JPediatr(RioJ).2014;90(2):102---104
www.jped.com.br
EDITORIAL
Amplitude
integrated
electroencephalogram
(aEEG):
has
it
found
its
niche
in
neonatal
intensive
care
unit?
夽
,
夽夽
Eletroencefalograma
de
Amplitude
Integrada
(aEEG):
será
que
ele
encontrou
seu
nicho
na
Unidade
de
Terapia
Intensiva
Neonatal?
Abbot
Laptook
Pediatrics,AlpertMedicalSchoolofBrownUniversity,NeonatalIntensiveCareUnit,WomenandInfantsHospitalofRhodeIsland, Providence,USA
There has been an important change in newborn inten-sive care for infants withencephalopathy assumed tobe ofahypoxic-ischemicorigin.Priorto2005,abrainspecific therapywasnotavailableandmanagementwaslimitedto intensivesupportivecare.Thelatterconsistedofcorrection ofphysiologic derangementsin blood pressure,acid-base, andminerals/electrolytes,treatmentofseizures,and sup-port of organ dysfunction, while waiting for the return of cerebral function. The demonstration that therapeu-tic hypothermia reduced death or disability in infants ≥
36 weeks gestation with perinatal hypoxia-ischemia has changedtheapproachtowardsinfantswithencephalopathy immediatelyafterbirth.Acriticalcharacteristicofthe ther-apy was that it needed to be initiated within 6hours of birthbasedonelegantlaboratorystudiesusingfetalsheep; thelatterconfirmedarelativelyshorttherapeuticwindow ofapproximately 6hoursafter ahypoxic-ischemic event.1
Giventhistimeframe,identificationofinfantsathighrisk of deathor disability was of paramount importance. The goal wastoavoid usinga new therapy withan uncertain
DOIoforiginalarticle:
http://dx.doi.org/10.1016/j.jped.2013.07.004
夽 Please cite this article as: Laptook A. Amplitude integrated
electroencephalogram(aEEG): hasitfoundits nicheinneonatal intensivecareunit?JPediatr(RioJ).2014;90:102---4.
夽夽SeepaperbyTosoPAetal.inpages143---8.
E-mail:[email protected]
safetyprofileamonginfantswhoinherentlywereatlowrisk ofanadverseoutcomefromhypoxia-ischemia.Initiationof clinical trialsof therapeutichypothermia,startingin 1999 withthe CoolCap trial,2 pushed the amplitude integrated
electroencephalogram (aEEG) totheforefront of diagnos-tic tools to facilitate identification of appropriate study candidates. The article by Tosoet al.,3 entitled‘‘Clinical
utilityofearlyamplitudeintegratedEEGmonitoringinterm newbornsatriskofneurologicalinjury’’,providesan appro-priatedescriptionofhowonecenterhasmovedfromusing theaEEGforinvestigativepurposesintorealworldclinical application. This article raises theissue of whetheraEEG hasfounditsplaceamongthediagnostictoolsusedwithin neonatalintensivecareunits.
Eligibility for many clinical trials in newborn inten-sive care consistsofdiscreet,categorical, readilydefined inclusion criteria such as birth weight, gestational age, or type/level of ventilator support. In contrast, inclusion criteria for newborn neuroprotection trials typically are tiered, whereby infants must demonstrate some evidence of impaired placental gas exchange (either biochemi-cally and/or clinically), followed by clinical evidence of moderate or severe encephalopathy using a neurological examination.Categorizing neurologicalfindingsafterbirth is a complex task,given transitional physiology,maternal medications/anesthesia, evolving neurological abnormali-ties (either toward improvement or deterioration), and non-hypoxic-ischemicetiologiesfor encephalopathy.Given these considerations and the subjectivity of neurological
Amplitudeintegratedelectroencephalogram(aEEG):hasitfounditsnicheinneonatalintensivecareunit? 103
examinations, some clinical trials desired a more objec-tivemeasureofcerebraldysfunction.TheaEEGappearsto have found a nicheby demonstratingthe electrical back-ground activity of the brain, which is highly correlated withthebackgroundpatternofconventional,fullmontage EEGrecordings. Abnormalitiesfound onaEEGearly in life have strong predictive indices for abnormal outcome at 1 year of age. For example, Toet et al. studied 72 term infants with evidence of perinatal hypoxia-ischemia with asinglechannelaEEGrecordedat 3and6hoursfollowing birth.Therecordingwasclassifiedbypatternrecognitionas continuous normal voltage, discontinuous normalvoltage, burst suppression, continuous low voltage, or flat trace.4
Follow-up at more than 1 year of age was accomplished in93% of thecohort.The abilitytopredict anormal out-come afteranormaltracing washigh. The sensitivityand specificity of abnormal patterns (burst suppression, con-tinuous low voltage, and flat trace) for predicting poor outcomes were 85% and 77%, respectively, at 3hours of age,andwas91%and86%,respectively, at6hoursofage. A meta-analysisof eight cohortstudies reported the pre-dictiveindicesofaEEGfordeathordisabilityamongterm infants withHIE:sensitivity was91%, specificitywas 88%, positivelikelihood ratiowas10.1, andthenegative likeli-hoodratiowas0.09.5Intheeraoftherapeutichypothermia,
onestudyreportedthatthepositivepredictivevalueofthe aEEGobtainedwithin6hoursofbirthforpredicting abnor-maloutcomeat18monthswas84%ininfantswithperinatal hypoxia-ischemia;moderatehypothermiareducedsuch pre-dictivevaluesduetheneuroprotectionassociatedwiththe therapy.6
As encouraging as these early aEEG studies were, not all clinical trials of therapeutic hypothermia have used the aEEG to identify eligible patients. In the Cochrane meta-analysis, only three of the six major clinical trials oftherapeutichypothermiaforperinatalhypoxia-ischemia usedaEEGforpatienteligibility.7Trialsthatdidnotusethe
aEEGlimitedtheirinclusioncriteriatobiochemicaland/or clinicalindicators ofimpaired placental gasexchangeand the presence of moderate or severe encephalopathy.8---10
WhethertrialsthatusedaEEGforeligibilityenrolledinfants withadifferentlevelofseverityofencephalopathy(which abrief neurologicalexamination maynotdetect) remains unclear.Incontrasttothecohortstudiesabove,the analy-sisof314aEEGrecordingsfromtheTOBYrandomizedtrialof hypothermia11indicatedthatthepositivepredictivevalueof
anabnormalaEEGforadverseoutcomeat18monthsofage (deathordisability)waslowerthanthatreportedincohort studies (0.59 and 0.51 for non-cooled and cooled infants byvoltagerecognition,respectively).Theseresultssuggest thathigherpredictiveindicesreportedfromobservational, non-randomizedtrialsthatincludedhistoricalcontrolsand sub-groupsfromrandomizedtrialsmaybesubjectto selec-tionbias.TheresultsfromtheTOBYtrialareinagreement withthereportfromtheNICHDNeonatalResearchNetwork of 108 infants, whichincluded 46infants from theNICHD wholebodycoolingtrial6and62infantswhowereenrolled
afterthetrial.12Thepositivepredictivevalueforanadverse
outcome at18 months(death or disability)was0.56, and didnotdifferwhethertheaEEGwasacquiredat<6hoursof ageorbetween6and9hoursofage.Similartotheresults oftheTOBYtrial andthereportfromThorsenetal.,6 the
positivepredictivevalueofaEEGwasreducedby hypother-miatherapy,reflectingtheneuroprotectionaffordedbythis treatment.
Wheredoes this leave a clinicianregarding the use of aEEGfordecidingwhethertherapeutichypothermiashould beinitiated?Intheabsenceofabiomarkerwithhighpositive andnegativepredictiveindicesforoutcomeat18monthsof age,aEEGisstillaveryvaluabletool,butitshouldbeusedin conjunctionwithaneurologicalexaminationforinfantswith evidenceofacuteimpairmentofgasexchange.Itmaybeof greatestuseininfantswhohavesomefeaturesof encepha-lopathy,when theexamination borders betweenmild and moderateseverity.Thisisespeciallyimportantforclinicians wholackexperiencewithneurologicalexamination,sinceit canbechallengingincriticallyillinfants.Inthepresenceof unequivocalmoderateorsevereencephalopathy,the pres-enceofa‘‘normal’’aEEGshouldnotprecludeinitiationof therapeutichypothermia,givenasuboptimalnegative pre-dictivevalueoftheaEEG.13
Other applications of aEEGhave emergedsince it was firstevaluated as a toolto identify infants for neuropro-tection.Itistechnically easytomaintainaEEGrecordings during the duration of therapeutic hypothermia; this has facilitatedexaminingtherecoveryofaEEGbackground pat-ternasanotherpotentialprognosticmarker.Thesestudies indicatethatthenaturalhistoryoftheaEEGpatternafter a putative perinatal event can be quite diverse. An ear-lierreturn tonormalof the background patternhas been associated with a better outcome at 24 months, espe-ciallyifthisoccursinthefirst24hoursafterbirth;14 some
authors have concluded that the recovery time toa nor-mal background is the best predictorof poor outcome in earlychildhood.6Otherreportsindicatethatthepresence,
timeofreturn,andqualityofsleep-wakecyclesreflectthe severityoftheperinatalhypoxic-ischemicevent.15
Further-more,thetimeof returnof sleep-wakecycle activityhas predictive value for neurodevelopment. In a consecutive series of 171 term infants born between 1992 and 2002, each increase in hour from birth to the return of sleep-wakecycleswasassociatedwitha0.96decreaseintheodds ofa goodoutcome at 12 to66 monthsof age (95% confi-denceinterval,0.94-0.98).15Smallercohortshavesuggested
similarconclusions.16Thebeneficialeffectsofhypothermia
ontheneurodevelopmentaloutcome isthoughttoexplain why the time to return of sleep-wake cycles is a better predictor of early childhood outcome for infants treated withhypothermiacomparedtothosekeptnormothermic.6
Notably, all of these reports are retrospective, cohort studies. An important observational cohort study entitled ‘‘Predictionofoutcomeinhypoxic-ischemicencephalopathy usingamplitude integratedEEG’’ is being performed asa secondarystudy totheNICHD Neonatal ResearchNetwork trial ‘‘Optimizing cooling strategies at < 6hours of age for neonatal hypoxic-ischemic encephalopathy’’ (Clinical-Trials.Gov:NCT01192776).Thissecondarystudyisdesigned totest the ability ofan aEEGacquired beyond6hoursof agetopredict deathor disabilityat18-22monthsinterm infantswithencephalopathyinthesettingofarandomized trial.
104 LaptookA
ofneonatalseizures,possibleclinical-electrographic disso-ciation,andtherealworldissuesofobtainingaconventional EEGonshortnoticeinmanyneonatalintensivecareunits, especiallyon weekends, evenings, or holidays. Given the limitednumberof channels andelectrodes ofan aEEG,it iswellrecognizedthatseizuresdistantfromtherecording electrodes will not be detected. Time compression facil-itates inspection and monitoring of background activity, but limits detection of short seizures. The identification of electrographic seizures using aEEG has improved with the inclusion of the raw EEG tracing on most current aEEG devices. Validated computerized seizure detection algorithmswill furtherenhance theutility of aEEG. Qual-ity assurance issues regarding the adequacy of training and expertise of providers within NICUs who interpret aEEG recordings is a difficult issue for seizure detection and characterization of background activity. Interpreta-tionof seizures is probably more challenging, since most cliniciansdonothave abackgroundin electroencephalog-raphy.
Toso et al. also describe an application of aEEG for infants withsevere respiratory distress. Infants with non-neurological conditionscan be challenging to assess by a conventionalneurologicalexamination.Infantswithsevere respiratory distresscan manifest decreased activity, poor tone, and sluggish response to stimuli, all secondary to theseverityoftheunderlyingpulmonarycondition. Assess-mentofconsciousnesslevel canbeperformed inverysick infants, but is often obscured by the sedative-hypnotic agents used in conjunction with respiratory support. The aEEGprovidesan attractivemeans toassess the integrity ofthecentralnervoussystemof infantswhoarecritically illwhenotherconventionalmonitoringtechniques(e.g.,full montageEEG)arenotavailable.AsaEEGisappliedto dif-ferent cohorts of infants, it will always be important to continuetocriticallyassesstherelationshipbetweenaEEG data and early childhood outcomes. Since most of these evaluationswill typicallybe performed in the absenceof arandomizedtrial, carefulstudy design willbenecessary inordertoacquireinformationinamannerasunbiasedas possible.
Conflict
of
interest
Theauthordeclaresnoconflictsofinterest.
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