eMedicine - Hypoxic-Ischemic Encephalopathy : Article by Tonse NK Raju, MD, DCH

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Hypoxic-Ischemic Encephalopathy

Last Updated: June 30, 2006

Synonyms and related keywords: hypoxic-ischemic encephalopathy, HIE, perinatal asphyxia, birth asphyxia, neonatal asphyxia, hypoxia, acidosis, ischemia

AUTHOR INFORMATION Section 1 of 10

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Author: Tonse NK Raju, MD, DCH, Medical Officer, Pregnancy and Perinatology Branch, Center for Developmental Biology and Perinatal Medicine, National Institutes of Child Health and Human Development, National Institutes of Health

Tonse NK Raju, MD, DCH, is a member of the following medical societies: American Academy of Pediatrics, American Association for the History of Medicine, American Osler Society, American Pediatric Society, College of Physicians of Philadelphia, and Society for Pediatric Research

Editor(s): Ted Rosenkrantz, MD, Head, Division of Neonatal-Perinatal Medicine, Professor, Departments of Pediatrics and Ob/Gyn, University of Connecticut School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Brian S Carter, MD, FAAP, Associate Professor, Associate Director, Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center; Consulting Staff, New Beginnings Family Birth Center, Gateway Medical Center; Carol L Wagner, MD, Professor of Pediatrics, Medical University of South Carolina; and Neil N Finer, MD, Professor, Department of Pediatrics, University of California at San Diego School of Medicine, Program Director, Division of Neonatology, University of California San Diego Medical Center

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INTRODUCTION

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Background: In spite of major advances in monitoring technology and knowledge of fetal and neonatal pathologies, perinatal asphyxia or, more appropriately, hypoxic-ischemic encephalopathy (HIE), remains a serious condition, causing 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 underlying cause remains unknown. The exact time of brain injury often remains uncertain, and an abnormal brain (eg, growth failure, impaired development) might be an underlying risk factor.

The American Academy of Pediatrics (AAP) and American College of Obstetrics and Gynecology (ACOG) published guidelines to assist in the diagnosis of severe HIE (see History).

Pathophysiology: Brain hypoxia and ischemia due to systemic hypoxemia, reduced cerebral blood flow (CBF), or both are the primary physiological processes that trigger HIE. The initial compensatory adjustment to an asphyxial event is an increase in the CBF due to hypoxia and hypercapnia. This is accompanied by a redistribution of cardiac output such that the brain receives an increased proportion of the cardiac output. A borderline increase in the systemic blood pressure (BP) further enhances the compensatory response. The BP increase is due to increased release of epinephrine; these are classic early cardiovascular compensatory responses to asphyxia.

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 to maintain the cerebral perfusion. The physiological 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 has been shown to be 60-100 mm Hg. However, such a range of BP in the human fetus and the newborn infant has not been studied with much rigor due to limitations of human experimentation in the fetus and newborn.

Limited data on the preterm infant suggests that a range of blood pressures exist over which cerebral blood flow is stable. Based on this human data, along with other animal data, some experts have postulated that in the healthy term newborn the BP range at which the CBF autoregulation is maintained is quite narrow (perhaps between 10-20 mm Hg, compared to the 40 mm Hg range in adults noted above). The autoregulatory zone may also be set at a lower level, about the mid point 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 (respectively) the CBF autoregulation is lost remains 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 is dependent on systemic BP. As BP falls, CBF falls below critical levels, and the brain continues to suffer from diminished blood supply and a lack of sufficient oxygen to meet its needs. This leads to intracellular energy failure. During the early phases of brain injury, brain temperature drops, and local release of the neurotransmitter, such as g-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 both the severity of the initial insult and the damage due to reperfusion injury and apoptosis (see Table 1). The extent, nature, severity, and the duration of the primary injury are all important in affecting the magnitude of the residual neurological damage.

Following the initial phase of energy failure from the asphyxial injury, cerebral metabolism may recover, only to deteriorate in the secondary phase, or reperfusion. This new phase of neuronal damage, starting at about 6-24 hours after the initial injury, is characterized by cerebral edema and apoptosis. This phase has been called the "delayed phase of neuronal injury." The duration of the delayed phase is not known precisely in the human fetus and newborn but appears to increase over the first 24-48 hours and then start to resolve thereafter.

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).

At the biochemical level, a large cascade of events follow HIE injury. Both hypoxia and ischemia increase the release of excitatory amino acids (EAAs), such as glutamate and aspartate, in the cerebral cortex and basal ganglia. EAAs cause neuronal death through the activation of receptor subtypes such as kainate, N-methyl-D-aspartate (NMDA), and amino-3-hydroxy-5-methyl-4 isoxazole propionate (AMPA). Activation of receptors with associated opening of ion channels (eg, NMDA) lead to increased intracellular and subcellular calcium concentration and cell death. A second important mechanism for the destruction of ion pumps is the lipid peroxidation of cell membranes, in which enzyme systems, such as the Na+/K+-ATPase, reside; this can cause cerebral edema and neuronal death. EAAs also increase the local release of nitric oxide (NO), which may exacerbate neuronal damage, although its mechanisms are unclear.

The EAAs may also disrupt the factors that control apoptosis, increasing the pace and extent of programmed cell death. One mechanism for apoptosis or programmed cell death is thought to be related to calcium influx into the cell and nucleus of the cell after activation of the EAAs. The regional differences in severity of injury may be explained by the fact that EAAs particularly affect the CA1 regions of the hippocampus, the developing oligodendroglia, and the subplate neurons along the borders of the periventricular region in the developing brain. This may be the basis for the disruption of long-term learning and memory faculties in infants with HIE.

Frequency:

In the US: In the United States and in most technologically advanced countries, the incidence of severe (stage 3) HIE is between 2-4 cases per 1000 births.

Internationally: HIE is reported to be high in countries with limited resources; however, precise figures are not available. The World Health Organization reports that approximately 1 million children worldwide die from a diagnosis of birth asphyxia, and about the same number may survive with significant long-term neurological disability.

Mortality/Morbidity: In severe HIE, the mortality rate has been reported to be 50-75% Most deaths (55%) occur in the first month, due to multiple organ failure or termination of care. Some infants with severe neurologic disabilities die in their infancy from aspiration pneumonia or systemic infections.

Among the infants who survive severe HIE, the sequelae include mental retardation, epilepsy, and cerebral palsy of varying degrees. The latter can be in the form of hemiplegia, paraplegia, or quadriplegia. Such infants need careful evaluation and support. They may need to be referred to specialized clinics capable of providing coordinated comprehensive follow-up care.

The incidence of long-term complications depends on the severity of HIE. Up to 80% of infants who survive severe HIE develop serious complications, 10-20% develop moderately serious disabilities, and up to 10% are normal. Among the infants who survive moderately severe HIE, 30-50% may suffer from serious long-term complications, and 10-20% with minor neurological morbidities. Infants with mild HIE tend to be free from serious CNS complications.

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 their school ages.

Race: No predilection exists.

Sex: No predilection exists.

Age: By definition, this disease is seen in the newborn period. Preterm infants can also suffer from HIE, but the pathology and manifestations are slightly 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.

CLINICAL

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History: Per the guidelines of the American Academy of Pediatrics (AAP) and the American College of Obstetrics and Gynecology (ACOG), all of the following must be present for the designation of asphyxia:

Profound metabolic or mixed acidemia (pH <7.00) 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 involvement (eg, of the kidney, lungs, liver, heart, intestines)

On rare occasions, difficulties with delivery, particularly problems with delivering the "after-coming" head in breech presentation, suggest an alternate diagnosis of hemorrhage in the posterior cerebral fossa, which is a rare condition.

However, infants may have experienced asphyxia or brain hypoxia remote from the time of delivery and may have exhibited the signs and symptoms of hypoxic encephalopathy at the time of birth and, therefore, may not meet all of the criteria set forth by the AAP and ACOG.

Physical: Clinical manifestations and course vary depending on HIE severity.

Mild HIE

Muscle tone may be increased slightly 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, may be observed.

By 3-4 days of life, the CNS examination findings become normal.

Moderately severe HIE

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 may occur within the first 24 hours of life.

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 HIE may be followed by sudden deterioration, suggesting ongoing brain cell dysfunction, injury, and death; during this period, seizure intensity might increase.

Severe HIE

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 occur early and often 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 BP are common during the period of reperfusion injury, as is death from cardiorespiratory failure.

Infants who survive severe HIE

The level of alertness improves by days 4-5 of life.
Hypotonia and feeding difficulties persist, requiring tube feeding for weeks to months.

Involvement of multiple organs besides the brain is a hallmark of HIE.

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.
Reduced myocardial contractility, severe hypotension, passive cardiac dilatation, and tricuspid regurgitation are noted frequently in severe HIE.
Patients may have severe pulmonary hypertension requiring assisted ventilation.
Renal failure presents as oliguria and, during recovery, as high-output tubular failure, leading to significant water and electrolyte imbalances.

Intestinal injuries may not be apparent in the first few days of life. Poor peristalsis and delayed gastric emptying are common; necrotizing enterocolitis occurs rarely.

The staging system proposed by Sarnat and Sarnat in 1976 is often useful in classifying the degree of encephalopathy. Stages I, II, and III correlate with the descriptions of mild, moderate, and severe encephalopathy described above.

Table 1. Sarnat and Sarnat's 3 Clinical Stages of Perinatal Hypoxic Ischemic Brain Injury

State 1 Stage 2 Stage 3

Level of Consciousness Hyperalert Lethargic or obtunded Stuporous

Neuromuscular Control

Muscle tone Normal Mild hypotonia Flaccid

Posture Mild distal flexion Strong distal flexion Intermittent decerebration

Stretch reflexes Overactive Overactive Decreased or absent

Segmental myoclonus Present Present Absent

Complex Reflexes

Suck Weak Weak or absent Absent

Moro Strong; low threshold Weak; incomplete; high threshold Absent

Oculovestibular Normal Overactive Weak or absent

Tonic neck Slight Strong Absent

Autonomic Function Generalized sympathetic Generalized parasympathetic Both systems depressed

Pupils Mydriasis Miosis Variable; often unequal; poor light reflex

Heart Rate Tachycardia Bradycardia Variable

Bronchial and Salivary Secretions Sparse Profuse Variable

Gastrointestinal Motility Normal or decreased Increased; diarrhea Variable

Seizures None Common; focal or multifocal Uncommon (excluding decerebration)

Electroencephalogram Findings Normal (awake) Early: low-voltage continuous delta and theta
Later: periodic pattern (awake)
Seizures: focal 1-to 1-Hz spike-and-wave Early: periodic pattern with Isopotential phases
Later: totally isopotential

Duration <24 h 2-14 Hours to weeks

DIFFERENTIALS

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Brain tumors
Developmental defects
Infections
Inherited metabolic disorders such as disorders of urea cyclase deficiency

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WORKUP

Section 5 of 10

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Lab Studies:

No specific test can always confirm or exclude a diagnosis of HIE, since a diagnosis of HIE is made based on the history and physical and neurological examinations. Many of the tests are performed to assess the severity of brain injury and to monitor the functional status of systemic organs. As always, the results of the tests should be interpreted in conjunction with the clinical history and the findings from physical examination.

Serum electrolytes: In severe HIE cases, daily assessment of serum electrolytes are of value until the infant's status improves. Markedly low serum sodium, potassium, and chloride in the presence of reduced urine flow and excessive weight gain may indicate acute tubular damage or inappropriate antidiuretic hormone (IADH), particularly during the initial 2-3 days of life.

Similar changes may be seen during recovery, with increased urine flow, might indicate ongoing tubular damage and excessive sodium loss relative to water loss.

Renal function studies: Serum creatinine, creatinine clearance, and BUN suffice in most cases.

Cardiac and liver enzymes values are an adjunct to assess the degree of hypoxic-ischemic injury to these other organs. These studies also provide some insight into injuries to other organs, such as the bowel.

Imaging Studies:

Routine imaging studies may or may not consistently reveal abnormal findings. Therefore, a normal cranial imaging study does not rule out HIE.

Cranial ultrasound: Although ultrasound is portable and convenient, the findings in many HIE may be imprecise. It can reveal intracerebral or intraventricular hemorrhage. However, visualization of posterior fossa may be difficult in routine ultrasound examination. Cerebral edema may be evident in the form of decreased ventricular size or indistinct sulci and gyral patterns.

o A CT scan of the head can be especially useful to confirm cerebral edema (obliteration of cerebral ventricles, blurring of sulci) manifested as narrowness of the lateral ventricles and flattening of gyri. Areas of reduced density that indicate evolving zones of infarction may be present. Evidence of hemorrhage in the ventricles or in the cerebral parenchyma may also be seen. Although intraventricular hemorrhages are rare in term infants, cerebral artery occlusions and infarctions can be detected with Doppler flow studies and confirmed with radiographic imaging using radio-opaque contrast materials.
In cases of suspected posterior cranial fossa hemorrhage, a CT scan may be diagnostic. An early diagnosis may help in obtaining early neurosurgical consultation and, possibly, surgical therapy.

� MRI is valuable in moderately severe and severe HIE, particularly to note the status of myelination, to note white-gray tissue injury, and to identify preexisting developmental defects of the brain. Diffusion-weighted MRI scans are also useful early in the course of treatment to identify those areas of the brain with edema. MRI is also useful during follow-up. In any newly diagnosed case of cerebral palsy, MRI should be considered, since it may help in establishing the cause. However, the interpretation of MRI in infants requires considerable expertise.

Echocardiography: In infants requiring inotropic support, echocardiography (ECHO) helps to define myocardial contractility and the existence of structural heart defects, if any.

Other Tests:

Choice of tests depends on the evolution of symptoms.
- 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 HIE. While a normal aEEG may not necessarily mean that the brain is normal, a severe or moderately severe aEEG abnormality may indicate brain injury and poor outcome. The abnormalities include wide fluctuations in the amplitude with the baseline voltages dropping to near zero and the peak amplitudes under 5 mV. Seizure spikes may be seen.
- Although many centers are using aEEG, note that considerable training is required for conducting and properly interpreting the aEEG tracings.
- Many studies have advocated continuous cerebral function monitoring for evaluation of HIE. This technique has not been widely used and may need further investigations to establish its value in assessing HIE infants.

Standard EEG: Usually obtained as soon as the infant is stable. Repeat EEGs can be obtained to assess the status of seizure control, and repeat EEGs are sometimes obtained just prior to discharge from the initial hospitalization. Improvement in the EEG over the first week in conjunction with improvement in the clinical condition may help predict a better long-term outcome.
Traditional, multichannel EEG is a test commonly performed in infants suspected of having seizures or manifesting symptoms of HIE. EEG is a valuable tool, especially to assess the location and severity of seizure disorder. Thus, even in the absence of obvious clinical seizures, traditional EEG should be obtained early, particularly in moderately severe and severe cases. In infants on assisted ventilation, drugs such as pancuronium bromide (for muscle paralysis) and morphine (for sedation) can mask the symptoms of early seizures. Large doses of anticonvulsant therapy may also alter the EEG tracings.
Generalized depression of the background rhythm and voltage, with varying degrees of superimposed seizures, are the early findingsA burst suppression pattern (ie, isoelectric EEG) is particularly ominous. If clinically correlated, this EEG pattern is usually regarded as representing irreversible brain injury, akin to the legal definition of brain death.

Special sensory evaluation: Screening for hearing is now mandatory in many states in the United States; in infants with HIE, a full-scale hearing test is preferable because of an increased incidence of deafness among infants with HIE 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.

Histologic Findings: The neuropathology of neonatal HIE varies considerably. Depending on the cause of HIE, more than one type of lesion may be seen in a single patient. Brain maturity at the time of the insult is an important factor in the evolution of neuropathology. In the preterm infant, the damage is at the germinal matrix area, leading to hemorrhage in the subependymal region, the germinal matrix, or the intraventricular region. In the full-term infant, the pathology is mainly in the cerebral cortex and in the basal ganglia. Selective neuronal necrosis is the most common neuropathology. Major sites of necrosis are the cerebral cortex, diencephalon, basal ganglia, brain stem, and cerebellum. The injuries correlate with clinical symptoms, such as disturbances of consciousness, seizures, hypotonia, oculomotor-vestibular abnormalities, and feeding difficulties.

Parasagittal cerebral necrosis: This lesion is bilateral, usually symmetrical, and occurs in the cerebral cortex and the subcortical white matter, especially in the parietooccipital sides. These regions represent the border zones of perfusion from major cerebral arteries.
Status marmoratus: In this lesion, the basal ganglia, especially the caudate nucleus, putamen, and thalamus, demonstrate neuronal loss, gliosis, and hypermyelination, leading to a marble white discoloration of these regions. This is the least common type of neuropathology, and its full evolution may take months to years.
Focal and multifocal ischemic brain necrosis: These lesions are relatively large, localized areas of necrosis of cerebral parenchyma, cortex, and subcortical white matter. The most frequently affected region is the zone perfused by the middle cerebral artery.
Periventricular leukomalacia: This lesion is characterized by necrosis of white matter, which is seen grossly as white spots adjacent to the external angle of the lateral ventricles. These sites are the border zones between penetrating branches of major cerebral arteries. These lesions are more common in preterm than in term infants.

TREATMENT Section 6 of 10

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Medical Care: Seizures are generally self-limited to the first days of life but may significantly compromise other body functions, such as maintenance of ventilation, oxygenation, and blood pressure. Additionally, seizures should be treated early and be well controlled, since even asymptomatic seizures (ie, seen only on EEG) may continue to injure the brain. Seizures should be treated with phenobarbital or lorazepam; phenytoin may be added if either of these medications fails to control the seizures.

Other aspects of supportive care are outlined as follows:

Maintain adequate ventilation, perfusion, and metabolic status; most infants with HIE need ventilatory support during the first week.

Prevent hypoxia, hypercapnia, and hypocapnia; the latter is due to inadvertent hyperventilation, which may lead to severe hypoperfusion of the brain.

Maintain the blood gases and acid-base status in the physiological ranges including partial pressure of arterial oxygen (PaO₂), 80-100 mm Hg; partial pressure of arterial carbon dioxide (PaCO₂), 35-40 mm Hg; and pH, 7.35-7.45.

Maintain the mean BP above 35 mm Hg (for term infants). Dopamine or dobutamine can be used to maintain adequate cardiac output.
Fluid and glucose homeostasis should be achieved. Avoid hypoglycemia or hyperglycemia, as both are known to cause brain injury.

Fluid and Glucose homeostasis: Avoid hypoglycemia or hyperglycemia, as both are known to cause brain injury.
In the first 2 days of life, restrict intravenous fluids to two thirds of the daily requirement for gestational age and nursing environment in light of the high frequency of acute tubular necrosis and IADH.
Individualize fluid and electrolyte therapy on the basis of clinical course, changes in weight, urine output, and the results of serum electrolyte and renal function studies. When infants begin to improve, urinary output increases, and fluid administration must be adjusted. Similarly, in high-output renal tubular failure, the fluid volume and electrolyte composition need to be adjusted. For infants on high-frequency ventilators, the administered fluid volumes must be increased because, in those infants, venous return may be impaired, which affects cardiac preload.

o Hypothermia is a new and evolving therapy. Although many experts contend that this is not the standard of care at the time of this writing, therapeutic hypothermia is slowly emerging as a possibly useful therapy for mild-to-moderate cases of HIE. This has been shown in several animal models of HIE, and a few, limited clinical trials that evaluated outcomes up to age 18-22 months. However, experts consider hypothermia to be an evolving therapy. Many components of the implementation protocol for hypothermia need to be optimized and refined, and the magnitude of risk versus benefit when applied to the general population of infants with HIE has yet to be established. A brief synopsis of therapeutic hypothermia for HIE is provided below.
- Brain cooling to about 3-4°C below the baseline temperature (ie, to 33-34°C) may be neuroprotective. The optimal level of hypothermia for maximal neuroprotection is not known. Extreme hypothermia may cause significant systemic side effects.
- The mechanism through which hypothermia is neuroprotective is not completely understood. The possible explanations include the following: 1) reduced metabolic rate and energy depletion; (2) decreased excitatory transmitter release; (3) reduced alterations in ion flux; (4) reduced apoptosis due to HIE; and (4) reduced vascular permeability, edema, and disruptions of blood-brain barrier functions.
- Up to 48-72 hours of cooling may be needed to prevent secondary neuronal loss. 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.
- Cooling must begin early, within 1 hour of injury, if possible; however, a favorable outcome may be possible if the cooling begins up to 6 hours after injury.
- Two methods have been used in clinical trials for brain cooling. In selective head cooling, a cap (Cool-Cap) 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 used as proxy for brain temperature, and cooling is maintained for 72 hours. Rewarming is then carried out gradually, over a 6-8 hour period. This system was made commercially available in 2005.
- The other method is to provide whole body hypothermia. The infant is placed over 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 rewarming protocol is similar to the selective head cooling method. The relative merits and limitations of these 2 methods have not been tested.
- In a multicenter randomized controlled trial, selective head cooling was tested in 234 infants with HIE. Term infants with moderate-to-severe neonatal encephalopathy were randomly assigned to either head cooling for 72 hours with rectal temperature maintained at 34-35 °C (n=116), or conventional care (n=118). Of the infants allocated to conventional care, 73/110 (66%) died or had severe disability at 18 months, whereas 59/108 (55%) of the infants assigned to head cooling died or had severe disability at 18 months (odds ratio 0.61; 95% CI 0.34-1.09, P=0.1). After adjustment for the severity of the initial amplitude integrated EEG (aEEG) changes with a logistic regression model, the odds ratio for hypothermia treatment was 0.57 (0.32-1.01, P=0.05). Predefined subgroup analysis suggested that head cooling had no effect in infants with the most severe aEEG changes but was beneficial in infants with less severe aEEG changes.
- In another large study, whole body hypothermia was tested; 102 infants with severe HIE were randomized to receive hypothermia (33.5 °C for 72 h), and 106 were given conventional care. Death or moderate or severe disability occurred in 44 percent in the hypothermia group and 62 percent in the control group. (Risk ratio, 0.72; 95 percent confidence interval, 0.54 to 0.95; P=0.01). The frequency of side effects were similar between the groups.
- Short-term follow up, up to 18-22 months of age, show a lower incidence of mortality and morbidity in infants treated with brain cooling. However, many issues remain unresolved with respect to the role of hypothermia in perinatal HIE, especially its applicability into general practice, appropriate selection of candidates, and overall risk-benefit ratios compared to the severity of HIE. These have been subject to several recent and upcoming reviews.
- Although clinical studies have been reassuring thus far, many theoretical concerns exist due to 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.

Surgical Care: In cases of posterior cranial fossa hematoma, surgical drainage may be lifesaving if no additional pathologies are present.

Consultations:

A pediatric neurologist should help assist in the management of seizures, interpretation of EEG, and overall care of the infant with HIE. The neurologist should also work with the primary care physician to address long-term disabilities.

A developmental specialist also can help plan for long-term assessments and care.

Diet: In most cases (particularly in moderately severe and severe HIE), the infant is restricted to nothing by mouth (NPO) during the first 3 days of life or until the general level of alertness and consciousness improves. Begin trophic feeding with dilute formula or expressed breast milk, about 5 mL every 3-4 hours. Monitor abdominal girth and the composition of stools and for signs of gastric retention; any of these may be an early indicator of necrotizing enterocolitis, for which infants with perinatal asphyxia are at high risk. Individualize increments in feeding volume and composition.

MEDICATION Section 7 of 10

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Providing standard intensive care support, correcting metabolic acidosis, limiting fluid intake to two-thirds the maintenance volume for the first 3-4 days, and seizure control are the main elements of treatment. Anticonvulsants are the only specific drugs used often in this condition.

Treat seizures early and control them as fully as possible. Even asymptomatic seizures (ie, seen only on EEG) may continue to injure the brain.

Drug Category: Anticonvulsants -- These agents are used to control seizures.
Drug Name
Phenobarbital (Luminal) -- DOC when clinical or EEG seizures are noted; is continued on the basis of both EEG and clinical status. In most cases, can be weaned and stopped during the first month of life; however, treatment is continued for several months to 1 year in infants with persistent neurological abnormalities and clinical or EEG evidence of seizures; EEG and clinical status should guide decision. In high doses, has been used prophylactically by a few researchers, but its efficacy has not been established. In infants who are heavily sedated or paralyzed, phenobarbital may be used prophylactically at standard dose.
Pediatric Dose 20 mg/kg IV over 10-15 min as loading dose; in refractory cases, additional 5-10 mg/kg IV as loading dose; followed by 3-5 mg/kg/d PO/IV/IM/PR divided bid, to begin no earlier than 12-24 h after loading dose; slow IV push gives most rapid control
In a few experimental studies, 20-40 mg/kg IV has been given prophylactically to achieve higher serum concentrations; however, this is not universally accepted
Contraindications Documented hypersensitivity; severe respiratory disease, marked impairment of liver function, and nephritic patients
Interactions May decrease effects of digitoxin, corticosteroids, carbamazepine, theophylline, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); coadministration with alcohol may produce additive CNS effects and death; valproic acid may increase phenobarbital toxicity; rifampin may decrease phenobarbital effects
Pregnancy D - Unsafe in pregnancy
Precautions May lead to respiratory distress, so respiratory status should be monitored; immediate assisted ventilatory support should be available
Monitor serum therapeutic concentrations, which should be 15-30 mcg/mL; prolonged serum half-life during the first 1-2 wk of life may cause drug accumulation, requiring adjustment of maintenance doses, due to low GFR in the first week of life and ATN (if present)
Allowing serum concentrations of 40 mcg/mL is not a universally accepted practice
Observe IV sites for extravasation and phlebitis
Drug Name
Phenytoin (Dilantin) -- Usually the third DOC in neonatal seizures; may be used in patients with seizures that do not respond to phenobarbital or lorazepam. Oral absorption is negligible for the first several months of life.
Pediatric Dose 15-20 mg/kg IV over >30 min as loading dose; followed by 4-8 mg/kg IV slow push q24h; rate of infusion not to exceed 0.5 mg/kg/min; flush IV line with 0.9% NaCl before and after administration
Contraindications Documented hypersensitivity; sinoatrial block, second- and third-degree AV block, sinus bradycardia, or Adams-Stokes syndrome; IM administration
Interactions Benzodiazepines, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, trimethoprim, and valproic acid may increase phenytoin toxicity
Phenytoin effects may decrease when taken concurrently with barbiturates, diazoxide, rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate
Phenytoin may decrease effects of acetaminophen, corticosteroids, doxycycline, haloperidol, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, valproic acid
Pregnancy D - Unsafe in pregnancy
Precautions Monitor serum concentrations, which should be 6-15 mcg/mL; monitor for bradycardia, arrhythmias, and hypotension during infusion; highly unstable in IV solution, avoid using in central lines because of risk of precipitation; incompatible in D5W or D10W or with dextrose plus amino acids and lipids, most antibiotics, heparin, insulin, and many other drugs (consult compatibility text); drug extravasation at IV site may lead to severe local necrosis
Drug Name
Lorazepam (Ativan) -- Second DOC for acute control of seizures refractory to phenobarbital.
By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.
Pediatric Dose 0.05-0.1 mg/kg/dose IV slow push; doses repeated on basis of clinical response
Contraindications Documented hypersensitivity; preexisting CNS depression and hypotension
Interactions CNS toxicity increases when used concurrently with alcohol, phenothiazines, barbiturates, or MAOIs
Pregnancy D - Unsafe in pregnancy
Precautions May cause respiratory depression and rhythmic myoclonic jerking in premature infants receiving lorazepam for sedation
Drug Category: Cardiovascular (inotropic) agents -- Increase 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, 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.
Drug Name
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.
Pediatric Dose 2-20 mcg/kg/min IV continuous infusion; begin at lower doses, increase on basis of systemic BP appropriate for age and gestational age
Contraindications Documented hypersensitivity; pheochromocytoma or ventricular fibrillation
Interactions Phenytoin, alpha- and beta-adrenergic blockers, general anesthesia, and MAOIs increase and prolong effects of dopamine
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions May cause tachycardia and arrhythmias; may increase pulmonary artery pressure; may reversibly suppress prolactin and thyrotropin secretion
Drug Name
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.
Pediatric Dose 2-25 mcg/kg/min IV continuous infusion; begin at lower doses, increase as needed on basis of BP and heart rate; wean on basis of BP response
Contraindications Documented hypersensitivity; idiopathic hypertrophic subaortic stenosis and atrial fibrillation or flutter
Interactions Beta-adrenergic blockers antagonize effects of dobutamine; general anesthetics may increase toxicity
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions May cause arrhythmias, hypertension, tachycardia, and vasodilation of cutaneous microcirculation; assess volume status before administering, since may cause hypotension, especially in infants with clear evidence of hypovolemia; may cause tissue sloughing at IV site, particularly when the drug infiltrates soft tissue

FOLLOW-UP Section 8 of 10

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Further Inpatient Care:

Close physical therapy and developmental evaluation are needed before discharge.

Further Outpatient Care:

As noted before, most infants do not need specific outpatient care. However, they should be monitored in a regular pediatric clinic. Severely disabled children may need to be monitored in multispecialty clinics and by a developmental neurologist.

In/Out Patient Meds:

Continuation of seizure medications should depend on evolving CNS symptoms and EEG findings.

In most infants who are developing normally and have a normal EEG before hospital discharge, phenobarbital is discontinued within 3-4 weeks of birth.

In those with significant CNS disability with or without persistent episodes of seizures, phenobarbital is continued for 3-6 months; the decision to wean off the drug depends on later changes in EEG and clinical course.

Transfer:

Infants delivered in a level I or II center may require transfer to a tertiary neonatal intensive care unit for definitive neurodiagnostic studies (EEG and neuroimaging) and consultation with a pediatric neurologist.

Deterrence/Prevention:

Most treatments discussed below are experimental. With the exception of hypothermia (still being evaluated) none has consistently shown efficacy in human infants.

Allopurinol: Slight improvements in survival and CBF were noted in a small group of infants tested with this free-radical scavenger in one clinical trial.

High-dose phenobarbital: In another study, 40 mg/kg phenobarbital was given over 1 hour to infants with severe HIE. Treated infants had fewer seizures (9 of 15) than untreated control infants (14 of 16). Treated infants also had fewer neurological deficits at age 3 years (4 of 15) than untreated infants (13 of 16). No other trials confirming these findings have been reported.

EAA antagonists: MK-801, an EAA antagonist, has shown promising results in experimental animals and in a limited number of adult trials. This drug has serious cardiovascular adverse effects.

Complications:

See Clinical.

Prognosis:

See Mortality/Morbidity for data on outcomes.

Accurate prediction of the severity of long-term complications is difficult, although the following pointers may be used:

Lack of spontaneous respiratory effort within 20-30 minutes of birth is associated with almost uniform mortality.

The presence of seizures is an ominous sign. The risk of poor neurological outcome is distinctly greater in such infants, particularly if seizures occur frequently and are difficult to control.

Abnormal clinical neurological 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.
An EEG done at about 7 days that has 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.

MISCELLANEOUS

Section 9 of 10

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Medical/Legal Pitfalls:

Birth asphyxia, birth injury, and perinatal asphyxia are terms often used incorrectly to describe HIE.

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 at any time in the perinatal period, namely, from conception through the first month of life.

The AAP and 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 neurological injury. Acute perinatal and intrapartum events have been found in only about 20% of children diagnosed as having cerebral palsy.

Counseling the parents with realistic explanations about their infant's clinical status and prognosis is always recommended.

BIBLIOGRAPHY

Section 10 of 10

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

American Academy of Pediatrics: Relation between perinatal factors and neurological outcome. In: Guidelines for Perinatal Care. 3rd ed. Elk Grove Village, Ill: American Academy of Pediatrics; 1992: 221-234.

Berger R, Garnier Y: Pathophysiology of perinatal brain damage. Brain Res Brain Res Rev 1999 Aug; 30(2): 107-34 [Medline].
de Haan HH, Hasaart TH: Neuronal death after perinatal asphyxia. Eur J Obstet Gynecol Reprod Biol 1995 Aug; 61(2): 123-7[Medline].
Depp R: Perinatal asphyxia: assessing its causal role and timing. Semin Pediatr Neurol 1995 Mar; 2(1): 3-36[Medline].
Gluckman PD, Wyatt JS, Azzopardi D, et al: Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicenter randomised trial. Lancet 2005; 365: 663-70[Medline].
Gluckman PD, Wyatt JS, Azzopardi D, et al: Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicenter randomised trial. Lancet 2005; 365: 663-70[Medline].
Gunn AJ, Gunn TR: The 'pharmacology' of neuronal rescue with cerebral hypothermia. Early Hum Dev 1998 Nov; 53(1): 19-35[Medline].
Hall RT, Hall FK, Daily DK: High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized, prospective study with three-year follow-up. J Pediatr 1998 Feb; 132(2): 345-8[Medline].
Latchaw RE, Truwit CE: Imaging of perinatal hypoxic-ischemic brain injury. Semin Pediatr Neurol 1995 Mar; 2(1): 72-89[Medline].
Latchaw RE, Truwit CE: Imaging of perinatal hypoxic-ischemic brain injury. Semin Pediatr Neurol 1995 Mar; 2(1): 72-89[Medline].
Papile LA, Rudolph AM, Heymann MA: Autoregulation of cerebral blood flow in the preterm fetal lamb. Pediatr Res 1985 Feb; 19(2): 159-61[Medline].
Papile LA, Rudolph AM, Heymann MA: Autoregulation of cerebral blood flow in the preterm fetal lamb. Pediatr Res 1985 Feb; 19(2): 159-61[Medline].
Patel J, Edwards AD: Prediction of outcome after perinatal asphyxia. Curr Opin Pediatr 1997 Apr; 9(2): 128-32[Medline].
Patel J, Edwards AD: Prediction of outcome after perinatal asphyxia. Curr Opin Pediatr 1997 Apr; 9(2): 128-32[Medline].
Rivkin MJ: Hypoxic-ischemic brain injury in the term newborn. Neuropathology, clinical aspects, and neuroimaging. Clin Perinatol 1997 Sep; 24(3): 607-25[Medline].
Roohey T, Raju TN, Moustogiannis AN: Animal models for the study of perinatal hypoxic-ischemic encephalopathy: a critical analysis. Early Hum Dev 1997 Jan 20; 47(2): 115-46[Medline].
Rosenkrantz TS, Diana D, Munson J: Regulation of cerebral blood flow velocity in nonasphyxiated, very low birth weight infants with hyaline membrane disease. J Perinatol 1988; 8(4): 303-8[Medline].
Rosenkrantz TS, Diana D, Munson J: Regulation of cerebral blood flow velocity in nonasphyxiated, very low birth weight infants with hyaline membrane disease. J Perinatol 1988; 8(4): 303-8[Medline].
Rowe JC, Holmes GL, Hafford J, et al: Prognostic value of the electroencephalogram in term and preterm infants following neonatal seizures. Electroencephalogr Clin Neurophysiol 1985 Mar; 60(3): 183-96[Medline].
Rowe JC, Holmes GL, Hafford J, et al: Prognostic value of the electroencephalogram in term and preterm infants following neonatal seizures. Electroencephalogr Clin Neurophysiol 1985 Mar; 60(3): 183-96[Medline].
Sarnat HB, Sarnat MS: Neonatal encephalopathy following fetal distress: A clinical and electroencphalographic study. Archives of Neurology 1976; 33: 696-705.
Sarnat HB, Sarnat MS: Neonatal encephalopathy following fetal distress: A clinical and electroencphalographic study. Archives of Neurology 1976; 33: 696-705.
Shankaran S, Laptook AR, Ehrenkranz RA, et al: Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005 Oct 13; 353(15): 1574-84[Medline].
Shankaran S, Laptook AR, Ehrenkranz RA, et al: Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005 Oct 13; 353(15): 1574-84[Medline].
Simon NP: Long-term neurodevelopmental outcome of asphyxiated newborns. Clin Perinatol 1999 Sep; 26(3): 767-78[Medline].
Simon NP: Long-term neurodevelopmental outcome of asphyxiated newborns. Clin Perinatol 1999 Sep; 26(3): 767-78[Medline].
Thorngren-Jerneck K, Alling C, Herbst A, et al: S100 Protein in Serum as a Prognostic Marker for Cerebral Injury in Term Newborn Infants with Hypoxic Ischemic Encephalopathy. Pediatr Res 2003 Nov 19;[Medline].
Thorngren-Jerneck K, Alling C, Herbst A, et al: S100 Protein in Serum as a Prognostic Marker for Cerebral Injury in Term Newborn Infants with Hypoxic Ischemic Encephalopathy. Pediatr Res 2003 Nov 19;[Medline].
Van Bel F, Shadid M, Moison RM, et al: Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics 1998 Feb; 101(2): 185-93[Medline][Full Text].
Van Bel F, Shadid M, Moison RM, et al: Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics 1998 Feb; 101(2): 185-93[Medline][Full Text].
Vannucci RC: Mechanisms of perinatal hypoxic-ischemic brain damage. Semin Perinatol 1993 Oct; 17(5): 330-7[Medline].
Vannucci RC, Perlman JM: Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics 1997 Dec; 100(6): 1004-14[Medline].
Vannucci RC, Yager JY, Vannucci SJ: Cerebral glucose and energy utilization during the evolution of hypoxic-ischemic brain damage in the immature rat. J Cereb Blood Flow Metab 1994 Mar; 14(2): 279-88[Medline].
Vannucci RC, Perlman JM: Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics 1997 Dec; 100(6): 1004-14[Medline].
Vannucci RC, Yager JY, Vannucci SJ: Cerebral glucose and energy utilization during the evolution of hypoxic-ischemic brain damage in the immature rat. J Cereb Blood Flow Metab 1994 Mar; 14(2): 279-88[Medline].

Hypoxic-Ischemic Encephalopathy excerpt