Sarnat HIE

https://emedicine.medscape.
com/article/973501-print
emedicine.medscape.com
Hypoxic-Ischemic
Encephalopathy
Updated: Jul 18, 2018
Author: Santina A Zanelli, MD; Chief Editor: Dharmendra J Nimavat, MD, FAAP
Overview
Practice Essentials
Perinatal asphyxia, more appropriately known as hypoxic-ischemic encephalopathy (HIE), is characterized by
clinical and laboratory evidence of acute or subacute brain injury due to asphyxia. The primary causes of this
condition are systemic hypoxemia and/or reduced cerebral blood flow (CBF) (see the image below). Birth
asphyxia causes 840,000 or 23% of all neonatal deaths worldwide.[1, 2, 3]
Fetal response to asphyxia illustrating the initial redistribution of blood flow to vital organs. With prolonged asphyxial insult
and failure of compensatory mechanisms, cerebral blood flow falls, leading to ischemic brain injury.
Signs and symptoms
Mild hypoxic-ischemic encephalopathy
Muscle tone may be slightly increased and deep tendon reflexes may be brisk during the first few days
Transient behavioral abnormalities, such as poor feeding, irritability, or excessive crying or sleepiness
(typically in an alternating pattern), may be observed
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https://emedicine.medscape.com/article/973501-print
Typically resolves in 24h
Moderately severe hypoxic-ischemic encephalopathy
The infant is lethargic, with significant hypotonia and diminished deep tendon reflexes
The grasping, Moro, and sucking reflexes may be sluggish or absent
The infant may experience occasional periods of apnea
Seizures typically occur early within the first 24 hours after birth
Full recovery within 1-2 weeks is possible and is associated with a better long-term outcome
Severe hypoxic-ischemic encephalopathy
Seizures can be delayed and severe and may be initially resistant to conventional treatments. The seizures are
usually generalized, and their frequency may increase during the 24-48 hours after onset, correlating with the
phase of reperfusion injury.
As the injury progresses, seizures subside and the electroencephalogram becomes isoelectric or shows a
burst suppression pattern. At that time, wakefulness may deteriorate further, and the fontanelle may bulge,
suggesting increasing cerebral edema. Other symptoms include the following:
Stupor or coma is typical; the infant may not respond to any physical stimulus except the most noxious.
Breathing may be irregular, and the infant often requires ventilatory support
Generalized hypotonia and depressed deep tendon reflexes are common
Neonatal reflexes (eg, sucking, swallowing, grasping, Moro) are absent
Disturbances of ocular motion, such as a skewed deviation of the eyes, nystagmus, bobbing, and loss of
"doll's eye" (ie, conjugate) movements may be revealed by cranial nerve examination
Pupils may be dilated, fixed, or poorly reactive to light
Irregularities of heart rate and blood pressure are common during the period of reperfusion injury, as is
death from cardiorespiratory failure
An initial period of well-being or mild hypoxic-ischemic encephalopathy may be followed by sudden

deterioration, suggesting ongoing brain cell dysfunction, injury, and death; during this period, seizure intensity
may increase.
See Clinical Presentation for more detail.
Diagnosis
Guidelines from the American Academy of Pediatrics (AAP) and the American College of Obstetrics and
Gynecology (ACOG) for HIE indicate that all of the following must be present for the designation of perinatal
asphyxia severe enough to result in acute neurologic injury:
Profound metabolic or mixed acidemia (pH < 7) in an umbilical artery blood sample, if obtained
Persistence of an Apgar score of 0-3 for longer than 5 minutes
Neonatal neurologic sequelae (eg, seizures, coma, hypotonia)
Multiple organ involvements (eg, kidney, lungs, liver, heart, intestines)
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Laboratory studies
Serum electrolyte levels
Renal function studies
Cardiac and liver enzymes - These values are an adjunct to assess the degree of hypoxic-ischemic
injury to the heart and liver
Coagulation system - Includes prothrombin time, partial thromboplastin time, and fibrinogen levels
Arterial blood gas - Blood gas monitoring is used to assess acid-base status and to avoid hyperoxia and
hypoxia, as well as hypercapnia and hypocapnia
Imaging studies
Magnetic resonance imaging (MRI) of the brain
Cranial ultrasonography
Echocardiography
Additional studies
Electroencephalography (EEG) - Standard and amplitude-integrated EEG
Hearing test - An increased incidence of deafness has been found among infants with hypoxic-ischemic
encephalopathy who require assisted ventilation
Retinal and ophthalmic examination
See Workup for more detail.
Management
Following initial resuscitation and stabilization, treatment of HIE is largely supportive and should focus on the
following[4, 5] :
Adequate ventilation
Perfusion and blood pressure management - Studies indicate that a mean blood pressure (BP) above
35-40 mm Hg is necessary to avoid decreased cerebral perfusion
Careful fluid management
Avoidance of hypoglycemia and hyperglycemia
Avoidance of hyperthermia - Hyperthermia has been shown to be associated with increased risk of
adverse outcomes in neonates with moderate to severe hypoxic-ischemic encephalopathy[6]
Treatment of seizures
Therapeutic hypothermia (33º-33.5ºC for 72h) followed by slow and controlled rewarming for infants with
moderate to severe HIE[7]
See Treatment and Medication for more detail.
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Background
Despite major advances in monitoring technology and knowledge of fetal and neonatal pathologies, hypoxic-
ischemic encephalopathy (HIE) remains a serious condition that causes significant mortality and long-term
morbidity.
HIE is characterized by clinical and laboratory evidence of acute or subacute brain injury due to asphyxia (ie,
hypoxia, acidosis). Most often, the exact timing and underlying cause remain unknown.
The American Academy of Pediatrics (AAP) and American College of Obstetrics and Gynecology (ACOG)
published guidelines to assist in the diagnosis of severe hypoxic-ischemic encephalopathy (see History).[8, 9]
Pathophysiology
Brain hypoxia and ischemia due to systemic hypoxemia, reduced cerebral blood flow (CBF), or both are the
primary physiologic processes that lead to hypoxic-ischemic encephalopathy (HIE).[1, 2, 3]
The initial compensatory adjustment to an asphyxial event is an increase in CBF due to hypoxia and
hypercapnia. This is accompanied by a redistribution of cardiac output to essential organs, including the brain,
heart, and adrenal glands. A blood pressure (BP) increase due to increased release of epinephrine further
enhances this compensatory response. See the image below.
Fetal response to asphyxia illustrating the initial redistribution of blood flow to vital organs. With prolonged asphyxial insult
and failure of compensatory mechanisms, cerebral blood flow falls, leading to ischemic brain injury.
In adults, CBF is maintained at a constant level despite a wide range in systemic BP. This phenomenon is
known as the cerebral autoregulation, which helps maintain cerebral perfusion. The physiologic aspects of
CBF autoregulation has been well studied in perinatal and adult experimental animals. In human adults, the BP
range at which CBF is maintained is 60-100 mm Hg.
Limited data in the human fetus and the newborn infant suggest that CBF is stable over much narrower range
of BPs.[10, 11] Some experts have postulated that, in the healthy term newborn, the BP range at which the
CBF autoregulation is maintained may be only between 10-20 mm Hg (compared with the 40 mm Hg range in
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adults noted above). In addition, the autoregulatory zone may also be set at a lower level, about the midpoint
of the normal BP range for the fetus and newborn. However, the precise upper and lower limits of the BP
values above and below which the CBF autoregulation is lost remain unknown for the human newborn.
In the fetus and newborn suffering from acute asphyxia, after the early compensatory adjustments fail, the CBF
can become pressure-passive, at which time brain perfusion depends on systemic BP. As BP falls, CBF falls
below critical levels, and the brain injury secondary to diminished blood supply and a lack of sufficient oxygen
occurs. This leads to intracellular energy failure. During the early phases of brain injury, brain temperature
drops, and local release of neurotransmitters, such as gamma-aminobutyric acid transaminase (GABA),
increase. These changes reduce cerebral oxygen demand, transiently minimizing the impact of asphyxia.
At the cellular level, neuronal injury in HIE is an evolving process. The magnitude of the final neuronal damage
depends on the duration and severity of the initial insult, combined with the effects of reperfusion injury, and
apoptosis. At the biochemical level, a large cascade of events follow hypoxic-ischemic injury.
Excitatory amino acid (EAA) receptor overactivation plays a critical role in the pathogenesis of neonatal
hypoxia-ischemia. During cerebral hypoxia-ischemia, the uptake of glutamate the major excitatory
neurotransmitter of the mammalian brain is impaired. This results in high synaptic levels of glutamate and EAA
receptor overactivation, including N-methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methyl-4 isoxazole
propionate (AMPA), and kainate receptors. NMDA receptors are permeable to Ca++ and Na+, whereas AMPA
and kainate receptors are permeable to Na+. Accumulation of Na+ coupled with the failure of energy
dependent enzymes such as Na+/ K+ -ATPase leads to rapid cytotoxic edema and necrotic cell death.
Activation of NMDA receptor leads to intracellular Ca++ accumulation and further pathologic cascades
activation.
EAAs accumulation also contributes to increasing the pace and extent of programmed cell death through
secondary Ca++ intake into the nucleus. The pattern of injury seen after hypoxia-ischemia demonstrate
regional susceptibility that can be largely explained by the excitatory circuity at this age (putamen, thalamus,
perirolandic cerebral cortex). Finally, developing oligodendroglia is uniquely susceptible to hypoxia-ischemia,
specifically excitotoxicity and free radical damage. This white matter injury may be the basis for the disruption
of long-term learning and memory faculties in infants with hypoxic-ischemic encephalopathy.
Intracellular Ca++ concentration increases following hypoxia-ischemia as a result of (1) NMDA receptor
activation, (2) release of Ca++ from intracellular stores (mitochondria and endoplasmic reticulum [ER]), and (3)
failure of Ca++ efflux mechanisms. Consequences of increases intracellular Ca++ concentration include
activation of phospholipases, endonucleases, proteases, and, in select neurons, nitric oxide synthase (NOS).
Activation of phospholipase A2 leads to release of Ca++ from the ER via activation of phospholipase C.
Activation of proteases and endonucleases results in cytoskeletal and DNA damage.
During the reperfusion period, free radical production increases due to activation of enzymes such as
cyclooxygenase, xanthine oxidase, and lipoxygenase. Free radical damage is further exacerbated in the
neonate because of immature antioxidant defenses. Free radicals can lead to lipid peroxidation as well as DNA
and protein damage and can trigger apoptosis. Finally, free radicals can combine with nitric oxide (NO) to form
peroxynitrite a highly toxic oxidant.
NMDA receptor activation results in activation of neuronal NOS vias PSD-95 and results in the early and
transient rise in NO concentration observed in the initial phase of hypoxia. Inducible NOS is expressed in
response to the marked inflammation secondary to cerebral ischemia and results in a second wave of NO
overproduction that can be prolonged for up to 4-7 days after the insult.
This excessive NO production plays an important role in the pathophysiology of perinatal hypoxic-ischemic
brain injury. NO neurotoxicity depends in large part on rapid reaction with superoxide to form peroxynitrite.[12]
This, in turn, leads to peroxynitrite-induced neurotoxicity, including lipid peroxidation, protein nitration and
oxidation, mitochondrial damage and remodeling, depletion of antioxidant reserve, and DNA damage.
Inflammatory mediators (cytokines and chemokines) have been implicated in the pathogenesis of hypoxic-
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ischemic encephalopathy and may represent a final common pathway of brain injury. Animal studies suggest
that cytokines, particularly interleukin (IL)-1b contributes to hypoxic-ischemic damage. The exact mechanisms
and which inflammatory mediators are involved in this process remains unclear.
Following the initial phase of energy failure from the asphyxial injury, cerebral metabolism may recover
following reperfusion, only to deteriorate in a secondary energy failure phase. This new phase of neuronal
damage, starting at about 6-24 hours after the initial injury, is characterized by mitochondrial dysfunction, and
initiation of the apoptotic cascade. This phase has been called the "delayed phase of neuronal injury."
The duration of the delayed phase is not precisely known in the human fetus and newborn but appears to
increase over the first 24-48 hours and then start to resolve thereafter. In the human infant, the duration of this
phase is correlated with adverse neurodevelopmental outcomes at 1 year and 4 years after insult.[13] See the
image below.
Pathophysiology of hypoxic-ischemic brain injury in the developing brain. During the initial phase of energy failure,
glutamate mediated excitotoxicity and Na+/K+ ATPase failure lead to necrotic cell death. After transient recovery of
cerebral energy metabolism, a secondary phase of apoptotic neuronal death occurs. ROS = Reactive oxygen species.
Additional factors that influence outcome include the nutritional status of the brain, severe intrauterine growth
restriction, preexisting brain pathology or developmental defects of the brain, and the frequency and severity of
seizure disorder that manifests at an early postnatal age (within hours of birth).[14, 15, 16, 17, 18, 19]
Etiology
Badawi et al investigated risk factors of neonatal encephalopathy in the Western Australian case control
study.[20] Of the 164 infants with moderate-to-severe neonatal encephalopathy, preconceptual and
antepartum risk factors were identified in 69% of cases; 24% of infants had a combination of antepartum and
intrapartum risk factors, whereas only 5% of infants had only intrapartum risk factors. In this study, 5% had no
identifiable risk factors. In a review of the literature, Graham et al found that cerebral palsy is associated with
intrapartum hypoxia-ischemia in only 14.5% of cases.[21]
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Epidemiology
United States data
In the United States and in most technologically advanced countries, the incidence of hypoxic-ischemic
encephalopathy (HIE) is 1-4 cases per 1000 births.
International data
The incidence of HIE is reportedly high in countries with limited resources; however, precise figures are not
available. Birth asphyxia is the cause of 23% of all neonatal deaths worldwide. It is one of the top 20 leading
causes of burden of disease in all age groups (in terms of disability life adjusted years) by the World Health
Organization and is the fifth largest cause of death of children younger than 5 years (8%). Although data are
limited, birth asphyxia is estimated to account for 920,000 neonatal deaths every year and is associated with
another 1.1 million intrapartum stillbirths. More than a million children who survive birth asphyxia develop
problems such as cerebral palsy, mental retardation, learning difficulties, and other disabilities.[22, 23]
Prognosis
Accurate prediction of the severity of long-term complications of hypoxic-ischemic encephalopathy (HIE) is
difficult, although clinical, laboratory, and imaging criteria have been used.[24] The following criteria have been
shown to be the most helpful in outlining likely outcomes:
Lack of spontaneous respiratory effort within 20-30 minutes of birth is almost always associated with
death.
The presence of seizures is an ominous sign. The risk of poor neurologic outcome is distinctly greater in
such infants, particularly if seizures occur frequently and are difficult to control.
Abnormal clinical neurologic findings persisting beyond the first 7-10 days of life usually indicate poor
prognosis. Among these, abnormalities of muscle tone and posture (hypotonia, rigidity, weakness)
should be carefully noted.
EEG at about 7 days that reveals normal background activity is a good prognostic sign.
Persistent feeding difficulties, which generally are due to abnormal tone of the muscles of sucking and
swallowing, also suggest significant CNS damage.
Poor head growth during the postnatal period and the first year of life is a sensitive finding predicting
higher frequency of neurologic deficits.
A Swedish retrospective population-based study comprising 692,428 live births of at least 36 gestational
weeks found that more than a quarter (29%) of all HIE births were associated with an obstetric emergency,
with parous women affected more than nulliparous women.[130] The investigators noted a strong association
of shoulder dystocia in nulliparas, and to uterine rupture in women with previous cesarean deliveries.[130]
Of note, the use of therapeutic hypothermia changes the prognostic value of clinical evaluation in infants with
HIE, and its impact on predicting outcomes is still under evaluation.[25]
Other early predictors of long-term neurodevelopmental outcomes are being actively investigated. Early
evidence indicates that biomarkers such as serum S100B and neuron-specific enolase may be helpful in
identifying infants with severe brain injury who may be candidates for novel neuroprotective or
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neuroregenerative therapies.[26]
Morbidity/mortality
In severe HIE, the mortality rate is reportedly 25-50%. Most deaths occur in the first days after birth due to
multiple organ failure or redirection of care to comfort measures as a result of the grim prognosis. Some infants
with severe neurologic disabilities die in their infancy from aspiration pneumonia or systemic infections.
The incidence of long-term complications depends on the severity of HIE. As many as 80% of infants who
survive severe HIE develop serious complications, 10-20% develop moderately serious disabilities, and as
many as 10% are healthy. Among the infants who survive moderately severe HIE, 30-50% may have serious
long-term complications, and 10-20% have minor neurologic morbidities. Infants with mild HIE tend to be free
from serious CNS complications.
Two therapeutic hypothermia trials provided updated information on mortality and the incidence of abnormal
neurodevelopmental outcomes infants with moderate to severe HIE.[27, 28] In these trials, 23-27% of infants
died prior to discharge from the neonatal intensive care unit (NICU), whereas the mortality rate at follow-up
18-22 months later was 37-38%. In these trials, neurodevelopmental outcomes at 18 months were as follows:
Mental development index (MDI): Scores of 85 or higher, 40%; 70-84, 21%; less than 70, 39%
Psychomotor development index (PDI): Scores of 85 or higher, 55%; 70-84, 10%; less than 70, 35-41%
Disabling cerebral palsy - 30%
Epilepsy - 16%
Blindness - 14-17%
Severe hearing impairment - 6%
Data from a randomized controlled trial was evaluated to determine the relationship between hypocarbia and
the outcome for neonatal patients with hypoxic-ischemic encephalopathy. The results found that a poor
outcome (death/disability at 18-22 mo) was associated with a minimum partial pressure of carbon dioxide
(PCO2) and cumulative PCO2 of less than 35 mm Hg; death and disability increased with greater exposure to
PCO2 of less than 35 mm Hg.[29]
Even in the absence of obvious neurologic deficits in the newborn period, long-term functional impairments
may be present. In a cohort of school-aged children with a history of moderately severe HIE, 15-20% had
significant learning difficulties, even in the absence of obvious signs of brain injury. Thus, all children who have
moderate or severe HIE should be monitored well into school age.[30, 31, 32]
Race-, sex-, and age-related demographics
No race or sex predilection has been noted.
By definition, HIE is seen in the newborn period. Preterm infants can also suffer from HIE, but the pathology
and clinical manifestations are different. Most often, the condition is noted in infants who are term at birth. The
symptoms of moderate-to-severe HIE are almost always manifested at birth or within a few hours after birth.
Patient Education
Parents are often concerned about infants' pain and distress, parental-infant bonding, and outcomes following
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hypothermia treatment.[128] Keys to reassuring parents of infants undergoing hyperthermia include consistent
communication, regular updates, and early, balanced discussions regarding potential long-term outcomes;
parental involvement in decision making; and having strong support mechanisms.[128]
Presentation
History
The 1996 guidelines from the American Academy of Pediatrics (AAP) and American College of Obstetrics and
Gynecology (ACOG) for hypoxic-ischemic encephalopathy (HIE) indicate that all of the following must be
present for the designation of perinatal asphyxia severe enough to result in acute neurologic injury[8, 9] :
Profound metabolic or mixed acidemia (pH < 7) in an umbilical artery blood sample, if obtained
Persistence of an Apgar score of 0-3 for longer than 5 minutes
Neonatal neurologic sequelae (eg, seizures, coma, hypotonia)
Multiple organ involvements (eg, kidney, lungs, liver, heart, intestines)
In rare instances, some babies will not fit the aforementioned criteria and the timing of the insult cannot be
precisely known; however early magnetic resonance imaging of the brain can sometimes provide some
insights.
Physical Examination
CNS Manifestations
Clinical central nervous system (CNS) manifestations and course vary depending on hypoxic-ischemic
encephalopathy (HIE) severity.
Mild hypoxic-ischemic encephalopathy
The infant seems hyperalert, muscle tone may be slightly decreased initially, and deep tendon reflexes may be
brisk during the first few days.
Transient behavioral abnormalities, such as poor feeding, irritability, or excessive crying or sleepiness (typically
in an alternating pattern), may be observed.
Typically resolves in less than 24 hours without any consequences.
Moderately severe hypoxic-ischemic encephalopathy
The infant is lethargic, with significant hypotonia and diminished deep tendon reflexes.
The grasping, Moro, and sucking reflexes may be sluggish or absent.
The infant may experience occasional periods of apnea.
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Seizures typically occur early within the first 24 hours after birth.
Full recovery within 1-2 weeks is possible and is associated with a better long-term outcome.
An initial period of well-being or mild hypoxic-ischemic encephalopathy may be followed by sudden

deterioration, suggesting ongoing brain cell dysfunction, injury, and death; during this period, seizure intensity
might increase.
Severe hypoxic-ischemic encephalopathy
Stupor or coma is typical. The infant may not respond to any physical stimulus.
Breathing may be irregular, and the infant often requires ventilatory support.
Generalized hypotonia and depressed deep tendon reflexes are common.
Neonatal reflexes (eg, sucking, swallowing, grasping, Moro) are absent.
Disturbances of ocular motion, such as a skewed deviation of the eyes, nystagmus, bobbing, and loss of "doll's
eye" (ie, conjugate) movements may be revealed by cranial nerve examination.
Pupils may be dilated, fixed, or poorly reactive to light.
Seizures are delayed, can be severe and may be initially resistant to conventional treatments. The seizures
are usually generalized, and their frequency may increase during the 24-48 hours after onset, correlating with
the phase of reperfusion injury. As the injury progresses, seizures subside and the EEG becomes isoelectric or
shows a burst suppression pattern. At that time, wakefulness may deteriorate further, and the fontanelle may
bulge, suggesting increasing cerebral edema.
Irregularities of heart rate and blood pressure (BP) are common during the period of reperfusion injury, as is
death from cardiorespiratory failure.
Infants who survive severe hypoxic-ischemic encephalopathy
The level of alertness improves by days 4-5 of life.
Hypotonia and feeding difficulties persist, requiring tube feeding for weeks to months.
Multiorgan Dysfunction
Multiorgan systems involvement is a hallmark of HIE.[33, 34] Organ systems involved following a hypoxic-
ischemic events include the following:
Heart (43-78%)
May present as reduced myocardial contractility, severe hypotension, passive cardiac dilatation, and tricuspid
regurgitation.
Lungs (71-86%)
Patients may have severe pulmonary hypertension requiring assisted ventilation.
Renal (46-72%)
Renal failure presents as oliguria and, during recovery, as high-output tubular failure, leading to significant
water and electrolyte imbalances.
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Liver (80-85%)
Elevated liver function test results, hyperammonemia, and coagulopathy can be seen. This may suggest
possible GI dysfunction. Poor peristalsis and delayed gastric emptying are common; necrotizing enterocolitis is
rare. Intestinal injuries may not be apparent in the first few days of life or until feeds are initiated.
Hematologic (32-54%)
Disturbances include increased nucleated RBCs, neutropenia or neutrophilia, thrombocytopenia, and

coagulopathy. Severely depressed respiratory and cardiac functions and signs of brainstem compression
suggest a life-threatening rupture of the vein of Galen (ie, great cerebral vein) with a hematoma in the posterior
cranial fossa.
Neurologic Findings
Cranial nerves
Lack of reflex activity mediated by the cranial nerves can indicate brainstem dysfunction.
Full-term infants should blink and sustain eye closure in response to a sustained light stimulus. Repeated
flashes of light should produce habituation (eg, attenuated blinking) after 3-4 stimuli. Virtually all full-term
newborns can track a ball of red wool, and the movement of stripes of at least one eighth of an inch or bigger
can elicit opticokinetic nystagmus. Objects and pictures with round contours and facial appearances also make
good targets for tracking in the newborn. Tracking is possible in infants with complete destruction of the
occipital cortex by virtue of a subcortical pulvinar-collicular system. Retinal hemorrhages are commonly
observed in the neonate after vaginal delivery and can result in decreased pupil response. Destruction of the
occipital cortex will also not affect pupillary response, because the responsible pathways leave the optic nerve
and travel to the Edinger-Westphal nucleus, which sends back axons via the bilateral oculomotor nerves
(consensual pupillary reflex).
Neurologic examination may be difficult in the small and frail premature infant, but weakness of the lower
extremities sometimes reflects the neuropathologic substrate of periventricular leukomalacia. Over time, the
patient with periventricular white-matter lesions develops spastic diplegia affecting the lower extremities more
than the upper extremities.
Blinking to light starts at 26 weeks’ gestational age, sustained eye closure to light is seen around 32 weeks,
and 90% of newborns track a ball of red wool by 34 weeks. Opticokinetic reflexes can be seen at 36 weeks.
The pupil starts reacting to light around 30 weeks, but the light reflex is not consistently assessable until the
gestational age of 32-35 weeks. Pupillary reflexes are reliably present at term. Extraocular movements can be
elicited by performing the doll's-eye maneuver at 25 weeks’ gestation and by performing caloric stimulation at
30 weeks’ gestation.
In infants aged 32-34 weeks’ gestation, suck and swallow are reasonably coordinated with breathing, but the
actions are not perfected until after term.
Patients with mild HIE often have mydriasis. Progression of the disease may produce miosis (even in the dark)
responsive to light, and in severe cases (stage 3 of Sarnat classification), the pupils are small or midpositioned
and poorly reactive to light, reflecting sympathetic or parasympathetic dysfunction.
The lack of pupillary, eye movement, corneal, gag, and cough reflexes may reflect damage to the brainstem,
where the cranial-nerve nuclei are located. Decreased respiratory drive or apnea can be from lesions of the
respiratory center, which overlap with vagal nuclei (ambiguous and solitaire) or medullary reticular formation.
Ventilatory disturbances in HIE may manifest as periodic breathing apnea (similar to Cheyne-Stokes
respiration) or just decreased respiratory drive.
Motor function
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Begin the motor examination of an infant with suspected HIE by qualitatively and quantitatively observing his or
her posture and spontaneous movements. Asymmetry in the amount of movement and posture is a subtle sign
of hemiparesis, but it may be the only focal feature of the examination. Slight stimulation (eg, gently touching
the patient) can increase motor activity in the term neonate and may be helpful in demonstrating asymmetrical
hemiparesis.
Eliciting the Moro reflex may be an excessive stimulus and mask a subtle asymmetry in limb movement.
Asymmetry in the Moro reflex is seen in peripheral lesions (eg, those due to brachial plexus injury).
Total absence or paucity of spontaneous movements, especially if associated with no reaction to painful stimuli
and generalized hypotonia, indicates brainstem dysfunction or severe, diffuse, or multifocal cortical damage.
Specific patterns of motor weakness indicate cerebral injury patterns. Patients with borderzone parasagittal
injury (ulegyria) tend to have proximal greater than distal weakness and upper extremity more than lower
extremity weakness (man-in-the-barrel). A unilateral, focal infarct, especially one involving the middle cerebral
artery, causes contralateral hemiparesis and focal seizures. Patients with selective neuronal necrosis may
have severe hypotonia, stupor, and coma.
Motor examination of a newborn with large unilateral lesions may reveal mild hemiparesis and seizures in as
many as 80%. The seizures are often partial (focal) and contralateral to the cortical lesion. Neonates with
severe bilateral infarcts may have quadriparesis. Moro and tonic neck reflexes do not habituate, reflecting the
lack of cortical modulation, which attenuates the response after repeated trials or sustained stimulus.
Newborns with diencephalic lesions cannot regulate their temperature and have problems with sleep-wake
cycles. The long-term sequelae of focal or multifocal cerebral necrosis include spastic hemiparesis and
quadriparesis (eg, bilateral hemiparesis), cognitive deficits, and seizures.
Foot-ankle dorsiflexion or triple flexion (eg, foot-ankle dorsiflexion, knee and hip flexion) after plantar
stimulation reflects only an intact spinal cord and sensory and motor nerves. Extensor movements (eg, arm
elevation above the level of the shoulders) are more sophisticated motor actions than the dorsiflexion or triple
flexion and require some cortical function.
A tonic neck reflex is performed by turning the patient's head to one side. The patient demonstrates arm and
leg extension on the side to which the head is turned and flexion on the opposite side (fencer's posture). The
tonic neck reflex posture should go away after several seconds, and its persistence is a sign of cortical
dysfunction.
Spasticity is a velocity-dependent increase in tone that is generally most prominent with limb extension in
muscle groups with antigravitational action (arm flexion, plantar extension). This sign can be seen over time in
infants with corticospinal tract damage caused by a hypoxic-ischemic insult. In the neonatal period, spasticity is
commonly noted first and is most prominent in the distal parts of the extremities. All fingers are flexed with the
thumb under the second to fifth fingers, a pattern commonly referred to as cortical thumbs. Fewer than 5-10
beats of ankle clonus may be present in healthy neonates, but infants with damage to the corticospinal tract
may have sustained ankle clonus. However, the initial motor manifestation will be flaccid hypotonia with
spasticity later developing.
When assessing muscle tone, the state of arousal and prematurity must be taken into account. In the acute
phase, tone is decreased in a generalized fashion affecting trunk and extremities. The flexor tone in the limbs
is best assessed in term infants by showing a discrepancy in the scoring system between Dubowitz neurologic
examination and morphologic examination. The infant looks like a “rag doll” when supported by a hand under
the chest (vertical suspension). Head lag is demonstrated by traction of the hands in a supine position. The
infant folds around the examiner's hand when lifted prone with a hand supporting the chest (horizontal
suspension).
Hip abduction may be seen with increased tone and even with decerebrate posturing (frog-leg posture).
Another manifestation of CNS dysfunction in the neonatal period is increased axial extensor tone with arching
of the back and neck extension or opisthotonus. Many infants simultaneously have decreased axial flexor tone
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(eg, major head lag on arm traction maneuver) and increased axial extensor tone. In many cases, limb and
axial hypotonia are present for several months before increased axial extensor tone or limb spasticity can be
detected. Increased active neck and trunk extensor tone are predictors of quadriparesis. Another sign of
spasticity that can develop relatively early is scissoring, where the previously abducted legs extend, become
rigid, and have extreme hip adduction such that they cross with stimulation or crying.
Seizures
HIE is often reported to be the most frequent cause of neonatal seizures. They usually occur 12-24 hours after
birth and are difficult to control with anticonvulsants. Large, unilateral infarcts occur with neonatal seizures in
as many as 80% of patients. Seizures are often partial (focal) and contralateral to the cortical lesion. About two
thirds of newborns with cerebral venous infarcts have seizures. Those with multiple or diffuse lesions and
cerebral venous infarcts often have multifocal or migratory seizures. Seizures are observed during physical
examination and may confirm the diagnosis. Observation often reveals clonic rhythmic contractions. When
holding the limb affected by clonic seizures, the examiner's hand shakes or feels limb movement. Limb flexion
or extension does not suppress the clonic activity, as it does in jitteriness and clonus. Newborn infants cannot
have generalized seizures due to immaturity of the neuronal pathways connecting the 2 halves of the brain.
Tonic, unilateral, or focal seizures consistently have an EEG signature. In the seizures, unilateral arm and leg
posturing is often accompanied by ipsilateral trunk flexion. Generalized tonic posturing (eg, extension of the
upper and lower extremities or extension of the legs and flexion of the arms) is related to an EEG seizure in
15% of affected neonates.
Tonic seizures can be seen in neonates with local anesthetic intoxication. Although generalized tonic posturing
is infrequently associated with electrical seizures, it is not a benign sign. Of neonates with tonic posturing and
an abnormal EEG background, 13% have normal development.
Mizrahi and Kellaway suggested the name brainstem release phenomena because tonic posturing and some
subtle seizure-like motor automatisms are probably the result of primitive brainstem and spinal motor patterns
liberated because the lack of inhibition from damaged forebrain structures.[35] However, this tonic posturing is
not a seizure and, thus, treatment with antiepileptics does not have benefit unless the infant is having other
semiology consistent with seizures.
Subtle seizures may be a part of the HIE picture. Subtle manifestations of neonatal seizures are confirmed on
EEG and include apnea; tonic eye deviation; sustained eye opening; slow, rhythmic, tongue thrusting; and
boxing, bicycling, and swimming movements. Most still accept that some subtle seizures may be correlated
with EEG results. However, publications since the late 1980s have shown that seizures are not as frequent as
previously thought and that they are unusual in patients close to term. Several other patterns of subtle
neonatal seizures are described without EEG confirmation. The lack of an EEG signature does not exclude
CNS pathology because neonates with HIE often have motor automatisms without EEG seizures.
Management is controversial, but treatment is not usually beneficial unless more overt seizure activity is
noted.[36]
Seizures may be difficult to clinically diagnose in the premature neonate. Subtle seizures associated with ictal
EEG changes are not rare in premature infants. The subtle patterns of neonatal seizures in the premature
infant include sustained eye opening, oral-buccal-lingual movements (smacking, drooling, chewing), pedaling
movements, grimacing, and autonomic manifestations.
Sarnat Staging System
The staging system proposed by Sarnat and Sarnat in 1976 is often useful in classifying the degree of
encephalopathy.[37] Stages I, II, and III correlate with the descriptions of mild, moderate, and severe
encephalopathy described above.
Table. Modified Sarnat Clinical Stages of Perinatal Hypoxic Ischemic Brain Injury [37] (Open Table in a new
window)
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MILD MODERATE SEVERE
Level of Alternating (hyperalert,

Lethargic or obtunded Stuporous
Consciousness lethargic,irritable)
Neuromuscular Control
Muscle tone Normal Hypotonia Flaccid
Intermittent
Decorticate (arms
Posture Normal decerebration (arms and
flexed/legs extended)
legs extended)
Hyperactive or
Stretch reflexes Normal or hyperactive Absent
decreased
Segmental
Present Present Absent
myoclonus
Complex Reflexes
Suck Weak Weak or absent Absent
Weak; incomplete; high

Moro Strong; low threshold Absent
threshold
Oculovestibular Normal Overactive Weak or absent
Tonic neck Slight Strong Absent
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Generalized Generalized
Autonomic Function Both systems depressed
sympathetic parasympathetic
Variable; often unequal;

Pupils Mydriasis Miosis
poor light reflex
Heart Rate Tachycardia Bradycardia Variable
Bronchial and
Sparse Profuse Variable
Salivary Secretions
GI Motility Normal or decreased Increased; diarrhea Variable
Common; focal or
Seizures None Delayed
multifocal
Early: low-voltage
continuous delta and
theta Early: periodic pattern
with Isopotential phases
EEG Findings Normal (awake) Later: periodic pattern
(awake) Later: totally isopotential
Seizures: focal 1-to 1-Hz
spike-and-wave
1-3 days
Duration 2-14 days Hours to weeks
Typically < 24h
DDx
Diagnostic Considerations
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Important considerations
Birth asphyxia, birth injury, and perinatal asphyxia are terms often used incorrectly to describe hypoxic-
ischemic encephalopathy (HIE).
A birth injury is a condition in which fetal or neonatal injury has occurred during the process of birth (ie, during
the first and second stages of labor). Examples include brachial plexus injury; fracture of the clavicle; forceps-
induced damage to the facial nerve or soft tissues; and cuts or bruises from scissors, clips, or scalp monitors.
Birth asphyxia is similar to birth injury in that asphyxia occurs during the first and second stages of labor when
the fetus was otherwise normal.
Perinatal asphyxia signifies that asphyxia occurred around the time of delivery of a newborn baby.
The American Academy of Pediatrics (AAP) and American College of Obstetrics and Gynecology
(ACOG) recommend using HIE because this term accurately describes the clinical condition, encephalopathy
from asphyxia, without implying the time of brain injury. The AAP and ACOG also advise not using the terms
perinatal asphyxia or birth asphyxia because it is difficult to identify the time of brain injury and nearly
impossible to ascertain that the brain had been "normal" before such injury.
All professional societies encourage accurate recording of objective information in the medical records,
including maternal and neonatal history and the clinical and laboratory findings.
The findings from brain imaging procedures and EEG help in the total assessment of the infant's clinical status.
No diagnostic tests conclusively prove that a given magnitude of asphyxia has led to a specific neurologic
injury. Acute perinatal and intrapartum events have been found only in about 20% of children diagnosed as
having cerebral palsy.
Counseling the parents with available information and explanations about their infant's clinical status and the
prognosis is always recommended.
Other problems to be considered

Several inborn errors of metabolism can present in the neonatal period (usually not present at birth) with
features similar to HIE.[38] Those include the following:
Nonketotic hyperglycinemia
Disorders of pyruvate metabolism
Urea cycle defects
Zellweger syndrome
Mitochondrial disorders
Other diagnoses should also be included in the differential diagnosis, including the following:
Neuromuscular disorders including neonatal myopathies
Brain tumors
Developmental defects
Infections
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Sulphite oxidase deficiency[39]
Differential Diagnoses
Genetics of Methylmalonic Acidemia
Genetics of Propionic Acidemia (Propionyl CoA Carboxylase Deficiency)
Workup
Workup
Approach Considerations
Diagnostic investigations of infants with hypoxic-ischemic encephalopathy (HIE) are directed at establishing
the severity and involvement of other organs, as well as to initiate an assessment of the prognosis. To that
extent, initial laboratory testing should include determination of cardiac, renal and liver dysfunction.
In the era of therapeutic hypothermia, continuous video-electroencephalographic (EEG) monitoring is essential

to assess encephalopathy severity and to monitor for seizures. Brain magnetic resonance imaging (MRI) is
typically delayed until after rewarming is complete, although earlier MRI may be helpful in circumstances in
which redirection of care is being considered.
Laboratory Studies
There are no specific tests to confirm or exclude a diagnosis of hypoxic-ischemic encephalopathy (HIE)
because the diagnosis is made on the basis of the history, physical, neurologic examinations, and laboratory
evidence. Many of these tests are performed to assess the likelihood of severe brain injury and to monitor the
functional status of the organ systems. As always, the results of the tests should be interpreted in conjunction
with the clinical history and the findings from the physical examination.
Laboratory studies should include the tests below.
Serum electrolyte levels
In severe cases, daily assessment of serum electrolytes are valuable until the infant's status improves.
Markedly low serum sodium, potassium, and chloride levels in the presence of reduced urine flow and
excessive weight gain may indicate acute tubular damage or syndrome of inappropriate antidiuretic hormone
(SIADH) secretion, particularly during the initial 2-3 days of life.
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Similar changes may be seen during recovery; increased urine flow may indicate ongoing tubular damage and
excessive sodium loss relative to water loss
Cardiac function studies
A cardiac enzymatic study gives an estimation of the extent of cardiac injury from asphyxia.
Renal function studies
Serum creatinine levels, creatinine clearance, and blood urea nitrogen (BUN) levels suffice in most cases.
Liver enzymes
These values are an adjunct to assess the degree of hypoxic-ischemic injury to these other organs. These
findings may also provide some insight into injuries to other organs, such as the liver. [40]
Coagulation system evaluation
This includes prothrombin time, partial thromboplastin time, fibrinogen levels, and serial platelet counts to
assess the synthetic functions of the liver as well as assess for consumptive coagulopathy or bone marrow
suppression.
Arterial blood gas (ABG)
Blood gas monitoring is used to assess acid-base status and to avoid hyperoxia and hypoxia as well as
hypercapnia and hypocapnia. During the period of shock, capillary blood gases may not be reliable.
Imaging Studies
Brain magnetic resonance imaging (MRI)
MRI is the imaging modality of choice for the diagnosis and follow-up of infants with moderate-to-severe
hypoxic-ischemic encephalopathy (HIE).[41, 42, 43, 44] Conventional MRI sequences (T1w and T2w) provide
information on the status of myelination and preexisting developmental defects of the brain. When performed
after the first day (and particularly after day 4), conventional images may accurately demonstrate the injury
pattern as area of hyperintensity. Conventional images are most helpful at age 7-10 days, when the diffusion-
weighted imaging (DWI) findings have pseudonormalized.
Following a severe asphyxial event, a central pattern of injury is seen with injury to (1) the deep gray matter (ie,
putamina, ventrolateral thalamus, hippocampi, dorsal brainstem, or lateral geniculate nucleus) and (2) the
perirolandic cortex. These areas contain the highest concentration of N-methyl-D-aspartate (NMDA) receptors
and are actively myelinating.
Less severe or partial insult results in injury to the intervascular boundaries areas and is also called watershed
injury. This type of lesions manifests in the infants as proximal extremity weakness or spasticity.
Decreased signal in the posterior limb of the internal capsule (PLIC) on T1w images may be noted. The
absence of normal signal (high intensity on T1w images) in the PLIC of infants older than 38 weeks' gestation
is a strong predictor of abnormal motor outcomes in these infants.[45]
DWI allows earlier identification of injury patterns in the first 24-48 hours. The MRI sequence identifies areas of
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edema and, hence, injured areas. DWI changes peak at 3-5 day and pseudonormalizes by the end of the first
week. In neonates, DWI changes may underestimate the extent of injury, most likely because of the
importance of apoptosis in the ultimate extent of neurologic injury.[41]
MRI is also a useful tool in the determination of prognosis. Studies indicate that infants with predominant
injuries to the basal ganglia or thalamus (BGT) have an unfavorable neurologic outcome when compared with
infants with a white matter predominant pattern of injury. Abnormal signals in the PLIC have also been
associated with poor neurologic outcome. In one study, severe BGT lesions on early MRI (performed at a
median of 10 d; range, 2-42 d) were strongly associated with motor impairment at 2 years. In addition,
abnormal PLIC signal was also highly correlated with inability to walk independently at 2 years, with a
sensitivity of 0.92 and a specificity of 0.77.[46]
In a study of MRIs at term-equivalent age from 3 cohorts of 325 very preterm infants, Kidokoro et al found 33%
(n=107) had some grade of brain injury (eg, periventricular leukomalacia, intraventricular/cerebellar
hemorrhage) and 10% (n=33) had severe brain injury.[47] The investigators noted severe brain injury and
impaired growth patterns were independently associated with perinatal risk factors and delayed cognitive
development.[47]
Both conventional images (T1- and T2-weighted) and diffusion techniques (DWI and ADC maps) have a good
specificity (>90%) and positive predictive value (>85%) in predicting death or major disability at age 2 years.
However, sensitivity and negative predictive values are low.[48]
MRI is also useful for follow-up. In any newly diagnosed case of cerebral palsy, MRI should be considered
because it may help in establishing the cause. Note that the interpretation of MRI in infants requires
considerable expertise.
Magnetic resonance spectroscopy (MRS) allows for quantification of intracellular molecules. Proton MRS
allows identification of cerebral lactate, which persist for weeks following a significant hypoxic-ischemic injury.
Phosphorous MRS allows for real-time quantification of ATP, phosphorus creatinine, inorganic phosphorous,
and intracellular pH levels.
Cranial ultrasonography
Although portable and convenient, cranial ultrasonography has a low sensitivity (50%) for the detection of
anomalies associated with HIE. Findings include global increase in cerebral echogenicity and obliteration of
cerebrospinal fluid (CSF) containing spaces suggestive of cerebral edema. Increase in the echogenicity of
deep gray matter structures may also be identified, typically when ultrasonography is performed after 7 days of
life. Finally, head ultrasonography has a very limited role to rule out intracerebral or intraventricular
hemorrhages, and it is not very useful to learn the extent of brain injury.
In small studies, ultrasonography-based semi-quantitative markers such as the white matter/gray matter
echogenicity ratio, as well as the resistive index, have emerged as potentially helpful tools to assess HIE
severity and to assist in prognosis formulation early in the disease course. These studies indicate that in
infants with HIE, white matter/gray matter echogenicity ratios are increased. Furthermore, neonates with a
resistive index below 0.6 have an increased risk of neurodevelopmental impairment at age 20-32 months.[49,
50]
Head computed tomography (CT) scanning
Head CT scanning is a rapid mode of screening and is very effective in detecting hemorrhage with the added
advantage of limited sedation need. However, evidence suggests that even a single CT scan exposes children
to potentially harmful radiation.[51, 52, 53] Additionally, CT scanning is not a sensitive modality for evaluation
of HIE because of the high water content in the neonatal brain and the high protein content of the
cerebrospinal fluid, which result in poor parenchymal contrast resolution.[54] Because of these concerns and
owing to the superiority of MRI in evaluating brain structures, head CT scanning is not recommended in the
evaluation of neonates with HIE.
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Echocardiography
Obtain an echocardiogram to evaluate the cardiac contractility and ejection fraction. Note that neonates with
HIE receiving therapeutic hypothermia may experience a reduction in cardiac output and descending aorta
blood flow.[125] Systemic organ perfusion and cerebral metabolism may be affected by preferential cerebral
distribution of cardiac output in conjunction with an increase in systemic peripheral vascular resistance.[125]
Other Tests
Amplitude-integrated electroencephalography (aEEG)
Several studies have shown that a single-channel aEEG performed within a few hours of birth can help
evaluate the severity of brain injury in the infant with hypoxic-ischemic encephalopathy (HIE).[55, 56, 57] The
abnormalities seen in infants with moderate-to-severe HIE include the following:
Discontinuous tracing characterized by a lower margin below 5 mV and an upper margin above 10 mV
Burst suppression pattern characterized by a background with minimum amplitude (0-2 mV) without
variability and occasional high voltage bursts (>25 mV)
Continuous low voltage pattern characterized by a continuous low voltage background (< 5 mV)
Inactive pattern with no detectable cortical activity
Seizures, usually seen as an abrupt rise in both the lower and upper margin
In addition, aEEG findings have been used as criteria for inclusion in the CoolCap trial of selective head
cooling.[27, 37, 58] However, some evidence argues against the use of aEEG as a tool to exclude infants with
HIE from receiving hypothermia therapy.
Although normal aEEG findings may not necessarily mean that the brain is healthy, a severe or moderately
severe aEEG abnormality may indicate brain injury and poor outcome. However, a rapid recovery (within 24 h)
of abnormal aEEG findings is associated with favorable outcome in 60% of cases. Finally, in a meta-analysis of
8 studies, Spitzmiller et al concluded that aEEG can accurately predict poor outcome with a sensitivity of 91%
(95% CI, 87-95) and a negative likelihood ratio of 0.09 (95% CI, 0.06-0.15).[59]
Note that considerable training is required for conducting and properly interpreting the aEEG findings. With
more recent advancement in technology, aEEG can alert the caregivers regarding seizure activity based on the
software recognition of a pattern.
Standard EEG
Traditional multichannel EEG is an integral part of the evaluation of infants diagnosed with HIE. It is a valuable
tool to assess the severity of the injury and evaluate for electrographic-only seizures (which are very common
in neonates with HIE).[60, 61] This is particularly important for infants on assisted ventilation requiring sedation
or paralysis. EEG can be very useful to help a clinician decide treatment options based on the report's findings.
Changes in EEG wave patterns evolve over time and are a reliable early indicator of the brain injury.[62]
Generalized depression of the background rhythm and voltage, with varying degrees of superimposed
seizures, are early findings. EEG characteristics associated with abnormal outcomes include (1) background
amplitude of less than 30 mV, (2) interburst interval of more than 30 seconds, (3) electrographic seizures, and
(4) absence of sleep-wake cycle at 48 hours.
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Caution in interpreting early severe background abnormalities needs to be applied because reverting to normal
background pattern in few days of life can be associated with normal outcomes. Note that large doses of
anticonvulsant therapy may alter the EEG findings.
Serial EEGs should be obtained to assess seizure control and evolution of background abnormalities. Early
EEGs are important not only to evaluate the degree of encephalopathy and the presence of seizures but may
also help establish early prognosis.[63] Serial EEGs are also helpful in establishing prognosis. Improvement in
the EEG findings over the first week, in conjunction with improvement in the clinical condition, may help predict
a better long-term outcome.[64]
Special sensory evaluation
Screening for hearing is now mandatory in many states in the United States; in infants with hypoxic-ischemic
encephalopathy, a full-scale hearing test is preferable because of an increased incidence of deafness among
infants with hypoxic-ischemic encephalopathy that require assisted ventilation.
Retinal and ophthalmic examination

This examination may be valuable, particularly as part of an evaluation for developmental abnormalities of the
brain.
Spectral-domain optical coherence tomography (SD-OCT) shows promise in the evaluation of prematurity on
early optic nerve development and of central nervous system development and anomalies.[65]
Histologic Findings
The impressive array of neuropathologic findings that can result from a hypoxic-ischemic event can be
primarily explained by the gestational time frame in which the event occurs. Prior to 20 weeks' gestation, fetal
macrophages are capable of removing necrotic debris via phagocytosis, resulting in a smooth cavity without a
gliotic response. Examples of lesions that can result from hypoxic-ischemic events in the second trimester
include hydranencephaly, porencephaly, and schizencephaly.
After 20 weeks' gestation, hypoxic-ischemic insults result in astrocyte activation with subsequent gliosis.
Subependymal germinal matrix hemorrhage is most common in premature infants, with hemorrhage involving
the germinal matrix, lateral ventricles, and/or the adjacent parenchyma. In the full-term infant, hypoxic-ischemic
events primarily result in lesions of the cerebral cortex, basal ganglia, thalamus, brain stem, or cerebellum. The
location and severity of the lesions correlate with clinical symptoms, such as disturbances of consciousness,
seizures, hypotonia, oculomotor-vestibular abnormalities, and feeding difficulties. The major neuropathologic
patterns of injury in hypoxic-ischemic encephalopathy are listed below. More than one pattern can be present.
Selective neuronal necrosis is the most common pattern of injury observed in hypoxic-ischemic
encephalopathy and is characterized by neuronal necrosis selective to areas with higher energy demands. The
following 5 major patterns have been described:
Diffuse: Sites of predilection for diffuse neuronal necrosis include the cerebral cortex (particularly the
hippocampus), deep nuclear structures (thalamus, basal ganglia), brain stem, cerebellum, and anterior
horn of the spinal cord.
Cerebral cortex (deep nuclear): A predominant cerebral cortex (deep nuclear) pattern of injury is present
in 35-85% of infants with hypoxic-ischemic encephalopathy.
Brain stem (deep nuclear): Brain stem (deep nuclear) is the predominant lesion in 15-20% of infants with
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hypoxic-ischemic encephalopathy. Some of these lesions can evolve to status marmoratus . The 3 major
features of status marmoratus include neuronal loss, gliosis and hypermyelination. This
hypermyelination is believed to be secondary to myelin sheath formation and deposition around the
prominent processes of reactive astrocytes. Patchy, white discoloration of the gray matter ("marbling") is
sometimes observed on gross examination. This marbling is the macroscopic correlate of the
hypermyelination and glial scarring seen on histologic examination. It is not seen in its complete form
until the end of the first year of life.
Pontosubicular: This is the least common pattern and can occur in infants aged 1-2 months or younger.
Cerebellar: This primarily occurs in premature infants.
An example of severe acute hypoxic-ischemic neuronal change with associated gliosis is shown in the images
below.
Severe acute hypoxic-ischemic neuronal change in the basal ganglia is noted. Histologic examination reveals severe
hypoxic-ischemic neuronal change, characterized by the presence of pyknotic and hyperchromatic nuclei, the loss of
cytoplasmic Nissl substance, and neuronal shrinkage and angulation (arrow). These alterations begin to appear
approximately 6 hours following hypoxic-ischemic insult. Reactive astrocytosis is evident approximately 24-48 hours after
the primary hypoxic-ischemic event.
Significant astrocytosis in the basal ganglia following hypoxic-ischemic insult is observed. An immunohistochemical stain
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for glial fibrillary acidic protein (GFAP) was performed on the same tissue shown in the previous image to demonstrate the
prominent gliosis secondary to the hypoxic-ischemic event. GFAP is a useful marker to study astrocytic response to injury.
This gliosis of the basal ganglia, along with subsequent hypermyelination, is responsible for the evolution of status
marmoratus over months to years.
Parasagittal cerebral injury is typically bilateral and involves the parasagittal areas of the cerebral cortex (see
the image below).
Bilateral acute infarctions of the frontal lobe are shown. The infarctions depicted in the figure (arrows) are consistent with
watershed infarctions secondary to global hypoperfusion. The lesions depicted in the image are consistent with an acute
ischemic event, occurring within 24 hours of death. The regions most susceptible to hypoperfusion include the end-artery
zones between the anterior, middle, and posterior cerebral arteries.
The regions of the cortex most susceptible to this type of injury are the end-artery zones between the anterior,
middle, and posterior cerebral arteries. These so-called watershed regions are particularly vulnerable to global
hypoperfusion events; the parieto-occipital cortex is most susceptible. Parasagittal cerebral injury is most
commonly seen in the full-term infant. Although most of these lesions are ischemic, approximately 25% are
associated with hemorrhagic events in the perinatal period.
Focal and multifocal ischemic brain necrosis lesions vary in terms of distribution and can be limited to a region
supplied by an occluded artery or can be diffuse in cases of global hypoperfusion. Ulegyria may result, with
preserved gyral crests adjacent to sulci marked by dyslamination, neuronal loss, and disorganized white
myelinated fibers (see the images below).
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A prior hypoxic-ischemic event involving the occipital lobe has resulted in a chronic lesion marked by dyslamination,
neuronal loss, and disorganized arrangements of myelinated white matter fibers. Grossly, the lesion was marked by
preserved gyral crests and involved sulci, resulting in prominent, mushroom-shaped gyri.
A Luxol-Fast Blue stain was performed on the same tissue shown in the previous image to demonstrate the haphazard
arrangement of myelinated white matter fibers projecting into the gray matter of the occipital cortex.
Periventricular leukomalacia (PVL), also called "white matter necrosis," is macroscopically characterized by the
presence of discrete cavities or foci of parenchymal softening in the periventricular areas. In some cases, PVL
can not be grossly appreciated. PVL is believed to be the result of compromised boundary zone perfusion
between the ventriculofugal and ventriculopetal arteries. This area is particularly vulnerable secondary to the
increased metabolic demands of white matter undergoing myelination. Microscopically, PVL manifests early as
geographic coagulative necrosis. As the lesion evolves, reactive astrocytes, activated microglia, and
macrophages become prominent in the lesional rim (see the images below).
Periventricular leukomalacia is depicted. This cystic lesion, present in the cingulate cortex, is consistent with
periventricular leukomalacia. Note the extensive hemorrhage within the cystic space as well as the hemosiderin-laden
macrophages around the lesional rim.
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Periventricular leukomalacia is depicted. This figure depicts the lesion seen in the previous image at higher magnification.
Extensive hemosiderin and reactive astrocytosis is present surrounding the lesion (center of field). Note the proximity of
the lesion to the ependymal lining of the lateral ventricle (far right).
Treatment
Medical Care
Therapeutic hypothermia is indicated for infants with moderate-to-severe hypoxic-ischemic encephalopathy
(HIE). Supportive management is also critical to prevent additional injury from seizure activity, poor perfusion,
electrolyte imbalance, and abnormal glycemic control.
Following initial resuscitation and stabilization, treatment of HIE includes hypothermia therapy for moderate to
severe encephalopathy as well as supportive measures focusing on adequate oxygenation, ventilation and
perfusion, careful fluid management, avoidance of hypoglycemia and hyperglycemia, and treatment of
seizures.[4, 5] Intervention strategies aim to avoid any further brain injury in these infants.[66]
In cases of posterior cranial fossa hematoma, surgical drainage may be lifesaving if no additional pathologies
are present.
In patients with HIE and suspected neonatal sepsis receiving gentamicin and hypothermia treatment, modified
gentamicin dosing regimens are required owing to the reduced clearance of this agent potentially leading to
toxicity in these infants from higher gentamicin concentrations during hypothermia therapy.[129]
Transfer
Infants who present in a level I or II center may require transfer to a tertiary neonatal intensive care unit (NICU)
for definitive neurodiagnostic studies (electroencephalography [EEG] and neuroimaging), consultation with a
pediatric neurologist, and evaluation for therapeutic hypothermia. Based on the current recommendations,
therapeutic hypothermia must be initiated within 6 hours after birth.[127] Timely referral is essential to provide
therapeutic hypothermia. If that window (of 6 hours) has passed, infants will still benefit from the expertise of
level III and higher centers.
Discharge considerations
Physical therapy and developmental evaluations are needed prior to discharge of patients with HIE. Even after
discharge, close monitoring and regular follow-ups are essential for better outcomes. Referring to early
intervention is a must at the time of discharge.
Continuation of seizure medications should depend on evolving central nervous system (CNS) symptoms and
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EEG findings. In most cases, antiseizure medications can be discontinued prior to NICU discharge. Follow-up
by a pediatric neurologist is recommended.
Initial Resuscitation and Stabilization

Delivery room management follows standard Neonatal Resuscitation Program (NRP) guidelines. Close
attention should be paid to appropriate oxygen delivery, perfusion status, avoidance of hypoglycemia and
hyperglycemia, as well as avoidance of hyperthermia.
A lot of attention has been focused on resuscitation with room air versus 100% oxygen in the delivery room.
Several clinical trials indicate that room air resuscitation for infants with perinatal asphyxia is as effective as
resuscitation with 100% oxygen. In addition, infants resuscitated with room air have a lower level of circulating
markers of oxidative stress. However, studies indicating that time to return to spontaneous circulation is
equivalent with room air resuscitation are lacking. Based on this evidence, International Liaison Committee on
Resuscitation (ILCOR) and NRP guidelines were updated and are now recommending the use of 21% oxygen
for the initial resuscitation of term infants. If despite effective ventilation, the infant does not improve, higher
concentrations of oxygen should be used and should be guided by the use of pulse oxymetry.[67, 68]
Supportive Care in Patients with Hypoxic-ischemic Encephalopathy

Most infants with severe hypoxic-ischemic encephalopathy (HIE) need ventilatory support during the first few
days after birth. Although animal data suggest that permissive hypercapnia may be neuroprotective, no such
evidence is available in newborn. Therefore, the role of mechanical ventilation is to maintain the blood gases
and acid-base status in the physiologic ranges and prevent hypoxia, hyperoxia, hypercapnia, and hypocapnia.
Hypocapnia in particular may lead to severe brain hypoperfusion and cellular alkalosis and has been
associated with worse neurodevelopmental outcomes. Of note, evidence indicates that increased FiO2 in the
first 6 hours of life is a significant risk factor for adverse outcomes in infants with hypoxic-ischemic
encephalopathy treated with hypothermia therapy. This association is independent of underlying respiratory
pathology and further emphasizes the benefit of resuscitation and stabilization with room air in this patient
population.[69]
Infants with HIE are also at risk for pulmonary hypertension and should be monitored. Inhaled nitric oxide (iNO)
may be used according to published guidelines if pulmonary hypertension is suspected.[70]
Perfusion and Blood Pressure Management

Studies indicate that a mean blood pressure (BP) above 35-40 mm Hg is necessary to avoid decreased
cerebral perfusion. Hypotension is common in infants with severe hypoxic-ischemic encephalopathy (HIE) and
is due to myocardial dysfunction, capillary leak syndrome, and hypovolemia; hypotension should be promptly
treated. Dopamine or dobutamine can be used to achieve adequate cardiac output in these patients. If a
cardiac injury is suspected, then administration of dobutamine or milrinone may be beneficial to support the
injured heart.
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Fluid and Electrolytes Management

Because of the concern for acute tubular necrosis (ATN) and syndrome of inappropriate antidiuretic hormone
(SIADH) secretion, fluid restriction is typically recommended for these infants until renal function and urine
output can be evaluated. However, this recommendation is not based on evidence from randomized controlled
trials.[71] Therefore, fluid and electrolyte management must be individualized on the basis of clinical course,
changes in weight, urine output, and the results of serum electrolyte and renal function studies.
The role of prophylactic theophylline, given early after birth, in reducing renal dysfunction after hypoxic-
ischemic encephalopathy (HIE) has been evaluated in 3 small randomized controlled trials.[72, 73, 74] In these
studies, a single dose of theophylline (5-8 mg/kg) given within 1 hour of birth resulted in (1) decreased severe
renal dysfunction (defined as creatinine level >1.5 mg/dL for 2 consecutive days); (2) increased creatine
clearance; (3) increased glomerular filtration rate (GFR); and (4) decreased b2 microglobulin excretion. The
clinical significance of these findings remains unclear. Larger studies are warranted to confirm the safety of
adenosine inhibitor use following HIE.
Fluid and glucose homeostasis should be achieved. Avoid hypoglycemia and hyperglycemia because both
may accentuate brain damage. Hypoglycemia in particular should be avoided. In a retrospective study, Salhab
et al showed that initial hypoglycemia (< 40 mg/dL) is significantly associated with adverse neurologic
outsomes.[75]
Hyperthermia Avoidance
Hyperthermia has been shown to be associated with increased risk of adverse outcomes in neonates with
moderate-to-severe hypoxic-ischemic encephalopathy (HIE).[6] In this observational secondary study, the risk
of death or moderate-to-severe disability was increased 3.6-fold to 4-fold for every 1°C increase in the mean of
the highest quartile of skin or esophageal temperature.
Treatment of Seizures
Hypoxic-ischemic encephalopathy (HIE) is the most common cause of seizures in the neonatal period.
Seizures are generally self-limited to the first days after birth but may significantly compromise other body
functions, such as maintenance of ventilation, oxygenation, and blood pressure. Additionally, studies suggest
that seizures, including asymptomatic electrographic seizures, may contribute to brain injury and increase the
risk of subsequent epilepsy.[76, 77, 78]
Current therapies available to treat neonates with seizures have limited efficacy, and safety concerns remain
specifically for infants undergoing therapeutic hypothermia. Antiseizure drugs used in this population include
phenobarbital, levetiracetam, phenytoin, lidocaine, and benzodiazepines. However, phenobarbital has been
shown to be effective in only 29-50% of cases,[79, 80, 81] and phenytoin only offers an additional 15%
efficacy. Benzodiazepines, particularly lorazepam, may offer some additional efficacy.[82, 83] Newer
antiseizure medications such as levetiracetam are increasingly used in infants with HIE and seizures despite
the lack of strong evidence regarding safety or efficacy in this population.
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Hypothermia Therapy
Extensive experimental data suggest that mild hypothermia (3-4°C below baseline temperature) applied within
a few hours (no later than 6 h) of injury is neuroprotective. The neuroprotective mechanisms are not
completely understood. Possible mechanisms include (1) reduced metabolic rate and energy depletion; (2)
decreased excitatory transmitter release; (3) reduced alterations in ion flux; (4) reduced apoptosis due to
hypoxic-ischemic encephalopathy; and (4) reduced vascular permeability, edema, and disruptions of blood-
brain barrier functions.[84, 85]
Randomized clinical trials
The clinical efficacy of therapeutic hypothermia in neonates with moderate-to-severe hypoxic-ischemic

encephalopathy (HIE) has been evaluated in multiple randomized controlled trials.[27, 28, 86, 87, 88, 89, 90,
91] for a total of greater than 1500 infants enrolled. Inclusion criteria varied slightly between studies and are
summarized as follows:
Near-term infants born at 36 weeks' gestation or more with birth weight of 1800-2000 g or more, younger
than 6 hours at admission. Some trials have enrolled infants as young as 35 weeks' gestation (Eicher
and ICE trial)
Evidence of acute event around the time of birth – Apgar score of 5 or less at 10 minutes after birth (In
the study by Shankaran et al, this needed to be in conjunction with either evidence of acute perinatal
event or need for assisted ventilation for at least 10 min.[28] ), severe acidosis, defined as pH level of
less than 7 or base deficit of 16 mmol/L or less (cord blood or any blood gas obtained within 1 h of birth),
continued need for resuscitation at 10 minutes after birth
Evidence of moderate to severe encephalopathy at birth – Clinically determined (at least 2 of the
following: lethargy, stupor, or coma; abnormal tone or posture; abnormal reflexes [suck, grasp, Moro,
gag, stretch reflexes]; decreased or absent spontaneous activity; autonomic dysfunction [including
bradycardia, abnormal pupils, apneas]; and clinical evidence of seizures), moderately or severely
abnormal amplitude-integrated electroencephalography (aEEG) background or seizures (CoolCap,
TOBY and Neo-Neuro, Neonatal Network trial)
All of these studies have shown benefits, and 9 independent meta-analyses have confirmed a consistent and
robust beneficial effect of therapeutic hypothermia for moderate-to-severe encephalopathy with a number
needed to treat between 5 and 9.
The 2013 cochrane review included 11 randomized controlled trials and 1505 infants and found that
therapeutic hypothermia resulted in the following:
A decrease in the combined outcomes of mortality/major neurodevelopmental disability at 18 months (8

studies, 1344 infants): relative risk [RR] 0.75 (0.68-0.83); number needed to benefit (NNTB) 7 (5-10)
A reduction in mortality (11 studies, 1468 infants): RR 0.75 (0.64-0.88); NNTB 11 (8-25)
A reduction in neurodevelopmental disability in survivors (8 studies, 917 infants): RR 0.77 (0.63-0.94);

NNTB 8 (5-14)
Adverse effects
Many theoretical concerns surround hypothermia and its side effects, which include coagulation defects,
leukocyte malfunctions, pulmonary hypertension, worsening of metabolic acidosis, and abnormalities of
cardiac rhythm, especially during rewarming.
Randomized trials have been reassuring thus far regarding the safety and applicability of therapeutic
hypothermia.[92] In a 2013 Cochrane review, significant adverse effects were limited to sinus bradycardia (RR
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11.59 [4.94-27.17]; number need to harm [NNTH] 11 [9-14]), and thrombocytopenia (RR 1.21 [1.05-1.40];
NNTH 17 [10-50]).
Long-term outcomes
School-age outcomes of infants in the NICHD trial were published in 2012.[93] At age of follow-up (6-7 years,
91% follow-up), the combined outcome of death or IQ score below 70 occurred in 62% of infants in the control
group versus 47% of infants in the hypothermia group (P = 0.06). More infants in the control group died (44%)
compared to 28% in the hypothermia group (P = 0.04). Reassuringly, this finding was not associated to
increased risk of neurodevelopmental disability in survivors with a risk of death or severe disability in 60% of
controls versus 41% in the hypothermia group (P = 0.03).[93]
In 2014, more follow-up results from the TOBY trial were published of children aged 6-7 years who had
asphyxia encephalopathy as infants and were treated with hypothermia.[94] There were 75 of 145 survivors
(52%) in the hypothermia group relative to 52 of 132 children (39%) in the control group. Children who
received hypothermia shortly after birth were significantly more likely to have an IQ of 85 or higher at age 6-7
years, and they were less likely to moderate-to-severe disability compared to the control group. The study was
insufficiently powered to determine whether hypothermia treatment led to positive neurocognitive effects at
older ages, although the investigators were able to establish that early assessment at ages 18-21 months
reliably predicted good functional outcomes at school age.[94]
Therapeutic hypothermia when applied within 6 hours of birth and maintained for 72 hours is the only therapy
currently available that improves the outcomes of infants with moderate-to-severe HIE.[95, 96]
Remaining questions
What is the optimal timing of initiation of hypothermia therapy?
Cooling must begin early, within 6 hours of injury. However, experimental evidence strongly suggest that the
earlier the better.
Reports on the feasibility and safety of cooling on transport indicate that initiation of hypothermia therapy at
referring centers is possible, provided that ongoing education is in place.[97] The ICE trial confirmed that a
simplified method using widely available icepacks is an effective way to provide hypothermia therapy in
referring centers while awaiting transfer to a tertiary neonatal intensive care unit (NICU).[88]
However, a favorable outcome may be possible if the cooling begins beyond 6 hours after injury. A current
National Institute of Child Health and Human Development (NICHD) study is evaluating the efficacy of delayed
hypothermia therapy for infants presenting at referral centers beyond 6 hours of life or with evolving
encephalopathy.
What is the optimal duration of hypothermia therapy?
The greater the severity of the initial injury, the longer the duration of hypothermia needed for optimal
neuroprotection. The optimal duration of brain cooling in the human newborn has not been established. A 2014
NICHD trial indicated that longer and deeper cooling does not provide additional benefits over current
protocols.[98]
What is the best method?
Two methods have been used in clinical trials: selective head cooling and whole body cooling.
In selective head cooling, a cap (CoolCap) with channels for circulating cold water is placed over the infant's
head, and a pumping device facilitates continuous circulation of cold water. Nasopharyngeal or rectal
temperature is then maintained at 34º-35°C for 72 hours.
In whole body hypothermia, the infant is placed on a commercially available cooling blanket, through which
29 of 45 6/22/2020, 1:15 PM
circulating cold water flows, so that the desired level of hypothermia is reached quickly and maintained for 72
hours.
The relative merits and limitations of these 2 methods have not been established; however, whole body
hypothermia is most widely used modality to provide therapeutic hypothermia.
What is the optimal rewarming method?
Rewarming is a critical period. In clinical trials, rewarming was carried out gradually, over 6-8 hours.
Can the use of aEEG improve candidates selection?
Predefined subgroup analysis in the CoolCap trial suggested that head cooling had no effect in infants with the
most severe aEEG changes.
The findings were beneficial only in infants with less severe aEEG changes.
Hypothermia therapy has been recommended as the standard of care since 2010 by the AHA and ILCOR:
"During the postresuscitation period in greater than or equal to 36-week gestation neonates with evolving
moderate or severe encephalopathy, hypothermia should be offered in the context of clearly defined protocols
similar to published trials.”
Hypothermia therapy should be conducted under strict protocols and reserved to regional referral centers
offering comprehensive multidisciplinary care and planning to conduct long-term neurodevelopmental follow-
up. Implementation requires thorough and ongoing education to avoid complications such as overcooling.[99]
Ideally, all infants should be registered in national registry whenever possible.
Future Neuroprotective Strategies

Several groups are investigating other neuroprotective strategies whether alone or in combination with
hypothermia therapy (summarized in the image below).[100]
Summary of potential neuroprotective strategies.
Promising avenues include the following:
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Prophylactic barbiturates: In a small randomized trial, high-dose phenobarbital (40 mg/kg) was given
over 1 hour to infants with severe hypoxic-ischemic encephalopathy. Treated infants had fewer seizures
(9 of 15) than untreated control infants (14 of 16). Treated infants also had fewer neurologic deficits at
age 3 years (4 of 15) than untreated infants (13 of 16).[101] In another small study, thiopental given
within 2 hours and over 24 hours, did not result in improved rate of seizures or neurodevelopmental
outcomes at 12 months.[102] Hypotension was more common in infants who received thiopental. Thus,
the role of prophylactic barbiturate remains unclear. Further studies are needed.[103]
Erythropoietin: In one study, low-dose erythropoietin (300-500 U/kg) administered for 2 weeks starting in
the first 48 hours of life decreased the incidence of death or moderate and severe disability at age 18
months (43.8% vs 24.6%; P < 0.05) in infants with moderate-to-severe hypoxic-ischemic
encephalopathy. Subgroup analysis indicated that only infants with moderate disability benefited from
this therapy.[104] Currently being evaluated in NCT 01913340.
Allopurinol: Slight improvements in survival and cerebral blood flow (CBF) were noted in a small group
of infants tested with this free-radical scavenger in one clinical trial.[105]
Excitatory amino acid (EAA) antagonists: MK-801, an EAA antagonist, has shown promising results in
experimental animals and in a limited number of adult trials. However, this drug has serious
cardiovascular adverse effects.
Stem cell therapy: The use of mesenchymal stem cells and autologous stem cells to treat infants with
hypoxic-ischemic encephalopathy (HIE) is under extensive study. Early evidence suggest this may be an
effective therapeutic avenue. More work is required to determine the type of cells, dose, timing, and
duration. In addition, more studies are also required to understand the underlying protective
mechanisms.[106, 107, 108]
Other adjuvant therapies under investigation include Xexon (NCT0271394 and NCT01545271),
topiramate (NCT01765218), and MgSO4 (NCT01646619).
Consultations
A pediatric neurologist should help assist in the management of seizures, interpretation of
electroencephalograms (EEGs), and overall care of the infant with hypoxic-ischemic encephalopathy (HIE).
The neurologist should also work with the primary care physician to address long-term disabilities.
Follow-up by a developmental pediatrician is also recommended to assist with planning for the infant's long-
term assessments of neurodevelopment and care.
Diet
In most cases (particularly in severe hypoxic-ischemic encephalopathy [HIE]), the infant is restricted to nothing
by mouth (NPO) until the general level of alertness and consciousness improves and the hemodynamic status
stabilizes. In addition, most infants undergoing therapeutic hypothermia should remain NPO until rewarmed. A
study of 51 neonates with HIE indicated that minimal enteral nutrition (1-2 mL/kg boluses every 3h) may be
safe in hemodynamically stable infants undergoing therapeutic hypothermia.[109]
Enteral feeds should be carefully initiated, and the use of trophic feeds is recommended for 24-48 hours (2
mL/kg every 3 h). Infants should be monitored carefully for signs and symptoms of necrotizing enterocolitis, for
31 of 45 6/22/2020, 1:15 PM
which infants with perinatal asphyxia are at high risk. Individualize increments in feeding volume and
composition.
Prevention
The use of intrapartum markers such as fetal heart rate monitoring are poor predictors of neonatal outcomes
and long-term risk of cerebral palsy.[110]
Most treatments under investigation have discussed earlier and remain experimental. With the exception of
therapeautic hypothermia, none has consistently shown efficacy in human infants.
Long-Term Monitoring
The goal of follow-up is to detect impairments and promote early intervention for those infants who require
it.[111]
Growth parameters including head circumference should be closely monitored in all infants with hypoxic-
ischemic encephalopathy (HIE).
Infants with moderate-to-severe HIE should be followed closely after neonatal intensive care unit (NICU)
discharge by a developmental pediatrician and, in some cases, a pediatric neurologist (if there is a history of
seizure and/or abnormal neurologic examination). Additionally, evaluation by a pediatric ophthalmologist
is recommended during the first year of life, because damage to the posterovisual cortex can occur. Standard
hearing test screening should occur prior to NICU discharge. A repeat hearing screen is also recommended in
the first 2 years of life.
If therapeutic hypothermia was used in the neonatal period, follow-up is recommended for the continued
evaluation of the long-term efficacy of this therapy. Data should be entered into the available registries, local
databases, or both, whenever possible.
Infants with mild HIE generally do well and do not require specialized follow-up.
Medication
Medication Summary
Providing standard intensive care support, correcting metabolic acidosis, close monitoring of the fluid status,
and seizure control are the main elements of treatment in patients with hypoxic-ischemic encephalopathy
(HIE). Anticonvulsants are the only specific drugs used often in this condition.
Treat seizures early and control them as fully as possible, including electrographic (EEG)-only seizures (ie,
seen only on EEG).
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Anticonvulsants
Class Summary
These agents are used to control seizures.
Phenobarbital (Luminal)
Often used as a first-line agent for clinical and electrographic-only neonatal seizures. The duration of therapy
will vary depending on both the EEG findings and clinical status. In most cases, can be weaned and stopped
prior to NICU discharge; however, treatment may need to be continued for several months in infants with
persistent neurologic abnormalities and clinical or EEG evidence of seizures.
Phenytoin (Dilantin)
Can be used in infants with refractory seizures that do not respond to phenobarbital, levetiracetam, or
lorazepam. Oral absorption is negligible for the first several months of life.
Lorazepam (Ativan)
Indicated for acute control of seizures refractory to phenobarbital.
By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, may depress all
levels of CNS, including limbic and reticular formation.
Anticonvulsants, Other
Levetiracetam (Keppra, Keppra XR, Spritam)

May be used as a first- or second-line agent in infants with seizures.
Anxiolytics, Benzodiazepines
Midazolam (Versed)
Can be used as a drip for infants with status epilepticus.
Cardiovascular (Inotropic) Agents
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Class Summary
These agents increase blood pressure (BP) and combat shock. Drugs in this category act primarily by
increasing systemic vascular resistance, cardiac contractility, and stroke volume, thus increasing cardiac
output.
Most inotropic agents also have dose and gestational age-dependent effects on vessels, particularly those of
the renal and GI systems. For the most part, these effects are beneficial but, at higher doses, the systemic side
effects may be unpredictable.
In experimental animals, cerebral blood flow (CBF) is unaffected by these drugs when used in recommended
therapeutic doses. However, no clear information is available on the effects of these drugs on CBF in
neonates.
Dopamine (Intropin)
Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect is dependent on the dose. Lower
doses predominantly stimulate dopaminergic receptors that in turn produce renal and mesenteric vasodilation.
Cardiac stimulation and renal vasodilation produced by higher doses.
Dobutamine (Dobutrex)
Second inotropic DOC, preferred by some as first choice in severe cardiogenic shock.
Produces vasodilation and increases inotropic state. At higher dosages may cause increased heart rate,
exacerbating myocardial ischemia.
Questions & Answers

Overview
What causes hypoxic-ischemic encephalopathy (HIE) and how is it characterized?
What are the signs and symptoms of mild hypoxic-ischemic encephalopathy (HIE)?
What are the signs and symptoms of moderately severe hypoxic-ischemic encephalopathy (HIE)?
What are the signs and symptoms of severe hypoxic-ischemic encephalopathy (HIE)?
How is acute neurologic injury recognized in hypoxic-ischemic encephalopathy (HIE)?
Which lab studies are performed in the evaluation for hypoxic-ischemic encephalopathy (HIE)?
Which imaging studies are performed in the evaluation for hypoxic-ischemic encephalopathy (HIE)?
Which exams should be included in the workup of hypoxic-ischemic encephalopathy (HIE)?
What is included in the management of hypoxic-ischemic encephalopathy (HIE)?
What is hypoxic-ischemic encephalopathy (HIE)?
What physiology processes lead to hypoxic-ischemic encephalopathy (HIE)?
34 of 45 6/22/2020, 1:15 PM
What is the pathophysiology of hypoxic-ischemic encephalopathy (HIE)?
What is the pathophysiology of reduced cerebral blood flow (CBF) in hypoxic-ischemic encephalopathy (HIE)?
What determines the magnitude of neuronal injury in hypoxic-ischemic encephalopathy (HIE)?
What is the role of excitatory amino acid (EAA) receptor overactivation in the pathogenesis of hypoxic-ischemic
encephalopathy (HIE)?
What is the role of intracellular Ca++ in the pathophysiology of hypoxic-ischemic encephalopathy (HIE)?
What is the role of NMDA receptor activation in the pathophysiology of hypoxic-ischemic encephalopathy
(HIE)?
What is the role of cytokines and chemokines in the pathophysiology of hypoxic-ischemic encephalopathy
(HIE)?
What is the energy failure phase in the pathophysiology of hypoxic-ischemic encephalopathy (HIE)?
Which factors influence the outcome in hypoxic-ischemic encephalopathy (HIE)?
How frequently does hypoxic-ischemic encephalopathy (HIE) occur in the absence of risk factors?
What is the prevalence of hypoxic-ischemic encephalopathy (HIE) in the US?
What is the global prevalence of hypoxic-ischemic encephalopathy (HIE)?
What is the prognosis of hypoxic-ischemic encephalopathy (HIE)?
What are the long-term sequelae and mortality rate for hypoxic-ischemic encephalopathy (HIE)?
When do the symptoms of hypoxic-ischemic encephalopathy (HIE) first appear?
What are the keys to reassuring parents of infants with hypoxic-ischemic encephalopathy (HIE) who are
undergoing hypothermia treatment?
Presentation
Which clinical history findings indicate hypoxic-ischemic encephalopathy (HIE)?
What determines the CNS manifestation of hypoxic-ischemic encephalopathy (HIE)?
What are the physical findings characteristic of mild hypoxic-ischemic encephalopathy (HIE)?
What are the physical findings characteristic of moderately severe hypoxic-ischemic encephalopathy (HIE)?
What are the physical findings characteristic of severe hypoxic-ischemic encephalopathy (HIE)?
What are physical findings in infants who survive severe hypoxic-ischemic encephalopathy (HIE)?
What are physical findings characteristic of multiorgan dysfunction in hypoxic-ischemic encephalopathy (HIE)?
Which cranial nerve findings are characteristic of hypoxic-ischemic encephalopathy (HIE)?
What is included in a motor function exam for hypoxic-ischemic encephalopathy (HIE), and what are the typical
findings?
How do motor function findings vary in hypoxic-ischemic encephalopathy (HIE) based on location of lesions?
What are motor function findings in the extremities characteristic of hypoxic-ischemic encephalopathy (HIE)?
35 of 45 6/22/2020, 1:15 PM
How is a tonic neck reflex performed in the evaluation of hypoxic-ischemic encephalopathy (HIE)?
What does a finding of spasticity indicate in the evaluation of hypoxic-ischemic encephalopathy (HIE)?
How is muscle tone assessed in the evaluation of hypoxic-ischemic encephalopathy (HIE)?
Which physical findings indicate CNS dysfunction in hypoxic-ischemic encephalopathy (HIE)?
How are seizures diagnosed in hypoxic-ischemic encephalopathy (HIE)?
What are the Sarnat clinical stages of hypoxic-ischemic encephalopathy (HIE)?
DDX
Why do the American Academy of Pediatrics (AAP) and American College of Obstetrics and Gynecology
(ACOG) advise against use of the terms perinatal asphyxia or birth asphyxia?
Which inborn errors of metabolism should be included in the differential diagnoses for hypoxic-ischemic
Which conditions should be included in the differential diagnoses of hypoxic-ischemic encephalopathy (HIE)?
What are the differential diagnoses for Hypoxic-Ischemic Encephalopathy?
Workup
What is the focus of the diagnostic workup for hypoxic-ischemic encephalopathy (HIE)?
What is the role of lab studies in the workup of hypoxic-ischemic encephalopathy (HIE)?
What is the role of serum electrolyte measurement in the workup of hypoxic-ischemic encephalopathy (HIE)?
What is the role of a cardiac enzymatic study in the workup of hypoxic-ischemic encephalopathy (HIE)?
Which renal function studies are performed in the workup of hypoxic-ischemic encephalopathy (HIE)?
What is the role of liver enzymes in the workup of hypoxic-ischemic encephalopathy (HIE)?
Which coagulation studies are performed in the workup of hypoxic-ischemic encephalopathy (HIE)?
What is the role of arterial blood gas (ABG) monitoring in the workup of hypoxic-ischemic encephalopathy
(HIE)?
What is the role of MRI in the workup of hypoxic-ischemic encephalopathy (HIE)?
What findings on MRI are characteristic of hypoxic-ischemic encephalopathy (HIE)?
What is the role of diffusion-weighted imaging (DWI) in the workup of hypoxic-ischemic encephalopathy (HIE)?
What is the role of MRI in determining the prognosis of hypoxic-ischemic encephalopathy (HIE)?
What is the role of magnetic resonance spectroscopy (MRS) in the workup of hypoxic-ischemic
What is the role of cranial ultrasonography in the workup of hypoxic-ischemic encephalopathy (HIE)?
What is the role of CT scanning in the workup of hypoxic-ischemic encephalopathy (HIE)?
What is the role of echocardiography in the workup of hypoxic-ischemic encephalopathy (HIE)?
36 of 45 6/22/2020, 1:15 PM
What is the role of amplitude-integrated electroencephalography (aEEG) in the workup of hypoxic-ischemic

What is the role of EEG in the workup of hypoxic-ischemic encephalopathy (HIE)?
When is a hearing screening indicated in the evaluation of hypoxic-ischemic encephalopathy (HIE)?
What is the role of ophthalmic exam in the workup of hypoxic-ischemic encephalopathy (HIE)?
How does the gestational time frame affect histologic findings in hypoxic-ischemic encephalopathy (HIE)?
What is the common histologic patterns of injury observed in hypoxic-ischemic encephalopathy (HIE)?
What is the histologic appearance of acute hypoxic-ischemic neuronal change in the basal ganglia?
What is the histologic appearance of parasagittal cerebral injury in hypoxic-ischemic encephalopathy (HIE)?
What is the histologic appearance of focal and multifocal ischemic brain necrosis lesions in hypoxic-ischemic
What is the histologic appearance of periventricular leukomalacia (PVL) in hypoxic-ischemic encephalopathy

(HIE)?
Treatment
What is included in medical care for hypoxic-ischemic encephalopathy (HIE)?
When is transfer to a tertiary NICU indicated in the treatment of hypoxic-ischemic encephalopathy (HIE)?
What are discharge considerations in neonates with hypoxic-ischemic encephalopathy (HIE)?
What is included in initial resuscitation and stabilization of infants with hypoxic-ischemic encephalopathy
(HIE)?
What is included in supportive care of infants with hypoxic-ischemic encephalopathy (HIE)?
How is hypotension managed in infants with hypoxic-ischemic encephalopathy (HIE)?
How are fluids and electrolytes managed in hypoxic-ischemic encephalopathy (HIE)?
What are the adverse effects of hyperthermia in infants with hypoxic-ischemic encephalopathy (HIE)?
How are seizures treated in infants with hypoxic-ischemic encephalopathy (HIE)?
What are the neuroprotective mechanisms of hypothermia in hypoxic-ischemic encephalopathy (HIE)?
What is the role of hypothermia therapy in the treatment of hypoxic-ischemic encephalopathy (HIE)?
What are the adverse effects of hypothermia therapy for hypoxic-ischemic encephalopathy (HIE)?
What are the long-term outcomes of hypothermia therapy for hypoxic-ischemic encephalopathy (HIE)?
When should hypothermia therapy be initiated for hypoxic-ischemic encephalopathy (HIE)?
What is the duration of hypothermia therapy for hypoxic-ischemic encephalopathy (HIE)?
What is the best method of hypothermia therapy for hypoxic-ischemic encephalopathy (HIE)?
How is rewarming accomplished following hypothermia therapy for hypoxic-ischemic encephalopathy (HIE)?
37 of 45 6/22/2020, 1:15 PM
What are the AHA and ILCOR guidelines for hypothermia therapy in hypoxic-ischemic encephalopathy (HIE)?
Which neuroprotective strategies for hypoxic-ischemic encephalopathy (HIE) are being investigated?
Which specialist consultations are helpful for the treatment of hypoxic-ischemic encephalopathy (HIE)?
Which dietary modifications are included in the treatment of hypoxic-ischemic encephalopathy (HIE)?
How is hypoxic-ischemic encephalopathy (HIE) prevented?
What is the goal of follow-up monitoring of hypoxic-ischemic encephalopathy (HIE)?
What is included in long-term monitoring of hypoxic-ischemic encephalopathy (HIE)?
Medications
Which medications are used in the treatment of hypoxic-ischemic encephalopathy (HIE)?
Which medications in the drug class Cardiovascular (Inotropic) Agents are used in the treatment of Hypoxic-
Ischemic Encephalopathy?
Which medications in the drug class Anxiolytics, Benzodiazepines are used in the treatment of Hypoxic-
Ischemic Encephalopathy?
Which medications in the drug class Anticonvulsants, Other are used in the treatment of Hypoxic-Ischemic
Encephalopathy?
Which medications in the drug class Anticonvulsants are used in the treatment of Hypoxic-Ischemic
Encephalopathy?
Contributor Information and Disclosures
Author
Santina A Zanelli, MD Associate Professor, Department of Pediatrics, Division of Neonatology, University of

Virginia Health System
Santina A Zanelli, MD is a member of the following medical societies: American Academy of Pediatrics,
American Epilepsy Society, Society for Neuroscience, Society for Pediatric Research
Disclosure: Nothing to disclose.
Coauthor(s)
Dirk P Stanley, MD Resident Physician, Department of Pathology, University of Virginia Health System
David A Kaufman, MD Professor of Pediatrics, Division of Neonatology, University of Virginia School of

Medicine
David A Kaufman, MD is a member of the following medical societies: American Academy of Pediatrics,
Medical Society of Virginia, Pediatric Infectious Diseases Society, Society for Pediatric Research, European
Society for Paediatric Infectious Diseases
38 of 45 6/22/2020, 1:15 PM
Specialty Editor Board
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of
Pharmacy; Editor-in-Chief, Medscape Drug Reference
Brian S Carter, MD, FAAP Professor of Pediatrics, University of Missouri-Kansas City School of Medicine;
Attending Physician, Division of Neonatology, Children's Mercy Hospital and Clinics; Faculty, Children's Mercy
Bioethics Center
Brian S Carter, MD, FAAP is a member of the following medical societies: Alpha Omega Alpha, American
Academy of Hospice and Palliative Medicine, American Academy of Pediatrics, American Pediatric Society,
American Society for Bioethics and Humanities, American Society of Law, Medicine & Ethics, Society for
Pediatric Research, National Hospice and Palliative Care Organization
Chief Editor
Dharmendra J Nimavat, MD, FAAP Associate Professor of Clinical Pediatrics, Department of Pediatrics,
Division of Neonatology, Southern Illinois University School of Medicine; Staff Neonatologist, Clinical Director,
NICU Regional Perinatal Center, HSHS St John's Children's Hospital
Dharmendra J Nimavat, MD, FAAP is a member of the following medical societies: American Academy of
Pediatrics, American Association of Physicians of Indian Origin
Additional Contributors
Ted Rosenkrantz, MD Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-

Perinatal Medicine, University of Connecticut School of Medicine
Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics,
American Pediatric Society, Eastern Society for Pediatric Research, American Medical Association,
Connecticut State Medical Society, Society for Pediatric Research
Acknowledgements
The authors and editors of Medscape Drugs & Diseases gratefully acknowledge the contributions of previous
author Tonse NK Raju, MD, to the development and writing of this article.
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Signs and symptoms

Mild hypoxic-ischemic encephalopathy

Typically resolves in 24h

Moderately severe hypoxic-ischemic encephalopathy

The grasping, Moro, and sucking reflexes may be sluggish or absent

The infant may experience occasional periods of apnea

Severe hypoxic-ischemic encephalopathy

Generalized hypotonia and depressed deep tendon reflexes are common

Neonatal reflexes (eg, sucking, swallowing, grasping, Moro) are absent

Pupils may be dilated, fixed, or poorly reactive to light

An initial period of well-being or mild hypoxic-ischemic encephalopathy may be followed by sudden

See Clinical Presentation for more detail.

Persistence of an Apgar score of 0-3 for longer than 5 minutes

Neonatal neurologic sequelae (eg, seizures, coma, hypotonia)

Multiple organ involvements (eg, kidney, lungs, liver, heart, intestines)

Serum electrolyte levels

Renal function studies

Magnetic resonance imaging (MRI) of the brain

Electroencephalography (EEG) - Standard and amplitude-integrated EEG

Retinal and ophthalmic examination

See Workup for more detail.

Careful fluid management

Avoidance of hypoglycemia and hyperglycemia

See Treatment and Medication for more detail.

Disabling cerebral palsy - 30%

Severe hearing impairment - 6%

Race-, sex-, and age-related demographics

No race or sex predilection has been noted.

Persistence of an Apgar score of 0-3 for longer than 5 minutes

Neonatal neurologic sequelae (eg, seizures, coma, hypotonia)

Multiple organ involvements (eg, kidney, lungs, liver, heart, intestines)

Mild hypoxic-ischemic encephalopathy

Typically resolves in less than 24 hours without any consequences.

Moderately severe hypoxic-ischemic encephalopathy

The grasping, Moro, and sucking reflexes may be sluggish or absent.

The infant may experience occasional periods of apnea.

An initial period of well-being or mild hypoxic-ischemic encephalopathy may be followed by sudden

Severe hypoxic-ischemic encephalopathy

Generalized hypotonia and depressed deep tendon reflexes are common.

Neonatal reflexes (eg, sucking, swallowing, grasping, Moro) are absent.

Pupils may be dilated, fixed, or poorly reactive to light.

Infants who survive severe hypoxic-ischemic encephalopathy

The level of alertness improves by days 4-5 of life.

Disturbances include increased nucleated RBCs, neutropenia or neutrophilia, thrombocytopenia, and

Sarnat Staging System

MILD MODERATE SEVERE

Level of Alternating (hyperalert,

Muscle tone Normal Hypotonia Flaccid

Suck Weak Weak or absent Absent

Weak; incomplete; high

Oculovestibular Normal Overactive Weak or absent

Tonic neck Slight Strong Absent

Variable; often unequal;

Heart Rate Tachycardia Bradycardia Variable

GI Motility Normal or decreased Increased; diarrhea Variable

Other problems to be considered

Disorders of pyruvate metabolism

Urea cycle defects

Neuromuscular disorders including neonatal myopathies

Sulphite oxidase deficiency[39]

Genetics of Propionic Acidemia (Propionyl CoA Carboxylase Deficiency)

In the era of therapeutic hypothermia, continuous video-electroencephalographic (EEG) monitoring is essential

Laboratory studies should include the tests below.