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Hypoxic–Ischemic Encephalopathy


Hypoxic–ischemic encephalopathy (HIE) following severe perinatal asphyxia (also referred to in the literature as perinatal hypoxia–ischemia or asphyxia neonatorum ) has an incidence of 1-2 per 1,000 live births in the Western world and is far more common in developing countries (see Chapter 8 ). Although metabolic disorders may mimic perinatal asphyxia, and genetic and placental factors may contribute to the clinical picture, brain imaging techniques have demonstrated acute changes in the brain of the term neonate after perinatal asphyxia occurs.

The chance of irreversible damage or death after severe perinatal asphyxia is high—up to 65% of patients enrolled in trials of neuroprotective strategies. Therapeutic hypothermia is neuroprotective, as has been demonstrated in several trials, and is standard therapy for (near-) term neonates with severe perinatal asphyxia and encephalopathy. Ongoing studies will aim at additive strategies to augment the neuroprotection of hypothermia.

Experiments in animals have demonstrated that the immature brain is more resistant to hypoxia–ischemia than the brain of the term neonate. The several reasons to explain this difference are a lower cerebral metabolic rate; lower sensitivity to neurotransmitters with potential neurotoxicity; and the greater plasticity of the immature central nervous system. Nevertheless, in the fetus and in the preterm neonate, cerebral hypoxia–ischemia is a major cause of acute mortality and, in survivors, morbidity. However, the neuropathology will be different from that of the full-term neonate (see Chapters 52 and 54).

Definitions

Hypoxic–Ischemic Encephalopathy

The term HIE describes abnormal neurologic behavior in the neonatal period after perinatal hypoxia–ischemia occurs. Previously, the term post-asphyxial encephalopathy was used, and some suggest that the term neonatal encephalopathy is best used because the cause of encephalopathy is not always obvious. This has also been suggested by the American College of Obstetricians and Gynecologists’ Task Force on Neonatal Encephalopathy.

The severity of HIE can be defined as mild, moderate, or severe, depending on clinical findings, as described by Sarnat and Sarnat ; this classification is widely used and is summarized in Table 54.1 . Other clinical scoring systems have been developed to assess the severity of HIE and are used to select infants for therapeutic hypothermia ( Table 54.2 ).

TABLE 54.1
Clinical Staging of Hypoxic–Ischemic Encephalopathy
Modified from Sarnat HB, et al. Hypoxic-ischemic encephalopathy following fetal distress: a clinical and electroencephalographic study. Arch Neurol . 1976;33:695.
Variable Stage I Stage II Stage III
Level of consciousness Alert Lethargy Coma
Muscle tone Normal or hypertonia Hypotonia Flaccidity
Tendon reflexes Increased Increased Depressed or absent
Myoclonus Present Present Absent
Seizures Absent Frequent Frequent
Complex Reflexes
Suck Active Weak Absent
Moro Exaggerated Incomplete Absent
Grasp Normal or exaggerated Exaggerated Absent
Doll's eye Normal Overactive Reduced or absent
Autonomic Function
Pupils Dilated, reactive Constrictive, reactive Variable or fixed
Respirations Regular Variations in rate and depth, periodic Ataxic, apneic
Heart rate Normal or tachycardia Bradycardia Bradycardia
Electroencephalogram Normal Low voltage, periodic paroxysmal Periodic or isoelectric

TABLE 54.2
Thompson Score
From Thompson CM, et al. The value of a scoring system for hypoxic–ischaemic encephalopathy in predicting neurodevelopmental outcome. Acta Paediatr . 1997;86:757-761.
Sign Score Day 1 Day 2 Day 3
0 1 2 3
Tone Normal Hypertonic Hypotonic Flaccid
Level of consciousness Normal Hyper alert stare Lethargic Comatose
Fits None Infrequent <3/day Frequent >2/day
Posture Normal Fisting, cycling Strong distal flexion Decerebrate
Moro Normal Partial Absent
Grasp Normal Poor Absent
Suck Normal Poor Absent ± bites
Respiration Normal Hyperventilation Brief apnea IPPV (apnea)
Fontanel Normal Full, not tense Tense
Total score per day
IPPV, Intermittent positive-pressure ventilation.

Hypoxia or Anoxia

This denotes a partial (hypoxia) or complete (anoxia) lack of oxygen supply to the brain or blood. Hypoxemia denotes lack of oxygen in blood.

Ischemia

Ischemia refers to reduction (partial) or cessation (total) of blood flow to an organ (e.g., the brain), compromising both oxygen and substrate delivery, such as glucose to the tissue. Global ischemia may occur as a result of reduced cardiac output, as in circulatory failure. Focal brain ischemia, or ischemic stroke, has been demonstrated more commonly during the last decade in both term and preterm neonates with the increased use of cranial magnetic resonance imaging (MRI), which is a sensitive technique to demonstrate stroke.

Perinatal Asphyxia

The term asphyxia , from the Greek word for suffocation, is used to describe the interrupted supply of oxygen through the placenta and umbilical cord to the fetus, leading to combined hypoxemia and hypercapnia. In case of total interruption of oxygen, within minutes, anaerobic glycolysis will occur and lactic acidosis, and thereby metabolic acidosis, will be produced. This can be measured by blood gas analysis. In addition, (fetal) bradycardia will develop and will add ischemia to the process and augment cerebral hypoxia and hypercapnia.

Pathophysiology

Systemic Adaptation to Hypoxic–Ischemic Insult

Severe fetal hypoxic–ischemic injury affects the entire organism, and these effects have been well studied in animal models. In particular studies, instrumented fetal sheep and monkeys in the 1960s and 1970s have been used to describe the physiologic and pathologic changes in the brain after hypoxia has occurred. Hypoxic–ischemic injury may occur at any time during pregnancy, the birth process, or the neonatal period. The pattern of brain damage is reflected by the gestational age of the fetus at the time that the injury occurs. Fetal hypoxic–ischemic injury may result from maternal, uteroplacental, or fetal problems ( Box 54.1 ). The fetus may survive maternal hypoxia–ischemia, such as transient hypoxia or hypotension. Correctable placental factors include hyperstimulation with oxytocic agents or intermittent cord compression, but these may cause irreversible brain damage before recovery occurs.

Box 54.1
Causes of Fetal Hypoxic–Ischemic Insult

Maternal

  • Cardiac arrest

  • Asphyxiation

  • Severe anaphylactoid reaction

  • Status epilepticus

  • Hypovolemic shock

Uteroplacental

  • Placental abruption

  • Cord prolapse

  • Uterine rupture

  • Hyperstimulation with oxytocic agents

Fetal

  • Fetomaternal hemorrhage

  • Twin-to-twin transfusion syndrome

  • Severe isoimmune hemolytic disease

  • Cardiac arrhythmia

Fetuses with brain damage occurring as a result of early in utero hypoxic–ischemic insult do survive, but in the majority of cases, severe maternal hypoxia in the second trimester of pregnancy will result in fetal death. Occasionally, there is a history of a catastrophic maternal illness, such as suffocation, anaphylaxis, or major physical trauma. In other situations, the antecedent pathogenic event is confined to the fetus, sometimes resulting in symmetric thalamic lesions, with or without an associated abnormality of the uteroplacental unit. Whatever the cause of the cerebral hypoxia–ischemia, the neuropathologic consequence is often devastating.

In the more mature fetus, a period of mild to moderate hypoxemia produces a consistent pattern of responses ( Fig. 54.1 ). Initially, there is fetal bradycardia with an immediate rise in blood pressure and, in particular, an increase in perfusion to the brain and other vital organs at the expense of the rest of the body. With ongoing hypoxemia, the fetal heart rate will decrease further, apnea will occur, and permanent brain injury occurs after 10-15 minutes. The fetus is very resistant to milder hypoxemia, and normal cardiovascular function will be maintained for up to an hour even with a partial pressure of oxygen (Pa o 2 ) of 15 mm Hg (normal fetal Pa o 2 is 25 mm Hg). With prolonged moderate hypoxia, cerebral perfusion will remain normal, but (asymmetric) fetal growth restriction will occur. In fetuses with such prolonged moderate hypoxia, lactate levels may be elevated, indicating that anaerobic glycolysis has occurred in some tissues. The rapid changes in blood gas values have been documented in numerous experiments ( Fig. 54.2 ).

Fig. 54.1, Physiologic responses of rhesus monkeys during asphyxia and on resuscitation. Brain damage was assessed histologically weeks or months after asphyxia.

Fig. 54.2, Changes in blood gas values in the term monkey fetus after acute, total asphyxia.

As the hypoxic insult becomes more severe, changes in regional cerebral blood flow occur. The brainstem is able to extract sufficient oxygen to maintain metabolism despite very low Pa o 2 at the expense of the cerebrum. Failing myocardial function may cause a fall in cardiac output, and the watershed areas of the cerebral hemispheres are most exposed to damage (see section on Vascular Territories ).

An acute hypoxic–ischemic insult, often referred to as a sentinel event, as may occur during cord prolapse or uterine rupture, is likely to damage the basal ganglia and brainstem, in contrast to the more chronic insult, which leads to damage in the cerebrum (see section on Neuropathology ).

Preconditioning

Preconditioning describes reduced sensitivity of the immature brain to injury, depending on whether it has been exposed to previous nondamaging hypoxic events some hours before the main hypoxic–ischemic insult. Preconditioning of immature rat pups by exposure to moderate hypoxia or inflammation before hypoxia–ischemia appears to be neuroprotective. Preconditioning may work through stabilizing hypoxia-inducible factor-1-alpha (HIF-1-alpha) during hypoxia. When dimerized with HIF-1-beta to HIF-1, it acts on hypoxia response elements in the promoter of hypoxia-responsive genes, which will lead to induction of genes encoding erythropoiesis, angiopoiesis, and antiapoptosis.

Perinatal Hypoxic–Ischemic Brain Damage

During the last decades, the processes leading to neuronal death in the neonate have been described in more detail. This knowledge is important when considering neuroprotective strategies (see section on Specific Neuroprotective Strategies ).

In contrast to adult ischemic stroke, neonatal hypoxia–ischemia is characterized in most cases by a combination of cerebral hypoxia (and ischemia during bradycardia), followed by reperfusion and potential excessive distribution of oxygen. The contribution of reperfusion to cerebral injury is recognized and has led to the restricted use of supplemental oxygen during neonatal resuscitation.

An acute hypoxic–ischemic insult leads to events that can be broadly categorized as early (primary) and delayed (secondary) neuronal death. Previously, two different patterns of cell death were reported in neonates. Necrosis is lytic destruction of cells, whereas apoptosis is programmed cell death, which is driven by adenosine triphosphate (ATP). More recently, these cell death patterns have been recognized to be in continuum. The final pathway is dependent on tissue circumstances such as oxygen content.

Early or primary neuronal damage occurs as a result of cytotoxic changes caused by failure of the microcirculation, inhibition of energy-producing molecular processes, increasing extracellular acidosis, and failure of Na + /K + –adenosine triphosphatase (ATPase) membrane pumps, which result in excessive leakage of Na + and Cl − into the cell with consequent accumulation of intracellular water (cytotoxic edema). Free radical production is also initiated, which further compromises neuronal integrity. If not reversed, these processes lead to neuronal death of the necrotic type within a short time of the acute insult.

Recovery and reperfusion, as occur with resuscitation, fuel the pathways to late (secondary) neuronal damage through a relatively large number of pathophysiologic mechanisms.

It has been demonstrated in experimental settings that secondary energy failure starts within 6-8 hours after the primary insult. The term energy failure reflects the fact that high energy phosphates are reduced as can be demonstrated in vivo using phosphorus magnetic resonance spectroscopy ( 31 P-MRS). This technique uses the intrinsic magnetic properties of some atomic nuclei, such as 31 P. The peaks described for the 31 P spectrum are beta-ATP, alpha-ATP, gamma-ATP, PCr, phosphodiesters, inorganic phosphate (Pi), and phosphomonoesters. Depletion of ATP and an increase in Pi, associated with a change in the PCr/Pi ratio, have been reported using 31 P-MRS. Secondary energy failure is a result of changes in mitochondria and may last up to 72 hours or even longer after the acute insult. Timing of moderate hypothermia for neuroprotection is based on this “therapeutic window” of 6 hours before the onset of secondary energy failure.

Secondary Neuronal Death

A complicated cascade of intracellular events is triggered by the initial hypoxic–ischemic insult, which results in either cell necrosis or apoptosis ( Fig. 54.3 ).

Fig. 54.3, Intracellular neurotoxic cascade and potential targets for neuroprotection after hypoxia–ischemia. After global hypoxia–ischemia, glutamate-induced excitotoxicity proceeds via N-methyl- d -aspartate receptor (NMDAR) activation, producing calcium ion (Ca 2+ ) influx and therefore activation of Ca 2+ -dependent nitric oxide synthase (NOS), particularly neuronal NOS. At high concentrations, NO • reacts with superoxide (O •− ) to produce peroxynitrite (ONOO − ), which, in turn, induces lipid peroxidation and mitochondrial nitrosylation. During the acute energy depletion, some cells undergo primary cell death. After reperfusion, the initial hypoxia-induced cytotoxic edema and accumulation of excitatory amino acids typically resolve in 30-60 minutes, with apparent recovery of cerebral oxidative metabolism. Mitochondrial failure is a key step leading to delayed cell death. Potential neuroprotective targets are indicated.

Glutamate Injury (Excitotoxicity)

Excessive neuroexcitatory activity occurs as a result of the asphyxial event, and this is mediated through glutamate toxicity. Glutamate activates N-methyl-D-aspartate (NMDA) receptors, which, in turn, cause calcium channels to open in an unregulated manner with excess entry of intracellular calcium ions (Ca 2+ ). The high concentrations of this ion activate lipases, proteases, endonucleases, and phospholipase C, which, in turn, break down organelle membranes. This sets up a variety of abnormal processes with release of free radicals, including nitric oxide (NO•) and superoxide ions. This has further adverse effects on cell membranes and leads to mitochondrial failure with the release of caspase-3 and eventual DNA fragmentation, poly(ADP-ribose) polymerase, which causes further energy failure of intracellular membrane function. This process also triggers an apoptotic response in the cell. The process of cell death is very different from that seen in adults, requiring specific neonatal animal models in the research of perinatal asphyxia.

Furthermore, cell death pathways differ between male and female rat pups ( Fig. 54.4 ). Some compounds like erythropoietin appear to be more protective in female than in male pups. The relevance of this gender difference for human neonates is not yet established. Clinical trials of erythropoietin for neuroprotection after perinatal asphyxia or stroke are ongoing.

Fig. 54.4, Pathways of apoptosis in neonatal male and female animals. AIF, apoptosis-inducing factor; PARP, poly(ADP-ribose) polymerase.

Free Radical Formation

Oxygen free radicals cause peroxidation of unsaturated fatty acids, and because the brain is especially rich in polyunsaturated phospholipids, it is especially susceptible to free radical attack. Mechanisms for quenching and inhibiting free radical production exist within the brain, but in the immature organ these mechanisms may be underdeveloped. Consequently, the human neonatal brain is at particular risk for oxygen free radical–induced injury. Brain arteriole endothelium is the main source of free radical production by the action of xanthine oxidase, but free radicals are also produced by activated neutrophils, microglia, and intraneuronal structures. During reperfusion, free radical production from the arteriolar endothelium results in blood–brain barrier leakage and release of platelet-activating factor, platelet adhesion, and neutrophil accumulation, which may contribute to cellular damage. Resuscitation of human neonates with 100% oxygen has led to prolonged changes in oxidized glutathione as a result of excessive production of oxygen free radicals.

A particularly important mechanism that exposes the newborn brain to oxygen free radical attack is the presence of free iron. Non–protein-bound (“free”) iron is found in higher concentration in the immature animal because of low transferrin levels. Free iron catalyzes mildly reactive oxygen species to more toxic free radicals through the Fenton reaction. There is evidence that after a hypoxic–ischemic insult, there is an increased presence of intraneuronal free iron within the first 24 hours that persists for several weeks.

The second important mechanism that leads to (nitrogen) free radicals is the production of neuronal-derived NO•. NO• is produced by three isoforms of the enzyme nitric oxide synthase (NOS): designated neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). Production of NO• is accelerated by intracellular Ca 2+ influx and NO• is neurotoxic in excessive concentrations. It is thought that up to 80% of NMDA toxicity is mediated through NO•. NO• also combines rapidly with superoxide to produce peroxynitrous acid, which gives rise to the free radical peroxynitrite. Excessive NO• can cause DNA strand breaks and induce neuronal apoptosis mediated through caspase-3 activation, and iNOS, produced during inflammatory processes, has also been reported to aggravate injury in the immature brain. However, NO• from endothelial cells (eNOS) is essential in maintaining cerebral perfusion. For neuroprotection, only nNOS- (and iNOS-) specific inhibitors can be used.

Apoptosis

Apoptosis (see Chapter 51 ), or programmed cell death, is perhaps the most important cause of neuronal death in the neonate following hypoxia–ischemia and resuscitation. It can be distinguished histologically from necrosis by shrinkage of affected cells with retention of the cell membrane. By contrast, necrosis is associated with cell rupture, which induces secondary inflammatory processes. DNA degradation develops in the apoptotic cell, giving a characteristic ladder appearance on gel electrophoresis.

Apoptosis is a gene-regulated process, and both proapoptotic and antiapoptotic genes, including BCL2 , Bax , APAF1 , and the caspase gene family, influence the process. A major role in the apoptotic mechanism is played by the caspase family of proteins, with caspase-3 identified as the execution protein. Inhibitors of caspase can block apoptosis and attenuate injury.

Apoptotic pathways have been shown to differ between males and females. Apoptosis via an apoptosis inducing factor–dependent pathway was demonstrated in cultured XY neurons, whereas a cytochrome c-dependent pathway was seen in XX neurons.

Cytokines

There is evidence that some proinflammatory cytokines (tumor necrosis factor-alpha, interleukin [IL]-1-beta, and IL-18) are activated after a hypoxic–ischemic insult in immature experimental animal models, and they may have neurotoxic properties. After hypoxic–ischemic insult, widespread expression of caspase-1 and IL-18 protein in microglia is found. These data suggest that hypoxic–ischemic insult may initiate an inflammatory response in the absence of infection, leading to neuronal injury.

Studies in animals and humans have shown that exposure to infection (gram-negative bacteria or lipopolysaccharide [LPS] in animal models) and chorioamnionitis in pregnant women significantly exacerbate clinical and neuronal injury.

Human Studies

Studies in human neonates have confirmed the presence of secondary energy failure after perinatal asphyxia. 31 P-MRS in affected term infants were usually normal within the first 6 hours after birth, suggesting that mitochondrial phosphorylation had initially recovered with resuscitation. After 8 hours, there was a significant decline in the high energy phosphates, such as phosphocreatine and ATP, with a further decline in the most severely affected infants at 48-72 hours. In some infants, recovery occurred to normal values within 7 days. The delayed fall in phosphocreatine/inorganic phosphate (PCr/Pi) ratio represents secondary energy failure.

In addition, proton magnetic resonance spectroscopy ( 1 H-MRS) may show some lactate in the neonatal brain on very early scans, but higher levels of lactate could be demonstrated after 48 hours in most affected infants. Studies using near-infrared spectroscopy (NIRS) have shown reduced oxygen uptake, and higher brain oxygen saturations in neonates with perinatal asphyxia, suggesting secondary energy failure. Diffusion weighted imaging (DWI) studies have demonstrated reduced diffusion of water molecules represented as the apparent diffusion coefficient (ADC), suggestive of cytotoxic edema returning to normal ADC values after approximately 1 week. In cystic areas, these ADC values will increase to above-normal values.

Doppler studies of major intracranial arteries demonstrated loss of normal carbon dioxide (CO 2 ) reactivity with high diastolic blood flow, first seen 12-24 hours after birth. Recently, MRI studies using arterial spin labeling (ASL) have demonstrated higher perfusion values in neonates with HIE and an adverse neurodevelopmental outcome.

Selective Vulnerability

In the human neonate, as well as in animal experiments, different patterns of brain injury following HIE have been demonstrated, depending on the developmental stage of the fetus, and severity and duration of the hypoxic–ischemic insult. The factors influencing brain injury after perinatal hypoxia–ischemia can be summarized as follows:

  • Cellular susceptibility

  • Maturity

  • Vascular territories

  • Regional susceptibility

  • Type of hypoxic–ischemic insult

  • Others, such as genetic predisposition and placental factors

Cellular Susceptibility

In the term neonate, the neuron is the most sensitive cellular element to hypoxic–ischemic insult. In the preterm neonate, neurons as well as precursors of oligodendrocytes are sensitive cell types.

Maturity

Gestational age plays an important role in the changing susceptibility of cerebral structures to hypoxic–ischemic insult for a number of reasons, including rapid changes in neuronal development, changing vascular watersheds, and biochemical variables within cells, such as relative proportions of excitotoxic and inhibitory expression. In addition, a low susceptibility of the immature myocardium compared with that of the term neonate may result in a more preserved cerebral perfusion during hypoxia.

Hypoxic–ischemic insults before 20 weeks’ gestational age, as may occur as the result of severe maternal illness, may lead to neuronal heterotopia or polymicrogyria because the insult to the fetal brain occurs during the stage of neuronal migration, which is not complete until 21 weeks of gestation. Insults affecting the brain during midgestation (26-36 weeks) predominantly damage white matter, leading to cystic periventricular leukomalacia, and may have secondary negative effects on growth of the deep gray matter or may increase the risk of intracranial hemorrhage. Primary hypoxic–ischemic injury to the basal ganglia and thalamus in preterm infants has been reported and resulted in a poor outcome. Insults near or at term (35 weeks and beyond) result predominantly in damage to the deep gray matter or the watershed areas of the brain.

Vascular Territories

Watershed injury refers to tissue damage that occurs in regions that are most vulnerable to reduction in cerebral perfusion as the result of having the most tenuous blood supply. These tissues are at the farthest points of arterial anastomoses and are exposed to damage when perfusion pressure falls, usually as the result of impaired cardiac output and low blood pressure. Watershed areas change with advancing development.

In the term brain, a cortical watershed area (the parasagittal region) is present among the three main arteries supplying each hemisphere. Volpe et al. used positron emission tomography (PET) to measure regional cerebral blood flow in 17 full-term newborns who had suffered asphyxia and found a consistent decrease in blood flow to the parasagittal region of both cerebral hemispheres in most of the infants. Modern techniques, such as DWI, have demonstrated these watershed-type lesions in the full-term neonate (see section on Neuroimaging ).

The depths of the sulci are also sensitive to hypoxic–ischemic insult as the result of being watershed areas at term. Reduction in perfusion in small vessels at the base of sulci during hypoxia–ischemia leads to columnar necrosis and may lead to ulegyria in the older child's brain.

Ischemic infarction (stroke) has been recognized more commonly with the increased use of MRI in neonates with or even without encephalopathy. Although infarction of a major cerebral artery has been found in neonates with a hypoxic–ischemic insult, thrombosis and embolus, vasospasm, maternal smoking, or hypoglycemia are more common etiologic factors. The location of the lesions and neurodevelopmental outcome is dependent on the cerebral artery involved.

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