Clinical Review & Education

Review

Hypoxic-Ischemic Encephalopathy
A Review for the Clinician
Martha Douglas-Escobar, MD; Michael D. Weiss, MD

Supplemental content at
IMPORTANCE Hypoxic-ischemic encephalopathy (HIE) occurs in 1 to 8 per 1000 live births in jamapediatrics.com
developed countries. Historically, the clinician has had little to offer neonates with HIE other
than systemic supportive care. Recently, the neuroprotective therapy of hypothermia has
emerged as the standard of care, and other complementary therapies are rapidly
transitioning from the basic science to clinical care.

OBJECTIVE To examine the pathophysiology of HIE and the state of the art for the clinical care
of neonates with HIE.

EVIDENCE REVIEW We performed a literature review using the PubMed database. Results
focused on reviews and articles published from January 1, 2004, through December 31, 2014.
Articles published earlier than 2004 were included when appropriate for historical
perspective. Our review emphasized evidence-based management practices for the clinician.

FINDINGS A total of 102 articles for critical review were selected based on their relevance to
the incidence of HIE, pathophysiology, neuroimaging, placental pathology, biomarkers,
current systemic supportive care, hypothermia, and emerging therapies for HIE and were
reviewed by both of us. Seventy-five publications were selected for inclusion in this article
based on their relevance to these topics. The publications highlight the emergence of
serum-based biomarkers, placental pathology, and magnetic resonance imaging as useful
tools to predict long-term outcomes. Hypothermia and systemic supportive care form the
cornerstone of therapy for HIE.
Author Affiliations: Department of
Pediatrics, University of California,
CONCLUSIONS AND RELEVANCE The pathophysiology of HIE is now better understood, and San Francisco (Douglas-Escobar);
treatment with hypothermia has become the foundation of therapy. Several neuroprotective Department of Pediatrics, University
of Florida, Gainesville (Weiss).
agents offer promise when combined with hypothermia and are entering clinical trials.
Corresponding Author: Michael D.
Weiss, MD, Department of Pediatrics,
JAMA Pediatr. 2015;169(4):397-403. doi:10.1001/jamapediatrics.2014.3269 University of Florida, 1600 SW Archer
Published online February 16, 2015. Rd, PO Box 100296, Gainesville, FL
32610 (mweiss@ufl.edu).

H
ypoxic-ischemic encephalopathy (HIE) is a major cause of
neurologic disabilities in term neonates despite the re-
cent widespread use of hypothermia therapy. The inci-
dence of HIE ranges from 1 to 8 per 1000 live births in developed
countries and is as high as 26 per 1000 live births in underdevel-
oped countries.1 Although the advent of therapeutic hypothermia
offers neuroprotection, the improvement in outcomes has been
modest. Therefore, new synergistic therapies are needed to im-
prove outcomes. This review is intended for the clinician and briefly
examines the pathophysiology of HIE in the context of clinical care
(more extensive reviews on this topic are found in Johnston et al2).
This review examines practical clinical information, such as diagnos-
tic considerations, and emphasizes evidence-based practices for neo-
nates with HIE (eTable 1 in the Supplement summarizes pertinent
publications from the past 5 years in each of these categories). The
review examines 75 articles (of the 102 selected for critical review),
with an emphasis on articles published between January 1, 2004,
and December 21, 2014.
Pathophysiology
Clinicians must understand the pathophysiology of injury during hy-
poxia-ischemia (HI) to manage this critical illness in neonates ap-
propriately because the injury evolves over the course of days and
possibly weeks (Figure 1).3 Furthermore, a bedside clinician who un-
derstands the pathophysiology of HIE will understand the mecha-
nism of action of the various emerging neuroprotective agents.
Adequate cerebral blood flow delivers oxygen and glucose to the
fetal brain. This blood flow helps the fetal brain maintain homeosta-
sis and meet cellular energy demands. A variety of conditions de-
crease placental perfusion or disrupt the delivery of oxygen and glu-
cose in the umbilical cord, including placental abruption, prolapse of
the umbilical cord, and uterine rupture. The hypoxia eventually leads
to a decrease in fetal cardiac output, which reduces cerebral blood
flow. If the decrease in cerebral blood flow is moderate, the cerebral
arteries shunt blood flow from the anterior circulation to the poste-

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 Clinical Review & Education Review
Figure 1. Schematic Overview of the Pathophysiological Features of Hypoxic-Ischemic Encephalopathy
Latent
Insult
Cell death
Multiple programmed
cell death pathways
Reperfusion
Response
Excitotoxicity
Glucose O2 delivery
Inflammation
ATP production
Oxidative stress
30 min
rior circulation to maintain adequate perfusion of the brainstem, cer-
ebellum, and basal ganglia.4 As a result, damage is restricted to the
cerebral cortex and watershed areas of the cerebral hemispheres.
Acute hypoxia causes an abrupt decrease in cerebral blood flow, which
produces injury to the basal ganglia and thalami.4
Decreased cerebral perfusion sets in motion a temporal se-
quence of injury, which clinicians have divided into distinct phases.
In the acute phase, the decreased cerebral blood flow reduces the
delivery of oxygen and glucose to the brain, which leads to anaero-
bic metabolism. As a result, production of adenosine triphosphate
decreases and that of lactic acid increases. The depletion in aden-
osine triphosphate reduces transcellular transport and leads to in-
tracellular accumulation of sodium, water, and calcium.5 When the
membrane depolarizes, the cell releases the excitatory amino acid
glutamate, and calcium flows into the cell via N-methyl-D-aspartate–
gated channels. This cascade of events perpetuates injury in a pro-
cess termed excitotoxicity. The peroxidation of free fatty acids by oxy-
gen free radicals leads to more cellular damage.3 The culmination
of energy failure, acidosis, glutamate release, lipid peroxidation, and
the toxic effects of nitric oxide leads to cell death via necrosis and
activates apoptotic cascades.3
Depending on the timing of injury and the degree of medical inter-
vention,apartialrecoveryoccursduringthe30to60minutesafterthe
acute insult or the primary phase of injury. This partial recovery ushers
in a latent phase of injury.6 The latent phase may last from 1 to 6 hours
andischaracterizedbyrecoveryofoxidativemetabolism,inflammation,
andcontinuationoftheactivatedapoptoticcascades.5 Asecondaryde-
terioration follows the latent phase in neonates with moderate to se-
vere injury. The secondary phase of injury occurs within approximately
6 to 15 hours after the injury. Cytotoxic edema, excitotoxicity, and sec-
ondary energy failure with nearly complete failure of mitochondrial ac-
tivity characterize this secondary phase, which leads to cell death and
clinical deterioration in neonates with moderate to severe injury.6 Sei-
zures typically occur in the secondary phase.7 A tertiary phase occurs
during the months after the acute insult and involves late cell death, re-
modeling of the injured brain, and astrogliosis.8
Diagnostic Considerations
A bedside test is not available for an accurate diagnosis of HIE in a
neonate. Physicians diagnose HIE based on the presence of a neu-
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Hypoxic-Ischemic Encephalopathy
Secondary Tertiary
Late cell death
Secondary
mitochondrial failure
Seizures Remodeling
Astrogliosis
Repair
6-12 h ≥3 d Months ATP indicates adenosine
triphosphate; O2, oxygen.
rologic dysfunction in the form of neonatal encephalopathy. Hall-
marks of neonatal encephalopathy are depression of the level of con-
sciousness, often with respiratory depression, abnormality of muscle
tone and power, disturbances of cranial nerve function, and
seizures.9 Evidence of low Apgar scores and metabolic acidosis (in
arterial cord oxygen or newborn blood oxygen levels) must accom-
pany the neurologic dysfunction.9 Metabolic acidosis strongly sug-
gests HI injury. Concomitant injury to other organs, such as the liver
(elevated transaminase level), the kidneys (elevated creatinine level),
and/or the heart (elevated creatine kinase–MB fraction and tro-
ponin T levels), provides further evidence of HI injury.10 In addi-
tion, the pattern of injury on magnetic resonance imaging (MRI) of
the brain may further confirm HIE.
Neonates with suspected HIE are classified according to the Sar-
nat staging system,11 which evaluates the level of consciousness,
muscle tone, tendon reflexes, complex reflexes, and autonomic func-
tion. The Sarnat stage classifies neonatal HIE into the following 3 cat-
egories: stage I (mild), stage II (moderate), and stage III (severe). En-
try criteria for therapeutic hypothermia include a modified version
of the Sarnat staging system.
Biomarkers
In neonates with HIE, monitoring and evaluation, outcome predic-
tion, and response to the hypothermia treatment are measured with
a combination of a neurologic examination, MRI, and electroen-
cephalography (EEG).12 However, unstable neonates may not tol-
erate transport for an MRI of the brain or the length of the MRI scan-
ning time. Moreover, hypothermia therapy may depress the
amplitude-integrated EEG (aEEG) and thus limit the early predic-
tive ability of aEEG. Improvement in aEEG tracings may be delayed
until the patient undergoes rewarming and is no longer sedated.13
Serum biomarkers may enable clinicians to stratify neonates with
HIE undergoing hypothermia into the following 3 groups based on
biomarker levels: (1) responders to hypothermia alone with good
neurodevelopmental prognosis, (2) nonresponders to hypother-
mia at high risk for surviving with neurologic injury and/or neurode-
velopmental deficits who then may be candidates for other clinical
interventions, and (3) neonates who will die. Biomarkers, such as
ubiquitin carboxyl-terminal esterase L1 (UCH-L1) and glial fibrillary
acidic protein (GFAP), have demonstrated predictive capabilities in
several studies (eTable 2 in the Supplement). Combining biomark-
ers with scoring systems may improve the sensitivity and specific-
jamapediatrics.com
 Hypoxic-Ischemic Encephalopathy
ity of outcome prediction (the Eunice Kennedy Shriver National In-
stitute of Child Health and Human Development HIE calculator is
found at http://hopefn3.org).
Placental Abnormalities
Only a small fraction of patients with HIE (15%-29%) have a docu-
mented sentinel event, such as a placental abruption, uterine rup-
ture, cord prolapse, or shoulder dystocia.14,15 In neonates without a
sentinel event, placental analysis can provide valuable information
regarding the cause and timing of the adverse events in utero. For
example, placentas with decreased maturation of the terminal villi
are associated with injury to the white matter/watershed areas and
basal ganglia.4 Immature placental villi increase the distance be-
tween the maternal and fetal blood with a net effect of reduced oxy-
gen diffusion to the fetus or fetal hypoxia. Placentas with reduced
weight can represent an adverse intrauterine environment owing
to decreased uteroplacental perfusion.4
Neuroimaging
Brain MRI is the preferred imaging choice in neonates with HIE and is
a useful tool to predict long-term outcomes (eTable 3 in the Supple-
ment). In the first week after birth, diffusion-weighted MRI of the brain
mayassistphysiciansinmakingmanagementdecisionsforpatientsun-
dergoingventilatorsupport.16 Diffusion-weightedimagingreferstoMRI
that is sensitive to water molecule diffusion.17 However, diffusion-
weighted imaging obtained during the first hours after the injury may
underestimate the final extent of injury.16 The sensitivity and specific-
ity of this technique can be improved by quantification of the appar-
ent diffusion coefficient, which is performed by voxelwise analysis of
the information contained within diffusion-weighted imaging.17 After
moderate or severe HIE, abnormal signal intensity is commonly de-
tected in the basal ganglia and thalami, corticospinal tract, white mat-
ter, and cortex.17 Neonates with a history of a sentinel event are likely
to sustain basal ganglia and thalamic lesions.16 These lesions are usu-
ally accompanied by abnormalities in the appearance of the interven-
ing posterior limb of the internal capsule.16
Abnormalities in the MRI of the brain correlate with outcomes.
Lower apparent diffusion coefficient values in the basal ganglia during
the first 7 days after HIE predict adverse neurologic outcomes.18 Inju-
ries to the posterior limb of the internal capsule and basal ganglia are
associated with motor deficits.19 Injury to the posterior limb of the in-
ternal capsule combined with diffuse basal ganglia injury and a periph-
eral(ie,hemisphericgrayandwhitematter)abnormalityareassociated
withdeath,hearingandvisualimpairments,andseverecerebralpalsy.20
Recently, the TOBY (Total Body Hypothermia for Neonatal Encepha-
lopathy) trial demonstrated that hypothermia does not influence the
ability of MRI to predict neurodevelopmental outcomes.21
Magnetic resonance spectroscopy allows for in vivo quantita-
tive analysis of brain metabolites and therefore may serve as an early
biomarker for brain injury. Findings on MRI without spectroscopy
could be normal for as long as 24 hours after an acute HI event (eg,
abruption), but magnetic resonance spectroscopy or diffusion-
weighted imaging detects early acute events. When clinicians add
magnetic resonance spectroscopy to standard MRI, scanning time
increases by only 6 to 7 minutes and may improve the predictive
value of the scan. An elevated ratio of lactate to N-acetyl aspartate
in the basal ganglia can predict long-term neurologic impairments
and can be seen in the first 48 hours of life.22
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Review Clinical Review & Education
The clinician should be cautious when predicting outcomes in
neonates with HIE who have normal findings or minor degrees of
brain injury on MRI. As many as 26% of neonates with HIE who un-
derwent hypothermia and had normal MRI findings experienced ab-
normal neurodevelopmental outcomes.23
Treatment
Systemic Support
Systemic support remains the foundation of care for neonates with
HIE. The goal of systemic support is to restore adequate cerebral
blood flow, which ensures delivery of the metabolic substrates oxy-
gen and glucose to prevent secondary brain injury (an overview of
recommendations is available in the eFigure in the Supplement). Sec-
ondary injury may occur because of other organ impairment. For ex-
ample, cardiac injury may result in decreased cardiac output and hy-
potension, which further decrease cerebral blood flow. Persistent
pulmonary hypertension of the newborn may worsen hypoxia. Al-
though systemic support is the foundation of therapy, evidence-
based optimal practice parameters are scarce. Researchers have not
validated most of the parameters with long-term follow-up of the
patients. We herein present a summary of a system-based ap-
proach to supportive care of neonates with HIE.
Respiratory System
Infants with an HI insult have metabolic changes that lead to less car-
bon dioxide (CO2) production. Respiratory compensation for the ini-
tial severe metabolic acidosis may lower CO2 levels. In addition, hy-
pothermia may reduce CO2 production.24 Patients with HIE need less
ventilator support to obtain a desirable CO2 level. Hypocapnia is
harmful in patients with HIE because it decreases cerebral perfu-
sion and oxygen release from hemoglobin. Hypocapnia is associ-
ated with death and poor neurodevelopmental outcomes.24,25
Hyperoxia can have a detrimental effect on neonates with HIE
because it increases oxidative stress and free radical production, es-
pecially during the reperfusion phase. Furthermore, hyperoxia is as-
sociated with death and poor long-term outcomes in neonates with
HIE.25 Infants with a history of respiratory depression at birth and
resultant HIE often undergo vigorous resuscitation at birth. As a re-
sult, hyperoxia and hypocapnia may exist after resuscitation, lead-
ing to worse outcomes.24,25 Therefore, normal oxygenation and nor-
mocapnia after newborn resuscitation may prevent secondary injury
(PaCO2, 40-55 mm Hg; PaO2, 50-100 mm Hg).
Cardiovascular System
Blood pressure must remain in a safe range to avoid hypotension,
which can produce a secondary ischemic injury. The ideal mean ar-
terial blood pressure (MAP) for term infants with HIE has not been
established. Because infants operate within a narrow blood pres-
sure range and because HI impairs cerebral autoregulation, ex-
perts recommend that MAP be maintained within the critical range
of 40 to 60 mm Hg unless the hemodynamics suggest a more op-
timal MAP.26 Organ-specific regional oximetry may indicate the op-
timal MAP for individual patients, helping to individualize care.27 The
use of echocardiography in patients with HIE is useful because the
treatment of low pressure is different in infants with poor cardiac
function vs neonates with normal function. Patients with HIE, good
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 Clinical Review & Education Review
cardiac function, and low blood pressure may require more vol-
ume, especially if clinical or historic evidence of hypovolemia (ie, se-
vere anemia, placental abruption, or cord compression) is found.
However, the unwarranted use of fluid therapy may exacerbate ce-
rebral edema.28
In patients with cardiac dysfunction, minimal evidence exists re-
garding the ideal method to augment MAP for infants with HIE. A
2002 Cochrane systemic review29 did not find conclusive evi-
dence regarding the use of dopamine for the prevention of morbid-
ity and mortality in patients with HIE. Furthermore, dopamine may
not be the ideal first-line agent for infants with evidence of pulmo-
nary hypertension and HIE because dopamine increases systemic
and pulmonary vascular resistance.30 Dobutamine can reduce af-
terload and therefore decrease the ratio of systemic to pulmonary
vascular resistance.31 Epinephrine at low to moderate doses in-
creases the cardiac index with no effects on the ratio of systemic to
pulmonary arterial pressures. In infants with HIE and pulmonary hy-
pertension with cardiac dysfunction, epinephrine may be the opti-
mal choice for blood pressure augmentation.30 In patients with HIE
and pulmonary hypertension, milrinone lactate may be advanta-
geous because milrinone increases myocardial contractility and acts
as a systemic and pulmonary vasodilator.32
Fluids, Electrolytes, and Nutrition
Research has not been conducted on the optimal initial rate of fluid
therapy and its long-term outcomes. To limit the consequences of
HIE, experts recommend carefully managing fluid therapy to avoid
fluid overload and thus prevent cerebral edema.33 Recommenda-
tions for neonatal fluid restriction are based on the experience of
restricting fluid intake in adults and older children with cerebral
edema to a target of 40 to 70 mL/kg/d.33
In normal conditions, the human brain relies almost entirely on
glucose to provide the substrate for metabolism.34 Neonatal cere-
bral glucose consumption may account for 70% of total glucose
consumption.34 Although the newborn brain can use other sub-
strates (ie, lactate or ketones) as an energy source, these alternate
substrates have an unpredictable supply and may not compensate
entirely for a decrease in glucose availability.34 During HI, anaero-
bic glycolysis depletes hepatic glycogen stores, and hepatic glu-
cose production rapidly becomes insufficient to meet cerebral meta-
bolic demands.34 Clinical observations demonstrate a correlation
between lower serum glucose concentrations and higher neonatal
Sarnat stages.35 In addition, initial hypoglycemia (ⱕ40 mg/dL [to
convert to millimoles per liter, multiply by 0.0555]) is an important
risk factor for perinatal brain injury in neonates with HI.36 There-
fore, strict monitoring of glucose levels is necessary to prevent and
treat hypoglycemia. Fluid restrictions can compromise appropri-
ate glucose delivery and may contribute to hypoglycemia.
Antiseizure Medications
Consensus has not been reached regarding the best medication for
treating seizures in patients with HIE. Clinicians frequently use phe-
nobarbital, but only 27% of seizures are controlled. Recently, topi-
ramate has emerged as a potential neonatal antiseizure medica-
tion. Topiramate modulates 2-(aminomethyl)phenylacetic acid,
kainate, and γ-aminobutyric acid–activated ion channels and voltage-
activated sodium and chloride channels. Animal models and 1 hu-
man pilot clinical trial37 showed that topiramate worked synergis-
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Hypoxic-Ischemic Encephalopathy
tically with hypothermia, but its efficacy in neonates is unknown.
Levetiracetam is also a promising antiseizure medication that de-
creases excitotoxicity and does not induce neuronal apoptosis, but
researchers have not yet evaluated its efficacy in large clinical trials.
Hypothermia
Therapeutic hypothermia is considered the standard of care for neo-
nates with HIE; the treatment uses mild hypothermia in the range
of 33.5°C to 35.0°C. Several large multicenter trials demonstrated
that the therapy is safe and efficacious (eTable 4 in the
Supplement).38-40 A recent meta-analysis reviewed outcomes of 7
hypothermia trials, including 1214 neonates who were randomized
to hypothermia or systemic supportive care.41 Therapeutic hypo-
thermia reduced the risk for death or major neurodevelopmental
disabilities at 18 months of age in neonates with moderate and se-
vere HIE.41
At present, the 2 types of treatment used include whole-body
hypothermia and selective head cooling. Although the 2 cooling
methods are equally effective, clinicians predominantly use whole-
body cooling owing to its reduced cost and ease of use.
Meta-analysis41 did not show a difference in the reduction of long-
term neurologic impairments between the 2 methods.
Recently, 2 of the original large multicenter hypothermia trials
published follow-up data on their original cohort of patients at school
age.42,43 The CoolCap Trial Group42 performed neurodevelopmen-
tal assessments on 46% of the original cohort and demonstrated a
correlation between the neurodevelopmental assessments at 18 to
22 months of age with the functional outcomes at 7 to 8 years of
age. The Eunice Kennedy Shriver National Institute of Child Health
and Human Development Neonatal Research Network whole-
body hypothermia trial43 demonstrated a significant reduction in
death, death or severe disability, and death or cerebral palsy at 6 to
7 years of age. The trial also demonstrated a strong trend in the pri-
mary outcome of death or IQ score of less than 70.43
Because little variability was evident in the therapeutic hypo-
thermia trials, the optimal timing for the initiation of hypothermia,
the depth and duration of hypothermia, and the safety of hypother-
mia for late preterm neonates are uncertain. These uncertainties are
being addressed in ongoing trials that examine the efficacy of ini-
tiation of hypothermia at 6 to 24 hours of age,44 longer durations
of hypothermia (120 hours) and a lower temperature of hypother-
mia (32°C),45 and whether neonates with HIE and a gestational age
of 33 to 35 weeks benefit from hypothermia.46
Recent data showed that the time to initiate hypothermia cor-
related with outcomes. Neonates undergoing earlier cooling therapy
(within 180 minutes of birth) had better outcomes compared with
those who underwent the therapy later (180-360 minutes after
birth).47 The results have stimulated interest in transporting neo-
nates with active hypothermia.48-50
Emerging Therapies
Although the pathophysiological features of HIE are complex, the
multiple steps leading to cellular damage provide many opportuni-
ties for therapeutic intervention. A search is currently under way to
identify other agents that may be synergistic with therapeutic hy-
pothermia. Potential agents include xenon, erythropoietin, mela-
tonin, and stem cell therapy. A brief discussion of these agents fol-
lows. These agents, along with other potential therapies, are
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 Hypoxic-Ischemic Encephalopathy
Figure 2. Complex Cascade of Events Producing Cellular Damage and Destruction After Hypoxia-Ischemia (HI)
Axon
Neurosynaptic Junction
Na+ Membrane depolarization
KA-AMPA
HI
Glutamate Glutamate
NMDA
2
1
Ca2+
7
During hypoxic-ischemic encephalopathy, an excessive amount of the
excitatory amino acid glutamate is released from the presynaptic terminal. This
excess glutamate leads to overstimulation of the glutamate receptors
(2-(aminomethyl)phenylacetic acid [AMPA], kainite [KA], and
N-methyl-D-aspartate [NMDA]) located on the postsynaptic neuron and leads to
excitotoxicity. Overstimulation of the KA and AMPA receptors causes sodium
(Na+) and chloride to enter the cell, which increases cell osmolality.
Overstimulation of the NMDA receptor triggers the influx of calcium (Ca2+).
The 3 aberrant cellular processes lead to apoptosis and necrosis. The various
summarized in Figure 2. More extensive reviews on emerging neu-
roprotective therapies are available.51
Because excitatory amino acids play an important role in the cas-
cade of events leading to cell death, researchers have identified phar-
macologic agents that inhibit excitatory amino acid release or block
their postsynaptic actions. Xenon, a noble gas currently used as an
inhaled anesthetic, is an N-methyl-D-aspartate receptor antago-
nist. Xenon may have other neuroprotective qualities, such as af-
fecting other ion channels and reducing neurotransmitter release in
general. Xenon is an attractive agent for use in infants with HIE be-
cause it easily crosses the blood-brain barrier, takes rapid effect, can
be rapidly withdrawn, and has myocardial protective properties with
very limited potential cardiovascular effects.52 A phase 1 trial using
xenon in combination with hypothermia was completed recently and
demonstrated xenon administration to be feasible with no adverse
cardiovascular or respiratory effects.53 A phase 2 study is currently
under way.
Erythropoietin is a naturally occurring glycoprotein frequently
used to stimulate erythropoiesis and is a safe and efficacious treat-
ment for anemia of prematurity.54 Erythropoietin is locally pro-
duced in the central nervous system and is found in elevated levels
in the cord blood of infants who have perinatal asphyxia.55 Eryth-
ropoietin has many possible mechanisms for neuroprotection. It pro-
vides neuroprotection against apoptosis and has an anti-
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Dendrite
Xanthine
Free radicals 8a
Uric acid
Angiogenesis
5 9 3
Lipases Lipid peroxidation
Neurogenesis
Ca2+ Nucleases
Cell membrane
destruction
NO synthase
Degradation
Free radicals
of
microtubules Free radicals 9
6 8 10
6 8 10
3 4 5 10
Apoptosis/necrosis
neuroprotective agents are illustrated at the points where they interfere with
the pathophysiological cascade. Solid arrows represent the pathophysiological
cascade that is unleashed as a result of HI injury; dashed arrows, interruption of
the cascade by the various neuroprotective agents (circled numbers). As in
Figure 1, the orange boxes represent excitotoxicity; blue boxes, oxidative
stress; yellow box, repair; light green box, cell death; and dark blue box, HI.
NO indicates nitric oxide; 1, magnesium; 2, xenon; 3, erythropoietin; 4, stem
cells; 5, N-acetylcysteine; 6, melatonin; 7, anticonvulsants; 8, antioxidants;
8a, allopurinol sodium; 9, BH4 (tetrahydrobiopterin); and 10, hydrogen sulfide.
inflammatory effect when bound to erythropoietin receptors on
astrocytes and microglial cells.56 Erythropoietin prevents nitric oxi-
de–induced death of neurons and protects neurons from the toxic
effects of glutamate.57 Erythropoietin is neurotrophic and affects
neurogenesis, differentiation, and repair after injury.58 In the study
by Zhu et al,59 neonates with moderate or severe HIE were random-
ized to receive erythropoietin or supportive care without hypother-
mia therapy. Erythropoietin was administered within 48 hours of
birth at a dose of 300 U/kg or 500 U/kg every other day for 2 weeks.
At 18 months of age, the erythropoietin group had reduced rates of
death and moderate or severe disability. The outcome was the same
when the 300- and 500-U/kg doses were compared. Researchers
saw these improvements only in patients with moderate, not se-
vere, HIE. Recently, a phase 1 pharmacokinetic study combined eryth-
ropoietin with hypothermia and demonstrated that participants tol-
erated doses up to 1000 U/kg. This dose produced plasma
concentrations similar to those in animal models of HI injury that are
neuroprotective.60
The pineal gland produces melatonin, a naturally occurring sub-
stance used for regulating the circadian rhythm. Melatonin has many
other effects that may benefit infants with HI injury. Melatonin serves
as a free radical scavenger of the hydroxyl radical, oxygen, and hy-
drogen peroxide. In addition, melatonin decreases inflammatory
cytokine levels and stimulates antioxidant enzymes, such as gluta-
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 Clinical Review & Education Review Hypoxic-Ischemic Encephalopathy

thione peroxidase and reductase, glucose-6-phosphate dehydro-
genase, and superoxide dismutase.61 In a cohort study of new-
borns with asphyxia, melatonin (10 mg by mouth given every 2 hours
for 8 doses) reduced malondialdehyde and nitrate/nitrite levels com-
pared with placebo.62 These reduced levels demonstrated a de-
crease in lipid peroxidation and nitric oxide production.
Stem cell therapy may be a good adjunctive therapy because
of its potential for benefit through several different mechanisms.
Stem cell transplant may increase levels of brain trophic factors and
antiapoptotic factors, decrease inflammation, preserve endoge-
nous tissue, and support replacement of damaged cells.8 A recent
pilot study showed better outcomes with the combination of hy-
pothermia plus autologous umbilical cord blood vs hypothermia
alone.63 Validation of the efficacy of stem cell therapy will require a
bigger sample size and protocols that standardize the source of cells,
doses, and method of delivery.
Conclusions
Great strides in the care of neonates with HIE have been made. The
advent of therapeutic hypothermia has armed the bedside clinician
with a therapy that helps reduce the long-term neurologic impair-
ments in 1 of 8 treated neonates. However, the fields of neonatology
and neonatal neurology should continue to search for neuroprotec-
tive strategies and long-term optimization of infant neuroplasticity.

ARTICLE INFORMATION
Accepted for Publication: November 2, 2014.
Published Online: February 16, 2015.
doi:10.1001/jamapediatrics.2014.3269.
Author Contributions: Drs Douglas-Escobar and
Weiss had full access to all the data in the study and
take responsibility for the integrity of the data and
the accuracy of the data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data:
Douglas-Escobar.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important
intellectual content: All authors.
Study supervision: All authors.
Conflict of Interest Disclosures: None reported.
Additional Contributions: Roger Hoover (News
and Public Affairs, University of Florida) provided
the artwork for Figures 1 and 2. He received no
financial compensation.
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