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Current Management of the Infant Who Presents withNeonatal Encephalopathy

Elena V. Wachtel, MD, MPH, FAAP, and
Karen D. Hendricks-Muñoz, MD, MPH, FAAP
Neonatal encephalopathy after perinatal hypoxic-ischemic insultis a major contributor to global child mortality and morbidity.Brain injury in term infants in response to hypoxic-ischemic insultis a complex process evolving over hours to days, which providesa unique window of opportunity for neuroprotective treatmentinterventions. Advances in neuroimaging, brain monitoring tech-niques, and tissue biomarkers have improved the ability todiagnose, monitor, and care for newborn infants with neonatalencephalopathy as well as predict their outcome. However,challenges remain in early identification of infants at risk forneonatal encephalopathy, determination of timing and extent ofhypoxic-ischemic brain injury, as well as optimal managementand treatment duration. Therapeutic hypothermia is the mostpromising neuroprotective intervention to date for infants with
moderate to severe neonatal encephalopathy after perinatal
rmnt

doi:10.1016/j.cppeds.2010.12.002

132

asphyxia and has currently been incorporated in many neonatalintensive care units in developed countries. However, only 1 in 6babies with encephalopathy will benefit from hypothermia ther-apy; many infants still develop significant adverse outcomes. Toenhance the outcome, specific diagnostic predictors are neededto identify patients likely to benefit from hypothermia treatment.Studies are needed to determine the efficacy of combined thera-peutic strategies with hypothermia therapy to achieve maximalneuroprotective effect. This review focuses on important conceptsin the pathophysiology, diagnosis, and management of infantswith neonatal encephalopathy due to perinatal asphyxia, includ-ing an overview of recently introduced novel therapies.

Curr Probl Pediatr Adolesc Health Care 2011;41:132-153

N eonatal encephalopathy continues to be animportant cause of death and disability innewborn infants.1,2 Because of advances in

bstetrical and neonatal care, survival rate and earlyutcomes have improved; however, the incidence ofevelopmental disabilities has not significantly de-lined.3 The risk for brain injury can occur at any time

during gestation, labor, and delivery and often isdifficult to accurately identify. Neonatal encephalopa-thy, also identified as perinatal hypoxia-ischemia, hasmultiple etiologies and continues to be a commonunderlying cause of brain injury and subsequent neu-rologic disability.4 Additionally, the disorder imposes

major burden on the individual, family, and society,ccounting for 15-28% of children with cerebral palsynd 25% of all cases of developmental delay.5,6 This

From the Department of Pediatrics, Division of Neonatology, New YorkUniversity School of Medicine, New York, NY.Curr Probl Pediatr Adolesc Health Care 2011;41:132-1531538-5442/$ - see front matter© 2011 Published by Mosby, Inc.

review focuses on important concepts in the patho-physiology, diagnosis, and management of infantswith neonatal encephalopathy due to perinatal as-phyxia, including an overview of recently introducednovel therapies.

DefinitionNeonatal encephalopathy is a clinical syndrome of

“disturbed neurological function in the earliest days oflife in the term infant, manifested by difficulty withinitiating and maintaining respiration, depression oftone and reflexes, subnormal level of consciousness,and often seizures.”7 Encephalopathy is a nonspecificesponse of the brain to injury, which may occur viaultiple casual pathways. Recognition of the cause of

eonatal neurologic illness remains challenging withoday’s current diagnostic criteria.8 During the perina-

tal period, hypoxemia, ischemia, or both occur be-cause of asphyxia, an impairment in the exchange ofrespiratory gases. The American College of Obstetrics
and Gynecology defines encephalopathy as an acute
Curr Probl Pediatr Adolesc Health Care, May/June 2011

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intrapartum event sufficient tocause neuronal injury evidencedby a metabolic acidosis (pH �7and base deficit �12) in fetal

mbilical cord arterial blood ob-ained at the delivery.9 Develop-

ment of early encephalopathy(hours to days after birth) is con-sidered essential to be confident about an underlyingperinatal insult. Therefore, newborn infants withevidence of an acute intrapartum insult and/ordifficult transition from fetal to neonatal life requir-ing resuscitation at birth should be carefully moni-tored for abnormal neurological symptoms as wellas clinical seizures. The Sarnat 3 stage gradingsystem of mild (stage 1), moderate (stage 2), andsevere neonatal encephalopathy (stage 3), based onclinical symptoms and electroencephalogram (EEG)evaluation, is widely accepted (Table 1).10 Thegrading system considers the responses of the neo-nate to handling, level of consciousness, changes inmuscle tone and reflexes, presence of seizures, andthe duration of the symptoms within 7 days afterbirth. Neonatal seizures are defined clinically asabnormal, stereotyped, paroxysmal alterations inneurological function.11 Challenges in diagnosis

Recognitionneonatal neremains chatoday’s curr

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TABLE 1. Distinguishing features of the 3 clinical stages of postanoxic e

Stage 1

evel of consciousness Hyperalert Letheuromuscular controlMuscle tone Normal MildPosture Mild distal flexion StroStretch reflexes Overactive OveSegmental myoclonus Present Pre

omplex reflexesSuck Weak WeaMoro Strong; low threshold WeaOculovestibular Normal OveTonic neck Slight StroAutonomic function Generalized sympathetic GenPupils Mydriasis MioHeart rate Tachycardia BraBronchial and salivarysecretions Spars ProGastrointestinal motility Normal or decreased IncrSeizures None ComElectroencephalogram findings Normal (awake) Ear

aLateSeiz

aDuration Less than 24 h 2-1

Reproduced with permission from Sarnat HB, Sarnat MS.10

and treatment are discussed later in the article. c


EpidemiologyNeonatal encephalopathy after peri-

natal hypoxic-ischemic insult is ofgreat public health importance as amajor contributor to global child mor-tality and morbidity. Global estimatesfor asphyxia-related deaths vary from0.7 to 1.2 million newborns out of 4

million of all neonatal deaths. Almost 99% of neonataldeaths arise in developing (low- and middle-income) coun-tries, in contrast to 1% of deaths in developed countries.12,13

The incidence of neonatal encephalopathy in the USA is 2-3per 1000 live term births.14 With an annual birth rate of 4

illion infants it is expected that 8000-12,000 infants wille diagnosed with this disorder each year. Most commontiologies include brain hemorrhage, focal cerebral infarc-ion, and injury because of hypoxia-ischemia.15 Much lessrequently, neonatal encephalopathy is the result of meta-olic or congenital abnormalities, meningitis, hypoglyce-ia, and hyperbilirubinemia. Neonatal encephalopathy does

ot always progress to permanent neurologic impairment.s many as 20% of term newborn infants with encepha-

opathy after perinatal asphyxia will die during the neonataleriod and 25% of those who survive will have permanenteurologic disability.16 Outcome of infants with mild en-

he cause oflogic illnessnging withdiagnostic.8

alopathy in the full-term newborn infant

Stage 2 Stage 3

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tive function at school age.17,18 A moderate degree ofeonatal encephalopathy can be associated with a spectrumf long-term disabilities ranging from normal outcome toignificant motor or cognitive disabilities. Up to 40% ofnfants with moderate neonatal encephalopathy after perina-al asphyxia and 100% of those with severe encephalopathyie or develop neurosensory impairments, including cere-ral palsy, mental retardation, and hearing loss.19 Cerebralalsy is a neurodevelopmental disability historically linkedith intrapartum asphyxia and refers to a group of perma-ent disorders affecting the development of movement andosture that result in activity limitation attribute to nonpro-ressive disturbances in early life.20,21 The prevalence oferebral palsy among term deliveries has remained constant,pproximating 2.0 per 1000 live births despite advances inbstetrical and neonatal care.22 Long-term outcome is foundo depend on the severity of neonatalncephalopathy and condition.16,19

Cognitive deficit in children after neo-natal encephalopathy, such as intellec-tual limitation, language problems,impairments in learning and in exec-utive function, or social skills, havebeen reported in the literature.23 In areview by Gonzalez and Miller24 it

as evident that survivors of moder-te to severe neonatal encephalopathyfter perinatal asphyxia are also at riskor cognitive deficits, with or withoutiagnosis of cerebral palsy. Thus,arly brain injury frequently results inifelong permanent disability and im-oses a major burden on the individ-al, family, and society. Clinicianseed awareness of the spectrum of abnormal neurologicalutcomes in infants with neonatal encephalopathy aftererinatal asphyxia for prognostication, available treatmentptions, and counseling of parents. An extended period ofeurodevelopmental follow-up of these high-risk infants islso required.

Pathophysiology of NeonatalEncephalopathy

The underlying mechanism for perinatal brain injuryis an interruption of placental blood flow followed byimpaired gas exchange that leads to cerebral deficits inoxygen and substrates.11 Infant gestational age, as well

As many asnewbornencephalo

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134

ischemic insult, will determine theextent and locations of neuronalinjury. The main mechanisms offetal defense against hypoxia-isch-emia, described in animal studies,include peripheral vasoconstric-tion and redistribution of bloodflow to the brain and heart at theexpense of visceral organs andskeletal muscle.25,26 However, thisprotective ability is overwhelmedif hypoxia-ischemia continues.

Perinatal brain injury is a com-plex evolving process initiatedduring the insult and extendinginto a recovery period (Fig 1).Following a reversible perinatal

hypoxia-ischemia, 2 major phases occur when neuro-nal death has been identified.27,28 The primary phasef neuronal brain injury occurs during a hypoxic-schemic insult, which, if uninterrupted, initiates aascade of deleterious biochemical events and necroticell death. This phase, primarily related to cellularypoxia, precludes oxidative phosphorylation and leadso depletion of high-energy phosphate reserves (eg,hosphocreatine) followed by a fall in intracellular pH. Inesponse to a switch to this anaerobic state, glycolysisecomes the sole source of adenosine triphosphate (ATP)roduction in the brain. Unlike oxidative phosphoryla-ion, which produces 36 molecules of ATP for everyolecule of glucose consumed, glycolysis is an ineffi-

ient method to generate ATP by substrate phosphoryla-

FIG 1. Evolution of brain injury in neonates after perinatalhypoxic-ischemic insult. (Reproduced with permission fromFerriero DM.1) (Color version of figure is available online.)

% of termants withthy afterxia will dieatal period

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glucose consumed. This primary en-ergy failure results in neuronalmembrane depolarization and lossof membrane ionic homeostasis.ATP must fall below 25% beforeneuronal injury begins to occur andinjury becomes irreversible if ATPlevels fall below 10%.29 At thispoint, synaptic function and neuro-nal conductivity cease and cellular influx of sodium(Na�), followed by chloride (Cl�) and water influx,eads to osmotic (cytotoxic) edema and necrotic celleath (Fig 2). In the more typical, less severe insult,ellular efflux of potassium (K�) induces a release of

glutamate into the synaptic cleft and because of a failureof energy-dependent reuptake, a massive accumulationof glutamate occurs.30 Glutamate is the most commonxcitatory neurotransmitter and in small amounts it isssential for neuronal function. However, when gluta-ate accumulates in large amounts, it exhibits neuronal

oxicity and under these conditions it has been called anxcitotoxin.31 Glutamate stimulates the N-methyl-D-as-

partate receptor-channel complex leading to calcium(Ca2�) influx into neuronal cells.32,33 Simultaneously,ecause intracellular Ca2� removal is an energy-depen-ent process of the Na�–Ca2� pump, removal of Ca2� is

also impaired. This massive accumulation of Ca2�

FIG 2. Relation between energy depletion and neuronal celldeath. Early cell death is primarily necrosis, and more impor-tant, later cell death is primarily apoptotic. (Reproduced withpermission from Volpe J.11)

Perinatal brcomplex evinitiated du

and extenrecove

within the cell cytoplasm induces production of nitric l


xide (NO) by activation of NO synthase. NO adverselyffects neurons by reacting with superoxide to formeroxynitrite, a toxic free-radical that is known to alterell membranes by increasing the activity of Ca2�

ATPase leading to further intracellular accumulation ofCa2�.34 Excessive intracellular Ca2� also activates cat-abolic enzymes, such as proteases, phospholipases, andendonucleases. Free radicals and catabolic enzymes de-stroy structural proteins, nucleic acids, and other cellularcontents, causing neuronal necrosis. The type of celldeath is dependent on severity of the insult and accumu-lated Ca2� concentrations. Indeed, cellular necrosis oc-curs with higher levels of intracellular Ca2� than thoseobserved in apoptosis.35 Furthermore, an elevation ofactate levels in cerebral tissue indicates globalmpairment of perfusion and is consistent withypoxia as well as eventual poor neurologic out-ome.36,37 The marked increase in cerebral lactic acid

levels damages not only neurons but also glial andmesenchymal cells.

Following successful resuscitationand restoration of cerebral bloodflow, oxygen, and glucose delivery,the concentration of phosphorusmetabolites and intracellular pHnormalizes with transient im-provement of cytotoxic edema.These events herald the “latentphase” and correspond to a thera-peutic window for neuroprotectiveinterventions, discussed later in

this article. The reperfusion is necessary for thereversal of deleterious events leading to necroticneuronal death during the primary phase of injury;however, reperfusion can simultaneously cause addi-tional (delayed) injury by attracting monocytes andsubsequent inflammatory response to the site of injury.The secondary phase of brain injury does not occur inall infants with perinatal asphyxia and is primarilydetermined by several factors, such as duration andseverity of hypoxic-ischemic insult, preconditioningevents, substrate availability, body temperature, andgestational maturation. The secondary phase of injuryoccurs slowly (hours to days) and with a normalintracellular pH and stable cardiorespiratory status38;owever, the cellular response during this phase ofeuronal injury is similar to the primary phase ofnjury. This phase is also characterized by a decreasen the ratio of phosphocreatine/inorganic phosphate

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the cascade of pathologic processes following reper-fusion triggers accumulation of excitotoxic amino ac-ids, increased cytosolic Ca2�, generation of free radicals,nd activation of phospholipases as well as other meta-olic events leading to further neuronal cell injury.39

Increased intracellular Ca2� also activates a cascade ofroteolytic enzymes. These proteolytic enzymes, espe-ially caspases or cystein proteases, will eventuallyrigger cellular nuclear fragmentation.40-43 Addition-lly, microglial activation after hypoxia-ischemia andeperfusion promotes release of reactive oxygen anditrogen species as well as cytokines, especially IL-1nd TNF-alpha.11 Therefore, the mechanism involved

in the secondary phase of injury includes excitotoxic-ity, inflammation, mitochondrial failure, apoptosis,and cytotoxic actions of activated microglia. It appearsthat the secondary energy failure isa consequence of the cascade ofthese events rather than a result ofcellular destruction. Indeed, theseverity of the secondary energyfailure has been shown to be asso-ciated with seizures and adverseneurological outcome.44

Patterns of Brain Injuryand Neuroimaging

Brain injury of term infants inresponse to hypoxic-ischemic insultis a complex process. Selective neu-ronal necrosis is the most commonlyobserved pattern of brain injury inneonates with hypoxic-ischemic en-cephalopathy and is dependent on the severity andtemporal characteristics of the insult.11 The finalpattern of neuronal injury also depends greatly onthe gestational age of the infant at the time of theperinatal hypoxia-ischemia and is most likely influ-enced by immaturity of newborn brain structuresand neuronal cells.45 Three major regional patternsof selective neuronal necrosis in full-term infantswith neonatal encephalopathy have been identi-fied.46-48 Severe prolonged hypoxic-ischemic in-ults result in diffuse neuronal injury. With moder-te to severe relatively prolonged insults, aredominance of cerebral cortical-deep nuclear neu-onal injury is most commonly observed. It involves

Selective neuis the mos

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136

f the basal ganglia and thalamus. With severebrupt hypoxia-ischemia, deep nuclear brain-stemeuronal injury predominance occurs.11 This abruptnsult possibly precludes an adaptive mechanism ofiversion of blood flow from the cerebral hemi-pheres to the most vital deep nuclear structures.nother common pattern of perinatal brain injury in

erm infants after hypoxia-ischemia occurs in thearasagittal end artery regions of the 3 majorerebral arteries, frequently referred to as a “water-hed injury” (Fig 3). This includes cerebral cortexnd the underlying subcortical white matter in thearasagittal regions and is bilateral in distribution.Computerized tomography can be used to define the

ite and extent of the injury and provide useful prognosticnformation.49,50 Because of advances in neuroimaging,

magnetic resonance imaging (MRI)techniques using diffusion weightedand diffusion tensor imaging allowgreater delineation of brain tissue,including detailed integrative neuro-nal pathways. Therefore, MRI hasbecome the primary and most sen-sitive method for evaluation of braininjury patterns, determination oftiming of injury, and prognostica-tion in newborn infants with en-cephalopathy.51-54 The predominantpattern of brain injury found to bemost strongly associated with long-term outcome, more so than theseverity of injury in any given re-gion, is injury to the basal gangliaand thalamus. In the study by Miller

et al,47 injury to basal ganglia and thalamus in termneonates with hypoxic-ischemic encephalopathy had anunfavorable neurological outcome compared withinjury patterns in the parasagittal watershed area.Abnormal signal intensity in the posterior limb ofthe internal capsule was also a strong predictor ofimpaired neurodevelopment by 12 months of age.55

Magnetic resonance spectroscopy (MRS), eitherproton or phosphorus variety, is able to evaluatecerebral tissue metabolic status, offering a comple-mentary diagnostic value to conventional MRI.56

Within the first 18 hours of brain injury or shortlythereafter, MRS can detect elevated cerebral lactateand a decline in high-energy phosphate compoundsthat correspond to secondary energy failure in

nal necrosisommonlyrn of brainates with

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insult. The elevation in lactatecorrelates with the severity of neo-natal encephalopathy and neuro-logical outcome.54,57,58 Changesin metabolic ratios can be used todiagnose the severity of encepha-lopathy and approximate timing ofinjury. N-acetyl-aspartate (NAA),one of the main cerebral metabo-lites, a marker for neurons/axons,is reduced in immature newbornbrain tissue and after hypoxic-ischemic neuronal injury.56 In aecently published meta-analysis by Thayyil et al59

that included 32 neuroimaging studies of newborninfants with neonatal encephalopathy, they demon-strated that MRS was more specific and sensitive fordetermination of neurodevelopmental outcome thanMRI. The elevation of lactate/NAA peak–area ratioin the basal ganglia was found to be the most usefulin identification of infants with a severe stage ofencephalopathy as well as a higher specificity of95% (95% CI: 88%-99%) and sensitivity of 82%(95% CI: 74%-89%), compared with MRI in prog-nostigation of unfavorable neurodevelopmental out-come. The authors concluded that the lactate/NAAratio is the most accurate quantitative MRS bio-marker for prediction of neurodevelopmental out-

FIG 3. Parasagittal cerebral injury showing distribution ofmajor cerebral arteries, lateral view. (Reproduced with permis-sion from Volpe J.11)

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Diagnosis and BiomarkersDiagnosis of neonatal encephalopathy and predic-

tion of the long-term outcome can be challenging.Assessing the proportion of neonatal encephalopa-thy that is due to perinatal asphyxia is difficultbecause of problems in identifying asphyxia and inrecognizing the cause of neonatal neurologic ill-ness.8 Encephalopathy can develop because ofcauses other than hypoxia-ischemia and rapid deter-mination to exclude these causes is equally impor-tant to afford any opportunity for successful inter-vention. Accurate diagnosis relies on a combination

of biomarkers suggestive of peri-natal asphyxia as well as devel-opment of clinical symptoms ofencephalopathy early after birth.According to the ACOG Com-mittee on Obstetric Practice,“Umbilical cord blood gas andacid– base assessment are themost objective determinations ofthe fetal metabolic condition atthe moment of birth.” The pres-ence of other acute perinatalevents, such as placental abrup-tion, hemorrhage, prolapsed um-bilical cord, abnormal fetal heartrate tracings, as well as abnormalApgar scores and need for resus-

citation after birth, may also be important indicatorsin establishing hypoxic-ischemic etiology of en-cephalopathy.60 However, these biomarkers are notlways available or reliable and most studies haveound them to be absent in a large majority ofeurologically symptomatic neonates.61-63 There-ore, determination of the timing of injury remainshallenging given that much of the injury occurs beforeirth and may be the result of more than a singlenjury.64,65 At present, there is no universal agreement onbjective laboratory markers as a gold standard to sup-ort the diagnosis of term intrapartum asphyxia.66 Evi-

dence of multiorgan failure in infants with severe en-cephalopathy is helpful and used as an additionaldiagnostic criterion in the recognition of the hypoxic-

t pattern ofund to beassociatedoutcome,

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Several tissue biomarkers suggestive of hypoxic-isch-emic brain injury in term infants with neonatal enceph-alopathy have also been identified in the systematicreview by Ramaswamy et al.68 A meta-analysis of 22tudies demonstrated an association between serum anderebrospinal fluid interleukin-1b, serum interleukin-6,nd CSF neuron-specific enolase with poor outcome ofeath or disability. Other biomarkers identified in thiseview, such as urine lactate/creatinine ratio, first urine100, and umbilical cord IL-6, also were shown to bessociated with poor outcome, although only in singletudies. Despite these results, the author concluded thatecause of study limitations larger multicenter trials areeeded to validate biomarkers as useful in clinical prac-ice.

Clinical PresentationChallenges remain in early iden-

tification of high-risk infants withneonatal encephalopathy. Badawiet al in a West Australian case-control study demonstrated that al-most 70% of cases had no clearevidence of adverse intrapartumevents, 24% had antepartum andintrapartum risk factors, and 5% ofcases had only intrapartum riskfactors.64,65 The severity of a peri-natal hypoxic-ischemic insult isdifficult to quantitate and manyinfants may only have transitoryneurologic signs of neonatal en-cephalopathy at the time of birth and complete recov-ery after stabilization. Clinical presentation of infantswith neonatal encephalopathy of varying etiologiescan overlap and therefore make it difficult to identifyetiology through the use of neurological examinationalone. Thus, it is very important to exclude othercauses of neonatal encephalopathy in symptomaticpatients with unclear perinatal history risk factors.Clinical presentation of infants with neonatal enceph-alopathy after perinatal asphyxia can range fromsubtle, with a hyperalert state or mild hypotonia, tosevere, consisting of stupor, coma, profound hypoto-nia, and absent reflexes (Table 1). Importantly, clinicalsubtle signs and symptoms of neonatal encephalopathyas well as difficulties in neonatal seizure recognition

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138

europrotective intervention. Neonatal seizures affect.5-3.5 per 1000 live term births in the US and areore common in the neonatal period than at any other

ime in life.11 Furthermore, seizures are very commonmong infants with neonatal encephalopathy becausef hypoxia-ischemia. The widely accepted classifica-ion of clinical seizures proposed by Volpe11 includesubtle, clonic, tonic, and myoclonic seizures, whichan be focal, multifocal, or generalized. They are oftenlassified as being either electroclinical, when electro-raphic changes and clinical symptoms occur, orlectrographic and clinically silent.69 It can be chal-

lenging for the clinician to diagnose neonatal sei-zures. In fact, only approximately 20-30% of elec-trographic neonatal seizures provoke obviousclinical signs.70-72 Electrographic seizures in neo-

nates have also been correlatedwith the subsequent developmentof cerebral palsy and microceph-aly.73 When prolonged, seizuresmay also exacerbate brain injuryinitiated by the precipitatingacute hypoxic-ischemic injury.Thus, accurate diagnosis, moni-toring, and effective treatment ofneonatal seizures are crucial.Recently, the cerebral functionmonitor, a single- or double-chan-nel amplitude-integrated EEG(aEEG), has been introduced forthe brain monitoring of neonateswith suspected encephalopathyand used primarily to define selec-tion criteria for hypothermia ther-

apy among infants with neonatal encephalopathy. TheaEEG provides the clinician with a method to identifythe presence of brain injury and determine the severityof encephalopathy and outcome.69 Continuous moni-oring with cerebral function monitor/aEEG has be-ome helpful to monitor for seizure activity during the2 hours of the cooling process, to monitor responseso antiepileptic drugs, and to identify changes in brainunction over time. The severity of clinical encepha-opathy has been shown to be a strong predictor ofeurodevelopmental outcome.74 However, clinically,t can be difficult to predict outcome for infants withncephalopathy, especially those with Sarnat stage 2ymptomatology. Infants with Sarnat stage 2 enceph-lopathy, which presents with clinical seizures, have a

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Thus, duration of the abnormal neurological symp-toms and aEEG/conventional EEG changes has beenhelpful in prognostigation. Infants who will not prog-ress to Sarnat stage 3 and who have clinical signs ofmoderate encephalopathy for less than 5 days willenerally have a normal outcome. Persistence of Sarnattage 2 symptoms for more than 7 days or abnormalerebral background activity on aEEG/conventionalEG is frequently associated with later neurologic im-airments. Murray et al75 found that normal or mildly

abnormal video EEG results within 6 hours after birthwere associated with normal neurodevelopmental out-comes at 24 months of age. In contrast, clinical factors,such as more severe grade of encephalopathy, a highernumber of neonatal seizures, use of the anticonvulsantmedication phenytoin, diffuse abnormalities on radio-logic imaging, and abnormal find-ings on neurologic examination atdischarge, are significantly associ-ated with abnormal neurologicoutcome by 2 years of age ininfants with intrapartum as-phyxia.76 Clinical evaluation ofthe infant with neonatal encepha-lopathy in assessment of outcomehas the most important value andshould be used together with otherspecialized diagnostic approaches.Indeed, the best early (within sev-eral hours of life) predictors ofoutcome in infants with encepha-lopathy are the identified severityof deficits on clinical examinationcoupled with the degree of abnor-mal EEG background activity (eg, sustained low-voltage, iso-electric, burst suppression patterns).77,78

Current TherapiesManagement in the Delivery Room

The treatment of depressed infants after intrapartumasphyxia includes resuscitation in the delivery roomthat follows the latest Neonatal Resuscitation Programguidelines.79 Because of the compelling evidenceutlining the deleterious effects of hyperoxia,80-82

recent recommendation for resuscitation of term new-born infants supports use of room air rather than 100%oxygen.83,84 After hypoxia-ischemia and primary en-

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TP will depend on oxygen and glucose supplyecessary for oxidative phosphorylation. Therefore,onditions that may delay the recovery from therimary phase of brain injury, such as hypoxia, hypo-lycemia, hypotension, and blood loss/anemia, muste corrected as soon as possible. Newborn infants withevere acidemia at birth (pH �7.0) and hypoglycemiainitial blood glucose �40 mg/dL) are 18 times moreikely to develop moderate to severe encephalopathyompared with severely acidemic infants with normallucose levels.85 In the course of resuscitation, routineeasures include warming. However, it should be

oted that hyperthermia has been shown to be associ-ted with worsening brain injury and should bevoided.86 Laptook et al found that the odds of death

and disability in infants with moderate to severeencephalopathy was increasedfourfold for each 1°C increase inthe highest quartile of skin oresophageal temperature.87,88 Ad-ditionally, excessive hypothermia(cold stress) should be avoided.Therefore, after establishment of ad-equate ventilation and circulation,newborns with suspected hypoxic-ischemic perinatal event should betransferred urgently to a neonatalintensive care unit (NICU) capableof initiation of hypothermia treat-ment and close monitoring and careof systemic and cerebral function. Ifthere is evidence of hypoxic-isch-emic encephalopathy, referral to thenearest cooling center should be ar-

anged as soon as possible given the short (6 hour)herapeutic window for initiation of neuroprotective hy-othermia therapy (Table 2). In consultation with ourooling center, we recommend that the radiant warmere switched off to achieve passive hypothermia whileaintaining core temperatures of 35°C � 0.5°C in

reparation for the transport.

Supportive Care

Postresuscitative management of infants with neona-tal encephalopathy due to perinatal asphyxia is com-plex and requires careful monitoring and immediateprovision of anticipatory care. Because many infantswith encephalopathy will develop multiorgan dysfunc-tion and alterations in the ability to maintain physio-

ence of an-ischemic

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tion to support organ function can have a significanteffect on outcome and should be provided in a NICU.General principles of supportivecare after resuscitation includecontinued cardiorespiratory sup-port, correction of hypoglycemia,severe metabolic acidosis, andelectrolyte abnormalities as wellas prompt treatment of hypoten-sion and seizures.

Respiratory Management. Ven-ilatory support is frequently re-uired for infants with neonatalncephalopathy because of respi-atory depression, apnea with sei-ures, and respiratory distress, if concurrent conditions,uch as sepsis, meconium aspiration, and/or persistentulmonary hypertension, are present. It is important tonsure adequate ventilation as changes in PCO2 canffect cerebral blood flow. If allowed to occur, hypo-apnia because of overventilation can cause cerebralasoconstriction and compromise oxygen and glucoseelivery to the brain. The association of hypocapniand periventricular leukomalacia in preterm infantsas been reported in the literature.89,90 In a study byannucci et al,91 immature animals subjected to

global ischemia and normocapnia had less severeevidence of brain injury compared with the sameanimals exposed to hypocapnia. Interestingly, eleva-tion of PCO2 to 50-55 mm Hg with hypoxia-ischemiaassociated with better outcome than when PCO2 waswithin normal limits or in the mid 30 mm Hg range.

TABLE 2. Guide for the delivery room management of depressed infantsinsult

Guide

ollow Neonatal Resuscitation ProgramGuidelines

Establish adequate

xygen For babies born at toxygen.83,84 If deoxygenation remaconsidered

entilation Avoid hypocapnia olucose Correct hypoglycemetabolic acidosis Correct severe meta

emperature Avoid hyperthermiaeferral to the Cooling Center In the presence of 1

Severe acidemia;10 min Apgar scoContinued need f

aMeasured in umbilical cord blood sample or any blood sample within 60 minu

After perinischemic ins

infants himpai

cerebroautore

However, significant hypercapnia can also be harmful f

140

o the brain tissue after hypoxia-ischemia. A recenteview by Fritz and Delivoria-Papadopoulos sum-

marized studies on newborn pig-lets and mechanisms of the new-born brain injury.92 Exposure for6 hours to PCO2 of either 65 mmHg or 80 mm Hg resulted in adecrease in cellular energy me-tabolism, including a decrease inhigh energy phosphates, altera-tions in nuclear enzyme activity,and apoptotic protein expressionin the cerebral cortex of theseanimals. Thus, extrapolating tothe human infant, careful moni-

toring of blood gases and/or end-tidal PCO2 levelso maintain normocapnia is of particular importancen the management of neonatal encephalopathy.Additionally, monitoring perfusion and oxygenation in

nfants with neonatal encephalopathy is of equal impor-ance. After perinatal hypoxic-ischemic insults, newbornnfants have serious impairment of cerebrovascular au-oregulation. Hypoxia may further exacerbate ischemicerebral injury by inducing pressure-passive cerebralirculation with only moderate decreases in arterial bloodressure.11 Cerebral tissue hypoxia leads to expression of

apoptotic proteins and other deleterious events that mayfurther contribute to neuronal cell death as describedearlier (see the pathogenesis of neonatal encephalopathy,above). Hyperoxia can also worsen brain injury afterperinatal asphyxia and ultimate outcome through reper-fusion and exacerbation of oxidative injury.93,94 Oxygen

k for the neonatal encephalopathy after perinatal hypoxic-ischemic

Specific Responses

lation/oxygenation and circulation

it is best to begin resuscitation with air rather than 100%effective ventilation there is no increase in heart rate or ifnacceptable, use of higher concentration of oxygen should be

rcapnia

acidosis

he following criteria:7 and/or base deficit �16a

5uscitation, including respiratory support by 10 min of life

f birth (arterial or venous).

l hypoxic-s, newborn

seriousnt ofscularation.

at ris

venti

ermspiteins u

r hypeiabolic

of tpH �re �or res

ataultavermeva

ree radicals are produced from hypoxanthine, a degra-


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pa

dation product of ATP, during reperfusion with highconcentrations of oxygen in the presence of xanthineoxidase.95 Formation of oxygen free radicals lead to achain of reactions that injure cellular membranes by lipidperoxidation. In term infants with neonatal encephalop-athy, hyperoxia in the first hours of life was found to bean independent factor for poor neurological out-come.80,81 It is therefore prudent to avoid both hypoxiaand hyperoxia in infants with encephalopathy after peri-natal asphyxia and maintain PaO2 levels within normalranges of 60-90 mm Hg.

Cardiovascular Management. Infants with neonatalncephalopathy frequently experience hypotension. Mostommonly it is related to left ventricular dysfunctionollowing hypoxic-ischemic insult,96 endothelial cellamage, and less frequently blood/volume loss becausef placental abruption/uterine rupture. Impaired autoreg-lation of cerebral blood flow has been demonstrated ineverely asphyxiated newborns.97 Cerebral circulationfter hypoxia-ischemia appears toe pressure passive11; thus, bloodressure must be monitored con-inuously and diligently to avoidystemic hypotension or hyperten-ion which may cause hemorrhage.reatment should be targeted to-ard the underlying cause of hypo-

ension: if there is reduced myocar-ial contractility, inotropic supports warranted (eg, dobutamine); if thenfant is hypovolemic, volume re-lacement/transfusion should be implemented; if hypo-ension not because of myocardial dysfunction or hypo-olemia, dopamine would be the drug of choice. Thesenterventions, along with continuous blood pressure andentral venous pressure monitoring, are vital in accom-lishing the goal of maintaining the arterial blood pres-ure within the normal range for gestational and chrono-ogical age.Fluid-Electrolytes/Glucose Management. Infantsith encephalopathy are at risk for developing cere-ral edema, swelling accompanied by increased intra-ranial pressure, as well as syndrome of inappropriatentidiuretic hormone (SIADH) secretion in the firstew days after birth. SIADH will manifest with fluidetention, weight gain, hyponatremia, and correspond-ng concentrated urine. Infants who have sustainedenal tubular injury may develop renal failure as wells salt wasting. As a result, it is imperative to fre-

Hypoglycemavoided at athe care of

neoencephalo

uently monitor levels of sodium and other electro- t


ytes, daily fluid balance, the weight of the infant, andrine output. Treatment includes restriction of fluidsnd replacement of electrolytes by the second day ofife or as indicated. Calcium and magnesium levels aresually low in the infant with birth asphyxia andikewise closely monitored and supplemented accord-ngly. Hypoglycemia should be avoided at any timeuring the care of the infant with neonatal encephalop-thy.85,98 Neurons require a continuous source of energy,

produced by breakdown of glucose into pyruvate, whichenters into the citric acid cycle to produce ATP underaerobic condition. Hyperglycemia, by contrast, can in-duce excessive production of tissue lactic acid andassociated derangement in pH homeostasis.99,100 Hyper-lycemia is found to accentuate neuronal injury in adultxperimental models but not in immature animals afterypoxia-ischemia101-103 and is most likely related toaturation differences in the rate of cerebral glucose

ptake and metabolism.104 Hyperglycemia can cause ahyperosmolar effect and consequenthemorrhage. Thus, until further evi-dence is recommended, it is best tomaintain a blood glucose concentra-tion within normal ranges (75-100mg/mL).11

Last, adequate nutritional supportto reduce tissue catabolism, negativenitrogen balance, and acidosis mustbe a mainstay of the supportivetreatment in these infants.

Treatment of Seizures. Althoughsome controversy still exists regarding the contributionof brief seizures to ongoing brain injury, seizures as asymptomatic expression of an acute hypoxic-ischemicneuronal injury may also be an exacerbating factor incausing brain injury.105-107 Seizures are known to beassociated with a marked increase in metabolic rate, aconsequent rapid fall in brain glucose, an increase inlactate, an excitatory amino acid release, and a decreasein high-energy phosphates.108 After perinatal asphyxia,neonates who had clinical seizures had an increasedlactate/choline ratio and decreased NAA, which wasassessed by MRS.109 Seizures are known to have dele-terious effects with reduction of cellular proliferation,differentiation, and migration as well as alteration inmyelination and formation of synapses.110 Whetherlinical manifestations are present or not, electro-raphic seizures correlate with increased morbiditynd mortality.111,112 It is therefore recommended to

should betime duringinfant withtalthy.85,98

ianythena

reat neonatal seizures aggressively after hypoxia-

141

icpc

i

dfdfsfi

ty.

ischemia to reduce the possibility of further brain injury.Common anticonvulsant therapy includes the following:phenobarbital, phosphenytoin, or lorazepam.113 There isno strong evidence that prophylactic anticonvulsant useprevents morbidity and mortality in neonates with en-cephalopathy.114 Because the secondary phase of braininjury and cerebral edema generally resolves within thefirst several days after perinatal asphyxia, seizures gen-erally resolve as well, and anticonvulsant therapy fre-quently can be discontinued before discharge, in consul-tation with the pediatric neurologist. Unfortunately, theefficacy of these antiepileptic drugs is limited and thereare known potential side effects. Control of seizures withmonotherapy phenobarbital or phenytoin has been re-ported to be only 50% effective and when other agentsare added control of seizures has been achieved only inapproximately 60% of neonates.115 Also, antiepilepticdrugs can produce electroclinical dissociation of seizures(electrographic seizures persist de-spite the disappearance of the clini-cal seizures), providing false clinicalimpression and reassurance.116

Newer antiepileptic drugs to treatneonatal seizures, such as topira-mate, levetiracetam, and bumet-anide,117-120 have shown safety andgood efficacy in the pediatric popu-lation to treat epilepsy, but random-ized controlled trial (RCTs), includ-ing long-term outcome results, areneeded before these therapies can berecommended in neonates withencephalopathy.

Other Management

Disseminated intravascular coagulation (DIC) is fre-quently observed in infants with severe encephalopathyafter hypoxia-ischemia. DIC is a secondary processassociated with endothelial vascular cell damage andderangements in homeostasis after perinatal asphyxia.DIC is manifested by diffuse fibrin deposition in themicrovasculature, consumption of coagulation factors,and clinical bleeding.121,122 Careful monitoring of thenfant’s coagulation profile, including complete bloodount as well as prompt treatment with fresh frozenlasma, coagulation factors, platelets, and vitamin K,ould be necessary to prevent adverse hemorrhage.Polycythemia and hyperviscosity may also occur in

Whethemanifestatio

or not, eleseizures co

increased mmortali

nfants with neonatal encephalopathy.11 Furthermore, t

142

uring moderate hypothermia therapy, discussed in theollowing section, blood flow slows down because ofecreased heart rate and cardiac output,28 which canurther compromise cerebral blood flow. Thus, in theetting of hypothermia therapy, partial exchange trans-usion treatment of associated polycythemia should benitiated at a lower hematocrit threshold (Hct �60%).

Therapeutic HypothermiaBefore publication of RCTs over the last several

years demonstrating the efficacy of hypothermia ther-apy, treatment of neonates with encephalopathy afterperinatal asphyxia was primarily supportive. Theknowledge that brain injury after hypoxia-ischemia isan evolving process has provided a “window ofopportunity” for therapeutic interventions that mayarrest or ameliorate secondary brain injury. Therapeu-

tic hypothermia aims to lower thetemperature of the vulnerable deepbrain structure to 32°C-34°C.Therapeutic hypothermia derivesmost of its protective effect from agraded reduction in metabolism,decreased energy use, reduced ac-cumulation of excitotoxic aminoacids, reduced nitric oxide produc-tion, suppression of free radicalactivity, suppression of the inflam-matory cascade and inhibition ofapoptosis with resultant reduction

in the extension of brain injury.38,123-127

There are two methods of hypothermia therapycurrently available for the neonate with encephalopa-thy: whole-body cooling (placing the infant on thecooling blanket or mattress circulated with coolantfluid to maintain esophageal/rectal temperature of33°C-34°C) and selective head cooling with mildsystemic hypothermia (circulating cold water in a capfitted around the head with mild body hypothermia to34°C-35°C rectal temperature). To date, both methodsof therapeutic hypothermia have generally been foundto be equally safe and effective, although a small studyby Rutherford et al reported a decrease in the inci-dence of severe cortical lesions on MRI in infants withencephalopathy treated with selective head coolingcompared with infants treated with whole-body cool-ing.128 These results could be due to differential

linicalare presentographiclate withbidity and111,112

r cnsctrrreor

emperature gradients demonstrated with selective


nm

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head cooling with associated colder temperature in thecortex.129,130 Nevertheless, presently more research iseeded to demonstrate whether one of these coolingethods is superior.The currently recommended timing for initiation anduration of cooling treatment was derived from thetudies of Gunn et al131-133 in fetal sheep exposed to0 minutes of cerebral ischemia. These studies showedneuroprotective effect of selective head cooling for

p to 72 hours. Prolonged hypothermia preventedecondary cytotoxic cerebral edema and had a signif-cant protective effect on neuronal loss in fetal sheep.his effect was only observed if cooling started before

he development of the secondary phase of injury orefore the onset of postischemic seizures. Neuropro-ection was most significant when cooling started 90inutes after induced cerebral ischemia as well ashen the delay in initiating cooling was extended to.5 hours, but not if cooling was started as late at 8.5ours after cerebral ischemia (Fig 4). Taken together,tudies in fetal sheep subjected to hypoxia-ischemiauggest that the potential window for treatment innimal models seems to be up to 6 hours post injury.hus, in translation from preclinical animal studies,

FIG 4. The results of the studies performed by Gun et al132-134 todetermine the effect of time of initiation of cooling on neuronalloss. Y axis shows percent neuronal loss, encompassing differentregions of the brain. Initiation of hypothermia is effective, butefficacy decreases as duration of time following ischemia in-creases. Cooling starting at 8.5 hours following ischemia was noteffective. Asterisks indicate differences (P � .005) compared withsham-cooled animals. (Reproduced with permission. AR Laptook,et al: Use of Therapeutic Hypothermia for Term Infants withHypoxic-Ischemic Encephalopathy. Pediatr Clin N Am2009;56:601-16.)

linical trials in humans incorporated a 6-hour thera-


eutic window into clinical protocols to maximize theeuroprotective effect of hypothermia therapy. A clin-cal trial in humans (National Institute of Child Healthnd Human Development trial (NICHD); 16 centersarticipating) is currently under way to explore ifherapeutic hypothermia initiated after 6 hours of lifeay be beneficial in reducing brain injury.

Evidence from Clinical Trials ofHypothermia on Infants withNeonatal Encephalopathy

To determine the impact of hypothermia treatmenton the human infant, several small feasibility studiesassessed hypothermia as a treatment for neonatalencephalopathy secondary to acute hypoxic ischemicperinatal events.134-137 The safety of mild hypother-

ia has been well established, as no serious adverseafety issues (eg, cardiac arrhythmia, persistent meta-olic acidosis, pulmonary hypertension, thrombocyto-enia, coagulopathy, and increased risk of infections)ave been reported in these trials. Reversible cardio-ascular side effects, such as sinus bradycardia andypotension, as well as an increase in late coagulopa-hy were reported. Most initial small trials notedmprovements in neurological outcome but these stud-es were not adequately powered to achieve statisticalignificance. These pilot studies led to the initiation ofeveral RCTs, 4 of which have been published to date:he Eicher et al trial,138 the CoolCap trial,139 the

NICHD trial,140 and the Total Body Hypothermia forNeonatal encephalopathy trial (TOBY).141 An addi-ional RCT, the Australian Infant Cooling Evaluationrial, is expected to publish long-term outcome data byhe end of 2010. The entry criteria in the RCTs,lthough slightly varied, included recruitment of in-ants of similar severity (moderate to severe enceph-lopathy) with identified evidence of intrapartum as-hyxia, such as low Apgar score, acidosis (pH �7.0),r significant base deficit (�16) on a sample ofmbilical or infant blood obtained within 60 minutesf life, and need for resuscitation. Two studies138,140

also required aEEG assessment of background cere-bral activity to determine the degree of encephalopa-thy and/or evidence of electrographic seizures asadditional inclusion criteria.

In a multicenter, relatively small RCT, Eicher etal138 reported neurologic outcome in 65 term new-
borns with moderate to severe encephalopathy ran-
143

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domized to either moderate systemic hypothermia(n � 32) vs normothermia/supportive care (n � 33).

hole-body hypothermia for outborn newborn infantsas initiated with icepacks (for 2 hours) and then

ontinued for 48 hours with a servo-controlled coolinglanket to maintain rectal temperature at 33 � 0.5°C.herefore, the mean time to target temperature forutborn infants was only 111 � 78 minutes. Therimary outcome of death or severe motor disabilityy 12 months occurred in 52% of hypothermia groupompared with 84% of the normothermic controls (P

0.019). Of note, 77% of the infants recruited for thetudy had severe encephalopathy. Reported adversevents related to whole-body hypothermia in this studyere bradycardia, higher prothrombin time, longerependence on pressors, and more transfusions withresh frozen plasma and platelets.The NICHD Neonatal Researchetwork Centers Trial was a mul-

icenter RCT that prospectivelynrolled 208 term newborn infantsith moderate to severe encepha-

opathy.140 Subjects were random-zed to treatment with whole-bodyooling achieved by placing annfant on a servo-controlled blan-et to esophageal temperature at3.5 � 0.5°C for 72 hours (102nfants), or to normothermia (106nfants). Adverse events were sim-lar in both groups. Death or mod-rate to severe disability occurredn 44% of the hypothermia groupnd 62% of the control group,esulting in a relative risk (RR) for hypothermia of.72 (95% CI 0.54-0.95, P � 0.01) and a numbereeded to treat (NNT) of 6 infants.Gluckman et al conducted the CoolCap trial,139 an

nternational RCT that enrolled 234 term infants withoderate to severe encephalopathy. In this trial, sub-

ects were randomized to either selective head coolingith target rectal temperature of 34°C-35°C or con-entional normothermic care. The primary outcomeas death or severe disability in survivors at 18onths of age. In addition, aEEG was included to

urther select eligible patients and more preciselyefine the severity of the encephalopathy. Of the 218nrolled infants for whom follow-up data were avail-ble, 55% of infants in the hypothermia group died or

The knowleinjury aft

ischemia isprocess ha

“window ofor the

interventioarrest or

secondary

eveloped severe disability compared with 66% of

144

nfants in the control group, OR: 0.61 (95% CI.34-1.09; P � 0.10). However, after adjustment for

illness severity which included the Apgar and modi-fied Sarnat scores, as well as the aEEG backgroundand presence of seizures, there was a significantoverall effect of hypothermia therapy for the entirecohort, OR: 0.52 (95% CI 0.28-0.70; P � 0.04).142

Further subgroup analysis suggested that head coolingwas beneficial in infants with less severe aEEGchanges consistent with moderate encephalopathy, butnot those with the most severe aEEG changes (P �0.009).

In 2009, Azzopardi et al published results of the TOBYtrial,141 a multicenter RCT in which 325 newborn infants�36 weeks gestation, less than 6 hours of age withevidence of moderate or severe encephalopathy, were

randomized to intensive care andwhole-body cooling (163 infants) orintensive care alone (162 infants).The inclusion criteria were the sameas in previous trials, including aEEGevaluation for severity of enceph-alopathy. The primary outcomewas death or severe disability at 18months and the secondary out-come was survival without severedisability and specific neurologicoutcomes (eg, cerebral palsy, Bay-ley Scales of Infant DevelopmentII scores, hearing loss, seizures,microcephaly, cortical visual im-pairment, multiple or severe neu-rodevelopmental abnormalities,etc). Results of the study showed

that hypothermia therapy of infants who had perinatalasphyxia did not significantly reduce the combinedrate of death or severe disability but resulted inimproved neurologic outcomes in survivors (NNT was6 infants). Infants in the hypothermia group had anincreased rate of survival without neurologic abnor-mality (RR: 1.57; 95% CI, 1.16-2.12; P � 0.003).Additionally, cooling resulted in a reduced risk ofcerebral palsy in survivors (RR: 0.67; 95% CI, 0.47-0.96; P � 0.03) and improved scores on MentalDevelopmental Index (MDI), Psychomotor Develop-mental Index (PDI) (P � 0.03 for each), and the GrossMotor Function Classification system (P � 0.01). Inthis study, there were no significant adverse eventsassociated with cooling. Prior concerns that cooling

that brainypoxia-evolving

rovided aportunity”euticthat mayelioratein injury.

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severe neurodevelopmental dis-ability or other adverse outcomeshave not been demonstrated in anyof the largest RCTs (Table 3). Tothe contrary, the results of thesetrials support the benefits of hypo-thermia treatment (Fig 5), despitethe relatively late initiation ofcooling (mean time of enrollment:4.8 hours in the CoolCap trial, 4.3hours in NICHD trial, and 4.7hours in TOBY trial).

Compelling evidence of the effect of hypothermiatherapy on brain tissue injury was further demon-strated in a nested substudy of the TOBY trial byRutherford et al.143 This study assessed brain tissuenjury after moderate hypothermia by MRI andound significant reduction in cerebral lesions char-cteristic of hypoxic-ischemic encephalopathy, in-luding lesions that predict later neurodevelopmen-al impairments (eg, basal ganglia/thalamus,osterior limb of the internal capsule, extensiveortical, or white matter lesions). Moderate hypo-hermia therapy was associated with statisticallyignificant reduction in lesions in basal ganglia orhalamus, OR: 0.36 (95% CI 0.15-0.84, P � 0.02),hite matter, OR: 0.30 (95% CI 0.12-0.77, P �

Prior concermight resulsurvival of

severe neurodisability oroutcomes h

demonstratelarge

TABLE 3. Neurodevelopmental outcome and severe hearing and visual immonths of age)

Neurodevelopmental Outcomes inSurvivors

CoolCap Trial

Cooled(n � 112)

Cont(n � 1

MDI �70 30% 39

DI �70 30% 41MDI �85 NA NAPDI �85 NA NACerebral palsyd 19% 31

evere neurologic disabilitye 19% 31ultiple neurodevelopmental disability 21% 31

No neurological abnormality NA NA

Severe hearing impairment 8% 6lindness 10% 17

aInfants with moderate hypoxic-ischemic encephalopathy.bInfants with severe hypoxic-ischemic encephalopathy.cP � 0.05.dDiagnosis of cerebral palsy is based on a gross motor performance score ofCoolCap trial.eSevere neurologic disability include any of the following: Bayley MDI �70, gro

.01), and abnormal signal intensity in posterior


limb of the internal capsule, OR:0.38 (95% CI 0.17-0.85, P �0.02). The author concluded thattherapeutic hypothermia resultedin significantly less brain tissueinjury in infants with hypoxic-ischemic encephalopathy andthat the predictive value of MRIfor subsequent neurological im-pairment is not affected by hypo-thermia.

Current Recommendations forHypothermia Therapy

In 2005, the American Academy of Pediatrics (AAP)Committee on the Fetus and Newborn recommendedthat, “Therapeutic hypothermia is a promising therapythat should be considered investigational until theshort-term safety and efficacy have been confirmed inthe additional human trials underway. Long-termsafety and efficacy remain to be defined.”144 Shortlyfter, the NICHD workshop concluded that hypother-ia therapy is “potentially promising”; however,

long-term efficacy and safety are yet to be estab-ished.”145 As such, the NICHD also stated that

hypothermia treatment should continue to be consid-

that coolingincreased

fants withvelopmentaler adverse

e not beenany of theCTs

ent in survivors from the CoolCap, NICHD, and TOBY Trials (18-22

NICHD Trial Toby Trial

Cooled(n � 102)

Control(n � 106)

Cooled(n � 163)

Control(n � 162)

21%a 30%a 24% 35%41%b 67%b

NA NA 24% 34%52% 40% 70% 55%c

NA NA 68% 53%c

19% 30% 28% 41%24% 38% 27% 36%15%35%

20%56%

19% 30%c

39%a 32%a 44% 28%c

16%b 8%b

4% 6% 4% 6%7% 14% 7% 11%

whole-body cooling trials and a classification of neuromotor disability in the

tor function level of 3-5, or bilateral cortical visual impairment.

nst inindeothavd in

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rol18)

%

%

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3-5 in

ered an investigational alternative therapy for the

145

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infant with hypoxic-ischemic encephalopathy. TheCoolCap system was approved by the US Food andDrug Administration in 2007 for neuroprotective ther-apy in infants with perinatal asphyxia and moderate tosevere encephalopathy. That same year, a meta-anal-ysis (comprising 638 term infants with moderate/severe encephalopathy and evidence of intrapartumasphyxia) published by the Cochrane Collaborationreported statistically significant and clinically impor-tant reduction in the combined outcome of mortality ormajor neurodevelopmental disability at 18 months ofage in infants treated with hypothermia, with RR �0.76 (95% CI 0.65-0.89) and a NNT of 7 infants.146

Cooling also resulted in significant reduction in mor-tality, RR 0.74 (95% CI 0.58-0.94), and in neurode-velopmental disability in survivors, RR 0.68 (95% CI0.51-0.92). Furthermore, a subgroup analysis of in-fants with severe encephalopathy (153 infants) dem-onstrated significant reduction in the death or majordisability in survivors, RR 0.8 (95% CI 0.68-0.94),and NNT � 6, which was not found in any of theindividual RCTs. Analysis of the pooled data in theCochrane Review led to the conclusion that therapeu-tic hypothermia is beneficial in the treatment ofhypoxic-ischemic encephalopathy and that coolingreduces mortality without increasing major disabilityin survivors. Other systematic reviews found the samebenefit and recommended application of therapeutichypothermia in clinical practice.147-149 The most recentmeta-analysis by Edwards et al,150 which included theCoolCap, NICHD, and TOBY trials in their analysis,further demonstrated that moderate hypothermia is asso-ciated with a consistent reduction in death and neurolog-

Eicher, et al

CoolCap NICHD TOBY0

25

50

75

100

Hypothermia

Control

P=.02 P=.04*

P=.01

*After adjustment for illness severity, aEEG background and presence of seizures

% D

eath

or D

isab

ility

FIG 5. Primary outcome of death or survival with neurodevel-opmental disability from the CoolCap, NICHD, and TOBYtrials (18-22 months of age). (Color version of figure isavailable online.)

ical impairment at 18 months (RR 0.81, 95% CI 0.71- s

146

.93, P � 0.002), with a NNT of 9. Hypothermia alsoncreased survival with normal neurological functionRR 1.53, 95% CI 1.22-1.93, P � 0.001) as well aseduced the rates of severe disability in survivors (P �

0.006), cerebral palsy (P � 0.004), and MDI/PDI �70P � 0.01 and P � 0.02, respectively). This accumulatedvidence has led to the incorporation of hypothermia intolinical practice in non-investigational settings. In Octo-er 2010, the AAP released a special report on Neonatalesuscitation which included acknowledgement of theon-investigational status of this therapy for infants withoderate to severe hypoxic-ischemic encephalopathy.84

They stated that “treatment should be consistent with theprotocols used in the randomized control trials.” Impor-tant questions remain, such as: Should hypothermiatherapy be confined to larger NICUs (level 3-4) withspecific availability of services? Is there a minimumnumber of infants that should be treated per year tomaintain the outcomes expected with this therapy? If so,what is that number?

To ensure optimal care for infants with neonatalencephalopathy, registries of infants with perinatalasphyxial encephalopathy should be established tofacilitate data collection and quality oversight regard-ing diagnosis, treatments, and outcome.

Other Potential NeuroprotectiveTherapies

Understanding the pathophysiology and evolution ofbrain injury in response to hypoxic-ischemic insult hasprovided a unique window of opportunity for assess-ment of neuroprotective treatment interventions. Sin-gle therapeutic agents or approaches may impact onlyone or two steps in the cascade of the complexneuronal injury process after hypoxic-ischemic injury.Currently, only hypothermia affects multiple pro-cesses in the events leading to neuronal injury afterhypoxia-ischemia. However, many potential neuropro-tective agents/interventions have been investigatedtargeting different pathways leading to neuronal celldeath during the secondary phase of injury. Thesepotential neuroprotective therapies can be grouped bythe mechanism of action/effect as follows: agents thatinhibit glutamate release, uptake, or blockade of glu-tamate receptors; blockade of free radical generationor removal; blockade of downstream effects and in-hibitors of inflammatory effects.11 This review de-
cribes some of the most promising interventions.

tbwwmasmti(mgNwac(mnTcdestnrmPip1iii

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Magnesium

Magnesium inhibits glutamate-mediated excitotox-icity (NMDA receptor antagonist) and prevents neu-ronal influx of Ca2�. In experimental animal models,he potential neuroprotective effect of magnesium haseen conflicting.151-154 A RCT by Ichiba et al,155 inhich 33 depressed term infants were recruited, 17ere pretreated with magnesium sulfate infusion (250g/kg for 3 days) within 24 hours of birth. Althoughrelatively small study, the results demonstrated a

hort-term neuroprotective benefit of magnesium aseasured by enhanced survival with normal computed

omography, EEG, and oral feeding by 14 days of lifen 12/17 compared with 5/16 untreated control infantsP � 0.04). A recent RCT used magnesium pretreat-ent of pregnant women (between 24 and 31 weeks of

estation) in labor conducted in 20 participatingICHD network sites.156 A total of 2241 eligibleomen were randomly assigned indouble-blinded fashion to re-

eive either IV magnesium sulfatea loading dose of 6 g over 20-30inutes, followed by a mainte-

ance dose of 2 g/h) or placebo.he primary outcome was theomposite of stillbirth or infanteath by one year of age or mod-rate to severe cerebral palsy (as-essed by 2 years of age). Al-hough the results of the study didot reach a statistically significanteduction in the rate of the primary outcome (11.3%agnesium sulfate group vs 11.7% placebo group;� 0.8), there was a significant reduction (P � 0.03)

n the rate of children with moderate or severe cerebralalsy alone (1.9% vs 8.5%; RR 1.12; 95% CI 0.85-.47). Further studies are necessary to assess themportant role of magnesium as a therapy for the termnfant with encephalopathy after perinatal hypoxic-schemic insult.

Xenon

Xenon, a noble gas that rapidly reaches equilibriumin the brain when inhaled, exerts a neuroprotectiveeffect via partial NMDA blockade. Xenon is aneffective anesthetic approved for use in Europe andpreviously used in neonates. It has a very rapid onsetand reversibility, with little to no metabolism by the

Currenhypother

multiple proevents leadi

injurhypoxia

body, and to date no reported or proven adverse


emodynamic side effects.157 In the study by Hobbst al, week-old rat pups were subjected to hypoxic-schemic insult for 90 minutes and then assigned toour treatment groups: normothermia/hypothermia,enon/no xenon.158 Pups treated with xenon in com-

bination with hypothermia demonstrated an additiveneuroprotective effect after hypoxia-ischemia thaneither treatment alone. This benefit was sustained withcomplete restoration of long-term functional outcomesand significantly improved histopathology. Xenon isin the early stages as a potential therapeutic agent forthe infant at risk for encephalopathy and may be abeneficial adjunct to hypothermia treatment in thispopulation.

Erythropoietin

Erythropoietin derives its neuroprotective propertiesthrough inhibition of apoptosis, neuronal excitotoxic-

ity, and inflammation. In experi-mental animal studies, erythropoi-etin has been shown to improveneurodevelopmental outcomes andreduce brain injury. A clinical trialby Zhu et al assessed neurologicaloutcome after erythropoietin treat-ment within 48 hours of birth interm infants with neonatal enceph-alopathy.159 Infants were ran-domly assigned to 3 treatmentgroups: those treated with 300U/kg of erythropoietin, those with500 U/kg of erythropoietin, and a

third treated with placebo. Infants treated with eryth-ropoietin displayed a significant reduction in compos-ite outcome of death or disability assessed at 18months of age (24.6% vs 43.8%; RR 0.62 95% CI0.41-0.94; P � 0.017). The primary outcomes werenot different between two erythropoietin doses. Fur-thermore, a subgroup analysis demonstrated that in-fants with moderate encephalopathy had the mostbenefit in protection from adverse neurological out-comes [6.4% vs 32.2%; RR 0.26 (95% CI 0.09-0.76);P � 0.001].

Free Radical Inhibitors

During hypoxic-ischemic insult, reduction in oxidativephosphorylation leads to an accumulation of adenosineand hypoxanthine, which is oxidated to xanthine leadingto accumulation of superoxide radicals. Free radical

, onlyaffects

sses in theto neuronalfterhemia.

tlymiace

ngy a

inhibitors (eg, deferoxamine, allopurinol, and indometh-

147

nainiagrttmpbmsgsabegnnhntNoafe

fl

bil

acin) block specific reactions in the production of xan-thines. In a small RCT, allopurinol demonstrated asignificant reduction in circulating concentrations of freeradicals, as well as a beneficial effect on cerebral perfu-sion and electrical brain activity in infants after perinatalasphyxia. No adverse toxic effects were identified.160 Asewborn infants are known to have a deficiency inntioxidant defenses, removal of free radicals in themmature brain after hypoxia-ischemia is an importanteuroprotective intervention. Administration of free rad-cal scavengers (eg, vitamin E, N-acetyl-cysteine) orntioxidant enzymes (eg, superoxide dismutase, catalase,lutathione peroxidase) may assist in removal of highlyeactive radicals. Because of the large molecular size ofhe antioxidant enzymes, their action is restricted largelyo the intravascular space. Thus, antioxidant enzymeimetics, with their lower molecular weights, have better

enetration across the blood–brainarrier.11 Neuroprotection by ad-inistration of antioxidant enzymes

eems to be more effective wheniven before a hypoxic-ischemic in-ult. Prophylactic administration ofntioxidants during pregnancy haseen investigated in animal mod-ls.161 Supplementation of pome-ranate juice (resveratol) to preg-ant mice resulted in reduction ofeuronal injury in pups subjected toypoxia-ischemia. Last, the combi-ation of systemic hypothermia (forwo hours) and administration of-acetylcysteine, 50 mg kg�1, dem-nstrated a significant reduction in brain infarct volumess well as an improvement in myelin expression andunctional outcomes in neonatal rats after hypoxic-isch-mic injury.162

While beyond the scope of this review, animal modelsof hypoxia-ischemia provide even more evidence ofpotentially effective neuroprotective therapies. However,animal models vary from the human infant in brainstructure and development, leaving many challenges forthe use of these therapies in the newborn infant. Futureclinical studies in infants with neonatal encephalopathyare urgently needed: (1) to develop reliable means ofidentifying at risk infants during pregnancy so hypoxicischemic encephalopathy can be prevented; (2) to targetthe multiple steps in the cascade leading to brain injury;(3) to determine the safety and efficacy of combining

Evidenceneuroprote

hypothermiaa NNT of 6

prevent 1 casign

neurodevdisa

hypothermia therapy with other therapeutic strategies to

148

urther enhance neuroprotective effects; and (4) to estab-ish safety profiles and optimal treatment regimens.

ConclusionsCurrently, 12,000 infants are at risk for hypoxic-ischemic

encephalopathy in the US annually. Hypothermia therapywith supportive care for the infant with neonatal encepha-lopathy has been demonstrated to significantly improve theneurologic outcome in full-term infants with moderate tosevere encephalopathy. Evidence supports a neuroprotectiveeffect of hypothermia therapy with a NNT of 6-9 infants toprevent 1 case of death or significant neurodevelopmentaldisability. It is important to note that hypothermia therapy isnot associated with an increase in the number of survivorswith greater neurodevelopmental disabilities. Many infantswill still die or survive with significant disability despite

hypothermia therapy. Thus, future re-search is needed for additional neuro-protective therapy in this vulnerablepopulation. Based on the favorableresults of a number of published clin-ical trials, hypothermia therapy is be-ing implemented conservatively nowin many neonatal intensive care units.However, many centers have chosento delay implementation of hypother-mia protocols or referral to a centerperforming hypothermia treatmentpending the availability of longer termefficacy and safety data. As a result,many term infants with neonatal en-cephalopathy after perinatal hypoxia-

ischemia are still not offered/referred for therapeutic hypo-thermia. Additionally, despite all therapies, the outcome forinfants with severe encephalopathy remains poor overall,and further investigation is needed to identify improvedsupportive therapies and other treatment options. Identifica-tion of specific diagnostic predictors for patients likely tobenefit from hypothermia treatment would allow for moretargeted selection and likely enhanced outcomes. Hypother-mia is a novel therapy that requires significant knowledge ofthe effects of cooling on all organ systems and its potentialimpact on medications or other interventions. Given thecurrent state of knowledge, adherence to the eligibilitycriteria used in any of the large RCTs, such as initiation oftreatment within the therapeutic window (before 6 hours oflife) and duration of hypothermia for 72 hours with slow

pports ae effect oferapy withinfants toof death orantpmentality.

suctiv

th-9seificelo

rewarming, is essential to provide the best care to critically


ill newborn infants with neonatal encephalopathy. Cur-rently, data on initiation of hypothermia after 6 hours of lifeand inclusion of late preterm or near term infants are notavailable and until this safety and efficacy data are availableit is strongly recommended to follow the current trialprotocols. Because the incidence of neonatal encephalopa-thy because of perinatal asphyxia is low, to maximize theneuroprotective effect of hypothermia therapy and subse-quent long-term outcome, this treatment should be confinedto large NICUs with cooling centers where available clinicalservices (eg, neurology, epileptology, radiology), trained/experienced personnel, and neurodevelopmental follow-upprograms are available. For referral NICUs or newbornnurseries it is important for care providers to developconnections with regional cooling centers, identify and refereligible infants with perinatal asphyxia early, and initiateappropriate supportive care to avoid conditions that mayworsen neurologic outcome (eg, hyperthermia, hypoglyce-mia, seizures).

It is important for pediatricians and other care providerswho attend deliveries or care for infants in newborn nurs-eries to be able to recognize eligible infants with neonatalencephalopathy who may benefit from this neuroprotectivetreatment. Regardless of treatment received, infants withmoderate to severe encephalopathy remain at high risk forneurodevelopmental disabilities and require close, long-term neurodevelopmental follow-up, with provision of ear-ly-intervention services and family support.

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