Mees G J Rinkel V L Feigin et al ldquoCal-cium antagonists for aneurysmal subarachnoid haemorrhagerdquoCochrane Database of Systematic Reviews no 3 Article IDCD000277 2007
[62] R-Q Huang F-G Jiang Z-M Feng and T-Y WangldquoNicardipine in the treatment of aneurysmal subarachnoidhaemorrhage a meta-analysis of published datardquo Acta Neuro-logica Belgica vol 113 no 1 pp 3ndash6 2013
[63] S Naidu A J Payne J Moodley M Hoffmann and EGouws ldquoRandomised study assessing the effect of phenytoinand magnesium sulphate on maternal cerebral circulationin eclampsia using transcranial Doppler ultrasoundrdquo BritishJournal of Obstetrics amp Gynaecology vol 103 no 2 pp 111ndash1161996
[64] D Reddy A Fallah J-A Petropoulos F Farrokhyar R LMacdonald and D Jichici ldquoProphylactic magnesium sulphatefor aneurysmal subarachnoid haemorrhage a systematic reviewand meta-analysisrdquo Neurocritical Care vol 21 no 2 pp 356ndash364 2014
[65] C M Bradford S Finfer A OrsquoConnor et al ldquoA ran-domised controlled trial of induced hypermagnesaemia follow-ing aneurysmal subarachnoid haemorrhagerdquo Critical Care andResuscitation vol 15 no 2 pp 119ndash125 2013
[66] S-H Su W Xu J Hai Y-F Wu and F Yu ldquoEffects of statins-use for patients with aneurysmal subarachnoid hemorrhagea meta-analysis of randomized controlled trialsrdquo ScientificReports vol 4 article 4573 2014
[67] J Guo Z Shi K Yang J H Tian and L Jiang ldquoEndothelinreceptor antagonists for subarachnoid hemorrhagerdquo CochraneDatabase of Systematic Reviews vol 9 Article ID CD0083542012
[68] J Shen J-W Pan Z-X Fan X-X Xiong and R-Y ZhanldquoDissociation of vasospasm-related morbidity and outcomesin patients with aneurysmal subarachnoid hemorrhage treatedwith clazosentan a meta-analysis of randomized controlledtrials a reviewrdquo Journal of Neurosurgery vol 119 no 1 pp 180ndash189 2013
[69] P Gomis J P Graftieaux R Sercombe D Hettler BScherpereel and P Rousseaux ldquoRandomized double-blindplacebo-controlled pilot trial of high-dose methylprednisolonein aneurysmal subarachnoid hemorrhagerdquo Journal of Neuro-surgery vol 112 no 3 pp 681ndash688 2010
[70] A H Kramer and J J Fletcher ldquoLocally-administered intrathe-cal thrombolytics following aneurysmal subarachnoid hem-orrhage a systematic review and meta-analysisrdquo NeurocriticalCare vol 14 no 3 pp 489ndash499 2011
[71] G J Liu Z J Wang Y F Wang et al ldquoSystematic assessmentand meta-analysis of the efficacy and safety of fasudil in thetreatment of cerebral vasospasm in patients with subarachnoidhemorrhagerdquo European Journal of Clinical Pharmacology vol68 no 2 pp 131ndash139 2012
[72] S Zhang LWangM Liu andBWu ldquoTirilazad for aneurysmalsubarachnoid haemorrhagerdquo Cochrane Database SystematicReview vol 2 Article ID CD006778 2010
[73] M-Y Tseng P J Hutchinson H K Richards et al ldquoAcutesystemic erythropoietin therapy to reduce delayed ischemicdeficits following aneurysmal subarachnoid hemorrhage aphase II randomized double-blind placebo-controlled trialclinical articlerdquo Journal of Neurosurgery vol 111 no 1 pp 171ndash180 2009
[74] H Kasuya ldquoDevelopment of nicardipine prolonged-releaseimplants after clipping for preventing cerebral vasospasm from
International Journal of Inflammation 13
laboratory to clinical trialrdquo Acta Neurochirurgica Supplemen-tum vol 115 pp 41ndash44 2013
[75] C Thome M Seiz G A Schubert et al ldquoNicardipine pelletsfor the prevention of cerebral vasospasmrdquoActaNeurochirurgicano 110 pp 209ndash211 2011
[76] T Nassar S Akkawi A Shina et al ldquoIn vitro and in vivo effectsof tPA and PAI-1 on blood vessel tonerdquo Blood vol 103 no 3 pp897ndash902 2004
[77] T Sugawara R Ayer V Jadhav W Chen T Tsubokawaand J H Zhang ldquoMechanisms of statin treatment in cerebralvasospasmrdquo Acta Neurochirurgica no 110 pp 9ndash11 2011
[78] M D Vergouwen R J De Haan M Vermeulen and YB Roos ldquoEffect of statin treatment on vasospasm delayedcerebral ischemia and functional outcome in patients withaneurysmal subarachnoid hemorrhage a systematic review andmeta-analysis updaterdquo Stroke vol 41 no 1 pp e47ndashe52 2010
[79] G E Thwaites N D Bang N H Dung et al ldquoDexamethasonefor the treatment of tuberculous meningitis in adolescents andadultsrdquoTheNew England Journal ofMedicine vol 351 no 17 pp1741ndash1811 2004
[80] G E Thwaites J Macmullen-Price T T H Chau et al ldquoSerialMRI to determine the effect of dexamethasone on the cerebralpathology of tuberculous meningitis an observational studyrdquoThe Lancet Neurology vol 6 no 3 pp 230ndash236 2007
[81] U K Misra J Kalita and P P Nair ldquoRole of aspirin in tuber-culous meningitis a randomized open label placebo controlledtrialrdquo Journal of the Neurological Sciences vol 293 no 1-2 pp12ndash17 2010
[82] P W G Elbers and C Ince ldquoBench-to-bedside review mech-anisms of critical illnessmdashclassifying microcirculatory flowabnormalities in distributive shockrdquoCritical Care vol 10 article221 2006
[83] S Trzeciak I Cinel R P Dellinger et al ldquoResuscitating themicrocirculation in sepsis the central role of nitric oxideemerging concepts for novel therapies and challenges forclinical trialsrdquo Academic Emergency Medicine vol 15 no 5 pp399ndash415 2008
[84] Y Sakr M-J Dubois D De Backer J Creteur and J-LVincent ldquoPersistent-microcirculatory alterations are associatedwith organ failure and death in patients with septic shockrdquoCritical Care Medicine vol 32 no 9 pp 1825ndash1831 2004
[85] P E Spronk J H Rommes C Schaar andC Ince ldquoThromboly-sis in fulminant purpura observations on changes in microcir-culatory perfusion during succesful treatmentrdquoThrombosis andHaemostasis vol 95 no 3 pp 576ndash578 2006
[86] J Creteur D De Backer Y Sakr M Koch and J-L VincentldquoSublingual capnometry tracks microcirculatory changes inseptic patientsrdquo Intensive Care Medicine vol 32 no 4 pp 516ndash523 2006
[87] D De Backer J Creteur J C Preiser M J Dubois and JL Vincent ldquoMicrovascular blood flow is altered in patientswith sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 1 pp 98ndash104 2002
[88] G M Ibrahim and R L Macdonald ldquoThe effects of fluid bal-ance and colloid administration on outcomes in patients withaneurysmal subarachnoid hemorrhage a propensity score-matched analysisrdquoNeurocritical Care vol 19 no 2 pp 140ndash1492013
[89] T W Yeo D A Lampah R Gitawati et al ldquoImpaired nitricoxide bioavailability and L-arginine-reversible endothelial dys-function in adults with falciparum malariardquo The Journal ofExperimental Medicine vol 204 no 11 pp 2693ndash2704 2007
[90] A R Fathi R M Pluta K D Bakhtian M Qi and R RLonser ldquoReversal of cerebral vasospasmvia intravenous sodiumnitrite after subarachnoid hemorrhage in primates laboratoryinvestigationrdquo Journal of Neurosurgery vol 115 no 6 pp 1213ndash1220 2011
[91] D de Backer J Creteur M J Dubois et al ldquoThe effects ofdobutamine on microcirculatory alterations in patients withseptic shock are independent of its systemic effectsrdquo CriticalCare Medicine vol 34 no 2 pp 403ndash408 2006
[92] C E Chapleau R P White and J T Robertson ldquoCerebralvasospasm effects of prostaglandin synthetase inhibitors invitrordquo Neurosurgery vol 6 no 2 pp 155ndash159 1980
[93] J L Frazier G Pradilla P P Wang and R J TamargoldquoInhibition of cerebral vasospasm by intracranial delivery ofibuprofen from a controlled-release polymer in a rabbit modelof subarachnoid hemorrhagerdquo Journal of Neurosurgery vol 101no 1 pp 93ndash98 2004
[94] G Pradilla Q A Thai F G Legnani et al ldquoLocal deliveryof ibuprofen via controlled-release polymers prevents angio-graphic vasospasm in a monkey model of subarachnoid hem-orrhagerdquo Neurosurgery vol 57 no 1 pp 184ndash189 2005
[95] R P White and J T Robertson ldquoComparison of piroxicammeclofenamate ibuprofen aspirin and prostacyclin efficacy ina chronic model of cerebral vasospasmrdquo Neurosurgery vol 12no 1 pp 40ndash46 1983
[96] T Fukumori E Tani Y Maeda and A Sukenaga ldquoEffectsof prostacyclin and indomethacin on experimental delayedcerebral vasospasmrdquo Journal of Neurosurgery vol 59 no 5 pp829ndash834 1983
[97] L Brandt B Ljunggren K-E Andersson B Hindfelt and TUski ldquoProstaglandin metabolism and prostacyclin in cerebralvasospasmrdquo General Pharmacology vol 14 no 1 pp 141ndash1431983
[98] T Hakan M Zafer Berkman T Ersoy I Karatas T Sanand S Arbak ldquoAnti-inflammatory effect of meloxicam onexperimental vasospasm in the rat femoral arteryrdquo Journal ofClinical Neuroscience vol 15 no 1 pp 55ndash59 2008
[99] LG Toussaint III J A Friedman E FMWijdicks et al ldquoInflu-ence of aspirin on outcome following aneurysmal subarachnoidhemorrhagerdquo Journal of Neurosurgery vol 101 no 6 pp 921ndash925 2004
[100] B A Gross P M R Lai K U Frerichs and R Du ldquoAspirin andaneurysmal subarachnoid haemorrhagerdquo World Neurosurgery2013
[101] S Yokobori AWatanabe R Nakae et al ldquoCerebral vasospasmsafter intraventricular hemorrhage from an arteriovenousmalformationmdashcase reportrdquo Neurologia Medico-Chirurgicavol 50 no 4 pp 320ndash323 2010
[102] B S Park Y S Won S S Choi and B M Kim ldquoSeveresymptomatic vasospasm following intraventricular hemorrhagefrom arteriovenous fistulardquo Journal of Korean NeurosurgicalSociety vol 45 no 5 pp 300ndash302 2009
[103] G Pradilla T Garzon-Muvdi J J Ruzevick et al ldquoSystemicL-citrulline prevents cerebral vasospasm in haptoglobin 2-2transgenicmice after subarachnoid hemorrhagerdquoNeurosurgeryvol 70 no 3 pp 747ndash757 2012
[104] G Chen J Wu C Sun et al ldquoPotential role of JAK2 in cere-bral vasospasm after experimental subarachnoid hemorrhagerdquoBrain Research vol 1214 pp 136ndash144 2008
[105] C L Lin A L Kwan A S Dumont et al ldquoAttenuationof experimental subarachnoid hemorrhage-induced increases
14 International Journal of Inflammation
in circulating intercellular adhesion molecule-1 and cerebralvasospasm by the endothelin-converting enzyme inhibitor CGS26303rdquo Journal of Neurosurgery vol 106 no 3 pp 442ndash4482007
[106] K Iseda S Ono K Onoda et al ldquoAntivasospastic and antiin-flammatory effects of caspase inhibitor in experimental sub-arachnoid hemorrhagerdquo Journal of Neurosurgery vol 107 no 1pp 128ndash135 2007
[107] C-L Lin A S Dumont T Calisaneller A-L Kwan S-L Hwong and K S Lee ldquoMonoclonal antibody against Eselectin attenuates subarachnoid hemorrhage-induced cerebralvasospasmrdquo Surgical Neurology vol 64 no 3 pp 201ndash206 2005
[108] R Echigo N Shimohata K Karatsu et al ldquoTrehalose treat-ment suppresses inflammation oxidative stress and vasospasminduced by experimental subarachnoid hemorrhagerdquo Journal ofTranslational Medicine vol 10 no 1 article 80 2012
[109] CWakadeM D KingM D Laird C H Alleyne Jr and KMDhandapani ldquoCurcumin attenuates vascular inflammation andcerebral vasospasm after subarachnoid hemorrhage in micerdquoAntioxidants amp Redox Signaling vol 11 no 1 pp 35ndash45 2009
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
2 International Journal of Inflammation
cerebral perfusion is dominated by pressures of CO2and
O2in the cerebral circulation Cerebral vasodilatation in
response to hypercapnia is dependent on formation of nitricoxide a mediator released in inflammation [7] After releaseby endothelium NO stimulates soluble guanylate cyclase invascular muscle resulting in an increase in the intracellu-lar concentration of guanosine 3101584051015840-cyclic monophosphate(cGMP) resulting in relaxation NO is generated from L-arginine by NO synthase It is the endothelial NO synthasewhich regulates cerebral blood vessel tone under basal con-ditions [7]
This review includes studies investigating outcomes likeradiological or clinical evidence for focal cerebral ischaemiaand infarction Cerebral vasospasm is a potentially pre-ventable and treatable cause of ischemic cerebral damageA current lack of established treatment options was themotivation for this review of cerebral vasospasm in condi-tions with inflammation of the brain The objective was toinvestigate whether there is evidence of cerebral vasospasmin all conditions associated with cerebral inflammation andwhether there are common pathways to vasospasm in allconditions with cerebral inflammation pointing to commontherapeutic options which may have been explored in onetype of cerebral inflammation but should be evaluated inall others with the aim of preventing irreversible cerebraldamage thus reducing morbidity and mortality
2 Methods
The literature search for this review used the databasePubMed (search from beginning of database until 31 July2014) entering search terms ldquocerebral vasospasmrdquo ldquoinflam-mationrdquo ldquomeningitisrdquo ldquobrain injuryrdquo ldquocerebral malariardquo ldquosub-arachnoid haemorrhagerdquo ldquo tumor necrosis factorrdquo ldquoendothe-linrdquo ldquonitric oxiderdquo ldquoarachidonic acidrdquo ldquorho-kinaserdquo ldquofasudilrdquoldquoerythropoietinrdquo ldquocalcium channel blockersrdquo ldquostatinsrdquo ldquotiri-lazadrdquo and ldquomagnesiumrdquo References of articles were screenedfor relevance and included where appropriate
3 Vasospasm in Cerebral Infection
31 Bacterial Meningitis Tuberculous meningitis is the formof cerebral inflammation in which vasculopathy has been thesubject of most detailed studies starting in the 19th century[8] Radiologically identifiable cerebral infarctions are com-mon in tuberculous meningitis and are present in 20 atinitial assessment and in a further 10 they occur after startof treatment [9]Threemain pathologies have been proposedvasculitis most prominent in vessels passing through thebasilar exudate proliferative changes with intimal thickeningwith resultant stenosis or occlusion and necrotizing vascularlesions The fibrinoid necrosis in supplied tissue found in theabsence of blood vessel wall infiltration raised the possibilityof vasospasm as an additional feature of the vasculopathyIn some instances infarction was found to have occurredwithout vasculitic changes or thrombosis compatible withvasospasm
Supportive of an important role for vasospasm in thepathology of tuberculous meningitis was also the poor corre-lation between angiographic findings and infarction [10 11]Thefirst direct evidence for vasospasm in bacterialmeningitiswas established in a case ofHaemophilus influenzaemeningi-tis [12] A prospective investigation of 22 adults with bacterialmeningitis by transcranial Doppler sonography related thedegree of arterial narrowing to outcome Low Glasgow comascales (lt7) on admission focal cerebral ischaemic deficitsand seizures were more frequent in patients with cerebralblood flow velocity gt210 cms compatible with vasospasmFatal outcome was only found with this high velocityPatients with minor or no vascular involvement had lessprominent initial impairment of consciousness [13] Otherinvestigations confirmed features of cerebral vasospasm inbacterial meningitis [14] Patients with features of vasospasmhad significantly increased concentrations of IL-1 and IL-6 but not endothelin-1 (ET-1) or thromboxane levels in theCSF Underlying mechanisms have been explored in a ratmodel where cerebral blood flow as measured by injectionand recovery ofmicrospheres from the brain tissuewas foundto be reduced in pneumococcal meningitis The cerebralblood flow could be restored by the endothelin-1 antagonistbosentan with a reduction in cortical cerebral injury [15]Strong evidence of a protective role of nitric oxide againstvasospasm in bacterial meningitis was derived from ananimal model of neonatal meningitis where inhibition ofNO synthase worsened outcome in some models of bacterialmeningitis leading to local cerebral ischaemia [16]
32 Cerebral Malaria There is accumulating evidence fordisseminated vasospasm triggered by inflammatory medi-ators produced locally in the vascular bed in response tothe sequestered infected red blood cells in cerebral malaria(CM) Reversible vasospasm could explain the rapid onsetbut also often rapid and complete resolution of symptoms ofCM Vascular obstruction by clumps of infected blood cellsplatelets and uninfected red blood cells tightly adhering toendothelium is less likely to be rapidly reversible withoutleaving irreversible neurological damage which occurs in aminority of patients with CM
In a seminal study of the morphology of arterioles in thebrain of patients who died of cerebral malaria Polder et aldemonstrated as early as 1990 that there is evidence of spasticcontraction of arterioles with folding of the whole vessel walland of the astrocytic plasma membrane and glial basementmembrane with total occlusion of the lumen [17] There waslight microscopic interruption of the flow at the arterio-lar level resulting in irregular perfusion of the capillariesNumerous cerebral capillaries were entirely empty Recent invivo studies on retinas in 34 patients with CM by fluoresceinangiography showed the abrupt pruning of larger arterioleswith normal perfusion right up to the point of nonperfusionsuggesting an arterial vasospasm Normal angiograms in sixpatients including two with neurological sequelae indicateda lack of longstanding vasoocclusion This observation wascompatible with a transient vasospasm [18] Evidence for atemporary vasoocclusion as seen in a vasospasm was also the
International Journal of Inflammation 3
macular retinal whitening which occurredwithoutmatchingzones of capillary nonperfusion at the time of the angiogramin 734 patients including four for whom the angiogram wasdelayed gt24 hours after admission
Therewas no evidence for a reduced global cerebral bloodflow on extracranial basal artery Doppler measurementsHigh CBFVwas recorded in 30 of children with CMduringadmission [19] This suggested that ischemic events hadpassed by the time the angiography was performed as wouldbe seen in a transient vasospasm In CM cerebral arteriolarvasospasmmay be mediated by tumor necrosis factor (TNF)The degree of TNF elevation in the cerebrospinal fluid ofchildren with CM has been associated with risk of neurologicdeficits [20] Gambian children homozygote for the TNF2allele a variant of the TNF-alpha gene promoter region has arelative risk of 7 for death or severe neurological sequelae dueto CM [21] A subsequent study confirmed the association ofthe TNF-308 A allele of the TNF promoter with CM [22]Release of TNFmay be triggered by the local deposition of IgEcontaining immune complexes (IC) through cross-linkingof CD23 on monocytesmacrophages in cerebral capillaries[23]
Increased levels of serum ICrsquos have previously beenassociated with vasospasm in subarachnoid haemorrhages[24] IC levels are increased in CM and this may be related toreduced clearance because of interleukin-4 mediated down-regulation of Fc-receptors [25] An erythrocyte complementreceptor type 1 (E-CR1) promoter allele associated withhigher E-CR1 expression and hence enhanced clearance ofICrsquos conferred protection against CM [26]
An interesting recent study found evidence of cerebralarteriolar vasospasm in the murine Plasmodium bergheiANKAmodel of CMwith retinal features of vascular collapsevery similar to the angiographic findings in humanswithCMThe researchers increased survival of mice with CM by useof nimodipine a blocker of the vasoconstriction mediatingL-type voltage-gated calcium channel which is used toprevent and treat vasospasm associated with perivascularinflammation in subarachnoid haemorrhage [27] Furthersupport for a role of cerebral arteriolar vasospasm in CM isprovided by the fact that in murine and human CM there isa low bioavailability of nitric oxide which is an importantvasodilator [28]
Haemolysis inmalaria also leads to consumption of nitricoxide which is bound to free haemoglobin and haemolysisreleases erythrocyte arginase an enzyme that metabolizesarginine This reduces the amount of arginine available forproduction of NO [29] Investigation of the association ofthe single nucleotide polymorphism in the neuronal nitricoxide synthase (nNOS) gene with cerebral malaria revealedthat the polymorphism associated with low basal transcrip-tional activity (-84 G- -rarrA and 276C- -rarrT) was associatedwith an increased risk of cerebral malaria [30] The singlenucleotide polymorphism -1173C-rarrT in the nitric oxidesynthase 2 promoter was associated with increased fastingurine and plasma nitric oxide metabolite concentrationsin Tanzanian children and was associated with protectionagainst cerebral malaria [31] In the P berghei ANKAmurinemodel NO supplementation in the form of a NO donor
prevented vasoconstriction and improved blood flow in pialvessels [32] Nitric oxide production is partially downreg-ulated by IL-12 and polymorphisms in the gene encodingthe IL-12 p40 subunit associated with increased IL-12 levelsled in homozygous form to decreased production of nitricoxide and increased mortality in Tanzanian children withCM but not with severe anaemia in Kenyan children [33]High levels of erythropoietin which has been shown toupregulate endothelial nitric oxide synthase were associatedwith protection against neurological sequelae in Africanchildren with CM [34]
33 Neurocysticercosis Infection of the central nervous sys-tem with the larval stage of Taenia solium (neurocysticerco-sis) is the most common helminthic infection of the CNSand a cause of stroke in areas where cysticercosis is endemicOver 50 of patients with subarachnoid involvement havehereby features of vasculitis Antiparasitic treatment has beenassociated with enhanced subarachnoid inflammation anddelayed cerebral infarcts The focal cerebral lesions found inthe absence of changes on conventional angiograms and withnormal transcranial Doppler ultrasound point to vasospasmin their aetiology [35]
4 Brain Injury
Evidence of traumatic cerebral vasospasm (TCV) has beendetected in military personnel with blast injuries to the headPatients with TCV were also likely to have an intracranialbleed traumatic aneurysm or significant cerebral lobarinjury As indicator of cerebral vasospasm they had elevatedcerebral blood flow velocities for approximately 14 days in onestudy and TCV was associated with increased mortality [36]
A link between inflammation and TCV provided a studyinvestigating risk factors for cerebral vasospasm in 46 adultsand children with TCV fever on admission was an indepen-dently strongly predictive risk factor for the development ofTCV (OR 222 95 CI 19 to 2568) Importantly patientswith hypothermia on admission did not develop TCV [37]Underlying mechanisms were explored in the newbornand juvenile pig model of brain injury which showed thatcerebrospinal fluid concentration of ET-1 was increased andNMDA receptor mediated vasodilation decreased and moreso in the immature brain [38] In humans investigatorsobserved that the loss of nitric oxide bioavailability anddecreased sensitivity to NO after traumatic brain injurywere found to be contributory to impaired cerebral vascularautoregulation
5 Subarachnoid Haemorrhage
Since the demonstration of arterial narrowing in the syn-drome of cerebral vasospasm of subarachnoid haemorrhage(SAH) in 1951 and the further emphasis in 1978 byWeir et alit has been proven that SAH gives rise to arterial narrowingand in turn ischaemia causing infarction and poor outcomeMost research into delayed deterioration after SAH has been
4 International Journal of Inflammation
conducted in concordance with this axiom with the goal ofinterrupting this perceived chain of events [39]
Autopsy studies in nonoperated SAH patients reportedthat 80 of fatal cases showed widely scattered trian-gular round or laminar ischemic lesions in the cortexAn ongoing clinical multicenter study reported that in 18post-SAH patients the occurrence of spreading depolar-ization with cortical spreading ischaemia was associatedwith delayed infarcts in brain computed tomography andmagnetic resonance imaging These findings indicate a newSAH-related mechanism of acute brain injury involving therelease of oxyhaemoglobin and ET-1 and NO deprivationall of which are found in SAH and can cause corticalspreading depression and ischaemia in experimental models[40] Endothelium-dependent dilation hereby seems to bereduced partly because of reduced expression of guanylatecyclase [41] Experimentally neurogenic and endothelium-dependent vasodilatation have been shown to be alteredby the presence of haemoglobin (Hb) in the bath [42] Amore complete review of this mechanism can be foundelsewhere [43] Cerebral vasomotor disturbances have beendemonstrated in humans after SAH inmeasurements of cere-bral blood flow by 133-xenon tomography One of the mostimportant functional consequences of SAH is the relativeloss of cerebrovascular dilatory capacity after acetazolamideinjection [44]The sources of NO in the cerebral arteries [45]are such that it has been supposed that Hb scavenging of NOcould induce vasospasm (VS) The prolonged presence of aperivascular clot seems necessary to maintain VS since clotremoval up to 3 days after haemorrhage reduces VS but after5 days it has little influence [46]
Prostaglandin E2 (PGE2) is the eicosanoid moleculepresent in the highest concentration in the CSF after SAHThe concentration increases by more than 25 times soonafter the haemorrhage and remains high for several days[47] This rise probably explains the fever usually found inSAH The production of PGE2 is induced by cyclooxygenase2 induction by inflammatory mediators including TNF inplatelets and microvessel endothelial cells [48 49] There isevidence of early increased TNF-concentration in the CSF ofpatients with SAH [47 50] PGE2 has been shown to inducecontraction in large cerebral arteries [51]
6 The Role of Inflammatory Mediators inGeneration of Vasospasm
The Interaction of Inflammatory Mediators with CerebralVasculature To enable an understanding of the pathomech-anisms involved in inflammation related cerebral vasospasmand resulting brain ischaemia it is important to analyse theinteraction of inflammatory mediators with each other andthe cerebral vasculature Amediator whichwas found to be ofkey importance in reduction of the risk of cerebral vasospasmin bacterial meningitis cerebral malaria brain injury andsubarachnoid haemorrhage is nitric oxide (NO)
NO can be inactivated by reaction with the superoxideanion resulting in the formation of peroxynitrite Inactivationof NO by superoxide anion may contribute to impaired
NO-mediated dilatation of cerebral blood vessels underconditions inwhich reactive oxygen species are produced likebrain injury and meningitis
Production of superoxide anions has also been reportedto occur in brain in response to seizures fluid-percussioninjury perivascular blood and ischaemia with reperfusionEndothelial NO synthase is downregulated by TNF and NOby a negative-feedback mechanism [52 53] In addition toinflammatory mediators sensory fibres originating in thetrigeminal ganglion modulate constrictor responses in thecerebral microcirculation in conditions like meningitis [7]
The most important factor leading to vasoconstrictionin cerebral blood vessels is ET-1 a 21 amino acid peptidewith three isopeptides produced by separate genes Only ET-1 is produced in cerebral endothelium and mediates cerebralvasoconstriction via endothelin-A (ETA) receptors ETA islocalized in vascular smooth muscle cells and stimulationleads to increase in intracellular calcium concentrationsleading to vasoconstriction ET-1 expression is enhanced bytransforming growth factor-beta haemoglobin interleukin-1 and TNF and can be inhibited by NO nitric oxide donordrugs and dilator prostanoids via an increase in cellularcGMP and natriuretic peptides via an increase in cAMPlevels NO can produce relaxation of some blood vessels fromsome species via activation of potassium channels [7]
Cerebral blood vessels can produce 20-hydroxyeicosate-traenoic acid from arachidonic acid via a P-450 enzymeThissubstance is a potent vasoconstrictor whichmay produce thiseffect by inhibition of activity of potassium channels [7]
A further potential mechanism involved in cerebralvasospasm in cerebral inflammation is inhibition of potas-sium channels Nicorandil which produces relaxation ofcerebral vessels by activation of potassium channels partiallyreverses vasospasm in an experimental model of subarach-noid haemorrhage
The effectiveness of other synthetic activators of potas-sium channels like aprikalim and cromakalim and CGRPindicate that activators of potassium channels in vascularmuscle may help in cerebral vasospasm in cerebral inflam-mation [7]
The etiological role of specific cytokines in vasospasm inbacterial meningitis in vivo was highlighted by a study whichdocumented a significant increase in IL-1-beta and IL-6 con-centrations in patients with elevated cerebrovascular bloodflow indicative of vasospasm in humans [14 54] A similareffect on vasospasm of IL-1 and IL-6 was suggested by a studyof cerebral blood flow in subarachnoid haemorrhage whereincreased cerebral blood flow velocities were associated withsignificantly increased CSF concentrations of IL-1 IL-6 andTNF High concentrations of these immunomediators incerebrospinal fluid (CSF) may exert vasoactive effects forexample IL-1 (MW 17 000Da) or IL-6 (MW 26 000Da)could easily get access to the walls of contiguous basalarteries from their adventitial side as even larger molecules(eg horseradish peroxidase MW 40 000Da) pass from thecisternamagna through the vessel wall to the basalmembranewithin minutes This is possible because by contrast withother arteries the surface of the major cerebral arteries is not
International Journal of Inflammation 5
confined by collagen or fibroblasts but is in direct contactwiththe CSF
An investigation in patients with SAH showed that levelsof IL-1-beta but not TNF-alpha were increased and correlatedwith the later development of vasospasm IL-1 acts throughG-protein coupled receptors in three ways which causecontraction of vascular smooth muscle (see Figure 1)
(1) Activation of phospholipase C generated phosphat-idylinositol trisphosphate causes calcium releasewhich leads to myosin light chain kinase activationleading to myosin light chain activation and calciumdependent vasospasm Phosphorylation of myosinlight chain (MLC) by MLC kinase is one of themost important steps for vascular smooth musclecontraction
(2) Activation of protein kinase C (PKC) through phos-pholipase C generated diacylglycerol (from phos-phatidylinositol (45) bisphosphate) can act throughphosphorylation and hence activation of the myosinlight chain kinase Prolonged contraction in cerebralvasospasm for up to two weeks can be mediated bythis mechanism
(3) PKC activation regulates MLC phosphorylation thro-ugh activation of rho-kinase and the myosin-bindingsubunit (MBS) of MLC phosphatase (MLCPh) Rho-kinase hereby phosphorylates MBS which results inthe inhibition of MLCPh [55] The reduced MLCPhactivity leads to increased phosphorylation and hencecontractility of the MLC resulting in calcium inde-pendent vasospasm Investigations in a porcinemodelrevealed that hydroxyfasudil a specific rho-kinaseinhibitor exerted an inhibitory effect on vasospasmboth in vitro and in vivo Western blot analysisshowed that during serotonin-induced contractionsthe extent of phosphorylation of the MBS was sig-nificantly greater in the spastic than in the controlsegment There was a highly significant correlationbetween the extent of MBS phosphorylation andcontractions [55]
Another key mechanism whereby IL-1 mediates vasosp-asm may be through platelet derived growth factor Thereceptors for this growth factor are also known to havetyrosine kinase activity and inhibition of tyrosine kinase isknown to reduce vasospasm in a swine model [56 57] Thisaction influences vascular reactivity to different agonists andmight be crucial for the regulation of cerebral artery toneduring vasospasm [58]
Calcium independent vasospasm may also be inducibleby haemoglobin released in trauma or subarachnoid haem-orrhage
Haemoglobin might cause contraction of major cerebralarteries by scavenging nitric oxide reducing neuronal nitricoxide synthase (NOS) in the adventitia of the cerebral arter-ies and evoking dysfunction of endothelial NO synthase Adecrease in nitric oxide availability might produce prolongedpathological contraction regardless of the concentration ofintracellular calcium Much of the work investigating the
genetic predisposition to cerebral vasospasm focused on theendothelial isoform of nitric oxide synthase Hemoglobinalso stimulates the production of endothelins and the imbal-ance of nitric oxide and endothelin could be an importantcause of pathological arterial contraction In gene transferexperiments eNOS overexpression in animal and humanintracranial arteries is vasoprotective after aneurysmal SAH[59] Several investigations confirmed the association of theT-786C genotype of eNOS with vasospasm For a summaryof key mediators in cerebral vasospasm their function anddisease studied see Table 1
7 Therapeutic Approaches toPrevention and Correction of VasospasmAssociated with Cerebral InflammationTested in Clinical Trials in Humans
The most extensive experience with treatment approachesto vasospasm in cerebral inflammation has been gatheredin the context of management of SAH Clinical trials inhumans have been reported for endothelin-1 antagonists cal-cium channel blockers including the cisternal placement ofcontrolled-release nicardipine intravenous magnesium sul-phate oral statins rho-kinase inhibitors tissue plasminogenactivator tirilazad erythropoietin and methylprednisoloneThe evidence from controlled trials has been summarized inTable 2
71 Endothelin-1A Receptor Antagonists The selective endo-thelin-1A receptor antagonist clazosentan was assessed ina randomized placebo controlled trial (CONSCIOUS-1)and led to a significant reduction of angiographic cerebralvasospasm in SAH but without reduction in the numberof cerebral ischaemia events Subsequent phase II trials(CONSCIOUS-2 and CONSCIOUS-3) in SAH did notdemonstrate any effect on morbidity or mortality A meta-analysis of 4 RCTswith 2024 participants confirmed this find-ing but showed a reduction in delayed ischemic neurologicaldeficit with the endothelin-1A receptor antagonist [67]
72 Calcium Channel Blockers Calcium antagonists have thepotential to prevent the occurrence of calcium dependentvasospasm and delayed ischemic neurological deficit byreducing calcium release (see Figure 1) They have beenapplied directly to the subarachnoid space [74] Intraopera-tive implantation of nicardipine prolonged-release implantsso-called pellets into the basal cistern in close contact to theproximal cerebral vasculature has been reported to reducethe occurrence of cerebral vasospasm and cerebral infarctionand lead to an improvement in clinical outcome in SAH [75]Themagnesium ion is an antagonistic competitor for calciumbinding sites thus having the potential to reduce calciumdependent vasospasm and has been used in the form ofintravenous magnesium sulphate in a number of trials (seeTable 2)
6 International Journal of Inflammation
GPCR
Macrophage
Interleukin-1
Lipopolysaccharide
Plasmodium falciparum antigens
Stimulation of interleukin-1 release
MLCK
PKC
MLCMLCK-P
Rho-kinase MBSMBS-P
MLCPh
Intracellular autoantigens (fromtissue injury)
PLC ≫ IP3 ≫ calcium releaseminusRho-kinase-P
Figure 1 Mechanism for induction of cerebral vasospasm by interleukin-1 (GPCR = G-protein coupled receptor PKC = protein kinase CMLCK = myosin light chain kinase MLC = myosin light chain MBS = myosin-binding subunit of myosin light chain phosphatase MLCPh=myosin light chain phosphatase -P indicates phosphorylated state PLC = phospholipase C and IP3 = phosphatidylinositol trisphosphate)
Table 1 Inflammatory mediators and their role in cerebral vasospasm
Mediator Function of mediator Disease model where role hasbeen established References
(i) Nitric oxide(i) Vasodilator(ii) Inhibitor of endothelin-1expression
(i) Cerebral malaria(ii) Bacterial meningitis(iii) Subarachnoid haemorrhage
[1 7 16 28 32 41 45]
(i) Endothelin-1 (i) Vasoconstrictor (i) Bacterial meningitis(ii) Subarachnoid haemorrhage [7 15]
(i) Interleukin-1(ii) Interferon gamma(iii) Tumor necrosis factor
(i) Activators of protein kinase C(ii) Stimulators of release ofendothelin-1
(i) Bacterial meningitis(ii) Cerebral malaria(iii) Subarachnoid haemorrhage
[7 14 56]
73 Tissue Plasminogen Activator A recent meta-analysis offive randomized controlled trials (465 patients) of tissue plas-minogen activator (tPA) or urokinase applied intrathecallyreduced development of poor outcome and delayed cerebralischaemia and vasospasm [70]Themechanism proposed forthis effect is probably not related to thrombolysis but to adirect effect of tPA on vascular tone It is clear that the effectof tPA is endothelial cell dependent and more specificallyNO synthase dependent tPA seems to bind to a receptorpresent in endothelial cells that mediates the stimulation ofNO synthase activity and thus inhibits the vasoconstrictiveeffect of phenylephrine [76]
74 Statins Statins can reduce vasospasm by upregulatingendothelial NO synthase expression A threefold increasein endothelial NO synthase mRNA protein and enzymatic
activity has been demonstrated following statin treatmentresulting in an increase in cerebral blood flow Statintreatment has attenuated cerebral vasospasm and preventeddelayed ischemic deficits in amurine SAHmodel [77] A pre-vious systematic review of 4 studies with a total of 190 patientsshowed no statistically significant effect on vasospasm ontranscranial Doppler studies delayed cerebral ischaemia ormortality [78] but a more recent review demonstrated areduction in mortality and delayed ischemic neurologicaldeficits [66]
75 Rho-Kinase Inhibitor The specific rho-kinase inhibitorfasudil hydrochloride was in a recent systematic review of8 studies (843 patients) shown to reduce the occurrenceof cerebral vasospasm and cerebral infarction significantlyand led to an improvement in clinical outcome [71] The
International Journal of Inflammation 7
Table2Medicationfortreatmento
fcerebralvasospasm
the
evidence
from
controlledtrialsin
humans
Interventio
nTy
peof
study
Patholog
yRe
sultsodd
sratio
(OR)
orrelativer
isk(RR)
foro
ccurrencein
interventio
ngrou
pcomparedto
grou
pwith
outintervention
Reference
Calcium
channel
blockers
Syste
maticreview
(SR)
(sixrand
omized
controlledtrials
(RCT
s))
Acuteb
rain
injury
DeathO
R091
[95
070ndash117
]Death
andsevere
disabilityOR085
[95
068
to10
7]In
thes
ubgrou
pof
traumaticsubarachno
idhaem
orrhagep
atients
pooled
odds
ratio
was
059
[95
CI037ndash0
94]three
RCTs
repo
rtingdeathandsevere
disabilityas
anou
tcom
einthis
subgroup
OR067
[95
CI046
ndash098]
[60]
Calcium
channel
blockers
SR(16RC
Ts)
Aneurysmal
subarachno
idhaem
orrhage(aSAH)
Overallcalcium
antagonists
redu
cedther
iskof
poor
outcom
ethe
relativer
isk(RR)
was
081
[95
CI072
to092]thec
orrespon
ding
numbero
fpatientsn
eededto
treatwas
19[95
CI1to51]foro
ral
nimod
ipinea
lone
theR
Rwas
067
[95
CI055
to081]foro
ther
calcium
antagonists
orintravenou
sadm
inistratio
nof
nimod
ipine
ther
esultsweren
otsta
tistic
allysig
nificantcalcium
antagonists
redu
cedtheo
ccurrenceo
fsecon
dary
ischaem
iaandshow
eda
favourabletre
ndforc
asefatality
for
magnesiu
minadditio
nto
standard
treatmentw
ithnimod
ipinetheR
Rwas
075
[95
CI057
to10
0]fora
poor
outcom
eand
066
[95
CI045
to096]for
clinicalsigns
ofsecond
aryisc
haem
ia
[61]
Nicardipine
SR(five
controlled
trials)
aSAH
Risk
ofpo
orou
tcom
e(deathvegetativ
estateord
ependency)
OR
058
(95
CI037ndash0
9)
Mortalityod
dsratio
045[95
CI015
to12
9][62]
Magnesiu
msulfate
Prospective
rand
omise
dstu
dyEclampsia
Sign
ificant
redu
ctionof
pulsa
tility
index(119875=0002)a
ndmeanflo
wvelocityin
middlec
erebralartery(119875=002)
[63]
Prop
hylactic
magnesiu
msulfate
SRof
tenrand
omized
parallelgroup
controlledtrials
aSAH
Glasgow
outcom
escaleandmod
ified
Rank
inscaleR
R093
(95
CI082
to10
6)m
ortality095
(95
CI076ndash117
)delay
edcerebral
ischaem
iaRR
054(95
CI038
to075)delay
edisc
hemic
neurologicaldeficit(D
IND)RR
of093
[95
CI062ndash139
]transcranialDop
pler
vasospasmR
R072
[95
CI051ndash103]
[64]
Indu
ced
hyperm
agnesaem
iaRC
TaSAH
Vasospasm
ondigitalsub
tractio
nangiograph
yOR
051[95CI
026
to10
2]neurologicalrecoveryORforw
orse
outcom
e071
[95
CI039
to13
2][65]
Statins
SR(sixRC
Ts)
aSAH
Incidenceo
fvasospasm
RR080[95
CI054ndash
117]poo
rneurologicalou
tcom
eRR
094[95
CI077to
116]
MortalityRR
030[95
CI014
ndash064]
DIN
DR
R058
[95
CI037
ndash092]
[66]
Endo
thelin
receptor
antagonists
SR(fo
urRC
Ts)
aSAH
Incidenceo
fDIN
Drela
tiver
isk08[95
CI067ndash0
95]
angiograph
icvasospasm
RR062[95CI
052
to072]
unfavourableou
tcom
eRR
087[95
CI074ndash102]m
ortalityRR
105[95
CI077
to14
5]
[67]
8 International Journal of Inflammation
Table2Con
tinued
Interventio
nTy
peof
study
Patholog
yRe
sultsodd
sratio
(OR)
orrelativer
isk(RR)
foro
ccurrencein
interventio
ngrou
pcomparedto
grou
pwith
outintervention
Reference
Endo
thelin-1Areceptor
antagonistClazosentan
SR(fo
urRC
Ts)
aSAH
Relativer
iskforincidence
ofDIN
Ds076
(95
CI062ndash0
92)
delay
edcerebralinfarctio
n079
[95
CI063ndash100]G
lasgow
outcom
escaleextend
edRR
112
[95
CI096ndash130]m
ortalityRR
10
2[95
CI070ndash149]
[68]
Intravenou
smethylpredn
isolone
RCT
aSAH
Symptom
aticvasospasm
265in
interventio
ngrou
pcompared
with
26in
placebogrou
pfunctio
naloutcomes
caleredu
cedin
the
methylpredn
isolone
grou
pwith
riskdifference193
[95
CI05ndash379]ou
tcom
epoo
rin15of
patie
ntsinthe
methylpredn
isolone
grou
pversus
34in
thep
lacebo
grou
p
[69]
Tissue
plasminogen
activ
ator
SR(five
RCTs)
aSAH
Overalluseo
fintrathecalthrombo
lytic
swas
associated
with
significantreductio
nsin
thed
evelo
pmento
fpoo
routcomes
(OR
052034ndash
078119875lt001)DIN
Ds(OR054034ndash
087119875=001)
andangiograph
icvasospasm
(OR032015
ndash070119875lt001)
[70]
Rho-kinase
inhibitor
SR(8
controlledtrials)
aSAH
Absenceo
fsym
ptom
aticvasospasmoccurrenceo
flow
density
areas
associated
with
vasospasm
onCT
and
occurrence
ofadversee
vents
weres
imilarb
etweenthetwogrou
psthe
clinicaloutcomes
were
morefavorablein
thefasud
ilgrou
pthan
inthen
imod
ipineg
roup
(119875=004)
[71]
Tirilazad
SR(five
RCTs)
aSAH
Therew
asno
significantd
ifference
betweenthetwogrou
psatthe
endof
follo
w-upforthe
prim
aryou
tcom
edeathOR
089[95CI
074
to10
6]orinpo
orou
tcom
e(deathvegetativ
estateorsevere
disability)
OR10
4[95
CI090
to12
1]few
erpatie
ntsd
evelop
eddelay
edcerebralisc
haem
iain
thetirilazadgrou
pthan
inthec
ontro
lgrou
pOR080
[95
CI069
to093]subgroup
analyses
didno
tdemon
stratea
nysig
nificantd
ifference
ineffectsof
tirilazadon
clinicaloutcomes
[72]
Erythrop
oietin
RCT
aSAH
Nodifferences
wered
emon
strated
intheincidence
ofvasospasm
andadversee
ventspatie
ntsreceiving
EPOhadad
ecreased
incidenceo
fseverev
asospasm
from
275to
75(119875=0037)
redu
cedDID
swith
newcerebralinfarctsfro
m40
0to
75
(119875=0001)as
hortened
duratio
nof
impaire
dautoregu
latio
n(ip
silateralsid
e119875lt0001)andmorefavorableou
tcom
eat
discharge(favorableG
lasgow
outcom
escalescore119875=0039)
amon
gthe7
1survivorsthe
EPOgrou
phadfewer
deficits
measured
with
NationalInstitutes
ofHealth
Stroke
Scale(medianscore2
versus
6119875=0008)
[73]
International Journal of Inflammation 9
mechanism is apart from a contribution to inhibition ofcalcium independent vasospasm (see above) probably alsoan increase of endothelial nitric oxide synthase (eNOS)expression by stabilizing eNOSmRNA which can contributeto an increase of NO level to enhance vasodilatation
76 Other Treatments Steroid treatment can inhibit cytokineexpression and has thus the potential to reduce cytokinemediated calcium dependent and independent vasospasmIn tuberculous meningitis adjuvant treatment with corticos-teroids has been indirectly associatedwith features of reducedvasculopathy which may include vasospasm
A large randomised controlled trial showed improvedmortality in tuberculous meningitis with adjuvant corti-costeroids but did not show a reduction in severe disabil-ity however an observational MRI study did suggest areduction in strokes in patients treated with corticosteroids[79 80] An open-label study of aspirin in the preventionof stroke and mortality in tuberculous meningitis found anonsignificant reduction in stroke and a significant reductionin mortality with a possible synergism with corticosteroids[81] Mechanisms responsible for a potential effect may bea reduction of the vasoconstricting effect of PGE2 The 21-aminosteroid tirilazad is a lipid peroxidation inhibitor whichinhibits free radical-induced lipid peroxidation (LP) by acombination of lipid peroxide scavenging and a membrane-stabilizing action that limits the propagation of LP reactionsbetween a lipid peroxide and an adjacent polyunsaturatedfatty acid There has been no consistent evidence of benefitin animal or human studies Erythropoietin may act throughincrease in expression of endothelial nitric oxide synthasethus increasing NO bioavailability
8 Conclusions and Perspectives forFuture Developments
There is evidence for common pathways leading tovasospasm in all forms of cerebral inflammation involvinginterleukin-1 tumor necrosis factor endothelin-1 andnitric oxide Treatments addressing the pathophysiologyof vasospasm in one form of cerebral inflammation maytherefore apply to all others Treatment of cerebral vasospasmhas been mainly investigated in aneurysmal SAH Agentsfor which there is likely to be clinical benefit are calciumantagonists statins and intrathecal plasminogen activators(see Table 2) The fact that there is calcium dependent andindependent vasospasm in inflammation (see Figure 1)shows that a combination of calcium antagonists with agentsinterfering with calcium independent vasospasm includingagents improving the bioavailability of nitric oxide is theway forward Future trials need to investigate their effectsin patients with all forms of cerebral inflammation leadingto neurological deficits attributable to vasospasm In vivocorrelates for reduction of vasospasm in the peripheralcirculation could be explored as a surrogate for reduction ofvasospasm in the cerebral (micro) vasculature
Strategies to improve microvascular recruitment whichhave been explored in models of septicaemia could poten-tially be applied to cerebral vasospasm Distributive shockwhich occurs during sepsis and septic shock is associatedwith an abnormal distribution of microvascular blood flowVasospasm of part of the arterioles supplying the capillary isa mechanism involved in this maldistribution The clinicalintroduction of new microcirculatory imaging techniquessuch as orthogonal polarization spectral and side-streamdark-field imaging (OPSSDF) has allowed direct obser-vation of the microcirculation at the bedside Images ofthe sublingual microcirculation during septic shock andresuscitation have revealed that the distributive defect ofblood flow occurs at the capillary level [82]
In rat models of cecal ligation and puncture investiga-tors have used intravital video microscopy to demonstratethat sepsis is characterized by decreased microcirculatoryflow velocity an abundance of stopped-flow microvesselsincreased heterogeneity of microcirculatory flow and lowdensity of perfused capillaries As thesemicrocirculatory flowalterations can occur in the absence of global hemodynamicderangements (eg absence of arterial hypotension) micro-circulatory dysfunction largely reflects intrinsic events occur-ring in the microvessels like localized vasospasm [83] Appli-cation ofmicrocirculatory recruitmentmaneuver procedureshas been shown to be effective in promotingmicrocirculatoryblood flow in clinical studies using OPSSDF imaging [84ndash87] Fluid resuscitation in combination with the nitric oxidedonor nitroglycerine was shown to recruit disturbed micro-circulation following pressure guided resuscitation in septicshock patients
It is important to note that application of colloids inpatients with SAH was associated with worse outcomescompared to matched controls in a subgroup analysis of theCONSCIOUS-1 prospective randomized trial of clazosentanfor the prevention of angiographic vasospasm [88] Futureresearch needs to investigate whether colloids can bind nitricoxide and make this vasodilator less available by binding it
Regarding future therapeutic interventions increasingnitric oxide bioavailability erythropoietin and L-argininewhich increased bioavailability of nitric oxide in patients withmalaria [89] need to be explored as adjunctive treatmentin children with cerebral malaria in randomised controlledtrials In vitro the availability of L-arginine does not appearto be a rate limiting step for the activity of the NO synthasebecause its half-saturating concentration is less than 3of theplasma and endothelial concentration of this substrate
The nitric oxide donor intravenous sodium nitrite hasbeen shown to prevent and reverse cerebrovascular spasmin primates and has been demonstrated to be safe foradministration in humans [90]
Support of pump function by dobutamine therapy hasbeen shown to improvemicrocirculatory flow independent ofimprovement of global hemodynamic parameters [91] Fluidapplication nitric oxide donors and dobutamine therapyneed to be explored in isolation but also as combinationof interventions to improve cerebral perfusion in cerebralinflammation associated with vasospasm
10 International Journal of Inflammation
A potential role of nonsteroidal anti-inflammatory drugswas revealed by landmark experiments on dog basilararteries Arachidonic acid induced sustained contractionsand these responses were markedly inhibited (95) bymeclofenamate and similarly by indomethacin but aspirinhad no such effect [92] In the rabbit basilar artery model ofcerebral vasospasm local intracranial delivery of ibuprofenaccomplished using controlled-release polymers preventedvasospasm when administered within 6 hours but notat either 12 or 24 hours [93] Delivery of ibuprofen viacontrolled-release polymers into the subarachnoid space ofmonkeys with subarachnoid haemorrhage prevented angio-graphic vasospasm after SAH as evident from patency of themiddle cerebral artery [94]
Piroxicam was more effective than the above-mentioneddrugs in the SAH dog model after angiographic analysisand analysis of behavioural changes [95] Early studiesusing prostacyclin found that isolated canine basilar arteriescontraction induced by prostaglandin E2 hemoglobin orserum was relaxed by prostacyclin but not indomethacin[96] In isolated human pial arteries prostacyclin relaxedhuman pial arteries contracted by either PGF2 alpha nora-drenaline serotonin or haemorrhagic CSF [97] In an animalstudy meloxicam reduced ultrastructural and morphometricvasospastic changes in rats with subarachnoid haemorrhage[98] Investigation comparing rate of subsequent permanentdisability from vasospasm and angiographic and delayedcerebral ischaemia in patients with SAH with and withoutaspirin intake found no association with poor outcome [99100]
There are new areas of pathophysiology research wherethe role of vasospasm needs to be explored thoroughly inorder to find avenues for therapeutic interventions Investi-gations could evaluate whether intraventricular haemorrhageoccurring commonly in the neonatal period in pretermneonates is associated with vasospasm increasing mor-bidity Case reports of intraventricular haemorrhage fromAV malformations and aneurysms in adults demonstratedvasospasm [101 102]
Future research needs to explore the usefulness of a num-ber of agents which have been demonstrated to reduce vaso-spasm in animal models including L-citrulline [103] januskinase-2 [104] endothelin converting enzyme inhibitors[105] caspase inhibitor Z-VAD-FMK [106] anti-E selectinmonoclonal antibodies [107] trehalose [108] and curcuminwhich was demonstrated to protect against the developmentof cerebral vasospasm and secondary cerebral infarctionafter subarachnoid haemorrhage in mice by its broad anti-inflammatory activity including limitation of superoxidegeneration and influence on inducible nitric oxide synthaseexpression [109]
Aggressive maintenance of normothermia or mildhypothermia in patients with military blast injury resultedin a dramatic reduction in the incidence of posttraumaticvasospasm from 475 to 5 Future studies need to confirmthis finding and investigate whether hypothermia can reducecerebral inflammation related ischemic damage to the brainin other conditions like bacterial meningitis or cerebralmalaria [37]
Conflict of Interests
The author declares that there is no conflict of interestsregarding the publication of this paper
References
[1] B Weir ldquoThe pathophysiology of cerebral vasospasmrdquo BritishJournal of Neurosurgery vol 9 no 3 pp 375ndash390 1995
[2] H Bode and A Harders ldquoTransient stenoses and occlusionsof main cerebral arteries in childrenmdashdiagnosis and control oftherapy by transcranial Doppler sonographyrdquo European Journalof Pediatrics vol 148 no 5 pp 406ndash411 1989
[3] K-F Lindegaard H Nornes S J Bakke W Sorteberg and PNakstad ldquoCerebral vasospasm diagnosis by means of angiogra-phy and blood velocity measurementsrdquo Acta Neurochirurgicavol 100 no 1-2 pp 12ndash24 1989
[4] C Lysakowski B Walder M C Costanza and M R TramerldquoTranscranial Doppler versus angiography in patients withvasospasm due to a ruptured cerebral aneurysm a systematicreviewrdquo Stroke vol 32 no 10 pp 2292ndash2298 2001
[5] R L Grubb Jr M E Raichle J O Eichling and M HGado ldquoEffects of subarachnoid hemorrhage on cerebral bloodvolume blood flow and oxygen utilization in humansrdquo Journalof Neurosurgery vol 46 no 4 pp 446ndash452 1977
[6] C-H Lu H-W Chang C-C Lui C-R Huang and W-NChang ldquoCerebral haemodynamics in acute bacterial meningitisin adultsrdquoQuaterly Journal of Medicine vol 99 no 12 pp 863ndash869 2006
[7] F Faraci and D D Heistad ldquoRegulation of the cerebralcirculation role of endothelium and potassium channelsrdquoPhysiological Reviews vol 78 no 1 pp 53ndash97 1998
[8] L Hektoen ldquoThe vascular changes in tuberculous meningitisespecially in tuberculous endarteritisrdquo Journal of ExperimentalMedicine vol 1 pp 112ndash163 1896
[9] G Thwaites ldquoTuberculosis of the central nervous systemrdquo inClinical Tuberculosis P D O Davies S B Gordon and GDavies Eds pp 151ndash165 CRC Press 5th edition 2014
[10] P M Dalal ldquoObservations on the involvement of cerebral ves-sels in tuberculousmeningitis in adultsrdquoAdvances in Neurologyvol 25 pp 149ndash159 1979
[11] L A Rojas-Echeverri J L Soto-Hernandez S Garza et alldquoPredictive value of digital subtraction angiography in patientswith tuberculous meningitisrdquo Neuroradiology vol 38 no 1 pp20ndash24 1996
[12] E L Lyons and N E Leeds ldquoThe angiographic demonstrationof arterial vascular disease in purulent meningitis report of acaserdquo Radiology vol 88 no 5 pp 935ndash938 1967
[13] S Ries U Schminke K Fassbender M Daffertshofer WSteinke andMHennerici ldquoCerebrovascular involvement in theacute phase of bacterial meningitisrdquo Journal of Neurology vol244 no 1 pp 51ndash55 1997
[14] K Fassbender S Ries U Schminke S Schneider and M Hen-nerici ldquoInflammatory cytokines in CSF in bacterial meningitisassociation with altered blood flow velocities in basal cerebralarteriesrdquo Journal of Neurology Neurosurgery amp Psychiatry vol61 no 1 pp 57ndash61 1996
[15] L A Pfister J H Tureen S Shaw et al ldquoEndothelin inhibitionimproves cerebral blood flow and is neuroprotective in pneu-mococcal meningitisrdquoAnnals of Neurology vol 47 pp 329ndash3352000
International Journal of Inflammation 11
[16] S L Leib Y S Kim S M Black J H Tureen and M GTauber ldquoInducible nitric oxide synthase and the effect of amin-oguanidine in experimental neonatal meningitisrdquo The Journalof Infectious Diseases vol 177 no 3 pp 692ndash700 1998
[17] T W Polder C R Jerusalem andW M C Eling ldquoMorpholog-ical characteristics of intracerebral arterioles in clinical (Plas-modium falciparum) and experimental (Plasmodium berghei)cerebral malariardquo Journal of the Neurological Sciences vol 101no 1 pp 35ndash46 1991
[18] N A V Beare S P Harding T E Taylor S Lewallen and MEMolyneux ldquoPerfusion abnormalities in childrenwith cerebralmalaria andmalarial retinopathyrdquo Journal of Infectious Diseasesvol 199 no 2 pp 263ndash271 2009
[19] C R J C Newton K Marsh N Peshu and F J KirkhamldquoPerturbations of cerebral hemodynamics in Kenyans withcerebral malariardquo Pediatric Neurology vol 15 no 1 pp 41ndash491996
[20] C C John A Panoskaltsis-Mortari R O Opoka et alldquoCerebrospinal fluid cytokine levels and cognitive impairmentin cerebral malariardquo American Journal of Tropical Medicine andHygiene vol 78 no 2 pp 198ndash205 2008
[21] W McGuire A V S Hill C E M Allsopp B M Greenwoodand D Kwiatkowski ldquoVariation in the TNF-120572 promoter regionassociated with susceptibility to cerebral malariardquo Nature vol371 no 6497 pp 508ndash510 1994
[22] W McGuire J C Knight A V S Hill C E M Allsopp B MGreenwood and D Kwiatkowski ldquoSevere malarial anemia andcerebral malaria are associated with different tumor necrosisfactor promoter allelesrdquo Journal of Infectious Diseases vol 179no 1 pp 287ndash290 1999
[23] B Dugas M D Mossalayi C Damais and J-P Kolb ldquoNitricoxide production by human monocytes Evidence for a role ofCD23rdquo Immunology Today vol 16 no 12 pp 574ndash580 1995
[24] L Pellettieri B Nilsson C-A Carlsson andU Nilsson ldquoSerumimmunocomplexes in patients with subarachnoid hemorrhagerdquoNeurosurgery vol 19 no 5 pp 767ndash771 1986
[25] M Eisenhut ldquoCauses of reduced immune complex clearance incerebralmalariardquoParasite Immunology vol 31 no 2 p 59 2009
[26] P Teeranaipong J Ohashi J Patarapotikul et al ldquoA functionalsingle-nucleotide polymorphism in the CR1 promoter regioncontributes to protection against cerebral malariardquo Journal ofInfectious Diseases vol 198 no 12 pp 1880ndash1891 2008
[27] P Cabrales G M Zanini D Meays J A Frangos and LJ M Carvalho ldquoMurine cerebral malaria is associated witha vasospasm-like microcirculatory dysfunction and survivalupon rescue treatment is markedly increased by nimodipinerdquoTheAmerican Journal of Pathology vol 176 no 3 pp 1306ndash13152010
[28] I Gramaglia P Sobolewski D Meays et al ldquoLow nitricoxide bioavailability contributes to the genesis of experimentalcerebral malariardquoNature Medicine vol 12 no 12 pp 1417ndash14222006
[29] T W Yeo D A Lampah E Tjitra et al ldquoRelationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavail-ability and perfusion in severe falciparum malariardquo Journal ofInfectious Diseases vol 200 no 10 pp 1522ndash1529 2009
[30] G Dhangadamajhi B N Mohapatra S K Kar and M RanjitldquoGenetic variation in neuronal nitric oxide synthase (nNOS)gene and susceptibility to cerebral malaria in Indian adultsrdquoInfection Genetics and Evolution vol 9 no 5 pp 908ndash911 2009
[31] M R Hobbs V Udhayakumar M C Levesque et al ldquoAnew NOS2 promoter polymorphism associated with increased
nitric oxide production and protection from severe malaria inTanzanian and Kenyan childrenrdquoThe Lancet vol 360 no 9344pp 1468ndash1475 2002
[32] P Cabrales G M Zanini D Meays J A Frangos and L JM Carvalho ldquoNitric oxide protection against murine cerebralmalaria is associated with improved cerebral microcirculatoryphysiologyrdquo The Journal of Infectious Diseases vol 203 no 10pp 1454ndash1463 2011
[33] G Morahan C S Boutlis D Huang et al ldquoA promoterpolymorphism in the gene encoding interleukin-12 p40 (IL12B)is associated with mortality from cerebral malaria and withreduced nitric oxide productionrdquo Genes amp Immunity vol 3 no7 pp 414ndash418 2002
[34] C Casals-Pascual R Idro N Gicheru et al ldquoHigh levels of ery-thropoietin are associated with protection against neurologicalsequelae in African children with cerebral malariardquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 105 no 7 pp 2634ndash2639 2008
[35] F C Chow C M Marra and T A Cho ldquoCerebrovasculardisease in central nervous system infectionsrdquo Seminars inNeurology vol 31 no 3 pp 286ndash306 2011
[36] R A Armonda R S Bell A H Vo et al ldquoWartime traumaticcerebral vasospasm recent review of combat casualtiesrdquoNeuro-surgery vol 59 no 6 pp 1215ndash1225 2006
[37] K Shahlaie K Keachie I M Hutchins et al ldquoRisk factorsfor posttraumatic vasospasm clinical articlerdquo Journal of Neu-rosurgery vol 115 no 3 pp 602ndash611 2011
[38] Y Udomphorn W M Armstead and M S Vavilala ldquoCerebralblood flow and autoregulation after pediatric traumatic braininjuryrdquo Pediatric Neurology vol 38 no 4 pp 225ndash234 2008
[39] R M Pluta J Hansen-Schwartz J Dreier et al ldquoCerebralvasospasm following subarachnoid hemorrhage time for a newworld of thoughtrdquo Neurological Research vol 31 no 2 pp 151ndash158 2009
[40] J Hansen-Schwartz P Vajkoczy R L Macdonald R MPluta and J H Zhang ldquoCerebral vasospasm looking beyondvasoconstrictionrdquo Trends in Pharmacological Sciences vol 28no 6 pp 252ndash256 2007
[41] H Kasuya B K A Weir M Nakane et al ldquoNitric oxidesynthase and guanylate cyclase levels in canine basilar arteryafter subarachnoid hemorrhagerdquo Journal of Neurosurgery vol82 no 2 pp 250ndash255 1995
[42] M D Linnik and T J F Lee ldquoEffect of hemoglobin on neuro-genic responses and cholinergic parameters in porcine cerebralarteriesrdquo Journal of Cerebral Blood Flow and Metabolism vol 9no 2 pp 219ndash225 1989
[43] CG Sobey and FM Faraci ldquoSubarachnoid haemorrhage whathappens to the cerebral arteriesrdquo Clinical and ExperimentalPharmacology and Physiology vol 25 no 11 pp 867ndash876 1998
[44] Y R T Dinh G Lot R Benrabah O Baroudy J Cophignonand J Seylaz ldquoAbnormal cerebral vasodilation in aneurys-mal subarachnoid hemorrhage use of serial 133Xe cerebralblood flow measurement plus acetazolamide to assess cerebralvasospasmrdquo Journal of Neurosurgery vol 79 no 4 pp 490ndash4931993
[45] T J F Lee ldquoNitric oxide and the cerebral vascular functionrdquoJournal of Biomedical Science vol 7 no 1 pp 16ndash26 2000
[46] M Stoodley R L Macdonald B Weir et al ldquoSubarachnoidhemorrhage as a cause of an adaptive response in cerebralarteriesrdquo Journal of Neurosurgery vol 93 no 3 pp 463ndash4702000
12 International Journal of Inflammation
[47] Y R Tran Dinh A Jomaa J Callebert et al ldquoOverexpressionof cyclooxygenase-2 in rabbit basilar artery endothelial cellsafter subarachnoid hemorrhagerdquo Neurosurgery vol 48 no 3pp 626ndash635 2001
[48] A Gecse B Kis Z Mezei and G Telegdy ldquoEffects of inflam-matory neuropeptides on the arachidonate cascade of plateletsrdquoInternational Archives of Allergy and Immunology vol 118 no2ndash4 pp 166ndash170 1999
[49] K S Mark W J Trickler and D W Miller ldquoTumornecrosis factor-120572 induces cyclooxygenase-2 expression andprostaglandin release in brain microvessel endothelial cellsrdquoJournal of Pharmacology and Experimental Therapeutics vol297 no 3 pp 1051ndash1058 2001
[50] T Tanazawa Y Suzuki M Anzai S Tsugane M Takayasu andM Shibuya ldquoVasodilation by intrathecal lipopolysaccharide ofthe cerebral arteries after subarachnoid haemorrhage in dogsrdquoActa Neurochirurgica vol 138 no 3 pp 330ndash337 1996
[51] N Toda M Kawakami and K Yoshida ldquoConstrictor action ofoxyhemoglobin in monkey and dog basilar arteries in vivo andin vitrordquo American Journal of Physiology Heart and CirculatoryPhysiology vol 260 no 2 pp H420ndashH425 1991
[52] M Yoshizumi M A Perrella J C Burnett Jr and M-E LeeldquoTumor necrosis factor downregulates an endothelial nitricoxide synthase mRNA by shortening its half-liferdquo CirculationResearch vol 73 no 1 pp 205ndash209 1993
[53] A Rengasamy and R A Johns ldquoRegulation of nitric oxidesynthase by nitric oxiderdquo Molecular Pharmacology vol 44 no1 pp 124ndash128 1993
[54] A L de Souza A C P de Oliveira C C Romano J SztajnbokA J S Duarte and A C Seguro ldquoInterleukin-6 activation inischemic stroke caused by Neisseria meningitidis serogroup CrdquoInternational Journal of Cardiology vol 127 no 3 pp e160ndashe1632008
[55] T Kandabashi H Shimokawa K Miyata et al ldquoInhibition ofmyosin phosphatase by upregulated Rho-kinase plays a key rolefor coronary artery spasm in a porcine model with interleukin-1120573rdquo Circulation vol 101 no 11 pp 1319ndash1323 2000
[56] D-H Nam J-S Kim S-C Hong et al ldquoExpression ofinterleukin-1120573 in lipopolysaccharide stimulated monocytesderived from patients with aneurysmal subarachnoid hem-orrhage is correlated with cerebral vasospasmrdquo NeuroscienceLetters vol 312 no 1 pp 41ndash44 2001
[57] A Ito H Shimokawa T Kadokami et al ldquoTyrosine kinaseinhibitor suppresses coronary arteriosclerotic changes andvasospastic responses induced by chronic treatment withinterleukin-1120573 in pigs in vivordquo Journal of Clinical Investigationvol 96 no 3 pp 1288ndash1294 1995
[58] H Yanamoto H Kataoka Y Nakajo and K Iihara ldquoThe roleof the host defense system in the development of cerebralvasospasm analogies between atherosclerosis and subarach-noid hemorrhagerdquo European Neurology vol 68 no 6 pp 329ndash343 2012
[59] A F Ducruet P R Gigante Z L Hickman et al ldquoGeneticdeterminants of cerebral vasospasm delayed cerebral ischemiaand outcome after aneurysmal subarachnoid hemorrhagerdquoJournal of Cerebral Blood Flow amp Metabolism vol 30 no 4 pp676ndash688 2010
[60] J Langham C Goldfrad G Teasdale D Shaw and KRowan ldquoCalcium channel blockers for acute traumatic braininjuryrdquoCochrane Database Systematic Reviews no 4 Article IDCD000565 2000
[61] S M Dorhout Mees G J Rinkel V L Feigin et al ldquoCal-cium antagonists for aneurysmal subarachnoid haemorrhagerdquoCochrane Database of Systematic Reviews no 3 Article IDCD000277 2007
[62] R-Q Huang F-G Jiang Z-M Feng and T-Y WangldquoNicardipine in the treatment of aneurysmal subarachnoidhaemorrhage a meta-analysis of published datardquo Acta Neuro-logica Belgica vol 113 no 1 pp 3ndash6 2013
[63] S Naidu A J Payne J Moodley M Hoffmann and EGouws ldquoRandomised study assessing the effect of phenytoinand magnesium sulphate on maternal cerebral circulationin eclampsia using transcranial Doppler ultrasoundrdquo BritishJournal of Obstetrics amp Gynaecology vol 103 no 2 pp 111ndash1161996
[64] D Reddy A Fallah J-A Petropoulos F Farrokhyar R LMacdonald and D Jichici ldquoProphylactic magnesium sulphatefor aneurysmal subarachnoid haemorrhage a systematic reviewand meta-analysisrdquo Neurocritical Care vol 21 no 2 pp 356ndash364 2014
[65] C M Bradford S Finfer A OrsquoConnor et al ldquoA ran-domised controlled trial of induced hypermagnesaemia follow-ing aneurysmal subarachnoid haemorrhagerdquo Critical Care andResuscitation vol 15 no 2 pp 119ndash125 2013
[66] S-H Su W Xu J Hai Y-F Wu and F Yu ldquoEffects of statins-use for patients with aneurysmal subarachnoid hemorrhagea meta-analysis of randomized controlled trialsrdquo ScientificReports vol 4 article 4573 2014
[67] J Guo Z Shi K Yang J H Tian and L Jiang ldquoEndothelinreceptor antagonists for subarachnoid hemorrhagerdquo CochraneDatabase of Systematic Reviews vol 9 Article ID CD0083542012
[68] J Shen J-W Pan Z-X Fan X-X Xiong and R-Y ZhanldquoDissociation of vasospasm-related morbidity and outcomesin patients with aneurysmal subarachnoid hemorrhage treatedwith clazosentan a meta-analysis of randomized controlledtrials a reviewrdquo Journal of Neurosurgery vol 119 no 1 pp 180ndash189 2013
[69] P Gomis J P Graftieaux R Sercombe D Hettler BScherpereel and P Rousseaux ldquoRandomized double-blindplacebo-controlled pilot trial of high-dose methylprednisolonein aneurysmal subarachnoid hemorrhagerdquo Journal of Neuro-surgery vol 112 no 3 pp 681ndash688 2010
[70] A H Kramer and J J Fletcher ldquoLocally-administered intrathe-cal thrombolytics following aneurysmal subarachnoid hem-orrhage a systematic review and meta-analysisrdquo NeurocriticalCare vol 14 no 3 pp 489ndash499 2011
[71] G J Liu Z J Wang Y F Wang et al ldquoSystematic assessmentand meta-analysis of the efficacy and safety of fasudil in thetreatment of cerebral vasospasm in patients with subarachnoidhemorrhagerdquo European Journal of Clinical Pharmacology vol68 no 2 pp 131ndash139 2012
[72] S Zhang LWangM Liu andBWu ldquoTirilazad for aneurysmalsubarachnoid haemorrhagerdquo Cochrane Database SystematicReview vol 2 Article ID CD006778 2010
[73] M-Y Tseng P J Hutchinson H K Richards et al ldquoAcutesystemic erythropoietin therapy to reduce delayed ischemicdeficits following aneurysmal subarachnoid hemorrhage aphase II randomized double-blind placebo-controlled trialclinical articlerdquo Journal of Neurosurgery vol 111 no 1 pp 171ndash180 2009
[74] H Kasuya ldquoDevelopment of nicardipine prolonged-releaseimplants after clipping for preventing cerebral vasospasm from
International Journal of Inflammation 13
laboratory to clinical trialrdquo Acta Neurochirurgica Supplemen-tum vol 115 pp 41ndash44 2013
[75] C Thome M Seiz G A Schubert et al ldquoNicardipine pelletsfor the prevention of cerebral vasospasmrdquoActaNeurochirurgicano 110 pp 209ndash211 2011
[76] T Nassar S Akkawi A Shina et al ldquoIn vitro and in vivo effectsof tPA and PAI-1 on blood vessel tonerdquo Blood vol 103 no 3 pp897ndash902 2004
[77] T Sugawara R Ayer V Jadhav W Chen T Tsubokawaand J H Zhang ldquoMechanisms of statin treatment in cerebralvasospasmrdquo Acta Neurochirurgica no 110 pp 9ndash11 2011
[78] M D Vergouwen R J De Haan M Vermeulen and YB Roos ldquoEffect of statin treatment on vasospasm delayedcerebral ischemia and functional outcome in patients withaneurysmal subarachnoid hemorrhage a systematic review andmeta-analysis updaterdquo Stroke vol 41 no 1 pp e47ndashe52 2010
[79] G E Thwaites N D Bang N H Dung et al ldquoDexamethasonefor the treatment of tuberculous meningitis in adolescents andadultsrdquoTheNew England Journal ofMedicine vol 351 no 17 pp1741ndash1811 2004
[80] G E Thwaites J Macmullen-Price T T H Chau et al ldquoSerialMRI to determine the effect of dexamethasone on the cerebralpathology of tuberculous meningitis an observational studyrdquoThe Lancet Neurology vol 6 no 3 pp 230ndash236 2007
[81] U K Misra J Kalita and P P Nair ldquoRole of aspirin in tuber-culous meningitis a randomized open label placebo controlledtrialrdquo Journal of the Neurological Sciences vol 293 no 1-2 pp12ndash17 2010
[82] P W G Elbers and C Ince ldquoBench-to-bedside review mech-anisms of critical illnessmdashclassifying microcirculatory flowabnormalities in distributive shockrdquoCritical Care vol 10 article221 2006
[83] S Trzeciak I Cinel R P Dellinger et al ldquoResuscitating themicrocirculation in sepsis the central role of nitric oxideemerging concepts for novel therapies and challenges forclinical trialsrdquo Academic Emergency Medicine vol 15 no 5 pp399ndash415 2008
[84] Y Sakr M-J Dubois D De Backer J Creteur and J-LVincent ldquoPersistent-microcirculatory alterations are associatedwith organ failure and death in patients with septic shockrdquoCritical Care Medicine vol 32 no 9 pp 1825ndash1831 2004
[85] P E Spronk J H Rommes C Schaar andC Ince ldquoThromboly-sis in fulminant purpura observations on changes in microcir-culatory perfusion during succesful treatmentrdquoThrombosis andHaemostasis vol 95 no 3 pp 576ndash578 2006
[86] J Creteur D De Backer Y Sakr M Koch and J-L VincentldquoSublingual capnometry tracks microcirculatory changes inseptic patientsrdquo Intensive Care Medicine vol 32 no 4 pp 516ndash523 2006
[87] D De Backer J Creteur J C Preiser M J Dubois and JL Vincent ldquoMicrovascular blood flow is altered in patientswith sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 1 pp 98ndash104 2002
[88] G M Ibrahim and R L Macdonald ldquoThe effects of fluid bal-ance and colloid administration on outcomes in patients withaneurysmal subarachnoid hemorrhage a propensity score-matched analysisrdquoNeurocritical Care vol 19 no 2 pp 140ndash1492013
[89] T W Yeo D A Lampah R Gitawati et al ldquoImpaired nitricoxide bioavailability and L-arginine-reversible endothelial dys-function in adults with falciparum malariardquo The Journal ofExperimental Medicine vol 204 no 11 pp 2693ndash2704 2007
[90] A R Fathi R M Pluta K D Bakhtian M Qi and R RLonser ldquoReversal of cerebral vasospasmvia intravenous sodiumnitrite after subarachnoid hemorrhage in primates laboratoryinvestigationrdquo Journal of Neurosurgery vol 115 no 6 pp 1213ndash1220 2011
[91] D de Backer J Creteur M J Dubois et al ldquoThe effects ofdobutamine on microcirculatory alterations in patients withseptic shock are independent of its systemic effectsrdquo CriticalCare Medicine vol 34 no 2 pp 403ndash408 2006
[92] C E Chapleau R P White and J T Robertson ldquoCerebralvasospasm effects of prostaglandin synthetase inhibitors invitrordquo Neurosurgery vol 6 no 2 pp 155ndash159 1980
[93] J L Frazier G Pradilla P P Wang and R J TamargoldquoInhibition of cerebral vasospasm by intracranial delivery ofibuprofen from a controlled-release polymer in a rabbit modelof subarachnoid hemorrhagerdquo Journal of Neurosurgery vol 101no 1 pp 93ndash98 2004
[94] G Pradilla Q A Thai F G Legnani et al ldquoLocal deliveryof ibuprofen via controlled-release polymers prevents angio-graphic vasospasm in a monkey model of subarachnoid hem-orrhagerdquo Neurosurgery vol 57 no 1 pp 184ndash189 2005
[95] R P White and J T Robertson ldquoComparison of piroxicammeclofenamate ibuprofen aspirin and prostacyclin efficacy ina chronic model of cerebral vasospasmrdquo Neurosurgery vol 12no 1 pp 40ndash46 1983
[96] T Fukumori E Tani Y Maeda and A Sukenaga ldquoEffectsof prostacyclin and indomethacin on experimental delayedcerebral vasospasmrdquo Journal of Neurosurgery vol 59 no 5 pp829ndash834 1983
[97] L Brandt B Ljunggren K-E Andersson B Hindfelt and TUski ldquoProstaglandin metabolism and prostacyclin in cerebralvasospasmrdquo General Pharmacology vol 14 no 1 pp 141ndash1431983
[98] T Hakan M Zafer Berkman T Ersoy I Karatas T Sanand S Arbak ldquoAnti-inflammatory effect of meloxicam onexperimental vasospasm in the rat femoral arteryrdquo Journal ofClinical Neuroscience vol 15 no 1 pp 55ndash59 2008
[99] LG Toussaint III J A Friedman E FMWijdicks et al ldquoInflu-ence of aspirin on outcome following aneurysmal subarachnoidhemorrhagerdquo Journal of Neurosurgery vol 101 no 6 pp 921ndash925 2004
[100] B A Gross P M R Lai K U Frerichs and R Du ldquoAspirin andaneurysmal subarachnoid haemorrhagerdquo World Neurosurgery2013
[101] S Yokobori AWatanabe R Nakae et al ldquoCerebral vasospasmsafter intraventricular hemorrhage from an arteriovenousmalformationmdashcase reportrdquo Neurologia Medico-Chirurgicavol 50 no 4 pp 320ndash323 2010
[102] B S Park Y S Won S S Choi and B M Kim ldquoSeveresymptomatic vasospasm following intraventricular hemorrhagefrom arteriovenous fistulardquo Journal of Korean NeurosurgicalSociety vol 45 no 5 pp 300ndash302 2009
[103] G Pradilla T Garzon-Muvdi J J Ruzevick et al ldquoSystemicL-citrulline prevents cerebral vasospasm in haptoglobin 2-2transgenicmice after subarachnoid hemorrhagerdquoNeurosurgeryvol 70 no 3 pp 747ndash757 2012
[104] G Chen J Wu C Sun et al ldquoPotential role of JAK2 in cere-bral vasospasm after experimental subarachnoid hemorrhagerdquoBrain Research vol 1214 pp 136ndash144 2008
[105] C L Lin A L Kwan A S Dumont et al ldquoAttenuationof experimental subarachnoid hemorrhage-induced increases
14 International Journal of Inflammation
in circulating intercellular adhesion molecule-1 and cerebralvasospasm by the endothelin-converting enzyme inhibitor CGS26303rdquo Journal of Neurosurgery vol 106 no 3 pp 442ndash4482007
[106] K Iseda S Ono K Onoda et al ldquoAntivasospastic and antiin-flammatory effects of caspase inhibitor in experimental sub-arachnoid hemorrhagerdquo Journal of Neurosurgery vol 107 no 1pp 128ndash135 2007
[107] C-L Lin A S Dumont T Calisaneller A-L Kwan S-L Hwong and K S Lee ldquoMonoclonal antibody against Eselectin attenuates subarachnoid hemorrhage-induced cerebralvasospasmrdquo Surgical Neurology vol 64 no 3 pp 201ndash206 2005
[108] R Echigo N Shimohata K Karatsu et al ldquoTrehalose treat-ment suppresses inflammation oxidative stress and vasospasminduced by experimental subarachnoid hemorrhagerdquo Journal ofTranslational Medicine vol 10 no 1 article 80 2012
[109] CWakadeM D KingM D Laird C H Alleyne Jr and KMDhandapani ldquoCurcumin attenuates vascular inflammation andcerebral vasospasm after subarachnoid hemorrhage in micerdquoAntioxidants amp Redox Signaling vol 11 no 1 pp 35ndash45 2009
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Research and TreatmentAIDS
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
International Journal of Inflammation 3
macular retinal whitening which occurredwithoutmatchingzones of capillary nonperfusion at the time of the angiogramin 734 patients including four for whom the angiogram wasdelayed gt24 hours after admission
Therewas no evidence for a reduced global cerebral bloodflow on extracranial basal artery Doppler measurementsHigh CBFVwas recorded in 30 of children with CMduringadmission [19] This suggested that ischemic events hadpassed by the time the angiography was performed as wouldbe seen in a transient vasospasm In CM cerebral arteriolarvasospasmmay be mediated by tumor necrosis factor (TNF)The degree of TNF elevation in the cerebrospinal fluid ofchildren with CM has been associated with risk of neurologicdeficits [20] Gambian children homozygote for the TNF2allele a variant of the TNF-alpha gene promoter region has arelative risk of 7 for death or severe neurological sequelae dueto CM [21] A subsequent study confirmed the association ofthe TNF-308 A allele of the TNF promoter with CM [22]Release of TNFmay be triggered by the local deposition of IgEcontaining immune complexes (IC) through cross-linkingof CD23 on monocytesmacrophages in cerebral capillaries[23]
Increased levels of serum ICrsquos have previously beenassociated with vasospasm in subarachnoid haemorrhages[24] IC levels are increased in CM and this may be related toreduced clearance because of interleukin-4 mediated down-regulation of Fc-receptors [25] An erythrocyte complementreceptor type 1 (E-CR1) promoter allele associated withhigher E-CR1 expression and hence enhanced clearance ofICrsquos conferred protection against CM [26]
An interesting recent study found evidence of cerebralarteriolar vasospasm in the murine Plasmodium bergheiANKAmodel of CMwith retinal features of vascular collapsevery similar to the angiographic findings in humanswithCMThe researchers increased survival of mice with CM by useof nimodipine a blocker of the vasoconstriction mediatingL-type voltage-gated calcium channel which is used toprevent and treat vasospasm associated with perivascularinflammation in subarachnoid haemorrhage [27] Furthersupport for a role of cerebral arteriolar vasospasm in CM isprovided by the fact that in murine and human CM there isa low bioavailability of nitric oxide which is an importantvasodilator [28]
Haemolysis inmalaria also leads to consumption of nitricoxide which is bound to free haemoglobin and haemolysisreleases erythrocyte arginase an enzyme that metabolizesarginine This reduces the amount of arginine available forproduction of NO [29] Investigation of the association ofthe single nucleotide polymorphism in the neuronal nitricoxide synthase (nNOS) gene with cerebral malaria revealedthat the polymorphism associated with low basal transcrip-tional activity (-84 G- -rarrA and 276C- -rarrT) was associatedwith an increased risk of cerebral malaria [30] The singlenucleotide polymorphism -1173C-rarrT in the nitric oxidesynthase 2 promoter was associated with increased fastingurine and plasma nitric oxide metabolite concentrationsin Tanzanian children and was associated with protectionagainst cerebral malaria [31] In the P berghei ANKAmurinemodel NO supplementation in the form of a NO donor
prevented vasoconstriction and improved blood flow in pialvessels [32] Nitric oxide production is partially downreg-ulated by IL-12 and polymorphisms in the gene encodingthe IL-12 p40 subunit associated with increased IL-12 levelsled in homozygous form to decreased production of nitricoxide and increased mortality in Tanzanian children withCM but not with severe anaemia in Kenyan children [33]High levels of erythropoietin which has been shown toupregulate endothelial nitric oxide synthase were associatedwith protection against neurological sequelae in Africanchildren with CM [34]
33 Neurocysticercosis Infection of the central nervous sys-tem with the larval stage of Taenia solium (neurocysticerco-sis) is the most common helminthic infection of the CNSand a cause of stroke in areas where cysticercosis is endemicOver 50 of patients with subarachnoid involvement havehereby features of vasculitis Antiparasitic treatment has beenassociated with enhanced subarachnoid inflammation anddelayed cerebral infarcts The focal cerebral lesions found inthe absence of changes on conventional angiograms and withnormal transcranial Doppler ultrasound point to vasospasmin their aetiology [35]
4 Brain Injury
Evidence of traumatic cerebral vasospasm (TCV) has beendetected in military personnel with blast injuries to the headPatients with TCV were also likely to have an intracranialbleed traumatic aneurysm or significant cerebral lobarinjury As indicator of cerebral vasospasm they had elevatedcerebral blood flow velocities for approximately 14 days in onestudy and TCV was associated with increased mortality [36]
A link between inflammation and TCV provided a studyinvestigating risk factors for cerebral vasospasm in 46 adultsand children with TCV fever on admission was an indepen-dently strongly predictive risk factor for the development ofTCV (OR 222 95 CI 19 to 2568) Importantly patientswith hypothermia on admission did not develop TCV [37]Underlying mechanisms were explored in the newbornand juvenile pig model of brain injury which showed thatcerebrospinal fluid concentration of ET-1 was increased andNMDA receptor mediated vasodilation decreased and moreso in the immature brain [38] In humans investigatorsobserved that the loss of nitric oxide bioavailability anddecreased sensitivity to NO after traumatic brain injurywere found to be contributory to impaired cerebral vascularautoregulation
5 Subarachnoid Haemorrhage
Since the demonstration of arterial narrowing in the syn-drome of cerebral vasospasm of subarachnoid haemorrhage(SAH) in 1951 and the further emphasis in 1978 byWeir et alit has been proven that SAH gives rise to arterial narrowingand in turn ischaemia causing infarction and poor outcomeMost research into delayed deterioration after SAH has been
4 International Journal of Inflammation
conducted in concordance with this axiom with the goal ofinterrupting this perceived chain of events [39]
Autopsy studies in nonoperated SAH patients reportedthat 80 of fatal cases showed widely scattered trian-gular round or laminar ischemic lesions in the cortexAn ongoing clinical multicenter study reported that in 18post-SAH patients the occurrence of spreading depolar-ization with cortical spreading ischaemia was associatedwith delayed infarcts in brain computed tomography andmagnetic resonance imaging These findings indicate a newSAH-related mechanism of acute brain injury involving therelease of oxyhaemoglobin and ET-1 and NO deprivationall of which are found in SAH and can cause corticalspreading depression and ischaemia in experimental models[40] Endothelium-dependent dilation hereby seems to bereduced partly because of reduced expression of guanylatecyclase [41] Experimentally neurogenic and endothelium-dependent vasodilatation have been shown to be alteredby the presence of haemoglobin (Hb) in the bath [42] Amore complete review of this mechanism can be foundelsewhere [43] Cerebral vasomotor disturbances have beendemonstrated in humans after SAH inmeasurements of cere-bral blood flow by 133-xenon tomography One of the mostimportant functional consequences of SAH is the relativeloss of cerebrovascular dilatory capacity after acetazolamideinjection [44]The sources of NO in the cerebral arteries [45]are such that it has been supposed that Hb scavenging of NOcould induce vasospasm (VS) The prolonged presence of aperivascular clot seems necessary to maintain VS since clotremoval up to 3 days after haemorrhage reduces VS but after5 days it has little influence [46]
Prostaglandin E2 (PGE2) is the eicosanoid moleculepresent in the highest concentration in the CSF after SAHThe concentration increases by more than 25 times soonafter the haemorrhage and remains high for several days[47] This rise probably explains the fever usually found inSAH The production of PGE2 is induced by cyclooxygenase2 induction by inflammatory mediators including TNF inplatelets and microvessel endothelial cells [48 49] There isevidence of early increased TNF-concentration in the CSF ofpatients with SAH [47 50] PGE2 has been shown to inducecontraction in large cerebral arteries [51]
6 The Role of Inflammatory Mediators inGeneration of Vasospasm
The Interaction of Inflammatory Mediators with CerebralVasculature To enable an understanding of the pathomech-anisms involved in inflammation related cerebral vasospasmand resulting brain ischaemia it is important to analyse theinteraction of inflammatory mediators with each other andthe cerebral vasculature Amediator whichwas found to be ofkey importance in reduction of the risk of cerebral vasospasmin bacterial meningitis cerebral malaria brain injury andsubarachnoid haemorrhage is nitric oxide (NO)
NO can be inactivated by reaction with the superoxideanion resulting in the formation of peroxynitrite Inactivationof NO by superoxide anion may contribute to impaired
NO-mediated dilatation of cerebral blood vessels underconditions inwhich reactive oxygen species are produced likebrain injury and meningitis
Production of superoxide anions has also been reportedto occur in brain in response to seizures fluid-percussioninjury perivascular blood and ischaemia with reperfusionEndothelial NO synthase is downregulated by TNF and NOby a negative-feedback mechanism [52 53] In addition toinflammatory mediators sensory fibres originating in thetrigeminal ganglion modulate constrictor responses in thecerebral microcirculation in conditions like meningitis [7]
The most important factor leading to vasoconstrictionin cerebral blood vessels is ET-1 a 21 amino acid peptidewith three isopeptides produced by separate genes Only ET-1 is produced in cerebral endothelium and mediates cerebralvasoconstriction via endothelin-A (ETA) receptors ETA islocalized in vascular smooth muscle cells and stimulationleads to increase in intracellular calcium concentrationsleading to vasoconstriction ET-1 expression is enhanced bytransforming growth factor-beta haemoglobin interleukin-1 and TNF and can be inhibited by NO nitric oxide donordrugs and dilator prostanoids via an increase in cellularcGMP and natriuretic peptides via an increase in cAMPlevels NO can produce relaxation of some blood vessels fromsome species via activation of potassium channels [7]
Cerebral blood vessels can produce 20-hydroxyeicosate-traenoic acid from arachidonic acid via a P-450 enzymeThissubstance is a potent vasoconstrictor whichmay produce thiseffect by inhibition of activity of potassium channels [7]
A further potential mechanism involved in cerebralvasospasm in cerebral inflammation is inhibition of potas-sium channels Nicorandil which produces relaxation ofcerebral vessels by activation of potassium channels partiallyreverses vasospasm in an experimental model of subarach-noid haemorrhage
The effectiveness of other synthetic activators of potas-sium channels like aprikalim and cromakalim and CGRPindicate that activators of potassium channels in vascularmuscle may help in cerebral vasospasm in cerebral inflam-mation [7]
The etiological role of specific cytokines in vasospasm inbacterial meningitis in vivo was highlighted by a study whichdocumented a significant increase in IL-1-beta and IL-6 con-centrations in patients with elevated cerebrovascular bloodflow indicative of vasospasm in humans [14 54] A similareffect on vasospasm of IL-1 and IL-6 was suggested by a studyof cerebral blood flow in subarachnoid haemorrhage whereincreased cerebral blood flow velocities were associated withsignificantly increased CSF concentrations of IL-1 IL-6 andTNF High concentrations of these immunomediators incerebrospinal fluid (CSF) may exert vasoactive effects forexample IL-1 (MW 17 000Da) or IL-6 (MW 26 000Da)could easily get access to the walls of contiguous basalarteries from their adventitial side as even larger molecules(eg horseradish peroxidase MW 40 000Da) pass from thecisternamagna through the vessel wall to the basalmembranewithin minutes This is possible because by contrast withother arteries the surface of the major cerebral arteries is not
International Journal of Inflammation 5
confined by collagen or fibroblasts but is in direct contactwiththe CSF
An investigation in patients with SAH showed that levelsof IL-1-beta but not TNF-alpha were increased and correlatedwith the later development of vasospasm IL-1 acts throughG-protein coupled receptors in three ways which causecontraction of vascular smooth muscle (see Figure 1)
(1) Activation of phospholipase C generated phosphat-idylinositol trisphosphate causes calcium releasewhich leads to myosin light chain kinase activationleading to myosin light chain activation and calciumdependent vasospasm Phosphorylation of myosinlight chain (MLC) by MLC kinase is one of themost important steps for vascular smooth musclecontraction
(2) Activation of protein kinase C (PKC) through phos-pholipase C generated diacylglycerol (from phos-phatidylinositol (45) bisphosphate) can act throughphosphorylation and hence activation of the myosinlight chain kinase Prolonged contraction in cerebralvasospasm for up to two weeks can be mediated bythis mechanism
(3) PKC activation regulates MLC phosphorylation thro-ugh activation of rho-kinase and the myosin-bindingsubunit (MBS) of MLC phosphatase (MLCPh) Rho-kinase hereby phosphorylates MBS which results inthe inhibition of MLCPh [55] The reduced MLCPhactivity leads to increased phosphorylation and hencecontractility of the MLC resulting in calcium inde-pendent vasospasm Investigations in a porcinemodelrevealed that hydroxyfasudil a specific rho-kinaseinhibitor exerted an inhibitory effect on vasospasmboth in vitro and in vivo Western blot analysisshowed that during serotonin-induced contractionsthe extent of phosphorylation of the MBS was sig-nificantly greater in the spastic than in the controlsegment There was a highly significant correlationbetween the extent of MBS phosphorylation andcontractions [55]
Another key mechanism whereby IL-1 mediates vasosp-asm may be through platelet derived growth factor Thereceptors for this growth factor are also known to havetyrosine kinase activity and inhibition of tyrosine kinase isknown to reduce vasospasm in a swine model [56 57] Thisaction influences vascular reactivity to different agonists andmight be crucial for the regulation of cerebral artery toneduring vasospasm [58]
Calcium independent vasospasm may also be inducibleby haemoglobin released in trauma or subarachnoid haem-orrhage
Haemoglobin might cause contraction of major cerebralarteries by scavenging nitric oxide reducing neuronal nitricoxide synthase (NOS) in the adventitia of the cerebral arter-ies and evoking dysfunction of endothelial NO synthase Adecrease in nitric oxide availability might produce prolongedpathological contraction regardless of the concentration ofintracellular calcium Much of the work investigating the
genetic predisposition to cerebral vasospasm focused on theendothelial isoform of nitric oxide synthase Hemoglobinalso stimulates the production of endothelins and the imbal-ance of nitric oxide and endothelin could be an importantcause of pathological arterial contraction In gene transferexperiments eNOS overexpression in animal and humanintracranial arteries is vasoprotective after aneurysmal SAH[59] Several investigations confirmed the association of theT-786C genotype of eNOS with vasospasm For a summaryof key mediators in cerebral vasospasm their function anddisease studied see Table 1
7 Therapeutic Approaches toPrevention and Correction of VasospasmAssociated with Cerebral InflammationTested in Clinical Trials in Humans
The most extensive experience with treatment approachesto vasospasm in cerebral inflammation has been gatheredin the context of management of SAH Clinical trials inhumans have been reported for endothelin-1 antagonists cal-cium channel blockers including the cisternal placement ofcontrolled-release nicardipine intravenous magnesium sul-phate oral statins rho-kinase inhibitors tissue plasminogenactivator tirilazad erythropoietin and methylprednisoloneThe evidence from controlled trials has been summarized inTable 2
71 Endothelin-1A Receptor Antagonists The selective endo-thelin-1A receptor antagonist clazosentan was assessed ina randomized placebo controlled trial (CONSCIOUS-1)and led to a significant reduction of angiographic cerebralvasospasm in SAH but without reduction in the numberof cerebral ischaemia events Subsequent phase II trials(CONSCIOUS-2 and CONSCIOUS-3) in SAH did notdemonstrate any effect on morbidity or mortality A meta-analysis of 4 RCTswith 2024 participants confirmed this find-ing but showed a reduction in delayed ischemic neurologicaldeficit with the endothelin-1A receptor antagonist [67]
72 Calcium Channel Blockers Calcium antagonists have thepotential to prevent the occurrence of calcium dependentvasospasm and delayed ischemic neurological deficit byreducing calcium release (see Figure 1) They have beenapplied directly to the subarachnoid space [74] Intraopera-tive implantation of nicardipine prolonged-release implantsso-called pellets into the basal cistern in close contact to theproximal cerebral vasculature has been reported to reducethe occurrence of cerebral vasospasm and cerebral infarctionand lead to an improvement in clinical outcome in SAH [75]Themagnesium ion is an antagonistic competitor for calciumbinding sites thus having the potential to reduce calciumdependent vasospasm and has been used in the form ofintravenous magnesium sulphate in a number of trials (seeTable 2)
6 International Journal of Inflammation
GPCR
Macrophage
Interleukin-1
Lipopolysaccharide
Plasmodium falciparum antigens
Stimulation of interleukin-1 release
MLCK
PKC
MLCMLCK-P
Rho-kinase MBSMBS-P
MLCPh
Intracellular autoantigens (fromtissue injury)
PLC ≫ IP3 ≫ calcium releaseminusRho-kinase-P
Figure 1 Mechanism for induction of cerebral vasospasm by interleukin-1 (GPCR = G-protein coupled receptor PKC = protein kinase CMLCK = myosin light chain kinase MLC = myosin light chain MBS = myosin-binding subunit of myosin light chain phosphatase MLCPh=myosin light chain phosphatase -P indicates phosphorylated state PLC = phospholipase C and IP3 = phosphatidylinositol trisphosphate)
Table 1 Inflammatory mediators and their role in cerebral vasospasm
Mediator Function of mediator Disease model where role hasbeen established References
(i) Nitric oxide(i) Vasodilator(ii) Inhibitor of endothelin-1expression
(i) Cerebral malaria(ii) Bacterial meningitis(iii) Subarachnoid haemorrhage
[1 7 16 28 32 41 45]
(i) Endothelin-1 (i) Vasoconstrictor (i) Bacterial meningitis(ii) Subarachnoid haemorrhage [7 15]
(i) Interleukin-1(ii) Interferon gamma(iii) Tumor necrosis factor
(i) Activators of protein kinase C(ii) Stimulators of release ofendothelin-1
(i) Bacterial meningitis(ii) Cerebral malaria(iii) Subarachnoid haemorrhage
[7 14 56]
73 Tissue Plasminogen Activator A recent meta-analysis offive randomized controlled trials (465 patients) of tissue plas-minogen activator (tPA) or urokinase applied intrathecallyreduced development of poor outcome and delayed cerebralischaemia and vasospasm [70]Themechanism proposed forthis effect is probably not related to thrombolysis but to adirect effect of tPA on vascular tone It is clear that the effectof tPA is endothelial cell dependent and more specificallyNO synthase dependent tPA seems to bind to a receptorpresent in endothelial cells that mediates the stimulation ofNO synthase activity and thus inhibits the vasoconstrictiveeffect of phenylephrine [76]
74 Statins Statins can reduce vasospasm by upregulatingendothelial NO synthase expression A threefold increasein endothelial NO synthase mRNA protein and enzymatic
activity has been demonstrated following statin treatmentresulting in an increase in cerebral blood flow Statintreatment has attenuated cerebral vasospasm and preventeddelayed ischemic deficits in amurine SAHmodel [77] A pre-vious systematic review of 4 studies with a total of 190 patientsshowed no statistically significant effect on vasospasm ontranscranial Doppler studies delayed cerebral ischaemia ormortality [78] but a more recent review demonstrated areduction in mortality and delayed ischemic neurologicaldeficits [66]
75 Rho-Kinase Inhibitor The specific rho-kinase inhibitorfasudil hydrochloride was in a recent systematic review of8 studies (843 patients) shown to reduce the occurrenceof cerebral vasospasm and cerebral infarction significantlyand led to an improvement in clinical outcome [71] The
International Journal of Inflammation 7
Table2Medicationfortreatmento
fcerebralvasospasm
the
evidence
from
controlledtrialsin
humans
Interventio
nTy
peof
study
Patholog
yRe
sultsodd
sratio
(OR)
orrelativer
isk(RR)
foro
ccurrencein
interventio
ngrou
pcomparedto
grou
pwith
outintervention
Reference
Calcium
channel
blockers
Syste
maticreview
(SR)
(sixrand
omized
controlledtrials
(RCT
s))
Acuteb
rain
injury
DeathO
R091
[95
070ndash117
]Death
andsevere
disabilityOR085
[95
068
to10
7]In
thes
ubgrou
pof
traumaticsubarachno
idhaem
orrhagep
atients
pooled
odds
ratio
was
059
[95
CI037ndash0
94]three
RCTs
repo
rtingdeathandsevere
disabilityas
anou
tcom
einthis
subgroup
OR067
[95
CI046
ndash098]
[60]
Calcium
channel
blockers
SR(16RC
Ts)
Aneurysmal
subarachno
idhaem
orrhage(aSAH)
Overallcalcium
antagonists
redu
cedther
iskof
poor
outcom
ethe
relativer
isk(RR)
was
081
[95
CI072
to092]thec
orrespon
ding
numbero
fpatientsn
eededto
treatwas
19[95
CI1to51]foro
ral
nimod
ipinea
lone
theR
Rwas
067
[95
CI055
to081]foro
ther
calcium
antagonists
orintravenou
sadm
inistratio
nof
nimod
ipine
ther
esultsweren
otsta
tistic
allysig
nificantcalcium
antagonists
redu
cedtheo
ccurrenceo
fsecon
dary
ischaem
iaandshow
eda
favourabletre
ndforc
asefatality
for
magnesiu
minadditio
nto
standard
treatmentw
ithnimod
ipinetheR
Rwas
075
[95
CI057
to10
0]fora
poor
outcom
eand
066
[95
CI045
to096]for
clinicalsigns
ofsecond
aryisc
haem
ia
[61]
Nicardipine
SR(five
controlled
trials)
aSAH
Risk
ofpo
orou
tcom
e(deathvegetativ
estateord
ependency)
OR
058
(95
CI037ndash0
9)
Mortalityod
dsratio
045[95
CI015
to12
9][62]
Magnesiu
msulfate
Prospective
rand
omise
dstu
dyEclampsia
Sign
ificant
redu
ctionof
pulsa
tility
index(119875=0002)a
ndmeanflo
wvelocityin
middlec
erebralartery(119875=002)
[63]
Prop
hylactic
magnesiu
msulfate
SRof
tenrand
omized
parallelgroup
controlledtrials
aSAH
Glasgow
outcom
escaleandmod
ified
Rank
inscaleR
R093
(95
CI082
to10
6)m
ortality095
(95
CI076ndash117
)delay
edcerebral
ischaem
iaRR
054(95
CI038
to075)delay
edisc
hemic
neurologicaldeficit(D
IND)RR
of093
[95
CI062ndash139
]transcranialDop
pler
vasospasmR
R072
[95
CI051ndash103]
[64]
Indu
ced
hyperm
agnesaem
iaRC
TaSAH
Vasospasm
ondigitalsub
tractio
nangiograph
yOR
051[95CI
026
to10
2]neurologicalrecoveryORforw
orse
outcom
e071
[95
CI039
to13
2][65]
Statins
SR(sixRC
Ts)
aSAH
Incidenceo
fvasospasm
RR080[95
CI054ndash
117]poo
rneurologicalou
tcom
eRR
094[95
CI077to
116]
MortalityRR
030[95
CI014
ndash064]
DIN
DR
R058
[95
CI037
ndash092]
[66]
Endo
thelin
receptor
antagonists
SR(fo
urRC
Ts)
aSAH
Incidenceo
fDIN
Drela
tiver
isk08[95
CI067ndash0
95]
angiograph
icvasospasm
RR062[95CI
052
to072]
unfavourableou
tcom
eRR
087[95
CI074ndash102]m
ortalityRR
105[95
CI077
to14
5]
[67]
8 International Journal of Inflammation
Table2Con
tinued
Interventio
nTy
peof
study
Patholog
yRe
sultsodd
sratio
(OR)
orrelativer
isk(RR)
foro
ccurrencein
interventio
ngrou
pcomparedto
grou
pwith
outintervention
Reference
Endo
thelin-1Areceptor
antagonistClazosentan
SR(fo
urRC
Ts)
aSAH
Relativer
iskforincidence
ofDIN
Ds076
(95
CI062ndash0
92)
delay
edcerebralinfarctio
n079
[95
CI063ndash100]G
lasgow
outcom
escaleextend
edRR
112
[95
CI096ndash130]m
ortalityRR
10
2[95
CI070ndash149]
[68]
Intravenou
smethylpredn
isolone
RCT
aSAH
Symptom
aticvasospasm
265in
interventio
ngrou
pcompared
with
26in
placebogrou
pfunctio
naloutcomes
caleredu
cedin
the
methylpredn
isolone
grou
pwith
riskdifference193
[95
CI05ndash379]ou
tcom
epoo
rin15of
patie
ntsinthe
methylpredn
isolone
grou
pversus
34in
thep
lacebo
grou
p
[69]
Tissue
plasminogen
activ
ator
SR(five
RCTs)
aSAH
Overalluseo
fintrathecalthrombo
lytic
swas
associated
with
significantreductio
nsin
thed
evelo
pmento
fpoo
routcomes
(OR
052034ndash
078119875lt001)DIN
Ds(OR054034ndash
087119875=001)
andangiograph
icvasospasm
(OR032015
ndash070119875lt001)
[70]
Rho-kinase
inhibitor
SR(8
controlledtrials)
aSAH
Absenceo
fsym
ptom
aticvasospasmoccurrenceo
flow
density
areas
associated
with
vasospasm
onCT
and
occurrence
ofadversee
vents
weres
imilarb
etweenthetwogrou
psthe
clinicaloutcomes
were
morefavorablein
thefasud
ilgrou
pthan
inthen
imod
ipineg
roup
(119875=004)
[71]
Tirilazad
SR(five
RCTs)
aSAH
Therew
asno
significantd
ifference
betweenthetwogrou
psatthe
endof
follo
w-upforthe
prim
aryou
tcom
edeathOR
089[95CI
074
to10
6]orinpo
orou
tcom
e(deathvegetativ
estateorsevere
disability)
OR10
4[95
CI090
to12
1]few
erpatie
ntsd
evelop
eddelay
edcerebralisc
haem
iain
thetirilazadgrou
pthan
inthec
ontro
lgrou
pOR080
[95
CI069
to093]subgroup
analyses
didno
tdemon
stratea
nysig
nificantd
ifference
ineffectsof
tirilazadon
clinicaloutcomes
[72]
Erythrop
oietin
RCT
aSAH
Nodifferences
wered
emon
strated
intheincidence
ofvasospasm
andadversee
ventspatie
ntsreceiving
EPOhadad
ecreased
incidenceo
fseverev
asospasm
from
275to
75(119875=0037)
redu
cedDID
swith
newcerebralinfarctsfro
m40
0to
75
(119875=0001)as
hortened
duratio
nof
impaire
dautoregu
latio
n(ip
silateralsid
e119875lt0001)andmorefavorableou
tcom
eat
discharge(favorableG
lasgow
outcom
escalescore119875=0039)
amon
gthe7
1survivorsthe
EPOgrou
phadfewer
deficits
measured
with
NationalInstitutes
ofHealth
Stroke
Scale(medianscore2
versus
6119875=0008)
[73]
International Journal of Inflammation 9
mechanism is apart from a contribution to inhibition ofcalcium independent vasospasm (see above) probably alsoan increase of endothelial nitric oxide synthase (eNOS)expression by stabilizing eNOSmRNA which can contributeto an increase of NO level to enhance vasodilatation
76 Other Treatments Steroid treatment can inhibit cytokineexpression and has thus the potential to reduce cytokinemediated calcium dependent and independent vasospasmIn tuberculous meningitis adjuvant treatment with corticos-teroids has been indirectly associatedwith features of reducedvasculopathy which may include vasospasm
A large randomised controlled trial showed improvedmortality in tuberculous meningitis with adjuvant corti-costeroids but did not show a reduction in severe disabil-ity however an observational MRI study did suggest areduction in strokes in patients treated with corticosteroids[79 80] An open-label study of aspirin in the preventionof stroke and mortality in tuberculous meningitis found anonsignificant reduction in stroke and a significant reductionin mortality with a possible synergism with corticosteroids[81] Mechanisms responsible for a potential effect may bea reduction of the vasoconstricting effect of PGE2 The 21-aminosteroid tirilazad is a lipid peroxidation inhibitor whichinhibits free radical-induced lipid peroxidation (LP) by acombination of lipid peroxide scavenging and a membrane-stabilizing action that limits the propagation of LP reactionsbetween a lipid peroxide and an adjacent polyunsaturatedfatty acid There has been no consistent evidence of benefitin animal or human studies Erythropoietin may act throughincrease in expression of endothelial nitric oxide synthasethus increasing NO bioavailability
8 Conclusions and Perspectives forFuture Developments
There is evidence for common pathways leading tovasospasm in all forms of cerebral inflammation involvinginterleukin-1 tumor necrosis factor endothelin-1 andnitric oxide Treatments addressing the pathophysiologyof vasospasm in one form of cerebral inflammation maytherefore apply to all others Treatment of cerebral vasospasmhas been mainly investigated in aneurysmal SAH Agentsfor which there is likely to be clinical benefit are calciumantagonists statins and intrathecal plasminogen activators(see Table 2) The fact that there is calcium dependent andindependent vasospasm in inflammation (see Figure 1)shows that a combination of calcium antagonists with agentsinterfering with calcium independent vasospasm includingagents improving the bioavailability of nitric oxide is theway forward Future trials need to investigate their effectsin patients with all forms of cerebral inflammation leadingto neurological deficits attributable to vasospasm In vivocorrelates for reduction of vasospasm in the peripheralcirculation could be explored as a surrogate for reduction ofvasospasm in the cerebral (micro) vasculature
Strategies to improve microvascular recruitment whichhave been explored in models of septicaemia could poten-tially be applied to cerebral vasospasm Distributive shockwhich occurs during sepsis and septic shock is associatedwith an abnormal distribution of microvascular blood flowVasospasm of part of the arterioles supplying the capillary isa mechanism involved in this maldistribution The clinicalintroduction of new microcirculatory imaging techniquessuch as orthogonal polarization spectral and side-streamdark-field imaging (OPSSDF) has allowed direct obser-vation of the microcirculation at the bedside Images ofthe sublingual microcirculation during septic shock andresuscitation have revealed that the distributive defect ofblood flow occurs at the capillary level [82]
In rat models of cecal ligation and puncture investiga-tors have used intravital video microscopy to demonstratethat sepsis is characterized by decreased microcirculatoryflow velocity an abundance of stopped-flow microvesselsincreased heterogeneity of microcirculatory flow and lowdensity of perfused capillaries As thesemicrocirculatory flowalterations can occur in the absence of global hemodynamicderangements (eg absence of arterial hypotension) micro-circulatory dysfunction largely reflects intrinsic events occur-ring in the microvessels like localized vasospasm [83] Appli-cation ofmicrocirculatory recruitmentmaneuver procedureshas been shown to be effective in promotingmicrocirculatoryblood flow in clinical studies using OPSSDF imaging [84ndash87] Fluid resuscitation in combination with the nitric oxidedonor nitroglycerine was shown to recruit disturbed micro-circulation following pressure guided resuscitation in septicshock patients
It is important to note that application of colloids inpatients with SAH was associated with worse outcomescompared to matched controls in a subgroup analysis of theCONSCIOUS-1 prospective randomized trial of clazosentanfor the prevention of angiographic vasospasm [88] Futureresearch needs to investigate whether colloids can bind nitricoxide and make this vasodilator less available by binding it
Regarding future therapeutic interventions increasingnitric oxide bioavailability erythropoietin and L-argininewhich increased bioavailability of nitric oxide in patients withmalaria [89] need to be explored as adjunctive treatmentin children with cerebral malaria in randomised controlledtrials In vitro the availability of L-arginine does not appearto be a rate limiting step for the activity of the NO synthasebecause its half-saturating concentration is less than 3of theplasma and endothelial concentration of this substrate
The nitric oxide donor intravenous sodium nitrite hasbeen shown to prevent and reverse cerebrovascular spasmin primates and has been demonstrated to be safe foradministration in humans [90]
Support of pump function by dobutamine therapy hasbeen shown to improvemicrocirculatory flow independent ofimprovement of global hemodynamic parameters [91] Fluidapplication nitric oxide donors and dobutamine therapyneed to be explored in isolation but also as combinationof interventions to improve cerebral perfusion in cerebralinflammation associated with vasospasm
10 International Journal of Inflammation
A potential role of nonsteroidal anti-inflammatory drugswas revealed by landmark experiments on dog basilararteries Arachidonic acid induced sustained contractionsand these responses were markedly inhibited (95) bymeclofenamate and similarly by indomethacin but aspirinhad no such effect [92] In the rabbit basilar artery model ofcerebral vasospasm local intracranial delivery of ibuprofenaccomplished using controlled-release polymers preventedvasospasm when administered within 6 hours but notat either 12 or 24 hours [93] Delivery of ibuprofen viacontrolled-release polymers into the subarachnoid space ofmonkeys with subarachnoid haemorrhage prevented angio-graphic vasospasm after SAH as evident from patency of themiddle cerebral artery [94]
Piroxicam was more effective than the above-mentioneddrugs in the SAH dog model after angiographic analysisand analysis of behavioural changes [95] Early studiesusing prostacyclin found that isolated canine basilar arteriescontraction induced by prostaglandin E2 hemoglobin orserum was relaxed by prostacyclin but not indomethacin[96] In isolated human pial arteries prostacyclin relaxedhuman pial arteries contracted by either PGF2 alpha nora-drenaline serotonin or haemorrhagic CSF [97] In an animalstudy meloxicam reduced ultrastructural and morphometricvasospastic changes in rats with subarachnoid haemorrhage[98] Investigation comparing rate of subsequent permanentdisability from vasospasm and angiographic and delayedcerebral ischaemia in patients with SAH with and withoutaspirin intake found no association with poor outcome [99100]
There are new areas of pathophysiology research wherethe role of vasospasm needs to be explored thoroughly inorder to find avenues for therapeutic interventions Investi-gations could evaluate whether intraventricular haemorrhageoccurring commonly in the neonatal period in pretermneonates is associated with vasospasm increasing mor-bidity Case reports of intraventricular haemorrhage fromAV malformations and aneurysms in adults demonstratedvasospasm [101 102]
Future research needs to explore the usefulness of a num-ber of agents which have been demonstrated to reduce vaso-spasm in animal models including L-citrulline [103] januskinase-2 [104] endothelin converting enzyme inhibitors[105] caspase inhibitor Z-VAD-FMK [106] anti-E selectinmonoclonal antibodies [107] trehalose [108] and curcuminwhich was demonstrated to protect against the developmentof cerebral vasospasm and secondary cerebral infarctionafter subarachnoid haemorrhage in mice by its broad anti-inflammatory activity including limitation of superoxidegeneration and influence on inducible nitric oxide synthaseexpression [109]
Aggressive maintenance of normothermia or mildhypothermia in patients with military blast injury resultedin a dramatic reduction in the incidence of posttraumaticvasospasm from 475 to 5 Future studies need to confirmthis finding and investigate whether hypothermia can reducecerebral inflammation related ischemic damage to the brainin other conditions like bacterial meningitis or cerebralmalaria [37]
Conflict of Interests
The author declares that there is no conflict of interestsregarding the publication of this paper
References
[1] B Weir ldquoThe pathophysiology of cerebral vasospasmrdquo BritishJournal of Neurosurgery vol 9 no 3 pp 375ndash390 1995
[2] H Bode and A Harders ldquoTransient stenoses and occlusionsof main cerebral arteries in childrenmdashdiagnosis and control oftherapy by transcranial Doppler sonographyrdquo European Journalof Pediatrics vol 148 no 5 pp 406ndash411 1989
[3] K-F Lindegaard H Nornes S J Bakke W Sorteberg and PNakstad ldquoCerebral vasospasm diagnosis by means of angiogra-phy and blood velocity measurementsrdquo Acta Neurochirurgicavol 100 no 1-2 pp 12ndash24 1989
[4] C Lysakowski B Walder M C Costanza and M R TramerldquoTranscranial Doppler versus angiography in patients withvasospasm due to a ruptured cerebral aneurysm a systematicreviewrdquo Stroke vol 32 no 10 pp 2292ndash2298 2001
[5] R L Grubb Jr M E Raichle J O Eichling and M HGado ldquoEffects of subarachnoid hemorrhage on cerebral bloodvolume blood flow and oxygen utilization in humansrdquo Journalof Neurosurgery vol 46 no 4 pp 446ndash452 1977
[6] C-H Lu H-W Chang C-C Lui C-R Huang and W-NChang ldquoCerebral haemodynamics in acute bacterial meningitisin adultsrdquoQuaterly Journal of Medicine vol 99 no 12 pp 863ndash869 2006
[7] F Faraci and D D Heistad ldquoRegulation of the cerebralcirculation role of endothelium and potassium channelsrdquoPhysiological Reviews vol 78 no 1 pp 53ndash97 1998
[8] L Hektoen ldquoThe vascular changes in tuberculous meningitisespecially in tuberculous endarteritisrdquo Journal of ExperimentalMedicine vol 1 pp 112ndash163 1896
[9] G Thwaites ldquoTuberculosis of the central nervous systemrdquo inClinical Tuberculosis P D O Davies S B Gordon and GDavies Eds pp 151ndash165 CRC Press 5th edition 2014
[10] P M Dalal ldquoObservations on the involvement of cerebral ves-sels in tuberculousmeningitis in adultsrdquoAdvances in Neurologyvol 25 pp 149ndash159 1979
[11] L A Rojas-Echeverri J L Soto-Hernandez S Garza et alldquoPredictive value of digital subtraction angiography in patientswith tuberculous meningitisrdquo Neuroradiology vol 38 no 1 pp20ndash24 1996
[12] E L Lyons and N E Leeds ldquoThe angiographic demonstrationof arterial vascular disease in purulent meningitis report of acaserdquo Radiology vol 88 no 5 pp 935ndash938 1967
[13] S Ries U Schminke K Fassbender M Daffertshofer WSteinke andMHennerici ldquoCerebrovascular involvement in theacute phase of bacterial meningitisrdquo Journal of Neurology vol244 no 1 pp 51ndash55 1997
[14] K Fassbender S Ries U Schminke S Schneider and M Hen-nerici ldquoInflammatory cytokines in CSF in bacterial meningitisassociation with altered blood flow velocities in basal cerebralarteriesrdquo Journal of Neurology Neurosurgery amp Psychiatry vol61 no 1 pp 57ndash61 1996
[15] L A Pfister J H Tureen S Shaw et al ldquoEndothelin inhibitionimproves cerebral blood flow and is neuroprotective in pneu-mococcal meningitisrdquoAnnals of Neurology vol 47 pp 329ndash3352000
International Journal of Inflammation 11
[16] S L Leib Y S Kim S M Black J H Tureen and M GTauber ldquoInducible nitric oxide synthase and the effect of amin-oguanidine in experimental neonatal meningitisrdquo The Journalof Infectious Diseases vol 177 no 3 pp 692ndash700 1998
[17] T W Polder C R Jerusalem andW M C Eling ldquoMorpholog-ical characteristics of intracerebral arterioles in clinical (Plas-modium falciparum) and experimental (Plasmodium berghei)cerebral malariardquo Journal of the Neurological Sciences vol 101no 1 pp 35ndash46 1991
[18] N A V Beare S P Harding T E Taylor S Lewallen and MEMolyneux ldquoPerfusion abnormalities in childrenwith cerebralmalaria andmalarial retinopathyrdquo Journal of Infectious Diseasesvol 199 no 2 pp 263ndash271 2009
[19] C R J C Newton K Marsh N Peshu and F J KirkhamldquoPerturbations of cerebral hemodynamics in Kenyans withcerebral malariardquo Pediatric Neurology vol 15 no 1 pp 41ndash491996
[20] C C John A Panoskaltsis-Mortari R O Opoka et alldquoCerebrospinal fluid cytokine levels and cognitive impairmentin cerebral malariardquo American Journal of Tropical Medicine andHygiene vol 78 no 2 pp 198ndash205 2008
[21] W McGuire A V S Hill C E M Allsopp B M Greenwoodand D Kwiatkowski ldquoVariation in the TNF-120572 promoter regionassociated with susceptibility to cerebral malariardquo Nature vol371 no 6497 pp 508ndash510 1994
[22] W McGuire J C Knight A V S Hill C E M Allsopp B MGreenwood and D Kwiatkowski ldquoSevere malarial anemia andcerebral malaria are associated with different tumor necrosisfactor promoter allelesrdquo Journal of Infectious Diseases vol 179no 1 pp 287ndash290 1999
[23] B Dugas M D Mossalayi C Damais and J-P Kolb ldquoNitricoxide production by human monocytes Evidence for a role ofCD23rdquo Immunology Today vol 16 no 12 pp 574ndash580 1995
[24] L Pellettieri B Nilsson C-A Carlsson andU Nilsson ldquoSerumimmunocomplexes in patients with subarachnoid hemorrhagerdquoNeurosurgery vol 19 no 5 pp 767ndash771 1986
[25] M Eisenhut ldquoCauses of reduced immune complex clearance incerebralmalariardquoParasite Immunology vol 31 no 2 p 59 2009
[26] P Teeranaipong J Ohashi J Patarapotikul et al ldquoA functionalsingle-nucleotide polymorphism in the CR1 promoter regioncontributes to protection against cerebral malariardquo Journal ofInfectious Diseases vol 198 no 12 pp 1880ndash1891 2008
[27] P Cabrales G M Zanini D Meays J A Frangos and LJ M Carvalho ldquoMurine cerebral malaria is associated witha vasospasm-like microcirculatory dysfunction and survivalupon rescue treatment is markedly increased by nimodipinerdquoTheAmerican Journal of Pathology vol 176 no 3 pp 1306ndash13152010
[28] I Gramaglia P Sobolewski D Meays et al ldquoLow nitricoxide bioavailability contributes to the genesis of experimentalcerebral malariardquoNature Medicine vol 12 no 12 pp 1417ndash14222006
[29] T W Yeo D A Lampah E Tjitra et al ldquoRelationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavail-ability and perfusion in severe falciparum malariardquo Journal ofInfectious Diseases vol 200 no 10 pp 1522ndash1529 2009
[30] G Dhangadamajhi B N Mohapatra S K Kar and M RanjitldquoGenetic variation in neuronal nitric oxide synthase (nNOS)gene and susceptibility to cerebral malaria in Indian adultsrdquoInfection Genetics and Evolution vol 9 no 5 pp 908ndash911 2009
[31] M R Hobbs V Udhayakumar M C Levesque et al ldquoAnew NOS2 promoter polymorphism associated with increased
nitric oxide production and protection from severe malaria inTanzanian and Kenyan childrenrdquoThe Lancet vol 360 no 9344pp 1468ndash1475 2002
[32] P Cabrales G M Zanini D Meays J A Frangos and L JM Carvalho ldquoNitric oxide protection against murine cerebralmalaria is associated with improved cerebral microcirculatoryphysiologyrdquo The Journal of Infectious Diseases vol 203 no 10pp 1454ndash1463 2011
[33] G Morahan C S Boutlis D Huang et al ldquoA promoterpolymorphism in the gene encoding interleukin-12 p40 (IL12B)is associated with mortality from cerebral malaria and withreduced nitric oxide productionrdquo Genes amp Immunity vol 3 no7 pp 414ndash418 2002
[34] C Casals-Pascual R Idro N Gicheru et al ldquoHigh levels of ery-thropoietin are associated with protection against neurologicalsequelae in African children with cerebral malariardquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 105 no 7 pp 2634ndash2639 2008
[35] F C Chow C M Marra and T A Cho ldquoCerebrovasculardisease in central nervous system infectionsrdquo Seminars inNeurology vol 31 no 3 pp 286ndash306 2011
[36] R A Armonda R S Bell A H Vo et al ldquoWartime traumaticcerebral vasospasm recent review of combat casualtiesrdquoNeuro-surgery vol 59 no 6 pp 1215ndash1225 2006
[37] K Shahlaie K Keachie I M Hutchins et al ldquoRisk factorsfor posttraumatic vasospasm clinical articlerdquo Journal of Neu-rosurgery vol 115 no 3 pp 602ndash611 2011
[38] Y Udomphorn W M Armstead and M S Vavilala ldquoCerebralblood flow and autoregulation after pediatric traumatic braininjuryrdquo Pediatric Neurology vol 38 no 4 pp 225ndash234 2008
[39] R M Pluta J Hansen-Schwartz J Dreier et al ldquoCerebralvasospasm following subarachnoid hemorrhage time for a newworld of thoughtrdquo Neurological Research vol 31 no 2 pp 151ndash158 2009
[40] J Hansen-Schwartz P Vajkoczy R L Macdonald R MPluta and J H Zhang ldquoCerebral vasospasm looking beyondvasoconstrictionrdquo Trends in Pharmacological Sciences vol 28no 6 pp 252ndash256 2007
[41] H Kasuya B K A Weir M Nakane et al ldquoNitric oxidesynthase and guanylate cyclase levels in canine basilar arteryafter subarachnoid hemorrhagerdquo Journal of Neurosurgery vol82 no 2 pp 250ndash255 1995
[42] M D Linnik and T J F Lee ldquoEffect of hemoglobin on neuro-genic responses and cholinergic parameters in porcine cerebralarteriesrdquo Journal of Cerebral Blood Flow and Metabolism vol 9no 2 pp 219ndash225 1989
[43] CG Sobey and FM Faraci ldquoSubarachnoid haemorrhage whathappens to the cerebral arteriesrdquo Clinical and ExperimentalPharmacology and Physiology vol 25 no 11 pp 867ndash876 1998
[44] Y R T Dinh G Lot R Benrabah O Baroudy J Cophignonand J Seylaz ldquoAbnormal cerebral vasodilation in aneurys-mal subarachnoid hemorrhage use of serial 133Xe cerebralblood flow measurement plus acetazolamide to assess cerebralvasospasmrdquo Journal of Neurosurgery vol 79 no 4 pp 490ndash4931993
[45] T J F Lee ldquoNitric oxide and the cerebral vascular functionrdquoJournal of Biomedical Science vol 7 no 1 pp 16ndash26 2000
[46] M Stoodley R L Macdonald B Weir et al ldquoSubarachnoidhemorrhage as a cause of an adaptive response in cerebralarteriesrdquo Journal of Neurosurgery vol 93 no 3 pp 463ndash4702000
12 International Journal of Inflammation
[47] Y R Tran Dinh A Jomaa J Callebert et al ldquoOverexpressionof cyclooxygenase-2 in rabbit basilar artery endothelial cellsafter subarachnoid hemorrhagerdquo Neurosurgery vol 48 no 3pp 626ndash635 2001
[48] A Gecse B Kis Z Mezei and G Telegdy ldquoEffects of inflam-matory neuropeptides on the arachidonate cascade of plateletsrdquoInternational Archives of Allergy and Immunology vol 118 no2ndash4 pp 166ndash170 1999
[49] K S Mark W J Trickler and D W Miller ldquoTumornecrosis factor-120572 induces cyclooxygenase-2 expression andprostaglandin release in brain microvessel endothelial cellsrdquoJournal of Pharmacology and Experimental Therapeutics vol297 no 3 pp 1051ndash1058 2001
[50] T Tanazawa Y Suzuki M Anzai S Tsugane M Takayasu andM Shibuya ldquoVasodilation by intrathecal lipopolysaccharide ofthe cerebral arteries after subarachnoid haemorrhage in dogsrdquoActa Neurochirurgica vol 138 no 3 pp 330ndash337 1996
[51] N Toda M Kawakami and K Yoshida ldquoConstrictor action ofoxyhemoglobin in monkey and dog basilar arteries in vivo andin vitrordquo American Journal of Physiology Heart and CirculatoryPhysiology vol 260 no 2 pp H420ndashH425 1991
[52] M Yoshizumi M A Perrella J C Burnett Jr and M-E LeeldquoTumor necrosis factor downregulates an endothelial nitricoxide synthase mRNA by shortening its half-liferdquo CirculationResearch vol 73 no 1 pp 205ndash209 1993
[53] A Rengasamy and R A Johns ldquoRegulation of nitric oxidesynthase by nitric oxiderdquo Molecular Pharmacology vol 44 no1 pp 124ndash128 1993
[54] A L de Souza A C P de Oliveira C C Romano J SztajnbokA J S Duarte and A C Seguro ldquoInterleukin-6 activation inischemic stroke caused by Neisseria meningitidis serogroup CrdquoInternational Journal of Cardiology vol 127 no 3 pp e160ndashe1632008
[55] T Kandabashi H Shimokawa K Miyata et al ldquoInhibition ofmyosin phosphatase by upregulated Rho-kinase plays a key rolefor coronary artery spasm in a porcine model with interleukin-1120573rdquo Circulation vol 101 no 11 pp 1319ndash1323 2000
[56] D-H Nam J-S Kim S-C Hong et al ldquoExpression ofinterleukin-1120573 in lipopolysaccharide stimulated monocytesderived from patients with aneurysmal subarachnoid hem-orrhage is correlated with cerebral vasospasmrdquo NeuroscienceLetters vol 312 no 1 pp 41ndash44 2001
[57] A Ito H Shimokawa T Kadokami et al ldquoTyrosine kinaseinhibitor suppresses coronary arteriosclerotic changes andvasospastic responses induced by chronic treatment withinterleukin-1120573 in pigs in vivordquo Journal of Clinical Investigationvol 96 no 3 pp 1288ndash1294 1995
[58] H Yanamoto H Kataoka Y Nakajo and K Iihara ldquoThe roleof the host defense system in the development of cerebralvasospasm analogies between atherosclerosis and subarach-noid hemorrhagerdquo European Neurology vol 68 no 6 pp 329ndash343 2012
[59] A F Ducruet P R Gigante Z L Hickman et al ldquoGeneticdeterminants of cerebral vasospasm delayed cerebral ischemiaand outcome after aneurysmal subarachnoid hemorrhagerdquoJournal of Cerebral Blood Flow amp Metabolism vol 30 no 4 pp676ndash688 2010
[60] J Langham C Goldfrad G Teasdale D Shaw and KRowan ldquoCalcium channel blockers for acute traumatic braininjuryrdquoCochrane Database Systematic Reviews no 4 Article IDCD000565 2000
[61] S M Dorhout Mees G J Rinkel V L Feigin et al ldquoCal-cium antagonists for aneurysmal subarachnoid haemorrhagerdquoCochrane Database of Systematic Reviews no 3 Article IDCD000277 2007
[62] R-Q Huang F-G Jiang Z-M Feng and T-Y WangldquoNicardipine in the treatment of aneurysmal subarachnoidhaemorrhage a meta-analysis of published datardquo Acta Neuro-logica Belgica vol 113 no 1 pp 3ndash6 2013
[63] S Naidu A J Payne J Moodley M Hoffmann and EGouws ldquoRandomised study assessing the effect of phenytoinand magnesium sulphate on maternal cerebral circulationin eclampsia using transcranial Doppler ultrasoundrdquo BritishJournal of Obstetrics amp Gynaecology vol 103 no 2 pp 111ndash1161996
[64] D Reddy A Fallah J-A Petropoulos F Farrokhyar R LMacdonald and D Jichici ldquoProphylactic magnesium sulphatefor aneurysmal subarachnoid haemorrhage a systematic reviewand meta-analysisrdquo Neurocritical Care vol 21 no 2 pp 356ndash364 2014
[65] C M Bradford S Finfer A OrsquoConnor et al ldquoA ran-domised controlled trial of induced hypermagnesaemia follow-ing aneurysmal subarachnoid haemorrhagerdquo Critical Care andResuscitation vol 15 no 2 pp 119ndash125 2013
[66] S-H Su W Xu J Hai Y-F Wu and F Yu ldquoEffects of statins-use for patients with aneurysmal subarachnoid hemorrhagea meta-analysis of randomized controlled trialsrdquo ScientificReports vol 4 article 4573 2014
[67] J Guo Z Shi K Yang J H Tian and L Jiang ldquoEndothelinreceptor antagonists for subarachnoid hemorrhagerdquo CochraneDatabase of Systematic Reviews vol 9 Article ID CD0083542012
[68] J Shen J-W Pan Z-X Fan X-X Xiong and R-Y ZhanldquoDissociation of vasospasm-related morbidity and outcomesin patients with aneurysmal subarachnoid hemorrhage treatedwith clazosentan a meta-analysis of randomized controlledtrials a reviewrdquo Journal of Neurosurgery vol 119 no 1 pp 180ndash189 2013
[69] P Gomis J P Graftieaux R Sercombe D Hettler BScherpereel and P Rousseaux ldquoRandomized double-blindplacebo-controlled pilot trial of high-dose methylprednisolonein aneurysmal subarachnoid hemorrhagerdquo Journal of Neuro-surgery vol 112 no 3 pp 681ndash688 2010
[70] A H Kramer and J J Fletcher ldquoLocally-administered intrathe-cal thrombolytics following aneurysmal subarachnoid hem-orrhage a systematic review and meta-analysisrdquo NeurocriticalCare vol 14 no 3 pp 489ndash499 2011
[71] G J Liu Z J Wang Y F Wang et al ldquoSystematic assessmentand meta-analysis of the efficacy and safety of fasudil in thetreatment of cerebral vasospasm in patients with subarachnoidhemorrhagerdquo European Journal of Clinical Pharmacology vol68 no 2 pp 131ndash139 2012
[72] S Zhang LWangM Liu andBWu ldquoTirilazad for aneurysmalsubarachnoid haemorrhagerdquo Cochrane Database SystematicReview vol 2 Article ID CD006778 2010
[73] M-Y Tseng P J Hutchinson H K Richards et al ldquoAcutesystemic erythropoietin therapy to reduce delayed ischemicdeficits following aneurysmal subarachnoid hemorrhage aphase II randomized double-blind placebo-controlled trialclinical articlerdquo Journal of Neurosurgery vol 111 no 1 pp 171ndash180 2009
[74] H Kasuya ldquoDevelopment of nicardipine prolonged-releaseimplants after clipping for preventing cerebral vasospasm from
International Journal of Inflammation 13
laboratory to clinical trialrdquo Acta Neurochirurgica Supplemen-tum vol 115 pp 41ndash44 2013
[75] C Thome M Seiz G A Schubert et al ldquoNicardipine pelletsfor the prevention of cerebral vasospasmrdquoActaNeurochirurgicano 110 pp 209ndash211 2011
[76] T Nassar S Akkawi A Shina et al ldquoIn vitro and in vivo effectsof tPA and PAI-1 on blood vessel tonerdquo Blood vol 103 no 3 pp897ndash902 2004
[77] T Sugawara R Ayer V Jadhav W Chen T Tsubokawaand J H Zhang ldquoMechanisms of statin treatment in cerebralvasospasmrdquo Acta Neurochirurgica no 110 pp 9ndash11 2011
[78] M D Vergouwen R J De Haan M Vermeulen and YB Roos ldquoEffect of statin treatment on vasospasm delayedcerebral ischemia and functional outcome in patients withaneurysmal subarachnoid hemorrhage a systematic review andmeta-analysis updaterdquo Stroke vol 41 no 1 pp e47ndashe52 2010
[79] G E Thwaites N D Bang N H Dung et al ldquoDexamethasonefor the treatment of tuberculous meningitis in adolescents andadultsrdquoTheNew England Journal ofMedicine vol 351 no 17 pp1741ndash1811 2004
[80] G E Thwaites J Macmullen-Price T T H Chau et al ldquoSerialMRI to determine the effect of dexamethasone on the cerebralpathology of tuberculous meningitis an observational studyrdquoThe Lancet Neurology vol 6 no 3 pp 230ndash236 2007
[81] U K Misra J Kalita and P P Nair ldquoRole of aspirin in tuber-culous meningitis a randomized open label placebo controlledtrialrdquo Journal of the Neurological Sciences vol 293 no 1-2 pp12ndash17 2010
[82] P W G Elbers and C Ince ldquoBench-to-bedside review mech-anisms of critical illnessmdashclassifying microcirculatory flowabnormalities in distributive shockrdquoCritical Care vol 10 article221 2006
[83] S Trzeciak I Cinel R P Dellinger et al ldquoResuscitating themicrocirculation in sepsis the central role of nitric oxideemerging concepts for novel therapies and challenges forclinical trialsrdquo Academic Emergency Medicine vol 15 no 5 pp399ndash415 2008
[84] Y Sakr M-J Dubois D De Backer J Creteur and J-LVincent ldquoPersistent-microcirculatory alterations are associatedwith organ failure and death in patients with septic shockrdquoCritical Care Medicine vol 32 no 9 pp 1825ndash1831 2004
[85] P E Spronk J H Rommes C Schaar andC Ince ldquoThromboly-sis in fulminant purpura observations on changes in microcir-culatory perfusion during succesful treatmentrdquoThrombosis andHaemostasis vol 95 no 3 pp 576ndash578 2006
[86] J Creteur D De Backer Y Sakr M Koch and J-L VincentldquoSublingual capnometry tracks microcirculatory changes inseptic patientsrdquo Intensive Care Medicine vol 32 no 4 pp 516ndash523 2006
[87] D De Backer J Creteur J C Preiser M J Dubois and JL Vincent ldquoMicrovascular blood flow is altered in patientswith sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 1 pp 98ndash104 2002
[88] G M Ibrahim and R L Macdonald ldquoThe effects of fluid bal-ance and colloid administration on outcomes in patients withaneurysmal subarachnoid hemorrhage a propensity score-matched analysisrdquoNeurocritical Care vol 19 no 2 pp 140ndash1492013
[89] T W Yeo D A Lampah R Gitawati et al ldquoImpaired nitricoxide bioavailability and L-arginine-reversible endothelial dys-function in adults with falciparum malariardquo The Journal ofExperimental Medicine vol 204 no 11 pp 2693ndash2704 2007
[90] A R Fathi R M Pluta K D Bakhtian M Qi and R RLonser ldquoReversal of cerebral vasospasmvia intravenous sodiumnitrite after subarachnoid hemorrhage in primates laboratoryinvestigationrdquo Journal of Neurosurgery vol 115 no 6 pp 1213ndash1220 2011
[91] D de Backer J Creteur M J Dubois et al ldquoThe effects ofdobutamine on microcirculatory alterations in patients withseptic shock are independent of its systemic effectsrdquo CriticalCare Medicine vol 34 no 2 pp 403ndash408 2006
[92] C E Chapleau R P White and J T Robertson ldquoCerebralvasospasm effects of prostaglandin synthetase inhibitors invitrordquo Neurosurgery vol 6 no 2 pp 155ndash159 1980
[93] J L Frazier G Pradilla P P Wang and R J TamargoldquoInhibition of cerebral vasospasm by intracranial delivery ofibuprofen from a controlled-release polymer in a rabbit modelof subarachnoid hemorrhagerdquo Journal of Neurosurgery vol 101no 1 pp 93ndash98 2004
[94] G Pradilla Q A Thai F G Legnani et al ldquoLocal deliveryof ibuprofen via controlled-release polymers prevents angio-graphic vasospasm in a monkey model of subarachnoid hem-orrhagerdquo Neurosurgery vol 57 no 1 pp 184ndash189 2005
[95] R P White and J T Robertson ldquoComparison of piroxicammeclofenamate ibuprofen aspirin and prostacyclin efficacy ina chronic model of cerebral vasospasmrdquo Neurosurgery vol 12no 1 pp 40ndash46 1983
[96] T Fukumori E Tani Y Maeda and A Sukenaga ldquoEffectsof prostacyclin and indomethacin on experimental delayedcerebral vasospasmrdquo Journal of Neurosurgery vol 59 no 5 pp829ndash834 1983
[97] L Brandt B Ljunggren K-E Andersson B Hindfelt and TUski ldquoProstaglandin metabolism and prostacyclin in cerebralvasospasmrdquo General Pharmacology vol 14 no 1 pp 141ndash1431983
[98] T Hakan M Zafer Berkman T Ersoy I Karatas T Sanand S Arbak ldquoAnti-inflammatory effect of meloxicam onexperimental vasospasm in the rat femoral arteryrdquo Journal ofClinical Neuroscience vol 15 no 1 pp 55ndash59 2008
[99] LG Toussaint III J A Friedman E FMWijdicks et al ldquoInflu-ence of aspirin on outcome following aneurysmal subarachnoidhemorrhagerdquo Journal of Neurosurgery vol 101 no 6 pp 921ndash925 2004
[100] B A Gross P M R Lai K U Frerichs and R Du ldquoAspirin andaneurysmal subarachnoid haemorrhagerdquo World Neurosurgery2013
[101] S Yokobori AWatanabe R Nakae et al ldquoCerebral vasospasmsafter intraventricular hemorrhage from an arteriovenousmalformationmdashcase reportrdquo Neurologia Medico-Chirurgicavol 50 no 4 pp 320ndash323 2010
[102] B S Park Y S Won S S Choi and B M Kim ldquoSeveresymptomatic vasospasm following intraventricular hemorrhagefrom arteriovenous fistulardquo Journal of Korean NeurosurgicalSociety vol 45 no 5 pp 300ndash302 2009
[103] G Pradilla T Garzon-Muvdi J J Ruzevick et al ldquoSystemicL-citrulline prevents cerebral vasospasm in haptoglobin 2-2transgenicmice after subarachnoid hemorrhagerdquoNeurosurgeryvol 70 no 3 pp 747ndash757 2012
[104] G Chen J Wu C Sun et al ldquoPotential role of JAK2 in cere-bral vasospasm after experimental subarachnoid hemorrhagerdquoBrain Research vol 1214 pp 136ndash144 2008
[105] C L Lin A L Kwan A S Dumont et al ldquoAttenuationof experimental subarachnoid hemorrhage-induced increases
14 International Journal of Inflammation
in circulating intercellular adhesion molecule-1 and cerebralvasospasm by the endothelin-converting enzyme inhibitor CGS26303rdquo Journal of Neurosurgery vol 106 no 3 pp 442ndash4482007
[106] K Iseda S Ono K Onoda et al ldquoAntivasospastic and antiin-flammatory effects of caspase inhibitor in experimental sub-arachnoid hemorrhagerdquo Journal of Neurosurgery vol 107 no 1pp 128ndash135 2007
[107] C-L Lin A S Dumont T Calisaneller A-L Kwan S-L Hwong and K S Lee ldquoMonoclonal antibody against Eselectin attenuates subarachnoid hemorrhage-induced cerebralvasospasmrdquo Surgical Neurology vol 64 no 3 pp 201ndash206 2005
[108] R Echigo N Shimohata K Karatsu et al ldquoTrehalose treat-ment suppresses inflammation oxidative stress and vasospasminduced by experimental subarachnoid hemorrhagerdquo Journal ofTranslational Medicine vol 10 no 1 article 80 2012
[109] CWakadeM D KingM D Laird C H Alleyne Jr and KMDhandapani ldquoCurcumin attenuates vascular inflammation andcerebral vasospasm after subarachnoid hemorrhage in micerdquoAntioxidants amp Redox Signaling vol 11 no 1 pp 35ndash45 2009
Submit your manuscripts athttpwwwhindawicom
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Disease Markers
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
4 International Journal of Inflammation
conducted in concordance with this axiom with the goal ofinterrupting this perceived chain of events [39]
Autopsy studies in nonoperated SAH patients reportedthat 80 of fatal cases showed widely scattered trian-gular round or laminar ischemic lesions in the cortexAn ongoing clinical multicenter study reported that in 18post-SAH patients the occurrence of spreading depolar-ization with cortical spreading ischaemia was associatedwith delayed infarcts in brain computed tomography andmagnetic resonance imaging These findings indicate a newSAH-related mechanism of acute brain injury involving therelease of oxyhaemoglobin and ET-1 and NO deprivationall of which are found in SAH and can cause corticalspreading depression and ischaemia in experimental models[40] Endothelium-dependent dilation hereby seems to bereduced partly because of reduced expression of guanylatecyclase [41] Experimentally neurogenic and endothelium-dependent vasodilatation have been shown to be alteredby the presence of haemoglobin (Hb) in the bath [42] Amore complete review of this mechanism can be foundelsewhere [43] Cerebral vasomotor disturbances have beendemonstrated in humans after SAH inmeasurements of cere-bral blood flow by 133-xenon tomography One of the mostimportant functional consequences of SAH is the relativeloss of cerebrovascular dilatory capacity after acetazolamideinjection [44]The sources of NO in the cerebral arteries [45]are such that it has been supposed that Hb scavenging of NOcould induce vasospasm (VS) The prolonged presence of aperivascular clot seems necessary to maintain VS since clotremoval up to 3 days after haemorrhage reduces VS but after5 days it has little influence [46]
Prostaglandin E2 (PGE2) is the eicosanoid moleculepresent in the highest concentration in the CSF after SAHThe concentration increases by more than 25 times soonafter the haemorrhage and remains high for several days[47] This rise probably explains the fever usually found inSAH The production of PGE2 is induced by cyclooxygenase2 induction by inflammatory mediators including TNF inplatelets and microvessel endothelial cells [48 49] There isevidence of early increased TNF-concentration in the CSF ofpatients with SAH [47 50] PGE2 has been shown to inducecontraction in large cerebral arteries [51]
6 The Role of Inflammatory Mediators inGeneration of Vasospasm
The Interaction of Inflammatory Mediators with CerebralVasculature To enable an understanding of the pathomech-anisms involved in inflammation related cerebral vasospasmand resulting brain ischaemia it is important to analyse theinteraction of inflammatory mediators with each other andthe cerebral vasculature Amediator whichwas found to be ofkey importance in reduction of the risk of cerebral vasospasmin bacterial meningitis cerebral malaria brain injury andsubarachnoid haemorrhage is nitric oxide (NO)
NO can be inactivated by reaction with the superoxideanion resulting in the formation of peroxynitrite Inactivationof NO by superoxide anion may contribute to impaired
NO-mediated dilatation of cerebral blood vessels underconditions inwhich reactive oxygen species are produced likebrain injury and meningitis
Production of superoxide anions has also been reportedto occur in brain in response to seizures fluid-percussioninjury perivascular blood and ischaemia with reperfusionEndothelial NO synthase is downregulated by TNF and NOby a negative-feedback mechanism [52 53] In addition toinflammatory mediators sensory fibres originating in thetrigeminal ganglion modulate constrictor responses in thecerebral microcirculation in conditions like meningitis [7]
The most important factor leading to vasoconstrictionin cerebral blood vessels is ET-1 a 21 amino acid peptidewith three isopeptides produced by separate genes Only ET-1 is produced in cerebral endothelium and mediates cerebralvasoconstriction via endothelin-A (ETA) receptors ETA islocalized in vascular smooth muscle cells and stimulationleads to increase in intracellular calcium concentrationsleading to vasoconstriction ET-1 expression is enhanced bytransforming growth factor-beta haemoglobin interleukin-1 and TNF and can be inhibited by NO nitric oxide donordrugs and dilator prostanoids via an increase in cellularcGMP and natriuretic peptides via an increase in cAMPlevels NO can produce relaxation of some blood vessels fromsome species via activation of potassium channels [7]
Cerebral blood vessels can produce 20-hydroxyeicosate-traenoic acid from arachidonic acid via a P-450 enzymeThissubstance is a potent vasoconstrictor whichmay produce thiseffect by inhibition of activity of potassium channels [7]
A further potential mechanism involved in cerebralvasospasm in cerebral inflammation is inhibition of potas-sium channels Nicorandil which produces relaxation ofcerebral vessels by activation of potassium channels partiallyreverses vasospasm in an experimental model of subarach-noid haemorrhage
The effectiveness of other synthetic activators of potas-sium channels like aprikalim and cromakalim and CGRPindicate that activators of potassium channels in vascularmuscle may help in cerebral vasospasm in cerebral inflam-mation [7]
The etiological role of specific cytokines in vasospasm inbacterial meningitis in vivo was highlighted by a study whichdocumented a significant increase in IL-1-beta and IL-6 con-centrations in patients with elevated cerebrovascular bloodflow indicative of vasospasm in humans [14 54] A similareffect on vasospasm of IL-1 and IL-6 was suggested by a studyof cerebral blood flow in subarachnoid haemorrhage whereincreased cerebral blood flow velocities were associated withsignificantly increased CSF concentrations of IL-1 IL-6 andTNF High concentrations of these immunomediators incerebrospinal fluid (CSF) may exert vasoactive effects forexample IL-1 (MW 17 000Da) or IL-6 (MW 26 000Da)could easily get access to the walls of contiguous basalarteries from their adventitial side as even larger molecules(eg horseradish peroxidase MW 40 000Da) pass from thecisternamagna through the vessel wall to the basalmembranewithin minutes This is possible because by contrast withother arteries the surface of the major cerebral arteries is not
International Journal of Inflammation 5
confined by collagen or fibroblasts but is in direct contactwiththe CSF
An investigation in patients with SAH showed that levelsof IL-1-beta but not TNF-alpha were increased and correlatedwith the later development of vasospasm IL-1 acts throughG-protein coupled receptors in three ways which causecontraction of vascular smooth muscle (see Figure 1)
(1) Activation of phospholipase C generated phosphat-idylinositol trisphosphate causes calcium releasewhich leads to myosin light chain kinase activationleading to myosin light chain activation and calciumdependent vasospasm Phosphorylation of myosinlight chain (MLC) by MLC kinase is one of themost important steps for vascular smooth musclecontraction
(2) Activation of protein kinase C (PKC) through phos-pholipase C generated diacylglycerol (from phos-phatidylinositol (45) bisphosphate) can act throughphosphorylation and hence activation of the myosinlight chain kinase Prolonged contraction in cerebralvasospasm for up to two weeks can be mediated bythis mechanism
(3) PKC activation regulates MLC phosphorylation thro-ugh activation of rho-kinase and the myosin-bindingsubunit (MBS) of MLC phosphatase (MLCPh) Rho-kinase hereby phosphorylates MBS which results inthe inhibition of MLCPh [55] The reduced MLCPhactivity leads to increased phosphorylation and hencecontractility of the MLC resulting in calcium inde-pendent vasospasm Investigations in a porcinemodelrevealed that hydroxyfasudil a specific rho-kinaseinhibitor exerted an inhibitory effect on vasospasmboth in vitro and in vivo Western blot analysisshowed that during serotonin-induced contractionsthe extent of phosphorylation of the MBS was sig-nificantly greater in the spastic than in the controlsegment There was a highly significant correlationbetween the extent of MBS phosphorylation andcontractions [55]
Another key mechanism whereby IL-1 mediates vasosp-asm may be through platelet derived growth factor Thereceptors for this growth factor are also known to havetyrosine kinase activity and inhibition of tyrosine kinase isknown to reduce vasospasm in a swine model [56 57] Thisaction influences vascular reactivity to different agonists andmight be crucial for the regulation of cerebral artery toneduring vasospasm [58]
Calcium independent vasospasm may also be inducibleby haemoglobin released in trauma or subarachnoid haem-orrhage
Haemoglobin might cause contraction of major cerebralarteries by scavenging nitric oxide reducing neuronal nitricoxide synthase (NOS) in the adventitia of the cerebral arter-ies and evoking dysfunction of endothelial NO synthase Adecrease in nitric oxide availability might produce prolongedpathological contraction regardless of the concentration ofintracellular calcium Much of the work investigating the
genetic predisposition to cerebral vasospasm focused on theendothelial isoform of nitric oxide synthase Hemoglobinalso stimulates the production of endothelins and the imbal-ance of nitric oxide and endothelin could be an importantcause of pathological arterial contraction In gene transferexperiments eNOS overexpression in animal and humanintracranial arteries is vasoprotective after aneurysmal SAH[59] Several investigations confirmed the association of theT-786C genotype of eNOS with vasospasm For a summaryof key mediators in cerebral vasospasm their function anddisease studied see Table 1
7 Therapeutic Approaches toPrevention and Correction of VasospasmAssociated with Cerebral InflammationTested in Clinical Trials in Humans
The most extensive experience with treatment approachesto vasospasm in cerebral inflammation has been gatheredin the context of management of SAH Clinical trials inhumans have been reported for endothelin-1 antagonists cal-cium channel blockers including the cisternal placement ofcontrolled-release nicardipine intravenous magnesium sul-phate oral statins rho-kinase inhibitors tissue plasminogenactivator tirilazad erythropoietin and methylprednisoloneThe evidence from controlled trials has been summarized inTable 2
71 Endothelin-1A Receptor Antagonists The selective endo-thelin-1A receptor antagonist clazosentan was assessed ina randomized placebo controlled trial (CONSCIOUS-1)and led to a significant reduction of angiographic cerebralvasospasm in SAH but without reduction in the numberof cerebral ischaemia events Subsequent phase II trials(CONSCIOUS-2 and CONSCIOUS-3) in SAH did notdemonstrate any effect on morbidity or mortality A meta-analysis of 4 RCTswith 2024 participants confirmed this find-ing but showed a reduction in delayed ischemic neurologicaldeficit with the endothelin-1A receptor antagonist [67]
72 Calcium Channel Blockers Calcium antagonists have thepotential to prevent the occurrence of calcium dependentvasospasm and delayed ischemic neurological deficit byreducing calcium release (see Figure 1) They have beenapplied directly to the subarachnoid space [74] Intraopera-tive implantation of nicardipine prolonged-release implantsso-called pellets into the basal cistern in close contact to theproximal cerebral vasculature has been reported to reducethe occurrence of cerebral vasospasm and cerebral infarctionand lead to an improvement in clinical outcome in SAH [75]Themagnesium ion is an antagonistic competitor for calciumbinding sites thus having the potential to reduce calciumdependent vasospasm and has been used in the form ofintravenous magnesium sulphate in a number of trials (seeTable 2)
6 International Journal of Inflammation
GPCR
Macrophage
Interleukin-1
Lipopolysaccharide
Plasmodium falciparum antigens
Stimulation of interleukin-1 release
MLCK
PKC
MLCMLCK-P
Rho-kinase MBSMBS-P
MLCPh
Intracellular autoantigens (fromtissue injury)
PLC ≫ IP3 ≫ calcium releaseminusRho-kinase-P
Figure 1 Mechanism for induction of cerebral vasospasm by interleukin-1 (GPCR = G-protein coupled receptor PKC = protein kinase CMLCK = myosin light chain kinase MLC = myosin light chain MBS = myosin-binding subunit of myosin light chain phosphatase MLCPh=myosin light chain phosphatase -P indicates phosphorylated state PLC = phospholipase C and IP3 = phosphatidylinositol trisphosphate)
Table 1 Inflammatory mediators and their role in cerebral vasospasm
Mediator Function of mediator Disease model where role hasbeen established References
(i) Nitric oxide(i) Vasodilator(ii) Inhibitor of endothelin-1expression
(i) Cerebral malaria(ii) Bacterial meningitis(iii) Subarachnoid haemorrhage
[1 7 16 28 32 41 45]
(i) Endothelin-1 (i) Vasoconstrictor (i) Bacterial meningitis(ii) Subarachnoid haemorrhage [7 15]
(i) Interleukin-1(ii) Interferon gamma(iii) Tumor necrosis factor
(i) Activators of protein kinase C(ii) Stimulators of release ofendothelin-1
(i) Bacterial meningitis(ii) Cerebral malaria(iii) Subarachnoid haemorrhage
[7 14 56]
73 Tissue Plasminogen Activator A recent meta-analysis offive randomized controlled trials (465 patients) of tissue plas-minogen activator (tPA) or urokinase applied intrathecallyreduced development of poor outcome and delayed cerebralischaemia and vasospasm [70]Themechanism proposed forthis effect is probably not related to thrombolysis but to adirect effect of tPA on vascular tone It is clear that the effectof tPA is endothelial cell dependent and more specificallyNO synthase dependent tPA seems to bind to a receptorpresent in endothelial cells that mediates the stimulation ofNO synthase activity and thus inhibits the vasoconstrictiveeffect of phenylephrine [76]
74 Statins Statins can reduce vasospasm by upregulatingendothelial NO synthase expression A threefold increasein endothelial NO synthase mRNA protein and enzymatic
activity has been demonstrated following statin treatmentresulting in an increase in cerebral blood flow Statintreatment has attenuated cerebral vasospasm and preventeddelayed ischemic deficits in amurine SAHmodel [77] A pre-vious systematic review of 4 studies with a total of 190 patientsshowed no statistically significant effect on vasospasm ontranscranial Doppler studies delayed cerebral ischaemia ormortality [78] but a more recent review demonstrated areduction in mortality and delayed ischemic neurologicaldeficits [66]
75 Rho-Kinase Inhibitor The specific rho-kinase inhibitorfasudil hydrochloride was in a recent systematic review of8 studies (843 patients) shown to reduce the occurrenceof cerebral vasospasm and cerebral infarction significantlyand led to an improvement in clinical outcome [71] The
International Journal of Inflammation 7
Table2Medicationfortreatmento
fcerebralvasospasm
the
evidence
from
controlledtrialsin
humans
Interventio
nTy
peof
study
Patholog
yRe
sultsodd
sratio
(OR)
orrelativer
isk(RR)
foro
ccurrencein
interventio
ngrou
pcomparedto
grou
pwith
outintervention
Reference
Calcium
channel
blockers
Syste
maticreview
(SR)
(sixrand
omized
controlledtrials
(RCT
s))
Acuteb
rain
injury
DeathO
R091
[95
070ndash117
]Death
andsevere
disabilityOR085
[95
068
to10
7]In
thes
ubgrou
pof
traumaticsubarachno
idhaem
orrhagep
atients
pooled
odds
ratio
was
059
[95
CI037ndash0
94]three
RCTs
repo
rtingdeathandsevere
disabilityas
anou
tcom
einthis
subgroup
OR067
[95
CI046
ndash098]
[60]
Calcium
channel
blockers
SR(16RC
Ts)
Aneurysmal
subarachno
idhaem
orrhage(aSAH)
Overallcalcium
antagonists
redu
cedther
iskof
poor
outcom
ethe
relativer
isk(RR)
was
081
[95
CI072
to092]thec
orrespon
ding
numbero
fpatientsn
eededto
treatwas
19[95
CI1to51]foro
ral
nimod
ipinea
lone
theR
Rwas
067
[95
CI055
to081]foro
ther
calcium
antagonists
orintravenou
sadm
inistratio
nof
nimod
ipine
ther
esultsweren
otsta
tistic
allysig
nificantcalcium
antagonists
redu
cedtheo
ccurrenceo
fsecon
dary
ischaem
iaandshow
eda
favourabletre
ndforc
asefatality
for
magnesiu
minadditio
nto
standard
treatmentw
ithnimod
ipinetheR
Rwas
075
[95
CI057
to10
0]fora
poor
outcom
eand
066
[95
CI045
to096]for
clinicalsigns
ofsecond
aryisc
haem
ia
[61]
Nicardipine
SR(five
controlled
trials)
aSAH
Risk
ofpo
orou
tcom
e(deathvegetativ
estateord
ependency)
OR
058
(95
CI037ndash0
9)
Mortalityod
dsratio
045[95
CI015
to12
9][62]
Magnesiu
msulfate
Prospective
rand
omise
dstu
dyEclampsia
Sign
ificant
redu
ctionof
pulsa
tility
index(119875=0002)a
ndmeanflo
wvelocityin
middlec
erebralartery(119875=002)
[63]
Prop
hylactic
magnesiu
msulfate
SRof
tenrand
omized
parallelgroup
controlledtrials
aSAH
Glasgow
outcom
escaleandmod
ified
Rank
inscaleR
R093
(95
CI082
to10
6)m
ortality095
(95
CI076ndash117
)delay
edcerebral
ischaem
iaRR
054(95
CI038
to075)delay
edisc
hemic
neurologicaldeficit(D
IND)RR
of093
[95
CI062ndash139
]transcranialDop
pler
vasospasmR
R072
[95
CI051ndash103]
[64]
Indu
ced
hyperm
agnesaem
iaRC
TaSAH
Vasospasm
ondigitalsub
tractio
nangiograph
yOR
051[95CI
026
to10
2]neurologicalrecoveryORforw
orse
outcom
e071
[95
CI039
to13
2][65]
Statins
SR(sixRC
Ts)
aSAH
Incidenceo
fvasospasm
RR080[95
CI054ndash
117]poo
rneurologicalou
tcom
eRR
094[95
CI077to
116]
MortalityRR
030[95
CI014
ndash064]
DIN
DR
R058
[95
CI037
ndash092]
[66]
Endo
thelin
receptor
antagonists
SR(fo
urRC
Ts)
aSAH
Incidenceo
fDIN
Drela
tiver
isk08[95
CI067ndash0
95]
angiograph
icvasospasm
RR062[95CI
052
to072]
unfavourableou
tcom
eRR
087[95
CI074ndash102]m
ortalityRR
105[95
CI077
to14
5]
[67]
8 International Journal of Inflammation
Table2Con
tinued
Interventio
nTy
peof
study
Patholog
yRe
sultsodd
sratio
(OR)
orrelativer
isk(RR)
foro
ccurrencein
interventio
ngrou
pcomparedto
grou
pwith
outintervention
Reference
Endo
thelin-1Areceptor
antagonistClazosentan
SR(fo
urRC
Ts)
aSAH
Relativer
iskforincidence
ofDIN
Ds076
(95
CI062ndash0
92)
delay
edcerebralinfarctio
n079
[95
CI063ndash100]G
lasgow
outcom
escaleextend
edRR
112
[95
CI096ndash130]m
ortalityRR
10
2[95
CI070ndash149]
[68]
Intravenou
smethylpredn
isolone
RCT
aSAH
Symptom
aticvasospasm
265in
interventio
ngrou
pcompared
with
26in
placebogrou
pfunctio
naloutcomes
caleredu
cedin
the
methylpredn
isolone
grou
pwith
riskdifference193
[95
CI05ndash379]ou
tcom
epoo
rin15of
patie
ntsinthe
methylpredn
isolone
grou
pversus
34in
thep
lacebo
grou
p
[69]
Tissue
plasminogen
activ
ator
SR(five
RCTs)
aSAH
Overalluseo
fintrathecalthrombo
lytic
swas
associated
with
significantreductio
nsin
thed
evelo
pmento
fpoo
routcomes
(OR
052034ndash
078119875lt001)DIN
Ds(OR054034ndash
087119875=001)
andangiograph
icvasospasm
(OR032015
ndash070119875lt001)
[70]
Rho-kinase
inhibitor
SR(8
controlledtrials)
aSAH
Absenceo
fsym
ptom
aticvasospasmoccurrenceo
flow
density
areas
associated
with
vasospasm
onCT
and
occurrence
ofadversee
vents
weres
imilarb
etweenthetwogrou
psthe
clinicaloutcomes
were
morefavorablein
thefasud
ilgrou
pthan
inthen
imod
ipineg
roup
(119875=004)
[71]
Tirilazad
SR(five
RCTs)
aSAH
Therew
asno
significantd
ifference
betweenthetwogrou
psatthe
endof
follo
w-upforthe
prim
aryou
tcom
edeathOR
089[95CI
074
to10
6]orinpo
orou
tcom
e(deathvegetativ
estateorsevere
disability)
OR10
4[95
CI090
to12
1]few
erpatie
ntsd
evelop
eddelay
edcerebralisc
haem
iain
thetirilazadgrou
pthan
inthec
ontro
lgrou
pOR080
[95
CI069
to093]subgroup
analyses
didno
tdemon
stratea
nysig
nificantd
ifference
ineffectsof
tirilazadon
clinicaloutcomes
[72]
Erythrop
oietin
RCT
aSAH
Nodifferences
wered
emon
strated
intheincidence
ofvasospasm
andadversee
ventspatie
ntsreceiving
EPOhadad
ecreased
incidenceo
fseverev
asospasm
from
275to
75(119875=0037)
redu
cedDID
swith
newcerebralinfarctsfro
m40
0to
75
(119875=0001)as
hortened
duratio
nof
impaire
dautoregu
latio
n(ip
silateralsid
e119875lt0001)andmorefavorableou
tcom
eat
discharge(favorableG
lasgow
outcom
escalescore119875=0039)
amon
gthe7
1survivorsthe
EPOgrou
phadfewer
deficits
measured
with
NationalInstitutes
ofHealth
Stroke
Scale(medianscore2
versus
6119875=0008)
[73]
International Journal of Inflammation 9
mechanism is apart from a contribution to inhibition ofcalcium independent vasospasm (see above) probably alsoan increase of endothelial nitric oxide synthase (eNOS)expression by stabilizing eNOSmRNA which can contributeto an increase of NO level to enhance vasodilatation
76 Other Treatments Steroid treatment can inhibit cytokineexpression and has thus the potential to reduce cytokinemediated calcium dependent and independent vasospasmIn tuberculous meningitis adjuvant treatment with corticos-teroids has been indirectly associatedwith features of reducedvasculopathy which may include vasospasm
A large randomised controlled trial showed improvedmortality in tuberculous meningitis with adjuvant corti-costeroids but did not show a reduction in severe disabil-ity however an observational MRI study did suggest areduction in strokes in patients treated with corticosteroids[79 80] An open-label study of aspirin in the preventionof stroke and mortality in tuberculous meningitis found anonsignificant reduction in stroke and a significant reductionin mortality with a possible synergism with corticosteroids[81] Mechanisms responsible for a potential effect may bea reduction of the vasoconstricting effect of PGE2 The 21-aminosteroid tirilazad is a lipid peroxidation inhibitor whichinhibits free radical-induced lipid peroxidation (LP) by acombination of lipid peroxide scavenging and a membrane-stabilizing action that limits the propagation of LP reactionsbetween a lipid peroxide and an adjacent polyunsaturatedfatty acid There has been no consistent evidence of benefitin animal or human studies Erythropoietin may act throughincrease in expression of endothelial nitric oxide synthasethus increasing NO bioavailability
8 Conclusions and Perspectives forFuture Developments
There is evidence for common pathways leading tovasospasm in all forms of cerebral inflammation involvinginterleukin-1 tumor necrosis factor endothelin-1 andnitric oxide Treatments addressing the pathophysiologyof vasospasm in one form of cerebral inflammation maytherefore apply to all others Treatment of cerebral vasospasmhas been mainly investigated in aneurysmal SAH Agentsfor which there is likely to be clinical benefit are calciumantagonists statins and intrathecal plasminogen activators(see Table 2) The fact that there is calcium dependent andindependent vasospasm in inflammation (see Figure 1)shows that a combination of calcium antagonists with agentsinterfering with calcium independent vasospasm includingagents improving the bioavailability of nitric oxide is theway forward Future trials need to investigate their effectsin patients with all forms of cerebral inflammation leadingto neurological deficits attributable to vasospasm In vivocorrelates for reduction of vasospasm in the peripheralcirculation could be explored as a surrogate for reduction ofvasospasm in the cerebral (micro) vasculature
Strategies to improve microvascular recruitment whichhave been explored in models of septicaemia could poten-tially be applied to cerebral vasospasm Distributive shockwhich occurs during sepsis and septic shock is associatedwith an abnormal distribution of microvascular blood flowVasospasm of part of the arterioles supplying the capillary isa mechanism involved in this maldistribution The clinicalintroduction of new microcirculatory imaging techniquessuch as orthogonal polarization spectral and side-streamdark-field imaging (OPSSDF) has allowed direct obser-vation of the microcirculation at the bedside Images ofthe sublingual microcirculation during septic shock andresuscitation have revealed that the distributive defect ofblood flow occurs at the capillary level [82]
In rat models of cecal ligation and puncture investiga-tors have used intravital video microscopy to demonstratethat sepsis is characterized by decreased microcirculatoryflow velocity an abundance of stopped-flow microvesselsincreased heterogeneity of microcirculatory flow and lowdensity of perfused capillaries As thesemicrocirculatory flowalterations can occur in the absence of global hemodynamicderangements (eg absence of arterial hypotension) micro-circulatory dysfunction largely reflects intrinsic events occur-ring in the microvessels like localized vasospasm [83] Appli-cation ofmicrocirculatory recruitmentmaneuver procedureshas been shown to be effective in promotingmicrocirculatoryblood flow in clinical studies using OPSSDF imaging [84ndash87] Fluid resuscitation in combination with the nitric oxidedonor nitroglycerine was shown to recruit disturbed micro-circulation following pressure guided resuscitation in septicshock patients
It is important to note that application of colloids inpatients with SAH was associated with worse outcomescompared to matched controls in a subgroup analysis of theCONSCIOUS-1 prospective randomized trial of clazosentanfor the prevention of angiographic vasospasm [88] Futureresearch needs to investigate whether colloids can bind nitricoxide and make this vasodilator less available by binding it
Regarding future therapeutic interventions increasingnitric oxide bioavailability erythropoietin and L-argininewhich increased bioavailability of nitric oxide in patients withmalaria [89] need to be explored as adjunctive treatmentin children with cerebral malaria in randomised controlledtrials In vitro the availability of L-arginine does not appearto be a rate limiting step for the activity of the NO synthasebecause its half-saturating concentration is less than 3of theplasma and endothelial concentration of this substrate
The nitric oxide donor intravenous sodium nitrite hasbeen shown to prevent and reverse cerebrovascular spasmin primates and has been demonstrated to be safe foradministration in humans [90]
Support of pump function by dobutamine therapy hasbeen shown to improvemicrocirculatory flow independent ofimprovement of global hemodynamic parameters [91] Fluidapplication nitric oxide donors and dobutamine therapyneed to be explored in isolation but also as combinationof interventions to improve cerebral perfusion in cerebralinflammation associated with vasospasm
10 International Journal of Inflammation
A potential role of nonsteroidal anti-inflammatory drugswas revealed by landmark experiments on dog basilararteries Arachidonic acid induced sustained contractionsand these responses were markedly inhibited (95) bymeclofenamate and similarly by indomethacin but aspirinhad no such effect [92] In the rabbit basilar artery model ofcerebral vasospasm local intracranial delivery of ibuprofenaccomplished using controlled-release polymers preventedvasospasm when administered within 6 hours but notat either 12 or 24 hours [93] Delivery of ibuprofen viacontrolled-release polymers into the subarachnoid space ofmonkeys with subarachnoid haemorrhage prevented angio-graphic vasospasm after SAH as evident from patency of themiddle cerebral artery [94]
Piroxicam was more effective than the above-mentioneddrugs in the SAH dog model after angiographic analysisand analysis of behavioural changes [95] Early studiesusing prostacyclin found that isolated canine basilar arteriescontraction induced by prostaglandin E2 hemoglobin orserum was relaxed by prostacyclin but not indomethacin[96] In isolated human pial arteries prostacyclin relaxedhuman pial arteries contracted by either PGF2 alpha nora-drenaline serotonin or haemorrhagic CSF [97] In an animalstudy meloxicam reduced ultrastructural and morphometricvasospastic changes in rats with subarachnoid haemorrhage[98] Investigation comparing rate of subsequent permanentdisability from vasospasm and angiographic and delayedcerebral ischaemia in patients with SAH with and withoutaspirin intake found no association with poor outcome [99100]
There are new areas of pathophysiology research wherethe role of vasospasm needs to be explored thoroughly inorder to find avenues for therapeutic interventions Investi-gations could evaluate whether intraventricular haemorrhageoccurring commonly in the neonatal period in pretermneonates is associated with vasospasm increasing mor-bidity Case reports of intraventricular haemorrhage fromAV malformations and aneurysms in adults demonstratedvasospasm [101 102]
Future research needs to explore the usefulness of a num-ber of agents which have been demonstrated to reduce vaso-spasm in animal models including L-citrulline [103] januskinase-2 [104] endothelin converting enzyme inhibitors[105] caspase inhibitor Z-VAD-FMK [106] anti-E selectinmonoclonal antibodies [107] trehalose [108] and curcuminwhich was demonstrated to protect against the developmentof cerebral vasospasm and secondary cerebral infarctionafter subarachnoid haemorrhage in mice by its broad anti-inflammatory activity including limitation of superoxidegeneration and influence on inducible nitric oxide synthaseexpression [109]
Aggressive maintenance of normothermia or mildhypothermia in patients with military blast injury resultedin a dramatic reduction in the incidence of posttraumaticvasospasm from 475 to 5 Future studies need to confirmthis finding and investigate whether hypothermia can reducecerebral inflammation related ischemic damage to the brainin other conditions like bacterial meningitis or cerebralmalaria [37]
Conflict of Interests
The author declares that there is no conflict of interestsregarding the publication of this paper
References
[1] B Weir ldquoThe pathophysiology of cerebral vasospasmrdquo BritishJournal of Neurosurgery vol 9 no 3 pp 375ndash390 1995
[2] H Bode and A Harders ldquoTransient stenoses and occlusionsof main cerebral arteries in childrenmdashdiagnosis and control oftherapy by transcranial Doppler sonographyrdquo European Journalof Pediatrics vol 148 no 5 pp 406ndash411 1989
[3] K-F Lindegaard H Nornes S J Bakke W Sorteberg and PNakstad ldquoCerebral vasospasm diagnosis by means of angiogra-phy and blood velocity measurementsrdquo Acta Neurochirurgicavol 100 no 1-2 pp 12ndash24 1989
[4] C Lysakowski B Walder M C Costanza and M R TramerldquoTranscranial Doppler versus angiography in patients withvasospasm due to a ruptured cerebral aneurysm a systematicreviewrdquo Stroke vol 32 no 10 pp 2292ndash2298 2001
[5] R L Grubb Jr M E Raichle J O Eichling and M HGado ldquoEffects of subarachnoid hemorrhage on cerebral bloodvolume blood flow and oxygen utilization in humansrdquo Journalof Neurosurgery vol 46 no 4 pp 446ndash452 1977
[6] C-H Lu H-W Chang C-C Lui C-R Huang and W-NChang ldquoCerebral haemodynamics in acute bacterial meningitisin adultsrdquoQuaterly Journal of Medicine vol 99 no 12 pp 863ndash869 2006
[7] F Faraci and D D Heistad ldquoRegulation of the cerebralcirculation role of endothelium and potassium channelsrdquoPhysiological Reviews vol 78 no 1 pp 53ndash97 1998
[8] L Hektoen ldquoThe vascular changes in tuberculous meningitisespecially in tuberculous endarteritisrdquo Journal of ExperimentalMedicine vol 1 pp 112ndash163 1896
[9] G Thwaites ldquoTuberculosis of the central nervous systemrdquo inClinical Tuberculosis P D O Davies S B Gordon and GDavies Eds pp 151ndash165 CRC Press 5th edition 2014
[10] P M Dalal ldquoObservations on the involvement of cerebral ves-sels in tuberculousmeningitis in adultsrdquoAdvances in Neurologyvol 25 pp 149ndash159 1979
[11] L A Rojas-Echeverri J L Soto-Hernandez S Garza et alldquoPredictive value of digital subtraction angiography in patientswith tuberculous meningitisrdquo Neuroradiology vol 38 no 1 pp20ndash24 1996
[12] E L Lyons and N E Leeds ldquoThe angiographic demonstrationof arterial vascular disease in purulent meningitis report of acaserdquo Radiology vol 88 no 5 pp 935ndash938 1967
[13] S Ries U Schminke K Fassbender M Daffertshofer WSteinke andMHennerici ldquoCerebrovascular involvement in theacute phase of bacterial meningitisrdquo Journal of Neurology vol244 no 1 pp 51ndash55 1997
[14] K Fassbender S Ries U Schminke S Schneider and M Hen-nerici ldquoInflammatory cytokines in CSF in bacterial meningitisassociation with altered blood flow velocities in basal cerebralarteriesrdquo Journal of Neurology Neurosurgery amp Psychiatry vol61 no 1 pp 57ndash61 1996
[15] L A Pfister J H Tureen S Shaw et al ldquoEndothelin inhibitionimproves cerebral blood flow and is neuroprotective in pneu-mococcal meningitisrdquoAnnals of Neurology vol 47 pp 329ndash3352000
International Journal of Inflammation 11
[16] S L Leib Y S Kim S M Black J H Tureen and M GTauber ldquoInducible nitric oxide synthase and the effect of amin-oguanidine in experimental neonatal meningitisrdquo The Journalof Infectious Diseases vol 177 no 3 pp 692ndash700 1998
[17] T W Polder C R Jerusalem andW M C Eling ldquoMorpholog-ical characteristics of intracerebral arterioles in clinical (Plas-modium falciparum) and experimental (Plasmodium berghei)cerebral malariardquo Journal of the Neurological Sciences vol 101no 1 pp 35ndash46 1991
[18] N A V Beare S P Harding T E Taylor S Lewallen and MEMolyneux ldquoPerfusion abnormalities in childrenwith cerebralmalaria andmalarial retinopathyrdquo Journal of Infectious Diseasesvol 199 no 2 pp 263ndash271 2009
[19] C R J C Newton K Marsh N Peshu and F J KirkhamldquoPerturbations of cerebral hemodynamics in Kenyans withcerebral malariardquo Pediatric Neurology vol 15 no 1 pp 41ndash491996
[20] C C John A Panoskaltsis-Mortari R O Opoka et alldquoCerebrospinal fluid cytokine levels and cognitive impairmentin cerebral malariardquo American Journal of Tropical Medicine andHygiene vol 78 no 2 pp 198ndash205 2008
[21] W McGuire A V S Hill C E M Allsopp B M Greenwoodand D Kwiatkowski ldquoVariation in the TNF-120572 promoter regionassociated with susceptibility to cerebral malariardquo Nature vol371 no 6497 pp 508ndash510 1994
[22] W McGuire J C Knight A V S Hill C E M Allsopp B MGreenwood and D Kwiatkowski ldquoSevere malarial anemia andcerebral malaria are associated with different tumor necrosisfactor promoter allelesrdquo Journal of Infectious Diseases vol 179no 1 pp 287ndash290 1999
[23] B Dugas M D Mossalayi C Damais and J-P Kolb ldquoNitricoxide production by human monocytes Evidence for a role ofCD23rdquo Immunology Today vol 16 no 12 pp 574ndash580 1995
[24] L Pellettieri B Nilsson C-A Carlsson andU Nilsson ldquoSerumimmunocomplexes in patients with subarachnoid hemorrhagerdquoNeurosurgery vol 19 no 5 pp 767ndash771 1986
[25] M Eisenhut ldquoCauses of reduced immune complex clearance incerebralmalariardquoParasite Immunology vol 31 no 2 p 59 2009
[26] P Teeranaipong J Ohashi J Patarapotikul et al ldquoA functionalsingle-nucleotide polymorphism in the CR1 promoter regioncontributes to protection against cerebral malariardquo Journal ofInfectious Diseases vol 198 no 12 pp 1880ndash1891 2008
[27] P Cabrales G M Zanini D Meays J A Frangos and LJ M Carvalho ldquoMurine cerebral malaria is associated witha vasospasm-like microcirculatory dysfunction and survivalupon rescue treatment is markedly increased by nimodipinerdquoTheAmerican Journal of Pathology vol 176 no 3 pp 1306ndash13152010
[28] I Gramaglia P Sobolewski D Meays et al ldquoLow nitricoxide bioavailability contributes to the genesis of experimentalcerebral malariardquoNature Medicine vol 12 no 12 pp 1417ndash14222006
[29] T W Yeo D A Lampah E Tjitra et al ldquoRelationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavail-ability and perfusion in severe falciparum malariardquo Journal ofInfectious Diseases vol 200 no 10 pp 1522ndash1529 2009
[30] G Dhangadamajhi B N Mohapatra S K Kar and M RanjitldquoGenetic variation in neuronal nitric oxide synthase (nNOS)gene and susceptibility to cerebral malaria in Indian adultsrdquoInfection Genetics and Evolution vol 9 no 5 pp 908ndash911 2009
[31] M R Hobbs V Udhayakumar M C Levesque et al ldquoAnew NOS2 promoter polymorphism associated with increased
nitric oxide production and protection from severe malaria inTanzanian and Kenyan childrenrdquoThe Lancet vol 360 no 9344pp 1468ndash1475 2002
[32] P Cabrales G M Zanini D Meays J A Frangos and L JM Carvalho ldquoNitric oxide protection against murine cerebralmalaria is associated with improved cerebral microcirculatoryphysiologyrdquo The Journal of Infectious Diseases vol 203 no 10pp 1454ndash1463 2011
[33] G Morahan C S Boutlis D Huang et al ldquoA promoterpolymorphism in the gene encoding interleukin-12 p40 (IL12B)is associated with mortality from cerebral malaria and withreduced nitric oxide productionrdquo Genes amp Immunity vol 3 no7 pp 414ndash418 2002
[34] C Casals-Pascual R Idro N Gicheru et al ldquoHigh levels of ery-thropoietin are associated with protection against neurologicalsequelae in African children with cerebral malariardquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 105 no 7 pp 2634ndash2639 2008
[35] F C Chow C M Marra and T A Cho ldquoCerebrovasculardisease in central nervous system infectionsrdquo Seminars inNeurology vol 31 no 3 pp 286ndash306 2011
[36] R A Armonda R S Bell A H Vo et al ldquoWartime traumaticcerebral vasospasm recent review of combat casualtiesrdquoNeuro-surgery vol 59 no 6 pp 1215ndash1225 2006
[37] K Shahlaie K Keachie I M Hutchins et al ldquoRisk factorsfor posttraumatic vasospasm clinical articlerdquo Journal of Neu-rosurgery vol 115 no 3 pp 602ndash611 2011
[38] Y Udomphorn W M Armstead and M S Vavilala ldquoCerebralblood flow and autoregulation after pediatric traumatic braininjuryrdquo Pediatric Neurology vol 38 no 4 pp 225ndash234 2008
[39] R M Pluta J Hansen-Schwartz J Dreier et al ldquoCerebralvasospasm following subarachnoid hemorrhage time for a newworld of thoughtrdquo Neurological Research vol 31 no 2 pp 151ndash158 2009
[40] J Hansen-Schwartz P Vajkoczy R L Macdonald R MPluta and J H Zhang ldquoCerebral vasospasm looking beyondvasoconstrictionrdquo Trends in Pharmacological Sciences vol 28no 6 pp 252ndash256 2007
[41] H Kasuya B K A Weir M Nakane et al ldquoNitric oxidesynthase and guanylate cyclase levels in canine basilar arteryafter subarachnoid hemorrhagerdquo Journal of Neurosurgery vol82 no 2 pp 250ndash255 1995
[42] M D Linnik and T J F Lee ldquoEffect of hemoglobin on neuro-genic responses and cholinergic parameters in porcine cerebralarteriesrdquo Journal of Cerebral Blood Flow and Metabolism vol 9no 2 pp 219ndash225 1989
[43] CG Sobey and FM Faraci ldquoSubarachnoid haemorrhage whathappens to the cerebral arteriesrdquo Clinical and ExperimentalPharmacology and Physiology vol 25 no 11 pp 867ndash876 1998
[44] Y R T Dinh G Lot R Benrabah O Baroudy J Cophignonand J Seylaz ldquoAbnormal cerebral vasodilation in aneurys-mal subarachnoid hemorrhage use of serial 133Xe cerebralblood flow measurement plus acetazolamide to assess cerebralvasospasmrdquo Journal of Neurosurgery vol 79 no 4 pp 490ndash4931993
[45] T J F Lee ldquoNitric oxide and the cerebral vascular functionrdquoJournal of Biomedical Science vol 7 no 1 pp 16ndash26 2000
[46] M Stoodley R L Macdonald B Weir et al ldquoSubarachnoidhemorrhage as a cause of an adaptive response in cerebralarteriesrdquo Journal of Neurosurgery vol 93 no 3 pp 463ndash4702000
12 International Journal of Inflammation
[47] Y R Tran Dinh A Jomaa J Callebert et al ldquoOverexpressionof cyclooxygenase-2 in rabbit basilar artery endothelial cellsafter subarachnoid hemorrhagerdquo Neurosurgery vol 48 no 3pp 626ndash635 2001
[48] A Gecse B Kis Z Mezei and G Telegdy ldquoEffects of inflam-matory neuropeptides on the arachidonate cascade of plateletsrdquoInternational Archives of Allergy and Immunology vol 118 no2ndash4 pp 166ndash170 1999
[49] K S Mark W J Trickler and D W Miller ldquoTumornecrosis factor-120572 induces cyclooxygenase-2 expression andprostaglandin release in brain microvessel endothelial cellsrdquoJournal of Pharmacology and Experimental Therapeutics vol297 no 3 pp 1051ndash1058 2001
[50] T Tanazawa Y Suzuki M Anzai S Tsugane M Takayasu andM Shibuya ldquoVasodilation by intrathecal lipopolysaccharide ofthe cerebral arteries after subarachnoid haemorrhage in dogsrdquoActa Neurochirurgica vol 138 no 3 pp 330ndash337 1996
[51] N Toda M Kawakami and K Yoshida ldquoConstrictor action ofoxyhemoglobin in monkey and dog basilar arteries in vivo andin vitrordquo American Journal of Physiology Heart and CirculatoryPhysiology vol 260 no 2 pp H420ndashH425 1991
[52] M Yoshizumi M A Perrella J C Burnett Jr and M-E LeeldquoTumor necrosis factor downregulates an endothelial nitricoxide synthase mRNA by shortening its half-liferdquo CirculationResearch vol 73 no 1 pp 205ndash209 1993
[53] A Rengasamy and R A Johns ldquoRegulation of nitric oxidesynthase by nitric oxiderdquo Molecular Pharmacology vol 44 no1 pp 124ndash128 1993
[54] A L de Souza A C P de Oliveira C C Romano J SztajnbokA J S Duarte and A C Seguro ldquoInterleukin-6 activation inischemic stroke caused by Neisseria meningitidis serogroup CrdquoInternational Journal of Cardiology vol 127 no 3 pp e160ndashe1632008
[55] T Kandabashi H Shimokawa K Miyata et al ldquoInhibition ofmyosin phosphatase by upregulated Rho-kinase plays a key rolefor coronary artery spasm in a porcine model with interleukin-1120573rdquo Circulation vol 101 no 11 pp 1319ndash1323 2000
[56] D-H Nam J-S Kim S-C Hong et al ldquoExpression ofinterleukin-1120573 in lipopolysaccharide stimulated monocytesderived from patients with aneurysmal subarachnoid hem-orrhage is correlated with cerebral vasospasmrdquo NeuroscienceLetters vol 312 no 1 pp 41ndash44 2001
[57] A Ito H Shimokawa T Kadokami et al ldquoTyrosine kinaseinhibitor suppresses coronary arteriosclerotic changes andvasospastic responses induced by chronic treatment withinterleukin-1120573 in pigs in vivordquo Journal of Clinical Investigationvol 96 no 3 pp 1288ndash1294 1995
[58] H Yanamoto H Kataoka Y Nakajo and K Iihara ldquoThe roleof the host defense system in the development of cerebralvasospasm analogies between atherosclerosis and subarach-noid hemorrhagerdquo European Neurology vol 68 no 6 pp 329ndash343 2012
[59] A F Ducruet P R Gigante Z L Hickman et al ldquoGeneticdeterminants of cerebral vasospasm delayed cerebral ischemiaand outcome after aneurysmal subarachnoid hemorrhagerdquoJournal of Cerebral Blood Flow amp Metabolism vol 30 no 4 pp676ndash688 2010
[60] J Langham C Goldfrad G Teasdale D Shaw and KRowan ldquoCalcium channel blockers for acute traumatic braininjuryrdquoCochrane Database Systematic Reviews no 4 Article IDCD000565 2000
[61] S M Dorhout Mees G J Rinkel V L Feigin et al ldquoCal-cium antagonists for aneurysmal subarachnoid haemorrhagerdquoCochrane Database of Systematic Reviews no 3 Article IDCD000277 2007
[62] R-Q Huang F-G Jiang Z-M Feng and T-Y WangldquoNicardipine in the treatment of aneurysmal subarachnoidhaemorrhage a meta-analysis of published datardquo Acta Neuro-logica Belgica vol 113 no 1 pp 3ndash6 2013
[63] S Naidu A J Payne J Moodley M Hoffmann and EGouws ldquoRandomised study assessing the effect of phenytoinand magnesium sulphate on maternal cerebral circulationin eclampsia using transcranial Doppler ultrasoundrdquo BritishJournal of Obstetrics amp Gynaecology vol 103 no 2 pp 111ndash1161996
[64] D Reddy A Fallah J-A Petropoulos F Farrokhyar R LMacdonald and D Jichici ldquoProphylactic magnesium sulphatefor aneurysmal subarachnoid haemorrhage a systematic reviewand meta-analysisrdquo Neurocritical Care vol 21 no 2 pp 356ndash364 2014
[65] C M Bradford S Finfer A OrsquoConnor et al ldquoA ran-domised controlled trial of induced hypermagnesaemia follow-ing aneurysmal subarachnoid haemorrhagerdquo Critical Care andResuscitation vol 15 no 2 pp 119ndash125 2013
[66] S-H Su W Xu J Hai Y-F Wu and F Yu ldquoEffects of statins-use for patients with aneurysmal subarachnoid hemorrhagea meta-analysis of randomized controlled trialsrdquo ScientificReports vol 4 article 4573 2014
[67] J Guo Z Shi K Yang J H Tian and L Jiang ldquoEndothelinreceptor antagonists for subarachnoid hemorrhagerdquo CochraneDatabase of Systematic Reviews vol 9 Article ID CD0083542012
[68] J Shen J-W Pan Z-X Fan X-X Xiong and R-Y ZhanldquoDissociation of vasospasm-related morbidity and outcomesin patients with aneurysmal subarachnoid hemorrhage treatedwith clazosentan a meta-analysis of randomized controlledtrials a reviewrdquo Journal of Neurosurgery vol 119 no 1 pp 180ndash189 2013
[69] P Gomis J P Graftieaux R Sercombe D Hettler BScherpereel and P Rousseaux ldquoRandomized double-blindplacebo-controlled pilot trial of high-dose methylprednisolonein aneurysmal subarachnoid hemorrhagerdquo Journal of Neuro-surgery vol 112 no 3 pp 681ndash688 2010
[70] A H Kramer and J J Fletcher ldquoLocally-administered intrathe-cal thrombolytics following aneurysmal subarachnoid hem-orrhage a systematic review and meta-analysisrdquo NeurocriticalCare vol 14 no 3 pp 489ndash499 2011
[71] G J Liu Z J Wang Y F Wang et al ldquoSystematic assessmentand meta-analysis of the efficacy and safety of fasudil in thetreatment of cerebral vasospasm in patients with subarachnoidhemorrhagerdquo European Journal of Clinical Pharmacology vol68 no 2 pp 131ndash139 2012
[72] S Zhang LWangM Liu andBWu ldquoTirilazad for aneurysmalsubarachnoid haemorrhagerdquo Cochrane Database SystematicReview vol 2 Article ID CD006778 2010
[73] M-Y Tseng P J Hutchinson H K Richards et al ldquoAcutesystemic erythropoietin therapy to reduce delayed ischemicdeficits following aneurysmal subarachnoid hemorrhage aphase II randomized double-blind placebo-controlled trialclinical articlerdquo Journal of Neurosurgery vol 111 no 1 pp 171ndash180 2009
[74] H Kasuya ldquoDevelopment of nicardipine prolonged-releaseimplants after clipping for preventing cerebral vasospasm from
International Journal of Inflammation 13
laboratory to clinical trialrdquo Acta Neurochirurgica Supplemen-tum vol 115 pp 41ndash44 2013
[75] C Thome M Seiz G A Schubert et al ldquoNicardipine pelletsfor the prevention of cerebral vasospasmrdquoActaNeurochirurgicano 110 pp 209ndash211 2011
[76] T Nassar S Akkawi A Shina et al ldquoIn vitro and in vivo effectsof tPA and PAI-1 on blood vessel tonerdquo Blood vol 103 no 3 pp897ndash902 2004
[77] T Sugawara R Ayer V Jadhav W Chen T Tsubokawaand J H Zhang ldquoMechanisms of statin treatment in cerebralvasospasmrdquo Acta Neurochirurgica no 110 pp 9ndash11 2011
[78] M D Vergouwen R J De Haan M Vermeulen and YB Roos ldquoEffect of statin treatment on vasospasm delayedcerebral ischemia and functional outcome in patients withaneurysmal subarachnoid hemorrhage a systematic review andmeta-analysis updaterdquo Stroke vol 41 no 1 pp e47ndashe52 2010
[79] G E Thwaites N D Bang N H Dung et al ldquoDexamethasonefor the treatment of tuberculous meningitis in adolescents andadultsrdquoTheNew England Journal ofMedicine vol 351 no 17 pp1741ndash1811 2004
[80] G E Thwaites J Macmullen-Price T T H Chau et al ldquoSerialMRI to determine the effect of dexamethasone on the cerebralpathology of tuberculous meningitis an observational studyrdquoThe Lancet Neurology vol 6 no 3 pp 230ndash236 2007
[81] U K Misra J Kalita and P P Nair ldquoRole of aspirin in tuber-culous meningitis a randomized open label placebo controlledtrialrdquo Journal of the Neurological Sciences vol 293 no 1-2 pp12ndash17 2010
[82] P W G Elbers and C Ince ldquoBench-to-bedside review mech-anisms of critical illnessmdashclassifying microcirculatory flowabnormalities in distributive shockrdquoCritical Care vol 10 article221 2006
[83] S Trzeciak I Cinel R P Dellinger et al ldquoResuscitating themicrocirculation in sepsis the central role of nitric oxideemerging concepts for novel therapies and challenges forclinical trialsrdquo Academic Emergency Medicine vol 15 no 5 pp399ndash415 2008
[84] Y Sakr M-J Dubois D De Backer J Creteur and J-LVincent ldquoPersistent-microcirculatory alterations are associatedwith organ failure and death in patients with septic shockrdquoCritical Care Medicine vol 32 no 9 pp 1825ndash1831 2004
[85] P E Spronk J H Rommes C Schaar andC Ince ldquoThromboly-sis in fulminant purpura observations on changes in microcir-culatory perfusion during succesful treatmentrdquoThrombosis andHaemostasis vol 95 no 3 pp 576ndash578 2006
[86] J Creteur D De Backer Y Sakr M Koch and J-L VincentldquoSublingual capnometry tracks microcirculatory changes inseptic patientsrdquo Intensive Care Medicine vol 32 no 4 pp 516ndash523 2006
[87] D De Backer J Creteur J C Preiser M J Dubois and JL Vincent ldquoMicrovascular blood flow is altered in patientswith sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 1 pp 98ndash104 2002
[88] G M Ibrahim and R L Macdonald ldquoThe effects of fluid bal-ance and colloid administration on outcomes in patients withaneurysmal subarachnoid hemorrhage a propensity score-matched analysisrdquoNeurocritical Care vol 19 no 2 pp 140ndash1492013
[89] T W Yeo D A Lampah R Gitawati et al ldquoImpaired nitricoxide bioavailability and L-arginine-reversible endothelial dys-function in adults with falciparum malariardquo The Journal ofExperimental Medicine vol 204 no 11 pp 2693ndash2704 2007
[90] A R Fathi R M Pluta K D Bakhtian M Qi and R RLonser ldquoReversal of cerebral vasospasmvia intravenous sodiumnitrite after subarachnoid hemorrhage in primates laboratoryinvestigationrdquo Journal of Neurosurgery vol 115 no 6 pp 1213ndash1220 2011
[91] D de Backer J Creteur M J Dubois et al ldquoThe effects ofdobutamine on microcirculatory alterations in patients withseptic shock are independent of its systemic effectsrdquo CriticalCare Medicine vol 34 no 2 pp 403ndash408 2006
[92] C E Chapleau R P White and J T Robertson ldquoCerebralvasospasm effects of prostaglandin synthetase inhibitors invitrordquo Neurosurgery vol 6 no 2 pp 155ndash159 1980
[93] J L Frazier G Pradilla P P Wang and R J TamargoldquoInhibition of cerebral vasospasm by intracranial delivery ofibuprofen from a controlled-release polymer in a rabbit modelof subarachnoid hemorrhagerdquo Journal of Neurosurgery vol 101no 1 pp 93ndash98 2004
[94] G Pradilla Q A Thai F G Legnani et al ldquoLocal deliveryof ibuprofen via controlled-release polymers prevents angio-graphic vasospasm in a monkey model of subarachnoid hem-orrhagerdquo Neurosurgery vol 57 no 1 pp 184ndash189 2005
[95] R P White and J T Robertson ldquoComparison of piroxicammeclofenamate ibuprofen aspirin and prostacyclin efficacy ina chronic model of cerebral vasospasmrdquo Neurosurgery vol 12no 1 pp 40ndash46 1983
[96] T Fukumori E Tani Y Maeda and A Sukenaga ldquoEffectsof prostacyclin and indomethacin on experimental delayedcerebral vasospasmrdquo Journal of Neurosurgery vol 59 no 5 pp829ndash834 1983
[97] L Brandt B Ljunggren K-E Andersson B Hindfelt and TUski ldquoProstaglandin metabolism and prostacyclin in cerebralvasospasmrdquo General Pharmacology vol 14 no 1 pp 141ndash1431983
[98] T Hakan M Zafer Berkman T Ersoy I Karatas T Sanand S Arbak ldquoAnti-inflammatory effect of meloxicam onexperimental vasospasm in the rat femoral arteryrdquo Journal ofClinical Neuroscience vol 15 no 1 pp 55ndash59 2008
[99] LG Toussaint III J A Friedman E FMWijdicks et al ldquoInflu-ence of aspirin on outcome following aneurysmal subarachnoidhemorrhagerdquo Journal of Neurosurgery vol 101 no 6 pp 921ndash925 2004
[100] B A Gross P M R Lai K U Frerichs and R Du ldquoAspirin andaneurysmal subarachnoid haemorrhagerdquo World Neurosurgery2013
[101] S Yokobori AWatanabe R Nakae et al ldquoCerebral vasospasmsafter intraventricular hemorrhage from an arteriovenousmalformationmdashcase reportrdquo Neurologia Medico-Chirurgicavol 50 no 4 pp 320ndash323 2010
[102] B S Park Y S Won S S Choi and B M Kim ldquoSeveresymptomatic vasospasm following intraventricular hemorrhagefrom arteriovenous fistulardquo Journal of Korean NeurosurgicalSociety vol 45 no 5 pp 300ndash302 2009
[103] G Pradilla T Garzon-Muvdi J J Ruzevick et al ldquoSystemicL-citrulline prevents cerebral vasospasm in haptoglobin 2-2transgenicmice after subarachnoid hemorrhagerdquoNeurosurgeryvol 70 no 3 pp 747ndash757 2012
[104] G Chen J Wu C Sun et al ldquoPotential role of JAK2 in cere-bral vasospasm after experimental subarachnoid hemorrhagerdquoBrain Research vol 1214 pp 136ndash144 2008
[105] C L Lin A L Kwan A S Dumont et al ldquoAttenuationof experimental subarachnoid hemorrhage-induced increases
14 International Journal of Inflammation
in circulating intercellular adhesion molecule-1 and cerebralvasospasm by the endothelin-converting enzyme inhibitor CGS26303rdquo Journal of Neurosurgery vol 106 no 3 pp 442ndash4482007
[106] K Iseda S Ono K Onoda et al ldquoAntivasospastic and antiin-flammatory effects of caspase inhibitor in experimental sub-arachnoid hemorrhagerdquo Journal of Neurosurgery vol 107 no 1pp 128ndash135 2007
[107] C-L Lin A S Dumont T Calisaneller A-L Kwan S-L Hwong and K S Lee ldquoMonoclonal antibody against Eselectin attenuates subarachnoid hemorrhage-induced cerebralvasospasmrdquo Surgical Neurology vol 64 no 3 pp 201ndash206 2005
[108] R Echigo N Shimohata K Karatsu et al ldquoTrehalose treat-ment suppresses inflammation oxidative stress and vasospasminduced by experimental subarachnoid hemorrhagerdquo Journal ofTranslational Medicine vol 10 no 1 article 80 2012
[109] CWakadeM D KingM D Laird C H Alleyne Jr and KMDhandapani ldquoCurcumin attenuates vascular inflammation andcerebral vasospasm after subarachnoid hemorrhage in micerdquoAntioxidants amp Redox Signaling vol 11 no 1 pp 35ndash45 2009
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Computational and Mathematical Methods in Medicine
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Research and TreatmentAIDS
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
International Journal of Inflammation 5
confined by collagen or fibroblasts but is in direct contactwiththe CSF
An investigation in patients with SAH showed that levelsof IL-1-beta but not TNF-alpha were increased and correlatedwith the later development of vasospasm IL-1 acts throughG-protein coupled receptors in three ways which causecontraction of vascular smooth muscle (see Figure 1)
(1) Activation of phospholipase C generated phosphat-idylinositol trisphosphate causes calcium releasewhich leads to myosin light chain kinase activationleading to myosin light chain activation and calciumdependent vasospasm Phosphorylation of myosinlight chain (MLC) by MLC kinase is one of themost important steps for vascular smooth musclecontraction
(2) Activation of protein kinase C (PKC) through phos-pholipase C generated diacylglycerol (from phos-phatidylinositol (45) bisphosphate) can act throughphosphorylation and hence activation of the myosinlight chain kinase Prolonged contraction in cerebralvasospasm for up to two weeks can be mediated bythis mechanism
(3) PKC activation regulates MLC phosphorylation thro-ugh activation of rho-kinase and the myosin-bindingsubunit (MBS) of MLC phosphatase (MLCPh) Rho-kinase hereby phosphorylates MBS which results inthe inhibition of MLCPh [55] The reduced MLCPhactivity leads to increased phosphorylation and hencecontractility of the MLC resulting in calcium inde-pendent vasospasm Investigations in a porcinemodelrevealed that hydroxyfasudil a specific rho-kinaseinhibitor exerted an inhibitory effect on vasospasmboth in vitro and in vivo Western blot analysisshowed that during serotonin-induced contractionsthe extent of phosphorylation of the MBS was sig-nificantly greater in the spastic than in the controlsegment There was a highly significant correlationbetween the extent of MBS phosphorylation andcontractions [55]
Another key mechanism whereby IL-1 mediates vasosp-asm may be through platelet derived growth factor Thereceptors for this growth factor are also known to havetyrosine kinase activity and inhibition of tyrosine kinase isknown to reduce vasospasm in a swine model [56 57] Thisaction influences vascular reactivity to different agonists andmight be crucial for the regulation of cerebral artery toneduring vasospasm [58]
Calcium independent vasospasm may also be inducibleby haemoglobin released in trauma or subarachnoid haem-orrhage
Haemoglobin might cause contraction of major cerebralarteries by scavenging nitric oxide reducing neuronal nitricoxide synthase (NOS) in the adventitia of the cerebral arter-ies and evoking dysfunction of endothelial NO synthase Adecrease in nitric oxide availability might produce prolongedpathological contraction regardless of the concentration ofintracellular calcium Much of the work investigating the
genetic predisposition to cerebral vasospasm focused on theendothelial isoform of nitric oxide synthase Hemoglobinalso stimulates the production of endothelins and the imbal-ance of nitric oxide and endothelin could be an importantcause of pathological arterial contraction In gene transferexperiments eNOS overexpression in animal and humanintracranial arteries is vasoprotective after aneurysmal SAH[59] Several investigations confirmed the association of theT-786C genotype of eNOS with vasospasm For a summaryof key mediators in cerebral vasospasm their function anddisease studied see Table 1
7 Therapeutic Approaches toPrevention and Correction of VasospasmAssociated with Cerebral InflammationTested in Clinical Trials in Humans
The most extensive experience with treatment approachesto vasospasm in cerebral inflammation has been gatheredin the context of management of SAH Clinical trials inhumans have been reported for endothelin-1 antagonists cal-cium channel blockers including the cisternal placement ofcontrolled-release nicardipine intravenous magnesium sul-phate oral statins rho-kinase inhibitors tissue plasminogenactivator tirilazad erythropoietin and methylprednisoloneThe evidence from controlled trials has been summarized inTable 2
71 Endothelin-1A Receptor Antagonists The selective endo-thelin-1A receptor antagonist clazosentan was assessed ina randomized placebo controlled trial (CONSCIOUS-1)and led to a significant reduction of angiographic cerebralvasospasm in SAH but without reduction in the numberof cerebral ischaemia events Subsequent phase II trials(CONSCIOUS-2 and CONSCIOUS-3) in SAH did notdemonstrate any effect on morbidity or mortality A meta-analysis of 4 RCTswith 2024 participants confirmed this find-ing but showed a reduction in delayed ischemic neurologicaldeficit with the endothelin-1A receptor antagonist [67]
72 Calcium Channel Blockers Calcium antagonists have thepotential to prevent the occurrence of calcium dependentvasospasm and delayed ischemic neurological deficit byreducing calcium release (see Figure 1) They have beenapplied directly to the subarachnoid space [74] Intraopera-tive implantation of nicardipine prolonged-release implantsso-called pellets into the basal cistern in close contact to theproximal cerebral vasculature has been reported to reducethe occurrence of cerebral vasospasm and cerebral infarctionand lead to an improvement in clinical outcome in SAH [75]Themagnesium ion is an antagonistic competitor for calciumbinding sites thus having the potential to reduce calciumdependent vasospasm and has been used in the form ofintravenous magnesium sulphate in a number of trials (seeTable 2)
6 International Journal of Inflammation
GPCR
Macrophage
Interleukin-1
Lipopolysaccharide
Plasmodium falciparum antigens
Stimulation of interleukin-1 release
MLCK
PKC
MLCMLCK-P
Rho-kinase MBSMBS-P
MLCPh
Intracellular autoantigens (fromtissue injury)
PLC ≫ IP3 ≫ calcium releaseminusRho-kinase-P
Figure 1 Mechanism for induction of cerebral vasospasm by interleukin-1 (GPCR = G-protein coupled receptor PKC = protein kinase CMLCK = myosin light chain kinase MLC = myosin light chain MBS = myosin-binding subunit of myosin light chain phosphatase MLCPh=myosin light chain phosphatase -P indicates phosphorylated state PLC = phospholipase C and IP3 = phosphatidylinositol trisphosphate)
Table 1 Inflammatory mediators and their role in cerebral vasospasm
Mediator Function of mediator Disease model where role hasbeen established References
(i) Nitric oxide(i) Vasodilator(ii) Inhibitor of endothelin-1expression
(i) Cerebral malaria(ii) Bacterial meningitis(iii) Subarachnoid haemorrhage
[1 7 16 28 32 41 45]
(i) Endothelin-1 (i) Vasoconstrictor (i) Bacterial meningitis(ii) Subarachnoid haemorrhage [7 15]
(i) Interleukin-1(ii) Interferon gamma(iii) Tumor necrosis factor
(i) Activators of protein kinase C(ii) Stimulators of release ofendothelin-1
(i) Bacterial meningitis(ii) Cerebral malaria(iii) Subarachnoid haemorrhage
[7 14 56]
73 Tissue Plasminogen Activator A recent meta-analysis offive randomized controlled trials (465 patients) of tissue plas-minogen activator (tPA) or urokinase applied intrathecallyreduced development of poor outcome and delayed cerebralischaemia and vasospasm [70]Themechanism proposed forthis effect is probably not related to thrombolysis but to adirect effect of tPA on vascular tone It is clear that the effectof tPA is endothelial cell dependent and more specificallyNO synthase dependent tPA seems to bind to a receptorpresent in endothelial cells that mediates the stimulation ofNO synthase activity and thus inhibits the vasoconstrictiveeffect of phenylephrine [76]
74 Statins Statins can reduce vasospasm by upregulatingendothelial NO synthase expression A threefold increasein endothelial NO synthase mRNA protein and enzymatic
activity has been demonstrated following statin treatmentresulting in an increase in cerebral blood flow Statintreatment has attenuated cerebral vasospasm and preventeddelayed ischemic deficits in amurine SAHmodel [77] A pre-vious systematic review of 4 studies with a total of 190 patientsshowed no statistically significant effect on vasospasm ontranscranial Doppler studies delayed cerebral ischaemia ormortality [78] but a more recent review demonstrated areduction in mortality and delayed ischemic neurologicaldeficits [66]
75 Rho-Kinase Inhibitor The specific rho-kinase inhibitorfasudil hydrochloride was in a recent systematic review of8 studies (843 patients) shown to reduce the occurrenceof cerebral vasospasm and cerebral infarction significantlyand led to an improvement in clinical outcome [71] The
International Journal of Inflammation 7
Table2Medicationfortreatmento
fcerebralvasospasm
the
evidence
from
controlledtrialsin
humans
Interventio
nTy
peof
study
Patholog
yRe
sultsodd
sratio
(OR)
orrelativer
isk(RR)
foro
ccurrencein
interventio
ngrou
pcomparedto
grou
pwith
outintervention
Reference
Calcium
channel
blockers
Syste
maticreview
(SR)
(sixrand
omized
controlledtrials
(RCT
s))
Acuteb
rain
injury
DeathO
R091
[95
070ndash117
]Death
andsevere
disabilityOR085
[95
068
to10
7]In
thes
ubgrou
pof
traumaticsubarachno
idhaem
orrhagep
atients
pooled
odds
ratio
was
059
[95
CI037ndash0
94]three
RCTs
repo
rtingdeathandsevere
disabilityas
anou
tcom
einthis
subgroup
OR067
[95
CI046
ndash098]
[60]
Calcium
channel
blockers
SR(16RC
Ts)
Aneurysmal
subarachno
idhaem
orrhage(aSAH)
Overallcalcium
antagonists
redu
cedther
iskof
poor
outcom
ethe
relativer
isk(RR)
was
081
[95
CI072
to092]thec
orrespon
ding
numbero
fpatientsn
eededto
treatwas
19[95
CI1to51]foro
ral
nimod
ipinea
lone
theR
Rwas
067
[95
CI055
to081]foro
ther
calcium
antagonists
orintravenou
sadm
inistratio
nof
nimod
ipine
ther
esultsweren
otsta
tistic
allysig
nificantcalcium
antagonists
redu
cedtheo
ccurrenceo
fsecon
dary
ischaem
iaandshow
eda
favourabletre
ndforc
asefatality
for
magnesiu
minadditio
nto
standard
treatmentw
ithnimod
ipinetheR
Rwas
075
[95
CI057
to10
0]fora
poor
outcom
eand
066
[95
CI045
to096]for
clinicalsigns
ofsecond
aryisc
haem
ia
[61]
Nicardipine
SR(five
controlled
trials)
aSAH
Risk
ofpo
orou
tcom
e(deathvegetativ
estateord
ependency)
OR
058
(95
CI037ndash0
9)
Mortalityod
dsratio
045[95
CI015
to12
9][62]
Magnesiu
msulfate
Prospective
rand
omise
dstu
dyEclampsia
Sign
ificant
redu
ctionof
pulsa
tility
index(119875=0002)a
ndmeanflo
wvelocityin
middlec
erebralartery(119875=002)
[63]
Prop
hylactic
magnesiu
msulfate
SRof
tenrand
omized
parallelgroup
controlledtrials
aSAH
Glasgow
outcom
escaleandmod
ified
Rank
inscaleR
R093
(95
CI082
to10
6)m
ortality095
(95
CI076ndash117
)delay
edcerebral
ischaem
iaRR
054(95
CI038
to075)delay
edisc
hemic
neurologicaldeficit(D
IND)RR
of093
[95
CI062ndash139
]transcranialDop
pler
vasospasmR
R072
[95
CI051ndash103]
[64]
Indu
ced
hyperm
agnesaem
iaRC
TaSAH
Vasospasm
ondigitalsub
tractio
nangiograph
yOR
051[95CI
026
to10
2]neurologicalrecoveryORforw
orse
outcom
e071
[95
CI039
to13
2][65]
Statins
SR(sixRC
Ts)
aSAH
Incidenceo
fvasospasm
RR080[95
CI054ndash
117]poo
rneurologicalou
tcom
eRR
094[95
CI077to
116]
MortalityRR
030[95
CI014
ndash064]
DIN
DR
R058
[95
CI037
ndash092]
[66]
Endo
thelin
receptor
antagonists
SR(fo
urRC
Ts)
aSAH
Incidenceo
fDIN
Drela
tiver
isk08[95
CI067ndash0
95]
angiograph
icvasospasm
RR062[95CI
052
to072]
unfavourableou
tcom
eRR
087[95
CI074ndash102]m
ortalityRR
105[95
CI077
to14
5]
[67]
8 International Journal of Inflammation
Table2Con
tinued
Interventio
nTy
peof
study
Patholog
yRe
sultsodd
sratio
(OR)
orrelativer
isk(RR)
foro
ccurrencein
interventio
ngrou
pcomparedto
grou
pwith
outintervention
Reference
Endo
thelin-1Areceptor
antagonistClazosentan
SR(fo
urRC
Ts)
aSAH
Relativer
iskforincidence
ofDIN
Ds076
(95
CI062ndash0
92)
delay
edcerebralinfarctio
n079
[95
CI063ndash100]G
lasgow
outcom
escaleextend
edRR
112
[95
CI096ndash130]m
ortalityRR
10
2[95
CI070ndash149]
[68]
Intravenou
smethylpredn
isolone
RCT
aSAH
Symptom
aticvasospasm
265in
interventio
ngrou
pcompared
with
26in
placebogrou
pfunctio
naloutcomes
caleredu
cedin
the
methylpredn
isolone
grou
pwith
riskdifference193
[95
CI05ndash379]ou
tcom
epoo
rin15of
patie
ntsinthe
methylpredn
isolone
grou
pversus
34in
thep
lacebo
grou
p
[69]
Tissue
plasminogen
activ
ator
SR(five
RCTs)
aSAH
Overalluseo
fintrathecalthrombo
lytic
swas
associated
with
significantreductio
nsin
thed
evelo
pmento
fpoo
routcomes
(OR
052034ndash
078119875lt001)DIN
Ds(OR054034ndash
087119875=001)
andangiograph
icvasospasm
(OR032015
ndash070119875lt001)
[70]
Rho-kinase
inhibitor
SR(8
controlledtrials)
aSAH
Absenceo
fsym
ptom
aticvasospasmoccurrenceo
flow
density
areas
associated
with
vasospasm
onCT
and
occurrence
ofadversee
vents
weres
imilarb
etweenthetwogrou
psthe
clinicaloutcomes
were
morefavorablein
thefasud
ilgrou
pthan
inthen
imod
ipineg
roup
(119875=004)
[71]
Tirilazad
SR(five
RCTs)
aSAH
Therew
asno
significantd
ifference
betweenthetwogrou
psatthe
endof
follo
w-upforthe
prim
aryou
tcom
edeathOR
089[95CI
074
to10
6]orinpo
orou
tcom
e(deathvegetativ
estateorsevere
disability)
OR10
4[95
CI090
to12
1]few
erpatie
ntsd
evelop
eddelay
edcerebralisc
haem
iain
thetirilazadgrou
pthan
inthec
ontro
lgrou
pOR080
[95
CI069
to093]subgroup
analyses
didno
tdemon
stratea
nysig
nificantd
ifference
ineffectsof
tirilazadon
clinicaloutcomes
[72]
Erythrop
oietin
RCT
aSAH
Nodifferences
wered
emon
strated
intheincidence
ofvasospasm
andadversee
ventspatie
ntsreceiving
EPOhadad
ecreased
incidenceo
fseverev
asospasm
from
275to
75(119875=0037)
redu
cedDID
swith
newcerebralinfarctsfro
m40
0to
75
(119875=0001)as
hortened
duratio
nof
impaire
dautoregu
latio
n(ip
silateralsid
e119875lt0001)andmorefavorableou
tcom
eat
discharge(favorableG
lasgow
outcom
escalescore119875=0039)
amon
gthe7
1survivorsthe
EPOgrou
phadfewer
deficits
measured
with
NationalInstitutes
ofHealth
Stroke
Scale(medianscore2
versus
6119875=0008)
[73]
International Journal of Inflammation 9
mechanism is apart from a contribution to inhibition ofcalcium independent vasospasm (see above) probably alsoan increase of endothelial nitric oxide synthase (eNOS)expression by stabilizing eNOSmRNA which can contributeto an increase of NO level to enhance vasodilatation
76 Other Treatments Steroid treatment can inhibit cytokineexpression and has thus the potential to reduce cytokinemediated calcium dependent and independent vasospasmIn tuberculous meningitis adjuvant treatment with corticos-teroids has been indirectly associatedwith features of reducedvasculopathy which may include vasospasm
A large randomised controlled trial showed improvedmortality in tuberculous meningitis with adjuvant corti-costeroids but did not show a reduction in severe disabil-ity however an observational MRI study did suggest areduction in strokes in patients treated with corticosteroids[79 80] An open-label study of aspirin in the preventionof stroke and mortality in tuberculous meningitis found anonsignificant reduction in stroke and a significant reductionin mortality with a possible synergism with corticosteroids[81] Mechanisms responsible for a potential effect may bea reduction of the vasoconstricting effect of PGE2 The 21-aminosteroid tirilazad is a lipid peroxidation inhibitor whichinhibits free radical-induced lipid peroxidation (LP) by acombination of lipid peroxide scavenging and a membrane-stabilizing action that limits the propagation of LP reactionsbetween a lipid peroxide and an adjacent polyunsaturatedfatty acid There has been no consistent evidence of benefitin animal or human studies Erythropoietin may act throughincrease in expression of endothelial nitric oxide synthasethus increasing NO bioavailability
8 Conclusions and Perspectives forFuture Developments
There is evidence for common pathways leading tovasospasm in all forms of cerebral inflammation involvinginterleukin-1 tumor necrosis factor endothelin-1 andnitric oxide Treatments addressing the pathophysiologyof vasospasm in one form of cerebral inflammation maytherefore apply to all others Treatment of cerebral vasospasmhas been mainly investigated in aneurysmal SAH Agentsfor which there is likely to be clinical benefit are calciumantagonists statins and intrathecal plasminogen activators(see Table 2) The fact that there is calcium dependent andindependent vasospasm in inflammation (see Figure 1)shows that a combination of calcium antagonists with agentsinterfering with calcium independent vasospasm includingagents improving the bioavailability of nitric oxide is theway forward Future trials need to investigate their effectsin patients with all forms of cerebral inflammation leadingto neurological deficits attributable to vasospasm In vivocorrelates for reduction of vasospasm in the peripheralcirculation could be explored as a surrogate for reduction ofvasospasm in the cerebral (micro) vasculature
Strategies to improve microvascular recruitment whichhave been explored in models of septicaemia could poten-tially be applied to cerebral vasospasm Distributive shockwhich occurs during sepsis and septic shock is associatedwith an abnormal distribution of microvascular blood flowVasospasm of part of the arterioles supplying the capillary isa mechanism involved in this maldistribution The clinicalintroduction of new microcirculatory imaging techniquessuch as orthogonal polarization spectral and side-streamdark-field imaging (OPSSDF) has allowed direct obser-vation of the microcirculation at the bedside Images ofthe sublingual microcirculation during septic shock andresuscitation have revealed that the distributive defect ofblood flow occurs at the capillary level [82]
In rat models of cecal ligation and puncture investiga-tors have used intravital video microscopy to demonstratethat sepsis is characterized by decreased microcirculatoryflow velocity an abundance of stopped-flow microvesselsincreased heterogeneity of microcirculatory flow and lowdensity of perfused capillaries As thesemicrocirculatory flowalterations can occur in the absence of global hemodynamicderangements (eg absence of arterial hypotension) micro-circulatory dysfunction largely reflects intrinsic events occur-ring in the microvessels like localized vasospasm [83] Appli-cation ofmicrocirculatory recruitmentmaneuver procedureshas been shown to be effective in promotingmicrocirculatoryblood flow in clinical studies using OPSSDF imaging [84ndash87] Fluid resuscitation in combination with the nitric oxidedonor nitroglycerine was shown to recruit disturbed micro-circulation following pressure guided resuscitation in septicshock patients
It is important to note that application of colloids inpatients with SAH was associated with worse outcomescompared to matched controls in a subgroup analysis of theCONSCIOUS-1 prospective randomized trial of clazosentanfor the prevention of angiographic vasospasm [88] Futureresearch needs to investigate whether colloids can bind nitricoxide and make this vasodilator less available by binding it
Regarding future therapeutic interventions increasingnitric oxide bioavailability erythropoietin and L-argininewhich increased bioavailability of nitric oxide in patients withmalaria [89] need to be explored as adjunctive treatmentin children with cerebral malaria in randomised controlledtrials In vitro the availability of L-arginine does not appearto be a rate limiting step for the activity of the NO synthasebecause its half-saturating concentration is less than 3of theplasma and endothelial concentration of this substrate
The nitric oxide donor intravenous sodium nitrite hasbeen shown to prevent and reverse cerebrovascular spasmin primates and has been demonstrated to be safe foradministration in humans [90]
Support of pump function by dobutamine therapy hasbeen shown to improvemicrocirculatory flow independent ofimprovement of global hemodynamic parameters [91] Fluidapplication nitric oxide donors and dobutamine therapyneed to be explored in isolation but also as combinationof interventions to improve cerebral perfusion in cerebralinflammation associated with vasospasm
10 International Journal of Inflammation
A potential role of nonsteroidal anti-inflammatory drugswas revealed by landmark experiments on dog basilararteries Arachidonic acid induced sustained contractionsand these responses were markedly inhibited (95) bymeclofenamate and similarly by indomethacin but aspirinhad no such effect [92] In the rabbit basilar artery model ofcerebral vasospasm local intracranial delivery of ibuprofenaccomplished using controlled-release polymers preventedvasospasm when administered within 6 hours but notat either 12 or 24 hours [93] Delivery of ibuprofen viacontrolled-release polymers into the subarachnoid space ofmonkeys with subarachnoid haemorrhage prevented angio-graphic vasospasm after SAH as evident from patency of themiddle cerebral artery [94]
Piroxicam was more effective than the above-mentioneddrugs in the SAH dog model after angiographic analysisand analysis of behavioural changes [95] Early studiesusing prostacyclin found that isolated canine basilar arteriescontraction induced by prostaglandin E2 hemoglobin orserum was relaxed by prostacyclin but not indomethacin[96] In isolated human pial arteries prostacyclin relaxedhuman pial arteries contracted by either PGF2 alpha nora-drenaline serotonin or haemorrhagic CSF [97] In an animalstudy meloxicam reduced ultrastructural and morphometricvasospastic changes in rats with subarachnoid haemorrhage[98] Investigation comparing rate of subsequent permanentdisability from vasospasm and angiographic and delayedcerebral ischaemia in patients with SAH with and withoutaspirin intake found no association with poor outcome [99100]
There are new areas of pathophysiology research wherethe role of vasospasm needs to be explored thoroughly inorder to find avenues for therapeutic interventions Investi-gations could evaluate whether intraventricular haemorrhageoccurring commonly in the neonatal period in pretermneonates is associated with vasospasm increasing mor-bidity Case reports of intraventricular haemorrhage fromAV malformations and aneurysms in adults demonstratedvasospasm [101 102]
Future research needs to explore the usefulness of a num-ber of agents which have been demonstrated to reduce vaso-spasm in animal models including L-citrulline [103] januskinase-2 [104] endothelin converting enzyme inhibitors[105] caspase inhibitor Z-VAD-FMK [106] anti-E selectinmonoclonal antibodies [107] trehalose [108] and curcuminwhich was demonstrated to protect against the developmentof cerebral vasospasm and secondary cerebral infarctionafter subarachnoid haemorrhage in mice by its broad anti-inflammatory activity including limitation of superoxidegeneration and influence on inducible nitric oxide synthaseexpression [109]
Aggressive maintenance of normothermia or mildhypothermia in patients with military blast injury resultedin a dramatic reduction in the incidence of posttraumaticvasospasm from 475 to 5 Future studies need to confirmthis finding and investigate whether hypothermia can reducecerebral inflammation related ischemic damage to the brainin other conditions like bacterial meningitis or cerebralmalaria [37]
Conflict of Interests
The author declares that there is no conflict of interestsregarding the publication of this paper
References
[1] B Weir ldquoThe pathophysiology of cerebral vasospasmrdquo BritishJournal of Neurosurgery vol 9 no 3 pp 375ndash390 1995
[2] H Bode and A Harders ldquoTransient stenoses and occlusionsof main cerebral arteries in childrenmdashdiagnosis and control oftherapy by transcranial Doppler sonographyrdquo European Journalof Pediatrics vol 148 no 5 pp 406ndash411 1989
[3] K-F Lindegaard H Nornes S J Bakke W Sorteberg and PNakstad ldquoCerebral vasospasm diagnosis by means of angiogra-phy and blood velocity measurementsrdquo Acta Neurochirurgicavol 100 no 1-2 pp 12ndash24 1989
[4] C Lysakowski B Walder M C Costanza and M R TramerldquoTranscranial Doppler versus angiography in patients withvasospasm due to a ruptured cerebral aneurysm a systematicreviewrdquo Stroke vol 32 no 10 pp 2292ndash2298 2001
[5] R L Grubb Jr M E Raichle J O Eichling and M HGado ldquoEffects of subarachnoid hemorrhage on cerebral bloodvolume blood flow and oxygen utilization in humansrdquo Journalof Neurosurgery vol 46 no 4 pp 446ndash452 1977
[6] C-H Lu H-W Chang C-C Lui C-R Huang and W-NChang ldquoCerebral haemodynamics in acute bacterial meningitisin adultsrdquoQuaterly Journal of Medicine vol 99 no 12 pp 863ndash869 2006
[7] F Faraci and D D Heistad ldquoRegulation of the cerebralcirculation role of endothelium and potassium channelsrdquoPhysiological Reviews vol 78 no 1 pp 53ndash97 1998
[8] L Hektoen ldquoThe vascular changes in tuberculous meningitisespecially in tuberculous endarteritisrdquo Journal of ExperimentalMedicine vol 1 pp 112ndash163 1896
[9] G Thwaites ldquoTuberculosis of the central nervous systemrdquo inClinical Tuberculosis P D O Davies S B Gordon and GDavies Eds pp 151ndash165 CRC Press 5th edition 2014
[10] P M Dalal ldquoObservations on the involvement of cerebral ves-sels in tuberculousmeningitis in adultsrdquoAdvances in Neurologyvol 25 pp 149ndash159 1979
[11] L A Rojas-Echeverri J L Soto-Hernandez S Garza et alldquoPredictive value of digital subtraction angiography in patientswith tuberculous meningitisrdquo Neuroradiology vol 38 no 1 pp20ndash24 1996
[12] E L Lyons and N E Leeds ldquoThe angiographic demonstrationof arterial vascular disease in purulent meningitis report of acaserdquo Radiology vol 88 no 5 pp 935ndash938 1967
[13] S Ries U Schminke K Fassbender M Daffertshofer WSteinke andMHennerici ldquoCerebrovascular involvement in theacute phase of bacterial meningitisrdquo Journal of Neurology vol244 no 1 pp 51ndash55 1997
[14] K Fassbender S Ries U Schminke S Schneider and M Hen-nerici ldquoInflammatory cytokines in CSF in bacterial meningitisassociation with altered blood flow velocities in basal cerebralarteriesrdquo Journal of Neurology Neurosurgery amp Psychiatry vol61 no 1 pp 57ndash61 1996
[15] L A Pfister J H Tureen S Shaw et al ldquoEndothelin inhibitionimproves cerebral blood flow and is neuroprotective in pneu-mococcal meningitisrdquoAnnals of Neurology vol 47 pp 329ndash3352000
International Journal of Inflammation 11
[16] S L Leib Y S Kim S M Black J H Tureen and M GTauber ldquoInducible nitric oxide synthase and the effect of amin-oguanidine in experimental neonatal meningitisrdquo The Journalof Infectious Diseases vol 177 no 3 pp 692ndash700 1998
[17] T W Polder C R Jerusalem andW M C Eling ldquoMorpholog-ical characteristics of intracerebral arterioles in clinical (Plas-modium falciparum) and experimental (Plasmodium berghei)cerebral malariardquo Journal of the Neurological Sciences vol 101no 1 pp 35ndash46 1991
[18] N A V Beare S P Harding T E Taylor S Lewallen and MEMolyneux ldquoPerfusion abnormalities in childrenwith cerebralmalaria andmalarial retinopathyrdquo Journal of Infectious Diseasesvol 199 no 2 pp 263ndash271 2009
[19] C R J C Newton K Marsh N Peshu and F J KirkhamldquoPerturbations of cerebral hemodynamics in Kenyans withcerebral malariardquo Pediatric Neurology vol 15 no 1 pp 41ndash491996
[20] C C John A Panoskaltsis-Mortari R O Opoka et alldquoCerebrospinal fluid cytokine levels and cognitive impairmentin cerebral malariardquo American Journal of Tropical Medicine andHygiene vol 78 no 2 pp 198ndash205 2008
[21] W McGuire A V S Hill C E M Allsopp B M Greenwoodand D Kwiatkowski ldquoVariation in the TNF-120572 promoter regionassociated with susceptibility to cerebral malariardquo Nature vol371 no 6497 pp 508ndash510 1994
[22] W McGuire J C Knight A V S Hill C E M Allsopp B MGreenwood and D Kwiatkowski ldquoSevere malarial anemia andcerebral malaria are associated with different tumor necrosisfactor promoter allelesrdquo Journal of Infectious Diseases vol 179no 1 pp 287ndash290 1999
[23] B Dugas M D Mossalayi C Damais and J-P Kolb ldquoNitricoxide production by human monocytes Evidence for a role ofCD23rdquo Immunology Today vol 16 no 12 pp 574ndash580 1995
[24] L Pellettieri B Nilsson C-A Carlsson andU Nilsson ldquoSerumimmunocomplexes in patients with subarachnoid hemorrhagerdquoNeurosurgery vol 19 no 5 pp 767ndash771 1986
[25] M Eisenhut ldquoCauses of reduced immune complex clearance incerebralmalariardquoParasite Immunology vol 31 no 2 p 59 2009
[26] P Teeranaipong J Ohashi J Patarapotikul et al ldquoA functionalsingle-nucleotide polymorphism in the CR1 promoter regioncontributes to protection against cerebral malariardquo Journal ofInfectious Diseases vol 198 no 12 pp 1880ndash1891 2008
[27] P Cabrales G M Zanini D Meays J A Frangos and LJ M Carvalho ldquoMurine cerebral malaria is associated witha vasospasm-like microcirculatory dysfunction and survivalupon rescue treatment is markedly increased by nimodipinerdquoTheAmerican Journal of Pathology vol 176 no 3 pp 1306ndash13152010
[28] I Gramaglia P Sobolewski D Meays et al ldquoLow nitricoxide bioavailability contributes to the genesis of experimentalcerebral malariardquoNature Medicine vol 12 no 12 pp 1417ndash14222006
[29] T W Yeo D A Lampah E Tjitra et al ldquoRelationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavail-ability and perfusion in severe falciparum malariardquo Journal ofInfectious Diseases vol 200 no 10 pp 1522ndash1529 2009
[30] G Dhangadamajhi B N Mohapatra S K Kar and M RanjitldquoGenetic variation in neuronal nitric oxide synthase (nNOS)gene and susceptibility to cerebral malaria in Indian adultsrdquoInfection Genetics and Evolution vol 9 no 5 pp 908ndash911 2009
[31] M R Hobbs V Udhayakumar M C Levesque et al ldquoAnew NOS2 promoter polymorphism associated with increased
nitric oxide production and protection from severe malaria inTanzanian and Kenyan childrenrdquoThe Lancet vol 360 no 9344pp 1468ndash1475 2002
[32] P Cabrales G M Zanini D Meays J A Frangos and L JM Carvalho ldquoNitric oxide protection against murine cerebralmalaria is associated with improved cerebral microcirculatoryphysiologyrdquo The Journal of Infectious Diseases vol 203 no 10pp 1454ndash1463 2011
[33] G Morahan C S Boutlis D Huang et al ldquoA promoterpolymorphism in the gene encoding interleukin-12 p40 (IL12B)is associated with mortality from cerebral malaria and withreduced nitric oxide productionrdquo Genes amp Immunity vol 3 no7 pp 414ndash418 2002
[34] C Casals-Pascual R Idro N Gicheru et al ldquoHigh levels of ery-thropoietin are associated with protection against neurologicalsequelae in African children with cerebral malariardquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 105 no 7 pp 2634ndash2639 2008
[35] F C Chow C M Marra and T A Cho ldquoCerebrovasculardisease in central nervous system infectionsrdquo Seminars inNeurology vol 31 no 3 pp 286ndash306 2011
[36] R A Armonda R S Bell A H Vo et al ldquoWartime traumaticcerebral vasospasm recent review of combat casualtiesrdquoNeuro-surgery vol 59 no 6 pp 1215ndash1225 2006
[37] K Shahlaie K Keachie I M Hutchins et al ldquoRisk factorsfor posttraumatic vasospasm clinical articlerdquo Journal of Neu-rosurgery vol 115 no 3 pp 602ndash611 2011
[38] Y Udomphorn W M Armstead and M S Vavilala ldquoCerebralblood flow and autoregulation after pediatric traumatic braininjuryrdquo Pediatric Neurology vol 38 no 4 pp 225ndash234 2008
[39] R M Pluta J Hansen-Schwartz J Dreier et al ldquoCerebralvasospasm following subarachnoid hemorrhage time for a newworld of thoughtrdquo Neurological Research vol 31 no 2 pp 151ndash158 2009
[40] J Hansen-Schwartz P Vajkoczy R L Macdonald R MPluta and J H Zhang ldquoCerebral vasospasm looking beyondvasoconstrictionrdquo Trends in Pharmacological Sciences vol 28no 6 pp 252ndash256 2007
[41] H Kasuya B K A Weir M Nakane et al ldquoNitric oxidesynthase and guanylate cyclase levels in canine basilar arteryafter subarachnoid hemorrhagerdquo Journal of Neurosurgery vol82 no 2 pp 250ndash255 1995
[42] M D Linnik and T J F Lee ldquoEffect of hemoglobin on neuro-genic responses and cholinergic parameters in porcine cerebralarteriesrdquo Journal of Cerebral Blood Flow and Metabolism vol 9no 2 pp 219ndash225 1989
[43] CG Sobey and FM Faraci ldquoSubarachnoid haemorrhage whathappens to the cerebral arteriesrdquo Clinical and ExperimentalPharmacology and Physiology vol 25 no 11 pp 867ndash876 1998
[44] Y R T Dinh G Lot R Benrabah O Baroudy J Cophignonand J Seylaz ldquoAbnormal cerebral vasodilation in aneurys-mal subarachnoid hemorrhage use of serial 133Xe cerebralblood flow measurement plus acetazolamide to assess cerebralvasospasmrdquo Journal of Neurosurgery vol 79 no 4 pp 490ndash4931993
[45] T J F Lee ldquoNitric oxide and the cerebral vascular functionrdquoJournal of Biomedical Science vol 7 no 1 pp 16ndash26 2000
[46] M Stoodley R L Macdonald B Weir et al ldquoSubarachnoidhemorrhage as a cause of an adaptive response in cerebralarteriesrdquo Journal of Neurosurgery vol 93 no 3 pp 463ndash4702000
12 International Journal of Inflammation
[47] Y R Tran Dinh A Jomaa J Callebert et al ldquoOverexpressionof cyclooxygenase-2 in rabbit basilar artery endothelial cellsafter subarachnoid hemorrhagerdquo Neurosurgery vol 48 no 3pp 626ndash635 2001
[48] A Gecse B Kis Z Mezei and G Telegdy ldquoEffects of inflam-matory neuropeptides on the arachidonate cascade of plateletsrdquoInternational Archives of Allergy and Immunology vol 118 no2ndash4 pp 166ndash170 1999
[49] K S Mark W J Trickler and D W Miller ldquoTumornecrosis factor-120572 induces cyclooxygenase-2 expression andprostaglandin release in brain microvessel endothelial cellsrdquoJournal of Pharmacology and Experimental Therapeutics vol297 no 3 pp 1051ndash1058 2001
[50] T Tanazawa Y Suzuki M Anzai S Tsugane M Takayasu andM Shibuya ldquoVasodilation by intrathecal lipopolysaccharide ofthe cerebral arteries after subarachnoid haemorrhage in dogsrdquoActa Neurochirurgica vol 138 no 3 pp 330ndash337 1996
[51] N Toda M Kawakami and K Yoshida ldquoConstrictor action ofoxyhemoglobin in monkey and dog basilar arteries in vivo andin vitrordquo American Journal of Physiology Heart and CirculatoryPhysiology vol 260 no 2 pp H420ndashH425 1991
[52] M Yoshizumi M A Perrella J C Burnett Jr and M-E LeeldquoTumor necrosis factor downregulates an endothelial nitricoxide synthase mRNA by shortening its half-liferdquo CirculationResearch vol 73 no 1 pp 205ndash209 1993
[53] A Rengasamy and R A Johns ldquoRegulation of nitric oxidesynthase by nitric oxiderdquo Molecular Pharmacology vol 44 no1 pp 124ndash128 1993
[54] A L de Souza A C P de Oliveira C C Romano J SztajnbokA J S Duarte and A C Seguro ldquoInterleukin-6 activation inischemic stroke caused by Neisseria meningitidis serogroup CrdquoInternational Journal of Cardiology vol 127 no 3 pp e160ndashe1632008
[55] T Kandabashi H Shimokawa K Miyata et al ldquoInhibition ofmyosin phosphatase by upregulated Rho-kinase plays a key rolefor coronary artery spasm in a porcine model with interleukin-1120573rdquo Circulation vol 101 no 11 pp 1319ndash1323 2000
[56] D-H Nam J-S Kim S-C Hong et al ldquoExpression ofinterleukin-1120573 in lipopolysaccharide stimulated monocytesderived from patients with aneurysmal subarachnoid hem-orrhage is correlated with cerebral vasospasmrdquo NeuroscienceLetters vol 312 no 1 pp 41ndash44 2001
[57] A Ito H Shimokawa T Kadokami et al ldquoTyrosine kinaseinhibitor suppresses coronary arteriosclerotic changes andvasospastic responses induced by chronic treatment withinterleukin-1120573 in pigs in vivordquo Journal of Clinical Investigationvol 96 no 3 pp 1288ndash1294 1995
[58] H Yanamoto H Kataoka Y Nakajo and K Iihara ldquoThe roleof the host defense system in the development of cerebralvasospasm analogies between atherosclerosis and subarach-noid hemorrhagerdquo European Neurology vol 68 no 6 pp 329ndash343 2012
[59] A F Ducruet P R Gigante Z L Hickman et al ldquoGeneticdeterminants of cerebral vasospasm delayed cerebral ischemiaand outcome after aneurysmal subarachnoid hemorrhagerdquoJournal of Cerebral Blood Flow amp Metabolism vol 30 no 4 pp676ndash688 2010
[60] J Langham C Goldfrad G Teasdale D Shaw and KRowan ldquoCalcium channel blockers for acute traumatic braininjuryrdquoCochrane Database Systematic Reviews no 4 Article IDCD000565 2000
[61] S M Dorhout Mees G J Rinkel V L Feigin et al ldquoCal-cium antagonists for aneurysmal subarachnoid haemorrhagerdquoCochrane Database of Systematic Reviews no 3 Article IDCD000277 2007
[62] R-Q Huang F-G Jiang Z-M Feng and T-Y WangldquoNicardipine in the treatment of aneurysmal subarachnoidhaemorrhage a meta-analysis of published datardquo Acta Neuro-logica Belgica vol 113 no 1 pp 3ndash6 2013
[63] S Naidu A J Payne J Moodley M Hoffmann and EGouws ldquoRandomised study assessing the effect of phenytoinand magnesium sulphate on maternal cerebral circulationin eclampsia using transcranial Doppler ultrasoundrdquo BritishJournal of Obstetrics amp Gynaecology vol 103 no 2 pp 111ndash1161996
[64] D Reddy A Fallah J-A Petropoulos F Farrokhyar R LMacdonald and D Jichici ldquoProphylactic magnesium sulphatefor aneurysmal subarachnoid haemorrhage a systematic reviewand meta-analysisrdquo Neurocritical Care vol 21 no 2 pp 356ndash364 2014
[65] C M Bradford S Finfer A OrsquoConnor et al ldquoA ran-domised controlled trial of induced hypermagnesaemia follow-ing aneurysmal subarachnoid haemorrhagerdquo Critical Care andResuscitation vol 15 no 2 pp 119ndash125 2013
[66] S-H Su W Xu J Hai Y-F Wu and F Yu ldquoEffects of statins-use for patients with aneurysmal subarachnoid hemorrhagea meta-analysis of randomized controlled trialsrdquo ScientificReports vol 4 article 4573 2014
[67] J Guo Z Shi K Yang J H Tian and L Jiang ldquoEndothelinreceptor antagonists for subarachnoid hemorrhagerdquo CochraneDatabase of Systematic Reviews vol 9 Article ID CD0083542012
[68] J Shen J-W Pan Z-X Fan X-X Xiong and R-Y ZhanldquoDissociation of vasospasm-related morbidity and outcomesin patients with aneurysmal subarachnoid hemorrhage treatedwith clazosentan a meta-analysis of randomized controlledtrials a reviewrdquo Journal of Neurosurgery vol 119 no 1 pp 180ndash189 2013
[69] P Gomis J P Graftieaux R Sercombe D Hettler BScherpereel and P Rousseaux ldquoRandomized double-blindplacebo-controlled pilot trial of high-dose methylprednisolonein aneurysmal subarachnoid hemorrhagerdquo Journal of Neuro-surgery vol 112 no 3 pp 681ndash688 2010
[70] A H Kramer and J J Fletcher ldquoLocally-administered intrathe-cal thrombolytics following aneurysmal subarachnoid hem-orrhage a systematic review and meta-analysisrdquo NeurocriticalCare vol 14 no 3 pp 489ndash499 2011
[71] G J Liu Z J Wang Y F Wang et al ldquoSystematic assessmentand meta-analysis of the efficacy and safety of fasudil in thetreatment of cerebral vasospasm in patients with subarachnoidhemorrhagerdquo European Journal of Clinical Pharmacology vol68 no 2 pp 131ndash139 2012
[72] S Zhang LWangM Liu andBWu ldquoTirilazad for aneurysmalsubarachnoid haemorrhagerdquo Cochrane Database SystematicReview vol 2 Article ID CD006778 2010
[73] M-Y Tseng P J Hutchinson H K Richards et al ldquoAcutesystemic erythropoietin therapy to reduce delayed ischemicdeficits following aneurysmal subarachnoid hemorrhage aphase II randomized double-blind placebo-controlled trialclinical articlerdquo Journal of Neurosurgery vol 111 no 1 pp 171ndash180 2009
[74] H Kasuya ldquoDevelopment of nicardipine prolonged-releaseimplants after clipping for preventing cerebral vasospasm from
International Journal of Inflammation 13
laboratory to clinical trialrdquo Acta Neurochirurgica Supplemen-tum vol 115 pp 41ndash44 2013
[75] C Thome M Seiz G A Schubert et al ldquoNicardipine pelletsfor the prevention of cerebral vasospasmrdquoActaNeurochirurgicano 110 pp 209ndash211 2011
[76] T Nassar S Akkawi A Shina et al ldquoIn vitro and in vivo effectsof tPA and PAI-1 on blood vessel tonerdquo Blood vol 103 no 3 pp897ndash902 2004
[77] T Sugawara R Ayer V Jadhav W Chen T Tsubokawaand J H Zhang ldquoMechanisms of statin treatment in cerebralvasospasmrdquo Acta Neurochirurgica no 110 pp 9ndash11 2011
[78] M D Vergouwen R J De Haan M Vermeulen and YB Roos ldquoEffect of statin treatment on vasospasm delayedcerebral ischemia and functional outcome in patients withaneurysmal subarachnoid hemorrhage a systematic review andmeta-analysis updaterdquo Stroke vol 41 no 1 pp e47ndashe52 2010
[79] G E Thwaites N D Bang N H Dung et al ldquoDexamethasonefor the treatment of tuberculous meningitis in adolescents andadultsrdquoTheNew England Journal ofMedicine vol 351 no 17 pp1741ndash1811 2004
[80] G E Thwaites J Macmullen-Price T T H Chau et al ldquoSerialMRI to determine the effect of dexamethasone on the cerebralpathology of tuberculous meningitis an observational studyrdquoThe Lancet Neurology vol 6 no 3 pp 230ndash236 2007
[81] U K Misra J Kalita and P P Nair ldquoRole of aspirin in tuber-culous meningitis a randomized open label placebo controlledtrialrdquo Journal of the Neurological Sciences vol 293 no 1-2 pp12ndash17 2010
[82] P W G Elbers and C Ince ldquoBench-to-bedside review mech-anisms of critical illnessmdashclassifying microcirculatory flowabnormalities in distributive shockrdquoCritical Care vol 10 article221 2006
[83] S Trzeciak I Cinel R P Dellinger et al ldquoResuscitating themicrocirculation in sepsis the central role of nitric oxideemerging concepts for novel therapies and challenges forclinical trialsrdquo Academic Emergency Medicine vol 15 no 5 pp399ndash415 2008
[84] Y Sakr M-J Dubois D De Backer J Creteur and J-LVincent ldquoPersistent-microcirculatory alterations are associatedwith organ failure and death in patients with septic shockrdquoCritical Care Medicine vol 32 no 9 pp 1825ndash1831 2004
[85] P E Spronk J H Rommes C Schaar andC Ince ldquoThromboly-sis in fulminant purpura observations on changes in microcir-culatory perfusion during succesful treatmentrdquoThrombosis andHaemostasis vol 95 no 3 pp 576ndash578 2006
[86] J Creteur D De Backer Y Sakr M Koch and J-L VincentldquoSublingual capnometry tracks microcirculatory changes inseptic patientsrdquo Intensive Care Medicine vol 32 no 4 pp 516ndash523 2006
[87] D De Backer J Creteur J C Preiser M J Dubois and JL Vincent ldquoMicrovascular blood flow is altered in patientswith sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 1 pp 98ndash104 2002
[88] G M Ibrahim and R L Macdonald ldquoThe effects of fluid bal-ance and colloid administration on outcomes in patients withaneurysmal subarachnoid hemorrhage a propensity score-matched analysisrdquoNeurocritical Care vol 19 no 2 pp 140ndash1492013
[89] T W Yeo D A Lampah R Gitawati et al ldquoImpaired nitricoxide bioavailability and L-arginine-reversible endothelial dys-function in adults with falciparum malariardquo The Journal ofExperimental Medicine vol 204 no 11 pp 2693ndash2704 2007
[90] A R Fathi R M Pluta K D Bakhtian M Qi and R RLonser ldquoReversal of cerebral vasospasmvia intravenous sodiumnitrite after subarachnoid hemorrhage in primates laboratoryinvestigationrdquo Journal of Neurosurgery vol 115 no 6 pp 1213ndash1220 2011
[91] D de Backer J Creteur M J Dubois et al ldquoThe effects ofdobutamine on microcirculatory alterations in patients withseptic shock are independent of its systemic effectsrdquo CriticalCare Medicine vol 34 no 2 pp 403ndash408 2006
[92] C E Chapleau R P White and J T Robertson ldquoCerebralvasospasm effects of prostaglandin synthetase inhibitors invitrordquo Neurosurgery vol 6 no 2 pp 155ndash159 1980
[93] J L Frazier G Pradilla P P Wang and R J TamargoldquoInhibition of cerebral vasospasm by intracranial delivery ofibuprofen from a controlled-release polymer in a rabbit modelof subarachnoid hemorrhagerdquo Journal of Neurosurgery vol 101no 1 pp 93ndash98 2004
[94] G Pradilla Q A Thai F G Legnani et al ldquoLocal deliveryof ibuprofen via controlled-release polymers prevents angio-graphic vasospasm in a monkey model of subarachnoid hem-orrhagerdquo Neurosurgery vol 57 no 1 pp 184ndash189 2005
[95] R P White and J T Robertson ldquoComparison of piroxicammeclofenamate ibuprofen aspirin and prostacyclin efficacy ina chronic model of cerebral vasospasmrdquo Neurosurgery vol 12no 1 pp 40ndash46 1983
[96] T Fukumori E Tani Y Maeda and A Sukenaga ldquoEffectsof prostacyclin and indomethacin on experimental delayedcerebral vasospasmrdquo Journal of Neurosurgery vol 59 no 5 pp829ndash834 1983
[97] L Brandt B Ljunggren K-E Andersson B Hindfelt and TUski ldquoProstaglandin metabolism and prostacyclin in cerebralvasospasmrdquo General Pharmacology vol 14 no 1 pp 141ndash1431983
[98] T Hakan M Zafer Berkman T Ersoy I Karatas T Sanand S Arbak ldquoAnti-inflammatory effect of meloxicam onexperimental vasospasm in the rat femoral arteryrdquo Journal ofClinical Neuroscience vol 15 no 1 pp 55ndash59 2008
[99] LG Toussaint III J A Friedman E FMWijdicks et al ldquoInflu-ence of aspirin on outcome following aneurysmal subarachnoidhemorrhagerdquo Journal of Neurosurgery vol 101 no 6 pp 921ndash925 2004
[100] B A Gross P M R Lai K U Frerichs and R Du ldquoAspirin andaneurysmal subarachnoid haemorrhagerdquo World Neurosurgery2013
[101] S Yokobori AWatanabe R Nakae et al ldquoCerebral vasospasmsafter intraventricular hemorrhage from an arteriovenousmalformationmdashcase reportrdquo Neurologia Medico-Chirurgicavol 50 no 4 pp 320ndash323 2010
[102] B S Park Y S Won S S Choi and B M Kim ldquoSeveresymptomatic vasospasm following intraventricular hemorrhagefrom arteriovenous fistulardquo Journal of Korean NeurosurgicalSociety vol 45 no 5 pp 300ndash302 2009
[103] G Pradilla T Garzon-Muvdi J J Ruzevick et al ldquoSystemicL-citrulline prevents cerebral vasospasm in haptoglobin 2-2transgenicmice after subarachnoid hemorrhagerdquoNeurosurgeryvol 70 no 3 pp 747ndash757 2012
[104] G Chen J Wu C Sun et al ldquoPotential role of JAK2 in cere-bral vasospasm after experimental subarachnoid hemorrhagerdquoBrain Research vol 1214 pp 136ndash144 2008
[105] C L Lin A L Kwan A S Dumont et al ldquoAttenuationof experimental subarachnoid hemorrhage-induced increases
14 International Journal of Inflammation
in circulating intercellular adhesion molecule-1 and cerebralvasospasm by the endothelin-converting enzyme inhibitor CGS26303rdquo Journal of Neurosurgery vol 106 no 3 pp 442ndash4482007
[106] K Iseda S Ono K Onoda et al ldquoAntivasospastic and antiin-flammatory effects of caspase inhibitor in experimental sub-arachnoid hemorrhagerdquo Journal of Neurosurgery vol 107 no 1pp 128ndash135 2007
[107] C-L Lin A S Dumont T Calisaneller A-L Kwan S-L Hwong and K S Lee ldquoMonoclonal antibody against Eselectin attenuates subarachnoid hemorrhage-induced cerebralvasospasmrdquo Surgical Neurology vol 64 no 3 pp 201ndash206 2005
[108] R Echigo N Shimohata K Karatsu et al ldquoTrehalose treat-ment suppresses inflammation oxidative stress and vasospasminduced by experimental subarachnoid hemorrhagerdquo Journal ofTranslational Medicine vol 10 no 1 article 80 2012
[109] CWakadeM D KingM D Laird C H Alleyne Jr and KMDhandapani ldquoCurcumin attenuates vascular inflammation andcerebral vasospasm after subarachnoid hemorrhage in micerdquoAntioxidants amp Redox Signaling vol 11 no 1 pp 35ndash45 2009
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
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Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
6 International Journal of Inflammation
GPCR
Macrophage
Interleukin-1
Lipopolysaccharide
Plasmodium falciparum antigens
Stimulation of interleukin-1 release
MLCK
PKC
MLCMLCK-P
Rho-kinase MBSMBS-P
MLCPh
Intracellular autoantigens (fromtissue injury)
PLC ≫ IP3 ≫ calcium releaseminusRho-kinase-P
Figure 1 Mechanism for induction of cerebral vasospasm by interleukin-1 (GPCR = G-protein coupled receptor PKC = protein kinase CMLCK = myosin light chain kinase MLC = myosin light chain MBS = myosin-binding subunit of myosin light chain phosphatase MLCPh=myosin light chain phosphatase -P indicates phosphorylated state PLC = phospholipase C and IP3 = phosphatidylinositol trisphosphate)
Table 1 Inflammatory mediators and their role in cerebral vasospasm
Mediator Function of mediator Disease model where role hasbeen established References
(i) Nitric oxide(i) Vasodilator(ii) Inhibitor of endothelin-1expression
(i) Cerebral malaria(ii) Bacterial meningitis(iii) Subarachnoid haemorrhage
[1 7 16 28 32 41 45]
(i) Endothelin-1 (i) Vasoconstrictor (i) Bacterial meningitis(ii) Subarachnoid haemorrhage [7 15]
(i) Interleukin-1(ii) Interferon gamma(iii) Tumor necrosis factor
(i) Activators of protein kinase C(ii) Stimulators of release ofendothelin-1
(i) Bacterial meningitis(ii) Cerebral malaria(iii) Subarachnoid haemorrhage
[7 14 56]
73 Tissue Plasminogen Activator A recent meta-analysis offive randomized controlled trials (465 patients) of tissue plas-minogen activator (tPA) or urokinase applied intrathecallyreduced development of poor outcome and delayed cerebralischaemia and vasospasm [70]Themechanism proposed forthis effect is probably not related to thrombolysis but to adirect effect of tPA on vascular tone It is clear that the effectof tPA is endothelial cell dependent and more specificallyNO synthase dependent tPA seems to bind to a receptorpresent in endothelial cells that mediates the stimulation ofNO synthase activity and thus inhibits the vasoconstrictiveeffect of phenylephrine [76]
74 Statins Statins can reduce vasospasm by upregulatingendothelial NO synthase expression A threefold increasein endothelial NO synthase mRNA protein and enzymatic
activity has been demonstrated following statin treatmentresulting in an increase in cerebral blood flow Statintreatment has attenuated cerebral vasospasm and preventeddelayed ischemic deficits in amurine SAHmodel [77] A pre-vious systematic review of 4 studies with a total of 190 patientsshowed no statistically significant effect on vasospasm ontranscranial Doppler studies delayed cerebral ischaemia ormortality [78] but a more recent review demonstrated areduction in mortality and delayed ischemic neurologicaldeficits [66]
75 Rho-Kinase Inhibitor The specific rho-kinase inhibitorfasudil hydrochloride was in a recent systematic review of8 studies (843 patients) shown to reduce the occurrenceof cerebral vasospasm and cerebral infarction significantlyand led to an improvement in clinical outcome [71] The
International Journal of Inflammation 7
Table2Medicationfortreatmento
fcerebralvasospasm
the
evidence
from
controlledtrialsin
humans
Interventio
nTy
peof
study
Patholog
yRe
sultsodd
sratio
(OR)
orrelativer
isk(RR)
foro
ccurrencein
interventio
ngrou
pcomparedto
grou
pwith
outintervention
Reference
Calcium
channel
blockers
Syste
maticreview
(SR)
(sixrand
omized
controlledtrials
(RCT
s))
Acuteb
rain
injury
DeathO
R091
[95
070ndash117
]Death
andsevere
disabilityOR085
[95
068
to10
7]In
thes
ubgrou
pof
traumaticsubarachno
idhaem
orrhagep
atients
pooled
odds
ratio
was
059
[95
CI037ndash0
94]three
RCTs
repo
rtingdeathandsevere
disabilityas
anou
tcom
einthis
subgroup
OR067
[95
CI046
ndash098]
[60]
Calcium
channel
blockers
SR(16RC
Ts)
Aneurysmal
subarachno
idhaem
orrhage(aSAH)
Overallcalcium
antagonists
redu
cedther
iskof
poor
outcom
ethe
relativer
isk(RR)
was
081
[95
CI072
to092]thec
orrespon
ding
numbero
fpatientsn
eededto
treatwas
19[95
CI1to51]foro
ral
nimod
ipinea
lone
theR
Rwas
067
[95
CI055
to081]foro
ther
calcium
antagonists
orintravenou
sadm
inistratio
nof
nimod
ipine
ther
esultsweren
otsta
tistic
allysig
nificantcalcium
antagonists
redu
cedtheo
ccurrenceo
fsecon
dary
ischaem
iaandshow
eda
favourabletre
ndforc
asefatality
for
magnesiu
minadditio
nto
standard
treatmentw
ithnimod
ipinetheR
Rwas
075
[95
CI057
to10
0]fora
poor
outcom
eand
066
[95
CI045
to096]for
clinicalsigns
ofsecond
aryisc
haem
ia
[61]
Nicardipine
SR(five
controlled
trials)
aSAH
Risk
ofpo
orou
tcom
e(deathvegetativ
estateord
ependency)
OR
058
(95
CI037ndash0
9)
Mortalityod
dsratio
045[95
CI015
to12
9][62]
Magnesiu
msulfate
Prospective
rand
omise
dstu
dyEclampsia
Sign
ificant
redu
ctionof
pulsa
tility
index(119875=0002)a
ndmeanflo
wvelocityin
middlec
erebralartery(119875=002)
[63]
Prop
hylactic
magnesiu
msulfate
SRof
tenrand
omized
parallelgroup
controlledtrials
aSAH
Glasgow
outcom
escaleandmod
ified
Rank
inscaleR
R093
(95
CI082
to10
6)m
ortality095
(95
CI076ndash117
)delay
edcerebral
ischaem
iaRR
054(95
CI038
to075)delay
edisc
hemic
neurologicaldeficit(D
IND)RR
of093
[95
CI062ndash139
]transcranialDop
pler
vasospasmR
R072
[95
CI051ndash103]
[64]
Indu
ced
hyperm
agnesaem
iaRC
TaSAH
Vasospasm
ondigitalsub
tractio
nangiograph
yOR
051[95CI
026
to10
2]neurologicalrecoveryORforw
orse
outcom
e071
[95
CI039
to13
2][65]
Statins
SR(sixRC
Ts)
aSAH
Incidenceo
fvasospasm
RR080[95
CI054ndash
117]poo
rneurologicalou
tcom
eRR
094[95
CI077to
116]
MortalityRR
030[95
CI014
ndash064]
DIN
DR
R058
[95
CI037
ndash092]
[66]
Endo
thelin
receptor
antagonists
SR(fo
urRC
Ts)
aSAH
Incidenceo
fDIN
Drela
tiver
isk08[95
CI067ndash0
95]
angiograph
icvasospasm
RR062[95CI
052
to072]
unfavourableou
tcom
eRR
087[95
CI074ndash102]m
ortalityRR
105[95
CI077
to14
5]
[67]
8 International Journal of Inflammation
Table2Con
tinued
Interventio
nTy
peof
study
Patholog
yRe
sultsodd
sratio
(OR)
orrelativer
isk(RR)
foro
ccurrencein
interventio
ngrou
pcomparedto
grou
pwith
outintervention
Reference
Endo
thelin-1Areceptor
antagonistClazosentan
SR(fo
urRC
Ts)
aSAH
Relativer
iskforincidence
ofDIN
Ds076
(95
CI062ndash0
92)
delay
edcerebralinfarctio
n079
[95
CI063ndash100]G
lasgow
outcom
escaleextend
edRR
112
[95
CI096ndash130]m
ortalityRR
10
2[95
CI070ndash149]
[68]
Intravenou
smethylpredn
isolone
RCT
aSAH
Symptom
aticvasospasm
265in
interventio
ngrou
pcompared
with
26in
placebogrou
pfunctio
naloutcomes
caleredu
cedin
the
methylpredn
isolone
grou
pwith
riskdifference193
[95
CI05ndash379]ou
tcom
epoo
rin15of
patie
ntsinthe
methylpredn
isolone
grou
pversus
34in
thep
lacebo
grou
p
[69]
Tissue
plasminogen
activ
ator
SR(five
RCTs)
aSAH
Overalluseo
fintrathecalthrombo
lytic
swas
associated
with
significantreductio
nsin
thed
evelo
pmento
fpoo
routcomes
(OR
052034ndash
078119875lt001)DIN
Ds(OR054034ndash
087119875=001)
andangiograph
icvasospasm
(OR032015
ndash070119875lt001)
[70]
Rho-kinase
inhibitor
SR(8
controlledtrials)
aSAH
Absenceo
fsym
ptom
aticvasospasmoccurrenceo
flow
density
areas
associated
with
vasospasm
onCT
and
occurrence
ofadversee
vents
weres
imilarb
etweenthetwogrou
psthe
clinicaloutcomes
were
morefavorablein
thefasud
ilgrou
pthan
inthen
imod
ipineg
roup
(119875=004)
[71]
Tirilazad
SR(five
RCTs)
aSAH
Therew
asno
significantd
ifference
betweenthetwogrou
psatthe
endof
follo
w-upforthe
prim
aryou
tcom
edeathOR
089[95CI
074
to10
6]orinpo
orou
tcom
e(deathvegetativ
estateorsevere
disability)
OR10
4[95
CI090
to12
1]few
erpatie
ntsd
evelop
eddelay
edcerebralisc
haem
iain
thetirilazadgrou
pthan
inthec
ontro
lgrou
pOR080
[95
CI069
to093]subgroup
analyses
didno
tdemon
stratea
nysig
nificantd
ifference
ineffectsof
tirilazadon
clinicaloutcomes
[72]
Erythrop
oietin
RCT
aSAH
Nodifferences
wered
emon
strated
intheincidence
ofvasospasm
andadversee
ventspatie
ntsreceiving
EPOhadad
ecreased
incidenceo
fseverev
asospasm
from
275to
75(119875=0037)
redu
cedDID
swith
newcerebralinfarctsfro
m40
0to
75
(119875=0001)as
hortened
duratio
nof
impaire
dautoregu
latio
n(ip
silateralsid
e119875lt0001)andmorefavorableou
tcom
eat
discharge(favorableG
lasgow
outcom
escalescore119875=0039)
amon
gthe7
1survivorsthe
EPOgrou
phadfewer
deficits
measured
with
NationalInstitutes
ofHealth
Stroke
Scale(medianscore2
versus
6119875=0008)
[73]
International Journal of Inflammation 9
mechanism is apart from a contribution to inhibition ofcalcium independent vasospasm (see above) probably alsoan increase of endothelial nitric oxide synthase (eNOS)expression by stabilizing eNOSmRNA which can contributeto an increase of NO level to enhance vasodilatation
76 Other Treatments Steroid treatment can inhibit cytokineexpression and has thus the potential to reduce cytokinemediated calcium dependent and independent vasospasmIn tuberculous meningitis adjuvant treatment with corticos-teroids has been indirectly associatedwith features of reducedvasculopathy which may include vasospasm
A large randomised controlled trial showed improvedmortality in tuberculous meningitis with adjuvant corti-costeroids but did not show a reduction in severe disabil-ity however an observational MRI study did suggest areduction in strokes in patients treated with corticosteroids[79 80] An open-label study of aspirin in the preventionof stroke and mortality in tuberculous meningitis found anonsignificant reduction in stroke and a significant reductionin mortality with a possible synergism with corticosteroids[81] Mechanisms responsible for a potential effect may bea reduction of the vasoconstricting effect of PGE2 The 21-aminosteroid tirilazad is a lipid peroxidation inhibitor whichinhibits free radical-induced lipid peroxidation (LP) by acombination of lipid peroxide scavenging and a membrane-stabilizing action that limits the propagation of LP reactionsbetween a lipid peroxide and an adjacent polyunsaturatedfatty acid There has been no consistent evidence of benefitin animal or human studies Erythropoietin may act throughincrease in expression of endothelial nitric oxide synthasethus increasing NO bioavailability
8 Conclusions and Perspectives forFuture Developments
There is evidence for common pathways leading tovasospasm in all forms of cerebral inflammation involvinginterleukin-1 tumor necrosis factor endothelin-1 andnitric oxide Treatments addressing the pathophysiologyof vasospasm in one form of cerebral inflammation maytherefore apply to all others Treatment of cerebral vasospasmhas been mainly investigated in aneurysmal SAH Agentsfor which there is likely to be clinical benefit are calciumantagonists statins and intrathecal plasminogen activators(see Table 2) The fact that there is calcium dependent andindependent vasospasm in inflammation (see Figure 1)shows that a combination of calcium antagonists with agentsinterfering with calcium independent vasospasm includingagents improving the bioavailability of nitric oxide is theway forward Future trials need to investigate their effectsin patients with all forms of cerebral inflammation leadingto neurological deficits attributable to vasospasm In vivocorrelates for reduction of vasospasm in the peripheralcirculation could be explored as a surrogate for reduction ofvasospasm in the cerebral (micro) vasculature
Strategies to improve microvascular recruitment whichhave been explored in models of septicaemia could poten-tially be applied to cerebral vasospasm Distributive shockwhich occurs during sepsis and septic shock is associatedwith an abnormal distribution of microvascular blood flowVasospasm of part of the arterioles supplying the capillary isa mechanism involved in this maldistribution The clinicalintroduction of new microcirculatory imaging techniquessuch as orthogonal polarization spectral and side-streamdark-field imaging (OPSSDF) has allowed direct obser-vation of the microcirculation at the bedside Images ofthe sublingual microcirculation during septic shock andresuscitation have revealed that the distributive defect ofblood flow occurs at the capillary level [82]
In rat models of cecal ligation and puncture investiga-tors have used intravital video microscopy to demonstratethat sepsis is characterized by decreased microcirculatoryflow velocity an abundance of stopped-flow microvesselsincreased heterogeneity of microcirculatory flow and lowdensity of perfused capillaries As thesemicrocirculatory flowalterations can occur in the absence of global hemodynamicderangements (eg absence of arterial hypotension) micro-circulatory dysfunction largely reflects intrinsic events occur-ring in the microvessels like localized vasospasm [83] Appli-cation ofmicrocirculatory recruitmentmaneuver procedureshas been shown to be effective in promotingmicrocirculatoryblood flow in clinical studies using OPSSDF imaging [84ndash87] Fluid resuscitation in combination with the nitric oxidedonor nitroglycerine was shown to recruit disturbed micro-circulation following pressure guided resuscitation in septicshock patients
It is important to note that application of colloids inpatients with SAH was associated with worse outcomescompared to matched controls in a subgroup analysis of theCONSCIOUS-1 prospective randomized trial of clazosentanfor the prevention of angiographic vasospasm [88] Futureresearch needs to investigate whether colloids can bind nitricoxide and make this vasodilator less available by binding it
Regarding future therapeutic interventions increasingnitric oxide bioavailability erythropoietin and L-argininewhich increased bioavailability of nitric oxide in patients withmalaria [89] need to be explored as adjunctive treatmentin children with cerebral malaria in randomised controlledtrials In vitro the availability of L-arginine does not appearto be a rate limiting step for the activity of the NO synthasebecause its half-saturating concentration is less than 3of theplasma and endothelial concentration of this substrate
The nitric oxide donor intravenous sodium nitrite hasbeen shown to prevent and reverse cerebrovascular spasmin primates and has been demonstrated to be safe foradministration in humans [90]
Support of pump function by dobutamine therapy hasbeen shown to improvemicrocirculatory flow independent ofimprovement of global hemodynamic parameters [91] Fluidapplication nitric oxide donors and dobutamine therapyneed to be explored in isolation but also as combinationof interventions to improve cerebral perfusion in cerebralinflammation associated with vasospasm
10 International Journal of Inflammation
A potential role of nonsteroidal anti-inflammatory drugswas revealed by landmark experiments on dog basilararteries Arachidonic acid induced sustained contractionsand these responses were markedly inhibited (95) bymeclofenamate and similarly by indomethacin but aspirinhad no such effect [92] In the rabbit basilar artery model ofcerebral vasospasm local intracranial delivery of ibuprofenaccomplished using controlled-release polymers preventedvasospasm when administered within 6 hours but notat either 12 or 24 hours [93] Delivery of ibuprofen viacontrolled-release polymers into the subarachnoid space ofmonkeys with subarachnoid haemorrhage prevented angio-graphic vasospasm after SAH as evident from patency of themiddle cerebral artery [94]
Piroxicam was more effective than the above-mentioneddrugs in the SAH dog model after angiographic analysisand analysis of behavioural changes [95] Early studiesusing prostacyclin found that isolated canine basilar arteriescontraction induced by prostaglandin E2 hemoglobin orserum was relaxed by prostacyclin but not indomethacin[96] In isolated human pial arteries prostacyclin relaxedhuman pial arteries contracted by either PGF2 alpha nora-drenaline serotonin or haemorrhagic CSF [97] In an animalstudy meloxicam reduced ultrastructural and morphometricvasospastic changes in rats with subarachnoid haemorrhage[98] Investigation comparing rate of subsequent permanentdisability from vasospasm and angiographic and delayedcerebral ischaemia in patients with SAH with and withoutaspirin intake found no association with poor outcome [99100]
There are new areas of pathophysiology research wherethe role of vasospasm needs to be explored thoroughly inorder to find avenues for therapeutic interventions Investi-gations could evaluate whether intraventricular haemorrhageoccurring commonly in the neonatal period in pretermneonates is associated with vasospasm increasing mor-bidity Case reports of intraventricular haemorrhage fromAV malformations and aneurysms in adults demonstratedvasospasm [101 102]
Future research needs to explore the usefulness of a num-ber of agents which have been demonstrated to reduce vaso-spasm in animal models including L-citrulline [103] januskinase-2 [104] endothelin converting enzyme inhibitors[105] caspase inhibitor Z-VAD-FMK [106] anti-E selectinmonoclonal antibodies [107] trehalose [108] and curcuminwhich was demonstrated to protect against the developmentof cerebral vasospasm and secondary cerebral infarctionafter subarachnoid haemorrhage in mice by its broad anti-inflammatory activity including limitation of superoxidegeneration and influence on inducible nitric oxide synthaseexpression [109]
Aggressive maintenance of normothermia or mildhypothermia in patients with military blast injury resultedin a dramatic reduction in the incidence of posttraumaticvasospasm from 475 to 5 Future studies need to confirmthis finding and investigate whether hypothermia can reducecerebral inflammation related ischemic damage to the brainin other conditions like bacterial meningitis or cerebralmalaria [37]
Conflict of Interests
The author declares that there is no conflict of interestsregarding the publication of this paper
References
[1] B Weir ldquoThe pathophysiology of cerebral vasospasmrdquo BritishJournal of Neurosurgery vol 9 no 3 pp 375ndash390 1995
[2] H Bode and A Harders ldquoTransient stenoses and occlusionsof main cerebral arteries in childrenmdashdiagnosis and control oftherapy by transcranial Doppler sonographyrdquo European Journalof Pediatrics vol 148 no 5 pp 406ndash411 1989
[3] K-F Lindegaard H Nornes S J Bakke W Sorteberg and PNakstad ldquoCerebral vasospasm diagnosis by means of angiogra-phy and blood velocity measurementsrdquo Acta Neurochirurgicavol 100 no 1-2 pp 12ndash24 1989
[4] C Lysakowski B Walder M C Costanza and M R TramerldquoTranscranial Doppler versus angiography in patients withvasospasm due to a ruptured cerebral aneurysm a systematicreviewrdquo Stroke vol 32 no 10 pp 2292ndash2298 2001
[5] R L Grubb Jr M E Raichle J O Eichling and M HGado ldquoEffects of subarachnoid hemorrhage on cerebral bloodvolume blood flow and oxygen utilization in humansrdquo Journalof Neurosurgery vol 46 no 4 pp 446ndash452 1977
[6] C-H Lu H-W Chang C-C Lui C-R Huang and W-NChang ldquoCerebral haemodynamics in acute bacterial meningitisin adultsrdquoQuaterly Journal of Medicine vol 99 no 12 pp 863ndash869 2006
[7] F Faraci and D D Heistad ldquoRegulation of the cerebralcirculation role of endothelium and potassium channelsrdquoPhysiological Reviews vol 78 no 1 pp 53ndash97 1998
[8] L Hektoen ldquoThe vascular changes in tuberculous meningitisespecially in tuberculous endarteritisrdquo Journal of ExperimentalMedicine vol 1 pp 112ndash163 1896
[9] G Thwaites ldquoTuberculosis of the central nervous systemrdquo inClinical Tuberculosis P D O Davies S B Gordon and GDavies Eds pp 151ndash165 CRC Press 5th edition 2014
[10] P M Dalal ldquoObservations on the involvement of cerebral ves-sels in tuberculousmeningitis in adultsrdquoAdvances in Neurologyvol 25 pp 149ndash159 1979
[11] L A Rojas-Echeverri J L Soto-Hernandez S Garza et alldquoPredictive value of digital subtraction angiography in patientswith tuberculous meningitisrdquo Neuroradiology vol 38 no 1 pp20ndash24 1996
[12] E L Lyons and N E Leeds ldquoThe angiographic demonstrationof arterial vascular disease in purulent meningitis report of acaserdquo Radiology vol 88 no 5 pp 935ndash938 1967
[13] S Ries U Schminke K Fassbender M Daffertshofer WSteinke andMHennerici ldquoCerebrovascular involvement in theacute phase of bacterial meningitisrdquo Journal of Neurology vol244 no 1 pp 51ndash55 1997
[14] K Fassbender S Ries U Schminke S Schneider and M Hen-nerici ldquoInflammatory cytokines in CSF in bacterial meningitisassociation with altered blood flow velocities in basal cerebralarteriesrdquo Journal of Neurology Neurosurgery amp Psychiatry vol61 no 1 pp 57ndash61 1996
[15] L A Pfister J H Tureen S Shaw et al ldquoEndothelin inhibitionimproves cerebral blood flow and is neuroprotective in pneu-mococcal meningitisrdquoAnnals of Neurology vol 47 pp 329ndash3352000
International Journal of Inflammation 11
[16] S L Leib Y S Kim S M Black J H Tureen and M GTauber ldquoInducible nitric oxide synthase and the effect of amin-oguanidine in experimental neonatal meningitisrdquo The Journalof Infectious Diseases vol 177 no 3 pp 692ndash700 1998
[17] T W Polder C R Jerusalem andW M C Eling ldquoMorpholog-ical characteristics of intracerebral arterioles in clinical (Plas-modium falciparum) and experimental (Plasmodium berghei)cerebral malariardquo Journal of the Neurological Sciences vol 101no 1 pp 35ndash46 1991
[18] N A V Beare S P Harding T E Taylor S Lewallen and MEMolyneux ldquoPerfusion abnormalities in childrenwith cerebralmalaria andmalarial retinopathyrdquo Journal of Infectious Diseasesvol 199 no 2 pp 263ndash271 2009
[19] C R J C Newton K Marsh N Peshu and F J KirkhamldquoPerturbations of cerebral hemodynamics in Kenyans withcerebral malariardquo Pediatric Neurology vol 15 no 1 pp 41ndash491996
[20] C C John A Panoskaltsis-Mortari R O Opoka et alldquoCerebrospinal fluid cytokine levels and cognitive impairmentin cerebral malariardquo American Journal of Tropical Medicine andHygiene vol 78 no 2 pp 198ndash205 2008
[21] W McGuire A V S Hill C E M Allsopp B M Greenwoodand D Kwiatkowski ldquoVariation in the TNF-120572 promoter regionassociated with susceptibility to cerebral malariardquo Nature vol371 no 6497 pp 508ndash510 1994
[22] W McGuire J C Knight A V S Hill C E M Allsopp B MGreenwood and D Kwiatkowski ldquoSevere malarial anemia andcerebral malaria are associated with different tumor necrosisfactor promoter allelesrdquo Journal of Infectious Diseases vol 179no 1 pp 287ndash290 1999
[23] B Dugas M D Mossalayi C Damais and J-P Kolb ldquoNitricoxide production by human monocytes Evidence for a role ofCD23rdquo Immunology Today vol 16 no 12 pp 574ndash580 1995
[24] L Pellettieri B Nilsson C-A Carlsson andU Nilsson ldquoSerumimmunocomplexes in patients with subarachnoid hemorrhagerdquoNeurosurgery vol 19 no 5 pp 767ndash771 1986
[25] M Eisenhut ldquoCauses of reduced immune complex clearance incerebralmalariardquoParasite Immunology vol 31 no 2 p 59 2009
[26] P Teeranaipong J Ohashi J Patarapotikul et al ldquoA functionalsingle-nucleotide polymorphism in the CR1 promoter regioncontributes to protection against cerebral malariardquo Journal ofInfectious Diseases vol 198 no 12 pp 1880ndash1891 2008
[27] P Cabrales G M Zanini D Meays J A Frangos and LJ M Carvalho ldquoMurine cerebral malaria is associated witha vasospasm-like microcirculatory dysfunction and survivalupon rescue treatment is markedly increased by nimodipinerdquoTheAmerican Journal of Pathology vol 176 no 3 pp 1306ndash13152010
[28] I Gramaglia P Sobolewski D Meays et al ldquoLow nitricoxide bioavailability contributes to the genesis of experimentalcerebral malariardquoNature Medicine vol 12 no 12 pp 1417ndash14222006
[29] T W Yeo D A Lampah E Tjitra et al ldquoRelationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavail-ability and perfusion in severe falciparum malariardquo Journal ofInfectious Diseases vol 200 no 10 pp 1522ndash1529 2009
[30] G Dhangadamajhi B N Mohapatra S K Kar and M RanjitldquoGenetic variation in neuronal nitric oxide synthase (nNOS)gene and susceptibility to cerebral malaria in Indian adultsrdquoInfection Genetics and Evolution vol 9 no 5 pp 908ndash911 2009
[31] M R Hobbs V Udhayakumar M C Levesque et al ldquoAnew NOS2 promoter polymorphism associated with increased
nitric oxide production and protection from severe malaria inTanzanian and Kenyan childrenrdquoThe Lancet vol 360 no 9344pp 1468ndash1475 2002
[32] P Cabrales G M Zanini D Meays J A Frangos and L JM Carvalho ldquoNitric oxide protection against murine cerebralmalaria is associated with improved cerebral microcirculatoryphysiologyrdquo The Journal of Infectious Diseases vol 203 no 10pp 1454ndash1463 2011
[33] G Morahan C S Boutlis D Huang et al ldquoA promoterpolymorphism in the gene encoding interleukin-12 p40 (IL12B)is associated with mortality from cerebral malaria and withreduced nitric oxide productionrdquo Genes amp Immunity vol 3 no7 pp 414ndash418 2002
[34] C Casals-Pascual R Idro N Gicheru et al ldquoHigh levels of ery-thropoietin are associated with protection against neurologicalsequelae in African children with cerebral malariardquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 105 no 7 pp 2634ndash2639 2008
[35] F C Chow C M Marra and T A Cho ldquoCerebrovasculardisease in central nervous system infectionsrdquo Seminars inNeurology vol 31 no 3 pp 286ndash306 2011
[36] R A Armonda R S Bell A H Vo et al ldquoWartime traumaticcerebral vasospasm recent review of combat casualtiesrdquoNeuro-surgery vol 59 no 6 pp 1215ndash1225 2006
[37] K Shahlaie K Keachie I M Hutchins et al ldquoRisk factorsfor posttraumatic vasospasm clinical articlerdquo Journal of Neu-rosurgery vol 115 no 3 pp 602ndash611 2011
[38] Y Udomphorn W M Armstead and M S Vavilala ldquoCerebralblood flow and autoregulation after pediatric traumatic braininjuryrdquo Pediatric Neurology vol 38 no 4 pp 225ndash234 2008
[39] R M Pluta J Hansen-Schwartz J Dreier et al ldquoCerebralvasospasm following subarachnoid hemorrhage time for a newworld of thoughtrdquo Neurological Research vol 31 no 2 pp 151ndash158 2009
[40] J Hansen-Schwartz P Vajkoczy R L Macdonald R MPluta and J H Zhang ldquoCerebral vasospasm looking beyondvasoconstrictionrdquo Trends in Pharmacological Sciences vol 28no 6 pp 252ndash256 2007
[41] H Kasuya B K A Weir M Nakane et al ldquoNitric oxidesynthase and guanylate cyclase levels in canine basilar arteryafter subarachnoid hemorrhagerdquo Journal of Neurosurgery vol82 no 2 pp 250ndash255 1995
[42] M D Linnik and T J F Lee ldquoEffect of hemoglobin on neuro-genic responses and cholinergic parameters in porcine cerebralarteriesrdquo Journal of Cerebral Blood Flow and Metabolism vol 9no 2 pp 219ndash225 1989
[43] CG Sobey and FM Faraci ldquoSubarachnoid haemorrhage whathappens to the cerebral arteriesrdquo Clinical and ExperimentalPharmacology and Physiology vol 25 no 11 pp 867ndash876 1998
[44] Y R T Dinh G Lot R Benrabah O Baroudy J Cophignonand J Seylaz ldquoAbnormal cerebral vasodilation in aneurys-mal subarachnoid hemorrhage use of serial 133Xe cerebralblood flow measurement plus acetazolamide to assess cerebralvasospasmrdquo Journal of Neurosurgery vol 79 no 4 pp 490ndash4931993
[45] T J F Lee ldquoNitric oxide and the cerebral vascular functionrdquoJournal of Biomedical Science vol 7 no 1 pp 16ndash26 2000
[46] M Stoodley R L Macdonald B Weir et al ldquoSubarachnoidhemorrhage as a cause of an adaptive response in cerebralarteriesrdquo Journal of Neurosurgery vol 93 no 3 pp 463ndash4702000
12 International Journal of Inflammation
[47] Y R Tran Dinh A Jomaa J Callebert et al ldquoOverexpressionof cyclooxygenase-2 in rabbit basilar artery endothelial cellsafter subarachnoid hemorrhagerdquo Neurosurgery vol 48 no 3pp 626ndash635 2001
[48] A Gecse B Kis Z Mezei and G Telegdy ldquoEffects of inflam-matory neuropeptides on the arachidonate cascade of plateletsrdquoInternational Archives of Allergy and Immunology vol 118 no2ndash4 pp 166ndash170 1999
[49] K S Mark W J Trickler and D W Miller ldquoTumornecrosis factor-120572 induces cyclooxygenase-2 expression andprostaglandin release in brain microvessel endothelial cellsrdquoJournal of Pharmacology and Experimental Therapeutics vol297 no 3 pp 1051ndash1058 2001
[50] T Tanazawa Y Suzuki M Anzai S Tsugane M Takayasu andM Shibuya ldquoVasodilation by intrathecal lipopolysaccharide ofthe cerebral arteries after subarachnoid haemorrhage in dogsrdquoActa Neurochirurgica vol 138 no 3 pp 330ndash337 1996
[51] N Toda M Kawakami and K Yoshida ldquoConstrictor action ofoxyhemoglobin in monkey and dog basilar arteries in vivo andin vitrordquo American Journal of Physiology Heart and CirculatoryPhysiology vol 260 no 2 pp H420ndashH425 1991
[52] M Yoshizumi M A Perrella J C Burnett Jr and M-E LeeldquoTumor necrosis factor downregulates an endothelial nitricoxide synthase mRNA by shortening its half-liferdquo CirculationResearch vol 73 no 1 pp 205ndash209 1993
[53] A Rengasamy and R A Johns ldquoRegulation of nitric oxidesynthase by nitric oxiderdquo Molecular Pharmacology vol 44 no1 pp 124ndash128 1993
[54] A L de Souza A C P de Oliveira C C Romano J SztajnbokA J S Duarte and A C Seguro ldquoInterleukin-6 activation inischemic stroke caused by Neisseria meningitidis serogroup CrdquoInternational Journal of Cardiology vol 127 no 3 pp e160ndashe1632008
[55] T Kandabashi H Shimokawa K Miyata et al ldquoInhibition ofmyosin phosphatase by upregulated Rho-kinase plays a key rolefor coronary artery spasm in a porcine model with interleukin-1120573rdquo Circulation vol 101 no 11 pp 1319ndash1323 2000
[56] D-H Nam J-S Kim S-C Hong et al ldquoExpression ofinterleukin-1120573 in lipopolysaccharide stimulated monocytesderived from patients with aneurysmal subarachnoid hem-orrhage is correlated with cerebral vasospasmrdquo NeuroscienceLetters vol 312 no 1 pp 41ndash44 2001
[57] A Ito H Shimokawa T Kadokami et al ldquoTyrosine kinaseinhibitor suppresses coronary arteriosclerotic changes andvasospastic responses induced by chronic treatment withinterleukin-1120573 in pigs in vivordquo Journal of Clinical Investigationvol 96 no 3 pp 1288ndash1294 1995
[58] H Yanamoto H Kataoka Y Nakajo and K Iihara ldquoThe roleof the host defense system in the development of cerebralvasospasm analogies between atherosclerosis and subarach-noid hemorrhagerdquo European Neurology vol 68 no 6 pp 329ndash343 2012
[59] A F Ducruet P R Gigante Z L Hickman et al ldquoGeneticdeterminants of cerebral vasospasm delayed cerebral ischemiaand outcome after aneurysmal subarachnoid hemorrhagerdquoJournal of Cerebral Blood Flow amp Metabolism vol 30 no 4 pp676ndash688 2010
[60] J Langham C Goldfrad G Teasdale D Shaw and KRowan ldquoCalcium channel blockers for acute traumatic braininjuryrdquoCochrane Database Systematic Reviews no 4 Article IDCD000565 2000
[61] S M Dorhout Mees G J Rinkel V L Feigin et al ldquoCal-cium antagonists for aneurysmal subarachnoid haemorrhagerdquoCochrane Database of Systematic Reviews no 3 Article IDCD000277 2007
[62] R-Q Huang F-G Jiang Z-M Feng and T-Y WangldquoNicardipine in the treatment of aneurysmal subarachnoidhaemorrhage a meta-analysis of published datardquo Acta Neuro-logica Belgica vol 113 no 1 pp 3ndash6 2013
[63] S Naidu A J Payne J Moodley M Hoffmann and EGouws ldquoRandomised study assessing the effect of phenytoinand magnesium sulphate on maternal cerebral circulationin eclampsia using transcranial Doppler ultrasoundrdquo BritishJournal of Obstetrics amp Gynaecology vol 103 no 2 pp 111ndash1161996
[64] D Reddy A Fallah J-A Petropoulos F Farrokhyar R LMacdonald and D Jichici ldquoProphylactic magnesium sulphatefor aneurysmal subarachnoid haemorrhage a systematic reviewand meta-analysisrdquo Neurocritical Care vol 21 no 2 pp 356ndash364 2014
[65] C M Bradford S Finfer A OrsquoConnor et al ldquoA ran-domised controlled trial of induced hypermagnesaemia follow-ing aneurysmal subarachnoid haemorrhagerdquo Critical Care andResuscitation vol 15 no 2 pp 119ndash125 2013
[66] S-H Su W Xu J Hai Y-F Wu and F Yu ldquoEffects of statins-use for patients with aneurysmal subarachnoid hemorrhagea meta-analysis of randomized controlled trialsrdquo ScientificReports vol 4 article 4573 2014
[67] J Guo Z Shi K Yang J H Tian and L Jiang ldquoEndothelinreceptor antagonists for subarachnoid hemorrhagerdquo CochraneDatabase of Systematic Reviews vol 9 Article ID CD0083542012
[68] J Shen J-W Pan Z-X Fan X-X Xiong and R-Y ZhanldquoDissociation of vasospasm-related morbidity and outcomesin patients with aneurysmal subarachnoid hemorrhage treatedwith clazosentan a meta-analysis of randomized controlledtrials a reviewrdquo Journal of Neurosurgery vol 119 no 1 pp 180ndash189 2013
[69] P Gomis J P Graftieaux R Sercombe D Hettler BScherpereel and P Rousseaux ldquoRandomized double-blindplacebo-controlled pilot trial of high-dose methylprednisolonein aneurysmal subarachnoid hemorrhagerdquo Journal of Neuro-surgery vol 112 no 3 pp 681ndash688 2010
[70] A H Kramer and J J Fletcher ldquoLocally-administered intrathe-cal thrombolytics following aneurysmal subarachnoid hem-orrhage a systematic review and meta-analysisrdquo NeurocriticalCare vol 14 no 3 pp 489ndash499 2011
[71] G J Liu Z J Wang Y F Wang et al ldquoSystematic assessmentand meta-analysis of the efficacy and safety of fasudil in thetreatment of cerebral vasospasm in patients with subarachnoidhemorrhagerdquo European Journal of Clinical Pharmacology vol68 no 2 pp 131ndash139 2012
[72] S Zhang LWangM Liu andBWu ldquoTirilazad for aneurysmalsubarachnoid haemorrhagerdquo Cochrane Database SystematicReview vol 2 Article ID CD006778 2010
[73] M-Y Tseng P J Hutchinson H K Richards et al ldquoAcutesystemic erythropoietin therapy to reduce delayed ischemicdeficits following aneurysmal subarachnoid hemorrhage aphase II randomized double-blind placebo-controlled trialclinical articlerdquo Journal of Neurosurgery vol 111 no 1 pp 171ndash180 2009
[74] H Kasuya ldquoDevelopment of nicardipine prolonged-releaseimplants after clipping for preventing cerebral vasospasm from
International Journal of Inflammation 13
laboratory to clinical trialrdquo Acta Neurochirurgica Supplemen-tum vol 115 pp 41ndash44 2013
[75] C Thome M Seiz G A Schubert et al ldquoNicardipine pelletsfor the prevention of cerebral vasospasmrdquoActaNeurochirurgicano 110 pp 209ndash211 2011
[76] T Nassar S Akkawi A Shina et al ldquoIn vitro and in vivo effectsof tPA and PAI-1 on blood vessel tonerdquo Blood vol 103 no 3 pp897ndash902 2004
[77] T Sugawara R Ayer V Jadhav W Chen T Tsubokawaand J H Zhang ldquoMechanisms of statin treatment in cerebralvasospasmrdquo Acta Neurochirurgica no 110 pp 9ndash11 2011
[78] M D Vergouwen R J De Haan M Vermeulen and YB Roos ldquoEffect of statin treatment on vasospasm delayedcerebral ischemia and functional outcome in patients withaneurysmal subarachnoid hemorrhage a systematic review andmeta-analysis updaterdquo Stroke vol 41 no 1 pp e47ndashe52 2010
[79] G E Thwaites N D Bang N H Dung et al ldquoDexamethasonefor the treatment of tuberculous meningitis in adolescents andadultsrdquoTheNew England Journal ofMedicine vol 351 no 17 pp1741ndash1811 2004
[80] G E Thwaites J Macmullen-Price T T H Chau et al ldquoSerialMRI to determine the effect of dexamethasone on the cerebralpathology of tuberculous meningitis an observational studyrdquoThe Lancet Neurology vol 6 no 3 pp 230ndash236 2007
[81] U K Misra J Kalita and P P Nair ldquoRole of aspirin in tuber-culous meningitis a randomized open label placebo controlledtrialrdquo Journal of the Neurological Sciences vol 293 no 1-2 pp12ndash17 2010
[82] P W G Elbers and C Ince ldquoBench-to-bedside review mech-anisms of critical illnessmdashclassifying microcirculatory flowabnormalities in distributive shockrdquoCritical Care vol 10 article221 2006
[83] S Trzeciak I Cinel R P Dellinger et al ldquoResuscitating themicrocirculation in sepsis the central role of nitric oxideemerging concepts for novel therapies and challenges forclinical trialsrdquo Academic Emergency Medicine vol 15 no 5 pp399ndash415 2008
[84] Y Sakr M-J Dubois D De Backer J Creteur and J-LVincent ldquoPersistent-microcirculatory alterations are associatedwith organ failure and death in patients with septic shockrdquoCritical Care Medicine vol 32 no 9 pp 1825ndash1831 2004
[85] P E Spronk J H Rommes C Schaar andC Ince ldquoThromboly-sis in fulminant purpura observations on changes in microcir-culatory perfusion during succesful treatmentrdquoThrombosis andHaemostasis vol 95 no 3 pp 576ndash578 2006
[86] J Creteur D De Backer Y Sakr M Koch and J-L VincentldquoSublingual capnometry tracks microcirculatory changes inseptic patientsrdquo Intensive Care Medicine vol 32 no 4 pp 516ndash523 2006
[87] D De Backer J Creteur J C Preiser M J Dubois and JL Vincent ldquoMicrovascular blood flow is altered in patientswith sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 1 pp 98ndash104 2002
[88] G M Ibrahim and R L Macdonald ldquoThe effects of fluid bal-ance and colloid administration on outcomes in patients withaneurysmal subarachnoid hemorrhage a propensity score-matched analysisrdquoNeurocritical Care vol 19 no 2 pp 140ndash1492013
[89] T W Yeo D A Lampah R Gitawati et al ldquoImpaired nitricoxide bioavailability and L-arginine-reversible endothelial dys-function in adults with falciparum malariardquo The Journal ofExperimental Medicine vol 204 no 11 pp 2693ndash2704 2007
[90] A R Fathi R M Pluta K D Bakhtian M Qi and R RLonser ldquoReversal of cerebral vasospasmvia intravenous sodiumnitrite after subarachnoid hemorrhage in primates laboratoryinvestigationrdquo Journal of Neurosurgery vol 115 no 6 pp 1213ndash1220 2011
[91] D de Backer J Creteur M J Dubois et al ldquoThe effects ofdobutamine on microcirculatory alterations in patients withseptic shock are independent of its systemic effectsrdquo CriticalCare Medicine vol 34 no 2 pp 403ndash408 2006
[92] C E Chapleau R P White and J T Robertson ldquoCerebralvasospasm effects of prostaglandin synthetase inhibitors invitrordquo Neurosurgery vol 6 no 2 pp 155ndash159 1980
[93] J L Frazier G Pradilla P P Wang and R J TamargoldquoInhibition of cerebral vasospasm by intracranial delivery ofibuprofen from a controlled-release polymer in a rabbit modelof subarachnoid hemorrhagerdquo Journal of Neurosurgery vol 101no 1 pp 93ndash98 2004
[94] G Pradilla Q A Thai F G Legnani et al ldquoLocal deliveryof ibuprofen via controlled-release polymers prevents angio-graphic vasospasm in a monkey model of subarachnoid hem-orrhagerdquo Neurosurgery vol 57 no 1 pp 184ndash189 2005
[95] R P White and J T Robertson ldquoComparison of piroxicammeclofenamate ibuprofen aspirin and prostacyclin efficacy ina chronic model of cerebral vasospasmrdquo Neurosurgery vol 12no 1 pp 40ndash46 1983
[96] T Fukumori E Tani Y Maeda and A Sukenaga ldquoEffectsof prostacyclin and indomethacin on experimental delayedcerebral vasospasmrdquo Journal of Neurosurgery vol 59 no 5 pp829ndash834 1983
[97] L Brandt B Ljunggren K-E Andersson B Hindfelt and TUski ldquoProstaglandin metabolism and prostacyclin in cerebralvasospasmrdquo General Pharmacology vol 14 no 1 pp 141ndash1431983
[98] T Hakan M Zafer Berkman T Ersoy I Karatas T Sanand S Arbak ldquoAnti-inflammatory effect of meloxicam onexperimental vasospasm in the rat femoral arteryrdquo Journal ofClinical Neuroscience vol 15 no 1 pp 55ndash59 2008
[99] LG Toussaint III J A Friedman E FMWijdicks et al ldquoInflu-ence of aspirin on outcome following aneurysmal subarachnoidhemorrhagerdquo Journal of Neurosurgery vol 101 no 6 pp 921ndash925 2004
[100] B A Gross P M R Lai K U Frerichs and R Du ldquoAspirin andaneurysmal subarachnoid haemorrhagerdquo World Neurosurgery2013
[101] S Yokobori AWatanabe R Nakae et al ldquoCerebral vasospasmsafter intraventricular hemorrhage from an arteriovenousmalformationmdashcase reportrdquo Neurologia Medico-Chirurgicavol 50 no 4 pp 320ndash323 2010
[102] B S Park Y S Won S S Choi and B M Kim ldquoSeveresymptomatic vasospasm following intraventricular hemorrhagefrom arteriovenous fistulardquo Journal of Korean NeurosurgicalSociety vol 45 no 5 pp 300ndash302 2009
[103] G Pradilla T Garzon-Muvdi J J Ruzevick et al ldquoSystemicL-citrulline prevents cerebral vasospasm in haptoglobin 2-2transgenicmice after subarachnoid hemorrhagerdquoNeurosurgeryvol 70 no 3 pp 747ndash757 2012
[104] G Chen J Wu C Sun et al ldquoPotential role of JAK2 in cere-bral vasospasm after experimental subarachnoid hemorrhagerdquoBrain Research vol 1214 pp 136ndash144 2008
[105] C L Lin A L Kwan A S Dumont et al ldquoAttenuationof experimental subarachnoid hemorrhage-induced increases
14 International Journal of Inflammation
in circulating intercellular adhesion molecule-1 and cerebralvasospasm by the endothelin-converting enzyme inhibitor CGS26303rdquo Journal of Neurosurgery vol 106 no 3 pp 442ndash4482007
[106] K Iseda S Ono K Onoda et al ldquoAntivasospastic and antiin-flammatory effects of caspase inhibitor in experimental sub-arachnoid hemorrhagerdquo Journal of Neurosurgery vol 107 no 1pp 128ndash135 2007
[107] C-L Lin A S Dumont T Calisaneller A-L Kwan S-L Hwong and K S Lee ldquoMonoclonal antibody against Eselectin attenuates subarachnoid hemorrhage-induced cerebralvasospasmrdquo Surgical Neurology vol 64 no 3 pp 201ndash206 2005
[108] R Echigo N Shimohata K Karatsu et al ldquoTrehalose treat-ment suppresses inflammation oxidative stress and vasospasminduced by experimental subarachnoid hemorrhagerdquo Journal ofTranslational Medicine vol 10 no 1 article 80 2012
[109] CWakadeM D KingM D Laird C H Alleyne Jr and KMDhandapani ldquoCurcumin attenuates vascular inflammation andcerebral vasospasm after subarachnoid hemorrhage in micerdquoAntioxidants amp Redox Signaling vol 11 no 1 pp 35ndash45 2009
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
International Journal of Inflammation 7
Table2Medicationfortreatmento
fcerebralvasospasm
the
evidence
from
controlledtrialsin
humans
Interventio
nTy
peof
study
Patholog
yRe
sultsodd
sratio
(OR)
orrelativer
isk(RR)
foro
ccurrencein
interventio
ngrou
pcomparedto
grou
pwith
outintervention
Reference
Calcium
channel
blockers
Syste
maticreview
(SR)
(sixrand
omized
controlledtrials
(RCT
s))
Acuteb
rain
injury
DeathO
R091
[95
070ndash117
]Death
andsevere
disabilityOR085
[95
068
to10
7]In
thes
ubgrou
pof
traumaticsubarachno
idhaem
orrhagep
atients
pooled
odds
ratio
was
059
[95
CI037ndash0
94]three
RCTs
repo
rtingdeathandsevere
disabilityas
anou
tcom
einthis
subgroup
OR067
[95
CI046
ndash098]
[60]
Calcium
channel
blockers
SR(16RC
Ts)
Aneurysmal
subarachno
idhaem
orrhage(aSAH)
Overallcalcium
antagonists
redu
cedther
iskof
poor
outcom
ethe
relativer
isk(RR)
was
081
[95
CI072
to092]thec
orrespon
ding
numbero
fpatientsn
eededto
treatwas
19[95
CI1to51]foro
ral
nimod
ipinea
lone
theR
Rwas
067
[95
CI055
to081]foro
ther
calcium
antagonists
orintravenou
sadm
inistratio
nof
nimod
ipine
ther
esultsweren
otsta
tistic
allysig
nificantcalcium
antagonists
redu
cedtheo
ccurrenceo
fsecon
dary
ischaem
iaandshow
eda
favourabletre
ndforc
asefatality
for
magnesiu
minadditio
nto
standard
treatmentw
ithnimod
ipinetheR
Rwas
075
[95
CI057
to10
0]fora
poor
outcom
eand
066
[95
CI045
to096]for
clinicalsigns
ofsecond
aryisc
haem
ia
[61]
Nicardipine
SR(five
controlled
trials)
aSAH
Risk
ofpo
orou
tcom
e(deathvegetativ
estateord
ependency)
OR
058
(95
CI037ndash0
9)
Mortalityod
dsratio
045[95
CI015
to12
9][62]
Magnesiu
msulfate
Prospective
rand
omise
dstu
dyEclampsia
Sign
ificant
redu
ctionof
pulsa
tility
index(119875=0002)a
ndmeanflo
wvelocityin
middlec
erebralartery(119875=002)
[63]
Prop
hylactic
magnesiu
msulfate
SRof
tenrand
omized
parallelgroup
controlledtrials
aSAH
Glasgow
outcom
escaleandmod
ified
Rank
inscaleR
R093
(95
CI082
to10
6)m
ortality095
(95
CI076ndash117
)delay
edcerebral
ischaem
iaRR
054(95
CI038
to075)delay
edisc
hemic
neurologicaldeficit(D
IND)RR
of093
[95
CI062ndash139
]transcranialDop
pler
vasospasmR
R072
[95
CI051ndash103]
[64]
Indu
ced
hyperm
agnesaem
iaRC
TaSAH
Vasospasm
ondigitalsub
tractio
nangiograph
yOR
051[95CI
026
to10
2]neurologicalrecoveryORforw
orse
outcom
e071
[95
CI039
to13
2][65]
Statins
SR(sixRC
Ts)
aSAH
Incidenceo
fvasospasm
RR080[95
CI054ndash
117]poo
rneurologicalou
tcom
eRR
094[95
CI077to
116]
MortalityRR
030[95
CI014
ndash064]
DIN
DR
R058
[95
CI037
ndash092]
[66]
Endo
thelin
receptor
antagonists
SR(fo
urRC
Ts)
aSAH
Incidenceo
fDIN
Drela
tiver
isk08[95
CI067ndash0
95]
angiograph
icvasospasm
RR062[95CI
052
to072]
unfavourableou
tcom
eRR
087[95
CI074ndash102]m
ortalityRR
105[95
CI077
to14
5]
[67]
8 International Journal of Inflammation
Table2Con
tinued
Interventio
nTy
peof
study
Patholog
yRe
sultsodd
sratio
(OR)
orrelativer
isk(RR)
foro
ccurrencein
interventio
ngrou
pcomparedto
grou
pwith
outintervention
Reference
Endo
thelin-1Areceptor
antagonistClazosentan
SR(fo
urRC
Ts)
aSAH
Relativer
iskforincidence
ofDIN
Ds076
(95
CI062ndash0
92)
delay
edcerebralinfarctio
n079
[95
CI063ndash100]G
lasgow
outcom
escaleextend
edRR
112
[95
CI096ndash130]m
ortalityRR
10
2[95
CI070ndash149]
[68]
Intravenou
smethylpredn
isolone
RCT
aSAH
Symptom
aticvasospasm
265in
interventio
ngrou
pcompared
with
26in
placebogrou
pfunctio
naloutcomes
caleredu
cedin
the
methylpredn
isolone
grou
pwith
riskdifference193
[95
CI05ndash379]ou
tcom
epoo
rin15of
patie
ntsinthe
methylpredn
isolone
grou
pversus
34in
thep
lacebo
grou
p
[69]
Tissue
plasminogen
activ
ator
SR(five
RCTs)
aSAH
Overalluseo
fintrathecalthrombo
lytic
swas
associated
with
significantreductio
nsin
thed
evelo
pmento
fpoo
routcomes
(OR
052034ndash
078119875lt001)DIN
Ds(OR054034ndash
087119875=001)
andangiograph
icvasospasm
(OR032015
ndash070119875lt001)
[70]
Rho-kinase
inhibitor
SR(8
controlledtrials)
aSAH
Absenceo
fsym
ptom
aticvasospasmoccurrenceo
flow
density
areas
associated
with
vasospasm
onCT
and
occurrence
ofadversee
vents
weres
imilarb
etweenthetwogrou
psthe
clinicaloutcomes
were
morefavorablein
thefasud
ilgrou
pthan
inthen
imod
ipineg
roup
(119875=004)
[71]
Tirilazad
SR(five
RCTs)
aSAH
Therew
asno
significantd
ifference
betweenthetwogrou
psatthe
endof
follo
w-upforthe
prim
aryou
tcom
edeathOR
089[95CI
074
to10
6]orinpo
orou
tcom
e(deathvegetativ
estateorsevere
disability)
OR10
4[95
CI090
to12
1]few
erpatie
ntsd
evelop
eddelay
edcerebralisc
haem
iain
thetirilazadgrou
pthan
inthec
ontro
lgrou
pOR080
[95
CI069
to093]subgroup
analyses
didno
tdemon
stratea
nysig
nificantd
ifference
ineffectsof
tirilazadon
clinicaloutcomes
[72]
Erythrop
oietin
RCT
aSAH
Nodifferences
wered
emon
strated
intheincidence
ofvasospasm
andadversee
ventspatie
ntsreceiving
EPOhadad
ecreased
incidenceo
fseverev
asospasm
from
275to
75(119875=0037)
redu
cedDID
swith
newcerebralinfarctsfro
m40
0to
75
(119875=0001)as
hortened
duratio
nof
impaire
dautoregu
latio
n(ip
silateralsid
e119875lt0001)andmorefavorableou
tcom
eat
discharge(favorableG
lasgow
outcom
escalescore119875=0039)
amon
gthe7
1survivorsthe
EPOgrou
phadfewer
deficits
measured
with
NationalInstitutes
ofHealth
Stroke
Scale(medianscore2
versus
6119875=0008)
[73]
International Journal of Inflammation 9
mechanism is apart from a contribution to inhibition ofcalcium independent vasospasm (see above) probably alsoan increase of endothelial nitric oxide synthase (eNOS)expression by stabilizing eNOSmRNA which can contributeto an increase of NO level to enhance vasodilatation
76 Other Treatments Steroid treatment can inhibit cytokineexpression and has thus the potential to reduce cytokinemediated calcium dependent and independent vasospasmIn tuberculous meningitis adjuvant treatment with corticos-teroids has been indirectly associatedwith features of reducedvasculopathy which may include vasospasm
A large randomised controlled trial showed improvedmortality in tuberculous meningitis with adjuvant corti-costeroids but did not show a reduction in severe disabil-ity however an observational MRI study did suggest areduction in strokes in patients treated with corticosteroids[79 80] An open-label study of aspirin in the preventionof stroke and mortality in tuberculous meningitis found anonsignificant reduction in stroke and a significant reductionin mortality with a possible synergism with corticosteroids[81] Mechanisms responsible for a potential effect may bea reduction of the vasoconstricting effect of PGE2 The 21-aminosteroid tirilazad is a lipid peroxidation inhibitor whichinhibits free radical-induced lipid peroxidation (LP) by acombination of lipid peroxide scavenging and a membrane-stabilizing action that limits the propagation of LP reactionsbetween a lipid peroxide and an adjacent polyunsaturatedfatty acid There has been no consistent evidence of benefitin animal or human studies Erythropoietin may act throughincrease in expression of endothelial nitric oxide synthasethus increasing NO bioavailability
8 Conclusions and Perspectives forFuture Developments
There is evidence for common pathways leading tovasospasm in all forms of cerebral inflammation involvinginterleukin-1 tumor necrosis factor endothelin-1 andnitric oxide Treatments addressing the pathophysiologyof vasospasm in one form of cerebral inflammation maytherefore apply to all others Treatment of cerebral vasospasmhas been mainly investigated in aneurysmal SAH Agentsfor which there is likely to be clinical benefit are calciumantagonists statins and intrathecal plasminogen activators(see Table 2) The fact that there is calcium dependent andindependent vasospasm in inflammation (see Figure 1)shows that a combination of calcium antagonists with agentsinterfering with calcium independent vasospasm includingagents improving the bioavailability of nitric oxide is theway forward Future trials need to investigate their effectsin patients with all forms of cerebral inflammation leadingto neurological deficits attributable to vasospasm In vivocorrelates for reduction of vasospasm in the peripheralcirculation could be explored as a surrogate for reduction ofvasospasm in the cerebral (micro) vasculature
Strategies to improve microvascular recruitment whichhave been explored in models of septicaemia could poten-tially be applied to cerebral vasospasm Distributive shockwhich occurs during sepsis and septic shock is associatedwith an abnormal distribution of microvascular blood flowVasospasm of part of the arterioles supplying the capillary isa mechanism involved in this maldistribution The clinicalintroduction of new microcirculatory imaging techniquessuch as orthogonal polarization spectral and side-streamdark-field imaging (OPSSDF) has allowed direct obser-vation of the microcirculation at the bedside Images ofthe sublingual microcirculation during septic shock andresuscitation have revealed that the distributive defect ofblood flow occurs at the capillary level [82]
In rat models of cecal ligation and puncture investiga-tors have used intravital video microscopy to demonstratethat sepsis is characterized by decreased microcirculatoryflow velocity an abundance of stopped-flow microvesselsincreased heterogeneity of microcirculatory flow and lowdensity of perfused capillaries As thesemicrocirculatory flowalterations can occur in the absence of global hemodynamicderangements (eg absence of arterial hypotension) micro-circulatory dysfunction largely reflects intrinsic events occur-ring in the microvessels like localized vasospasm [83] Appli-cation ofmicrocirculatory recruitmentmaneuver procedureshas been shown to be effective in promotingmicrocirculatoryblood flow in clinical studies using OPSSDF imaging [84ndash87] Fluid resuscitation in combination with the nitric oxidedonor nitroglycerine was shown to recruit disturbed micro-circulation following pressure guided resuscitation in septicshock patients
It is important to note that application of colloids inpatients with SAH was associated with worse outcomescompared to matched controls in a subgroup analysis of theCONSCIOUS-1 prospective randomized trial of clazosentanfor the prevention of angiographic vasospasm [88] Futureresearch needs to investigate whether colloids can bind nitricoxide and make this vasodilator less available by binding it
Regarding future therapeutic interventions increasingnitric oxide bioavailability erythropoietin and L-argininewhich increased bioavailability of nitric oxide in patients withmalaria [89] need to be explored as adjunctive treatmentin children with cerebral malaria in randomised controlledtrials In vitro the availability of L-arginine does not appearto be a rate limiting step for the activity of the NO synthasebecause its half-saturating concentration is less than 3of theplasma and endothelial concentration of this substrate
The nitric oxide donor intravenous sodium nitrite hasbeen shown to prevent and reverse cerebrovascular spasmin primates and has been demonstrated to be safe foradministration in humans [90]
Support of pump function by dobutamine therapy hasbeen shown to improvemicrocirculatory flow independent ofimprovement of global hemodynamic parameters [91] Fluidapplication nitric oxide donors and dobutamine therapyneed to be explored in isolation but also as combinationof interventions to improve cerebral perfusion in cerebralinflammation associated with vasospasm
10 International Journal of Inflammation
A potential role of nonsteroidal anti-inflammatory drugswas revealed by landmark experiments on dog basilararteries Arachidonic acid induced sustained contractionsand these responses were markedly inhibited (95) bymeclofenamate and similarly by indomethacin but aspirinhad no such effect [92] In the rabbit basilar artery model ofcerebral vasospasm local intracranial delivery of ibuprofenaccomplished using controlled-release polymers preventedvasospasm when administered within 6 hours but notat either 12 or 24 hours [93] Delivery of ibuprofen viacontrolled-release polymers into the subarachnoid space ofmonkeys with subarachnoid haemorrhage prevented angio-graphic vasospasm after SAH as evident from patency of themiddle cerebral artery [94]
Piroxicam was more effective than the above-mentioneddrugs in the SAH dog model after angiographic analysisand analysis of behavioural changes [95] Early studiesusing prostacyclin found that isolated canine basilar arteriescontraction induced by prostaglandin E2 hemoglobin orserum was relaxed by prostacyclin but not indomethacin[96] In isolated human pial arteries prostacyclin relaxedhuman pial arteries contracted by either PGF2 alpha nora-drenaline serotonin or haemorrhagic CSF [97] In an animalstudy meloxicam reduced ultrastructural and morphometricvasospastic changes in rats with subarachnoid haemorrhage[98] Investigation comparing rate of subsequent permanentdisability from vasospasm and angiographic and delayedcerebral ischaemia in patients with SAH with and withoutaspirin intake found no association with poor outcome [99100]
There are new areas of pathophysiology research wherethe role of vasospasm needs to be explored thoroughly inorder to find avenues for therapeutic interventions Investi-gations could evaluate whether intraventricular haemorrhageoccurring commonly in the neonatal period in pretermneonates is associated with vasospasm increasing mor-bidity Case reports of intraventricular haemorrhage fromAV malformations and aneurysms in adults demonstratedvasospasm [101 102]
Future research needs to explore the usefulness of a num-ber of agents which have been demonstrated to reduce vaso-spasm in animal models including L-citrulline [103] januskinase-2 [104] endothelin converting enzyme inhibitors[105] caspase inhibitor Z-VAD-FMK [106] anti-E selectinmonoclonal antibodies [107] trehalose [108] and curcuminwhich was demonstrated to protect against the developmentof cerebral vasospasm and secondary cerebral infarctionafter subarachnoid haemorrhage in mice by its broad anti-inflammatory activity including limitation of superoxidegeneration and influence on inducible nitric oxide synthaseexpression [109]
Aggressive maintenance of normothermia or mildhypothermia in patients with military blast injury resultedin a dramatic reduction in the incidence of posttraumaticvasospasm from 475 to 5 Future studies need to confirmthis finding and investigate whether hypothermia can reducecerebral inflammation related ischemic damage to the brainin other conditions like bacterial meningitis or cerebralmalaria [37]
Conflict of Interests
The author declares that there is no conflict of interestsregarding the publication of this paper
References
[1] B Weir ldquoThe pathophysiology of cerebral vasospasmrdquo BritishJournal of Neurosurgery vol 9 no 3 pp 375ndash390 1995
[2] H Bode and A Harders ldquoTransient stenoses and occlusionsof main cerebral arteries in childrenmdashdiagnosis and control oftherapy by transcranial Doppler sonographyrdquo European Journalof Pediatrics vol 148 no 5 pp 406ndash411 1989
[3] K-F Lindegaard H Nornes S J Bakke W Sorteberg and PNakstad ldquoCerebral vasospasm diagnosis by means of angiogra-phy and blood velocity measurementsrdquo Acta Neurochirurgicavol 100 no 1-2 pp 12ndash24 1989
[4] C Lysakowski B Walder M C Costanza and M R TramerldquoTranscranial Doppler versus angiography in patients withvasospasm due to a ruptured cerebral aneurysm a systematicreviewrdquo Stroke vol 32 no 10 pp 2292ndash2298 2001
[5] R L Grubb Jr M E Raichle J O Eichling and M HGado ldquoEffects of subarachnoid hemorrhage on cerebral bloodvolume blood flow and oxygen utilization in humansrdquo Journalof Neurosurgery vol 46 no 4 pp 446ndash452 1977
[6] C-H Lu H-W Chang C-C Lui C-R Huang and W-NChang ldquoCerebral haemodynamics in acute bacterial meningitisin adultsrdquoQuaterly Journal of Medicine vol 99 no 12 pp 863ndash869 2006
[7] F Faraci and D D Heistad ldquoRegulation of the cerebralcirculation role of endothelium and potassium channelsrdquoPhysiological Reviews vol 78 no 1 pp 53ndash97 1998
[8] L Hektoen ldquoThe vascular changes in tuberculous meningitisespecially in tuberculous endarteritisrdquo Journal of ExperimentalMedicine vol 1 pp 112ndash163 1896
[9] G Thwaites ldquoTuberculosis of the central nervous systemrdquo inClinical Tuberculosis P D O Davies S B Gordon and GDavies Eds pp 151ndash165 CRC Press 5th edition 2014
[10] P M Dalal ldquoObservations on the involvement of cerebral ves-sels in tuberculousmeningitis in adultsrdquoAdvances in Neurologyvol 25 pp 149ndash159 1979
[11] L A Rojas-Echeverri J L Soto-Hernandez S Garza et alldquoPredictive value of digital subtraction angiography in patientswith tuberculous meningitisrdquo Neuroradiology vol 38 no 1 pp20ndash24 1996
[12] E L Lyons and N E Leeds ldquoThe angiographic demonstrationof arterial vascular disease in purulent meningitis report of acaserdquo Radiology vol 88 no 5 pp 935ndash938 1967
[13] S Ries U Schminke K Fassbender M Daffertshofer WSteinke andMHennerici ldquoCerebrovascular involvement in theacute phase of bacterial meningitisrdquo Journal of Neurology vol244 no 1 pp 51ndash55 1997
[14] K Fassbender S Ries U Schminke S Schneider and M Hen-nerici ldquoInflammatory cytokines in CSF in bacterial meningitisassociation with altered blood flow velocities in basal cerebralarteriesrdquo Journal of Neurology Neurosurgery amp Psychiatry vol61 no 1 pp 57ndash61 1996
[15] L A Pfister J H Tureen S Shaw et al ldquoEndothelin inhibitionimproves cerebral blood flow and is neuroprotective in pneu-mococcal meningitisrdquoAnnals of Neurology vol 47 pp 329ndash3352000
International Journal of Inflammation 11
[16] S L Leib Y S Kim S M Black J H Tureen and M GTauber ldquoInducible nitric oxide synthase and the effect of amin-oguanidine in experimental neonatal meningitisrdquo The Journalof Infectious Diseases vol 177 no 3 pp 692ndash700 1998
[17] T W Polder C R Jerusalem andW M C Eling ldquoMorpholog-ical characteristics of intracerebral arterioles in clinical (Plas-modium falciparum) and experimental (Plasmodium berghei)cerebral malariardquo Journal of the Neurological Sciences vol 101no 1 pp 35ndash46 1991
[18] N A V Beare S P Harding T E Taylor S Lewallen and MEMolyneux ldquoPerfusion abnormalities in childrenwith cerebralmalaria andmalarial retinopathyrdquo Journal of Infectious Diseasesvol 199 no 2 pp 263ndash271 2009
[19] C R J C Newton K Marsh N Peshu and F J KirkhamldquoPerturbations of cerebral hemodynamics in Kenyans withcerebral malariardquo Pediatric Neurology vol 15 no 1 pp 41ndash491996
[20] C C John A Panoskaltsis-Mortari R O Opoka et alldquoCerebrospinal fluid cytokine levels and cognitive impairmentin cerebral malariardquo American Journal of Tropical Medicine andHygiene vol 78 no 2 pp 198ndash205 2008
[21] W McGuire A V S Hill C E M Allsopp B M Greenwoodand D Kwiatkowski ldquoVariation in the TNF-120572 promoter regionassociated with susceptibility to cerebral malariardquo Nature vol371 no 6497 pp 508ndash510 1994
[22] W McGuire J C Knight A V S Hill C E M Allsopp B MGreenwood and D Kwiatkowski ldquoSevere malarial anemia andcerebral malaria are associated with different tumor necrosisfactor promoter allelesrdquo Journal of Infectious Diseases vol 179no 1 pp 287ndash290 1999
[23] B Dugas M D Mossalayi C Damais and J-P Kolb ldquoNitricoxide production by human monocytes Evidence for a role ofCD23rdquo Immunology Today vol 16 no 12 pp 574ndash580 1995
[24] L Pellettieri B Nilsson C-A Carlsson andU Nilsson ldquoSerumimmunocomplexes in patients with subarachnoid hemorrhagerdquoNeurosurgery vol 19 no 5 pp 767ndash771 1986
[25] M Eisenhut ldquoCauses of reduced immune complex clearance incerebralmalariardquoParasite Immunology vol 31 no 2 p 59 2009
[26] P Teeranaipong J Ohashi J Patarapotikul et al ldquoA functionalsingle-nucleotide polymorphism in the CR1 promoter regioncontributes to protection against cerebral malariardquo Journal ofInfectious Diseases vol 198 no 12 pp 1880ndash1891 2008
[27] P Cabrales G M Zanini D Meays J A Frangos and LJ M Carvalho ldquoMurine cerebral malaria is associated witha vasospasm-like microcirculatory dysfunction and survivalupon rescue treatment is markedly increased by nimodipinerdquoTheAmerican Journal of Pathology vol 176 no 3 pp 1306ndash13152010
[28] I Gramaglia P Sobolewski D Meays et al ldquoLow nitricoxide bioavailability contributes to the genesis of experimentalcerebral malariardquoNature Medicine vol 12 no 12 pp 1417ndash14222006
[29] T W Yeo D A Lampah E Tjitra et al ldquoRelationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavail-ability and perfusion in severe falciparum malariardquo Journal ofInfectious Diseases vol 200 no 10 pp 1522ndash1529 2009
[30] G Dhangadamajhi B N Mohapatra S K Kar and M RanjitldquoGenetic variation in neuronal nitric oxide synthase (nNOS)gene and susceptibility to cerebral malaria in Indian adultsrdquoInfection Genetics and Evolution vol 9 no 5 pp 908ndash911 2009
[31] M R Hobbs V Udhayakumar M C Levesque et al ldquoAnew NOS2 promoter polymorphism associated with increased
nitric oxide production and protection from severe malaria inTanzanian and Kenyan childrenrdquoThe Lancet vol 360 no 9344pp 1468ndash1475 2002
[32] P Cabrales G M Zanini D Meays J A Frangos and L JM Carvalho ldquoNitric oxide protection against murine cerebralmalaria is associated with improved cerebral microcirculatoryphysiologyrdquo The Journal of Infectious Diseases vol 203 no 10pp 1454ndash1463 2011
[33] G Morahan C S Boutlis D Huang et al ldquoA promoterpolymorphism in the gene encoding interleukin-12 p40 (IL12B)is associated with mortality from cerebral malaria and withreduced nitric oxide productionrdquo Genes amp Immunity vol 3 no7 pp 414ndash418 2002
[34] C Casals-Pascual R Idro N Gicheru et al ldquoHigh levels of ery-thropoietin are associated with protection against neurologicalsequelae in African children with cerebral malariardquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 105 no 7 pp 2634ndash2639 2008
[35] F C Chow C M Marra and T A Cho ldquoCerebrovasculardisease in central nervous system infectionsrdquo Seminars inNeurology vol 31 no 3 pp 286ndash306 2011
[36] R A Armonda R S Bell A H Vo et al ldquoWartime traumaticcerebral vasospasm recent review of combat casualtiesrdquoNeuro-surgery vol 59 no 6 pp 1215ndash1225 2006
[37] K Shahlaie K Keachie I M Hutchins et al ldquoRisk factorsfor posttraumatic vasospasm clinical articlerdquo Journal of Neu-rosurgery vol 115 no 3 pp 602ndash611 2011
[38] Y Udomphorn W M Armstead and M S Vavilala ldquoCerebralblood flow and autoregulation after pediatric traumatic braininjuryrdquo Pediatric Neurology vol 38 no 4 pp 225ndash234 2008
[39] R M Pluta J Hansen-Schwartz J Dreier et al ldquoCerebralvasospasm following subarachnoid hemorrhage time for a newworld of thoughtrdquo Neurological Research vol 31 no 2 pp 151ndash158 2009
[40] J Hansen-Schwartz P Vajkoczy R L Macdonald R MPluta and J H Zhang ldquoCerebral vasospasm looking beyondvasoconstrictionrdquo Trends in Pharmacological Sciences vol 28no 6 pp 252ndash256 2007
[41] H Kasuya B K A Weir M Nakane et al ldquoNitric oxidesynthase and guanylate cyclase levels in canine basilar arteryafter subarachnoid hemorrhagerdquo Journal of Neurosurgery vol82 no 2 pp 250ndash255 1995
[42] M D Linnik and T J F Lee ldquoEffect of hemoglobin on neuro-genic responses and cholinergic parameters in porcine cerebralarteriesrdquo Journal of Cerebral Blood Flow and Metabolism vol 9no 2 pp 219ndash225 1989
[43] CG Sobey and FM Faraci ldquoSubarachnoid haemorrhage whathappens to the cerebral arteriesrdquo Clinical and ExperimentalPharmacology and Physiology vol 25 no 11 pp 867ndash876 1998
[44] Y R T Dinh G Lot R Benrabah O Baroudy J Cophignonand J Seylaz ldquoAbnormal cerebral vasodilation in aneurys-mal subarachnoid hemorrhage use of serial 133Xe cerebralblood flow measurement plus acetazolamide to assess cerebralvasospasmrdquo Journal of Neurosurgery vol 79 no 4 pp 490ndash4931993
[45] T J F Lee ldquoNitric oxide and the cerebral vascular functionrdquoJournal of Biomedical Science vol 7 no 1 pp 16ndash26 2000
[46] M Stoodley R L Macdonald B Weir et al ldquoSubarachnoidhemorrhage as a cause of an adaptive response in cerebralarteriesrdquo Journal of Neurosurgery vol 93 no 3 pp 463ndash4702000
12 International Journal of Inflammation
[47] Y R Tran Dinh A Jomaa J Callebert et al ldquoOverexpressionof cyclooxygenase-2 in rabbit basilar artery endothelial cellsafter subarachnoid hemorrhagerdquo Neurosurgery vol 48 no 3pp 626ndash635 2001
[48] A Gecse B Kis Z Mezei and G Telegdy ldquoEffects of inflam-matory neuropeptides on the arachidonate cascade of plateletsrdquoInternational Archives of Allergy and Immunology vol 118 no2ndash4 pp 166ndash170 1999
[49] K S Mark W J Trickler and D W Miller ldquoTumornecrosis factor-120572 induces cyclooxygenase-2 expression andprostaglandin release in brain microvessel endothelial cellsrdquoJournal of Pharmacology and Experimental Therapeutics vol297 no 3 pp 1051ndash1058 2001
[50] T Tanazawa Y Suzuki M Anzai S Tsugane M Takayasu andM Shibuya ldquoVasodilation by intrathecal lipopolysaccharide ofthe cerebral arteries after subarachnoid haemorrhage in dogsrdquoActa Neurochirurgica vol 138 no 3 pp 330ndash337 1996
[51] N Toda M Kawakami and K Yoshida ldquoConstrictor action ofoxyhemoglobin in monkey and dog basilar arteries in vivo andin vitrordquo American Journal of Physiology Heart and CirculatoryPhysiology vol 260 no 2 pp H420ndashH425 1991
[52] M Yoshizumi M A Perrella J C Burnett Jr and M-E LeeldquoTumor necrosis factor downregulates an endothelial nitricoxide synthase mRNA by shortening its half-liferdquo CirculationResearch vol 73 no 1 pp 205ndash209 1993
[53] A Rengasamy and R A Johns ldquoRegulation of nitric oxidesynthase by nitric oxiderdquo Molecular Pharmacology vol 44 no1 pp 124ndash128 1993
[54] A L de Souza A C P de Oliveira C C Romano J SztajnbokA J S Duarte and A C Seguro ldquoInterleukin-6 activation inischemic stroke caused by Neisseria meningitidis serogroup CrdquoInternational Journal of Cardiology vol 127 no 3 pp e160ndashe1632008
[55] T Kandabashi H Shimokawa K Miyata et al ldquoInhibition ofmyosin phosphatase by upregulated Rho-kinase plays a key rolefor coronary artery spasm in a porcine model with interleukin-1120573rdquo Circulation vol 101 no 11 pp 1319ndash1323 2000
[56] D-H Nam J-S Kim S-C Hong et al ldquoExpression ofinterleukin-1120573 in lipopolysaccharide stimulated monocytesderived from patients with aneurysmal subarachnoid hem-orrhage is correlated with cerebral vasospasmrdquo NeuroscienceLetters vol 312 no 1 pp 41ndash44 2001
[57] A Ito H Shimokawa T Kadokami et al ldquoTyrosine kinaseinhibitor suppresses coronary arteriosclerotic changes andvasospastic responses induced by chronic treatment withinterleukin-1120573 in pigs in vivordquo Journal of Clinical Investigationvol 96 no 3 pp 1288ndash1294 1995
[58] H Yanamoto H Kataoka Y Nakajo and K Iihara ldquoThe roleof the host defense system in the development of cerebralvasospasm analogies between atherosclerosis and subarach-noid hemorrhagerdquo European Neurology vol 68 no 6 pp 329ndash343 2012
[59] A F Ducruet P R Gigante Z L Hickman et al ldquoGeneticdeterminants of cerebral vasospasm delayed cerebral ischemiaand outcome after aneurysmal subarachnoid hemorrhagerdquoJournal of Cerebral Blood Flow amp Metabolism vol 30 no 4 pp676ndash688 2010
[60] J Langham C Goldfrad G Teasdale D Shaw and KRowan ldquoCalcium channel blockers for acute traumatic braininjuryrdquoCochrane Database Systematic Reviews no 4 Article IDCD000565 2000
[61] S M Dorhout Mees G J Rinkel V L Feigin et al ldquoCal-cium antagonists for aneurysmal subarachnoid haemorrhagerdquoCochrane Database of Systematic Reviews no 3 Article IDCD000277 2007
[62] R-Q Huang F-G Jiang Z-M Feng and T-Y WangldquoNicardipine in the treatment of aneurysmal subarachnoidhaemorrhage a meta-analysis of published datardquo Acta Neuro-logica Belgica vol 113 no 1 pp 3ndash6 2013
[63] S Naidu A J Payne J Moodley M Hoffmann and EGouws ldquoRandomised study assessing the effect of phenytoinand magnesium sulphate on maternal cerebral circulationin eclampsia using transcranial Doppler ultrasoundrdquo BritishJournal of Obstetrics amp Gynaecology vol 103 no 2 pp 111ndash1161996
[64] D Reddy A Fallah J-A Petropoulos F Farrokhyar R LMacdonald and D Jichici ldquoProphylactic magnesium sulphatefor aneurysmal subarachnoid haemorrhage a systematic reviewand meta-analysisrdquo Neurocritical Care vol 21 no 2 pp 356ndash364 2014
[65] C M Bradford S Finfer A OrsquoConnor et al ldquoA ran-domised controlled trial of induced hypermagnesaemia follow-ing aneurysmal subarachnoid haemorrhagerdquo Critical Care andResuscitation vol 15 no 2 pp 119ndash125 2013
[66] S-H Su W Xu J Hai Y-F Wu and F Yu ldquoEffects of statins-use for patients with aneurysmal subarachnoid hemorrhagea meta-analysis of randomized controlled trialsrdquo ScientificReports vol 4 article 4573 2014
[67] J Guo Z Shi K Yang J H Tian and L Jiang ldquoEndothelinreceptor antagonists for subarachnoid hemorrhagerdquo CochraneDatabase of Systematic Reviews vol 9 Article ID CD0083542012
[68] J Shen J-W Pan Z-X Fan X-X Xiong and R-Y ZhanldquoDissociation of vasospasm-related morbidity and outcomesin patients with aneurysmal subarachnoid hemorrhage treatedwith clazosentan a meta-analysis of randomized controlledtrials a reviewrdquo Journal of Neurosurgery vol 119 no 1 pp 180ndash189 2013
[69] P Gomis J P Graftieaux R Sercombe D Hettler BScherpereel and P Rousseaux ldquoRandomized double-blindplacebo-controlled pilot trial of high-dose methylprednisolonein aneurysmal subarachnoid hemorrhagerdquo Journal of Neuro-surgery vol 112 no 3 pp 681ndash688 2010
[70] A H Kramer and J J Fletcher ldquoLocally-administered intrathe-cal thrombolytics following aneurysmal subarachnoid hem-orrhage a systematic review and meta-analysisrdquo NeurocriticalCare vol 14 no 3 pp 489ndash499 2011
[71] G J Liu Z J Wang Y F Wang et al ldquoSystematic assessmentand meta-analysis of the efficacy and safety of fasudil in thetreatment of cerebral vasospasm in patients with subarachnoidhemorrhagerdquo European Journal of Clinical Pharmacology vol68 no 2 pp 131ndash139 2012
[72] S Zhang LWangM Liu andBWu ldquoTirilazad for aneurysmalsubarachnoid haemorrhagerdquo Cochrane Database SystematicReview vol 2 Article ID CD006778 2010
[73] M-Y Tseng P J Hutchinson H K Richards et al ldquoAcutesystemic erythropoietin therapy to reduce delayed ischemicdeficits following aneurysmal subarachnoid hemorrhage aphase II randomized double-blind placebo-controlled trialclinical articlerdquo Journal of Neurosurgery vol 111 no 1 pp 171ndash180 2009
[74] H Kasuya ldquoDevelopment of nicardipine prolonged-releaseimplants after clipping for preventing cerebral vasospasm from
International Journal of Inflammation 13
laboratory to clinical trialrdquo Acta Neurochirurgica Supplemen-tum vol 115 pp 41ndash44 2013
[75] C Thome M Seiz G A Schubert et al ldquoNicardipine pelletsfor the prevention of cerebral vasospasmrdquoActaNeurochirurgicano 110 pp 209ndash211 2011
[76] T Nassar S Akkawi A Shina et al ldquoIn vitro and in vivo effectsof tPA and PAI-1 on blood vessel tonerdquo Blood vol 103 no 3 pp897ndash902 2004
[77] T Sugawara R Ayer V Jadhav W Chen T Tsubokawaand J H Zhang ldquoMechanisms of statin treatment in cerebralvasospasmrdquo Acta Neurochirurgica no 110 pp 9ndash11 2011
[78] M D Vergouwen R J De Haan M Vermeulen and YB Roos ldquoEffect of statin treatment on vasospasm delayedcerebral ischemia and functional outcome in patients withaneurysmal subarachnoid hemorrhage a systematic review andmeta-analysis updaterdquo Stroke vol 41 no 1 pp e47ndashe52 2010
[79] G E Thwaites N D Bang N H Dung et al ldquoDexamethasonefor the treatment of tuberculous meningitis in adolescents andadultsrdquoTheNew England Journal ofMedicine vol 351 no 17 pp1741ndash1811 2004
[80] G E Thwaites J Macmullen-Price T T H Chau et al ldquoSerialMRI to determine the effect of dexamethasone on the cerebralpathology of tuberculous meningitis an observational studyrdquoThe Lancet Neurology vol 6 no 3 pp 230ndash236 2007
[81] U K Misra J Kalita and P P Nair ldquoRole of aspirin in tuber-culous meningitis a randomized open label placebo controlledtrialrdquo Journal of the Neurological Sciences vol 293 no 1-2 pp12ndash17 2010
[82] P W G Elbers and C Ince ldquoBench-to-bedside review mech-anisms of critical illnessmdashclassifying microcirculatory flowabnormalities in distributive shockrdquoCritical Care vol 10 article221 2006
[83] S Trzeciak I Cinel R P Dellinger et al ldquoResuscitating themicrocirculation in sepsis the central role of nitric oxideemerging concepts for novel therapies and challenges forclinical trialsrdquo Academic Emergency Medicine vol 15 no 5 pp399ndash415 2008
[84] Y Sakr M-J Dubois D De Backer J Creteur and J-LVincent ldquoPersistent-microcirculatory alterations are associatedwith organ failure and death in patients with septic shockrdquoCritical Care Medicine vol 32 no 9 pp 1825ndash1831 2004
[85] P E Spronk J H Rommes C Schaar andC Ince ldquoThromboly-sis in fulminant purpura observations on changes in microcir-culatory perfusion during succesful treatmentrdquoThrombosis andHaemostasis vol 95 no 3 pp 576ndash578 2006
[86] J Creteur D De Backer Y Sakr M Koch and J-L VincentldquoSublingual capnometry tracks microcirculatory changes inseptic patientsrdquo Intensive Care Medicine vol 32 no 4 pp 516ndash523 2006
[87] D De Backer J Creteur J C Preiser M J Dubois and JL Vincent ldquoMicrovascular blood flow is altered in patientswith sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 1 pp 98ndash104 2002
[88] G M Ibrahim and R L Macdonald ldquoThe effects of fluid bal-ance and colloid administration on outcomes in patients withaneurysmal subarachnoid hemorrhage a propensity score-matched analysisrdquoNeurocritical Care vol 19 no 2 pp 140ndash1492013
[89] T W Yeo D A Lampah R Gitawati et al ldquoImpaired nitricoxide bioavailability and L-arginine-reversible endothelial dys-function in adults with falciparum malariardquo The Journal ofExperimental Medicine vol 204 no 11 pp 2693ndash2704 2007
[90] A R Fathi R M Pluta K D Bakhtian M Qi and R RLonser ldquoReversal of cerebral vasospasmvia intravenous sodiumnitrite after subarachnoid hemorrhage in primates laboratoryinvestigationrdquo Journal of Neurosurgery vol 115 no 6 pp 1213ndash1220 2011
[91] D de Backer J Creteur M J Dubois et al ldquoThe effects ofdobutamine on microcirculatory alterations in patients withseptic shock are independent of its systemic effectsrdquo CriticalCare Medicine vol 34 no 2 pp 403ndash408 2006
[92] C E Chapleau R P White and J T Robertson ldquoCerebralvasospasm effects of prostaglandin synthetase inhibitors invitrordquo Neurosurgery vol 6 no 2 pp 155ndash159 1980
[93] J L Frazier G Pradilla P P Wang and R J TamargoldquoInhibition of cerebral vasospasm by intracranial delivery ofibuprofen from a controlled-release polymer in a rabbit modelof subarachnoid hemorrhagerdquo Journal of Neurosurgery vol 101no 1 pp 93ndash98 2004
[94] G Pradilla Q A Thai F G Legnani et al ldquoLocal deliveryof ibuprofen via controlled-release polymers prevents angio-graphic vasospasm in a monkey model of subarachnoid hem-orrhagerdquo Neurosurgery vol 57 no 1 pp 184ndash189 2005
[95] R P White and J T Robertson ldquoComparison of piroxicammeclofenamate ibuprofen aspirin and prostacyclin efficacy ina chronic model of cerebral vasospasmrdquo Neurosurgery vol 12no 1 pp 40ndash46 1983
[96] T Fukumori E Tani Y Maeda and A Sukenaga ldquoEffectsof prostacyclin and indomethacin on experimental delayedcerebral vasospasmrdquo Journal of Neurosurgery vol 59 no 5 pp829ndash834 1983
[97] L Brandt B Ljunggren K-E Andersson B Hindfelt and TUski ldquoProstaglandin metabolism and prostacyclin in cerebralvasospasmrdquo General Pharmacology vol 14 no 1 pp 141ndash1431983
[98] T Hakan M Zafer Berkman T Ersoy I Karatas T Sanand S Arbak ldquoAnti-inflammatory effect of meloxicam onexperimental vasospasm in the rat femoral arteryrdquo Journal ofClinical Neuroscience vol 15 no 1 pp 55ndash59 2008
[99] LG Toussaint III J A Friedman E FMWijdicks et al ldquoInflu-ence of aspirin on outcome following aneurysmal subarachnoidhemorrhagerdquo Journal of Neurosurgery vol 101 no 6 pp 921ndash925 2004
[100] B A Gross P M R Lai K U Frerichs and R Du ldquoAspirin andaneurysmal subarachnoid haemorrhagerdquo World Neurosurgery2013
[101] S Yokobori AWatanabe R Nakae et al ldquoCerebral vasospasmsafter intraventricular hemorrhage from an arteriovenousmalformationmdashcase reportrdquo Neurologia Medico-Chirurgicavol 50 no 4 pp 320ndash323 2010
[102] B S Park Y S Won S S Choi and B M Kim ldquoSeveresymptomatic vasospasm following intraventricular hemorrhagefrom arteriovenous fistulardquo Journal of Korean NeurosurgicalSociety vol 45 no 5 pp 300ndash302 2009
[103] G Pradilla T Garzon-Muvdi J J Ruzevick et al ldquoSystemicL-citrulline prevents cerebral vasospasm in haptoglobin 2-2transgenicmice after subarachnoid hemorrhagerdquoNeurosurgeryvol 70 no 3 pp 747ndash757 2012
[104] G Chen J Wu C Sun et al ldquoPotential role of JAK2 in cere-bral vasospasm after experimental subarachnoid hemorrhagerdquoBrain Research vol 1214 pp 136ndash144 2008
[105] C L Lin A L Kwan A S Dumont et al ldquoAttenuationof experimental subarachnoid hemorrhage-induced increases
14 International Journal of Inflammation
in circulating intercellular adhesion molecule-1 and cerebralvasospasm by the endothelin-converting enzyme inhibitor CGS26303rdquo Journal of Neurosurgery vol 106 no 3 pp 442ndash4482007
[106] K Iseda S Ono K Onoda et al ldquoAntivasospastic and antiin-flammatory effects of caspase inhibitor in experimental sub-arachnoid hemorrhagerdquo Journal of Neurosurgery vol 107 no 1pp 128ndash135 2007
[107] C-L Lin A S Dumont T Calisaneller A-L Kwan S-L Hwong and K S Lee ldquoMonoclonal antibody against Eselectin attenuates subarachnoid hemorrhage-induced cerebralvasospasmrdquo Surgical Neurology vol 64 no 3 pp 201ndash206 2005
[108] R Echigo N Shimohata K Karatsu et al ldquoTrehalose treat-ment suppresses inflammation oxidative stress and vasospasminduced by experimental subarachnoid hemorrhagerdquo Journal ofTranslational Medicine vol 10 no 1 article 80 2012
[109] CWakadeM D KingM D Laird C H Alleyne Jr and KMDhandapani ldquoCurcumin attenuates vascular inflammation andcerebral vasospasm after subarachnoid hemorrhage in micerdquoAntioxidants amp Redox Signaling vol 11 no 1 pp 35ndash45 2009
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
8 International Journal of Inflammation
Table2Con
tinued
Interventio
nTy
peof
study
Patholog
yRe
sultsodd
sratio
(OR)
orrelativer
isk(RR)
foro
ccurrencein
interventio
ngrou
pcomparedto
grou
pwith
outintervention
Reference
Endo
thelin-1Areceptor
antagonistClazosentan
SR(fo
urRC
Ts)
aSAH
Relativer
iskforincidence
ofDIN
Ds076
(95
CI062ndash0
92)
delay
edcerebralinfarctio
n079
[95
CI063ndash100]G
lasgow
outcom
escaleextend
edRR
112
[95
CI096ndash130]m
ortalityRR
10
2[95
CI070ndash149]
[68]
Intravenou
smethylpredn
isolone
RCT
aSAH
Symptom
aticvasospasm
265in
interventio
ngrou
pcompared
with
26in
placebogrou
pfunctio
naloutcomes
caleredu
cedin
the
methylpredn
isolone
grou
pwith
riskdifference193
[95
CI05ndash379]ou
tcom
epoo
rin15of
patie
ntsinthe
methylpredn
isolone
grou
pversus
34in
thep
lacebo
grou
p
[69]
Tissue
plasminogen
activ
ator
SR(five
RCTs)
aSAH
Overalluseo
fintrathecalthrombo
lytic
swas
associated
with
significantreductio
nsin
thed
evelo
pmento
fpoo
routcomes
(OR
052034ndash
078119875lt001)DIN
Ds(OR054034ndash
087119875=001)
andangiograph
icvasospasm
(OR032015
ndash070119875lt001)
[70]
Rho-kinase
inhibitor
SR(8
controlledtrials)
aSAH
Absenceo
fsym
ptom
aticvasospasmoccurrenceo
flow
density
areas
associated
with
vasospasm
onCT
and
occurrence
ofadversee
vents
weres
imilarb
etweenthetwogrou
psthe
clinicaloutcomes
were
morefavorablein
thefasud
ilgrou
pthan
inthen
imod
ipineg
roup
(119875=004)
[71]
Tirilazad
SR(five
RCTs)
aSAH
Therew
asno
significantd
ifference
betweenthetwogrou
psatthe
endof
follo
w-upforthe
prim
aryou
tcom
edeathOR
089[95CI
074
to10
6]orinpo
orou
tcom
e(deathvegetativ
estateorsevere
disability)
OR10
4[95
CI090
to12
1]few
erpatie
ntsd
evelop
eddelay
edcerebralisc
haem
iain
thetirilazadgrou
pthan
inthec
ontro
lgrou
pOR080
[95
CI069
to093]subgroup
analyses
didno
tdemon
stratea
nysig
nificantd
ifference
ineffectsof
tirilazadon
clinicaloutcomes
[72]
Erythrop
oietin
RCT
aSAH
Nodifferences
wered
emon
strated
intheincidence
ofvasospasm
andadversee
ventspatie
ntsreceiving
EPOhadad
ecreased
incidenceo
fseverev
asospasm
from
275to
75(119875=0037)
redu
cedDID
swith
newcerebralinfarctsfro
m40
0to
75
(119875=0001)as
hortened
duratio
nof
impaire
dautoregu
latio
n(ip
silateralsid
e119875lt0001)andmorefavorableou
tcom
eat
discharge(favorableG
lasgow
outcom
escalescore119875=0039)
amon
gthe7
1survivorsthe
EPOgrou
phadfewer
deficits
measured
with
NationalInstitutes
ofHealth
Stroke
Scale(medianscore2
versus
6119875=0008)
[73]
International Journal of Inflammation 9
mechanism is apart from a contribution to inhibition ofcalcium independent vasospasm (see above) probably alsoan increase of endothelial nitric oxide synthase (eNOS)expression by stabilizing eNOSmRNA which can contributeto an increase of NO level to enhance vasodilatation
76 Other Treatments Steroid treatment can inhibit cytokineexpression and has thus the potential to reduce cytokinemediated calcium dependent and independent vasospasmIn tuberculous meningitis adjuvant treatment with corticos-teroids has been indirectly associatedwith features of reducedvasculopathy which may include vasospasm
A large randomised controlled trial showed improvedmortality in tuberculous meningitis with adjuvant corti-costeroids but did not show a reduction in severe disabil-ity however an observational MRI study did suggest areduction in strokes in patients treated with corticosteroids[79 80] An open-label study of aspirin in the preventionof stroke and mortality in tuberculous meningitis found anonsignificant reduction in stroke and a significant reductionin mortality with a possible synergism with corticosteroids[81] Mechanisms responsible for a potential effect may bea reduction of the vasoconstricting effect of PGE2 The 21-aminosteroid tirilazad is a lipid peroxidation inhibitor whichinhibits free radical-induced lipid peroxidation (LP) by acombination of lipid peroxide scavenging and a membrane-stabilizing action that limits the propagation of LP reactionsbetween a lipid peroxide and an adjacent polyunsaturatedfatty acid There has been no consistent evidence of benefitin animal or human studies Erythropoietin may act throughincrease in expression of endothelial nitric oxide synthasethus increasing NO bioavailability
8 Conclusions and Perspectives forFuture Developments
There is evidence for common pathways leading tovasospasm in all forms of cerebral inflammation involvinginterleukin-1 tumor necrosis factor endothelin-1 andnitric oxide Treatments addressing the pathophysiologyof vasospasm in one form of cerebral inflammation maytherefore apply to all others Treatment of cerebral vasospasmhas been mainly investigated in aneurysmal SAH Agentsfor which there is likely to be clinical benefit are calciumantagonists statins and intrathecal plasminogen activators(see Table 2) The fact that there is calcium dependent andindependent vasospasm in inflammation (see Figure 1)shows that a combination of calcium antagonists with agentsinterfering with calcium independent vasospasm includingagents improving the bioavailability of nitric oxide is theway forward Future trials need to investigate their effectsin patients with all forms of cerebral inflammation leadingto neurological deficits attributable to vasospasm In vivocorrelates for reduction of vasospasm in the peripheralcirculation could be explored as a surrogate for reduction ofvasospasm in the cerebral (micro) vasculature
Strategies to improve microvascular recruitment whichhave been explored in models of septicaemia could poten-tially be applied to cerebral vasospasm Distributive shockwhich occurs during sepsis and septic shock is associatedwith an abnormal distribution of microvascular blood flowVasospasm of part of the arterioles supplying the capillary isa mechanism involved in this maldistribution The clinicalintroduction of new microcirculatory imaging techniquessuch as orthogonal polarization spectral and side-streamdark-field imaging (OPSSDF) has allowed direct obser-vation of the microcirculation at the bedside Images ofthe sublingual microcirculation during septic shock andresuscitation have revealed that the distributive defect ofblood flow occurs at the capillary level [82]
In rat models of cecal ligation and puncture investiga-tors have used intravital video microscopy to demonstratethat sepsis is characterized by decreased microcirculatoryflow velocity an abundance of stopped-flow microvesselsincreased heterogeneity of microcirculatory flow and lowdensity of perfused capillaries As thesemicrocirculatory flowalterations can occur in the absence of global hemodynamicderangements (eg absence of arterial hypotension) micro-circulatory dysfunction largely reflects intrinsic events occur-ring in the microvessels like localized vasospasm [83] Appli-cation ofmicrocirculatory recruitmentmaneuver procedureshas been shown to be effective in promotingmicrocirculatoryblood flow in clinical studies using OPSSDF imaging [84ndash87] Fluid resuscitation in combination with the nitric oxidedonor nitroglycerine was shown to recruit disturbed micro-circulation following pressure guided resuscitation in septicshock patients
It is important to note that application of colloids inpatients with SAH was associated with worse outcomescompared to matched controls in a subgroup analysis of theCONSCIOUS-1 prospective randomized trial of clazosentanfor the prevention of angiographic vasospasm [88] Futureresearch needs to investigate whether colloids can bind nitricoxide and make this vasodilator less available by binding it
Regarding future therapeutic interventions increasingnitric oxide bioavailability erythropoietin and L-argininewhich increased bioavailability of nitric oxide in patients withmalaria [89] need to be explored as adjunctive treatmentin children with cerebral malaria in randomised controlledtrials In vitro the availability of L-arginine does not appearto be a rate limiting step for the activity of the NO synthasebecause its half-saturating concentration is less than 3of theplasma and endothelial concentration of this substrate
The nitric oxide donor intravenous sodium nitrite hasbeen shown to prevent and reverse cerebrovascular spasmin primates and has been demonstrated to be safe foradministration in humans [90]
Support of pump function by dobutamine therapy hasbeen shown to improvemicrocirculatory flow independent ofimprovement of global hemodynamic parameters [91] Fluidapplication nitric oxide donors and dobutamine therapyneed to be explored in isolation but also as combinationof interventions to improve cerebral perfusion in cerebralinflammation associated with vasospasm
10 International Journal of Inflammation
A potential role of nonsteroidal anti-inflammatory drugswas revealed by landmark experiments on dog basilararteries Arachidonic acid induced sustained contractionsand these responses were markedly inhibited (95) bymeclofenamate and similarly by indomethacin but aspirinhad no such effect [92] In the rabbit basilar artery model ofcerebral vasospasm local intracranial delivery of ibuprofenaccomplished using controlled-release polymers preventedvasospasm when administered within 6 hours but notat either 12 or 24 hours [93] Delivery of ibuprofen viacontrolled-release polymers into the subarachnoid space ofmonkeys with subarachnoid haemorrhage prevented angio-graphic vasospasm after SAH as evident from patency of themiddle cerebral artery [94]
Piroxicam was more effective than the above-mentioneddrugs in the SAH dog model after angiographic analysisand analysis of behavioural changes [95] Early studiesusing prostacyclin found that isolated canine basilar arteriescontraction induced by prostaglandin E2 hemoglobin orserum was relaxed by prostacyclin but not indomethacin[96] In isolated human pial arteries prostacyclin relaxedhuman pial arteries contracted by either PGF2 alpha nora-drenaline serotonin or haemorrhagic CSF [97] In an animalstudy meloxicam reduced ultrastructural and morphometricvasospastic changes in rats with subarachnoid haemorrhage[98] Investigation comparing rate of subsequent permanentdisability from vasospasm and angiographic and delayedcerebral ischaemia in patients with SAH with and withoutaspirin intake found no association with poor outcome [99100]
There are new areas of pathophysiology research wherethe role of vasospasm needs to be explored thoroughly inorder to find avenues for therapeutic interventions Investi-gations could evaluate whether intraventricular haemorrhageoccurring commonly in the neonatal period in pretermneonates is associated with vasospasm increasing mor-bidity Case reports of intraventricular haemorrhage fromAV malformations and aneurysms in adults demonstratedvasospasm [101 102]
Future research needs to explore the usefulness of a num-ber of agents which have been demonstrated to reduce vaso-spasm in animal models including L-citrulline [103] januskinase-2 [104] endothelin converting enzyme inhibitors[105] caspase inhibitor Z-VAD-FMK [106] anti-E selectinmonoclonal antibodies [107] trehalose [108] and curcuminwhich was demonstrated to protect against the developmentof cerebral vasospasm and secondary cerebral infarctionafter subarachnoid haemorrhage in mice by its broad anti-inflammatory activity including limitation of superoxidegeneration and influence on inducible nitric oxide synthaseexpression [109]
Aggressive maintenance of normothermia or mildhypothermia in patients with military blast injury resultedin a dramatic reduction in the incidence of posttraumaticvasospasm from 475 to 5 Future studies need to confirmthis finding and investigate whether hypothermia can reducecerebral inflammation related ischemic damage to the brainin other conditions like bacterial meningitis or cerebralmalaria [37]
Conflict of Interests
The author declares that there is no conflict of interestsregarding the publication of this paper
References
[1] B Weir ldquoThe pathophysiology of cerebral vasospasmrdquo BritishJournal of Neurosurgery vol 9 no 3 pp 375ndash390 1995
[2] H Bode and A Harders ldquoTransient stenoses and occlusionsof main cerebral arteries in childrenmdashdiagnosis and control oftherapy by transcranial Doppler sonographyrdquo European Journalof Pediatrics vol 148 no 5 pp 406ndash411 1989
[3] K-F Lindegaard H Nornes S J Bakke W Sorteberg and PNakstad ldquoCerebral vasospasm diagnosis by means of angiogra-phy and blood velocity measurementsrdquo Acta Neurochirurgicavol 100 no 1-2 pp 12ndash24 1989
[4] C Lysakowski B Walder M C Costanza and M R TramerldquoTranscranial Doppler versus angiography in patients withvasospasm due to a ruptured cerebral aneurysm a systematicreviewrdquo Stroke vol 32 no 10 pp 2292ndash2298 2001
[5] R L Grubb Jr M E Raichle J O Eichling and M HGado ldquoEffects of subarachnoid hemorrhage on cerebral bloodvolume blood flow and oxygen utilization in humansrdquo Journalof Neurosurgery vol 46 no 4 pp 446ndash452 1977
[6] C-H Lu H-W Chang C-C Lui C-R Huang and W-NChang ldquoCerebral haemodynamics in acute bacterial meningitisin adultsrdquoQuaterly Journal of Medicine vol 99 no 12 pp 863ndash869 2006
[7] F Faraci and D D Heistad ldquoRegulation of the cerebralcirculation role of endothelium and potassium channelsrdquoPhysiological Reviews vol 78 no 1 pp 53ndash97 1998
[8] L Hektoen ldquoThe vascular changes in tuberculous meningitisespecially in tuberculous endarteritisrdquo Journal of ExperimentalMedicine vol 1 pp 112ndash163 1896
[9] G Thwaites ldquoTuberculosis of the central nervous systemrdquo inClinical Tuberculosis P D O Davies S B Gordon and GDavies Eds pp 151ndash165 CRC Press 5th edition 2014
[10] P M Dalal ldquoObservations on the involvement of cerebral ves-sels in tuberculousmeningitis in adultsrdquoAdvances in Neurologyvol 25 pp 149ndash159 1979
[11] L A Rojas-Echeverri J L Soto-Hernandez S Garza et alldquoPredictive value of digital subtraction angiography in patientswith tuberculous meningitisrdquo Neuroradiology vol 38 no 1 pp20ndash24 1996
[12] E L Lyons and N E Leeds ldquoThe angiographic demonstrationof arterial vascular disease in purulent meningitis report of acaserdquo Radiology vol 88 no 5 pp 935ndash938 1967
[13] S Ries U Schminke K Fassbender M Daffertshofer WSteinke andMHennerici ldquoCerebrovascular involvement in theacute phase of bacterial meningitisrdquo Journal of Neurology vol244 no 1 pp 51ndash55 1997
[14] K Fassbender S Ries U Schminke S Schneider and M Hen-nerici ldquoInflammatory cytokines in CSF in bacterial meningitisassociation with altered blood flow velocities in basal cerebralarteriesrdquo Journal of Neurology Neurosurgery amp Psychiatry vol61 no 1 pp 57ndash61 1996
[15] L A Pfister J H Tureen S Shaw et al ldquoEndothelin inhibitionimproves cerebral blood flow and is neuroprotective in pneu-mococcal meningitisrdquoAnnals of Neurology vol 47 pp 329ndash3352000
International Journal of Inflammation 11
[16] S L Leib Y S Kim S M Black J H Tureen and M GTauber ldquoInducible nitric oxide synthase and the effect of amin-oguanidine in experimental neonatal meningitisrdquo The Journalof Infectious Diseases vol 177 no 3 pp 692ndash700 1998
[17] T W Polder C R Jerusalem andW M C Eling ldquoMorpholog-ical characteristics of intracerebral arterioles in clinical (Plas-modium falciparum) and experimental (Plasmodium berghei)cerebral malariardquo Journal of the Neurological Sciences vol 101no 1 pp 35ndash46 1991
[18] N A V Beare S P Harding T E Taylor S Lewallen and MEMolyneux ldquoPerfusion abnormalities in childrenwith cerebralmalaria andmalarial retinopathyrdquo Journal of Infectious Diseasesvol 199 no 2 pp 263ndash271 2009
[19] C R J C Newton K Marsh N Peshu and F J KirkhamldquoPerturbations of cerebral hemodynamics in Kenyans withcerebral malariardquo Pediatric Neurology vol 15 no 1 pp 41ndash491996
[20] C C John A Panoskaltsis-Mortari R O Opoka et alldquoCerebrospinal fluid cytokine levels and cognitive impairmentin cerebral malariardquo American Journal of Tropical Medicine andHygiene vol 78 no 2 pp 198ndash205 2008
[21] W McGuire A V S Hill C E M Allsopp B M Greenwoodand D Kwiatkowski ldquoVariation in the TNF-120572 promoter regionassociated with susceptibility to cerebral malariardquo Nature vol371 no 6497 pp 508ndash510 1994
[22] W McGuire J C Knight A V S Hill C E M Allsopp B MGreenwood and D Kwiatkowski ldquoSevere malarial anemia andcerebral malaria are associated with different tumor necrosisfactor promoter allelesrdquo Journal of Infectious Diseases vol 179no 1 pp 287ndash290 1999
[23] B Dugas M D Mossalayi C Damais and J-P Kolb ldquoNitricoxide production by human monocytes Evidence for a role ofCD23rdquo Immunology Today vol 16 no 12 pp 574ndash580 1995
[24] L Pellettieri B Nilsson C-A Carlsson andU Nilsson ldquoSerumimmunocomplexes in patients with subarachnoid hemorrhagerdquoNeurosurgery vol 19 no 5 pp 767ndash771 1986
[25] M Eisenhut ldquoCauses of reduced immune complex clearance incerebralmalariardquoParasite Immunology vol 31 no 2 p 59 2009
[26] P Teeranaipong J Ohashi J Patarapotikul et al ldquoA functionalsingle-nucleotide polymorphism in the CR1 promoter regioncontributes to protection against cerebral malariardquo Journal ofInfectious Diseases vol 198 no 12 pp 1880ndash1891 2008
[27] P Cabrales G M Zanini D Meays J A Frangos and LJ M Carvalho ldquoMurine cerebral malaria is associated witha vasospasm-like microcirculatory dysfunction and survivalupon rescue treatment is markedly increased by nimodipinerdquoTheAmerican Journal of Pathology vol 176 no 3 pp 1306ndash13152010
[28] I Gramaglia P Sobolewski D Meays et al ldquoLow nitricoxide bioavailability contributes to the genesis of experimentalcerebral malariardquoNature Medicine vol 12 no 12 pp 1417ndash14222006
[29] T W Yeo D A Lampah E Tjitra et al ldquoRelationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavail-ability and perfusion in severe falciparum malariardquo Journal ofInfectious Diseases vol 200 no 10 pp 1522ndash1529 2009
[30] G Dhangadamajhi B N Mohapatra S K Kar and M RanjitldquoGenetic variation in neuronal nitric oxide synthase (nNOS)gene and susceptibility to cerebral malaria in Indian adultsrdquoInfection Genetics and Evolution vol 9 no 5 pp 908ndash911 2009
[31] M R Hobbs V Udhayakumar M C Levesque et al ldquoAnew NOS2 promoter polymorphism associated with increased
nitric oxide production and protection from severe malaria inTanzanian and Kenyan childrenrdquoThe Lancet vol 360 no 9344pp 1468ndash1475 2002
[32] P Cabrales G M Zanini D Meays J A Frangos and L JM Carvalho ldquoNitric oxide protection against murine cerebralmalaria is associated with improved cerebral microcirculatoryphysiologyrdquo The Journal of Infectious Diseases vol 203 no 10pp 1454ndash1463 2011
[33] G Morahan C S Boutlis D Huang et al ldquoA promoterpolymorphism in the gene encoding interleukin-12 p40 (IL12B)is associated with mortality from cerebral malaria and withreduced nitric oxide productionrdquo Genes amp Immunity vol 3 no7 pp 414ndash418 2002
[34] C Casals-Pascual R Idro N Gicheru et al ldquoHigh levels of ery-thropoietin are associated with protection against neurologicalsequelae in African children with cerebral malariardquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 105 no 7 pp 2634ndash2639 2008
[35] F C Chow C M Marra and T A Cho ldquoCerebrovasculardisease in central nervous system infectionsrdquo Seminars inNeurology vol 31 no 3 pp 286ndash306 2011
[36] R A Armonda R S Bell A H Vo et al ldquoWartime traumaticcerebral vasospasm recent review of combat casualtiesrdquoNeuro-surgery vol 59 no 6 pp 1215ndash1225 2006
[37] K Shahlaie K Keachie I M Hutchins et al ldquoRisk factorsfor posttraumatic vasospasm clinical articlerdquo Journal of Neu-rosurgery vol 115 no 3 pp 602ndash611 2011
[38] Y Udomphorn W M Armstead and M S Vavilala ldquoCerebralblood flow and autoregulation after pediatric traumatic braininjuryrdquo Pediatric Neurology vol 38 no 4 pp 225ndash234 2008
[39] R M Pluta J Hansen-Schwartz J Dreier et al ldquoCerebralvasospasm following subarachnoid hemorrhage time for a newworld of thoughtrdquo Neurological Research vol 31 no 2 pp 151ndash158 2009
[40] J Hansen-Schwartz P Vajkoczy R L Macdonald R MPluta and J H Zhang ldquoCerebral vasospasm looking beyondvasoconstrictionrdquo Trends in Pharmacological Sciences vol 28no 6 pp 252ndash256 2007
[41] H Kasuya B K A Weir M Nakane et al ldquoNitric oxidesynthase and guanylate cyclase levels in canine basilar arteryafter subarachnoid hemorrhagerdquo Journal of Neurosurgery vol82 no 2 pp 250ndash255 1995
[42] M D Linnik and T J F Lee ldquoEffect of hemoglobin on neuro-genic responses and cholinergic parameters in porcine cerebralarteriesrdquo Journal of Cerebral Blood Flow and Metabolism vol 9no 2 pp 219ndash225 1989
[43] CG Sobey and FM Faraci ldquoSubarachnoid haemorrhage whathappens to the cerebral arteriesrdquo Clinical and ExperimentalPharmacology and Physiology vol 25 no 11 pp 867ndash876 1998
[44] Y R T Dinh G Lot R Benrabah O Baroudy J Cophignonand J Seylaz ldquoAbnormal cerebral vasodilation in aneurys-mal subarachnoid hemorrhage use of serial 133Xe cerebralblood flow measurement plus acetazolamide to assess cerebralvasospasmrdquo Journal of Neurosurgery vol 79 no 4 pp 490ndash4931993
[45] T J F Lee ldquoNitric oxide and the cerebral vascular functionrdquoJournal of Biomedical Science vol 7 no 1 pp 16ndash26 2000
[46] M Stoodley R L Macdonald B Weir et al ldquoSubarachnoidhemorrhage as a cause of an adaptive response in cerebralarteriesrdquo Journal of Neurosurgery vol 93 no 3 pp 463ndash4702000
12 International Journal of Inflammation
[47] Y R Tran Dinh A Jomaa J Callebert et al ldquoOverexpressionof cyclooxygenase-2 in rabbit basilar artery endothelial cellsafter subarachnoid hemorrhagerdquo Neurosurgery vol 48 no 3pp 626ndash635 2001
[48] A Gecse B Kis Z Mezei and G Telegdy ldquoEffects of inflam-matory neuropeptides on the arachidonate cascade of plateletsrdquoInternational Archives of Allergy and Immunology vol 118 no2ndash4 pp 166ndash170 1999
[49] K S Mark W J Trickler and D W Miller ldquoTumornecrosis factor-120572 induces cyclooxygenase-2 expression andprostaglandin release in brain microvessel endothelial cellsrdquoJournal of Pharmacology and Experimental Therapeutics vol297 no 3 pp 1051ndash1058 2001
[50] T Tanazawa Y Suzuki M Anzai S Tsugane M Takayasu andM Shibuya ldquoVasodilation by intrathecal lipopolysaccharide ofthe cerebral arteries after subarachnoid haemorrhage in dogsrdquoActa Neurochirurgica vol 138 no 3 pp 330ndash337 1996
[51] N Toda M Kawakami and K Yoshida ldquoConstrictor action ofoxyhemoglobin in monkey and dog basilar arteries in vivo andin vitrordquo American Journal of Physiology Heart and CirculatoryPhysiology vol 260 no 2 pp H420ndashH425 1991
[52] M Yoshizumi M A Perrella J C Burnett Jr and M-E LeeldquoTumor necrosis factor downregulates an endothelial nitricoxide synthase mRNA by shortening its half-liferdquo CirculationResearch vol 73 no 1 pp 205ndash209 1993
[53] A Rengasamy and R A Johns ldquoRegulation of nitric oxidesynthase by nitric oxiderdquo Molecular Pharmacology vol 44 no1 pp 124ndash128 1993
[54] A L de Souza A C P de Oliveira C C Romano J SztajnbokA J S Duarte and A C Seguro ldquoInterleukin-6 activation inischemic stroke caused by Neisseria meningitidis serogroup CrdquoInternational Journal of Cardiology vol 127 no 3 pp e160ndashe1632008
[55] T Kandabashi H Shimokawa K Miyata et al ldquoInhibition ofmyosin phosphatase by upregulated Rho-kinase plays a key rolefor coronary artery spasm in a porcine model with interleukin-1120573rdquo Circulation vol 101 no 11 pp 1319ndash1323 2000
[56] D-H Nam J-S Kim S-C Hong et al ldquoExpression ofinterleukin-1120573 in lipopolysaccharide stimulated monocytesderived from patients with aneurysmal subarachnoid hem-orrhage is correlated with cerebral vasospasmrdquo NeuroscienceLetters vol 312 no 1 pp 41ndash44 2001
[57] A Ito H Shimokawa T Kadokami et al ldquoTyrosine kinaseinhibitor suppresses coronary arteriosclerotic changes andvasospastic responses induced by chronic treatment withinterleukin-1120573 in pigs in vivordquo Journal of Clinical Investigationvol 96 no 3 pp 1288ndash1294 1995
[58] H Yanamoto H Kataoka Y Nakajo and K Iihara ldquoThe roleof the host defense system in the development of cerebralvasospasm analogies between atherosclerosis and subarach-noid hemorrhagerdquo European Neurology vol 68 no 6 pp 329ndash343 2012
[59] A F Ducruet P R Gigante Z L Hickman et al ldquoGeneticdeterminants of cerebral vasospasm delayed cerebral ischemiaand outcome after aneurysmal subarachnoid hemorrhagerdquoJournal of Cerebral Blood Flow amp Metabolism vol 30 no 4 pp676ndash688 2010
[60] J Langham C Goldfrad G Teasdale D Shaw and KRowan ldquoCalcium channel blockers for acute traumatic braininjuryrdquoCochrane Database Systematic Reviews no 4 Article IDCD000565 2000
[61] S M Dorhout Mees G J Rinkel V L Feigin et al ldquoCal-cium antagonists for aneurysmal subarachnoid haemorrhagerdquoCochrane Database of Systematic Reviews no 3 Article IDCD000277 2007
[62] R-Q Huang F-G Jiang Z-M Feng and T-Y WangldquoNicardipine in the treatment of aneurysmal subarachnoidhaemorrhage a meta-analysis of published datardquo Acta Neuro-logica Belgica vol 113 no 1 pp 3ndash6 2013
[63] S Naidu A J Payne J Moodley M Hoffmann and EGouws ldquoRandomised study assessing the effect of phenytoinand magnesium sulphate on maternal cerebral circulationin eclampsia using transcranial Doppler ultrasoundrdquo BritishJournal of Obstetrics amp Gynaecology vol 103 no 2 pp 111ndash1161996
[64] D Reddy A Fallah J-A Petropoulos F Farrokhyar R LMacdonald and D Jichici ldquoProphylactic magnesium sulphatefor aneurysmal subarachnoid haemorrhage a systematic reviewand meta-analysisrdquo Neurocritical Care vol 21 no 2 pp 356ndash364 2014
[65] C M Bradford S Finfer A OrsquoConnor et al ldquoA ran-domised controlled trial of induced hypermagnesaemia follow-ing aneurysmal subarachnoid haemorrhagerdquo Critical Care andResuscitation vol 15 no 2 pp 119ndash125 2013
[66] S-H Su W Xu J Hai Y-F Wu and F Yu ldquoEffects of statins-use for patients with aneurysmal subarachnoid hemorrhagea meta-analysis of randomized controlled trialsrdquo ScientificReports vol 4 article 4573 2014
[67] J Guo Z Shi K Yang J H Tian and L Jiang ldquoEndothelinreceptor antagonists for subarachnoid hemorrhagerdquo CochraneDatabase of Systematic Reviews vol 9 Article ID CD0083542012
[68] J Shen J-W Pan Z-X Fan X-X Xiong and R-Y ZhanldquoDissociation of vasospasm-related morbidity and outcomesin patients with aneurysmal subarachnoid hemorrhage treatedwith clazosentan a meta-analysis of randomized controlledtrials a reviewrdquo Journal of Neurosurgery vol 119 no 1 pp 180ndash189 2013
[69] P Gomis J P Graftieaux R Sercombe D Hettler BScherpereel and P Rousseaux ldquoRandomized double-blindplacebo-controlled pilot trial of high-dose methylprednisolonein aneurysmal subarachnoid hemorrhagerdquo Journal of Neuro-surgery vol 112 no 3 pp 681ndash688 2010
[70] A H Kramer and J J Fletcher ldquoLocally-administered intrathe-cal thrombolytics following aneurysmal subarachnoid hem-orrhage a systematic review and meta-analysisrdquo NeurocriticalCare vol 14 no 3 pp 489ndash499 2011
[71] G J Liu Z J Wang Y F Wang et al ldquoSystematic assessmentand meta-analysis of the efficacy and safety of fasudil in thetreatment of cerebral vasospasm in patients with subarachnoidhemorrhagerdquo European Journal of Clinical Pharmacology vol68 no 2 pp 131ndash139 2012
[72] S Zhang LWangM Liu andBWu ldquoTirilazad for aneurysmalsubarachnoid haemorrhagerdquo Cochrane Database SystematicReview vol 2 Article ID CD006778 2010
[73] M-Y Tseng P J Hutchinson H K Richards et al ldquoAcutesystemic erythropoietin therapy to reduce delayed ischemicdeficits following aneurysmal subarachnoid hemorrhage aphase II randomized double-blind placebo-controlled trialclinical articlerdquo Journal of Neurosurgery vol 111 no 1 pp 171ndash180 2009
[74] H Kasuya ldquoDevelopment of nicardipine prolonged-releaseimplants after clipping for preventing cerebral vasospasm from
International Journal of Inflammation 13
laboratory to clinical trialrdquo Acta Neurochirurgica Supplemen-tum vol 115 pp 41ndash44 2013
[75] C Thome M Seiz G A Schubert et al ldquoNicardipine pelletsfor the prevention of cerebral vasospasmrdquoActaNeurochirurgicano 110 pp 209ndash211 2011
[76] T Nassar S Akkawi A Shina et al ldquoIn vitro and in vivo effectsof tPA and PAI-1 on blood vessel tonerdquo Blood vol 103 no 3 pp897ndash902 2004
[77] T Sugawara R Ayer V Jadhav W Chen T Tsubokawaand J H Zhang ldquoMechanisms of statin treatment in cerebralvasospasmrdquo Acta Neurochirurgica no 110 pp 9ndash11 2011
[78] M D Vergouwen R J De Haan M Vermeulen and YB Roos ldquoEffect of statin treatment on vasospasm delayedcerebral ischemia and functional outcome in patients withaneurysmal subarachnoid hemorrhage a systematic review andmeta-analysis updaterdquo Stroke vol 41 no 1 pp e47ndashe52 2010
[79] G E Thwaites N D Bang N H Dung et al ldquoDexamethasonefor the treatment of tuberculous meningitis in adolescents andadultsrdquoTheNew England Journal ofMedicine vol 351 no 17 pp1741ndash1811 2004
[80] G E Thwaites J Macmullen-Price T T H Chau et al ldquoSerialMRI to determine the effect of dexamethasone on the cerebralpathology of tuberculous meningitis an observational studyrdquoThe Lancet Neurology vol 6 no 3 pp 230ndash236 2007
[81] U K Misra J Kalita and P P Nair ldquoRole of aspirin in tuber-culous meningitis a randomized open label placebo controlledtrialrdquo Journal of the Neurological Sciences vol 293 no 1-2 pp12ndash17 2010
[82] P W G Elbers and C Ince ldquoBench-to-bedside review mech-anisms of critical illnessmdashclassifying microcirculatory flowabnormalities in distributive shockrdquoCritical Care vol 10 article221 2006
[83] S Trzeciak I Cinel R P Dellinger et al ldquoResuscitating themicrocirculation in sepsis the central role of nitric oxideemerging concepts for novel therapies and challenges forclinical trialsrdquo Academic Emergency Medicine vol 15 no 5 pp399ndash415 2008
[84] Y Sakr M-J Dubois D De Backer J Creteur and J-LVincent ldquoPersistent-microcirculatory alterations are associatedwith organ failure and death in patients with septic shockrdquoCritical Care Medicine vol 32 no 9 pp 1825ndash1831 2004
[85] P E Spronk J H Rommes C Schaar andC Ince ldquoThromboly-sis in fulminant purpura observations on changes in microcir-culatory perfusion during succesful treatmentrdquoThrombosis andHaemostasis vol 95 no 3 pp 576ndash578 2006
[86] J Creteur D De Backer Y Sakr M Koch and J-L VincentldquoSublingual capnometry tracks microcirculatory changes inseptic patientsrdquo Intensive Care Medicine vol 32 no 4 pp 516ndash523 2006
[87] D De Backer J Creteur J C Preiser M J Dubois and JL Vincent ldquoMicrovascular blood flow is altered in patientswith sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 1 pp 98ndash104 2002
[88] G M Ibrahim and R L Macdonald ldquoThe effects of fluid bal-ance and colloid administration on outcomes in patients withaneurysmal subarachnoid hemorrhage a propensity score-matched analysisrdquoNeurocritical Care vol 19 no 2 pp 140ndash1492013
[89] T W Yeo D A Lampah R Gitawati et al ldquoImpaired nitricoxide bioavailability and L-arginine-reversible endothelial dys-function in adults with falciparum malariardquo The Journal ofExperimental Medicine vol 204 no 11 pp 2693ndash2704 2007
[90] A R Fathi R M Pluta K D Bakhtian M Qi and R RLonser ldquoReversal of cerebral vasospasmvia intravenous sodiumnitrite after subarachnoid hemorrhage in primates laboratoryinvestigationrdquo Journal of Neurosurgery vol 115 no 6 pp 1213ndash1220 2011
[91] D de Backer J Creteur M J Dubois et al ldquoThe effects ofdobutamine on microcirculatory alterations in patients withseptic shock are independent of its systemic effectsrdquo CriticalCare Medicine vol 34 no 2 pp 403ndash408 2006
[92] C E Chapleau R P White and J T Robertson ldquoCerebralvasospasm effects of prostaglandin synthetase inhibitors invitrordquo Neurosurgery vol 6 no 2 pp 155ndash159 1980
[93] J L Frazier G Pradilla P P Wang and R J TamargoldquoInhibition of cerebral vasospasm by intracranial delivery ofibuprofen from a controlled-release polymer in a rabbit modelof subarachnoid hemorrhagerdquo Journal of Neurosurgery vol 101no 1 pp 93ndash98 2004
[94] G Pradilla Q A Thai F G Legnani et al ldquoLocal deliveryof ibuprofen via controlled-release polymers prevents angio-graphic vasospasm in a monkey model of subarachnoid hem-orrhagerdquo Neurosurgery vol 57 no 1 pp 184ndash189 2005
[95] R P White and J T Robertson ldquoComparison of piroxicammeclofenamate ibuprofen aspirin and prostacyclin efficacy ina chronic model of cerebral vasospasmrdquo Neurosurgery vol 12no 1 pp 40ndash46 1983
[96] T Fukumori E Tani Y Maeda and A Sukenaga ldquoEffectsof prostacyclin and indomethacin on experimental delayedcerebral vasospasmrdquo Journal of Neurosurgery vol 59 no 5 pp829ndash834 1983
[97] L Brandt B Ljunggren K-E Andersson B Hindfelt and TUski ldquoProstaglandin metabolism and prostacyclin in cerebralvasospasmrdquo General Pharmacology vol 14 no 1 pp 141ndash1431983
[98] T Hakan M Zafer Berkman T Ersoy I Karatas T Sanand S Arbak ldquoAnti-inflammatory effect of meloxicam onexperimental vasospasm in the rat femoral arteryrdquo Journal ofClinical Neuroscience vol 15 no 1 pp 55ndash59 2008
[99] LG Toussaint III J A Friedman E FMWijdicks et al ldquoInflu-ence of aspirin on outcome following aneurysmal subarachnoidhemorrhagerdquo Journal of Neurosurgery vol 101 no 6 pp 921ndash925 2004
[100] B A Gross P M R Lai K U Frerichs and R Du ldquoAspirin andaneurysmal subarachnoid haemorrhagerdquo World Neurosurgery2013
[101] S Yokobori AWatanabe R Nakae et al ldquoCerebral vasospasmsafter intraventricular hemorrhage from an arteriovenousmalformationmdashcase reportrdquo Neurologia Medico-Chirurgicavol 50 no 4 pp 320ndash323 2010
[102] B S Park Y S Won S S Choi and B M Kim ldquoSeveresymptomatic vasospasm following intraventricular hemorrhagefrom arteriovenous fistulardquo Journal of Korean NeurosurgicalSociety vol 45 no 5 pp 300ndash302 2009
[103] G Pradilla T Garzon-Muvdi J J Ruzevick et al ldquoSystemicL-citrulline prevents cerebral vasospasm in haptoglobin 2-2transgenicmice after subarachnoid hemorrhagerdquoNeurosurgeryvol 70 no 3 pp 747ndash757 2012
[104] G Chen J Wu C Sun et al ldquoPotential role of JAK2 in cere-bral vasospasm after experimental subarachnoid hemorrhagerdquoBrain Research vol 1214 pp 136ndash144 2008
[105] C L Lin A L Kwan A S Dumont et al ldquoAttenuationof experimental subarachnoid hemorrhage-induced increases
14 International Journal of Inflammation
in circulating intercellular adhesion molecule-1 and cerebralvasospasm by the endothelin-converting enzyme inhibitor CGS26303rdquo Journal of Neurosurgery vol 106 no 3 pp 442ndash4482007
[106] K Iseda S Ono K Onoda et al ldquoAntivasospastic and antiin-flammatory effects of caspase inhibitor in experimental sub-arachnoid hemorrhagerdquo Journal of Neurosurgery vol 107 no 1pp 128ndash135 2007
[107] C-L Lin A S Dumont T Calisaneller A-L Kwan S-L Hwong and K S Lee ldquoMonoclonal antibody against Eselectin attenuates subarachnoid hemorrhage-induced cerebralvasospasmrdquo Surgical Neurology vol 64 no 3 pp 201ndash206 2005
[108] R Echigo N Shimohata K Karatsu et al ldquoTrehalose treat-ment suppresses inflammation oxidative stress and vasospasminduced by experimental subarachnoid hemorrhagerdquo Journal ofTranslational Medicine vol 10 no 1 article 80 2012
[109] CWakadeM D KingM D Laird C H Alleyne Jr and KMDhandapani ldquoCurcumin attenuates vascular inflammation andcerebral vasospasm after subarachnoid hemorrhage in micerdquoAntioxidants amp Redox Signaling vol 11 no 1 pp 35ndash45 2009
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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International Journal of Inflammation 9
mechanism is apart from a contribution to inhibition ofcalcium independent vasospasm (see above) probably alsoan increase of endothelial nitric oxide synthase (eNOS)expression by stabilizing eNOSmRNA which can contributeto an increase of NO level to enhance vasodilatation
76 Other Treatments Steroid treatment can inhibit cytokineexpression and has thus the potential to reduce cytokinemediated calcium dependent and independent vasospasmIn tuberculous meningitis adjuvant treatment with corticos-teroids has been indirectly associatedwith features of reducedvasculopathy which may include vasospasm
A large randomised controlled trial showed improvedmortality in tuberculous meningitis with adjuvant corti-costeroids but did not show a reduction in severe disabil-ity however an observational MRI study did suggest areduction in strokes in patients treated with corticosteroids[79 80] An open-label study of aspirin in the preventionof stroke and mortality in tuberculous meningitis found anonsignificant reduction in stroke and a significant reductionin mortality with a possible synergism with corticosteroids[81] Mechanisms responsible for a potential effect may bea reduction of the vasoconstricting effect of PGE2 The 21-aminosteroid tirilazad is a lipid peroxidation inhibitor whichinhibits free radical-induced lipid peroxidation (LP) by acombination of lipid peroxide scavenging and a membrane-stabilizing action that limits the propagation of LP reactionsbetween a lipid peroxide and an adjacent polyunsaturatedfatty acid There has been no consistent evidence of benefitin animal or human studies Erythropoietin may act throughincrease in expression of endothelial nitric oxide synthasethus increasing NO bioavailability
8 Conclusions and Perspectives forFuture Developments
There is evidence for common pathways leading tovasospasm in all forms of cerebral inflammation involvinginterleukin-1 tumor necrosis factor endothelin-1 andnitric oxide Treatments addressing the pathophysiologyof vasospasm in one form of cerebral inflammation maytherefore apply to all others Treatment of cerebral vasospasmhas been mainly investigated in aneurysmal SAH Agentsfor which there is likely to be clinical benefit are calciumantagonists statins and intrathecal plasminogen activators(see Table 2) The fact that there is calcium dependent andindependent vasospasm in inflammation (see Figure 1)shows that a combination of calcium antagonists with agentsinterfering with calcium independent vasospasm includingagents improving the bioavailability of nitric oxide is theway forward Future trials need to investigate their effectsin patients with all forms of cerebral inflammation leadingto neurological deficits attributable to vasospasm In vivocorrelates for reduction of vasospasm in the peripheralcirculation could be explored as a surrogate for reduction ofvasospasm in the cerebral (micro) vasculature
Strategies to improve microvascular recruitment whichhave been explored in models of septicaemia could poten-tially be applied to cerebral vasospasm Distributive shockwhich occurs during sepsis and septic shock is associatedwith an abnormal distribution of microvascular blood flowVasospasm of part of the arterioles supplying the capillary isa mechanism involved in this maldistribution The clinicalintroduction of new microcirculatory imaging techniquessuch as orthogonal polarization spectral and side-streamdark-field imaging (OPSSDF) has allowed direct obser-vation of the microcirculation at the bedside Images ofthe sublingual microcirculation during septic shock andresuscitation have revealed that the distributive defect ofblood flow occurs at the capillary level [82]
In rat models of cecal ligation and puncture investiga-tors have used intravital video microscopy to demonstratethat sepsis is characterized by decreased microcirculatoryflow velocity an abundance of stopped-flow microvesselsincreased heterogeneity of microcirculatory flow and lowdensity of perfused capillaries As thesemicrocirculatory flowalterations can occur in the absence of global hemodynamicderangements (eg absence of arterial hypotension) micro-circulatory dysfunction largely reflects intrinsic events occur-ring in the microvessels like localized vasospasm [83] Appli-cation ofmicrocirculatory recruitmentmaneuver procedureshas been shown to be effective in promotingmicrocirculatoryblood flow in clinical studies using OPSSDF imaging [84ndash87] Fluid resuscitation in combination with the nitric oxidedonor nitroglycerine was shown to recruit disturbed micro-circulation following pressure guided resuscitation in septicshock patients
It is important to note that application of colloids inpatients with SAH was associated with worse outcomescompared to matched controls in a subgroup analysis of theCONSCIOUS-1 prospective randomized trial of clazosentanfor the prevention of angiographic vasospasm [88] Futureresearch needs to investigate whether colloids can bind nitricoxide and make this vasodilator less available by binding it
Regarding future therapeutic interventions increasingnitric oxide bioavailability erythropoietin and L-argininewhich increased bioavailability of nitric oxide in patients withmalaria [89] need to be explored as adjunctive treatmentin children with cerebral malaria in randomised controlledtrials In vitro the availability of L-arginine does not appearto be a rate limiting step for the activity of the NO synthasebecause its half-saturating concentration is less than 3of theplasma and endothelial concentration of this substrate
The nitric oxide donor intravenous sodium nitrite hasbeen shown to prevent and reverse cerebrovascular spasmin primates and has been demonstrated to be safe foradministration in humans [90]
Support of pump function by dobutamine therapy hasbeen shown to improvemicrocirculatory flow independent ofimprovement of global hemodynamic parameters [91] Fluidapplication nitric oxide donors and dobutamine therapyneed to be explored in isolation but also as combinationof interventions to improve cerebral perfusion in cerebralinflammation associated with vasospasm
10 International Journal of Inflammation
A potential role of nonsteroidal anti-inflammatory drugswas revealed by landmark experiments on dog basilararteries Arachidonic acid induced sustained contractionsand these responses were markedly inhibited (95) bymeclofenamate and similarly by indomethacin but aspirinhad no such effect [92] In the rabbit basilar artery model ofcerebral vasospasm local intracranial delivery of ibuprofenaccomplished using controlled-release polymers preventedvasospasm when administered within 6 hours but notat either 12 or 24 hours [93] Delivery of ibuprofen viacontrolled-release polymers into the subarachnoid space ofmonkeys with subarachnoid haemorrhage prevented angio-graphic vasospasm after SAH as evident from patency of themiddle cerebral artery [94]
Piroxicam was more effective than the above-mentioneddrugs in the SAH dog model after angiographic analysisand analysis of behavioural changes [95] Early studiesusing prostacyclin found that isolated canine basilar arteriescontraction induced by prostaglandin E2 hemoglobin orserum was relaxed by prostacyclin but not indomethacin[96] In isolated human pial arteries prostacyclin relaxedhuman pial arteries contracted by either PGF2 alpha nora-drenaline serotonin or haemorrhagic CSF [97] In an animalstudy meloxicam reduced ultrastructural and morphometricvasospastic changes in rats with subarachnoid haemorrhage[98] Investigation comparing rate of subsequent permanentdisability from vasospasm and angiographic and delayedcerebral ischaemia in patients with SAH with and withoutaspirin intake found no association with poor outcome [99100]
There are new areas of pathophysiology research wherethe role of vasospasm needs to be explored thoroughly inorder to find avenues for therapeutic interventions Investi-gations could evaluate whether intraventricular haemorrhageoccurring commonly in the neonatal period in pretermneonates is associated with vasospasm increasing mor-bidity Case reports of intraventricular haemorrhage fromAV malformations and aneurysms in adults demonstratedvasospasm [101 102]
Future research needs to explore the usefulness of a num-ber of agents which have been demonstrated to reduce vaso-spasm in animal models including L-citrulline [103] januskinase-2 [104] endothelin converting enzyme inhibitors[105] caspase inhibitor Z-VAD-FMK [106] anti-E selectinmonoclonal antibodies [107] trehalose [108] and curcuminwhich was demonstrated to protect against the developmentof cerebral vasospasm and secondary cerebral infarctionafter subarachnoid haemorrhage in mice by its broad anti-inflammatory activity including limitation of superoxidegeneration and influence on inducible nitric oxide synthaseexpression [109]
Aggressive maintenance of normothermia or mildhypothermia in patients with military blast injury resultedin a dramatic reduction in the incidence of posttraumaticvasospasm from 475 to 5 Future studies need to confirmthis finding and investigate whether hypothermia can reducecerebral inflammation related ischemic damage to the brainin other conditions like bacterial meningitis or cerebralmalaria [37]
Conflict of Interests
The author declares that there is no conflict of interestsregarding the publication of this paper
References
[1] B Weir ldquoThe pathophysiology of cerebral vasospasmrdquo BritishJournal of Neurosurgery vol 9 no 3 pp 375ndash390 1995
[2] H Bode and A Harders ldquoTransient stenoses and occlusionsof main cerebral arteries in childrenmdashdiagnosis and control oftherapy by transcranial Doppler sonographyrdquo European Journalof Pediatrics vol 148 no 5 pp 406ndash411 1989
[3] K-F Lindegaard H Nornes S J Bakke W Sorteberg and PNakstad ldquoCerebral vasospasm diagnosis by means of angiogra-phy and blood velocity measurementsrdquo Acta Neurochirurgicavol 100 no 1-2 pp 12ndash24 1989
[4] C Lysakowski B Walder M C Costanza and M R TramerldquoTranscranial Doppler versus angiography in patients withvasospasm due to a ruptured cerebral aneurysm a systematicreviewrdquo Stroke vol 32 no 10 pp 2292ndash2298 2001
[5] R L Grubb Jr M E Raichle J O Eichling and M HGado ldquoEffects of subarachnoid hemorrhage on cerebral bloodvolume blood flow and oxygen utilization in humansrdquo Journalof Neurosurgery vol 46 no 4 pp 446ndash452 1977
[6] C-H Lu H-W Chang C-C Lui C-R Huang and W-NChang ldquoCerebral haemodynamics in acute bacterial meningitisin adultsrdquoQuaterly Journal of Medicine vol 99 no 12 pp 863ndash869 2006
[7] F Faraci and D D Heistad ldquoRegulation of the cerebralcirculation role of endothelium and potassium channelsrdquoPhysiological Reviews vol 78 no 1 pp 53ndash97 1998
[8] L Hektoen ldquoThe vascular changes in tuberculous meningitisespecially in tuberculous endarteritisrdquo Journal of ExperimentalMedicine vol 1 pp 112ndash163 1896
[9] G Thwaites ldquoTuberculosis of the central nervous systemrdquo inClinical Tuberculosis P D O Davies S B Gordon and GDavies Eds pp 151ndash165 CRC Press 5th edition 2014
[10] P M Dalal ldquoObservations on the involvement of cerebral ves-sels in tuberculousmeningitis in adultsrdquoAdvances in Neurologyvol 25 pp 149ndash159 1979
[11] L A Rojas-Echeverri J L Soto-Hernandez S Garza et alldquoPredictive value of digital subtraction angiography in patientswith tuberculous meningitisrdquo Neuroradiology vol 38 no 1 pp20ndash24 1996
[12] E L Lyons and N E Leeds ldquoThe angiographic demonstrationof arterial vascular disease in purulent meningitis report of acaserdquo Radiology vol 88 no 5 pp 935ndash938 1967
[13] S Ries U Schminke K Fassbender M Daffertshofer WSteinke andMHennerici ldquoCerebrovascular involvement in theacute phase of bacterial meningitisrdquo Journal of Neurology vol244 no 1 pp 51ndash55 1997
[14] K Fassbender S Ries U Schminke S Schneider and M Hen-nerici ldquoInflammatory cytokines in CSF in bacterial meningitisassociation with altered blood flow velocities in basal cerebralarteriesrdquo Journal of Neurology Neurosurgery amp Psychiatry vol61 no 1 pp 57ndash61 1996
[15] L A Pfister J H Tureen S Shaw et al ldquoEndothelin inhibitionimproves cerebral blood flow and is neuroprotective in pneu-mococcal meningitisrdquoAnnals of Neurology vol 47 pp 329ndash3352000
International Journal of Inflammation 11
[16] S L Leib Y S Kim S M Black J H Tureen and M GTauber ldquoInducible nitric oxide synthase and the effect of amin-oguanidine in experimental neonatal meningitisrdquo The Journalof Infectious Diseases vol 177 no 3 pp 692ndash700 1998
[17] T W Polder C R Jerusalem andW M C Eling ldquoMorpholog-ical characteristics of intracerebral arterioles in clinical (Plas-modium falciparum) and experimental (Plasmodium berghei)cerebral malariardquo Journal of the Neurological Sciences vol 101no 1 pp 35ndash46 1991
[18] N A V Beare S P Harding T E Taylor S Lewallen and MEMolyneux ldquoPerfusion abnormalities in childrenwith cerebralmalaria andmalarial retinopathyrdquo Journal of Infectious Diseasesvol 199 no 2 pp 263ndash271 2009
[19] C R J C Newton K Marsh N Peshu and F J KirkhamldquoPerturbations of cerebral hemodynamics in Kenyans withcerebral malariardquo Pediatric Neurology vol 15 no 1 pp 41ndash491996
[20] C C John A Panoskaltsis-Mortari R O Opoka et alldquoCerebrospinal fluid cytokine levels and cognitive impairmentin cerebral malariardquo American Journal of Tropical Medicine andHygiene vol 78 no 2 pp 198ndash205 2008
[21] W McGuire A V S Hill C E M Allsopp B M Greenwoodand D Kwiatkowski ldquoVariation in the TNF-120572 promoter regionassociated with susceptibility to cerebral malariardquo Nature vol371 no 6497 pp 508ndash510 1994
[22] W McGuire J C Knight A V S Hill C E M Allsopp B MGreenwood and D Kwiatkowski ldquoSevere malarial anemia andcerebral malaria are associated with different tumor necrosisfactor promoter allelesrdquo Journal of Infectious Diseases vol 179no 1 pp 287ndash290 1999
[23] B Dugas M D Mossalayi C Damais and J-P Kolb ldquoNitricoxide production by human monocytes Evidence for a role ofCD23rdquo Immunology Today vol 16 no 12 pp 574ndash580 1995
[24] L Pellettieri B Nilsson C-A Carlsson andU Nilsson ldquoSerumimmunocomplexes in patients with subarachnoid hemorrhagerdquoNeurosurgery vol 19 no 5 pp 767ndash771 1986
[25] M Eisenhut ldquoCauses of reduced immune complex clearance incerebralmalariardquoParasite Immunology vol 31 no 2 p 59 2009
[26] P Teeranaipong J Ohashi J Patarapotikul et al ldquoA functionalsingle-nucleotide polymorphism in the CR1 promoter regioncontributes to protection against cerebral malariardquo Journal ofInfectious Diseases vol 198 no 12 pp 1880ndash1891 2008
[27] P Cabrales G M Zanini D Meays J A Frangos and LJ M Carvalho ldquoMurine cerebral malaria is associated witha vasospasm-like microcirculatory dysfunction and survivalupon rescue treatment is markedly increased by nimodipinerdquoTheAmerican Journal of Pathology vol 176 no 3 pp 1306ndash13152010
[28] I Gramaglia P Sobolewski D Meays et al ldquoLow nitricoxide bioavailability contributes to the genesis of experimentalcerebral malariardquoNature Medicine vol 12 no 12 pp 1417ndash14222006
[29] T W Yeo D A Lampah E Tjitra et al ldquoRelationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavail-ability and perfusion in severe falciparum malariardquo Journal ofInfectious Diseases vol 200 no 10 pp 1522ndash1529 2009
[30] G Dhangadamajhi B N Mohapatra S K Kar and M RanjitldquoGenetic variation in neuronal nitric oxide synthase (nNOS)gene and susceptibility to cerebral malaria in Indian adultsrdquoInfection Genetics and Evolution vol 9 no 5 pp 908ndash911 2009
[31] M R Hobbs V Udhayakumar M C Levesque et al ldquoAnew NOS2 promoter polymorphism associated with increased
nitric oxide production and protection from severe malaria inTanzanian and Kenyan childrenrdquoThe Lancet vol 360 no 9344pp 1468ndash1475 2002
[32] P Cabrales G M Zanini D Meays J A Frangos and L JM Carvalho ldquoNitric oxide protection against murine cerebralmalaria is associated with improved cerebral microcirculatoryphysiologyrdquo The Journal of Infectious Diseases vol 203 no 10pp 1454ndash1463 2011
[33] G Morahan C S Boutlis D Huang et al ldquoA promoterpolymorphism in the gene encoding interleukin-12 p40 (IL12B)is associated with mortality from cerebral malaria and withreduced nitric oxide productionrdquo Genes amp Immunity vol 3 no7 pp 414ndash418 2002
[34] C Casals-Pascual R Idro N Gicheru et al ldquoHigh levels of ery-thropoietin are associated with protection against neurologicalsequelae in African children with cerebral malariardquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 105 no 7 pp 2634ndash2639 2008
[35] F C Chow C M Marra and T A Cho ldquoCerebrovasculardisease in central nervous system infectionsrdquo Seminars inNeurology vol 31 no 3 pp 286ndash306 2011
[36] R A Armonda R S Bell A H Vo et al ldquoWartime traumaticcerebral vasospasm recent review of combat casualtiesrdquoNeuro-surgery vol 59 no 6 pp 1215ndash1225 2006
[37] K Shahlaie K Keachie I M Hutchins et al ldquoRisk factorsfor posttraumatic vasospasm clinical articlerdquo Journal of Neu-rosurgery vol 115 no 3 pp 602ndash611 2011
[38] Y Udomphorn W M Armstead and M S Vavilala ldquoCerebralblood flow and autoregulation after pediatric traumatic braininjuryrdquo Pediatric Neurology vol 38 no 4 pp 225ndash234 2008
[39] R M Pluta J Hansen-Schwartz J Dreier et al ldquoCerebralvasospasm following subarachnoid hemorrhage time for a newworld of thoughtrdquo Neurological Research vol 31 no 2 pp 151ndash158 2009
[40] J Hansen-Schwartz P Vajkoczy R L Macdonald R MPluta and J H Zhang ldquoCerebral vasospasm looking beyondvasoconstrictionrdquo Trends in Pharmacological Sciences vol 28no 6 pp 252ndash256 2007
[41] H Kasuya B K A Weir M Nakane et al ldquoNitric oxidesynthase and guanylate cyclase levels in canine basilar arteryafter subarachnoid hemorrhagerdquo Journal of Neurosurgery vol82 no 2 pp 250ndash255 1995
[42] M D Linnik and T J F Lee ldquoEffect of hemoglobin on neuro-genic responses and cholinergic parameters in porcine cerebralarteriesrdquo Journal of Cerebral Blood Flow and Metabolism vol 9no 2 pp 219ndash225 1989
[43] CG Sobey and FM Faraci ldquoSubarachnoid haemorrhage whathappens to the cerebral arteriesrdquo Clinical and ExperimentalPharmacology and Physiology vol 25 no 11 pp 867ndash876 1998
[44] Y R T Dinh G Lot R Benrabah O Baroudy J Cophignonand J Seylaz ldquoAbnormal cerebral vasodilation in aneurys-mal subarachnoid hemorrhage use of serial 133Xe cerebralblood flow measurement plus acetazolamide to assess cerebralvasospasmrdquo Journal of Neurosurgery vol 79 no 4 pp 490ndash4931993
[45] T J F Lee ldquoNitric oxide and the cerebral vascular functionrdquoJournal of Biomedical Science vol 7 no 1 pp 16ndash26 2000
[46] M Stoodley R L Macdonald B Weir et al ldquoSubarachnoidhemorrhage as a cause of an adaptive response in cerebralarteriesrdquo Journal of Neurosurgery vol 93 no 3 pp 463ndash4702000
12 International Journal of Inflammation
[47] Y R Tran Dinh A Jomaa J Callebert et al ldquoOverexpressionof cyclooxygenase-2 in rabbit basilar artery endothelial cellsafter subarachnoid hemorrhagerdquo Neurosurgery vol 48 no 3pp 626ndash635 2001
[48] A Gecse B Kis Z Mezei and G Telegdy ldquoEffects of inflam-matory neuropeptides on the arachidonate cascade of plateletsrdquoInternational Archives of Allergy and Immunology vol 118 no2ndash4 pp 166ndash170 1999
[49] K S Mark W J Trickler and D W Miller ldquoTumornecrosis factor-120572 induces cyclooxygenase-2 expression andprostaglandin release in brain microvessel endothelial cellsrdquoJournal of Pharmacology and Experimental Therapeutics vol297 no 3 pp 1051ndash1058 2001
[50] T Tanazawa Y Suzuki M Anzai S Tsugane M Takayasu andM Shibuya ldquoVasodilation by intrathecal lipopolysaccharide ofthe cerebral arteries after subarachnoid haemorrhage in dogsrdquoActa Neurochirurgica vol 138 no 3 pp 330ndash337 1996
[51] N Toda M Kawakami and K Yoshida ldquoConstrictor action ofoxyhemoglobin in monkey and dog basilar arteries in vivo andin vitrordquo American Journal of Physiology Heart and CirculatoryPhysiology vol 260 no 2 pp H420ndashH425 1991
[52] M Yoshizumi M A Perrella J C Burnett Jr and M-E LeeldquoTumor necrosis factor downregulates an endothelial nitricoxide synthase mRNA by shortening its half-liferdquo CirculationResearch vol 73 no 1 pp 205ndash209 1993
[53] A Rengasamy and R A Johns ldquoRegulation of nitric oxidesynthase by nitric oxiderdquo Molecular Pharmacology vol 44 no1 pp 124ndash128 1993
[54] A L de Souza A C P de Oliveira C C Romano J SztajnbokA J S Duarte and A C Seguro ldquoInterleukin-6 activation inischemic stroke caused by Neisseria meningitidis serogroup CrdquoInternational Journal of Cardiology vol 127 no 3 pp e160ndashe1632008
[55] T Kandabashi H Shimokawa K Miyata et al ldquoInhibition ofmyosin phosphatase by upregulated Rho-kinase plays a key rolefor coronary artery spasm in a porcine model with interleukin-1120573rdquo Circulation vol 101 no 11 pp 1319ndash1323 2000
[56] D-H Nam J-S Kim S-C Hong et al ldquoExpression ofinterleukin-1120573 in lipopolysaccharide stimulated monocytesderived from patients with aneurysmal subarachnoid hem-orrhage is correlated with cerebral vasospasmrdquo NeuroscienceLetters vol 312 no 1 pp 41ndash44 2001
[57] A Ito H Shimokawa T Kadokami et al ldquoTyrosine kinaseinhibitor suppresses coronary arteriosclerotic changes andvasospastic responses induced by chronic treatment withinterleukin-1120573 in pigs in vivordquo Journal of Clinical Investigationvol 96 no 3 pp 1288ndash1294 1995
[58] H Yanamoto H Kataoka Y Nakajo and K Iihara ldquoThe roleof the host defense system in the development of cerebralvasospasm analogies between atherosclerosis and subarach-noid hemorrhagerdquo European Neurology vol 68 no 6 pp 329ndash343 2012
[59] A F Ducruet P R Gigante Z L Hickman et al ldquoGeneticdeterminants of cerebral vasospasm delayed cerebral ischemiaand outcome after aneurysmal subarachnoid hemorrhagerdquoJournal of Cerebral Blood Flow amp Metabolism vol 30 no 4 pp676ndash688 2010
[60] J Langham C Goldfrad G Teasdale D Shaw and KRowan ldquoCalcium channel blockers for acute traumatic braininjuryrdquoCochrane Database Systematic Reviews no 4 Article IDCD000565 2000
[61] S M Dorhout Mees G J Rinkel V L Feigin et al ldquoCal-cium antagonists for aneurysmal subarachnoid haemorrhagerdquoCochrane Database of Systematic Reviews no 3 Article IDCD000277 2007
[62] R-Q Huang F-G Jiang Z-M Feng and T-Y WangldquoNicardipine in the treatment of aneurysmal subarachnoidhaemorrhage a meta-analysis of published datardquo Acta Neuro-logica Belgica vol 113 no 1 pp 3ndash6 2013
[63] S Naidu A J Payne J Moodley M Hoffmann and EGouws ldquoRandomised study assessing the effect of phenytoinand magnesium sulphate on maternal cerebral circulationin eclampsia using transcranial Doppler ultrasoundrdquo BritishJournal of Obstetrics amp Gynaecology vol 103 no 2 pp 111ndash1161996
[64] D Reddy A Fallah J-A Petropoulos F Farrokhyar R LMacdonald and D Jichici ldquoProphylactic magnesium sulphatefor aneurysmal subarachnoid haemorrhage a systematic reviewand meta-analysisrdquo Neurocritical Care vol 21 no 2 pp 356ndash364 2014
[65] C M Bradford S Finfer A OrsquoConnor et al ldquoA ran-domised controlled trial of induced hypermagnesaemia follow-ing aneurysmal subarachnoid haemorrhagerdquo Critical Care andResuscitation vol 15 no 2 pp 119ndash125 2013
[66] S-H Su W Xu J Hai Y-F Wu and F Yu ldquoEffects of statins-use for patients with aneurysmal subarachnoid hemorrhagea meta-analysis of randomized controlled trialsrdquo ScientificReports vol 4 article 4573 2014
[67] J Guo Z Shi K Yang J H Tian and L Jiang ldquoEndothelinreceptor antagonists for subarachnoid hemorrhagerdquo CochraneDatabase of Systematic Reviews vol 9 Article ID CD0083542012
[68] J Shen J-W Pan Z-X Fan X-X Xiong and R-Y ZhanldquoDissociation of vasospasm-related morbidity and outcomesin patients with aneurysmal subarachnoid hemorrhage treatedwith clazosentan a meta-analysis of randomized controlledtrials a reviewrdquo Journal of Neurosurgery vol 119 no 1 pp 180ndash189 2013
[69] P Gomis J P Graftieaux R Sercombe D Hettler BScherpereel and P Rousseaux ldquoRandomized double-blindplacebo-controlled pilot trial of high-dose methylprednisolonein aneurysmal subarachnoid hemorrhagerdquo Journal of Neuro-surgery vol 112 no 3 pp 681ndash688 2010
[70] A H Kramer and J J Fletcher ldquoLocally-administered intrathe-cal thrombolytics following aneurysmal subarachnoid hem-orrhage a systematic review and meta-analysisrdquo NeurocriticalCare vol 14 no 3 pp 489ndash499 2011
[71] G J Liu Z J Wang Y F Wang et al ldquoSystematic assessmentand meta-analysis of the efficacy and safety of fasudil in thetreatment of cerebral vasospasm in patients with subarachnoidhemorrhagerdquo European Journal of Clinical Pharmacology vol68 no 2 pp 131ndash139 2012
[72] S Zhang LWangM Liu andBWu ldquoTirilazad for aneurysmalsubarachnoid haemorrhagerdquo Cochrane Database SystematicReview vol 2 Article ID CD006778 2010
[73] M-Y Tseng P J Hutchinson H K Richards et al ldquoAcutesystemic erythropoietin therapy to reduce delayed ischemicdeficits following aneurysmal subarachnoid hemorrhage aphase II randomized double-blind placebo-controlled trialclinical articlerdquo Journal of Neurosurgery vol 111 no 1 pp 171ndash180 2009
[74] H Kasuya ldquoDevelopment of nicardipine prolonged-releaseimplants after clipping for preventing cerebral vasospasm from
International Journal of Inflammation 13
laboratory to clinical trialrdquo Acta Neurochirurgica Supplemen-tum vol 115 pp 41ndash44 2013
[75] C Thome M Seiz G A Schubert et al ldquoNicardipine pelletsfor the prevention of cerebral vasospasmrdquoActaNeurochirurgicano 110 pp 209ndash211 2011
[76] T Nassar S Akkawi A Shina et al ldquoIn vitro and in vivo effectsof tPA and PAI-1 on blood vessel tonerdquo Blood vol 103 no 3 pp897ndash902 2004
[77] T Sugawara R Ayer V Jadhav W Chen T Tsubokawaand J H Zhang ldquoMechanisms of statin treatment in cerebralvasospasmrdquo Acta Neurochirurgica no 110 pp 9ndash11 2011
[78] M D Vergouwen R J De Haan M Vermeulen and YB Roos ldquoEffect of statin treatment on vasospasm delayedcerebral ischemia and functional outcome in patients withaneurysmal subarachnoid hemorrhage a systematic review andmeta-analysis updaterdquo Stroke vol 41 no 1 pp e47ndashe52 2010
[79] G E Thwaites N D Bang N H Dung et al ldquoDexamethasonefor the treatment of tuberculous meningitis in adolescents andadultsrdquoTheNew England Journal ofMedicine vol 351 no 17 pp1741ndash1811 2004
[80] G E Thwaites J Macmullen-Price T T H Chau et al ldquoSerialMRI to determine the effect of dexamethasone on the cerebralpathology of tuberculous meningitis an observational studyrdquoThe Lancet Neurology vol 6 no 3 pp 230ndash236 2007
[81] U K Misra J Kalita and P P Nair ldquoRole of aspirin in tuber-culous meningitis a randomized open label placebo controlledtrialrdquo Journal of the Neurological Sciences vol 293 no 1-2 pp12ndash17 2010
[82] P W G Elbers and C Ince ldquoBench-to-bedside review mech-anisms of critical illnessmdashclassifying microcirculatory flowabnormalities in distributive shockrdquoCritical Care vol 10 article221 2006
[83] S Trzeciak I Cinel R P Dellinger et al ldquoResuscitating themicrocirculation in sepsis the central role of nitric oxideemerging concepts for novel therapies and challenges forclinical trialsrdquo Academic Emergency Medicine vol 15 no 5 pp399ndash415 2008
[84] Y Sakr M-J Dubois D De Backer J Creteur and J-LVincent ldquoPersistent-microcirculatory alterations are associatedwith organ failure and death in patients with septic shockrdquoCritical Care Medicine vol 32 no 9 pp 1825ndash1831 2004
[85] P E Spronk J H Rommes C Schaar andC Ince ldquoThromboly-sis in fulminant purpura observations on changes in microcir-culatory perfusion during succesful treatmentrdquoThrombosis andHaemostasis vol 95 no 3 pp 576ndash578 2006
[86] J Creteur D De Backer Y Sakr M Koch and J-L VincentldquoSublingual capnometry tracks microcirculatory changes inseptic patientsrdquo Intensive Care Medicine vol 32 no 4 pp 516ndash523 2006
[87] D De Backer J Creteur J C Preiser M J Dubois and JL Vincent ldquoMicrovascular blood flow is altered in patientswith sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 1 pp 98ndash104 2002
[88] G M Ibrahim and R L Macdonald ldquoThe effects of fluid bal-ance and colloid administration on outcomes in patients withaneurysmal subarachnoid hemorrhage a propensity score-matched analysisrdquoNeurocritical Care vol 19 no 2 pp 140ndash1492013
[89] T W Yeo D A Lampah R Gitawati et al ldquoImpaired nitricoxide bioavailability and L-arginine-reversible endothelial dys-function in adults with falciparum malariardquo The Journal ofExperimental Medicine vol 204 no 11 pp 2693ndash2704 2007
[90] A R Fathi R M Pluta K D Bakhtian M Qi and R RLonser ldquoReversal of cerebral vasospasmvia intravenous sodiumnitrite after subarachnoid hemorrhage in primates laboratoryinvestigationrdquo Journal of Neurosurgery vol 115 no 6 pp 1213ndash1220 2011
[91] D de Backer J Creteur M J Dubois et al ldquoThe effects ofdobutamine on microcirculatory alterations in patients withseptic shock are independent of its systemic effectsrdquo CriticalCare Medicine vol 34 no 2 pp 403ndash408 2006
[92] C E Chapleau R P White and J T Robertson ldquoCerebralvasospasm effects of prostaglandin synthetase inhibitors invitrordquo Neurosurgery vol 6 no 2 pp 155ndash159 1980
[93] J L Frazier G Pradilla P P Wang and R J TamargoldquoInhibition of cerebral vasospasm by intracranial delivery ofibuprofen from a controlled-release polymer in a rabbit modelof subarachnoid hemorrhagerdquo Journal of Neurosurgery vol 101no 1 pp 93ndash98 2004
[94] G Pradilla Q A Thai F G Legnani et al ldquoLocal deliveryof ibuprofen via controlled-release polymers prevents angio-graphic vasospasm in a monkey model of subarachnoid hem-orrhagerdquo Neurosurgery vol 57 no 1 pp 184ndash189 2005
[95] R P White and J T Robertson ldquoComparison of piroxicammeclofenamate ibuprofen aspirin and prostacyclin efficacy ina chronic model of cerebral vasospasmrdquo Neurosurgery vol 12no 1 pp 40ndash46 1983
[96] T Fukumori E Tani Y Maeda and A Sukenaga ldquoEffectsof prostacyclin and indomethacin on experimental delayedcerebral vasospasmrdquo Journal of Neurosurgery vol 59 no 5 pp829ndash834 1983
[97] L Brandt B Ljunggren K-E Andersson B Hindfelt and TUski ldquoProstaglandin metabolism and prostacyclin in cerebralvasospasmrdquo General Pharmacology vol 14 no 1 pp 141ndash1431983
[98] T Hakan M Zafer Berkman T Ersoy I Karatas T Sanand S Arbak ldquoAnti-inflammatory effect of meloxicam onexperimental vasospasm in the rat femoral arteryrdquo Journal ofClinical Neuroscience vol 15 no 1 pp 55ndash59 2008
[99] LG Toussaint III J A Friedman E FMWijdicks et al ldquoInflu-ence of aspirin on outcome following aneurysmal subarachnoidhemorrhagerdquo Journal of Neurosurgery vol 101 no 6 pp 921ndash925 2004
[100] B A Gross P M R Lai K U Frerichs and R Du ldquoAspirin andaneurysmal subarachnoid haemorrhagerdquo World Neurosurgery2013
[101] S Yokobori AWatanabe R Nakae et al ldquoCerebral vasospasmsafter intraventricular hemorrhage from an arteriovenousmalformationmdashcase reportrdquo Neurologia Medico-Chirurgicavol 50 no 4 pp 320ndash323 2010
[102] B S Park Y S Won S S Choi and B M Kim ldquoSeveresymptomatic vasospasm following intraventricular hemorrhagefrom arteriovenous fistulardquo Journal of Korean NeurosurgicalSociety vol 45 no 5 pp 300ndash302 2009
[103] G Pradilla T Garzon-Muvdi J J Ruzevick et al ldquoSystemicL-citrulline prevents cerebral vasospasm in haptoglobin 2-2transgenicmice after subarachnoid hemorrhagerdquoNeurosurgeryvol 70 no 3 pp 747ndash757 2012
[104] G Chen J Wu C Sun et al ldquoPotential role of JAK2 in cere-bral vasospasm after experimental subarachnoid hemorrhagerdquoBrain Research vol 1214 pp 136ndash144 2008
[105] C L Lin A L Kwan A S Dumont et al ldquoAttenuationof experimental subarachnoid hemorrhage-induced increases
14 International Journal of Inflammation
in circulating intercellular adhesion molecule-1 and cerebralvasospasm by the endothelin-converting enzyme inhibitor CGS26303rdquo Journal of Neurosurgery vol 106 no 3 pp 442ndash4482007
[106] K Iseda S Ono K Onoda et al ldquoAntivasospastic and antiin-flammatory effects of caspase inhibitor in experimental sub-arachnoid hemorrhagerdquo Journal of Neurosurgery vol 107 no 1pp 128ndash135 2007
[107] C-L Lin A S Dumont T Calisaneller A-L Kwan S-L Hwong and K S Lee ldquoMonoclonal antibody against Eselectin attenuates subarachnoid hemorrhage-induced cerebralvasospasmrdquo Surgical Neurology vol 64 no 3 pp 201ndash206 2005
[108] R Echigo N Shimohata K Karatsu et al ldquoTrehalose treat-ment suppresses inflammation oxidative stress and vasospasminduced by experimental subarachnoid hemorrhagerdquo Journal ofTranslational Medicine vol 10 no 1 article 80 2012
[109] CWakadeM D KingM D Laird C H Alleyne Jr and KMDhandapani ldquoCurcumin attenuates vascular inflammation andcerebral vasospasm after subarachnoid hemorrhage in micerdquoAntioxidants amp Redox Signaling vol 11 no 1 pp 35ndash45 2009
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
10 International Journal of Inflammation
A potential role of nonsteroidal anti-inflammatory drugswas revealed by landmark experiments on dog basilararteries Arachidonic acid induced sustained contractionsand these responses were markedly inhibited (95) bymeclofenamate and similarly by indomethacin but aspirinhad no such effect [92] In the rabbit basilar artery model ofcerebral vasospasm local intracranial delivery of ibuprofenaccomplished using controlled-release polymers preventedvasospasm when administered within 6 hours but notat either 12 or 24 hours [93] Delivery of ibuprofen viacontrolled-release polymers into the subarachnoid space ofmonkeys with subarachnoid haemorrhage prevented angio-graphic vasospasm after SAH as evident from patency of themiddle cerebral artery [94]
Piroxicam was more effective than the above-mentioneddrugs in the SAH dog model after angiographic analysisand analysis of behavioural changes [95] Early studiesusing prostacyclin found that isolated canine basilar arteriescontraction induced by prostaglandin E2 hemoglobin orserum was relaxed by prostacyclin but not indomethacin[96] In isolated human pial arteries prostacyclin relaxedhuman pial arteries contracted by either PGF2 alpha nora-drenaline serotonin or haemorrhagic CSF [97] In an animalstudy meloxicam reduced ultrastructural and morphometricvasospastic changes in rats with subarachnoid haemorrhage[98] Investigation comparing rate of subsequent permanentdisability from vasospasm and angiographic and delayedcerebral ischaemia in patients with SAH with and withoutaspirin intake found no association with poor outcome [99100]
There are new areas of pathophysiology research wherethe role of vasospasm needs to be explored thoroughly inorder to find avenues for therapeutic interventions Investi-gations could evaluate whether intraventricular haemorrhageoccurring commonly in the neonatal period in pretermneonates is associated with vasospasm increasing mor-bidity Case reports of intraventricular haemorrhage fromAV malformations and aneurysms in adults demonstratedvasospasm [101 102]
Future research needs to explore the usefulness of a num-ber of agents which have been demonstrated to reduce vaso-spasm in animal models including L-citrulline [103] januskinase-2 [104] endothelin converting enzyme inhibitors[105] caspase inhibitor Z-VAD-FMK [106] anti-E selectinmonoclonal antibodies [107] trehalose [108] and curcuminwhich was demonstrated to protect against the developmentof cerebral vasospasm and secondary cerebral infarctionafter subarachnoid haemorrhage in mice by its broad anti-inflammatory activity including limitation of superoxidegeneration and influence on inducible nitric oxide synthaseexpression [109]
Aggressive maintenance of normothermia or mildhypothermia in patients with military blast injury resultedin a dramatic reduction in the incidence of posttraumaticvasospasm from 475 to 5 Future studies need to confirmthis finding and investigate whether hypothermia can reducecerebral inflammation related ischemic damage to the brainin other conditions like bacterial meningitis or cerebralmalaria [37]
Conflict of Interests
The author declares that there is no conflict of interestsregarding the publication of this paper
References
[1] B Weir ldquoThe pathophysiology of cerebral vasospasmrdquo BritishJournal of Neurosurgery vol 9 no 3 pp 375ndash390 1995
[2] H Bode and A Harders ldquoTransient stenoses and occlusionsof main cerebral arteries in childrenmdashdiagnosis and control oftherapy by transcranial Doppler sonographyrdquo European Journalof Pediatrics vol 148 no 5 pp 406ndash411 1989
[3] K-F Lindegaard H Nornes S J Bakke W Sorteberg and PNakstad ldquoCerebral vasospasm diagnosis by means of angiogra-phy and blood velocity measurementsrdquo Acta Neurochirurgicavol 100 no 1-2 pp 12ndash24 1989
[4] C Lysakowski B Walder M C Costanza and M R TramerldquoTranscranial Doppler versus angiography in patients withvasospasm due to a ruptured cerebral aneurysm a systematicreviewrdquo Stroke vol 32 no 10 pp 2292ndash2298 2001
[5] R L Grubb Jr M E Raichle J O Eichling and M HGado ldquoEffects of subarachnoid hemorrhage on cerebral bloodvolume blood flow and oxygen utilization in humansrdquo Journalof Neurosurgery vol 46 no 4 pp 446ndash452 1977
[6] C-H Lu H-W Chang C-C Lui C-R Huang and W-NChang ldquoCerebral haemodynamics in acute bacterial meningitisin adultsrdquoQuaterly Journal of Medicine vol 99 no 12 pp 863ndash869 2006
[7] F Faraci and D D Heistad ldquoRegulation of the cerebralcirculation role of endothelium and potassium channelsrdquoPhysiological Reviews vol 78 no 1 pp 53ndash97 1998
[8] L Hektoen ldquoThe vascular changes in tuberculous meningitisespecially in tuberculous endarteritisrdquo Journal of ExperimentalMedicine vol 1 pp 112ndash163 1896
[9] G Thwaites ldquoTuberculosis of the central nervous systemrdquo inClinical Tuberculosis P D O Davies S B Gordon and GDavies Eds pp 151ndash165 CRC Press 5th edition 2014
[10] P M Dalal ldquoObservations on the involvement of cerebral ves-sels in tuberculousmeningitis in adultsrdquoAdvances in Neurologyvol 25 pp 149ndash159 1979
[11] L A Rojas-Echeverri J L Soto-Hernandez S Garza et alldquoPredictive value of digital subtraction angiography in patientswith tuberculous meningitisrdquo Neuroradiology vol 38 no 1 pp20ndash24 1996
[12] E L Lyons and N E Leeds ldquoThe angiographic demonstrationof arterial vascular disease in purulent meningitis report of acaserdquo Radiology vol 88 no 5 pp 935ndash938 1967
[13] S Ries U Schminke K Fassbender M Daffertshofer WSteinke andMHennerici ldquoCerebrovascular involvement in theacute phase of bacterial meningitisrdquo Journal of Neurology vol244 no 1 pp 51ndash55 1997
[14] K Fassbender S Ries U Schminke S Schneider and M Hen-nerici ldquoInflammatory cytokines in CSF in bacterial meningitisassociation with altered blood flow velocities in basal cerebralarteriesrdquo Journal of Neurology Neurosurgery amp Psychiatry vol61 no 1 pp 57ndash61 1996
[15] L A Pfister J H Tureen S Shaw et al ldquoEndothelin inhibitionimproves cerebral blood flow and is neuroprotective in pneu-mococcal meningitisrdquoAnnals of Neurology vol 47 pp 329ndash3352000
International Journal of Inflammation 11
[16] S L Leib Y S Kim S M Black J H Tureen and M GTauber ldquoInducible nitric oxide synthase and the effect of amin-oguanidine in experimental neonatal meningitisrdquo The Journalof Infectious Diseases vol 177 no 3 pp 692ndash700 1998
[17] T W Polder C R Jerusalem andW M C Eling ldquoMorpholog-ical characteristics of intracerebral arterioles in clinical (Plas-modium falciparum) and experimental (Plasmodium berghei)cerebral malariardquo Journal of the Neurological Sciences vol 101no 1 pp 35ndash46 1991
[18] N A V Beare S P Harding T E Taylor S Lewallen and MEMolyneux ldquoPerfusion abnormalities in childrenwith cerebralmalaria andmalarial retinopathyrdquo Journal of Infectious Diseasesvol 199 no 2 pp 263ndash271 2009
[19] C R J C Newton K Marsh N Peshu and F J KirkhamldquoPerturbations of cerebral hemodynamics in Kenyans withcerebral malariardquo Pediatric Neurology vol 15 no 1 pp 41ndash491996
[20] C C John A Panoskaltsis-Mortari R O Opoka et alldquoCerebrospinal fluid cytokine levels and cognitive impairmentin cerebral malariardquo American Journal of Tropical Medicine andHygiene vol 78 no 2 pp 198ndash205 2008
[21] W McGuire A V S Hill C E M Allsopp B M Greenwoodand D Kwiatkowski ldquoVariation in the TNF-120572 promoter regionassociated with susceptibility to cerebral malariardquo Nature vol371 no 6497 pp 508ndash510 1994
[22] W McGuire J C Knight A V S Hill C E M Allsopp B MGreenwood and D Kwiatkowski ldquoSevere malarial anemia andcerebral malaria are associated with different tumor necrosisfactor promoter allelesrdquo Journal of Infectious Diseases vol 179no 1 pp 287ndash290 1999
[23] B Dugas M D Mossalayi C Damais and J-P Kolb ldquoNitricoxide production by human monocytes Evidence for a role ofCD23rdquo Immunology Today vol 16 no 12 pp 574ndash580 1995
[24] L Pellettieri B Nilsson C-A Carlsson andU Nilsson ldquoSerumimmunocomplexes in patients with subarachnoid hemorrhagerdquoNeurosurgery vol 19 no 5 pp 767ndash771 1986
[25] M Eisenhut ldquoCauses of reduced immune complex clearance incerebralmalariardquoParasite Immunology vol 31 no 2 p 59 2009
[26] P Teeranaipong J Ohashi J Patarapotikul et al ldquoA functionalsingle-nucleotide polymorphism in the CR1 promoter regioncontributes to protection against cerebral malariardquo Journal ofInfectious Diseases vol 198 no 12 pp 1880ndash1891 2008
[27] P Cabrales G M Zanini D Meays J A Frangos and LJ M Carvalho ldquoMurine cerebral malaria is associated witha vasospasm-like microcirculatory dysfunction and survivalupon rescue treatment is markedly increased by nimodipinerdquoTheAmerican Journal of Pathology vol 176 no 3 pp 1306ndash13152010
[28] I Gramaglia P Sobolewski D Meays et al ldquoLow nitricoxide bioavailability contributes to the genesis of experimentalcerebral malariardquoNature Medicine vol 12 no 12 pp 1417ndash14222006
[29] T W Yeo D A Lampah E Tjitra et al ldquoRelationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavail-ability and perfusion in severe falciparum malariardquo Journal ofInfectious Diseases vol 200 no 10 pp 1522ndash1529 2009
[30] G Dhangadamajhi B N Mohapatra S K Kar and M RanjitldquoGenetic variation in neuronal nitric oxide synthase (nNOS)gene and susceptibility to cerebral malaria in Indian adultsrdquoInfection Genetics and Evolution vol 9 no 5 pp 908ndash911 2009
[31] M R Hobbs V Udhayakumar M C Levesque et al ldquoAnew NOS2 promoter polymorphism associated with increased
nitric oxide production and protection from severe malaria inTanzanian and Kenyan childrenrdquoThe Lancet vol 360 no 9344pp 1468ndash1475 2002
[32] P Cabrales G M Zanini D Meays J A Frangos and L JM Carvalho ldquoNitric oxide protection against murine cerebralmalaria is associated with improved cerebral microcirculatoryphysiologyrdquo The Journal of Infectious Diseases vol 203 no 10pp 1454ndash1463 2011
[33] G Morahan C S Boutlis D Huang et al ldquoA promoterpolymorphism in the gene encoding interleukin-12 p40 (IL12B)is associated with mortality from cerebral malaria and withreduced nitric oxide productionrdquo Genes amp Immunity vol 3 no7 pp 414ndash418 2002
[34] C Casals-Pascual R Idro N Gicheru et al ldquoHigh levels of ery-thropoietin are associated with protection against neurologicalsequelae in African children with cerebral malariardquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 105 no 7 pp 2634ndash2639 2008
[35] F C Chow C M Marra and T A Cho ldquoCerebrovasculardisease in central nervous system infectionsrdquo Seminars inNeurology vol 31 no 3 pp 286ndash306 2011
[36] R A Armonda R S Bell A H Vo et al ldquoWartime traumaticcerebral vasospasm recent review of combat casualtiesrdquoNeuro-surgery vol 59 no 6 pp 1215ndash1225 2006
[37] K Shahlaie K Keachie I M Hutchins et al ldquoRisk factorsfor posttraumatic vasospasm clinical articlerdquo Journal of Neu-rosurgery vol 115 no 3 pp 602ndash611 2011
[38] Y Udomphorn W M Armstead and M S Vavilala ldquoCerebralblood flow and autoregulation after pediatric traumatic braininjuryrdquo Pediatric Neurology vol 38 no 4 pp 225ndash234 2008
[39] R M Pluta J Hansen-Schwartz J Dreier et al ldquoCerebralvasospasm following subarachnoid hemorrhage time for a newworld of thoughtrdquo Neurological Research vol 31 no 2 pp 151ndash158 2009
[40] J Hansen-Schwartz P Vajkoczy R L Macdonald R MPluta and J H Zhang ldquoCerebral vasospasm looking beyondvasoconstrictionrdquo Trends in Pharmacological Sciences vol 28no 6 pp 252ndash256 2007
[41] H Kasuya B K A Weir M Nakane et al ldquoNitric oxidesynthase and guanylate cyclase levels in canine basilar arteryafter subarachnoid hemorrhagerdquo Journal of Neurosurgery vol82 no 2 pp 250ndash255 1995
[42] M D Linnik and T J F Lee ldquoEffect of hemoglobin on neuro-genic responses and cholinergic parameters in porcine cerebralarteriesrdquo Journal of Cerebral Blood Flow and Metabolism vol 9no 2 pp 219ndash225 1989
[43] CG Sobey and FM Faraci ldquoSubarachnoid haemorrhage whathappens to the cerebral arteriesrdquo Clinical and ExperimentalPharmacology and Physiology vol 25 no 11 pp 867ndash876 1998
[44] Y R T Dinh G Lot R Benrabah O Baroudy J Cophignonand J Seylaz ldquoAbnormal cerebral vasodilation in aneurys-mal subarachnoid hemorrhage use of serial 133Xe cerebralblood flow measurement plus acetazolamide to assess cerebralvasospasmrdquo Journal of Neurosurgery vol 79 no 4 pp 490ndash4931993
[45] T J F Lee ldquoNitric oxide and the cerebral vascular functionrdquoJournal of Biomedical Science vol 7 no 1 pp 16ndash26 2000
[46] M Stoodley R L Macdonald B Weir et al ldquoSubarachnoidhemorrhage as a cause of an adaptive response in cerebralarteriesrdquo Journal of Neurosurgery vol 93 no 3 pp 463ndash4702000
12 International Journal of Inflammation
[47] Y R Tran Dinh A Jomaa J Callebert et al ldquoOverexpressionof cyclooxygenase-2 in rabbit basilar artery endothelial cellsafter subarachnoid hemorrhagerdquo Neurosurgery vol 48 no 3pp 626ndash635 2001
[48] A Gecse B Kis Z Mezei and G Telegdy ldquoEffects of inflam-matory neuropeptides on the arachidonate cascade of plateletsrdquoInternational Archives of Allergy and Immunology vol 118 no2ndash4 pp 166ndash170 1999
[49] K S Mark W J Trickler and D W Miller ldquoTumornecrosis factor-120572 induces cyclooxygenase-2 expression andprostaglandin release in brain microvessel endothelial cellsrdquoJournal of Pharmacology and Experimental Therapeutics vol297 no 3 pp 1051ndash1058 2001
[50] T Tanazawa Y Suzuki M Anzai S Tsugane M Takayasu andM Shibuya ldquoVasodilation by intrathecal lipopolysaccharide ofthe cerebral arteries after subarachnoid haemorrhage in dogsrdquoActa Neurochirurgica vol 138 no 3 pp 330ndash337 1996
[51] N Toda M Kawakami and K Yoshida ldquoConstrictor action ofoxyhemoglobin in monkey and dog basilar arteries in vivo andin vitrordquo American Journal of Physiology Heart and CirculatoryPhysiology vol 260 no 2 pp H420ndashH425 1991
[52] M Yoshizumi M A Perrella J C Burnett Jr and M-E LeeldquoTumor necrosis factor downregulates an endothelial nitricoxide synthase mRNA by shortening its half-liferdquo CirculationResearch vol 73 no 1 pp 205ndash209 1993
[53] A Rengasamy and R A Johns ldquoRegulation of nitric oxidesynthase by nitric oxiderdquo Molecular Pharmacology vol 44 no1 pp 124ndash128 1993
[54] A L de Souza A C P de Oliveira C C Romano J SztajnbokA J S Duarte and A C Seguro ldquoInterleukin-6 activation inischemic stroke caused by Neisseria meningitidis serogroup CrdquoInternational Journal of Cardiology vol 127 no 3 pp e160ndashe1632008
[55] T Kandabashi H Shimokawa K Miyata et al ldquoInhibition ofmyosin phosphatase by upregulated Rho-kinase plays a key rolefor coronary artery spasm in a porcine model with interleukin-1120573rdquo Circulation vol 101 no 11 pp 1319ndash1323 2000
[56] D-H Nam J-S Kim S-C Hong et al ldquoExpression ofinterleukin-1120573 in lipopolysaccharide stimulated monocytesderived from patients with aneurysmal subarachnoid hem-orrhage is correlated with cerebral vasospasmrdquo NeuroscienceLetters vol 312 no 1 pp 41ndash44 2001
[57] A Ito H Shimokawa T Kadokami et al ldquoTyrosine kinaseinhibitor suppresses coronary arteriosclerotic changes andvasospastic responses induced by chronic treatment withinterleukin-1120573 in pigs in vivordquo Journal of Clinical Investigationvol 96 no 3 pp 1288ndash1294 1995
[58] H Yanamoto H Kataoka Y Nakajo and K Iihara ldquoThe roleof the host defense system in the development of cerebralvasospasm analogies between atherosclerosis and subarach-noid hemorrhagerdquo European Neurology vol 68 no 6 pp 329ndash343 2012
[59] A F Ducruet P R Gigante Z L Hickman et al ldquoGeneticdeterminants of cerebral vasospasm delayed cerebral ischemiaand outcome after aneurysmal subarachnoid hemorrhagerdquoJournal of Cerebral Blood Flow amp Metabolism vol 30 no 4 pp676ndash688 2010
[60] J Langham C Goldfrad G Teasdale D Shaw and KRowan ldquoCalcium channel blockers for acute traumatic braininjuryrdquoCochrane Database Systematic Reviews no 4 Article IDCD000565 2000
[61] S M Dorhout Mees G J Rinkel V L Feigin et al ldquoCal-cium antagonists for aneurysmal subarachnoid haemorrhagerdquoCochrane Database of Systematic Reviews no 3 Article IDCD000277 2007
[62] R-Q Huang F-G Jiang Z-M Feng and T-Y WangldquoNicardipine in the treatment of aneurysmal subarachnoidhaemorrhage a meta-analysis of published datardquo Acta Neuro-logica Belgica vol 113 no 1 pp 3ndash6 2013
[63] S Naidu A J Payne J Moodley M Hoffmann and EGouws ldquoRandomised study assessing the effect of phenytoinand magnesium sulphate on maternal cerebral circulationin eclampsia using transcranial Doppler ultrasoundrdquo BritishJournal of Obstetrics amp Gynaecology vol 103 no 2 pp 111ndash1161996
[64] D Reddy A Fallah J-A Petropoulos F Farrokhyar R LMacdonald and D Jichici ldquoProphylactic magnesium sulphatefor aneurysmal subarachnoid haemorrhage a systematic reviewand meta-analysisrdquo Neurocritical Care vol 21 no 2 pp 356ndash364 2014
[65] C M Bradford S Finfer A OrsquoConnor et al ldquoA ran-domised controlled trial of induced hypermagnesaemia follow-ing aneurysmal subarachnoid haemorrhagerdquo Critical Care andResuscitation vol 15 no 2 pp 119ndash125 2013
[66] S-H Su W Xu J Hai Y-F Wu and F Yu ldquoEffects of statins-use for patients with aneurysmal subarachnoid hemorrhagea meta-analysis of randomized controlled trialsrdquo ScientificReports vol 4 article 4573 2014
[67] J Guo Z Shi K Yang J H Tian and L Jiang ldquoEndothelinreceptor antagonists for subarachnoid hemorrhagerdquo CochraneDatabase of Systematic Reviews vol 9 Article ID CD0083542012
[68] J Shen J-W Pan Z-X Fan X-X Xiong and R-Y ZhanldquoDissociation of vasospasm-related morbidity and outcomesin patients with aneurysmal subarachnoid hemorrhage treatedwith clazosentan a meta-analysis of randomized controlledtrials a reviewrdquo Journal of Neurosurgery vol 119 no 1 pp 180ndash189 2013
[69] P Gomis J P Graftieaux R Sercombe D Hettler BScherpereel and P Rousseaux ldquoRandomized double-blindplacebo-controlled pilot trial of high-dose methylprednisolonein aneurysmal subarachnoid hemorrhagerdquo Journal of Neuro-surgery vol 112 no 3 pp 681ndash688 2010
[70] A H Kramer and J J Fletcher ldquoLocally-administered intrathe-cal thrombolytics following aneurysmal subarachnoid hem-orrhage a systematic review and meta-analysisrdquo NeurocriticalCare vol 14 no 3 pp 489ndash499 2011
[71] G J Liu Z J Wang Y F Wang et al ldquoSystematic assessmentand meta-analysis of the efficacy and safety of fasudil in thetreatment of cerebral vasospasm in patients with subarachnoidhemorrhagerdquo European Journal of Clinical Pharmacology vol68 no 2 pp 131ndash139 2012
[72] S Zhang LWangM Liu andBWu ldquoTirilazad for aneurysmalsubarachnoid haemorrhagerdquo Cochrane Database SystematicReview vol 2 Article ID CD006778 2010
[73] M-Y Tseng P J Hutchinson H K Richards et al ldquoAcutesystemic erythropoietin therapy to reduce delayed ischemicdeficits following aneurysmal subarachnoid hemorrhage aphase II randomized double-blind placebo-controlled trialclinical articlerdquo Journal of Neurosurgery vol 111 no 1 pp 171ndash180 2009
[74] H Kasuya ldquoDevelopment of nicardipine prolonged-releaseimplants after clipping for preventing cerebral vasospasm from
International Journal of Inflammation 13
laboratory to clinical trialrdquo Acta Neurochirurgica Supplemen-tum vol 115 pp 41ndash44 2013
[75] C Thome M Seiz G A Schubert et al ldquoNicardipine pelletsfor the prevention of cerebral vasospasmrdquoActaNeurochirurgicano 110 pp 209ndash211 2011
[76] T Nassar S Akkawi A Shina et al ldquoIn vitro and in vivo effectsof tPA and PAI-1 on blood vessel tonerdquo Blood vol 103 no 3 pp897ndash902 2004
[77] T Sugawara R Ayer V Jadhav W Chen T Tsubokawaand J H Zhang ldquoMechanisms of statin treatment in cerebralvasospasmrdquo Acta Neurochirurgica no 110 pp 9ndash11 2011
[78] M D Vergouwen R J De Haan M Vermeulen and YB Roos ldquoEffect of statin treatment on vasospasm delayedcerebral ischemia and functional outcome in patients withaneurysmal subarachnoid hemorrhage a systematic review andmeta-analysis updaterdquo Stroke vol 41 no 1 pp e47ndashe52 2010
[79] G E Thwaites N D Bang N H Dung et al ldquoDexamethasonefor the treatment of tuberculous meningitis in adolescents andadultsrdquoTheNew England Journal ofMedicine vol 351 no 17 pp1741ndash1811 2004
[80] G E Thwaites J Macmullen-Price T T H Chau et al ldquoSerialMRI to determine the effect of dexamethasone on the cerebralpathology of tuberculous meningitis an observational studyrdquoThe Lancet Neurology vol 6 no 3 pp 230ndash236 2007
[81] U K Misra J Kalita and P P Nair ldquoRole of aspirin in tuber-culous meningitis a randomized open label placebo controlledtrialrdquo Journal of the Neurological Sciences vol 293 no 1-2 pp12ndash17 2010
[82] P W G Elbers and C Ince ldquoBench-to-bedside review mech-anisms of critical illnessmdashclassifying microcirculatory flowabnormalities in distributive shockrdquoCritical Care vol 10 article221 2006
[83] S Trzeciak I Cinel R P Dellinger et al ldquoResuscitating themicrocirculation in sepsis the central role of nitric oxideemerging concepts for novel therapies and challenges forclinical trialsrdquo Academic Emergency Medicine vol 15 no 5 pp399ndash415 2008
[84] Y Sakr M-J Dubois D De Backer J Creteur and J-LVincent ldquoPersistent-microcirculatory alterations are associatedwith organ failure and death in patients with septic shockrdquoCritical Care Medicine vol 32 no 9 pp 1825ndash1831 2004
[85] P E Spronk J H Rommes C Schaar andC Ince ldquoThromboly-sis in fulminant purpura observations on changes in microcir-culatory perfusion during succesful treatmentrdquoThrombosis andHaemostasis vol 95 no 3 pp 576ndash578 2006
[86] J Creteur D De Backer Y Sakr M Koch and J-L VincentldquoSublingual capnometry tracks microcirculatory changes inseptic patientsrdquo Intensive Care Medicine vol 32 no 4 pp 516ndash523 2006
[87] D De Backer J Creteur J C Preiser M J Dubois and JL Vincent ldquoMicrovascular blood flow is altered in patientswith sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 1 pp 98ndash104 2002
[88] G M Ibrahim and R L Macdonald ldquoThe effects of fluid bal-ance and colloid administration on outcomes in patients withaneurysmal subarachnoid hemorrhage a propensity score-matched analysisrdquoNeurocritical Care vol 19 no 2 pp 140ndash1492013
[89] T W Yeo D A Lampah R Gitawati et al ldquoImpaired nitricoxide bioavailability and L-arginine-reversible endothelial dys-function in adults with falciparum malariardquo The Journal ofExperimental Medicine vol 204 no 11 pp 2693ndash2704 2007
[90] A R Fathi R M Pluta K D Bakhtian M Qi and R RLonser ldquoReversal of cerebral vasospasmvia intravenous sodiumnitrite after subarachnoid hemorrhage in primates laboratoryinvestigationrdquo Journal of Neurosurgery vol 115 no 6 pp 1213ndash1220 2011
[91] D de Backer J Creteur M J Dubois et al ldquoThe effects ofdobutamine on microcirculatory alterations in patients withseptic shock are independent of its systemic effectsrdquo CriticalCare Medicine vol 34 no 2 pp 403ndash408 2006
[92] C E Chapleau R P White and J T Robertson ldquoCerebralvasospasm effects of prostaglandin synthetase inhibitors invitrordquo Neurosurgery vol 6 no 2 pp 155ndash159 1980
[93] J L Frazier G Pradilla P P Wang and R J TamargoldquoInhibition of cerebral vasospasm by intracranial delivery ofibuprofen from a controlled-release polymer in a rabbit modelof subarachnoid hemorrhagerdquo Journal of Neurosurgery vol 101no 1 pp 93ndash98 2004
[94] G Pradilla Q A Thai F G Legnani et al ldquoLocal deliveryof ibuprofen via controlled-release polymers prevents angio-graphic vasospasm in a monkey model of subarachnoid hem-orrhagerdquo Neurosurgery vol 57 no 1 pp 184ndash189 2005
[95] R P White and J T Robertson ldquoComparison of piroxicammeclofenamate ibuprofen aspirin and prostacyclin efficacy ina chronic model of cerebral vasospasmrdquo Neurosurgery vol 12no 1 pp 40ndash46 1983
[96] T Fukumori E Tani Y Maeda and A Sukenaga ldquoEffectsof prostacyclin and indomethacin on experimental delayedcerebral vasospasmrdquo Journal of Neurosurgery vol 59 no 5 pp829ndash834 1983
[97] L Brandt B Ljunggren K-E Andersson B Hindfelt and TUski ldquoProstaglandin metabolism and prostacyclin in cerebralvasospasmrdquo General Pharmacology vol 14 no 1 pp 141ndash1431983
[98] T Hakan M Zafer Berkman T Ersoy I Karatas T Sanand S Arbak ldquoAnti-inflammatory effect of meloxicam onexperimental vasospasm in the rat femoral arteryrdquo Journal ofClinical Neuroscience vol 15 no 1 pp 55ndash59 2008
[99] LG Toussaint III J A Friedman E FMWijdicks et al ldquoInflu-ence of aspirin on outcome following aneurysmal subarachnoidhemorrhagerdquo Journal of Neurosurgery vol 101 no 6 pp 921ndash925 2004
[100] B A Gross P M R Lai K U Frerichs and R Du ldquoAspirin andaneurysmal subarachnoid haemorrhagerdquo World Neurosurgery2013
[101] S Yokobori AWatanabe R Nakae et al ldquoCerebral vasospasmsafter intraventricular hemorrhage from an arteriovenousmalformationmdashcase reportrdquo Neurologia Medico-Chirurgicavol 50 no 4 pp 320ndash323 2010
[102] B S Park Y S Won S S Choi and B M Kim ldquoSeveresymptomatic vasospasm following intraventricular hemorrhagefrom arteriovenous fistulardquo Journal of Korean NeurosurgicalSociety vol 45 no 5 pp 300ndash302 2009
[103] G Pradilla T Garzon-Muvdi J J Ruzevick et al ldquoSystemicL-citrulline prevents cerebral vasospasm in haptoglobin 2-2transgenicmice after subarachnoid hemorrhagerdquoNeurosurgeryvol 70 no 3 pp 747ndash757 2012
[104] G Chen J Wu C Sun et al ldquoPotential role of JAK2 in cere-bral vasospasm after experimental subarachnoid hemorrhagerdquoBrain Research vol 1214 pp 136ndash144 2008
[105] C L Lin A L Kwan A S Dumont et al ldquoAttenuationof experimental subarachnoid hemorrhage-induced increases
14 International Journal of Inflammation
in circulating intercellular adhesion molecule-1 and cerebralvasospasm by the endothelin-converting enzyme inhibitor CGS26303rdquo Journal of Neurosurgery vol 106 no 3 pp 442ndash4482007
[106] K Iseda S Ono K Onoda et al ldquoAntivasospastic and antiin-flammatory effects of caspase inhibitor in experimental sub-arachnoid hemorrhagerdquo Journal of Neurosurgery vol 107 no 1pp 128ndash135 2007
[107] C-L Lin A S Dumont T Calisaneller A-L Kwan S-L Hwong and K S Lee ldquoMonoclonal antibody against Eselectin attenuates subarachnoid hemorrhage-induced cerebralvasospasmrdquo Surgical Neurology vol 64 no 3 pp 201ndash206 2005
[108] R Echigo N Shimohata K Karatsu et al ldquoTrehalose treat-ment suppresses inflammation oxidative stress and vasospasminduced by experimental subarachnoid hemorrhagerdquo Journal ofTranslational Medicine vol 10 no 1 article 80 2012
[109] CWakadeM D KingM D Laird C H Alleyne Jr and KMDhandapani ldquoCurcumin attenuates vascular inflammation andcerebral vasospasm after subarachnoid hemorrhage in micerdquoAntioxidants amp Redox Signaling vol 11 no 1 pp 35ndash45 2009
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Research and TreatmentAIDS
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
International Journal of Inflammation 11
[16] S L Leib Y S Kim S M Black J H Tureen and M GTauber ldquoInducible nitric oxide synthase and the effect of amin-oguanidine in experimental neonatal meningitisrdquo The Journalof Infectious Diseases vol 177 no 3 pp 692ndash700 1998
[17] T W Polder C R Jerusalem andW M C Eling ldquoMorpholog-ical characteristics of intracerebral arterioles in clinical (Plas-modium falciparum) and experimental (Plasmodium berghei)cerebral malariardquo Journal of the Neurological Sciences vol 101no 1 pp 35ndash46 1991
[18] N A V Beare S P Harding T E Taylor S Lewallen and MEMolyneux ldquoPerfusion abnormalities in childrenwith cerebralmalaria andmalarial retinopathyrdquo Journal of Infectious Diseasesvol 199 no 2 pp 263ndash271 2009
[19] C R J C Newton K Marsh N Peshu and F J KirkhamldquoPerturbations of cerebral hemodynamics in Kenyans withcerebral malariardquo Pediatric Neurology vol 15 no 1 pp 41ndash491996
[20] C C John A Panoskaltsis-Mortari R O Opoka et alldquoCerebrospinal fluid cytokine levels and cognitive impairmentin cerebral malariardquo American Journal of Tropical Medicine andHygiene vol 78 no 2 pp 198ndash205 2008
[21] W McGuire A V S Hill C E M Allsopp B M Greenwoodand D Kwiatkowski ldquoVariation in the TNF-120572 promoter regionassociated with susceptibility to cerebral malariardquo Nature vol371 no 6497 pp 508ndash510 1994
[22] W McGuire J C Knight A V S Hill C E M Allsopp B MGreenwood and D Kwiatkowski ldquoSevere malarial anemia andcerebral malaria are associated with different tumor necrosisfactor promoter allelesrdquo Journal of Infectious Diseases vol 179no 1 pp 287ndash290 1999
[23] B Dugas M D Mossalayi C Damais and J-P Kolb ldquoNitricoxide production by human monocytes Evidence for a role ofCD23rdquo Immunology Today vol 16 no 12 pp 574ndash580 1995
[24] L Pellettieri B Nilsson C-A Carlsson andU Nilsson ldquoSerumimmunocomplexes in patients with subarachnoid hemorrhagerdquoNeurosurgery vol 19 no 5 pp 767ndash771 1986
[25] M Eisenhut ldquoCauses of reduced immune complex clearance incerebralmalariardquoParasite Immunology vol 31 no 2 p 59 2009
[26] P Teeranaipong J Ohashi J Patarapotikul et al ldquoA functionalsingle-nucleotide polymorphism in the CR1 promoter regioncontributes to protection against cerebral malariardquo Journal ofInfectious Diseases vol 198 no 12 pp 1880ndash1891 2008
[27] P Cabrales G M Zanini D Meays J A Frangos and LJ M Carvalho ldquoMurine cerebral malaria is associated witha vasospasm-like microcirculatory dysfunction and survivalupon rescue treatment is markedly increased by nimodipinerdquoTheAmerican Journal of Pathology vol 176 no 3 pp 1306ndash13152010
[28] I Gramaglia P Sobolewski D Meays et al ldquoLow nitricoxide bioavailability contributes to the genesis of experimentalcerebral malariardquoNature Medicine vol 12 no 12 pp 1417ndash14222006
[29] T W Yeo D A Lampah E Tjitra et al ldquoRelationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavail-ability and perfusion in severe falciparum malariardquo Journal ofInfectious Diseases vol 200 no 10 pp 1522ndash1529 2009
[30] G Dhangadamajhi B N Mohapatra S K Kar and M RanjitldquoGenetic variation in neuronal nitric oxide synthase (nNOS)gene and susceptibility to cerebral malaria in Indian adultsrdquoInfection Genetics and Evolution vol 9 no 5 pp 908ndash911 2009
[31] M R Hobbs V Udhayakumar M C Levesque et al ldquoAnew NOS2 promoter polymorphism associated with increased
nitric oxide production and protection from severe malaria inTanzanian and Kenyan childrenrdquoThe Lancet vol 360 no 9344pp 1468ndash1475 2002
[32] P Cabrales G M Zanini D Meays J A Frangos and L JM Carvalho ldquoNitric oxide protection against murine cerebralmalaria is associated with improved cerebral microcirculatoryphysiologyrdquo The Journal of Infectious Diseases vol 203 no 10pp 1454ndash1463 2011
[33] G Morahan C S Boutlis D Huang et al ldquoA promoterpolymorphism in the gene encoding interleukin-12 p40 (IL12B)is associated with mortality from cerebral malaria and withreduced nitric oxide productionrdquo Genes amp Immunity vol 3 no7 pp 414ndash418 2002
[34] C Casals-Pascual R Idro N Gicheru et al ldquoHigh levels of ery-thropoietin are associated with protection against neurologicalsequelae in African children with cerebral malariardquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 105 no 7 pp 2634ndash2639 2008
[35] F C Chow C M Marra and T A Cho ldquoCerebrovasculardisease in central nervous system infectionsrdquo Seminars inNeurology vol 31 no 3 pp 286ndash306 2011
[36] R A Armonda R S Bell A H Vo et al ldquoWartime traumaticcerebral vasospasm recent review of combat casualtiesrdquoNeuro-surgery vol 59 no 6 pp 1215ndash1225 2006
[37] K Shahlaie K Keachie I M Hutchins et al ldquoRisk factorsfor posttraumatic vasospasm clinical articlerdquo Journal of Neu-rosurgery vol 115 no 3 pp 602ndash611 2011
[38] Y Udomphorn W M Armstead and M S Vavilala ldquoCerebralblood flow and autoregulation after pediatric traumatic braininjuryrdquo Pediatric Neurology vol 38 no 4 pp 225ndash234 2008
[39] R M Pluta J Hansen-Schwartz J Dreier et al ldquoCerebralvasospasm following subarachnoid hemorrhage time for a newworld of thoughtrdquo Neurological Research vol 31 no 2 pp 151ndash158 2009
[40] J Hansen-Schwartz P Vajkoczy R L Macdonald R MPluta and J H Zhang ldquoCerebral vasospasm looking beyondvasoconstrictionrdquo Trends in Pharmacological Sciences vol 28no 6 pp 252ndash256 2007
[41] H Kasuya B K A Weir M Nakane et al ldquoNitric oxidesynthase and guanylate cyclase levels in canine basilar arteryafter subarachnoid hemorrhagerdquo Journal of Neurosurgery vol82 no 2 pp 250ndash255 1995
[42] M D Linnik and T J F Lee ldquoEffect of hemoglobin on neuro-genic responses and cholinergic parameters in porcine cerebralarteriesrdquo Journal of Cerebral Blood Flow and Metabolism vol 9no 2 pp 219ndash225 1989
[43] CG Sobey and FM Faraci ldquoSubarachnoid haemorrhage whathappens to the cerebral arteriesrdquo Clinical and ExperimentalPharmacology and Physiology vol 25 no 11 pp 867ndash876 1998
[44] Y R T Dinh G Lot R Benrabah O Baroudy J Cophignonand J Seylaz ldquoAbnormal cerebral vasodilation in aneurys-mal subarachnoid hemorrhage use of serial 133Xe cerebralblood flow measurement plus acetazolamide to assess cerebralvasospasmrdquo Journal of Neurosurgery vol 79 no 4 pp 490ndash4931993
[45] T J F Lee ldquoNitric oxide and the cerebral vascular functionrdquoJournal of Biomedical Science vol 7 no 1 pp 16ndash26 2000
[46] M Stoodley R L Macdonald B Weir et al ldquoSubarachnoidhemorrhage as a cause of an adaptive response in cerebralarteriesrdquo Journal of Neurosurgery vol 93 no 3 pp 463ndash4702000
12 International Journal of Inflammation
[47] Y R Tran Dinh A Jomaa J Callebert et al ldquoOverexpressionof cyclooxygenase-2 in rabbit basilar artery endothelial cellsafter subarachnoid hemorrhagerdquo Neurosurgery vol 48 no 3pp 626ndash635 2001
[48] A Gecse B Kis Z Mezei and G Telegdy ldquoEffects of inflam-matory neuropeptides on the arachidonate cascade of plateletsrdquoInternational Archives of Allergy and Immunology vol 118 no2ndash4 pp 166ndash170 1999
[49] K S Mark W J Trickler and D W Miller ldquoTumornecrosis factor-120572 induces cyclooxygenase-2 expression andprostaglandin release in brain microvessel endothelial cellsrdquoJournal of Pharmacology and Experimental Therapeutics vol297 no 3 pp 1051ndash1058 2001
[50] T Tanazawa Y Suzuki M Anzai S Tsugane M Takayasu andM Shibuya ldquoVasodilation by intrathecal lipopolysaccharide ofthe cerebral arteries after subarachnoid haemorrhage in dogsrdquoActa Neurochirurgica vol 138 no 3 pp 330ndash337 1996
[51] N Toda M Kawakami and K Yoshida ldquoConstrictor action ofoxyhemoglobin in monkey and dog basilar arteries in vivo andin vitrordquo American Journal of Physiology Heart and CirculatoryPhysiology vol 260 no 2 pp H420ndashH425 1991
[52] M Yoshizumi M A Perrella J C Burnett Jr and M-E LeeldquoTumor necrosis factor downregulates an endothelial nitricoxide synthase mRNA by shortening its half-liferdquo CirculationResearch vol 73 no 1 pp 205ndash209 1993
[53] A Rengasamy and R A Johns ldquoRegulation of nitric oxidesynthase by nitric oxiderdquo Molecular Pharmacology vol 44 no1 pp 124ndash128 1993
[54] A L de Souza A C P de Oliveira C C Romano J SztajnbokA J S Duarte and A C Seguro ldquoInterleukin-6 activation inischemic stroke caused by Neisseria meningitidis serogroup CrdquoInternational Journal of Cardiology vol 127 no 3 pp e160ndashe1632008
[55] T Kandabashi H Shimokawa K Miyata et al ldquoInhibition ofmyosin phosphatase by upregulated Rho-kinase plays a key rolefor coronary artery spasm in a porcine model with interleukin-1120573rdquo Circulation vol 101 no 11 pp 1319ndash1323 2000
[56] D-H Nam J-S Kim S-C Hong et al ldquoExpression ofinterleukin-1120573 in lipopolysaccharide stimulated monocytesderived from patients with aneurysmal subarachnoid hem-orrhage is correlated with cerebral vasospasmrdquo NeuroscienceLetters vol 312 no 1 pp 41ndash44 2001
[57] A Ito H Shimokawa T Kadokami et al ldquoTyrosine kinaseinhibitor suppresses coronary arteriosclerotic changes andvasospastic responses induced by chronic treatment withinterleukin-1120573 in pigs in vivordquo Journal of Clinical Investigationvol 96 no 3 pp 1288ndash1294 1995
[58] H Yanamoto H Kataoka Y Nakajo and K Iihara ldquoThe roleof the host defense system in the development of cerebralvasospasm analogies between atherosclerosis and subarach-noid hemorrhagerdquo European Neurology vol 68 no 6 pp 329ndash343 2012
[59] A F Ducruet P R Gigante Z L Hickman et al ldquoGeneticdeterminants of cerebral vasospasm delayed cerebral ischemiaand outcome after aneurysmal subarachnoid hemorrhagerdquoJournal of Cerebral Blood Flow amp Metabolism vol 30 no 4 pp676ndash688 2010
[60] J Langham C Goldfrad G Teasdale D Shaw and KRowan ldquoCalcium channel blockers for acute traumatic braininjuryrdquoCochrane Database Systematic Reviews no 4 Article IDCD000565 2000
[61] S M Dorhout Mees G J Rinkel V L Feigin et al ldquoCal-cium antagonists for aneurysmal subarachnoid haemorrhagerdquoCochrane Database of Systematic Reviews no 3 Article IDCD000277 2007
[62] R-Q Huang F-G Jiang Z-M Feng and T-Y WangldquoNicardipine in the treatment of aneurysmal subarachnoidhaemorrhage a meta-analysis of published datardquo Acta Neuro-logica Belgica vol 113 no 1 pp 3ndash6 2013
[63] S Naidu A J Payne J Moodley M Hoffmann and EGouws ldquoRandomised study assessing the effect of phenytoinand magnesium sulphate on maternal cerebral circulationin eclampsia using transcranial Doppler ultrasoundrdquo BritishJournal of Obstetrics amp Gynaecology vol 103 no 2 pp 111ndash1161996
[64] D Reddy A Fallah J-A Petropoulos F Farrokhyar R LMacdonald and D Jichici ldquoProphylactic magnesium sulphatefor aneurysmal subarachnoid haemorrhage a systematic reviewand meta-analysisrdquo Neurocritical Care vol 21 no 2 pp 356ndash364 2014
[65] C M Bradford S Finfer A OrsquoConnor et al ldquoA ran-domised controlled trial of induced hypermagnesaemia follow-ing aneurysmal subarachnoid haemorrhagerdquo Critical Care andResuscitation vol 15 no 2 pp 119ndash125 2013
[66] S-H Su W Xu J Hai Y-F Wu and F Yu ldquoEffects of statins-use for patients with aneurysmal subarachnoid hemorrhagea meta-analysis of randomized controlled trialsrdquo ScientificReports vol 4 article 4573 2014
[67] J Guo Z Shi K Yang J H Tian and L Jiang ldquoEndothelinreceptor antagonists for subarachnoid hemorrhagerdquo CochraneDatabase of Systematic Reviews vol 9 Article ID CD0083542012
[68] J Shen J-W Pan Z-X Fan X-X Xiong and R-Y ZhanldquoDissociation of vasospasm-related morbidity and outcomesin patients with aneurysmal subarachnoid hemorrhage treatedwith clazosentan a meta-analysis of randomized controlledtrials a reviewrdquo Journal of Neurosurgery vol 119 no 1 pp 180ndash189 2013
[69] P Gomis J P Graftieaux R Sercombe D Hettler BScherpereel and P Rousseaux ldquoRandomized double-blindplacebo-controlled pilot trial of high-dose methylprednisolonein aneurysmal subarachnoid hemorrhagerdquo Journal of Neuro-surgery vol 112 no 3 pp 681ndash688 2010
[70] A H Kramer and J J Fletcher ldquoLocally-administered intrathe-cal thrombolytics following aneurysmal subarachnoid hem-orrhage a systematic review and meta-analysisrdquo NeurocriticalCare vol 14 no 3 pp 489ndash499 2011
[71] G J Liu Z J Wang Y F Wang et al ldquoSystematic assessmentand meta-analysis of the efficacy and safety of fasudil in thetreatment of cerebral vasospasm in patients with subarachnoidhemorrhagerdquo European Journal of Clinical Pharmacology vol68 no 2 pp 131ndash139 2012
[72] S Zhang LWangM Liu andBWu ldquoTirilazad for aneurysmalsubarachnoid haemorrhagerdquo Cochrane Database SystematicReview vol 2 Article ID CD006778 2010
[73] M-Y Tseng P J Hutchinson H K Richards et al ldquoAcutesystemic erythropoietin therapy to reduce delayed ischemicdeficits following aneurysmal subarachnoid hemorrhage aphase II randomized double-blind placebo-controlled trialclinical articlerdquo Journal of Neurosurgery vol 111 no 1 pp 171ndash180 2009
[74] H Kasuya ldquoDevelopment of nicardipine prolonged-releaseimplants after clipping for preventing cerebral vasospasm from
International Journal of Inflammation 13
laboratory to clinical trialrdquo Acta Neurochirurgica Supplemen-tum vol 115 pp 41ndash44 2013
[75] C Thome M Seiz G A Schubert et al ldquoNicardipine pelletsfor the prevention of cerebral vasospasmrdquoActaNeurochirurgicano 110 pp 209ndash211 2011
[76] T Nassar S Akkawi A Shina et al ldquoIn vitro and in vivo effectsof tPA and PAI-1 on blood vessel tonerdquo Blood vol 103 no 3 pp897ndash902 2004
[77] T Sugawara R Ayer V Jadhav W Chen T Tsubokawaand J H Zhang ldquoMechanisms of statin treatment in cerebralvasospasmrdquo Acta Neurochirurgica no 110 pp 9ndash11 2011
[78] M D Vergouwen R J De Haan M Vermeulen and YB Roos ldquoEffect of statin treatment on vasospasm delayedcerebral ischemia and functional outcome in patients withaneurysmal subarachnoid hemorrhage a systematic review andmeta-analysis updaterdquo Stroke vol 41 no 1 pp e47ndashe52 2010
[79] G E Thwaites N D Bang N H Dung et al ldquoDexamethasonefor the treatment of tuberculous meningitis in adolescents andadultsrdquoTheNew England Journal ofMedicine vol 351 no 17 pp1741ndash1811 2004
[80] G E Thwaites J Macmullen-Price T T H Chau et al ldquoSerialMRI to determine the effect of dexamethasone on the cerebralpathology of tuberculous meningitis an observational studyrdquoThe Lancet Neurology vol 6 no 3 pp 230ndash236 2007
[81] U K Misra J Kalita and P P Nair ldquoRole of aspirin in tuber-culous meningitis a randomized open label placebo controlledtrialrdquo Journal of the Neurological Sciences vol 293 no 1-2 pp12ndash17 2010
[82] P W G Elbers and C Ince ldquoBench-to-bedside review mech-anisms of critical illnessmdashclassifying microcirculatory flowabnormalities in distributive shockrdquoCritical Care vol 10 article221 2006
[83] S Trzeciak I Cinel R P Dellinger et al ldquoResuscitating themicrocirculation in sepsis the central role of nitric oxideemerging concepts for novel therapies and challenges forclinical trialsrdquo Academic Emergency Medicine vol 15 no 5 pp399ndash415 2008
[84] Y Sakr M-J Dubois D De Backer J Creteur and J-LVincent ldquoPersistent-microcirculatory alterations are associatedwith organ failure and death in patients with septic shockrdquoCritical Care Medicine vol 32 no 9 pp 1825ndash1831 2004
[85] P E Spronk J H Rommes C Schaar andC Ince ldquoThromboly-sis in fulminant purpura observations on changes in microcir-culatory perfusion during succesful treatmentrdquoThrombosis andHaemostasis vol 95 no 3 pp 576ndash578 2006
[86] J Creteur D De Backer Y Sakr M Koch and J-L VincentldquoSublingual capnometry tracks microcirculatory changes inseptic patientsrdquo Intensive Care Medicine vol 32 no 4 pp 516ndash523 2006
[87] D De Backer J Creteur J C Preiser M J Dubois and JL Vincent ldquoMicrovascular blood flow is altered in patientswith sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 1 pp 98ndash104 2002
[88] G M Ibrahim and R L Macdonald ldquoThe effects of fluid bal-ance and colloid administration on outcomes in patients withaneurysmal subarachnoid hemorrhage a propensity score-matched analysisrdquoNeurocritical Care vol 19 no 2 pp 140ndash1492013
[89] T W Yeo D A Lampah R Gitawati et al ldquoImpaired nitricoxide bioavailability and L-arginine-reversible endothelial dys-function in adults with falciparum malariardquo The Journal ofExperimental Medicine vol 204 no 11 pp 2693ndash2704 2007
[90] A R Fathi R M Pluta K D Bakhtian M Qi and R RLonser ldquoReversal of cerebral vasospasmvia intravenous sodiumnitrite after subarachnoid hemorrhage in primates laboratoryinvestigationrdquo Journal of Neurosurgery vol 115 no 6 pp 1213ndash1220 2011
[91] D de Backer J Creteur M J Dubois et al ldquoThe effects ofdobutamine on microcirculatory alterations in patients withseptic shock are independent of its systemic effectsrdquo CriticalCare Medicine vol 34 no 2 pp 403ndash408 2006
[92] C E Chapleau R P White and J T Robertson ldquoCerebralvasospasm effects of prostaglandin synthetase inhibitors invitrordquo Neurosurgery vol 6 no 2 pp 155ndash159 1980
[93] J L Frazier G Pradilla P P Wang and R J TamargoldquoInhibition of cerebral vasospasm by intracranial delivery ofibuprofen from a controlled-release polymer in a rabbit modelof subarachnoid hemorrhagerdquo Journal of Neurosurgery vol 101no 1 pp 93ndash98 2004
[94] G Pradilla Q A Thai F G Legnani et al ldquoLocal deliveryof ibuprofen via controlled-release polymers prevents angio-graphic vasospasm in a monkey model of subarachnoid hem-orrhagerdquo Neurosurgery vol 57 no 1 pp 184ndash189 2005
[95] R P White and J T Robertson ldquoComparison of piroxicammeclofenamate ibuprofen aspirin and prostacyclin efficacy ina chronic model of cerebral vasospasmrdquo Neurosurgery vol 12no 1 pp 40ndash46 1983
[96] T Fukumori E Tani Y Maeda and A Sukenaga ldquoEffectsof prostacyclin and indomethacin on experimental delayedcerebral vasospasmrdquo Journal of Neurosurgery vol 59 no 5 pp829ndash834 1983
[97] L Brandt B Ljunggren K-E Andersson B Hindfelt and TUski ldquoProstaglandin metabolism and prostacyclin in cerebralvasospasmrdquo General Pharmacology vol 14 no 1 pp 141ndash1431983
[98] T Hakan M Zafer Berkman T Ersoy I Karatas T Sanand S Arbak ldquoAnti-inflammatory effect of meloxicam onexperimental vasospasm in the rat femoral arteryrdquo Journal ofClinical Neuroscience vol 15 no 1 pp 55ndash59 2008
[99] LG Toussaint III J A Friedman E FMWijdicks et al ldquoInflu-ence of aspirin on outcome following aneurysmal subarachnoidhemorrhagerdquo Journal of Neurosurgery vol 101 no 6 pp 921ndash925 2004
[100] B A Gross P M R Lai K U Frerichs and R Du ldquoAspirin andaneurysmal subarachnoid haemorrhagerdquo World Neurosurgery2013
[101] S Yokobori AWatanabe R Nakae et al ldquoCerebral vasospasmsafter intraventricular hemorrhage from an arteriovenousmalformationmdashcase reportrdquo Neurologia Medico-Chirurgicavol 50 no 4 pp 320ndash323 2010
[102] B S Park Y S Won S S Choi and B M Kim ldquoSeveresymptomatic vasospasm following intraventricular hemorrhagefrom arteriovenous fistulardquo Journal of Korean NeurosurgicalSociety vol 45 no 5 pp 300ndash302 2009
[103] G Pradilla T Garzon-Muvdi J J Ruzevick et al ldquoSystemicL-citrulline prevents cerebral vasospasm in haptoglobin 2-2transgenicmice after subarachnoid hemorrhagerdquoNeurosurgeryvol 70 no 3 pp 747ndash757 2012
[104] G Chen J Wu C Sun et al ldquoPotential role of JAK2 in cere-bral vasospasm after experimental subarachnoid hemorrhagerdquoBrain Research vol 1214 pp 136ndash144 2008
[105] C L Lin A L Kwan A S Dumont et al ldquoAttenuationof experimental subarachnoid hemorrhage-induced increases
14 International Journal of Inflammation
in circulating intercellular adhesion molecule-1 and cerebralvasospasm by the endothelin-converting enzyme inhibitor CGS26303rdquo Journal of Neurosurgery vol 106 no 3 pp 442ndash4482007
[106] K Iseda S Ono K Onoda et al ldquoAntivasospastic and antiin-flammatory effects of caspase inhibitor in experimental sub-arachnoid hemorrhagerdquo Journal of Neurosurgery vol 107 no 1pp 128ndash135 2007
[107] C-L Lin A S Dumont T Calisaneller A-L Kwan S-L Hwong and K S Lee ldquoMonoclonal antibody against Eselectin attenuates subarachnoid hemorrhage-induced cerebralvasospasmrdquo Surgical Neurology vol 64 no 3 pp 201ndash206 2005
[108] R Echigo N Shimohata K Karatsu et al ldquoTrehalose treat-ment suppresses inflammation oxidative stress and vasospasminduced by experimental subarachnoid hemorrhagerdquo Journal ofTranslational Medicine vol 10 no 1 article 80 2012
[109] CWakadeM D KingM D Laird C H Alleyne Jr and KMDhandapani ldquoCurcumin attenuates vascular inflammation andcerebral vasospasm after subarachnoid hemorrhage in micerdquoAntioxidants amp Redox Signaling vol 11 no 1 pp 35ndash45 2009
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
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Diabetes ResearchJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
12 International Journal of Inflammation
[47] Y R Tran Dinh A Jomaa J Callebert et al ldquoOverexpressionof cyclooxygenase-2 in rabbit basilar artery endothelial cellsafter subarachnoid hemorrhagerdquo Neurosurgery vol 48 no 3pp 626ndash635 2001
[48] A Gecse B Kis Z Mezei and G Telegdy ldquoEffects of inflam-matory neuropeptides on the arachidonate cascade of plateletsrdquoInternational Archives of Allergy and Immunology vol 118 no2ndash4 pp 166ndash170 1999
[49] K S Mark W J Trickler and D W Miller ldquoTumornecrosis factor-120572 induces cyclooxygenase-2 expression andprostaglandin release in brain microvessel endothelial cellsrdquoJournal of Pharmacology and Experimental Therapeutics vol297 no 3 pp 1051ndash1058 2001
[50] T Tanazawa Y Suzuki M Anzai S Tsugane M Takayasu andM Shibuya ldquoVasodilation by intrathecal lipopolysaccharide ofthe cerebral arteries after subarachnoid haemorrhage in dogsrdquoActa Neurochirurgica vol 138 no 3 pp 330ndash337 1996
[51] N Toda M Kawakami and K Yoshida ldquoConstrictor action ofoxyhemoglobin in monkey and dog basilar arteries in vivo andin vitrordquo American Journal of Physiology Heart and CirculatoryPhysiology vol 260 no 2 pp H420ndashH425 1991
[52] M Yoshizumi M A Perrella J C Burnett Jr and M-E LeeldquoTumor necrosis factor downregulates an endothelial nitricoxide synthase mRNA by shortening its half-liferdquo CirculationResearch vol 73 no 1 pp 205ndash209 1993
[53] A Rengasamy and R A Johns ldquoRegulation of nitric oxidesynthase by nitric oxiderdquo Molecular Pharmacology vol 44 no1 pp 124ndash128 1993
[54] A L de Souza A C P de Oliveira C C Romano J SztajnbokA J S Duarte and A C Seguro ldquoInterleukin-6 activation inischemic stroke caused by Neisseria meningitidis serogroup CrdquoInternational Journal of Cardiology vol 127 no 3 pp e160ndashe1632008
[55] T Kandabashi H Shimokawa K Miyata et al ldquoInhibition ofmyosin phosphatase by upregulated Rho-kinase plays a key rolefor coronary artery spasm in a porcine model with interleukin-1120573rdquo Circulation vol 101 no 11 pp 1319ndash1323 2000
[56] D-H Nam J-S Kim S-C Hong et al ldquoExpression ofinterleukin-1120573 in lipopolysaccharide stimulated monocytesderived from patients with aneurysmal subarachnoid hem-orrhage is correlated with cerebral vasospasmrdquo NeuroscienceLetters vol 312 no 1 pp 41ndash44 2001
[57] A Ito H Shimokawa T Kadokami et al ldquoTyrosine kinaseinhibitor suppresses coronary arteriosclerotic changes andvasospastic responses induced by chronic treatment withinterleukin-1120573 in pigs in vivordquo Journal of Clinical Investigationvol 96 no 3 pp 1288ndash1294 1995
[58] H Yanamoto H Kataoka Y Nakajo and K Iihara ldquoThe roleof the host defense system in the development of cerebralvasospasm analogies between atherosclerosis and subarach-noid hemorrhagerdquo European Neurology vol 68 no 6 pp 329ndash343 2012
[59] A F Ducruet P R Gigante Z L Hickman et al ldquoGeneticdeterminants of cerebral vasospasm delayed cerebral ischemiaand outcome after aneurysmal subarachnoid hemorrhagerdquoJournal of Cerebral Blood Flow amp Metabolism vol 30 no 4 pp676ndash688 2010
[60] J Langham C Goldfrad G Teasdale D Shaw and KRowan ldquoCalcium channel blockers for acute traumatic braininjuryrdquoCochrane Database Systematic Reviews no 4 Article IDCD000565 2000
[61] S M Dorhout Mees G J Rinkel V L Feigin et al ldquoCal-cium antagonists for aneurysmal subarachnoid haemorrhagerdquoCochrane Database of Systematic Reviews no 3 Article IDCD000277 2007
[62] R-Q Huang F-G Jiang Z-M Feng and T-Y WangldquoNicardipine in the treatment of aneurysmal subarachnoidhaemorrhage a meta-analysis of published datardquo Acta Neuro-logica Belgica vol 113 no 1 pp 3ndash6 2013
[63] S Naidu A J Payne J Moodley M Hoffmann and EGouws ldquoRandomised study assessing the effect of phenytoinand magnesium sulphate on maternal cerebral circulationin eclampsia using transcranial Doppler ultrasoundrdquo BritishJournal of Obstetrics amp Gynaecology vol 103 no 2 pp 111ndash1161996
[64] D Reddy A Fallah J-A Petropoulos F Farrokhyar R LMacdonald and D Jichici ldquoProphylactic magnesium sulphatefor aneurysmal subarachnoid haemorrhage a systematic reviewand meta-analysisrdquo Neurocritical Care vol 21 no 2 pp 356ndash364 2014
[65] C M Bradford S Finfer A OrsquoConnor et al ldquoA ran-domised controlled trial of induced hypermagnesaemia follow-ing aneurysmal subarachnoid haemorrhagerdquo Critical Care andResuscitation vol 15 no 2 pp 119ndash125 2013
[66] S-H Su W Xu J Hai Y-F Wu and F Yu ldquoEffects of statins-use for patients with aneurysmal subarachnoid hemorrhagea meta-analysis of randomized controlled trialsrdquo ScientificReports vol 4 article 4573 2014
[67] J Guo Z Shi K Yang J H Tian and L Jiang ldquoEndothelinreceptor antagonists for subarachnoid hemorrhagerdquo CochraneDatabase of Systematic Reviews vol 9 Article ID CD0083542012
[68] J Shen J-W Pan Z-X Fan X-X Xiong and R-Y ZhanldquoDissociation of vasospasm-related morbidity and outcomesin patients with aneurysmal subarachnoid hemorrhage treatedwith clazosentan a meta-analysis of randomized controlledtrials a reviewrdquo Journal of Neurosurgery vol 119 no 1 pp 180ndash189 2013
[69] P Gomis J P Graftieaux R Sercombe D Hettler BScherpereel and P Rousseaux ldquoRandomized double-blindplacebo-controlled pilot trial of high-dose methylprednisolonein aneurysmal subarachnoid hemorrhagerdquo Journal of Neuro-surgery vol 112 no 3 pp 681ndash688 2010
[70] A H Kramer and J J Fletcher ldquoLocally-administered intrathe-cal thrombolytics following aneurysmal subarachnoid hem-orrhage a systematic review and meta-analysisrdquo NeurocriticalCare vol 14 no 3 pp 489ndash499 2011
[71] G J Liu Z J Wang Y F Wang et al ldquoSystematic assessmentand meta-analysis of the efficacy and safety of fasudil in thetreatment of cerebral vasospasm in patients with subarachnoidhemorrhagerdquo European Journal of Clinical Pharmacology vol68 no 2 pp 131ndash139 2012
[72] S Zhang LWangM Liu andBWu ldquoTirilazad for aneurysmalsubarachnoid haemorrhagerdquo Cochrane Database SystematicReview vol 2 Article ID CD006778 2010
[73] M-Y Tseng P J Hutchinson H K Richards et al ldquoAcutesystemic erythropoietin therapy to reduce delayed ischemicdeficits following aneurysmal subarachnoid hemorrhage aphase II randomized double-blind placebo-controlled trialclinical articlerdquo Journal of Neurosurgery vol 111 no 1 pp 171ndash180 2009
[74] H Kasuya ldquoDevelopment of nicardipine prolonged-releaseimplants after clipping for preventing cerebral vasospasm from
International Journal of Inflammation 13
laboratory to clinical trialrdquo Acta Neurochirurgica Supplemen-tum vol 115 pp 41ndash44 2013
[75] C Thome M Seiz G A Schubert et al ldquoNicardipine pelletsfor the prevention of cerebral vasospasmrdquoActaNeurochirurgicano 110 pp 209ndash211 2011
[76] T Nassar S Akkawi A Shina et al ldquoIn vitro and in vivo effectsof tPA and PAI-1 on blood vessel tonerdquo Blood vol 103 no 3 pp897ndash902 2004
[77] T Sugawara R Ayer V Jadhav W Chen T Tsubokawaand J H Zhang ldquoMechanisms of statin treatment in cerebralvasospasmrdquo Acta Neurochirurgica no 110 pp 9ndash11 2011
[78] M D Vergouwen R J De Haan M Vermeulen and YB Roos ldquoEffect of statin treatment on vasospasm delayedcerebral ischemia and functional outcome in patients withaneurysmal subarachnoid hemorrhage a systematic review andmeta-analysis updaterdquo Stroke vol 41 no 1 pp e47ndashe52 2010
[79] G E Thwaites N D Bang N H Dung et al ldquoDexamethasonefor the treatment of tuberculous meningitis in adolescents andadultsrdquoTheNew England Journal ofMedicine vol 351 no 17 pp1741ndash1811 2004
[80] G E Thwaites J Macmullen-Price T T H Chau et al ldquoSerialMRI to determine the effect of dexamethasone on the cerebralpathology of tuberculous meningitis an observational studyrdquoThe Lancet Neurology vol 6 no 3 pp 230ndash236 2007
[81] U K Misra J Kalita and P P Nair ldquoRole of aspirin in tuber-culous meningitis a randomized open label placebo controlledtrialrdquo Journal of the Neurological Sciences vol 293 no 1-2 pp12ndash17 2010
[82] P W G Elbers and C Ince ldquoBench-to-bedside review mech-anisms of critical illnessmdashclassifying microcirculatory flowabnormalities in distributive shockrdquoCritical Care vol 10 article221 2006
[83] S Trzeciak I Cinel R P Dellinger et al ldquoResuscitating themicrocirculation in sepsis the central role of nitric oxideemerging concepts for novel therapies and challenges forclinical trialsrdquo Academic Emergency Medicine vol 15 no 5 pp399ndash415 2008
[84] Y Sakr M-J Dubois D De Backer J Creteur and J-LVincent ldquoPersistent-microcirculatory alterations are associatedwith organ failure and death in patients with septic shockrdquoCritical Care Medicine vol 32 no 9 pp 1825ndash1831 2004
[85] P E Spronk J H Rommes C Schaar andC Ince ldquoThromboly-sis in fulminant purpura observations on changes in microcir-culatory perfusion during succesful treatmentrdquoThrombosis andHaemostasis vol 95 no 3 pp 576ndash578 2006
[86] J Creteur D De Backer Y Sakr M Koch and J-L VincentldquoSublingual capnometry tracks microcirculatory changes inseptic patientsrdquo Intensive Care Medicine vol 32 no 4 pp 516ndash523 2006
[87] D De Backer J Creteur J C Preiser M J Dubois and JL Vincent ldquoMicrovascular blood flow is altered in patientswith sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 1 pp 98ndash104 2002
[88] G M Ibrahim and R L Macdonald ldquoThe effects of fluid bal-ance and colloid administration on outcomes in patients withaneurysmal subarachnoid hemorrhage a propensity score-matched analysisrdquoNeurocritical Care vol 19 no 2 pp 140ndash1492013
[89] T W Yeo D A Lampah R Gitawati et al ldquoImpaired nitricoxide bioavailability and L-arginine-reversible endothelial dys-function in adults with falciparum malariardquo The Journal ofExperimental Medicine vol 204 no 11 pp 2693ndash2704 2007
[90] A R Fathi R M Pluta K D Bakhtian M Qi and R RLonser ldquoReversal of cerebral vasospasmvia intravenous sodiumnitrite after subarachnoid hemorrhage in primates laboratoryinvestigationrdquo Journal of Neurosurgery vol 115 no 6 pp 1213ndash1220 2011
[91] D de Backer J Creteur M J Dubois et al ldquoThe effects ofdobutamine on microcirculatory alterations in patients withseptic shock are independent of its systemic effectsrdquo CriticalCare Medicine vol 34 no 2 pp 403ndash408 2006
[92] C E Chapleau R P White and J T Robertson ldquoCerebralvasospasm effects of prostaglandin synthetase inhibitors invitrordquo Neurosurgery vol 6 no 2 pp 155ndash159 1980
[93] J L Frazier G Pradilla P P Wang and R J TamargoldquoInhibition of cerebral vasospasm by intracranial delivery ofibuprofen from a controlled-release polymer in a rabbit modelof subarachnoid hemorrhagerdquo Journal of Neurosurgery vol 101no 1 pp 93ndash98 2004
[94] G Pradilla Q A Thai F G Legnani et al ldquoLocal deliveryof ibuprofen via controlled-release polymers prevents angio-graphic vasospasm in a monkey model of subarachnoid hem-orrhagerdquo Neurosurgery vol 57 no 1 pp 184ndash189 2005
[95] R P White and J T Robertson ldquoComparison of piroxicammeclofenamate ibuprofen aspirin and prostacyclin efficacy ina chronic model of cerebral vasospasmrdquo Neurosurgery vol 12no 1 pp 40ndash46 1983
[96] T Fukumori E Tani Y Maeda and A Sukenaga ldquoEffectsof prostacyclin and indomethacin on experimental delayedcerebral vasospasmrdquo Journal of Neurosurgery vol 59 no 5 pp829ndash834 1983
[97] L Brandt B Ljunggren K-E Andersson B Hindfelt and TUski ldquoProstaglandin metabolism and prostacyclin in cerebralvasospasmrdquo General Pharmacology vol 14 no 1 pp 141ndash1431983
[98] T Hakan M Zafer Berkman T Ersoy I Karatas T Sanand S Arbak ldquoAnti-inflammatory effect of meloxicam onexperimental vasospasm in the rat femoral arteryrdquo Journal ofClinical Neuroscience vol 15 no 1 pp 55ndash59 2008
[99] LG Toussaint III J A Friedman E FMWijdicks et al ldquoInflu-ence of aspirin on outcome following aneurysmal subarachnoidhemorrhagerdquo Journal of Neurosurgery vol 101 no 6 pp 921ndash925 2004
[100] B A Gross P M R Lai K U Frerichs and R Du ldquoAspirin andaneurysmal subarachnoid haemorrhagerdquo World Neurosurgery2013
[101] S Yokobori AWatanabe R Nakae et al ldquoCerebral vasospasmsafter intraventricular hemorrhage from an arteriovenousmalformationmdashcase reportrdquo Neurologia Medico-Chirurgicavol 50 no 4 pp 320ndash323 2010
[102] B S Park Y S Won S S Choi and B M Kim ldquoSeveresymptomatic vasospasm following intraventricular hemorrhagefrom arteriovenous fistulardquo Journal of Korean NeurosurgicalSociety vol 45 no 5 pp 300ndash302 2009
[103] G Pradilla T Garzon-Muvdi J J Ruzevick et al ldquoSystemicL-citrulline prevents cerebral vasospasm in haptoglobin 2-2transgenicmice after subarachnoid hemorrhagerdquoNeurosurgeryvol 70 no 3 pp 747ndash757 2012
[104] G Chen J Wu C Sun et al ldquoPotential role of JAK2 in cere-bral vasospasm after experimental subarachnoid hemorrhagerdquoBrain Research vol 1214 pp 136ndash144 2008
[105] C L Lin A L Kwan A S Dumont et al ldquoAttenuationof experimental subarachnoid hemorrhage-induced increases
14 International Journal of Inflammation
in circulating intercellular adhesion molecule-1 and cerebralvasospasm by the endothelin-converting enzyme inhibitor CGS26303rdquo Journal of Neurosurgery vol 106 no 3 pp 442ndash4482007
[106] K Iseda S Ono K Onoda et al ldquoAntivasospastic and antiin-flammatory effects of caspase inhibitor in experimental sub-arachnoid hemorrhagerdquo Journal of Neurosurgery vol 107 no 1pp 128ndash135 2007
[107] C-L Lin A S Dumont T Calisaneller A-L Kwan S-L Hwong and K S Lee ldquoMonoclonal antibody against Eselectin attenuates subarachnoid hemorrhage-induced cerebralvasospasmrdquo Surgical Neurology vol 64 no 3 pp 201ndash206 2005
[108] R Echigo N Shimohata K Karatsu et al ldquoTrehalose treat-ment suppresses inflammation oxidative stress and vasospasminduced by experimental subarachnoid hemorrhagerdquo Journal ofTranslational Medicine vol 10 no 1 article 80 2012
[109] CWakadeM D KingM D Laird C H Alleyne Jr and KMDhandapani ldquoCurcumin attenuates vascular inflammation andcerebral vasospasm after subarachnoid hemorrhage in micerdquoAntioxidants amp Redox Signaling vol 11 no 1 pp 35ndash45 2009
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
International Journal of Inflammation 13
laboratory to clinical trialrdquo Acta Neurochirurgica Supplemen-tum vol 115 pp 41ndash44 2013
[75] C Thome M Seiz G A Schubert et al ldquoNicardipine pelletsfor the prevention of cerebral vasospasmrdquoActaNeurochirurgicano 110 pp 209ndash211 2011
[76] T Nassar S Akkawi A Shina et al ldquoIn vitro and in vivo effectsof tPA and PAI-1 on blood vessel tonerdquo Blood vol 103 no 3 pp897ndash902 2004
[77] T Sugawara R Ayer V Jadhav W Chen T Tsubokawaand J H Zhang ldquoMechanisms of statin treatment in cerebralvasospasmrdquo Acta Neurochirurgica no 110 pp 9ndash11 2011
[78] M D Vergouwen R J De Haan M Vermeulen and YB Roos ldquoEffect of statin treatment on vasospasm delayedcerebral ischemia and functional outcome in patients withaneurysmal subarachnoid hemorrhage a systematic review andmeta-analysis updaterdquo Stroke vol 41 no 1 pp e47ndashe52 2010
[79] G E Thwaites N D Bang N H Dung et al ldquoDexamethasonefor the treatment of tuberculous meningitis in adolescents andadultsrdquoTheNew England Journal ofMedicine vol 351 no 17 pp1741ndash1811 2004
[80] G E Thwaites J Macmullen-Price T T H Chau et al ldquoSerialMRI to determine the effect of dexamethasone on the cerebralpathology of tuberculous meningitis an observational studyrdquoThe Lancet Neurology vol 6 no 3 pp 230ndash236 2007
[81] U K Misra J Kalita and P P Nair ldquoRole of aspirin in tuber-culous meningitis a randomized open label placebo controlledtrialrdquo Journal of the Neurological Sciences vol 293 no 1-2 pp12ndash17 2010
[82] P W G Elbers and C Ince ldquoBench-to-bedside review mech-anisms of critical illnessmdashclassifying microcirculatory flowabnormalities in distributive shockrdquoCritical Care vol 10 article221 2006
[83] S Trzeciak I Cinel R P Dellinger et al ldquoResuscitating themicrocirculation in sepsis the central role of nitric oxideemerging concepts for novel therapies and challenges forclinical trialsrdquo Academic Emergency Medicine vol 15 no 5 pp399ndash415 2008
[84] Y Sakr M-J Dubois D De Backer J Creteur and J-LVincent ldquoPersistent-microcirculatory alterations are associatedwith organ failure and death in patients with septic shockrdquoCritical Care Medicine vol 32 no 9 pp 1825ndash1831 2004
[85] P E Spronk J H Rommes C Schaar andC Ince ldquoThromboly-sis in fulminant purpura observations on changes in microcir-culatory perfusion during succesful treatmentrdquoThrombosis andHaemostasis vol 95 no 3 pp 576ndash578 2006
[86] J Creteur D De Backer Y Sakr M Koch and J-L VincentldquoSublingual capnometry tracks microcirculatory changes inseptic patientsrdquo Intensive Care Medicine vol 32 no 4 pp 516ndash523 2006
[87] D De Backer J Creteur J C Preiser M J Dubois and JL Vincent ldquoMicrovascular blood flow is altered in patientswith sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 1 pp 98ndash104 2002
[88] G M Ibrahim and R L Macdonald ldquoThe effects of fluid bal-ance and colloid administration on outcomes in patients withaneurysmal subarachnoid hemorrhage a propensity score-matched analysisrdquoNeurocritical Care vol 19 no 2 pp 140ndash1492013
[89] T W Yeo D A Lampah R Gitawati et al ldquoImpaired nitricoxide bioavailability and L-arginine-reversible endothelial dys-function in adults with falciparum malariardquo The Journal ofExperimental Medicine vol 204 no 11 pp 2693ndash2704 2007
[90] A R Fathi R M Pluta K D Bakhtian M Qi and R RLonser ldquoReversal of cerebral vasospasmvia intravenous sodiumnitrite after subarachnoid hemorrhage in primates laboratoryinvestigationrdquo Journal of Neurosurgery vol 115 no 6 pp 1213ndash1220 2011
[91] D de Backer J Creteur M J Dubois et al ldquoThe effects ofdobutamine on microcirculatory alterations in patients withseptic shock are independent of its systemic effectsrdquo CriticalCare Medicine vol 34 no 2 pp 403ndash408 2006
[92] C E Chapleau R P White and J T Robertson ldquoCerebralvasospasm effects of prostaglandin synthetase inhibitors invitrordquo Neurosurgery vol 6 no 2 pp 155ndash159 1980
[93] J L Frazier G Pradilla P P Wang and R J TamargoldquoInhibition of cerebral vasospasm by intracranial delivery ofibuprofen from a controlled-release polymer in a rabbit modelof subarachnoid hemorrhagerdquo Journal of Neurosurgery vol 101no 1 pp 93ndash98 2004
[94] G Pradilla Q A Thai F G Legnani et al ldquoLocal deliveryof ibuprofen via controlled-release polymers prevents angio-graphic vasospasm in a monkey model of subarachnoid hem-orrhagerdquo Neurosurgery vol 57 no 1 pp 184ndash189 2005
[95] R P White and J T Robertson ldquoComparison of piroxicammeclofenamate ibuprofen aspirin and prostacyclin efficacy ina chronic model of cerebral vasospasmrdquo Neurosurgery vol 12no 1 pp 40ndash46 1983
[96] T Fukumori E Tani Y Maeda and A Sukenaga ldquoEffectsof prostacyclin and indomethacin on experimental delayedcerebral vasospasmrdquo Journal of Neurosurgery vol 59 no 5 pp829ndash834 1983
[97] L Brandt B Ljunggren K-E Andersson B Hindfelt and TUski ldquoProstaglandin metabolism and prostacyclin in cerebralvasospasmrdquo General Pharmacology vol 14 no 1 pp 141ndash1431983
[98] T Hakan M Zafer Berkman T Ersoy I Karatas T Sanand S Arbak ldquoAnti-inflammatory effect of meloxicam onexperimental vasospasm in the rat femoral arteryrdquo Journal ofClinical Neuroscience vol 15 no 1 pp 55ndash59 2008
[99] LG Toussaint III J A Friedman E FMWijdicks et al ldquoInflu-ence of aspirin on outcome following aneurysmal subarachnoidhemorrhagerdquo Journal of Neurosurgery vol 101 no 6 pp 921ndash925 2004
[100] B A Gross P M R Lai K U Frerichs and R Du ldquoAspirin andaneurysmal subarachnoid haemorrhagerdquo World Neurosurgery2013
[101] S Yokobori AWatanabe R Nakae et al ldquoCerebral vasospasmsafter intraventricular hemorrhage from an arteriovenousmalformationmdashcase reportrdquo Neurologia Medico-Chirurgicavol 50 no 4 pp 320ndash323 2010
[102] B S Park Y S Won S S Choi and B M Kim ldquoSeveresymptomatic vasospasm following intraventricular hemorrhagefrom arteriovenous fistulardquo Journal of Korean NeurosurgicalSociety vol 45 no 5 pp 300ndash302 2009
[103] G Pradilla T Garzon-Muvdi J J Ruzevick et al ldquoSystemicL-citrulline prevents cerebral vasospasm in haptoglobin 2-2transgenicmice after subarachnoid hemorrhagerdquoNeurosurgeryvol 70 no 3 pp 747ndash757 2012
[104] G Chen J Wu C Sun et al ldquoPotential role of JAK2 in cere-bral vasospasm after experimental subarachnoid hemorrhagerdquoBrain Research vol 1214 pp 136ndash144 2008
[105] C L Lin A L Kwan A S Dumont et al ldquoAttenuationof experimental subarachnoid hemorrhage-induced increases
14 International Journal of Inflammation
in circulating intercellular adhesion molecule-1 and cerebralvasospasm by the endothelin-converting enzyme inhibitor CGS26303rdquo Journal of Neurosurgery vol 106 no 3 pp 442ndash4482007
[106] K Iseda S Ono K Onoda et al ldquoAntivasospastic and antiin-flammatory effects of caspase inhibitor in experimental sub-arachnoid hemorrhagerdquo Journal of Neurosurgery vol 107 no 1pp 128ndash135 2007
[107] C-L Lin A S Dumont T Calisaneller A-L Kwan S-L Hwong and K S Lee ldquoMonoclonal antibody against Eselectin attenuates subarachnoid hemorrhage-induced cerebralvasospasmrdquo Surgical Neurology vol 64 no 3 pp 201ndash206 2005
[108] R Echigo N Shimohata K Karatsu et al ldquoTrehalose treat-ment suppresses inflammation oxidative stress and vasospasminduced by experimental subarachnoid hemorrhagerdquo Journal ofTranslational Medicine vol 10 no 1 article 80 2012
[109] CWakadeM D KingM D Laird C H Alleyne Jr and KMDhandapani ldquoCurcumin attenuates vascular inflammation andcerebral vasospasm after subarachnoid hemorrhage in micerdquoAntioxidants amp Redox Signaling vol 11 no 1 pp 35ndash45 2009
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
14 International Journal of Inflammation
in circulating intercellular adhesion molecule-1 and cerebralvasospasm by the endothelin-converting enzyme inhibitor CGS26303rdquo Journal of Neurosurgery vol 106 no 3 pp 442ndash4482007
[106] K Iseda S Ono K Onoda et al ldquoAntivasospastic and antiin-flammatory effects of caspase inhibitor in experimental sub-arachnoid hemorrhagerdquo Journal of Neurosurgery vol 107 no 1pp 128ndash135 2007
[107] C-L Lin A S Dumont T Calisaneller A-L Kwan S-L Hwong and K S Lee ldquoMonoclonal antibody against Eselectin attenuates subarachnoid hemorrhage-induced cerebralvasospasmrdquo Surgical Neurology vol 64 no 3 pp 201ndash206 2005
[108] R Echigo N Shimohata K Karatsu et al ldquoTrehalose treat-ment suppresses inflammation oxidative stress and vasospasminduced by experimental subarachnoid hemorrhagerdquo Journal ofTranslational Medicine vol 10 no 1 article 80 2012
[109] CWakadeM D KingM D Laird C H Alleyne Jr and KMDhandapani ldquoCurcumin attenuates vascular inflammation andcerebral vasospasm after subarachnoid hemorrhage in micerdquoAntioxidants amp Redox Signaling vol 11 no 1 pp 35ndash45 2009
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom