Hypoxic-ischemic encephalopathy

Abstract
Hypoxic-ischemic encephalopathy (HIE) is one of the most important complications found in the newborn period. It is the result of a deprivation of oxygen and glucose to the neural tissue, which may be the result of either hypoxemia or ischemia. Experimental animal research and clinical observations in humans have noted that the pattern of injury occurs in 2 phases. The first phase is a primary energy failure related to the insult, and then a second energy failure occurs some hours later. The combined effects of cellular energy failure, acidosis, glutamate release, intracellular accumulation of calcium, lipid peroxidation, and nitric oxide neurotoxicity destroy essential components of the cell, culminating in cell death. The clinical presentation depends on the severity, timing, and duration of the insult, with symptoms typically evolving over approximately 72 hours. Hypothermia strategies are aimed at targeting this narrow window of opportunity to ameliorate the brain injury.


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Hypoxic-ischemic encephalopathy (HIE) is often one of the most devastating sequelae encountered in the newborn period. Although the predominant injury affects the brain, almost every organ system in the body is negatively impacted. Cerebral palsy (CP), seizure activity, and varying degrees of developmental delays are some of the chronic disabilities seen in survivors. Hypoxia and especially ischemia, in which there is decreased perfusion of the brain with oxygen and glucose, are usually the result of asphyxia. Experimental animal research and clinical observations in humans have noted that the pattern of injury occurs in 2 phases. The first is a primary energy failure related to the insult, and the second is an energy failure that occurs some hours later. Hypothermia strategies are aimed at targeting this narrow window of opportunity to ameliorate the brain injury. This article will review the etiology, biochemical and physiological events, clinical symptoms, treatment strategies, including those for hypothermia, and future avenues of research as they relate to HIE.

ETIOLOGY
Hypoxic-ischemic encephalopathy is the result of a deprivation of oxygen and glucose to the neural tissue, which may be the result of either hypoxemia or ischemia. Hypoxemia is a decrease in the amount of oxygen circulating in the blood. Ischemia is a decrease in the flow of blood available to perfuse the brain. Of the two, ischemia is the most problematic because less oxygen and glucose are delivered to the brain. Asphyxia is defined as an impairment to the exchange of oxygen and carbon dioxide (CO2). The increase in CO2 promotes an initial increase in cerebral blood flow and contributes to acidosis. Annually, asphyxia is responsible for approximately 23% of 4 million neonatal deaths globally.1 The rate of HIE is approximately 1 to 2 per 1000 term newborns in developed countries, with a mortality rate of 10% to 20%.2 There is a 10% risk of death in neonates who develop a moderate encephalopathy and a 30% risk of neurodevelopmental sequelae in those who survive.3 A severe encephalopathy is associated with a 60% risk of death and virtually guaranteed disabilities in survivors.3

According to Volpe, approximately 20% of neonatal HIE is primarily related to antepartum events that lead to hypoxic-ischemic fetal insults.4 Maternal conditions such as hypotension, placental vasculopathy, and insulin-dependent diabetes mellitus may predispose the fetus to intrapartum hypoxia-ischemia such that there is little reserve to compensate for the stresses of labor.5,6 Intrapartum events such as prolapsed cord, abruption placentae, and traumatic delivery have been linked to 35% of HIE cases.4 Sophisticated neuroimaging techniques, such as magnetic resonance imaging (MRI), have documented evidence of acute brain injury in neonates with clinical encephalopathy who were born with evidence of intrapartum asphyxia.7,8 It is thought that a combination of both antepartum and intrapartum untoward events is responsible for approximately 35% of HIE cases.4

Conditions in the neonatal period may be responsible for as much as 10% of HIE cases.4 These include congenital heart disease, severe pulmonary disease, severe recurrent apnea, and cardiac failure secondary to a large patent ductus arteriosus. The preterm infant is more affected than the term infant.

Because of the limitations in determining the actual timing of the insult, it may be difficult to identify/quantitate the antepartum contribution separately from the intrapartum. It is argued that other events besides intrapartum hypoxia may be responsible for HIE or CP, as less than 25% of these infants have symptoms of hypoxia-ischemia at birth.9 The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists have defined neonatal HIE as an encephalopathy associated with hypoxia that occurs in the intrapartum period with no evidence of other anomalies.9 They also identified 4 criteria that must be present to define an intrapartum event that is capable of resulting in HIE or CP (Box 1). Other criteria may suggest an intrapartum origin if they occur within approximately 48 hours of delivery.


Box 1. Criteria for defining an intrapartum hypoxic event


BIOCHEMICAL AND PHYSIOLOGICAL EVENTS
As mentioned above, glucose and oxygen play key roles in the pathogenesis of injury. Glucose is delivered to the brain via a carrier-mediated, facilitated diffusion, a much faster process than simple diffusion alone.10 In the brain, glucose is phosphorylated to glucose-6-phosphate, with the major end product being pyruvate under aerobic conditions. Pyruvate then enters the mitochondrion to be converted to acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is important in energy production via the citric acid cycle.10 Within the mitochondrion, the electron transport system, citric acid cycle, and acetyl-CoA generate adenosine triphosphate (ATP) from adenosine diphosphate.10 Under aerobic conditions, 38 molecules of ATP are generated for each molecule of glucose oxidized. The ATP is then transported from the mitochondrion to be used for transport or synthetic purposes. The transport processes involve impulse transmission and maintenance of calcium (Ca2+) within the neurons. The synthetic processes include neurotransmitters, membrane lipids, and structural and functional proteins.10

When a hypoxic-ischemic event occurs and an anaerobic state is induced, ATP is produced solely through glycolysis.10 Lactate results as the principal product, which gives off only 2 molecules of ATP. In response, glycolysis is increased as much as 10-fold.11 There is also a concomitant increase in the net uptake of glucose from the blood as well as an increase in glycogenolysis.11 Inefficient anaerobic metabolism continues to excessively consume glucose such that glucose delivery cannot meet the demand. As a result, ATP and brain glucose levels fall within minutes. Ischemia further compounds the hypoxia because the impaired circulation rapidly increases lactate and tissue acidosis. After approximately 6 minutes in a rat model, brain glucose levels were 70% lower, whereas blood glucose values were 100% higher.11 Thus, a ?normal? chemstrip or blood glucose reading may have little relationship to the brain glucose value under anaerobic conditions.

Asphyxia initially results in a redistribution of cardiac output, with as much as a 30% to 175% increase in cerebral blood flow.12 Continued asphyxia leads to a decrease in cardiac output and hypotension. Cerebral blood vessels lose the ability to respond to changes in blood flow, lactate, tissue acidosis, and increasing CO2. Loss of cerebral autoregulation and hypotension result in a decrease in cerebral blood flow. Cerebral edema, a result of damaged blood vessel walls becoming ?leaky,? sets into motion the cascade of biochemical events.

As the energy stores are failing, the transcellular ion pump (sodium-potassium-ATPase pump) begins to fail. Sodium, calcium, and water accumulate inside the glial cell, causing a cytotoxic edema. The cellular edema further decreases oxygen and glucose delivery to the neurons. Alteration of the charge on the cell's membrane causes it to become depolarized and opens calcium channels, facilitating cytosolic accumulation of calcium. The depolarization initiates a release of excitatory neurotransmitters, specifically glutamate from the axon terminals.

The increase in cytosolic calcium activates phospholipases, proteases, and endonucleases. Phospholipase A2 releases free fatty acids such as arachidonic acid by hydrolyzing membrane phospholipid. Arachidonic acid increases the release of glutamate and interferes with oxidative phosphorylation. Proteases destroy proteins within the cell. Activation of endonucleases, in combination with xanthine and prostaglandins, generates free radicals. Free radicals, molecules which contain an odd number of electrons, are chemically reactive and induce peroxidation of unsaturated fatty acids.13 The most commonly generated free radical is superoxide anion, which is converted to hydrogen peroxide by superoxide dismutase.4 Hydrogen peroxide is detoxified by catalase and glutathione peroxidase unless free iron is available.4 Asphyxia converts the nontoxic ?ferric? state of free ion to the dangerous ?ferrous? form, which is able to react with free radicals.12 In this environment, superoxide radicals react with hydrogen peroxide to produce deadly hydroxyl radicals.13

High levels of calcium ions accumulating within the cytoplasm induce production of nitric oxide (NO), a free radical. Neuronal nitric oxide synthase is initially increased and improves blood flow to the neurons.14 Neuronal nitric oxide synthase soon generates NO that diffuses to adjacent cells that are susceptible to NO toxicity. Nitric oxide quickly reacts with superoxide anions to form a highly toxic reactive nitrogen species and peroxynitrite.14 The peroxynitrite radical contributes to cell death by energy depletion, mitochondrial impairment, and future disruption of calcium homeostasis.14 It also stimulates cyclooxygenase activity and reenters the presynaptic neuron to further increase the release of glutamate.12 In addition, free fatty acids accumulate within the cell and undergo peroxidation by oxygen free radicals.

Within 1 to 4 hours following an asphyxia insult, inflammatory mediators are found. Interleukin-1[beta], tumor necrosis factor [alpha] (TNF [alpha]), and [alpha] and [beta] chemokines are produced, followed by neutrophil invasion of the site of injury. Inflammatory mediators have an indirect toxic effect in that they induce glial cells to produce neurotoxic factors such as excitatory amino acids. The influx of Ca2+ into the presynaptic nerve ending releases glutamate.14 Glutamate accumulates because ATP depletion leads to failure in the major reuptake and removal mechanisms such that glutamate excess produces excitotoxicity.14 Most important, the release of inflammatory mediators perpetuates the excitotoxic injury. The combined effects of cellular energy failure, acidosis, glutamate release, intracellular accumulation of calcium, lipid peroxidation, and NO neurotoxicity destroy essential components of the cell, culminating in cell death.

Immediately when cerebral circulation and oxygenation is restored, the acute cellular hypoxic depolarization is resolved and cellular energy metabolism is restored.12 During this phase of reperfusion, high energy phosphate levels return to baseline levels, lactate levels improve, and glutamate is cleared.14 A secondary or delayed brain injury becomes apparent by 8 to 16 hours that reaches a nadir at 24 to 48 hours that is evidenced by a second decline in high energy phosphate levels.14 There is a decrease in the ratio of phosphocreatine/inorganic phosphate and an unchanged intracellular pH. Nitric oxide initially vasodilates the cerebral circulation and later inhibits activity within the mitochondria. An exaggerated calcium influx, further injury to the sodium-potassium-ATPase pump, and enhanced release of glutamate by NO occur. Free fatty acids generate arachidonic acids and prostaglandins, while xanthine oxidase converts hypoxanthine to uric acid. In the microvascular system, free radicals activate adhesion molecules in platelets and leukocytes. The vessels become occluded, with decreased blood flow and delivery of oxygen and glucose, and the injury is perpetuated. Despite an upregulation of the main antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase, their increased levels are inadequate to scavenge the free radicals.13

Clinical deterioration, seizure activity, cytotoxic edema, and a release of excitatory neurotransmitters occur. The mitochondria are dysfunctional, secondary to extended reactions from the primary insult due to the influx of calcium influx, ongoing generation of oxygen free radicals, and NO formation. Studies from a rat model demonstrate that neuronal protein loss (total creatine and adenine nucleotides) is seen at 6 hours and is very apparent by 18 hours.15 The findings indicate that the secondary energy depletion is a consequence of the events that cause cellular destruction rather than the cause.14,15 The time until the occurrence of the secondary energy failure provides a window of opportunity for possible interventions that may ameliorate the injury.

Depending on the severity of the asphyxial event, 3 distinct patterns of brain injury have been noted in the term neonate. A mild to moderate insult, such as prolonged partial hypoxia-ischemia, has been correlated to a cortical and subcortical injury in a watershed parasagittal distribution.16 Acute profound asphyxia results in damage to the thalami, basal ganglia, hippocampi, mesencephalic structures, and perirolandic cortex while leaving the cortex relatively intact.16,17 A diffuse, destructive anoxic-ischemic injury causes extensive injury to the cortex and the white matter as depicted by multicystic encephalopathy.14,16 The mode of cell death may be necrosis and/or apoptosis, dependent on the severity of the insult and the maturational state of the cell.

Necrosis of the cell occurs within minutes to hours as a result of a severe insult. It is characterized by cell swelling, disintegration of the cellular membrane leading to cell rupture. Release of the intracellular components activates phagocytosis and the inflammatory process. Apoptosis occurs over hours to days as a result of a less severe insult. It is an active process of cell shrinkage, nuclear pyknosis (the nucleus loses density), chromatin condensation, and genomic fragmentation. Because the inflammatory process is not involved, it is difficult to discern. Necrotic cells are found more commonly in the central area of the severe, acute injury or core of the insult. Apoptosis is found in the penumbra, an area of evolving cell injury that surrounds the core. Cells in the penumbra are initially sustained by anaerobic glycolysis. However, within hours, the injury becomes irreversible, the area of infarction enlarges such that the cells within penumbra become more damaged.

CLINICAL SYMPTOMS OF HIE
The clinical presentation depends on the severity, timing, and duration of the insult, with symptoms typically evolving over approximately 72 hours.4 Symptoms that appear during the first 12 hours are presumed to be secondary to cerebral hemisphere depression.4 The neonate is not easily arousable, with minimal to absent response to sensory input. Respiratory patterns may range from a type of periodic breathing to respiratory failure. Generalized hypotonia is present with minimal spontaneous movements. If there is involvement of the basal ganglia, tone may be increased. There are spontaneous eye movements with intact papillary responses to light. The size of the pupils vary, with dilated reactive pupils found in neonates less affected and constricted reactive pupils in those with more severe insults.4 Approximately 50% to 60% of those severely affected will demonstrate seizures, with onset within the first 6 to 12 hours of life. Virtually all asphyxiated neonates express subtle seizures such as rowing or bicycling, blinking, tongue or lip smacking, sucking movements, and apnea. Full-term neonates demonstrate clonic movements that move in a random pattern known as multifocal clonic seizures. As many as 80% of neonates with focal cerebral infarcts will demonstrate focal seizures.4

During the next 12 to 24 hours, there may be an apparent increase in the neonate's level of awareness, although those severely affected typically remain unresponsive. The improvement in consciousness is not associated with any other signs of improvement in neurological function. Indeed, 15% to 20% of neonates first show seizure activity at this time that requires immediate intervention.4 Apneic episodes are found in 50% of neonates and 35% to 50% exhibit moderate to severe jitteriness. Full-term neonates may show weakness in the hip-shoulder distribution.4 If the basal ganglia were involved, there may be an increase in hypertonia. Deep tendon reflexes and the Moro reflex may be exaggerated.

In the 24 to 72 hours postinjury, the neonate with severe HIE often deteriorates and succumbs. Decreased level of consciousness, deep stupor, fixed pupils, and respiratory failure may be seen. The less severely affected neonate may exhibit constricted pupils that remain reactive to light. Brain-stem oculomotor disturbances are apparent as seen by loss of responsiveness of the eyes to the doll's eyes maneuver and to cold caloric stimulation.4 Delayed cell death has been postulated to be responsible for the slow progression to brain death, given the evidence for a delayed deterioration of the brain's energy state as discussed above.4

For those neonates who survive the first 72 hours, there is typically a slow improvement. They continue to demonstrate a mild to moderate stupor although the level of consciousness increases. Because of damage to cranial nerves V, VII, IX, X, and XII, the suck, swallow, and gag reflexes are disturbed. Feeding difficulties are commonly extreme enough that tube feedings or gastrostomy tubes are required for weeks to months. Generalized hypotonia is common in those neonates with selective neuronal necrosis that involves the basal ganglia and thalamus.4

CLINICAL MANAGEMENT
The diagnosis is made through a careful history to note the presence of maternal factors that may have resulted in uteroplacental insufficiency antenatally. Events surrounding labor and delivery should be explored to determine whether there was decreased placental blood flow, nonreassuring fetal heart rate variability, and the presence of meconium, for example. The immediate transition to extrauterine life should also be evaluated in light of Apgar scores, the need and response to resuscitative measures, and overall clinical condition of the neonate. Although the Apgar score is not a predictor of outcome, neonates with a continued low score of less than 6 have been shown to develop neurologic abnormalities.18

Once in the neonatal intensive care unit (NICU), a thorough physical and neurological examination should be done. The nurse should note the presence of jitteriness, seizures, pattern of breathing, tone, and other clinical sequelae as discussed above (routine nursing NICU care will not be discussed here). Diagnostic tests should rule out liver, renal, or cardiopulmonary dysfunction in addition to the usual complete blood cell count with differential and blood chemistry panels. Given the clinical condition of the neonate, it is important to monitor for hypoglycemia, hypocalcemia, hyponatremia, hypoxia, and acidosis. Hypoglycemia may be due to the enhanced anaerobic glycolysis in an attempt to preserve cellular energy levels.4,14 Fifteen percent of neonates diagnosed with intrauterine asphyxia had blood glucose values less than 40 mg/dL in the first 30 minutes of life.19

Perinatal asphyxia has also been associated with increased levels of lactate in blood and cerebrospinal fluid (CSF) and an elevated lactate/creatinine ratio in urine.14,20 Elevations in levels of excitatory amino acids, especially glutamate, aspartate, and glycine, found in the CSF within the first day of life have been correlated with severity of injury.21 Increased levels of free radicals, indicators of lipid peroxidation, and antioxidant enzymes have also been noted.22,23 Creatine kinase-BB is a brain-specific protein that when found in the CSF may provide information regarding brain injury.24 S100[beta] protein is found in neural glial and Schwann cells and may serve as a biochemical marker for HIE.25

A lumbar puncture should be done in the symptomatic neonate in which a diagnosis cannot be made with certainly to rule out infectious etiologies and hemorrhage. An electroencephalogram (EEG) may provide information regarding the type and severity of brain injury suffered.4,26 Amplitude-integrated EEG and sequential EEGs have been valuable in estimating neurodevelopmental outcomes.4,27 Brain ultrasound is typically a part of the initial diagnostic workup; however, the scan may be negative in almost 50% of neonates.4 Ultrasound, however, is very good at evaluating the extent of periventricular leukomalacia, as well as locating hemorrhagic complications.28 Computed tomography is very helpful in identifying focal and multifocal ischemic brain injuries several weeks after the insult.4

Magnetic resonance imaging is the tool of choice for evaluating hypoxic-ischemic injuries, both in the immediate period and also for long-term follow-up.29 Magnetic resonance imaging is not only able to document brain injury patterns but also may be predictive of the severity of the neurodevelopmental outcome. Diffusion-weighted MRI, based on the molecular diffusion of water, is more sensitive than the conventional MRI and is capable of detecting abnormalities within the first 24 to 48 hours of birth.4 Other diagnostic modalities may include magnetic resonance (MR) spectroscopy, phosphorus MR spectroscopy, and proton MR spectroscopy.4

TREATMENT STRATEGIES
Supportive strategies include adequate perfusion, ventilation, and oxygenation. Maintaining perfusion pressure within normal limits is necessary to avoid hemorrhagic complications due to systemic hypertension and ischemic injury due to systemic hypotension. Prevention of hypoxemia is essential to prevent additional neuronal and white matter injury. On the other hand, hyperoxia also must be avoided as it is thought that it may result in decreased cerebral blood flow and further any injury.30 As with oxygen, attention must be paid to CO2. Hypercarbia not only adds to acidosis but also more importantly promotes a pressure-passive cerebral circulation. Hypocarbia, especially values less than 20 mm Hg, is associated with impaired cerebral blood flow due to vasoconstriction and has been correlated with adverse neurological outcomes.30

Volpe suggests that the blood glucose level be maintained between 75 and 100 mg/d, although more research is needed on what constitutes an optimal range for the neonate with HIE.4 Seizures also need to be controlled, as they accelerate the brain's metabolic rate. Seizures are also associated with hypoxemia and hypercarbia. Observation for the development of inappropriate antidiuretic hormone syndrome should be done to prevent fluid overload, cerebral edema, and secondary brain swelling.4

NEUROPROTECTIVE INTERVENTIONS
As discussed above, there appears to be a therapeutic window prior to the secondary energy failure. A Cochrane review of 8 randomized controlled trials found that therapeutic hypothermia was beneficial to term neonates with HIE and that cooling decreased mortality without increasing morbidity.31 The exact mechanism by which hypothermia is neuroprotective has not yet been fully elucidated. It is thought that cells programmed for apoptosis are modified such that they survive.32 The brain's metabolic rate may be decreased, weakening the response of excitatory amino acids such as glutamate, slowing the uptake of glutamate, and decreasing production of NO and free radicals.4

Four pilot studies of hypothermia in human newborns reported no serious adverse effects.33?36 Sinus bradycardia and increased blood pressure and oxygen requirements were reversible with rewarming.35 From results obtained in animal studies, it was concluded that cooling should be initiated as early as possible after the brain injury and not later than 6 hours; body temperature should be cooled to 32?C to 34?C for whole-body cooling and 34?C to 35?C for head cooling; and hypothermia should be maintained for 48 to 72 hours.37 It is currently recommended that therapeutic hypothermia be considered as an evolving therapy, and in general, that it should be used only in NICUs with the expertise who strictly follow the guidelines of the protocols utilized in the CoolCap and NICHD trials.1,37 Selective head cooling did not show a statistically significant reduction in mortality although there was a significant decrease in major neurodevelopmental disability.31 Total body cooling demonstrated a significant decrease in mortality and major neurodevelopmental disability.31 A systematic review of hypothermia for the treatment of HIE found that systemic or selective head cooling reduced the combined outcome of death or neurodevelopmental disability, as well as death and moderate to severe neurodevelopmental disability when analyzed separately.1 Although potentially very promising for the treatment of HIE, and the lack of serious adverse effects, long-term efficacy and safety have not yet been established.37

HYPOTHERMIA PROTOCOL
Cooling must be initiated within 6 hours of birth as research has demonstrated this period as an optimal time for hypothermia to decrease the extent of the brain injury.38?40 Thus, the NICU must be prepared and well organized given the time constraint. The first step is to screen the infant for eligibility before accepting him for the therapy (Box 2). When the infant meets the criteria, the equipment is quickly assembled to the bedside and the blanket is precooled, but hung behind the radiant warmer. Because a thorough physical and neurological examination is required to determine eligibility for the protocol, the infant is admitted to a prewarmed radiant warmer on servo control. In addition to an amplified EEG, head ultrasound, and an echocardiogram, the physician will note the infant's level of consciousness, posture, tone, presence of any spontaneous activity, and quality of primitive reflexes (suck, Moro) and evaluate the autonomic nervous system (quality of respiration, heart rate, and pupils).

Box 2. Criteria for whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy


Immediately after establishing eligibility, the infant is placed on the precooled blanket with 1 regular hospital baby blanket under him. An esophageal temperature probe is inserted through a nare to a level of T 6?9, which corresponds to approximately 2 cm above the diaphragm. Placement is confirmed radiographically. The esophageal temperature probe is connected to the temperature cable and the radiant warmer is turned to manual control with the heater in the off position (Fig 1).

Figure 1. Infant on cooling blanket with esophageal temperature probe connected to the temperature cable in the foreground.


The radiant warmer temperature probe is left on the abdomen. The Blanketrol II is turned to auto control to keep the esophageal temperature 33.5?C (92.3?F) for 72 hours. An acceptable range is 32.5? to 34.5?C (90.5?F?94.1?F) and although some fluctuation is to be expected, it should be no more than 1?C higher or lower than the acceptable range. To better stabilize the temperature of the water flowing through the blanket, 2 blankets may be connected together, with one blanket under the infant and one hung behind the radiant warmer (Fig 2).

Figure 2. Infant on cooling blanket with Blanketrol II system in background and the second blanket hanging behind the radiant warmer. Note the cyanotic extremities associated with cold stress.


A specific hypothermia flow sheet is used to record the set point, patient esophageal temperature, skin temperature, and blanket (water) temperature every 15 minutes for the first 4 hours of cooling and every hour thereafter. On the standard nursing flow sheet, axillary temperature, blood pressure, and heart rate are recorded every hour, with axillary temperature being recorded every 4 hours after 12 hours of cooling. The axillary temperature will again be taken hourly once the rewarming period begins at 72 hours. In addition to noting the vital signs, it is also important that attention be given to skin integrity. Skin condition is documented every 4 hours, and the patient is gently repositioned using the rolls that were placed for nesting (Figs 1 and 2).

Nursing care of the infant includes developmental positioning with hands to midline and knees aligned with shoulders if possible. Typical NICU supportive care is also provided as for example, mechanical ventilation, pressors, fluids, and hematological conditions. A low resting heart rate is expected given the body temperature. Blood pressure fluctuations are also anticipated given the critical status of the neonate. It is also imperative that the bedside nurse ensure that the radiant warmer heater is not turned on during the 72 hours of cooling. Because of the effect of cold stress, blood flow to the extremities is typically decreased. Thus, values obtained from pulse oximetry should be interpreted with caution. The nurse must also adjust the temperature on the blood gas analyzer to the infant's actual temperature when processing blood gases.

Exactly at 72 hours of hypothermia, the gradual rewarming period begins. The cooling machine is turned to the warming mode and the auto control is increased by 0.5?C every hour for 6 hours until the set temper is 36.5?C. The esophageal probe is removed and the cooling blanket is turned off. At that point, the radiant warmer heater is turned on with the servo control set to 0.5?C greater than the infant's skin temperature. The servo control set point is increased 0.5?C every hour until the skin or axillary temperature reaches 36.5?C. The nursing/medical plan of care anticipates what supportive care the neonate needs as the temperature returns to normal.

In addition to the standard discharge protocol (automatic brainstem response, discharge medications, hepatitis B vaccine, and state screen), a Whole Body Hypothermia Discharge checklist must be completed prior to the neonate leaving the NICU. It documents that a brain MRI test and developmental evaluation have been completed, as well as the appointments at the follow-up high-risk clinic and the neurologist and pediatrician offices. Early Childhood Intervention and Home Health nursing referrals are also made as warranted.

Other neuroprotective strategies under investigation include oxygen free radical inhibitors and scavengers and excitatory amino acid antagonists. Allopurinol is a xanthine oxidase inhibitor and free radical scavenger. Studies using allopurinol in term neonates with asphyxia found beneficial effects on free radical formation and cerebral hemodynamics.41,42 Glutamate receptor antagonists such as N-methyl-d-aspartate (NMDA) have been extensively studied. Available N-methyl-d-aspartate agonists include magnesium sulfate, a medication widely used as a tocolytic agent and to treat preeclampsia. Magnesium blocks the neuronal influx of calcium within the ion channel, a major variable in the cascade of injury. Although studies show conflicting results, retrospective observations in premature neonates who were exposed to antenatal magnesium sulfate show a decreased incidence of CP at 3 years of age.43

CONCLUSION
Hypoxic-ischemic encephalopathy is associated with high mortality and severe morbidity in term neonates who have suffered a hypoxic-ischemic or asphyxia injury. An overview of the pathophysiology underlying HIE reveals the knowledge at the molecular and cellular levels that has been learned over the past 10 years. Although our understanding of the processes is enhanced, there remain considerable gaps yet to be elucidated. Hypothermia currently appears to be the best treatment modality, although there are many questions yet to be answered regarding its optimal use, timing, what level of hypothermia should be used, and which strategy (head vs total body cooling) ultimately will produce the best outcome. There is the prospect of exciting novel therapies ahead that specifically target the various levels of the cascade that may ultimately interfere with sequences to prevent or ameliorate cell death. It is likely that a combination of hypothermia, excitatory amino acid antagonists, and oxygen free radical inhibitors/scavengers will provide the best chance for recovery for the neonate affected by HIE.