www.jped.com.br
REVIEW
ARTICLE
Hypothermia
therapy
for
newborns
with
hypoxic
ischemic
encephalopathy
夽
Rita
C.
Silveira
a,b,
Renato
S.
Procianoy
a,b,∗aDepartmentofPediatrics,UniversidadeFederaldoRioGrandedoSul(UFRGS),PortoAlegre,RS,Brazil
bNeonatologyService,HospitaldeClínicasdePortoAlegre,PortoAlegre,RS,Brazil
Received31July2015;accepted3August2015 Availableonline4September2015
KEYWORDS
Hypothermia; Neonates;
Perinatalasphyxia; Hypoxic-ischemic encephalopathy; Outcomes
Abstract
Objective: Therapeutichypothermia reduces cerebralinjury and improves theneurological outcome secondarytohypoxic ischemic encephalopathyinnewborns. Ithas beenindicated forasphyxiatedfull-termornear-termnewborninfantswithclinicalsignsofhypoxic-ischemic encephalopathy(HIE).
Sources: A searchwasperformedfor articles ontherapeutic hypothermiainnewborns with perinatalasphyxiainPubMed;theauthorschosethoseconsideredmostsignificant.
Summaryofthefindings: There are two therapeutic hypothermia methods: selective head coolingandtotalbodycooling.Thetargetbodytemperatureis34.5◦Cforselectivehead cool-ingand33.5◦Cfortotalbodycooling.Temperatureslowerthan32◦Carelessneuroprotective, and temperaturesbelow 30◦Care very dangerous, with severe complications. Therapeutic hypothermiamuststartwithinthefirst 6hafterbirth, asstudieshaveshown thatthis rep-resentsthetherapeuticwindowforthehypoxic-ischemicevent.Therapymustbemaintained for72h,withverystrictcontrolofthenewborn’sbodytemperature.Ithasbeenshownthat therapeutichypothermiaiseffectiveinreducingneurologicimpairment,especiallyinfull-term ornear-termnewbornswithmoderatehypoxic-ischemicencephalopathy.
Conclusion: Therapeutichypothermiaisaneuroprotective techniqueindicated for newborn infantswithperinatalasphyxiaandhypoxic-ischemicencephalopathy.
©2015SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.Allrightsreserved.
夽
Pleasecitethisarticleas:SilveiraRC,ProcianoyRS.Hypothermiatherapyfornewbornswithhypoxicischemicencephalopathy.JPediatr (RioJ).2015;S91:78---83.
∗Correspondingauthor.
E-mail:rprocianoy@gmail.com(R.S.Procianoy).
http://dx.doi.org/10.1016/j.jped.2015.07.004
PALAVRAS-CHAVE
Hipotermia terapêutica; Recém-nascidos; Asfixiaperinatal; Encefalopatia hipóxicoisquêmica; Desfechos
Hipotermiaterapêuticapararecém-nascidoscomencefalopatiahipóxicoisquêmica
Resumo
Objetivo: Ahipotermiaterapêuticareduzalesãocerebralemelhoraodesfechoneurológico derecém-nascidosapósinsultohipóxicoisquemico.Indicadapararecém-nascidosatermoou próximodotermocomevidênciadeasfixiaperinataleEncefalopatiaHipóxicoIsquemica(EHI). Fontesdosdados: FoifeitaumaprocuranoPubMedporpublicac¸õessobrehipotermia terapêu-ticaemrecém-nascidoscomasfixiaperinataleselecionadasaquelasjulgadasmaisrelevantes pelosautores.
Síntesedosdados: Háduastécnicasderesfriamentocorpórea:hipotermiaseletivadacabec¸a ehipotermiacorpóreatotal.Atemperaturaderesfriamentodeveser34,5◦Cparaseletivade cabec¸ae33,5◦Cparacorpóreatotal;temperaturasinferioresa32◦Csãomenos neuroprote-toraseabaixode30◦Cháefeitosadversossistêmicosgraves.Indica-seoiníciodahipotermia terapêuticaaté6horasapósonascimento,poisestudosevidenciaramqueestaéajanela ter-apêuticadaagressãohipóxicoeisquêmica.A hipotermiadevesermantidapor72horascom rigorosamonitorizac¸ãodatemperaturacorporaldorecém-nascido.Ahipotermiatemsido efe-tivaemreduzirseqüelasneurológicas,principalmenteemrecém-nascidosdetermooupróximo dotermo comencefalopatia hipóxicoisquêmicamoderadaeemmelhoraroprognósticoem longoprazodosrecém-nascidoscomEHI.
Conclusão: A hipotermia terapêutica é uma técnica neuroprotetora indicada para recém-nascidoscomasfixiaperinatal.
©2015SociedadeBrasileiradePediatria.PublicadoporElsevierEditoraLtda.Todososdireitos reservados.
Introduction
Morethanadecade ago,experimentalevidence,and sub-sequently, good-quality clinical trials initially appeared, suggestingthattherapeutichypothermiareducesbrain dam-age and improves neurological outcome after neonatal hypoxic-ischemic injury.1---4 The best result in terms of therapeutic hypothermia prognosis seems to be in mild to moderate injuries, while the real benefit has been questionedforinfantswithsevereencephalopathy.A mul-ticenter study by the NICHD (National Institute of Child HealthandHumanDevelopment)showedthatcases persist-ingwithseverehypoxic-ischemicencephalopathy(HIE)signs andalteredneurologicalassessmentatthedischargefrom theneonatologyserviceafter72hoftherapeutic hypother-miahadhighermortalityormorbidityinthefollow-upat18 monthsoflife.5
The extent of cerebral injury following a hypoxic-ischemic insultbasically dependsonthebalancebetween thecausativemechanismsofirreversibleinjury,such neu-ronalnecrosisor persistentinflammation,andendogenous protection (acute phase response, recovery, and neu-ronalrepair).The neuroprotectivestrategyoftherapeutic hypothermia involves themodulation of some irreversible injurymechanisms,suchasinflammatorycascadeinhibition, reducedproductionofreactiveoxygenspecies,reductionin themetabolic ratewithreducedoxygen consumption and carbon dioxide production, and an endogenous neuropro-tectiveeffect.6---9
Theobjectiveofthisreviewistounderstandthe mech-anismofaction oftherapeutic hypothermia,searchingfor evidenceintheliteraturetoestablishthetypeofnewborn thatisagoodcandidateforthistypeoftherapy,describing
theprotocol, possible complications, and supportive care forthemanagementofnewbornssubmittedtotherapeutic hypothermia.
Mechanism
of
action
of
therapeutic
hypothermia
Hypothermiaresultsinareductionofcerebralmetabolism byapproximately5%foreach1◦Cdecreaseinbody
temper-ature,whichdelaystheonsetofanoxiccelldepolarization. Thereductionin excitatoryaminoacids suchasaspartate and glutamate, during the ischemic phase of therapeutic hypothermia,is due to the factthat they promote depo-larizationdelayandintracellularcalciuminfluxreduction. These effects have been demonstrated in different man-nersinexperimentalmodelsofischemiaandreperfusionin rodentsaftercardiacarrestinyoungadultdogs,orduring andimmediately afterhypoxic-ischemicinjuryinnewborn pigs.8
Hypoxia-ischemia-reperfusioninjury in thecentral ner-voussystemactivatesapro-inflammatorycascadeofevents characterizedbyleukocyteinflux,including polymorphonu-clearcellsandmonocytes,andmicroglialactivation.Many oftheseinflammatoryreactionsaremediatedbycytokines, especially neuronal apoptosis modulation. The cytokines withbest-knownactionsintheCNSare:TNF-␣,IL-1,and IL-6.Part of theneuroprotective effectofhypothermia is duetoproinflammatorypathwayblockade.6,8
IL-1, IL-8, and PAF (platelet activating factor) occurs through several interactions.10 Furthermore, through the actionsofsolublereceptors,IL-6,IL-1,andTNF-␣increase theexpressionofadhesionmolecules,especially intercellu-laradhesionmolecule-1(ICAM-1)inendothelialcellsandin astrocytes,facilitatingleukocyteinfiltrationandincreasing leukocyte activation, with consequent promotion of sys-temicinflammatoryresponseasthefinal result.Cytokines inducenitricoxidesynthetaseenzyme,which,togetherwith TNF-␣ and IL-1, promotes neurotoxic effects.8,9 Caspase activationmayinducelocalinflammatoryresponseinvolving energyconsumption and increase in thenumber of apop-toticneurons,withthepossibilityofinjuryreversal,which isneuroprotective.6
Inexperimentalmodels,prolongedhypothermia mecha-nism(72h)inducedthereductionofnecrosisandneuronal apoptosis.7,11 Cytochrome C suppression by mitochondria wasdemonstrated,aswellasactivationofcaspase3inthe cortex, thalamus, and hippocampusof rats withHIE that receivedhypothermiatherapyfor72h.11
Therapeutic
window
Hypoxic-ischemicinsultinvolvesanongoinginjuryprocess, where the severity of HIE depends on the duration and extent of this process. The central role of therapeutic hypothermiainneuroprotectioninvolvestheinterruptionor reductionofthisprocess;essentiallydividedintoacuteor primaryphase,in which some neural cells dieandothers recover,at leastpartially;thelatent phase,withpartially recoveredoxidativemetabolism,evenwithsuppressed elec-troencephalographic activity9; and the secondary phase, which occurs after moderate to severe injury, initiating hours later, on average within 6 up to 15h, clinically manifestedbythe presenceof seizures,cytotoxicedema, accumulation of excitatory amino acids, and failure of mitochondrialoxidative activity, which is the main factor associatedwithneuronaldeath.
Itisimportant toactbeforethesecondary phase, dur-ingthetherapeuticwindowofopportunitywhenapoptotic neuronsareabletorecover.The degree of energyfailure determinesthetypeofneuronaldamage(death)duringthe early and late stages, and the degree of trophic support influencesangiogenesisandneurogenesisduringthe recov-eryphaseofHIE.
Although exactly when the brain injury becomes irreversiblehasyet tobe preciselyestablished, thereare consistent data indicating that the latency phase, also knownastheearlyphaseofrecoveryfromtransient restora-tionofcerebral oxidativemetabolism,beforethestart of thesecondaryphaseofenergyfailure,representsthebest window for therapeutic intervention.8 Because this is an ongoingprocess,thesephasesareclose,andthereforethe transitiontothemomentofirreversiblecelldeathisalmost imperceptible.11,12
Since the first series of clinical cases of perinatal asphyxia,therapeutichypothermiainitiationhasbeen indi-cated within 6h after birth, due to all the experimental evidencedemonstratingthatthisrepresentsthetherapeutic windowtoinhibitorreducethehypoxic-ischemicinjury.11
Meet both criteria:
1. Evidence of perinatal asphyxiaumbilical cord blood Umbilical cord blood gas analysis or in the first hour of life with pH < 7.0 or EB < -16
Or history of perinatal acute event (placental abruption, cord prolapse)
Or Apgar score ≤5 in the 10th minute of life Or need for ventilation beyond the tenth minute of life and
2. Evidence of moderate to severe encephalopathy before 6 hours of life: Seizures, level of consciousness, spontaneous activity, posture, tone, reflexes, and autonomic system.
Figure1 Therapeutichypothermiaindication.
Selection
of
newborn
candidates
for
therapeutic
hypothermia
Inthe2010Consensus,theInternationalConsensuson Car-diopulmonaryResuscitation(ILCOR)includedtheindication of therapeutic hypothermiafor every newbornat termor neartermwhohaddevelopedmoderatetosevereHIE,using aspecificprotocolandfollow-upcoordinatedbytheregional referencecaresystem.13
Overall, the indication of therapeutic hypothermia for newbornsfollowstherecommendationsfoundonthesiteof theBrazilianSocietyofPediatricsandILCOR13,14:newborns withgestationalage>35weeks,birthweight>1800g,who havefewerthan6hoflife,andmeetthefollowingcriteria.14 Evidenceofperinatalasphyxia:umbilicalcordbloodgas analysis or in the first hour of life with pH <7.0 or base excess(EB)<−16or historyofperinatalacuteevent
(pla-centalabruption,cordprolapse),orApgarscoreof5orless inthe10thminuteoflife,orneedformechanical ventila-tionbeyondthe10thminuteoflife,oranyofthefollowing associatedwithevidence ofmoderate tosevere encepha-lopathy before6h oflife: seizure,level ofconsciousness, spontaneousactivity,posture,tone,reflexes,andautonomic system(Fig.1).14
approximatelyhalf ofthenewbornswithHIEsubmittedto therapeutichypothermia.17---19
Amplitude-integratedelectroencephalogram(aEEG) has been used in a few studies to decide whether a new-born with encephalopathy is a candidate for therapeutic hypothermia.20,21 In neonates with mild HIE,a study with a smallsample sizeshowedtobe moreeffective in iden-tifyingwhichpatientswithencephalopathywoulddevelop severeneurologicaldiseases.22
The use of aEEG is relevant considering that the time todecidewhetheranewbornisacandidatefortherapeutic hypothermiaislimited,andanymistakesregardingthestart ofsuchapromisingtreatmentshouldbeavoided; neverthe-less,theaEEGisnotroutinelyusedtoselectcandidatesfor thistypeoftherapy.13---15,23
Results
and
prognosis
after
therapeutic
hypothermia
Hypothermia has been effective in reducing neurological sequelae,particularlyinnewbornswithmoderateHIE,and inimprovingthelong-termprognosisofnewbornswithHIE. Meta-analysisstudieshaveshownthattheuseof therapeu-tichypothermiadecreasesmortalityandimprovesprognosis regardingtheneurodevelopmentofinfantswithHIE.1,4,5
There is evidence from three large randomized trials and two small clinical trials demonstrating that induced hypothermia (33.5---34.5◦C), when started within the 6-h
windowafterthebirthoffull-termasphyxiatednewborns, isbeneficialinreducingmortalityandneurodevelopmental delay assessed by theBayley scale in the follow-upat 18 monthsoflife.20,21,24---26 Theresultsarebetterifthereare well-organized protocols for hypothermia indication and induction,aswellasadequaterewarming.1,24
In the context of the newborn candidate for thera-peutic hypothermia, it has been observed that maternal hyperthermia is associated withhigh incidenceof perina-talrespiratorydepression,neonatalseizures,cerebralpalsy, and higher neonatalmortality, confirming the deleterious effectof hyperthermia. Itis possible that in situationsof maternalchorioamnionitisandfetalinflammatoryresponse syndrome in utero, the result of therapeutic hypother-mia is limited. In the presence of infection/inflammation in a randomized clinical trial of therapeutic hypothermia afterencephalopathysecondarytobacterialmeningitis,the choice of therapeutic hypothermia was ineffective.27 MRI data obtained after therapeutic hypothermia in a small prospectivestudyofnewbornswhosemothershad histolog-icalchorioamnionitis demonstrated that hypothermia was lesseffectiveinthisinfectiouscondition.28
Hyperthermia after neonatal HIE is associated with highermortalityandadverseneurologicaloutcomeat18---22 monthsof age and at 6---7years of age,withlower intel-ligence scores and an up to 3.5-fold higher incidence of moderatetoseverecerebralpalsyinnewborninfantswith highertemperaturesinthefirstdaysafterbirth.29,30 There-fore, high temperature after the hypoxic ischemic insult representsan additionalrisk factor for adverse outcomes and,avoidinghyperthermia isasimportantastherapeutic hypothermiainthesecases.
Theresultsoftherapeutichypothermiaarestrongly influ-enced by the severity of HIE. Several experimental and clinical studies have concluded that the neuroprotective actionoftherapeutichypothermiaislesseffectiveinsevere HIE,partlybecausethelatencyperiodisevenshorter,with higherenergyfailureandacceleratedneuronalnecrosisof corticalgray matter, basal ganglia,thalamus, andserious damagetothewhitematter,associatedwithcerebralpalsy atvaryinglevels.1Ameta-analysisshowedthattherapeutic hypothermia wassignificantly protective for the outcome deathanddisabilityin casesofHIE,withbetterresultsin moderatethaninseverecases.Thechallengeistoableto individualizethedecisiontoinitiatetherapeutic hypother-miainsevere cases,especiallysincetheestablishment of encephalopathyseverityisdifficult,imprecise,and subjec-tivewhenbasedonlyonclinicalevaluation.4
All patients undergoing hypothermia therapy should be followed longitudinally to establish the long-term outcome.5,13 Moreover, for the hypothermia to be effec-tive, a high level of neonatal intensive care support is required; notall centers arecapable of performing ther-apeutichypothermia.
Protocol:
establishing
safety
and
efficacy
Randomized clinical trials have employedtwo body cool-ing techniques in order to inhibit, reduce, and improve brainlesion evolution and neurological sequelae resulting fromHIE:selectiveheadhypothermia20withtemperatures reducedto34.5◦C,andtotalbodyhypothermiawith
tem-peraturereducedto33.5◦C4,24;bothtechniquesrecommend
the maintenance of hypothermia for 72h. According to ILCOR,bothtechniquesareappropriate,andtherewarming phasemustbeslowandgradual,conductedovera4-hperiod withanincrease of 0.5◦C per houruntilthe temperature
reaches36.5◦C;thisprocessaimstopreventcomplications
causedbyrapidrewarming.1,13,15
Selectiveheadcoolingisperformedwithahelmet,and total body cooling with a thermal mattress in which the infant is placed, with a servo control apparatus to regu-latethemattresstemperaturehigherorloweraccordingto thepatient’stemperature.21,24 The useoficepacks isnot thebestmethodbecausethemonitoringofthermalcontrol isprecarious, although arandomizedstudy employedthis techniquein moderate HIE,recommending it asan alter-native if started within 6h after the event and until the newbornis able to betransferred toa referral center to undergotherapeutichypothermia.31
The temperature must remain above 33◦C during the
entire hypothermia period;temperatures below 32◦C are
less neuroprotective, and very severe systemic adverse effects and increased mortalityhave been observed with temperatures below 30◦C.1,13,15 To ensure the
effective-nessand safety of total body cooling, the esophageal or rectaltemperature should be maintained at 33.5◦C, and
for selective head cooling, at 34.5◦C; the temperature
temperature (32◦C) or both; the study was interrupted
beforetheestimatedsamplesizewasachieved.32
AllprotocolsofstudiesonneuroprotectionafterHIEwith therapeutichypothermiahadsimilarinclusioncriteria (ges-tational age>35---36 weeks, significant acidosis or severe depression at birth, moderate to severe encephalopathy withorwithoutaEEG).Inthemajority,theexclusioncriteria wereageolderthan6hoflife,chromosomalabnormalities, andmajorcongenitalmalformationsorsevereintrauterine growthrestriction.3,20,21,24---26
Althougharecentstudyconsecutivelycompared83cases of therapeutic hypothermia, including 34 newborns sub-mitted to selective head cooling and 49 to total body cooling,thefindingsofbraindamagebaseduponMRIwere more severe and frequent in the selective head cooling group,suggestinggreaterneuroprotectioninnewbornswho weresubmittedtothetotalbodycoolingtechnique33; how-ever, other studies suggest the same benefit with both techniques.1
Intheabsenceofadequateconditions,ventilation,and hemodynamic support, as well as constant temperature monitoringateverystage,cooling,andrewarming, thera-peutichypothermiaforneonatalHIEhasshownunfavorable resultsand isnot recommended,asitincreasesmortality intheseconditions.34 Proceduralsafetyrequiresmonthsof multidisciplinary team training, with emphasis on under-standingthemultisystemicinvolvementrelatedtoperinatal asphyxia,associatedwithpotentialsystemiccomplications ofthistreatmentmodality.35
The possible adverse effects of hypothermia therapy should be carefully monitored, such as hypotension and prolongedQTinterval,thrombocytopenia,andclotting dis-orders in general (altered prothrombin time --- PT and activatedpartialthromboplastin time--- aPTT),skin burns andscleredema,andmetabolicandelectrolyticdisorders.35 It is important to recognize that some events are not directly related to therapeutic hypothermia but rather to multiorgan dysfunction, which characterizes hypoxic ischemic syndrome andoverlaps withthe adverse effects ofneonataltherapeutichypothermia.Oneexampleis per-sistent pulmonary hypertension (PPH),directly associated withperinatalasphyxiaand,conversely,hyperthermiacan cause hemoconcentration, hyperviscosity, and pulmonary vasoconstriction.10,35 A meta-analysis of four randomized clinicaltrialsshowednohypoglycemiainthegroup submit-tedtotherapeutichypothermia.1
These adverse events are more associated with lower temperatures than those recommended in the protocols, thustheimportanceofcarefulmonitoring.Adequate knowl-edge of how hypothermia affects all organ systems of asphyxiatednewborns thatarealreadyseverelyill is crit-icaltopreventandavoidthecomplicationsofexaggerated cooling.35
Thepharmacokineticsofsomedrugsisalteredbycooling. Inanobservational study,newborns withHIEtreated with hypothermiaandreceivingnormal morphineinfusionshad significantlyhigherserumconcentrationsofthelatterwhen comparedto the group with normal temperature. There-fore,therateofmorphineinfusionmustbelowerthanthat usuallyrecommendedduringtherapeutichypothermia.36
All the evidence suggests that the neuroprotective responseistime-dependent(therapeuticwindow)andthat
effectivenessdependsoninitiatingtheprotocolinupto6h. Inpractice,itisnecessarytoconsideratthistime,thatthe cribshouldbealreadyoff andthethermometershouldbe inserted(ifitistransesophageal,achestX-rayisobtained to assess whether it is well placed; i.e., middle-third of theesophagus).Bycontinuallyassessingbodytemperature, evenbeforeusingthetotalbodyhypothermiamattress,the physiciansensurethesafetyandcarequalityoftheprotocol. After72h,therewarmingphaseshouldbecarefully moni-tored,asfluctuationsincerebralbloodflowareassociated withbrainhemorrhageafterfastrewarming.Near-infrared spectroscopy (NIRS) is an effective tool to monitor brain perfusionchangesinnewbornswithHIEsubmittedto ther-apeutichypothermia.37
Conclusion
Therapeutic hypothermia significantly reduces morbidity and mortality for many asphyxiated newborns. However, somestilldieorsurvivewithsequelaeat varyinglevelsin outpatientfollow-up,demonstratingthe needfor associa-tionwithotherneuroprotectivestrategies.Thesafetyand effectiveness ofprotocolsperformed in referencecenters must becontinuouslyassessed.In thisreview,evidence is providedthatsupportsthebenefitoftherapeutic hypother-miaininfantswithmoderateencephalopathy.Afuturegoal willbefindingwaystoimprovetherapyeffectiveness.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
References
1.Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA. Hypothermiafor neonatalhypoxic ischemic encephalopathy: anupdatedsystematicreviewandmeta-analysis.ArchPediatr AdolescMed.2012;166:558---66.
2.ShankaranS,LaptookA, Wright LL,Ehrenkranz RA,Donovan EF,FanaroffAA,et al.Whole-bodyhypothermiafor neonatal encephalopathy: animal observations as a basis for a ran-domized, controlled pilot study in term infants. Pediatrics. 2002;110:377---85.
3.ThoresenM,WhitelawA.Therapeutichypothermiafor hypoxic-ischaemicencephalopathy in the newborn infant. Curr Opin Neurol.2005;18:111---6.
4.EdwardsAD,BrocklehurstP,GunnAJ,HallidayH,JuszczakE, LeveneM,etal.Neurologicaloutcomesat18monthsofage aftermoderatehypothermiafor perinatal hypoxicischaemic encephalopathy:synthesisandmeta-analysisoftrialdata.Br MedJ.2010;340:c363.
5.ShankaranS,LaptookAR,TysonJE,EhrenkranzRA,BannCM, HigginsRD,et al. Evolutionofencephalopathy duringwhole bodyhypothermia for neonatal hypoxic-ischemic encephalo-pathy.JPediatr.2012;160:567---72.
6.YuanJ,YanknerBA.Apoptosisinthenervoussystem.Nature. 2000;407:802---9.
7.NorthingtonFJ,GrahamEM,MartinLJ.Apoptosisinperinatal hypoxic-ischemicbraininjury:howimportantisitandshouldit beinhibited?BrainRes.2005;50:244---57.
9.DruryPP,BennetL,GunnAJ.Mechanismsofhypothermic neu-roprotection.SeminFetalNeonatalMed.2010;15:287---92.
10.Silveira RC, Procianoy RS. Interleukin-6 and tumor necrosis factor-alevelsinplasmaandcerebrospinalfluidofterm new-bornsinfantswithhypoxic-ischemicencephalopathy.JPediatr. 2003;143:625---9.
11.Ohmura A, Nakajima W, Ishida A, Yasuoka N, Kawamura M, MiuraS, et al. Prolongedhypothermiaprotects neonatalrat brainagainsthypoxic-ischemiabyreducingbothapoptosisand necrosis.BrainDev.2005;27:517---26.
12.Northington FJ, Chavez-Valdez R, Martin LJ. Neuronal cell death in neonatal hypoxia-ischemia. Ann Neurol. 2011;69: 743---58.
13.Perlman JM, Wyllie J, Kattwinkel J, Atkins DL, Chameides L,Goldsmith JP, etal. Part11: neonatalresuscitation: 2010 internationalconsensusoncardiopulmonaryresuscitationand emergencycardiovascularcaresciencewithtreatment recom-mendations.Circulation.2010;122:S516---38.
14.Procianoy RS. Hipotermia terapêutica. SBP. Departamento de Neonatologia. Documento científico [cited 2015 Jul 25].Availablefrom: http://www.sbp.com.br/pdfs/hipotermia-terapeutica.pdf.
15.JacobsSE,BergM,HuntR,Tarnow-MordiWO,InderTE,Davis PG.Coolingfor newbornswithhypoxicischaemic encephalo-pathy.CochraneDatabaseSystRev.2013;1:CD003311.
16.MillerSP,RamaswamyV,MichelsonD,BarkovichAJ,Holshouser B,WycliffeN,etal.Patternsofbraininjuryintermneonatal encephalopathy.JPediatr.2005;146:453---60.
17.GunnAJ,WyattJS,WhitelawA,BarksJ,AzzopardiD,Ballard R,etal.Therapeutichypothermiachangestheprognosticvalue ofclinicalevaluation ofneonatal encephalopathy.JPediatr. 2008;152:55---8.
18.MurrayDM,BoylanGB,RyanCA,ConnollyS.EarlyEEGfindingsin hypoxic-ischemicencephalopathypredictoutcomesat2years. Pediatrics.2009;124:e459---67.
19.Nash KB, BonifacioSL, GlassHC, Sullivan JE, BarkovichAJ, Ferriero DM, et al. Video-EEG monitoring in newborns with hypoxic-ischemicencephalopathy treated with hypothermia. Neurology.2011;76:556---62.
20.GluckmanPD,WyattJS,AzzopardiD,BallardR,EdwardsAD, FerrieroDM,etal.Selectiveheadcoolingwithmildsystemic hypothermiaafterneonatalencephalopathy:multicentre ran-domisedtrial.Lancet.2005;365:663---70.
21.Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, JuszczakE, et al. Moderate hypothermia to treat perinatal asphyxialencephalopathy.NEnglJMed.2009;361:1349---58.
22.TosoPA,GonzálezAJ,PérezME,KattanJ,FabresJG,TapiaJL, etal.ClinicalutilityofearlyamplitudeintegratedEEGin mon-itoringtermnewbornsatriskofneurologicalinjury.JPediatr (RioJ).2014;90:143---8.
23.Shankaran S, Pappas A, McDonald SA, Laptook AR, Bara R, EhrenkranzRA, etal. Predictivevalueofanearlyamplitude integratedelectroencephalogramandneurologicexamination. Pediatrics.2011;128:e112---20.
24.Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypother-mia for neonates with hypoxic-ischemic encephalopathy. N EnglJMed.2005;353:1574---84.
25.Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, KaufmanDA,et al.Moderatehypothermiainneonatal ence-phalopathy:efficacyoutcomes.PediatrNeurol.2005;32:11---7.
26.LinZL,YuHM,LinJ,ChenSQ,LiangZQ,ZhangZY.Mild hypother-miaviaselectiveheadcoolingas neuroprotectivetherapyin termneonateswithperinatalasphyxia:anexperiencefroma singleneonatalintensivecareunit.JPerinatol.2006;26:180---4.
27.Mourvillier B, Tubach F, van de Beek D, Garot D, Pichon N, Georges H, et al. Induced hypothermia in severe bacterial meningitis: a randomized clinical trial. JAMA. 2013;310:2174---83.
28.Wintermark P, Boyd T, Gregas MC, Labrecque M, Hansen A. Placental pathology in asphyxiated newborns meeting the criteria for therapeutic hypothermia. Am JObstet Gynecol. 2010;203:579e1---9.
29.LaptookA,Tyson J,ShankaranS,McDonald S,EhrenkranzR, FanaroffA,etal.Elevatedtemperatureafterhypoxic-ischemic encephalopathy:riskfactorforadverseoutcomes.Pediatrics. 2008;122:491---9.
30.LaptookAR,McDonaldSA,ShankaranS,StephensBE,VohrBR, GuilletR,etal.Elevatedtemperatureand6-to7-yearoutcome ofneonatalencephalopathy.AnnNeurol.2013;73:520---8.
31.Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ, et al. Whole-body hypothermiafor term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med. 2011;165:692---700.
32.ShankaranS,LaptookAR,PappasA,McDonaldSA,DasA,Tyson JE,etal.Effectofdepthanddurationofcoolingondeathsinthe NICUamongneonateswithhypoxicischemicencephalopathy:a randomizedclinicaltrial.JAMA.2014;312:2629---39.
33.SarkarS,DonnSM,BapurajJR,BhagatI,BarksJD.Distribution andseverityofhypoxic-ischaemiclesionsonbrainMRIfollowing therapeuticcooling:selectiveheadversuswholebodycooling. ArchDisChildFetalNeonatalEd.2012;97:F335---9.
34.PauliahSS, ShankaranS, Wade A, CadyEB,Thayyil S. Ther-apeutic hypothermia for neonatal encephalopathy in low-andmiddle-incomecountries:asystematicreviewand meta-analysis.PLOSONE.2013;8:e58834.
35.SarkarS,BarksJD. Systemiccomplicationsandhypothermia. SeminFetalNeonatalMed.2010;15:270---5.
36.Róka A, Melinda KT, Vásárhelyi B, Machay T, Azzopardi D, SzabóM.Elevatedmorphineconcentrationsinneonatestreated withmorphineandprolongedhypothermiaforhypoxicischemic encephalopathy.Pediatrics.2008;121:e844---9.
