Hypoxic-Ischemic Encephalopathy

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]

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.

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.

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]

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]

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]

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.

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]

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.

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)

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.

 

 

 

 

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.

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]

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]

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.

Parasagittal cerebral injury is typically bilateral and involves the parasagittal areas of the cerebral cortex (see the image below).

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).

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).

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.

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]

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]

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.

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 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.

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.

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.

Several groups are investigating other neuroprotective strategies whether alone or in combination with hypothermia therapy (summarized in the image below).[100]

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).

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.

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.

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.

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.

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). 

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.

Levetiracetam (Keppra, Keppra XR, Spritam)

May be used as a first- or second-line agent in infants with seizures.

Midazolam (Versed)

Can be used as a drip for infants with status epilepticus.

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.