Hypoxic-Ischemic Encephalopathy: Practice Essentials

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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 hypoxic-ischemic
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
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

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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)
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.
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 hypoxic-ischemic
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 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-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]
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 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 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.
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.
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
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 (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)
MILD MODERATE SEVERE
Level of Alternating (hyperalert,

Lethargic or obtunded Stuporous
Consciousness lethargic,irritable)
Neuromuscular Control
Muscle tone Normal Hypotonia Flaccid
Decorticate (arms Intermittent decerebration (arms

Posture Normal
flexed/legs extended) and legs extended)
Stretch reflexes Normal or hyperactive Hyperactive or decreased Absent
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
Generalized
Autonomic Function Generalized sympathetic Both systems depressed
parasympathetic
Variable; often unequal; poor light

Pupils Mydriasis Miosis
reflex
Heart Rate Tachycardia Bradycardia Variable
Bronchial and
Sparse Profuse Variable
Salivary Secretions
GI Motility Normal or decreased Increased; diarrhea Variable
Seizures None Common; focal or multifocal Delayed
EEG Findings Normal (awake) Early: low-voltage Early: periodic pattern with
continuous delta and theta Isopotential phases
Later: periodic pattern Later: totally isopotential

(awake)
Seizures: focal 1-to 1-Hz

spike-and-wave
1-3 days
Duration 2-14 days Hours to weeks
Typically < 24h
DDx
Diagnostic Considerations
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
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.
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 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.
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.
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 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 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).
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.
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 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.
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.
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 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 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:
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 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).
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

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)?
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)?
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 encephalopathy (HIE)?
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 encephalopathy (HIE)?
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)?
What is the role of amplitude-integrated electroencephalography (aEEG) in the workup of hypoxic-ischemic encephalopathy
(HIE)?
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 encephalopathy
(HIE)?
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)?
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
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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Hypoxic-Ischemic Encephalopathy: Practice Essentials

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Signs and symptoms

Typically resolves in 24h

Moderately severe hypoxic-ischemic encephalopathy

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

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

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.

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.

Patients may have severe pulmonary hypertension requiring assisted ventilation.

Sarnat Staging System

MILD MODERATE SEVERE

Level of Alternating (hyperalert,

Muscle tone Normal Hypotonia Flaccid

Decorticate (arms Intermittent decerebration (arms

Stretch reflexes Normal or hyperactive Hyperactive or decreased Absent

Suck Weak Weak or absent Absent

Weak; incomplete; high

Oculovestibular Normal Overactive Weak or absent

Tonic neck Slight Strong Absent

Variable; often unequal; poor light

Heart Rate Tachycardia Bradycardia Variable

GI Motility Normal or decreased Increased; diarrhea Variable

Seizures None Common; focal or multifocal Delayed

Later: periodic pattern Later: totally isopotential

Seizures: focal 1-to 1-Hz

Other problems to be considered

Disorders of pyruvate metabolism

Urea cycle defects

Neuromuscular disorders including neonatal myopathies

Sulphite oxidase deficiency[39]