Hypoxic-Ischemic Encephalopathy - Medscape Reference

Perinatal asphyxia, more appropriately known as hypoxic-ischemic encephalopathy (HIE), is characterized by clinical and laboratory evidence ... ForYou News&Perspective Drugs&Diseases CME&Education Academy Video DecisionPoint Edition: English Medscape English Deutsch Español Français Português UKNew Univadis LogIn SignUpIt'sFree! EnglishEdition Medscape English Deutsch Español Français Português UKNew Univadis X UnivadisfromMedscape Register LogIn NoResults NoResults ForYou News&Perspective Drugs&Diseases CME&Education Academy Video DecisionPoint close PleaseconfirmthatyouwouldliketologoutofMedscape. Ifyoulogout,youwillberequiredtoenteryourusernameandpasswordthenexttimeyouvisit. Logout Cancel https://profreg.medscape.com/px/getpracticeprofile.do?method=getProfessionalProfile&urlCache=aHR0cHM6Ly9lbWVkaWNpbmUubWVkc2NhcGUuY29tL2FydGljbGUvOTczNTAxLW92ZXJ2aWV3 processing.... Drugs&Diseases > Pediatrics:CardiacDiseaseandCriticalCareMedicine Hypoxic-IschemicEncephalopathy Updated:Jul18,2018 Author:SantinaAZanelli,MD;ChiefEditor:DharmendraJNimavat,MD,FAAP more... Share Email Print Feedback Close Facebook Twitter LinkedIn WhatsApp Sections Hypoxic-IschemicEncephalopathy Sections Hypoxic-IschemicEncephalopathy Overview PracticeEssentials Background Pathophysiology Etiology Epidemiology Prognosis PatientEducation ShowAll Presentation History PhysicalExamination ShowAll DDx Workup ApproachConsiderations LaboratoryStudies ImagingStudies OtherTests HistologicFindings ShowAll Treatment MedicalCare InitialResuscitationandStabilization SupportiveCareinPatientswithHypoxic-ischemicEncephalopathy PerfusionandBloodPressureManagement FluidandElectrolytesManagement HyperthermiaAvoidance TreatmentofSeizures HypothermiaTherapy FutureNeuroprotectiveStrategies Consultations Diet Prevention Long-TermMonitoring ShowAll Medication MedicationSummary Anticonvulsants Anticonvulsants,Other Anxiolytics,Benzodiazepines Cardiovascular(Inotropic)Agents ShowAll Questions&Answers MediaGallery Tables References Overview PracticeEssentials Perinatalasphyxia,moreappropriatelyknownashypoxic-ischemicencephalopathy(HIE),ischaracterizedbyclinicalandlaboratoryevidenceofacuteorsubacutebraininjuryduetoasphyxia.Theprimarycausesofthisconditionaresystemichypoxemiaand/orreducedcerebralbloodflow(CBF)(seetheimagebelow).Birthasphyxiacauses840,000or23%ofallneonataldeathsworldwide. [1,2,3] Fetalresponsetoasphyxiaillustratingtheinitialredistributionofbloodflowtovitalorgans.Withprolongedhypoxic-ischemicinsultandfailureofcompensatorymechanisms,cerebralbloodflowfalls,leadingtoischemicbraininjury. ViewMediaGallery Signsandsymptoms Mildhypoxic-ischemicencephalopathy Muscletonemaybeslightlyincreasedanddeeptendonreflexesmaybebriskduringthefirstfewdays Transientbehavioralabnormalities,suchaspoorfeeding,irritability,orexcessivecryingorsleepiness(typicallyinanalternatingpattern),maybeobserved Typicallyresolvesin24h Moderatelyseverehypoxic-ischemicencephalopathy Theinfantislethargic,withsignificanthypotoniaanddiminisheddeeptendonreflexes Thegrasping,Moro,andsuckingreflexesmaybesluggishorabsent Theinfantmayexperienceoccasionalperiodsofapnea Seizurestypicallyoccurearlywithinthefirst24hoursafterbirth Fullrecoverywithin1-2weeksispossibleandisassociatedwithabetterlong-termoutcome Severehypoxic-ischemicencephalopathy Seizurescanbedelayedandsevereandmaybeinitiallyresistanttoconventionaltreatments.Theseizuresareusuallygeneralized,andtheirfrequencymayincreaseduringthe24-48hoursafteronset,correlatingwiththephaseofreperfusioninjury. Astheinjuryprogresses,seizuressubsideandtheelectroencephalogrambecomesisoelectricorshowsaburstsuppressionpattern.Atthattime,wakefulnessmaydeterioratefurther,andthefontanellemaybulge,suggestingincreasingcerebraledema.Othersymptomsincludethefollowing: Stupororcomaistypical;theinfantmaynotrespondtoanyphysicalstimulusexceptthemostnoxious. Breathingmaybeirregular,andtheinfantoftenrequiresventilatorysupport Generalizedhypotoniaanddepresseddeeptendonreflexesarecommon Neonatalreflexes(eg,sucking,swallowing,grasping,Moro)areabsent Disturbancesofocularmotion,suchasaskeweddeviationoftheeyes,nystagmus,bobbing,andlossof"doll'seye"(ie,conjugate)movementsmayberevealedbycranialnerveexamination Pupilsmaybedilated,fixed,orpoorlyreactivetolight Irregularitiesofheartrateandbloodpressurearecommonduringtheperiodofreperfusioninjury,asisdeathfromcardiorespiratoryfailure Aninitialperiodofwell-beingormildhypoxic-ischemicencephalopathymaybefollowedbysuddendeterioration,suggestingongoingbraincelldysfunction,injury,anddeath;duringthisperiod,seizureintensitymayincrease. SeeClinicalPresentationformoredetail. Diagnosis GuidelinesfromtheAmericanAcademyofPediatrics(AAP)andtheAmericanCollegeofObstetricsandGynecology(ACOG)forHIEindicatethatallofthefollowingmustbepresentforthedesignationofperinatalasphyxiasevereenoughtoresultinacuteneurologicinjury: Profoundmetabolicormixedacidemia(pH<7)inanumbilicalarterybloodsample,ifobtained PersistenceofanApgarscoreof0-3forlongerthan5minutes Neonatalneurologicsequelae(eg,seizures,coma,hypotonia) Multipleorganinvolvements(eg,kidney,lungs,liver,heart,intestines) Laboratorystudies Serumelectrolytelevels Renalfunctionstudies Cardiacandliverenzymes-Thesevaluesareanadjuncttoassessthedegreeofhypoxic-ischemicinjurytotheheartandliver Coagulationsystem-Includesprothrombintime,partialthromboplastintime,andfibrinogenlevels Arterialbloodgas-Bloodgasmonitoringisusedtoassessacid-basestatusandtoavoidhyperoxiaandhypoxia,aswellashypercapniaandhypocapnia Imagingstudies Magneticresonanceimaging(MRI)ofthebrain Cranialultrasonography Echocardiography Additionalstudies Electroencephalography(EEG)-Standardandamplitude-integratedEEG Hearingtest-Anincreasedincidenceofdeafnesshasbeenfoundamonginfantswithhypoxic-ischemicencephalopathywhorequireassistedventilation Retinalandophthalmicexamination SeeWorkupformoredetail. Management Followinginitialresuscitationandstabilization,treatmentofHIEislargelysupportiveandshouldfocusonthefollowing [4,5]: Adequateventilation Perfusionandbloodpressuremanagement-Studiesindicatethatameanbloodpressure(BP)above35-40mmHgisnecessarytoavoiddecreasedcerebralperfusion Carefulfluidmanagement Avoidanceofhypoglycemiaandhyperglycemia Avoidanceofhyperthermia-Hyperthermiahasbeenshowntobeassociatedwithincreasedriskofadverseoutcomesinneonateswithmoderatetoseverehypoxic-ischemicencephalopathy [6] Treatmentofseizures Therapeutichypothermia(33º-33.5ºCfor72h)followedbyslowandcontrolledrewarmingforinfantswithmoderatetosevereHIE [7] SeeTreatmentandMedicationformoredetail. Next: Background Despitemajoradvancesinmonitoringtechnologyandknowledgeoffetalandneonatalpathologies,hypoxic-ischemicencephalopathy(HIE)remainsaseriousconditionthatcausessignificantmortalityandlong-termmorbidity. HIEischaracterizedbyclinicalandlaboratoryevidenceofacuteorsubacutebraininjuryduetoasphyxia(ie,hypoxia,acidosis).Mostoften,theexacttimingandunderlyingcauseremainunknown. TheAmericanAcademyofPediatrics(AAP)andAmericanCollegeofObstetricsandGynecology(ACOG)publishedguidelinestoassistinthediagnosisofseverehypoxic-ischemicencephalopathy(seeHistory). [8,9] Previous Next: Pathophysiology Brainhypoxiaandischemiaduetosystemichypoxemia,reducedcerebralbloodflow(CBF),orbotharetheprimaryphysiologicprocessesthatleadtohypoxic-ischemicencephalopathy(HIE). [1,2,3] TheinitialcompensatoryadjustmenttoanasphyxialeventisanincreaseinCBFduetohypoxiaandhypercapnia.Thisisaccompaniedbyaredistributionofcardiacoutputtoessentialorgans,includingthebrain,heart,andadrenalglands.Abloodpressure(BP)increaseduetoincreasedreleaseofepinephrinefurtherenhancesthiscompensatoryresponse.Seetheimagebelow. Fetalresponsetoasphyxiaillustratingtheinitialredistributionofbloodflowtovitalorgans.Withprolongedhypoxic-ischemicinsultandfailureofcompensatorymechanisms,cerebralbloodflowfalls,leadingtoischemicbraininjury. ViewMediaGallery Inadults,CBFismaintainedataconstantleveldespiteawiderangeinsystemicBP.Thisphenomenonisknownasthecerebralautoregulation,whichhelpsmaintaincerebralperfusion.ThephysiologicaspectsofCBFautoregulationhasbeenwellstudiedinperinatalandadultexperimentalanimals.Inhumanadults,theBPrangeatwhichCBFismaintainedis60-100mmHg. LimiteddatainthehumanfetusandthenewborninfantsuggestthatCBFisstableovermuchnarrowerrangeofBPs. [10,11]Someexpertshavepostulatedthat,inthehealthytermnewborn,theBPrangeatwhichtheCBFautoregulationismaintainedmaybeonlybetween10-20mmHg(comparedwiththe40mmHgrangeinadultsnotedabove).Inaddition,theautoregulatoryzonemayalsobesetatalowerlevel,aboutthemidpointofthenormalBPrangeforthefetusandnewborn.However,thepreciseupperandlowerlimitsoftheBPvaluesaboveandbelowwhichtheCBFautoregulationislostremainunknownforthehumannewborn. Inthefetusandnewbornsufferingfromacuteasphyxia,aftertheearlycompensatoryadjustmentsfail,theCBFcanbecomepressure-passive,atwhichtimebrainperfusiondependsonsystemicBP.AsBPfalls,CBFfallsbelowcriticallevels,andthebraininjurysecondarytodiminishedbloodsupplyandalackofsufficientoxygenoccurs.Thisleadstointracellularenergyfailure.Duringtheearlyphasesofbraininjury,braintemperaturedrops,andlocalreleaseofneurotransmitters,suchasgamma-aminobutyricacidtransaminase(GABA),increase.Thesechangesreducecerebraloxygendemand,transientlyminimizingtheimpactofasphyxia. Atthecellularlevel,neuronalinjuryinHIEisanevolvingprocess.Themagnitudeofthefinalneuronaldamagedependsonthedurationandseverityoftheinitialinsult,combinedwiththeeffectsofreperfusioninjury,andapoptosis.Atthebiochemicallevel,alargecascadeofeventsfollowhypoxic-ischemicinjury. Excitatoryaminoacid(EAA)receptoroveractivationplaysacriticalroleinthepathogenesisofneonatalhypoxia-ischemia.Duringcerebralhypoxia-ischemia,theuptakeofglutamatethemajorexcitatoryneurotransmitterofthemammalianbrainisimpaired.ThisresultsinhighsynapticlevelsofglutamateandEAAreceptoroveractivation,includingN-methyl-D-aspartate(NMDA),amino-3-hydroxy-5-methyl-4isoxazolepropionate(AMPA),andkainatereceptors.NMDAreceptorsarepermeabletoCa++andNa+,whereasAMPAandkainatereceptorsarepermeabletoNa+.AccumulationofNa+coupledwiththefailureofenergydependentenzymessuchasNa+/K+-ATPaseleadstorapidcytotoxicedemaandnecroticcelldeath.ActivationofNMDAreceptorleadstointracellularCa++accumulationandfurtherpathologiccascadesactivation. EAAsaccumulationalsocontributestoincreasingthepaceandextentofprogrammedcelldeaththroughsecondaryCa++intakeintothenucleus.Thepatternofinjuryseenafterhypoxia-ischemiademonstrateregionalsusceptibilitythatcanbelargelyexplainedbytheexcitatorycircuityatthisage(putamen,thalamus,perirolandiccerebralcortex).Finally,developingoligodendrogliaisuniquelysusceptibletohypoxia-ischemia,specificallyexcitotoxicityandfreeradicaldamage.Thiswhitematterinjurymaybethebasisforthedisruptionoflong-termlearningandmemoryfacultiesininfantswithhypoxic-ischemicencephalopathy. IntracellularCa++concentrationincreasesfollowinghypoxia-ischemiaasaresultof(1)NMDAreceptoractivation,(2)releaseofCa++fromintracellularstores(mitochondriaandendoplasmicreticulum[ER]),and(3)failureofCa++effluxmechanisms.ConsequencesofincreasesintracellularCa++concentrationincludeactivationofphospholipases,endonucleases,proteases,and,inselectneurons,nitricoxidesynthase(NOS).ActivationofphospholipaseA2leadstoreleaseofCa++fromtheERviaactivationofphospholipaseC.ActivationofproteasesandendonucleasesresultsincytoskeletalandDNAdamage. Duringthereperfusionperiod,freeradicalproductionincreasesduetoactivationofenzymessuchascyclooxygenase,xanthineoxidase,andlipoxygenase.Freeradicaldamageisfurtherexacerbatedintheneonatebecauseofimmatureantioxidantdefenses.FreeradicalscanleadtolipidperoxidationaswellasDNAandproteindamageandcantriggerapoptosis.Finally,freeradicalscancombinewithnitricoxide(NO)toformperoxynitriteahighlytoxicoxidant. NMDAreceptoractivationresultsinactivationofneuronalNOSviasPSD-95andresultsintheearlyandtransientriseinNOconcentrationobservedintheinitialphaseofhypoxia.InducibleNOSisexpressedinresponsetothemarkedinflammationsecondarytocerebralischemiaandresultsinasecondwaveofNOoverproductionthatcanbeprolongedforupto4-7daysaftertheinsult. ThisexcessiveNOproductionplaysanimportantroleinthepathophysiologyofperinatalhypoxic-ischemicbraininjury.NOneurotoxicitydependsinlargepartonrapidreactionwithsuperoxidetoformperoxynitrite. [12]This,inturn,leadstoperoxynitrite-inducedneurotoxicity,includinglipidperoxidation,proteinnitrationandoxidation,mitochondrialdamageandremodeling,depletionofantioxidantreserve,andDNAdamage. Inflammatorymediators(cytokinesandchemokines)havebeenimplicatedinthepathogenesisofhypoxic-ischemicencephalopathyandmayrepresentafinalcommonpathwayofbraininjury.Animalstudiessuggestthatcytokines,particularlyinterleukin(IL)-1bcontributestohypoxic-ischemicdamage.Theexactmechanismsandwhichinflammatorymediatorsareinvolvedinthisprocessremainsunclear. Followingtheinitialphaseofenergyfailurefromtheasphyxialinjury,cerebralmetabolismmayrecoverfollowingreperfusion,onlytodeteriorateinasecondaryenergyfailurephase.Thisnewphaseofneuronaldamage,startingatabout6-24hoursaftertheinitialinjury,ischaracterizedbymitochondrialdysfunction,andinitiationoftheapoptoticcascade.Thisphasehasbeencalledthe"delayedphaseofneuronalinjury." Thedurationofthedelayedphaseisnotpreciselyknowninthehumanfetusandnewbornbutappearstoincreaseoverthefirst24-48hoursandthenstarttoresolvethereafter.Inthehumaninfant,thedurationofthisphaseiscorrelatedwithadverseneurodevelopmentaloutcomesat1yearand4yearsafterinsult. [13]Seetheimagebelow. Pathophysiologyofhypoxic-ischemicbraininjuryinthedevelopingbrain.Duringtheinitialphaseofenergyfailure,glutamatemediatedexcitotoxicityandNa+/K+ATPasefailureleadtonecroticcelldeath.Aftertransientrecoveryofcerebralenergymetabolism,asecondaryphaseofapoptoticneuronaldeathoccurs.ROS=Reactiveoxygenspecies. ViewMediaGallery Additionalfactorsthatinfluenceoutcomeincludethenutritionalstatusofthebrain,severeintrauterinegrowthrestriction,preexistingbrainpathologyordevelopmentaldefectsofthebrain,andthefrequencyandseverityofseizuredisorderthatmanifestsatanearlypostnatalage(withinhoursofbirth). [14,15,16,17,18,19] Previous Next: Etiology BadawietalinvestigatedriskfactorsofneonatalencephalopathyintheWesternAustraliancasecontrolstudy. [20] Ofthe164infantswithmoderate-to-severeneonatalencephalopathy,preconceptualandantepartumriskfactorswereidentifiedin69%ofcases;24%ofinfantshadacombinationofantepartumandintrapartumriskfactors,whereasonly5%ofinfantshadonlyintrapartumriskfactors.Inthisstudy,5%hadnoidentifiableriskfactors.Inareviewoftheliterature,Grahametalfoundthatcerebralpalsyisassociatedwithintrapartumhypoxia-ischemiainonly14.5%ofcases. [21] Previous Next: Epidemiology UnitedStatesdata IntheUnitedStatesandinmosttechnologicallyadvancedcountries,theincidenceofhypoxic-ischemicencephalopathy(HIE)is1-4casesper1000births. Internationaldata TheincidenceofHIEisreportedlyhighincountrieswithlimitedresources;however,precisefiguresarenotavailable.Birthasphyxiaisthecauseof23%ofallneonataldeathsworldwide.Itisoneofthetop20leadingcausesofburdenofdiseaseinallagegroups(intermsofdisabilitylifeadjustedyears)bytheWorldHealthOrganizationandisthefifthlargestcauseofdeathofchildrenyoungerthan5years(8%).Althoughdataarelimited,birthasphyxiaisestimatedtoaccountfor920,000neonataldeathseveryyearandisassociatedwithanother1.1millionintrapartumstillbirths.Morethanamillionchildrenwhosurvivebirthasphyxiadevelopproblemssuchas cerebralpalsy, mentalretardation,learningdifficulties,andotherdisabilities. [22,23] Previous Next: Prognosis Accuratepredictionoftheseverityoflong-termcomplicationsofhypoxic-ischemicencephalopathy(HIE)isdifficult,althoughclinical,laboratory,andimagingcriteriahavebeenused. [24]Thefollowingcriteriahavebeenshowntobethemosthelpfulinoutlininglikelyoutcomes: Lackofspontaneousrespiratoryeffortwithin20-30minutesofbirthisalmostalwaysassociatedwithdeath. Thepresenceofseizuresisanominoussign.Theriskofpoorneurologicoutcomeisdistinctlygreaterinsuchinfants,particularlyifseizuresoccurfrequentlyandaredifficulttocontrol. Abnormalclinicalneurologicfindingspersistingbeyondthefirst7-10daysoflifeusuallyindicatepoorprognosis.Amongthese,abnormalitiesofmuscletoneandposture(hypotonia,rigidity,weakness)shouldbecarefullynoted. EEGatabout7daysthatrevealsnormalbackgroundactivityisagoodprognosticsign. Persistentfeedingdifficulties,whichgenerallyareduetoabnormaltoneofthemusclesofsuckingandswallowing,alsosuggestsignificantCNSdamage. Poorheadgrowthduringthepostnatalperiodandthefirstyearoflifeisasensitivefindingpredictinghigherfrequencyofneurologicdeficits. ASwedishretrospectivepopulation-basedstudycomprising692,428livebirthsofatleast36gestationalweeksfoundthatmorethanaquarter(29%)ofallHIEbirthswereassociatedwithanobstetricemergency,withparouswomenaffectedmorethannulliparouswomen. [130] Theinvestigatorsnotedastrongassociationofshoulderdystociainnulliparas,andtouterineruptureinwomenwithpreviouscesareandeliveries. [130] Ofnote,theuseoftherapeutichypothermiachangestheprognosticvalueofclinicalevaluationininfantswithHIE,anditsimpactonpredictingoutcomesisstillunderevaluation. [25] Otherearlypredictorsoflong-termneurodevelopmentaloutcomesarebeingactivelyinvestigated.EarlyevidenceindicatesthatbiomarkerssuchasserumS100Bandneuron-specificenolasemaybehelpfulinidentifyinginfantswithseverebraininjurywhomaybecandidatesfornovelneuroprotectiveorneuroregenerativetherapies. [26] Morbidity/mortality InsevereHIE,themortalityrateisreportedly25-50%.Mostdeathsoccurinthefirstdaysafterbirthduetomultipleorganfailureorredirectionofcaretocomfortmeasuresasaresultofthegrimprognosis.Someinfantswithsevereneurologicdisabilitiesdieintheirinfancyfromaspirationpneumoniaorsystemicinfections. Theincidenceoflong-termcomplicationsdependsontheseverityofHIE.Asmanyas80%ofinfantswhosurvivesevereHIEdevelopseriouscomplications,10-20%developmoderatelyseriousdisabilities,andasmanyas10%arehealthy.AmongtheinfantswhosurvivemoderatelysevereHIE,30-50%mayhaveseriouslong-termcomplications,and10-20%haveminorneurologicmorbidities.InfantswithmildHIEtendtobefreefromseriousCNScomplications. TwotherapeutichypothermiatrialsprovidedupdatedinformationonmortalityandtheincidenceofabnormalneurodevelopmentaloutcomesinfantswithmoderatetosevereHIE. [27,28]Inthesetrials,23-27%ofinfantsdiedpriortodischargefromtheneonatalintensivecareunit(NICU),whereasthemortalityrateatfollow-up18-22monthslaterwas37-38%.Inthesetrials,neurodevelopmentaloutcomesat18monthswereasfollows: Mentaldevelopmentindex(MDI):Scoresof85orhigher,40%;70-84,21%;lessthan70,39% Psychomotordevelopmentindex(PDI):Scoresof85orhigher,55%;70-84,10%;lessthan70,35-41% Disablingcerebralpalsy-30% Epilepsy-16% Blindness-14-17% Severehearingimpairment-6% Datafromarandomizedcontrolledtrialwasevaluatedtodeterminetherelationshipbetweenhypocarbiaandtheoutcomeforneonatalpatientswithhypoxic-ischemicencephalopathy.Theresultsfoundthatapooroutcome(death/disabilityat18-22mo)wasassociatedwithaminimumpartialpressureofcarbondioxide(PCO2)andcumulativePCO2oflessthan35mmHg;deathanddisabilityincreasedwithgreaterexposuretoPCO2oflessthan35mmHg. [29] Evenintheabsenceofobviousneurologicdeficitsinthenewbornperiod,long-termfunctionalimpairmentsmaybepresent.Inacohortofschool-agedchildrenwithahistoryofmoderatelysevereHIE,15-20%hadsignificantlearningdifficulties,evenintheabsenceofobvioussignsofbraininjury.Thus,allchildrenwhohavemoderateorsevereHIEshouldbemonitoredwellintoschoolage. [30,31,32] Race-,sex-,andage-relateddemographics Noraceorsexpredilectionhasbeennoted. Bydefinition,HIEisseeninthenewbornperiod.PreterminfantscanalsosufferfromHIE,butthepathologyandclinicalmanifestationsaredifferent.Mostoften,theconditionisnotedininfantswhoaretermatbirth.Thesymptomsofmoderate-to-severeHIEarealmostalwaysmanifestedatbirthorwithinafewhoursafterbirth. Previous Next: PatientEducation Parentsareoftenconcernedaboutinfants'painanddistress,parental-infantbonding,andoutcomesfollowinghypothermiatreatment. [128]Keystoreassuringparentsofinfantsundergoinghyperthermiainclude consistentcommunication,regularupdates,andearly,balanceddiscussionsregardingpotentiallong-termoutcomes;parentalinvolvementindecisionmaking;andhavingstrongsupportmechanisms. [128] Previous ClinicalPresentation     References FerrieroDM.Neonatalbraininjury.NEnglJMed.2004Nov4.351(19):1985-95.[QxMDMEDLINELink]. PerlmanJM.Braininjuryintheterminfant.SeminPerinatol.2004Dec.28(6):415-24.[QxMDMEDLINELink]. GrowJ,BarksJD.Pathogenesisofhypoxic-ischemiccerebralinjuryintheterminfant:currentconcepts.ClinPerinatol.2002Dec.29(4):585-602,v.[QxMDMEDLINELink]. ShankaranS.Thepostnatalmanagementoftheasphyxiatedterminfant.ClinPerinatol.2002Dec.29(4):675-92.[QxMDMEDLINELink]. StolaA,PerlmanJ.Post-resuscitationstrategiestoavoidongoinginjuryfollowingintrapartumhypoxia-ischemia.SeminFetalNeonatalMed.2008Dec.13(6):424-31.[QxMDMEDLINELink]. 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ChoiDW,ParkJH,LeeSY,AnSH.Effectofhypothermiatreatmentongentamicinpharmacokineticsinneonateswithhypoxic-ischaemicencephalopathy:Asystematicreviewandmeta-analysis.JClinPharmTher.2018Aug.43(4):484-92.[QxMDMEDLINELink]. LiljestromL,WikstromAK,JonssonM.Obstetricemergenciesasantecedentstoneonatalhypoxicischemicencephalopathy,doesparitymatter?.ActaObstetGynecolScand.2018Jul6.[QxMDMEDLINELink]. MediaGallery Fetalresponsetoasphyxiaillustratingtheinitialredistributionofbloodflowtovitalorgans.Withprolongedhypoxic-ischemicinsultandfailureofcompensatorymechanisms,cerebralbloodflowfalls,leadingtoischemicbraininjury. Pathophysiologyofhypoxic-ischemicbraininjuryinthedevelopingbrain.Duringtheinitialphaseofenergyfailure,glutamatemediatedexcitotoxicityandNa+/K+ATPasefailureleadtonecroticcelldeath.Aftertransientrecoveryofcerebralenergymetabolism,asecondaryphaseofapoptoticneuronaldeathoccurs.ROS=Reactiveoxygenspecies. Severeacutehypoxic-ischemicneuronalchangeinthebasalgangliaisnoted.Histologicexaminationrevealsseverehypoxic-ischemicneuronalchange,characterizedbythepresenceofpyknoticandhyperchromaticnuclei,thelossofcytoplasmicNisslsubstance,andneuronalshrinkageandangulation(arrow).Thesealterationsbegintoappearapproximately6hoursfollowinghypoxic-ischemicinsult.Reactiveastrocytosisisevidentapproximately24-48hoursaftertheprimaryhypoxic-ischemicevent. Significantastrocytosisinthebasalgangliafollowinghypoxic-ischemicinsultisobserved.Animmunohistochemicalstainforglialfibrillaryacidicprotein(GFAP)wasperformedonthesametissueshowninthepreviousimagetodemonstratetheprominentgliosissecondarytothehypoxic-ischemicevent.GFAPisausefulmarkertostudyastrocyticresponsetoinjury.Thisgliosisofthebasalganglia,alongwithsubsequenthypermyelination,isresponsiblefortheevolutionofstatusmarmoratusovermonthstoyears. Bilateralacuteinfarctionsofthefrontallobeareshown.Theinfarctionsdepictedinthefigure(arrows)areconsistentwithwatershedinfarctionssecondarytoglobalhypoperfusion.Thelesionsdepictedintheimageareconsistentwithanacuteischemicevent,occurringwithin24hoursofdeath.Theregionsmostsusceptibletohypoperfusionincludetheend-arteryzonesbetweentheanterior,middle,andposteriorcerebralarteries. Apriorhypoxic-ischemiceventinvolvingtheoccipitallobehasresultedinachroniclesionmarkedbydyslamination,neuronalloss,anddisorganizedarrangementsofmyelinatedwhitematterfibers.Grossly,thelesionwasmarkedbypreservedgyralcrestsandinvolvedsulci,resultinginprominent,mushroom-shapedgyri. ALuxol-FastBluestainwasperformedonthesametissueshowninthepreviousimagetodemonstratethehaphazardarrangementofmyelinatedwhitematterfibersprojectingintothegraymatteroftheoccipitalcortex. Randomizedcontrolledtrialsoftherapeutichypothermiaformoderate-to-severehypoxic-ischemicencephalopathy(HIE). Periventricularleukomalaciaisdepicted.Thiscysticlesion,presentinthecingulatecortex,isconsistentwithperiventricularleukomalacia.Notetheextensivehemorrhagewithinthecysticspaceaswellasthehemosiderin-ladenmacrophagesaroundthelesionalrim. Periventricularleukomalaciaisdepicted.Thisfiguredepictsthelesionseeninthepreviousimageathighermagnification.Extensivehemosiderinandreactiveastrocytosisispresentsurroundingthelesion(centeroffield).Notetheproximityofthelesiontotheependymalliningofthelateralventricle(farright). Summaryofpotentialneuroprotectivestrategies. of 11 Tables Table.ModifiedSarnatClinicalStagesofPerinatalHypoxicIschemicBrainInjury [37] Table.ModifiedSarnatClinicalStagesofPerinatalHypoxicIschemicBrainInjury [37]   MILD MODERATE SEVERE LevelofConsciousness Alternating(hyperalert,lethargic,irritable) Lethargicorobtunded Stuporous NeuromuscularControl Muscletone Normal Hypotonia Flaccid Posture Normal Decorticate(armsflexed/legsextended) Intermittentdecerebration(armsandlegsextended) Stretchreflexes Normalorhyperactive Hyperactiveordecreased Absent Segmentalmyoclonus Present Present Absent ComplexReflexes Suck Weak Weakorabsent Absent Moro Strong;lowthreshold Weak;incomplete;highthreshold Absent Oculovestibular Normal Overactive Weakorabsent Tonicneck Slight Strong Absent AutonomicFunction Generalizedsympathetic Generalizedparasympathetic Bothsystemsdepressed Pupils Mydriasis Miosis Variable;oftenunequal;poorlightreflex HeartRate Tachycardia Bradycardia Variable BronchialandSalivarySecretions Sparse Profuse Variable GIMotility Normalordecreased Increased;diarrhea Variable Seizures None Common;focalormultifocal Delayed EEGFindings Normal(awake) Early:low-voltagecontinuousdeltaandthetaLater:periodicpattern(awake)Seizures:focal1-to1-Hzspike-and-wave Early:periodicpatternwithIsopotentialphasesLater:totallyisopotential Duration 1-3daysTypically<24h 2-14days Hourstoweeks BacktoList ContributorInformationandDisclosures Author SantinaAZanelli,MD AssociateProfessor,DepartmentofPediatrics,DivisionofNeonatology,UniversityofVirginiaHealthSystem SantinaAZanelli,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofPediatrics,AmericanEpilepsySociety,SocietyforNeuroscience,SocietyforPediatricResearchDisclosure:Nothingtodisclose. Coauthor(s) DirkPStanley,MD ResidentPhysician,DepartmentofPathology,UniversityofVirginiaHealthSystemDisclosure:Nothingtodisclose. DavidAKaufman,MD ProfessorofPediatrics,DivisionofNeonatology,UniversityofVirginiaSchoolofMedicine DavidAKaufman,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofPediatrics,MedicalSocietyofVirginia,PediatricInfectiousDiseasesSociety,SocietyforPediatricResearch,EuropeanSocietyforPaediatricInfectiousDiseasesDisclosure:Nothingtodisclose. SpecialtyEditorBoard MaryLWindle,PharmD AdjunctAssociateProfessor,UniversityofNebraskaMedicalCenterCollegeofPharmacy;Editor-in-Chief,MedscapeDrugReferenceDisclosure:Nothingtodisclose. BrianSCarter,MD,FAAP ProfessorofPediatrics,UniversityofMissouri-KansasCitySchoolofMedicine;AttendingPhysician,DivisionofNeonatology,Children'sMercyHospitalandClinics;Faculty,Children'sMercyBioethicsCenter BrianSCarter,MD,FAAPisamemberofthefollowingmedicalsocieties:AlphaOmegaAlpha,AmericanAcademyofHospiceandPalliativeMedicine,AmericanAcademyofPediatrics,AmericanPediatricSociety,AmericanSocietyforBioethicsandHumanities,AmericanSocietyofLaw,Medicine&Ethics,SocietyforPediatricResearch,NationalHospiceandPalliativeCareOrganizationDisclosure:Nothingtodisclose. ChiefEditor DharmendraJNimavat,MD,FAAP AssociateProfessorofClinicalPediatrics,DepartmentofPediatrics,DivisionofNeonatology,SouthernIllinoisUniversitySchoolofMedicine;StaffNeonatologist,ClinicalDirector,NICURegionalPerinatalCenter,HSHSStJohn'sChildren'sHospital DharmendraJNimavat,MD,FAAPisamemberofthefollowingmedicalsocieties:AmericanAcademyofPediatrics,AmericanAssociationofPhysiciansofIndianOriginDisclosure:Nothingtodisclose. AdditionalContributors TedRosenkrantz,MD Professor,DepartmentsofPediatricsandObstetrics/Gynecology,DivisionofNeonatal-PerinatalMedicine,UniversityofConnecticutSchoolofMedicine TedRosenkrantz,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofPediatrics,AmericanPediatricSociety,EasternSocietyforPediatricResearch,AmericanMedicalAssociation,ConnecticutStateMedicalSociety,SocietyforPediatricResearchDisclosure:Nothingtodisclose. Acknowledgements TheauthorsandeditorsofMedscapeDrugs&DiseasesgratefullyacknowledgethecontributionsofpreviousauthorTonseNKRaju,MD,tothedevelopmentandwritingofthisarticle. Close Whatwouldyouliketoprint? Whatwouldyouliketoprint? 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