Pathophysiology and the Monitoring Methods for Cardiac Arrest Associated Brain Injury

18 Pages·2017·1.18 MB·English

International Journal o f
Molecular Sciences
Review
Pathophysiology and the Monitoring Methods for
Cardiac Arrest Associated Brain Injury
CesarReis1,†,OnatAkyol1,†,CamilaAraujo1,†,LeiHuang1,2,BudbazarEnkhjargal1,
JayMalaguit1,VadimGospodarev1andJohnH.Zhang1,2,3,*
1 DepartmentofPhysiologyandPharmacology,LomaLindaUniversitySchoolofMedicine,
11041CampusStreet,RisleyHall,Room219,LomaLinda,CA92354,USA;[email protected](C.R.);
[email protected](O.A.);[email protected](C.A.);[email protected](L.H.);
[email protected](B.E.);[email protected](J.M.);[email protected](V.G.)
2 DepartmentofAnesthesiology,LomaLindaUniversityMedicalCenter,LomaLinda,CA92354,USA
3 DepartmentofNeurosurgery,LomaLindaUniversitySchoolofMedicine,LomaLinda,CA92354,USA
* Correspondence:[email protected];Tel.:[phone]
† Theseauthorscontributedequallytothiswork.
AcademicEditor:XiaofengJia
Received:1October2016;Accepted:4January2017;Published:11January2017
Abstract: Cardiac arrest (CA) is a well-known cause of global brain ischemia. After CA and
subsequentlossofconsciousness, oxygentensionstartstodeclineandleadstoaseriesofcellular
changesthatwillleadtocellulardeath,ifnotreversedimmediately,withbrainedemaasaresult.
Theelectroencephalographicactivitystartstochangeaswell.Althoughincreasedintracranialpressure
(ICP)isnotadirectresultofcardiacarrest,itcanstilloccurduetohypoxic-ischemicencephalopathy
induced changes in brain tissue, and is a measure of brain edema after CA and ischemic brain
injury. Inthisreview,wewilldiscussthepathophysiologyofbrainedemaafterCA,someavailable
techniques,andmethodstomonitorbrainoxygen,electroencephalography(EEG),ICP(intracranial
pressure),andmicrodialysisonitsmeasurementofcerebralmetabolismanditsusefulnessbothin
clinicalpracticeandpossiblebasicscienceresearchindevelopment. Withthisreview,wehopeto
gainknowledgeofthemorepersonalizedinformationaboutpatientstatusandspecificsoftheirbrain
injury,andthusfacilitatingthephysicians’decisionmakingintermsofwhichtreatmentstopursue.
Keywords: ICP monitoring; cerebral autoregulation; Electrophysiologic monitoring; brain injury
aftercardiacarrest; brainoxygenmonitoring; microdialysis; metabolictracingandcardiacarrest
braininjury;intracranialpressure
1. Introduction
Cardiacarrest(CA)hasayearlyincidenceofapproximately50–110per100,000peopleworldwide[1]
andhasbecomealeadingcauseofcomaandadmissiontotheintensivecareunit(ICU).Progressin
advancedlifesupport,accesstoemergentcoronaryangiography,andsupportforcerebralperfusion
havecontributedtoanincreaseinCAsurvival[2]. DuetotheseverityofbraindysfunctionafterCA
fromglobalischemia-reperfusioninjury,thereisaneedtounderstandtheprognosisofpatientsinthe
ICUandtheirchancesofsurvival. Caregiverswanttoascertainapatient’schanceofsurvivalandhow
serioustheirconditionis[3]. Thus,integrationoftracingmethodssuchaselectroencephalography
(EEG), Intracranial pressure monitoring (ICP), brain oxygen monitoring, and microdialysis may
providevaluableinformationregardingbraindysfunctionafterCA.Inthisreview,wewillprovidean
updatedcriticaloverviewoftheavailabletracingmethodsforbraininjuryafterCAinadults.
Explosive growth of technology and information has occurred over the years and clinicians
approach their daily practice differently compared to previous generations of medical practice.
Int.J.Mol.Sci.2017,18,129;doi:10.3390/ijms18010129 www.mdpi.com/journal/ijms
Int.J.Mol.Sci.2017,18,129 2of18
Areasonableexplanationtakesintoconsiderationthefactthatadvancesinpre-mortemnon-invasive
diagnostic methods are available for doctors, with less need to perform pre-mortem biopsies.
Advances in imaging, clinical laboratory studies, and surgical and nonsurgical tissue sampling
techniquesoverthepastseveraldecadesprovidethetoolsneededtobetterdiagnoseanddetectpre
mortempathologies,thusyieldingagreaternumberofantemortemdiagnosesandshiftingphysicians’
attitudeawayfromneedingtoperformadetailedautopsytoacquireinformation[4]. Inaddition,
doctorsarenotgettingtrainedinautopsiessincetheAccreditationCouncilforMedicalEducation
(ACGME)programhaseliminatedtheautopsyrequirementinresidencyeducation[5]. Nonetheless,
some data support the continued value of autopsy in spite of medical diagnostic advancements
becausetheyservetoincreasetheaccuracyofdeathcertificates,enhanceidentificationofemergingor
reemergingpathogens/disease,andprovideaneducationalformatforclinicians,pathologists,and
students[5].Anotherchallengeisthelargeheterogeneityinthepopulationsofhumansendingupwith
cardiacarrest,whichmakeschoosingarepresentativeexperimentalmodelofcardiacarrestdifficult.
Results are profoundlyheterogeneous, since there isan arrayof comorbidities. Thereis a needto
improve experimental models since animal models are designed mainly to serve a monothematic
purpose. Thiscouldbedonebycombiningcommoncomorbiditiessuchasdiabetesmellitus,obesity,
andhypertensioninanexperimentalanimalmodeltobetterrepresenttheheterogeneityofthehuman
populationexperiencingcardiacarrest[6].
ThePubMedsearchforthisreviewfocusedonoriginalarticles,reviewpapersandclinicaltrials
publishedinpeer-reviewedjournals;however,thereareseveralchallengesinidentifyingtheexact
intracranial events after cardiac arrest. Major problems regarding this issue include inadequate
pre-mortemtissuesampling,difficultiesinbraintissueacquisitionandanalysisaftercardiacarrest,
challenges in establishing a representative invivo experimental model that directly projects and
describeseithermolecularorgrosseventsfollowingcardiacarrest,andtheexistenceofpopulation
heterogeneityinpostcardiacarrestclinicalresearch. Inordertominimizeandexcludetheseeffectsin
thisreview,weprimarilyfocusedonstroke-modelslikeglobalhypoxia-ischemiaandoxygendeprived
celllinestudies. Inthisreview,wealsoinvolvedandcitedtheclinicaltrialswhosetargetedpopulation
hasadiagnosisofcardiacarrestwithvariousetiologies.
2. Methods
Forthisreview,multiplesearcheswereconductedinordertofindtheappropriatearticlesforeach
subsection. InthesectionentitledPathophysiology,aPubMedBooleansearchwasperformedusing
“cardiacarrestandpathophysiologyandbrain”,1820articleswerefound. AnotherBooleansearch
wasperformedusing“globalbrainischemiaandpathophysiology”, and1852articleswerefound.
Forty-threesourceswereused. InthesectionentitledElectrophysiologicMonitoringofBrainInjury
after Cardiac Arrest, PubMed search criteria included “EEG and cardiac arrest”. These keywords
wereusedtofindreviewpapersandoriginalarticlesinlasttenyearsand437articleswerefound,
and19paperswereselected. InthesectionentitledIntracranialPressureMonitoringandCerebral
Autoregulation,PubMedresearchdatabasewassearchedusingthefollowingkeywords: “Cerebral
edemaandcardiacarrest”andfound382results. Reviewpaperswereavoided,andthisnarrowed
downthesearchto3papersofinterestbasedoncriteriaofclinicalstudyanduseofexperimental
animalmodels. “Intracranialpressuremonitoring”searchfound4872results. Reviewpaperswere
avoided, andthisnarroweddownthesearchto10papersbasedoncriteriaofclinicalstudiesand
experimentalanimalmodels. “Cerebralautoregulationandcardiacarrest”searchfound210results.
Reviewpaperswereavoided,andthisnarroweddownthesearchtoonepaperbasedoncriteriaof
clinicalstudy. Thetotalnumberofcitationsusedfor“IntracranialPressureMonitoringandCerebral
Autoregulation” was 14. In the section entitled Brain Oxygen Monitoring, several searches were
performed. Asearchusingkeywords“Near-infraredspectroscopyandCerebralOximetry”yielded
700results,and4wereselected. Asearchusingkeywords“Cerebralischemiaandoximetry”found
340articles,and3wereselected. Asearchusingkeywords“meanarterialpressureandcardiacarrest”
Int.J.Mol.Sci.2017,18,129 3of18
found 1478 articles, and 2 were selected. Lastly, a search using keywords “cerebral oximetry and
cardiacarrest”yielded121resultsand6wereselected. Categoriesforinclusionincludedclinically
relevantandtranslatable,includinganimalstudies,monitoringmethodsalreadybeingimplemented
intheclinicalsetting,measuredorwasinvolvedincontinuousmeasurementofbraintissueoxygen
content/saturation, and more recent publications took priority. In the section entitled Metabolic
ImagingModalitiesforCardiacArrestBrainInjury, PubMedsearchusedthefollowingkeywords,
“metabolicimagingandcardiacarrestandbrain”and44searchresultswerefound.Anadditionalsetof
keywordsincluded“molecularimagingandcardiacarrestandbrain”and16searchresultswerefound.
Totalnumberofcitationsusedforthissectionwas6. InthesectionentitledMicrodialysis,aPubMed
Booleansearchwasconductedusingthekeywords“Microdialysisandcardiacarrest”. Eighty-five
articles were found. Excluding papers except for those published in last five years left 70 articles.
Inclusioncriteriaalsoincludedusingreviewsforbackgroundinformationandthenfocusingonclinical
trials. Fourteenpaperswereutilizedinthissection.
3. Pathophysiology
The brain is extremely susceptible to global cerebral ischemia associated with cardiac arrest.
Hosmann and colleagues, working with monkeys, found that consciousness was lost within 10 s
after the onset of circulatory arrest and EEG activity becomes isoelectric within 20 s [7]. There was
arapidlydecliningcerebraltissueoxygentensionto0inabout2mininapigmodelofcardiacarrest[8].
Whenundergoingcompletedglobalcerebralischemia,energysubstratesadenosinetriphosphate(ATP)in
caninebraintissuesdepletedrapidlyto25%–30%ofbaselinelevelwithinthefirst4min(Figure1)[9,10].
Once the storage of ATP is completely consumed, the dysfunction of cell membrane ion pumps
and the disruption of cellular ionic homoeostasis occur (Figure 1). The interstitial K+ concentration
rapidly increases, membrane depolarization and a large influx of Na+, Cl− and water into cells,
constitutingcytotoxicedema[11,12].Thecalciumeffluxpumpsfailandvoltage-gatedcalciumchannels
open, contributing to a massive cytosol Ca2+ accumulation followed by the release of intracellular
excitatoryaminoacidssuchasglutamateandaspiratebypresynapticterminals[13]. Whenactivatedby
glutamate,N-methyl-D-aspartate(NMDA)receptorsactivateCa2+ionchannelsandfurtherincrease
Ca2+ conductanceintotheintracellularspace;αamino-3-hydroxy-5-methyl-4-isoxasolepropionicacid
(AMPA)receptorsactivateNa+ionchannelsallowingsodiuminflux.Asacriticalfactor,elevatedlevels
ofintracellularCa2+exertcytotoxiceffectsatmultiplelevels,leadingtothemitochondrialdysfunction
and free radical production [14], lipolysis and production of free fatty acids (FFAs) associated
with phospholipases (PLA2) activation [15]. Mitochondrial Ca2+ overload cause the induction of
inner mitochondrial membrane permeability transition (MPT), which then leads to disruption of
mitochondrialmembraneintegrity,irreversibleoxidativedamage,andthelossofATPproduction,
finallyresultingincelldeath(Figure1)[16,17]. Ifreperfusionstarts,itenhancestheproductionof
alargeamountofreactiveoxygenspecies(ROS)originatingprimarilyfrommitochondrialcomplexesI
andIIIoftheelectrontransportchain,intheformsofasuperoxideanion(O −),H O ,andhydroxyl
2 2 2
radical(OH−)[18]. Itoverwhelmstheendogenousmitochondrialandcytoplasmicscavengingsystems
causingoxidativedamagetothemitochondriaandconsequentlythecell[19]. Otherhighlyreactive
freeradicals,namelyreactivenitrogenspecies(RNS)areproducedbyproteinnitrosylationdueto
thereactionofnitricoxide(NO)andsuperoxideanions,whichcanalsoleadtothedysregulationof
cellularhomeostasis. ThemajortargetsofROS/RNSarelipids,andtheperoxidativeactionofROS
promotestheinactivationofkeymetabolicenzymesthatregulateglucosemetabolism. ROS/RNScan
alsocausecellulardamageanddeathincerebralischemiaandreperfusionindirectlybyactivating
avarietyofsignalingpathways[20,21].
Theinitialcellswelling(cytotoxicedema)isatranslocationofinterstitialwaterintointracellular
compartmentfollowingthedisturbanceofionichemostasis(Figure1); onlyafterthebeginningof
reperfusionanetaccumulationofbrainwaterinterstitiallyoccursfollowingincreasedmicrovascular
permeability[22].Increasedcerebralmicrovascularpermeabilityhasbeenobservedintheexperimental
Int.J.Mol.Sci.2017,18,129 4of18
CAmodels[22–24]. Consistently,inCApatients,computedtomography(CT)andmagneticresonance
imaging(MRI)scanninghavealsoshowndiffusebrainedemaformationpredictingpoorneurological
outcomes[25–27]. BrainedemacanleadtoanelevatedICPduetothelimitedspaceforexpansionin
thecrania[27,28]. Tissueswellingincreasescapillary–tissuediffusiondistanceandimpairsoxygen
Int. J. Mol. Sci. 2017, 18, 129 4 of 17
(O )/wasteexchange,eventuallyleadingtolossoftissuefunction[22].ThemechanismsofCA-induced
2
cerebirmalpeadires moxaygfoenrm (Oa2t)i/ownasatree elxickhealnygme, uevlteinfatuctaollryi alel.adRiencge tnot lloys,sp oefr tiivssausec ufulanrctpioono [l2o2]f. aTqhue ampeocrhiann-i4sm(As QP4)
hasboefe nCAsu-igndguescetedd caerseobrnael kedeeymma efcohrmanaitsiomn bareec aliukseelyt hmisulbtirfaacintorpiarel.d Roemceinntalyn,t pweraitvearsccuhlaarn npeololc oonf trols
theraatqeulaipmoirtino-f4w (AaQtePr4i)n hflaus xbedeun rsiungggecsetreedb arsa olneed keemya mfeocrhmanaitsimon baecnadusiet itshitsh berarieng purleadtionmginsiatnet owfaotesrm otic
channel controls the rate limit of water influx during cerebral edema formation and it is the regulating
agentsforbrainwaterefflux[29].
site of osmotic agents for brain water efflux [29].
If global ischemia endures without resuscitation, severe cerebral ischemia renders the
If global ischemia endures without resuscitation, severe cerebral ischemia renders the mitochondria
mitochondria completely dysfunctional for ATP production, leading to necrotic cell death [30].
completely dysfunctional for ATP production, leading to necrotic cell death [30]. Although reperfusion
Althoughreperfusionuponcardiopulmonaryresuscitation(CPR)andreturnofspontaneouscirculation
upon cardiopulmonary resuscitation (CPR) and return of spontaneous circulation (ROSC) can recover
(ROSnCe)ucraonnarle AcoTvPe lrevneelsu rtoo nata lleAasTt P70le%v–e8l0s%to ofa tnoleramsatl7 l0ev%e–ls8 (0F%iguorfen 1o)r, mit adloleesv neolst c(oFmigpulreete1ly) ,rietsdtooree snot
compcleeltle fluynrcetisoton raes cdeelllafyuendc ntieounroansadl edleaaythed fonlleouwrso nina lthdee vauthlnfeorlalbolwe bsrianint hreegviounlns e[2r0a]b. lebrainregions[20].

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thebroani nthcee lblrualianr cfeullnucltairo fnudncuteiotno ddueec rtoea dseecdreAasTePd (AATdPe n(Aodsienneotsrinipeh torispphhoaspteh)a,tien)c, rienacrseeadseedx ceixtacittoartoyraym ino
acidsa,manindo tahceidfsa, ilaunrde tohfe Cfaaillcuiruem of eCfflaulcxiupmu meffplutxo pwumorpk .toI CwPor(kin. tIrCaPc e(rinetbrraaclerPerbersasl uPrree)s,suRrOe)S, R(rOeSa ctive
(reactive oxygen species), RNS (reactive nitrogen species). The thin arrows indicate the increase or
oxygenspecies),RNS(reactivenitrogenspecies).Thethinarrowsindicatetheincreaseordecreaseof
decrease of either a substance or diagrams the consequences of cardiac arrest.
eitherasubstanceordiagramstheconsequencesofcardiacarrest.
An important feature of global ischemia reperfusion injury after CA and resuscitation is a
Asunbsitmanptioalr tdaenlatyf beaettwureeeno tfheg elonbda olf isshcohret minisaultr eapnedr cfuelsl idoenatihn. jTuhryis “adfteelaryCedA apaonpdtotriec snuesucriotantailo n is
asubdsteaantht”ia gledneelraayllyb eotcwcueresn setvheeraeln ddayosf ashndo rits imnsoustl teavniddencte linl dtheea tChA. T1 hreisgi“odne olfa ytheed haipppoopctaomtipcunse. uItr onal
deatha”lsgoe oncecruarlsl ywoitchciun rtshes epvaertrsa olfd tahyes CaAn3d riesgmiono sotf ehvipidpeoncatminptuhse, sCtrAia1turmeg ainodn loafytehrse 2h ainpdp o5 cinam cepreubsr.aIlt also
occurcsorwteixt h[3in1,3th2]e. Tphaer tdsiosrfutphteioCn Aof3 mreitgociohnonodfrihailp mpeomcabmrapneu sin,tsetgrriiatytu umndaenrldielsa tyheer ms2aina nmdec5hiannicsemre bral
of neuronal apoptosis by releasing pro-apoptotic proteins such as cytochrome C and apoptosis-
cortex[31,32]. Thedisruptionofmitochondrialmembraneintegrityunderliesthemainmechanismof
inducing factor Smac [33,34]. Cytochrome C interacts with the cell death protein (CED-4) homolog,
neuronalapoptosisbyreleasingpro-apoptoticproteinssuchascytochromeCandapoptosis-inducing
Apaf-1, and deoxyadenosine triphosphate, forming the apoptosome and leading to caspase-9
factorSmac[33,34].CytochromeCinteractswiththecelldeathprotein(CED-4)homolog,Apaf-1,and
activation [35–38]. Caspase-9 then activates caspase-3, followed by downstream caspase-2, -6, -8, and
deoxyadenosine triphosphate, forming the apoptosome and leading to caspase-9 activation [35–38].
-10 activations [39]. Smac binds inhibitor-of-apoptosis proteins (IAPs), thereby promoting activation
Caspaofs ec-a9spthaseen-3a c[4ti0v,4a1t]e.s Tchaes pdaoswen-3s,trfeoalmlo wcaesdpabsyesd coawn nclsetarevae mmacnasyp sausbes-t2r,a-te6 ,p-r8o,taeninds -i1n0cluacdtiinvga tpioolnys [39].
Smac(AbiDnPd-sriibnohseib) iptoolry-mofe-arapsoe p(PtoAsRisP)p [r4o2t]e, ilneasd(iInAgP tos) D,tNhAer ienbjuyrpy raonmd osutibnsgeqaucetnivtlayt iaopnopotfotciacs cpealls dee-3ath[4. 0,41].
ThedEomwenrgstirnega emvicdaesnpcae saelssoc aimnpclliecaavtees mthaen inytrsiunbsisct rcaatsepapsreo itnedinespienncdleundti mngecphoalnyis(mA DunPd-reirblyoisneg) npeoulyromne rase
(PARaPp)o[p4t2o]s,isle. aTdhien agptooptDosNisA inidnujucirnyg afnacdtosru (bAsIeFq),u eenndtolynuacpleoapsteo Gtic acnedl lBdcle-a2/tahd.eEnomveirrugsi nEg1Be v1i9d keDncae- also
interacting protein (BNIP3) constitutes this set of proapoptotic proteins released from mitochondrial
transition pores [18]. In addition, apoptotic signaling can be trigged extrinsically through members
Int.J.Mol.Sci.2017,18,129 5of18
implicatestheintrinsiccaspaseindependentmechanismunderlyingneuronapoptosis.Theapoptosis
inducingfactor(AIF),endonucleaseGandBcl-2/adenovirusE1B19kDa-interactingprotein(BNIP3)
constitutes this set of proapoptotic proteins released from mitochondrial transition pores [18].
Inaddition,apoptoticsignalingcanbetriggedextrinsicallythroughmembersofthedeathreceptor
family,suchasFas,andtumornecrosisfactor(TNF)receptor. ThebindingofextracellularFasligand
Int. J. Mol. Sci. 2017, 18, x 5 of 17
(FasL) to Fas-associated death domain (FADD) protein can activate procaspase-8 and subsequent
caspaseo-f3 thpea dthewatha yre.cCepatsopr afasme-il8y,i ssuaclhs oasa Fbalse, atnodt rtuumnocra tneecarnosdis afcactitvora (tTeNBFc)l -r2ecienpttoerr.a Tchtien bginddoinmg aoifn (BID),
extracellular Fas ligand (FasL) to Fas-associated death domain (FADD) protein can activate
apro-apoptoticmemberofBcl-2family,subsequentlyinitiatingcytochromeCreleaseandapoptosis[18].
procaspase-8 and subsequent caspase-3 pathway. Caspase-8 is also able to truncate and activate Bcl-
Inflammationplaysanimportantroleinglobalbrainischemia. Thepost-resuscitationdiseases
2 interacting domain (BID), a pro-apoptotic member of Bcl-2 family, subsequently initiating cytochrome
have been suggested as a sepsis-like syndrome, involving a systemic inflammatory response in
C release and apoptosis [18].
a cardiac arInreflsatmpmaattiieonn tp[la4y3s] .anA imftpeorrtCanAt raolned inr gelsoubsalc ibtraatiino insc,haemraiap. iTdhee pleovsta-rteiosunscoitfatvioanr idoisuesasceys tokines
and solhuabvlee breeecne psutoggrsesotecdc uasr sa isneptshise-lbikleo osydnsdtrroemame, iansvoelavrinlyg aas sy3sthem(Fici ginufrlaem2m).atTohrye rleesvpeolnsseo finc ya tokines
such ascainrdteiarcl eaurrkeisnt -p6ataienndt [s4o3]l.u Abflteert uCmA oarndn erecsruossciistaftiaocnt,o ar rraepciedp etloevraItIioanr eof wvaerliloucos rcryetolaktiendes wanidth tissue
soluble receptors occurs in the bloodstream as early as 3 h (Figure 2). The levels of cytokines such as
hypoxia marker lactate [43]. In a mice model of cardiac arrest, resuscitation resulted in the rapid
interleukin-6 and soluble tumor necrosis factor receptor II are well correlated with tissue hypoxia
infiltration of neutrophil and pro-inflammatory T-lymphocytes into the brain, starting within 3 h
marker lactate [43]. In a mice model of cardiac arrest, resuscitation resulted in the rapid infiltration
ofresuscitationandlastingforthethreedays[44,45]. Theactivationofresidentmicrogliainitiated
of neutrophil and pro-inflammatory T-lymphocytes into the brain, starting within 3 h of resuscitation
withinmanidn luatsetisnga ffoter rthteh tehroene sdeatyos f[4c4a,4r5d].i aTchea arcrteivsattaionnd ofd reevsiedleonpt emdicorovgelira hinoituiartsedto wditahiyns maifntuerterse asftuesr citation
(Figuret2h)e[ 4o6ns].etT ohfe caarcdtiiavca tairorensto afnTdo ldl-elviekleopreedce opvteorr hsoaunrds tsou dbasyesq aufetenrt lryesnusuccitlaetaiornf a(Fctigour-rκe B2)c [o4n6]t.r iTbhuet etothe
pro-inflaacmtivmataitoonr oyf gTeonll-eliskter raencsepcrtoiprst iaonnd isnubhsueqmuaenntlcye nllulcinleeasr f[a4c7to].r-SκuBc chonTtorilbl-ultiek teor tehcee pprtoo-irnsf/laNmFm-κatBorsyi gnaling
genes transcription in human cell lines [47]. Such Toll-like receptors/NF-κB signaling on monocytes
onmonocytescontributestopost-resuscitationsyndrome[48]. Infiltratingperipheralleukocytesand
contributes to post-resuscitation syndrome [48]. Infiltrating peripheral leukocytes and brain residual
brainresidualmicrogliaandmacrophagesfurthertriggerinfiltrationofperipheralimmunecells,by
microglia and macrophages further trigger infiltration of peripheral immune cells, by releasing ROS
releasinagnRd OpSroa-inndflapmrmo-aintoflrya mcymtoaktionreys, cwythoickhin iens ,tuwrhn icahffeicnt tmuricnroagflfieacl tamctiivcraotigolni.a lTahcist ivvaictiioouns. cTyhclies vicious
cyclecocnotnrtirbibuutteess ttoo oonnggooinign gsesceocnodnardya nreyunroenuarl oinnjuarlyi n[4ju9,r5y0][. 49,50].

Figure2F.igCuarer d2.i aCcaradriraecs atrarensdt atnhde trhees ruesltuilntignga cactitvivaattiioonn ooff ththe einifnlaflmammamtorayt ocrayscacdaes cisa ddeemisondsetrmatoedn sotnr atedon
thefigutrhee afibgourvee a.bIonvflea. mInfmlamatmioantioisn dise dpeipcitcetdeda ass aa ffaaccttoorr ththata ctocnotrnibtruitbeus ttoe ssetcoosnedcaoryn ndeaurryonnael uinrjounrya linjury
anddeaatnhd. dTehateh.d Tahseh deadshliende lirneep rreepsreensetnstsa ad diviviissiioonn ooff tthhe ebrbarian iannadn pderpipehreirpyh. eTrhyis. fTighuirse fishgouwres tshheo wsthe
migration of cells from the blood into the brain. The arrows in green demonstrate the factors that will
migrationofcellsfromthebloodintothebrain.Thearrowsingreendemonstratethefactorsthatwill
lead to Secondary Neuronal Injury and Neuronal Death. Penetration of Microglia in the brain also
leadtoSecondaryNeuronalInjuryandNeuronalDeath. PenetrationofMicrogliainthebrainalso
leads to stimulation of Cytokines, inflammation, and ROS (reactive oxygen species). The upward
leadstofasctiimngu alrartoiwons ionfdiCcaytteo tkhien iensc,reiansflea inm am cearttiaoinn ,faacntodr RorO ceSll( arfetaecr tciavredioaxc yargreenst.s Gpeercriye Ss)h.aTwh, Meuicprowglairad facing
arrowsainndd inceautreotnhs,e 2i5n Jcurleya 2s0e0i5n bay ccererattaivine fcaocmtmoroonsr; cHeellmaafttoelrogciastr,d Sieagcmaernrteesdt .NGeuetrrroyphSihlsa, w31, MAuigcurostg liaand
neurons2,00295, CJurelyati2v0e0 C5obmymcornesa. t ivecommons;Hematologist,SegmentedNeutrophils,31August2009,
CreativeCommons.
Int.J.Mol.Sci.2017,18,129 6of18
Inthenextsections,wewillreviewthetracingmethodsthatmonitorbraininjuryandedema,
facilitating the understanding of some of the pathophysiological mechanism above. In addition,
wewilldiscussthemethodsavailabletomonitorbrainfunctionafterCAandtheirapplicationand
updatesinresearchandclinicalpractice.
4. ElectrophysiologicMonitoringofBrainInjuryafterCardiacArrest
EEG,anelectricalphenomenonofthebrain, wasdiscoveredmorethanonecenturyago, and
haslastedseveraldecades. ScientistsaretryingtouseEEGasaprognosticpredictorandfindoutits
advantagesafterCAandhumanbraininjury.Currently,themostusefulmethodofElectrophysiological
MonitoringofBrainInjuryafterCAisanEEG.Mostpatientssuccumbduetohypoxicbraindamage;
evenaftersuccessfulcardiopulmonaryresuscitationfollowingCA,predictionofbraininjuryduringor
afterCAremainsanimportantissueguidingthedecisiontocontinueorwithdrawaltreatment,and
organdonation. TheprognosticpredictionofEEGisanimportantdiagnosticcriterionofbraininjury,
suchasclinicalsymptomsandbiochemicalmarkers. TechnicaladvantagesofEEGrecordingincluding
continuousEEG,quantitativeEEG,andamplitude-integratedEEGareusedtopredictpatientoutcomes
afterCA.Moreover,somatosensory,motor,auditory,andvisualevokedpotentialsinEEGprovide
informationaboutdegreeoffunctionaldamageofbrainafterCA[51].
HumanandanimalstudieshaveshownthatEEGisawell-describedmethodtomonitoracute
braininjuryafterCA.ThestudiesdemonstratedthatEEGisausefulmonitorforseizureandischemia
detectionand,hasawell-describedroleforEEGinconvulsivestatusepilepticusafterCA[52]. Recently,
severalreviewpapershavesummarizedElectrophysiologicMonitoringofBrainInjuryafterCAwith
therapeutichypothermia(TH),astandardmethodfortreatmentofCA[51,52]. Thus,mostEEGrecords
havebeendoneinCAwiththerapeutichypothermiainhumans. Recentstudiesshowedthatbispectral
index(<40,acalculatedsummaryofrawEEGdataincludingfrequencyandamplitude)[53,54],burst
suppression(aquantitativeEGGparameter)[55,56],periodicdischarges(commonlyrecognizedpatterns
ofabnormalEEG)[57,58],epileptiformdischarges(anuncommonEEGpatternincludingperiodicspike,
sharpandslowwavecomplexandmorecommoninpeoplewithepilepsy)[59],stimulus-induced
rhythmicperiodic,orictaldischarges(aspectrumofstimulation-inducedEEGpattern)[60]intheEEG
recordsaftersuccessfulresuscitationwithnon-therapeutichypothermiamayindicatepoorprognosis.
Inaddition,anon-reactiveEEG[61,62]maypredictpoorprognosisinpatientswithouttherapeutic
hypothermia,whilerhythmicdeltaactivitymayindicatebetterprognosis[55,58]afterCA[63].
TheabsenceordiscontinuationofreactivityincontinuousEEGisastrongpredictorofoutcome
independentoftemperatureandsedatives[64]. BilateralabsenceofcorticalN20component,anearly
cortical response in EEG, on median nerve somatosensory evoked potentials (SSEPs) was one of
themostspecificpredictorsofpooroutcomeinthe2006AmericanAcademyofNeurologypractice
parameters[65]. However,onestudyfoundthatbilateralabsenceofN20potentialsdoesnotguarantee
pooroutcomeamongsttherapeutichypothermia-treatedCApatients[66]. Recently,acasereportin
ayoungpatientshowedthathighly-preservedanteriorcortico-thalamicintegrityisassociatedwith
thepresenceofconsciousawarenessindependentfromthedegreeofinjurytootherbrainareas[67].
BorjiginandcolleaguesdescribedtheCAstages,whichbeganatthelastheartbeatintheEEG,and
showedthatgammaoscillationsindicateahighlyarousedbrain. Furthermore,theydemonstrated
thatthemammalianbrainhasthepotentialforhighlevelsofinternalinformationprocessingduring
clinicaldeath[68].
Cellular electrophysiology, such as multi-unit activity and local field potentials, has strong
potentialforimprovingprognosticationafterCA,buttheystillrequirefurtherinvestigationbefore
beingtranslatedintoinvivostudiesandclinicalpractice[51].StudiesshowedthatacontinuousEEGis
morepreciseforevaluationofbraininjuryafterCA[69],especiallytodetectnon-convulsiveepileptic
status. ThisstatusisacriticalconditionthatcouldbeinducedbyCA,causingexacerbationofbrain
injury,andpooroutcomes[70]. Diagnosisandanti-convulsiveepilepticstatustherapymightbeone
bestwaytoprotectbraininjuryafterCA.
Int.J.Mol.Sci.2017,18,129 7of18
MorecomparablestudiesarerecommendedforscientificevidencetoaccuratelydescribeEEG
characterization after CA with and without therapeutic hypothermia. They also need to describe
outcomes after CA that are altered under hypothermic conditions. Several limitations should be
consideredinthefurtherstudies. Asadiagnostictool,waveform-basedEEGanalysisissubjectiveand
laborious,withresultsdependingontheinterpreter’sexpertise[71]. Moststudiespublishedarecase
reports. Thereisalackoflargenumberstudies,andanimalexperimentsinvariousclinicalcontext
usingdifferentmeasuresofthebrainactivityandfunctioncollected.Inaddition,dataareheterogenetic
bytheuseofvariousdevices[71]. TheoptimalmontageandnumberofelectrodestorecordEEGin
theICUisuncertainandEEGrecordingisdependentonacertainnumberofelectrodes,theirnature,
formandplacement. Thus,perspective,directionofclinicalapplicationofEEG,andstudiesshould
beconsideredinordertoestablishstandardizedsettingswithconstanttimeofEEGrecordingafter
CA,anduseofcontinuedEEGrecordingsasaprognosticpredictorinEEG,suchasN20andcerebral
recoveryindex. FutureimprovementofEEGusingcurrentadvantagesofEEGdevicesmightbefinest
andspecificpredictionmethodofElectrophysiologicalMonitoringofBrainInjuryafterCA.
5. IntracranialPressureMonitoringandCerebralAutoregulation
Cerebral edema is an important cause of secondary brain injury following CA and must be
carefullymonitoredinordertodecreasetheriskofcomaandchanceofmortalityamongstindividuals
thatexperiencesuchadevastatingevent[27,29].
Increased intracerebral pressure (ICP) is not a direct result of cardiac arrest, as evidenced by
a clinical study conducted by Sakabe and colleagues who found that ICP persistently remained
below20mmHginfiveoutofsixpatientsfollowingcardiopulmonaryresuscitation[72]. Nonetheless,
cerebraledemacanstilloccurandthereforeanincreaseinICP,duetohypoxic-ischemicencephalopathy
inducedchangesinbraintissue. Brainswellingwasfoundinagroupofpatientsthatexperienced
CAasaresultofrespiratorydistressbasedonresultsofaclinicalstudyconductedbyMorimotoand
colleagues,whichcouldeventuallyleadtocerebralherniationandbraindeath[27]. ICPmonitoringis
animportantclinicaltoolduetoastrongassociationbetweenhighICPs(>20mmHg)andincreased
ratesofmortalitybasedonoutcomesinpatientswithseveretraumaticbraininjury[73]. Indications
for ICP monitoring, especially in post-CA patients presenting with initially unremarkable cranial
computedtomography(CT)neuroimaging,canbedeterminedbasedonapredictivemodel,which
includespatients’age(>40years),systolicbloodpressure(<90mmHg)andsignsofdecerebrateor
decorticateposturing[74,75].
The most commonly used ICP monitoring devices are categorized based on their location of
placement: parenchymal and ventricular. Both types are minimally associated with infection and
bleedingwithgreaterriskofcomplicationstypicallyseeninuseofextracranialventriculardrainICP
monitors[76]. Inordertodecreasethechanceofcausingfurthercomplicationsinpatientsthatare
alreadyincriticalconditionduetointracranialhypertension,non-invasiveICPmonitoringtechniques
arecurrentlybeingdeveloped.TheseincludetranscranialDopplerdevices,opticnervesheathdiameter
(ONSD) measurements and even pupillometry [77–79]. Unfortunately, due to limited studies and
lackofreproducibleresults,thesenovelnon-invasiveICPmonitoringdevicesarenotwidelyusedin
clinicalpractice.
Besides the obvious danger of cerebral herniation, the other concern associated with having
increasedICPisadecreaseincerebralperfusionpressure(normal=60mmHg),whichisderivedfrom
meanarterialpressure(MAP)—ICP.Inanon-pathologicstate,cerebralautoregulationisresponsiblefor
maintenanceofcerebralbloodflow(CBF)inlightoftheconstantlyfluctuatingMAP.Whileconducting
aclinicalstudy,Sundgreenandcolleaguesfoundthatinamajorityofpatientsintheacutephaseof
cardiacarrest,cerebralautoregulationwaseitherabsentorright-shifted,therebysuggestingthatMAP
shouldbemaintainedathigherlevelstomaintainpropercerebralperfusion,whichwasmeasuredvia
transcranialDopplerultrasonography[80].
Int.J.Mol.Sci.2017,18,129 8of18
However, the aforementioned advances in ICP monitoring and understanding of cerebral
autoregulation would have never seen the light of day unless results from animal studies were
translatedintoclinicaltrials,interventionsandinnovations.
Experimental studies are often a required precursor to clinical trials that test differences in
interventiontherapies’effectivenessinaclinicalsetting.Mirskiandcolleaguesquestionedthedifference
ineffectivenessbetweenadministrationofmannitolandhypertonicsalineinreductionandcontrolof
ICP,thelatterofwhichwasfoundtobemoreeffectiveinrats,atleastinthefirst8h[81]. Whileother
rodent studies conducted by Hiploylee and colleagues came to the conclusion that there are no
differenceswhencomparingICPreadingsfromepiduralvs.intraparenchymalmonitoringlocations[82],
therebygivingcliniciansabasistoconfirmsuchfindingsthroughclinicaltrials,yieldingresultsthat
would allow less invasive ICP monitoring options for patients requiring such care. Furthermore,
studieswhichutilizedultrasoundinICPmonitoringandanovelmethodofepiduralICPrecording,
suchasthoseconductedbyLimbrick,andUldall,respectively,arethedrivingforcebehindprogress
andinnovationwhenitcomestonovelmethodsforlong-termICPmonitoring,whichishighlysought
afterinboththebasicscience,aswellasintheclinicalsetting[83,84].
6. BrainOxygenMonitoring
Whilemethodsexistformonitoringcerebraloxygencontentperioperatively,nostandardized
method of continuous cerebral oxygen monitoring currently exists for patients undergoing
an out-of-hospital (OHCA) or in-hospital CA (IHCA). Parnia and colleagues state that the ability
todetectandquantifycerebralischemiainreal-time,duringCPRisofvitalclinicalimportance[85].
Patients,withapost-clinicaldeterminationofCAhavesuboptimallevelsofcerebraloxygencontent
whichmayleadtosecondaryischemicinjuries(i.e.,sterileinflammatorycascade).
Manyofthemoreestablishedmethodsofcontinuouscerebraloxygenmonitoringareinvasive,
such as monitoring catheters, and or unfeasible (e.g., constant fMRI, CT monitoring) for both
out-of-hospitalandin-hospitalCApatients.Inaddition,neuromonitoringsuchastranscranialDoppler
sonography and jugular oxygen content (SjvO ) are unavailable to out-of-hospital patients [86].
2
In addition, jugular oxygen content (SjvO ) is unavailable to those experiencing OHCA [86].
2
Forinstance,thetreatmentofbraininjuriessuchastraumaticbraininjuryallowsfortheplacement
ofmonitoringcatheterssuchastheNeurovent-PTOandLicox[87]. Despitetheaccuracyofregional
oxygensaturationprovidedbyprobessuchasthese,itmightnotbeclinicallyprudentforpatients
concurrentlyundergoingbothOHCAand/orIHCA.Inotherwords,theaccuracyoftheseoxymetric
probesishinderedbytheirinvasivenessandinabilitytobeutilizedduringCPR.
Anon-invasivemethodofaccessingcerebraloxygencontentmaycomefromdeterminingmean
arterialpressure(MAP).Kilgannonandcolleaguespostulatedwhetheranassociationbetweenmean
arterial pressure (MAP) and neurological outcome could be found [88]. In the observation of CA
patientsoveraperiodof6hpost-return-of-spontaneous-circulation(ROSC),theydiscoveredthat40%
ofpatientswithanaverageMAPpressureabove70mmHgwereassociatedwithagoodneurological
outcome[88]. AcountertotheconclusionbyKilgannonandcolleaguesarguesthatcentralvenous
pressure (CVP) is a more accurate indicator of cerebral oxygen saturation than MAP [89]. A pilot
studyconductedbyAmelootandcolleaguesfoundthataprolongedCVPover5mmHgincreased
thelikelihoodofrecoverywithapoorneurologicaloutcome[89]. Dataanalysisofsimultaneously
recordedCVPandcerebraltissueoxygen(SctO )contentvianear-infraredspectroscopy(NIRS)showed
2
anassociationbetweenahighCVP(>20mmHg)andadecreaseinSctO content[89]. Additional
2
analysis between CVP and MAP showed CVP to associate more closely to changes in SctO [89].
2
Unfortunately, the measurement of CVP requires the insertion of a venous catheter, a procedure
that cannot be conducted on OHCA patients, specifically during CPR. However, multifactorial
measurementsofSctO withrespecttoMAPandCVPmaybeofanincreasedbenefittoIHCApatients.
2
Studieshaveemergedregardingthefeasibilityandaccuracyofnear-infraredspectroscopy(NIRS)
fornon-invasivecerebraloximetry[90]. NIRSutilizesinfraredlight(700–1100nm)todeterminethe
Int.J.Mol.Sci.2017,18,129 9of18
differenceinabsorptionbetweenoxyhemoglobinanddeoxyhemoglobin[91]. Theuseofnear-infrared
spectroscopyduringCPRhasproducedmultiplestudiesresultinginacorrelationbetweenhigher
regional oxygen saturation and a higher chance of return of spontaneous circulation [85,92,93].
However,anotherstudyindicatedthatthehighregionaloxygensaturationandpossibilityofreturnof
spontaneouscirculationwasnotsignificanttodeterminesurvivabilitytodischarge[94].
There are pitfalls with cerebral oximetry with near-infrared spectroscopy. Meng and
colleagues[95]suggeststhattheregionalareasampledbynear-infraredspectroscopyissuperficial
and may not detect deeper regions that may be vulnerable to ischemic insults post-CA. However,
morestudiesinvolvingnear-infraredspectroscopybothduringCPRandpost-returnofspontaneous
circulationwithlargersamplesizesshouldbeconductedtodeterminewhetherahighregionaloxygen
saturationincreasesalikelihoodofafavorableneurologicaloutcome.
7. MetabolicImagingModalitiesforCardiacArrestBrainInjury
PotentialpredictionofneurologicoutcomeafterCAinducedbraininjuryhasbeenoneofthe
mainaimsofadvancedneuroimagingtechniques. Evidencefromclinicalstudieshaspointedoutthe
first72haftercardiopulmonaryresuscitationtobeapoorpredictionforcerebralprognosis. Thus,
reducingthelackofcertaintyinneurologicprognosispredictionshouldbetheleadingpurposeof
advancedmolecularimagingtechniqueswheremaintenanceandmodulationofcellularpathways
causingbraininjurycanimproveneurologicoutcomesaswell[96].
BraininjuryfollowingCAinvolvesperiodsofglobalhypoxia-ischemia, reperfusionrecovery,
glutamate consumption, and GABA-induced pathways [97]. Yi Zhang and colleagues compared
ventricularfibrillationandasphyxialCAbraininjurymodelsinpigswith18F-fluorodeoxyglucose
PET/CTtechniquetoevaluatethemetabolicactivityintheresidualcerebraltissue. Themetabolic
activityintwodifferentCAmodelswasfounddecreasedcomparedtoshamintheparietalandfrontal
lobeaswellasbrainstemandcerebellumat24hafterspontaneousrecirculation.Anadditionalreduced
cerebralglucosemetabolismintheasphyxialCAgrouphadbeendetectedtobemoresignificantthan
intheventricularfibrillationgroup. Ontheotherhand,authorsemphasizedthelongerCPRduration
intheasphyxialCAgroupcomparedtotheventricularfibrillationgroupand,therefore,itsassociation
withpoorneurologicprognosis[98]. However,anolderandverylimitedsamplesizedclinicalstudy
bySchaafsmaandcolleaguesreportednobeneficialeffectsof18F-fluorodeoxyglucosePETtechnique
inmeansofspecifyingneurologicprognosisafterCA[99].
Clinically,DavidKHandcolleaguesreportedabroadliteraturereviewinordertocorrelatethe
association between levels of evidence and quality of previous studies for predicting the accurate
neurologic outcomes with molecular neuroimaging techniques in post-CA patients. This review
discussedtheprosandconsofPositronEmissionTomography(PET)andSingle-PhotonEmission
Computed Tomography (SPECT) in prognostication. However, limited sample sizes, variability
in imaging times, and inadequate standardization methods in previous clinical research were
present [100]. Krep and colleagues investigated the combination of diffusion-weighted imaging
(DWI),1H-protonspectroscopy(H-MRS)andperfusion-weightedimaging(PWI)inanexperimental
cat study and monitored the variations of regional cerebral blood flow after cerebral recirculation
alongwithlactateandcreatininemeasurementsduringthefirst6hafterCA.Despitethefavorable
results,thelowerstatisticalpowerandinadequatemodelstandardizationthroughtheexperimentare
themainrestrictedfactorsfortheirresults[101].
Magneticresonancespectroscopy(MRS)isafavorableadvancedneuroimagingtechniquefor
assessingmetaboliteconcentrationalterationsinischemicbraininjury. InmeansofCAbraininjury,
Tangandcolleagues[102]analyzedbrainmetabolitesafterCAandexhibitedlowerlevelsofNAA/Cr
(reduced N-acetyl aspartate (NAA)-to-creatine ratio) and NAA/Cho (reduced N-acetyl aspartate
(NAA)-to-Cho ratio) at 6 h after spontaneous recirculation although Cho/Cr levels was found
increased. Furthermore, in that study, hypothermia has a lessening effect on NAA/Cr decrease
andCho/CrincreaseafterCA.Paralleltotheirstudy, Suandcolleaguesusedsinglevoxelproton
Int.J.Mol.Sci.2017,18,129 10of18
magnetic resonance spectroscopy in CA pig model and found lactic acid production was reduced
inhypothermiagroup[103]. ChanKandcolleaguesdesignedanexperimentalratstudyaimedto
investigatetheH-MRSefficacyforevaluatingneuroprotectivemetabolicchangesduringhypothermia
withCA.Authorsdemonstratedthetransientchangesofglucose,choline,tau,myo-inositol,NAA
andlactateincerebralcortexandthalamusasaresultofhypothermia[104]. Moreanimalandclinical
researchwithmagneticresonancespectroscopyarenecessaryinordertoestablishasagoldstandardfor
monitoringthetherapeuticeffectsofhypothermiaandenhancethemetabolicimpactsofhypothermia
duringCAbraininjury[102].
8. Microdialysis
Microdialysisisamethodofneuromonitoringconsistingofaprobecoveredinasemi-permeable
membrane,whichisinsertedintotheinterstitialtissueofthebrain. Asolution,usuallynormalsaline
orartificialcerebralspinalfluid,isperfusedthroughtheprobeandintothetissue,allowingcerebral
fluid,alongwithsomesmallmolecules,topassivelydiffuseintothemembranewheretheextracellular
concentrationofsoluteismeasured. Commonsolutesofinterestincludefreeions,neurotransmitters,
andotherbiomarkersandmetabolites[105].
CA often leads to a cessation of blood flow to the brain, creating areas of ischemia and
consequentlybraindamage.Reperfusionistypicallythefirstinthelineoftreatmentsadministered;yet
itisnotwithoutrisk. Reperfusioninjuryincludesabroaddescriptionofdamagesthatcanoccurwith
restorationofcerebralbloodflow. Althoughthesemoleculareventsarelargelyunknown,research
inthisfieldisquicklygrowing. Duringischemia,cellularfunctionisalteredandoneoftheknown
pathways of damage is that of mitochondrial dysfunction. The downstream cascade is believed
to begin in the mitochondria, the lack of oxygen results in anaerobic respiration, and in time, cell
death[106]. Whentreatingacutebraininjuryitisimperativetomanagethesedownstreamcascades,
suchasinflammationandedema,inordertopreventtheworseningoftheinitialcondition. Through
closelyobservingthephysiologicalchangesoccurringintheinjuredbrain,itbecomespossiblefor
physicianstodeterminethepatients’exactneedsanddevelopaneffectivetreatmentplanthatmay
preventorlessentheeffectsofsecondaryinjuries[107]. Themostcommonapplicationofmicrodialysis
is thus measuring cerebral metabolism through observing the levels of lactate (Figure 3), glycerol,
pyruvate,glutamate[108],evenfreeionsintheextracellularspace[109],andglucose[110].
Althoughithasbeenusedextensivelyasaresearchtool,furtherdevelopmentsofmicrodialysis
allowittobeusedinclinicalsettingstobettermonitorpatientswhohavesufferedseverebraininjury.
Changesinlevelsoflactate,pyruvate,glycerolandglutamateactasbiomarkersandallowcliniciansto
determinethecurrentstateofapatient’sbrain,aswelltopossiblyaidintheinterventionofsecondary
injurysuchashypoxia, glucosedepravation[111]edema, andinflammation[107]. Bymonitoring
the biochemical state of the brain, it is possible to further examine the mechanisms in action, and
providemoretargetedtreatment. Acommonmeasurementusedtomonitorcerebralmetabolismis
theratiooflactatetopyruvate,orLPR(LactatePyruvateratio). Anincreaseinthisratioiscorrelated
withneuronaldeclineduetoischemiaorpost-ischemicmitochondrialdysfunction[112]. Iftheratio
is increased due to an increase in lactate, while maintaining a relatively normal level of pyruvate,
itindicatesincreasedmitochondrialdysfunction(Figure3);howeverifthereisanincreaseinratio
with a normal lactate concentration and a marked decrease in pyruvate, ischemia is the outcome
indicated[113]. TwoDanishstudies,onebyNielsenandtheotherbyJacobsensupportedthebedside
useofmicrodialysistodistinguishbetweenmetabolicchangesrelatingtoischemiaandmitochondrial
dysfunction[112,114].
HosmannandcolleaguesusedrodentstocreateamicrodialysisCAmodel,usingmicrodialysisas
aneuro-monitortodeterminecerebralmetabolismduringbaseline,CA,cardiopulmonaryresuscitation,
reperfusion, and death. Significant results include the possible distinction between survivors and
non-survivors. Non-survivors demonstrated with a marked increase in glutamate compared to
survivingrodentswithin8minofCPR.Ontheotherhand,survivorswerecharacterizedwithhigher