What Is Ischemic Hypoxia?

Ischemic hypoxic encephalopathy (HIE) is a brain lesion caused by ischemia and hypoxia caused by various causes. The most common is neonatal ischemic hypoxic encephalopathy, but it can also occur at other ages. Neonatal ischemic hypoxic encephalopathy is a brain lesion caused by hypoxia in perinatal newborns. Common causes include intrauterine distress caused by various reasons, such as umbilical cord around the neck and abnormal amniotic fluid. It is also common in childbirth. Process and postnatal asphyxia and hypoxia, a few can be seen in brain damage caused by other causes. The disease mostly occurs in term infants, but can also occur in preterm infants. The fetal heart rate may increase or decrease during delivery, or the second stage of labor may be prolonged, the amniotic fluid may be contaminated by meconium, a history of suffocation at birth, changes in consciousness, muscle tone, respiratory rhythm, reversal, etc. may occur even after resuscitation. Non-neonatal ischemic hypoxic encephalopathy is seen in severe cerebral ischemia and hypoxia caused by various causes. Common respiratory cardiac arrest is also seen in shock, CO poisoning, status epilepticus, and myasthenia gravis.

Basic Information

English name

hypoxic-ischemic encephalopathy

Visiting department

Neurology

Multiple groups

Term newborn

Common symptoms

Cyanosis of lips, disturbance of consciousness, seizures

Causes and pathogenesis of ischemic hypoxic encephalopathy

The cause of the disease is mainly cerebral ischemia and hypoxia caused by various reasons.

Neonatal HIE is mainly seen in term neonates with severe asphyxia and has a significant history of intrauterine distress. Hypoxia due to intrauterine ischemia affects the energy supply of fetal brain cells. The brain's energy source is different from other organs, and almost all is oxidized by glucose. Neonatal brain metabolism is the most vigorous. The brain's energy accounts for half of the body's oxygen energy, but there is very little glycogen in the brain, and glucose and oxygen are all supplied by the blood. Therefore, ischemia and hypoxia first affect brain metabolism.

Under hypoxic conditions, the glycolysis of the brain increases 3 to 10 times, a large amount of pyruvate is reduced to lactic acid, and intracellular acidosis develops rapidly and severely. During glycolysis, only a small amount of ATP is produced. Due to insufficient energy sources, brain cells cannot maintain the difference in ion concentrations inside and outside the cell membrane. K ⁺ , Mg ²⁺ , HPO ₄ ⁺ escape from the cell, and Na ⁺ and Ca ²⁺ enter the cell. The oxidative metabolism of brain cells is impaired. The autoregulation function of cerebral blood vessels is reduced during hypoxia, and cerebral blood flow perfusion is susceptible to the decrease of systemic blood pressure; swelling of stellate cells around blood vessels and vesicular degeneration of endothelial cells make the lumen narrow or even occluded. When cerebral blood flow is restored, blood still cannot flow to these ischemic areas, causing regional ischemia or infarction, and subsequent development causes irreversible damage to the brain parenchyma. Vascular permeability increases during hypoxia, the accumulation of certain metabolites in tissues, and increased secretion of antidiuretic hormones, etc., to form cerebral edema, increase intracranial pressure, further reduce cerebral blood flow, and cause serious brain cell metabolic disorders , And later form brain atrophy.

At present, the role of reperfusion injury in the pathogenesis of HIE is receiving increasing attention. When the brain tissue is transferred from hypoperfusion to reperfusion, a series of pathophysiological changes will occur. For example, a large increase in oxygen free radicals leads to cell membrane breakdown, blood-brain barrier disruption, and cerebral edema; Ca ^{2+ influx} impairs mitochondrial oxidative phosphorylation, causing neurological metabolic disorders; excitatory amino acids such as glutamic acid and aspartate Acid increases in the brain, causing Na ⁺ and Ca ²⁺ to flow in, causing nerve cells to swell and cause death. Certain humoral factors, such as B-endorphin, vasopressin, and atrial natriuretic peptide, all have elevated blood concentrations during HIE, and also play a role in the pathogenesis of HIE.

Clinical manifestations of ischemic hypoxic encephalopathy

History of hypoxia

Neonatal HIE clinically has an abnormal obstetric history of intrauterine ischemia and hypoxia, such as umbilical cord around the neck, around the body, placenta previa or placental abruption, mothers with severe pregnancy-induced hypertension, and prolonged labor. Adult HIE has a clear history of cerebral ischemia and hypoxia, such as respiratory arrest.

2. Symptoms

Neonatal HIE can manifest as intrauterine distress, such as marked reduction in fetal movement, fetal heart rate <120 beats / min, and meconium-contaminated amniotic fluid appear cloudy. Apgar scores are significantly lower after birth, or manifested as lip cyanosis, etc., requiring artificial assisted breathing, and the following abnormal neurological symptoms may appear shortly after birth (within 12 hours): disturbances of consciousness such as excessive excitement (irritability, limb tremors, spontaneity) Increased movements, long eye opening time, gaze, etc.), lethargy (3 times crying on the soles of the feet), dullness (5 times crying on the soles of the feet), and even coma; changes in the muscle tension of the limbs, such as increased, weakened, or even softness ; Original reflection abnormalities, such as hug reflection is too active, weakened or disappeared, sucking reflection weakened or disappeared. Convulsions or frequent seizures may occur when the condition is severe, and cardia tension increases due to cerebral edema. Adult HIE, after a clear history of hypoxic brain tissue, appears to have disturbances of consciousness, mental disorders, seizures, etc. In severe cases, symptoms of brain stem damage may occur, showing symptoms of central respiratory failure such as respiratory rhythm irregularity, slowed breathing, and apnea. Pupils shrink or expand, respond to light slowly or even disappear, and some children have nystagmus.

3. Clinical indexing

HIE can be divided into mild, moderate and severe according to the severity. It should be noted that the symptoms of HIE gradually progress after birth, and some cases can be converted from excitement to suppression or even coma, reaching the maximum level at 72 hours, and gradually improving after 72 hours. Therefore, the changes of the condition should be closely observed within two or three days after birth. Intracranial hemorrhage can sometimes coexist with HIE, which complicates the symptoms and must be distinguished. In addition to the reference to the obstetric history, if there are clinically exciting brain stem symptoms that last more than 3 days, and appear earlier and recover quickly, you should consider whether there is hemorrhage on the cerebral hemisphere surface or posterior cranial fossa, and CT examination should be done in time. Confirmed.

(1) Mild main manifestations are irritating excitement, which is most obvious within 24 hours and disappears for 2 to 3 days. Limbs muscle tension is normal or slightly increased, and autonomic activity increases; normal reflexes are normal or slightly active; no convulsions, no cardia Increased tension. Usually no treatment is needed and the prognosis is good.

(2) Moderately suppress symptoms, showing drowsiness or sluggishness, weak crying; lower limb muscle tension, especially in upper limbs, and less spontaneous movements; weakened original reflexes, incomplete reflexes of hug reflexes, and less milk; part Children have increased intracranial pressure and convulsions. In most patients, the symptoms disappear within 1 week, and in a few patients, the symptoms last longer, and there may be sequelae.

(3) Severe coma is predominant, limb muscle tension disappears, showing a soft state, no spontaneous movement, and primitive reflexes also disappear. Most patients have increased intracranial pressure and convulsions, sometimes with frequent seizures, which are difficult to control even with adequate sedatives. Some patients show symptoms of brainstem, showing irregular breathing rhythms, apnea, diminished or enlarged pupils, and unresponsiveness or disappearance of light. Some patients died within 1 week, and survivors were more likely to have sequelae.

Ischemic hypoxic encephalopathy

1. CT or MRI of the head

The purpose of imaging examination is to further clarify the location and scope of HIE lesions and determine the presence or absence of intracranial hemorrhage and types of bleeding. Dynamic serial examinations have certain significance in assessing prognosis. As the lesions continue to progress after birth, the imaging findings will be different at different stages of the disease. Cerebral edema is usually the main part within 3 days after birth, and it is also possible to check for intracranial hemorrhage. If you want to check hypoxic-ischemic damage or intraventricular hemorrhage, it is advisable to use 5 to 10 days after birth, and 3 to 4 weeks later. A review will help determine permanent brain damage.

(1) CT examination The CT value of brain parenchyma (unit: Hu) should be measured during HIE CT scan of newborns. The CT value of white matter in normal term infants is above 20, and 18 is low density. It is necessary to exclude the normal low-density phenomenon related to the brain development of the newborn, that is, the low-density in the frontal, occipital, and full-term areas of preterm infants is normal.

HIE CT indexing criteria: Mild: scattered, low-density white matter, distributed in 2 lobes. Moderate: Low density white matter shadows more than 2 brain lobes, white matter gray matter contrast is blurred. Severe: diffuse low-density white matter shadow, gray matter white matter boundary disappeared, but the basal ganglia and cerebellum still have normal density. The bilateral cerebral hemispheres showed diffuse low-density shadows, and the ventricles narrowed or even disappeared, suggesting the presence of cerebral edema. The symmetrical density of bilateral basal ganglia and thalamus increased, suggesting the presence of basal ganglia thalamic injury. Decreased unilateral brain tissue density in the aorta distribution area, suggesting the presence of cerebral aorta and branch infarcts. A symmetrical low-density shadow around the ventricle, especially above the anterior horn of the lateral ventricle, suggests softening of the white matter around the ventricle, often accompanied by intraventricular hemorrhage. Moderate and severe HIE 60% to 70% with subarachnoid hemorrhage (SAH). However, some adult patients with severe HIE had no abnormalities in CT of the skull within 2 to 4 hours after the onset, which may be related to the insensitivity of CT in the early stage.

(2) Early MRI findings of neonatal HIE include extensive cerebral edema, intracranial hemorrhage, subcortical and paraventricular white matter damage, and abnormal signals in the thalamus, basal ganglia, and dorsal side of the brainstem; late stage can be expressed as white matter around the ventricle Softening and brain injury in the watershed area are equivalent. In the early stage (within 10 days) of MRI in adults, MRI can be manifested as cerebral edema, disappearance of the gray matter boundary, lamellar necrosis of the cerebral cortex, and intracranial hemorrhage; late stage (10 days to 6 months) can be manifested as subcortical white matter and deep white matter demyelination. Sheath changes, selective neuronal necrosis, extensive brain damage, and brain atrophy.

2. B-mode ultrasound (B-ultrasound) examination of the skull

Coronal and sagittal fan-shaped ultrasound examinations were performed using the infant's forehead as a window. It can be operated by the bedside, without the effects of radiation, and can be tracked and checked many times, which has many advantages. It showed clear brain edema, parenchymal lesions and enlarged ventricles.

A B-ultrasound examination of the newborn with HIE found that: Mild echoes widely distributed throughout the brain parenchyma with narrowing or disappearance of ventricles, sulci, and hemisphere fissures, and weakening of cerebral arterial pulses, suggesting the presence of cerebral edema. The basal ganglia and thalamus exhibit bilaterally symmetric strong echo reflexes, suggesting the presence of basal ganglia and thalamus damage, often coexisting with cerebral edema. A localized strong echo reflex is seen in the cerebral arterial distribution area, suggesting that there are infarcts of the aorta and its branches, most of which are unilateral, especially the left. In the coronal section, the laterally ventricular anterior angle of the lateral ventricle shows an inverted triangle with bilateral symmetrically strong echo areas; in the sagittal section, there is an irregularly distributed strong echo area along the lateral ventricle, suggesting that there is softening of the white matter around the ventricle, often Coexisting with intraventricular hemorrhage.

3. EEG examination

Neonatal HIE EEG waveforms are characterized by low voltage, isopotential, and burst suppression waves. Mild abnormal EEG manifests as a D-wave with a background rhythm showing a continuous low voltage of 5 to 25 LV. There is no fast H-wave and A-wave superimposed on the D wave, which is common in normal term EEG. Moderate anomalies are high voltage waves that explode on the suppression background. The amplitude can be as high as 180 LV, and the suppression time lasts 2 to 4 seconds. In severe anomalies, the blast wave was reduced to about 50 LV, and the suppression time lasted for 20 to 97 seconds. The suppression background was an equipotential of 0 to 5 LV or a low voltage of 5 to 15 LV.

The abnormal degree of HIE EEG examination is basically consistent with the clinical division, so the EEG can be used to judge the severity of HIE within one week. When clinical symptoms are difficult to judge due to the influence of drugs or other pathological factors, EEG is more valuable for judging the severity and clinical division. EEG also has reference value for judging the prognosis. After two weeks of treatment, although the clinical symptoms have improved, but the EEG has not yet fully recovered, there are still isopotential, low voltage or burst suppression waves, suggesting that the function of cerebral nerve cells has not yet Complete recovery should continue treatment, otherwise it will affect the prognosis.

4. Determination of serum enzyme activity

Neonatal asphyxia can cause multiple organ damage, and a large number of enzymes escape from the injured cells to the blood. It is generally believed that the activities of CPK, LDH and AST in the serum of asphyxiated infants can only indicate the degree of asphyxia and cannot truly reflect the degree of damage to myocardial cells or brain cells. Foreign literature reports that the activity of CPK, LDH, and AST in serum has nothing to do with the severity of HIE and cannot be used as a basis for diagnosis and clinical division, but it is related to the prognosis to a certain extent, that is, the serum enzyme activity of patients with poor prognosis is significantly more significant than that of patients with normal prognosis. Increase can be used as a basis for early prognosis. However, some scholars have reported that such as CPK activity> 2000U / L, LDH> 900U / L, AST> 150U / L, suggesting that the probability of poor prognosis is greater. The half-life of serum enzyme activity is short, reaching a peak within 24 hours, and blood should be collected within 1 day after birth to determine its activity. CPK's brain-type isoenzymes (CK-BB) are mainly present in neurons and astrocytes in the brain. They are released from the cells when the brain is injured, and they have a greater specificity. The measurement is helpful for the condition of HIE Severity judgment and early prognosis.

5. Cerebrospinal fluid examination

In order to reduce the disturbance to the child, cerebrospinal fluid examination should be avoided, and it should be done only when purulent meningitis needs to be ruled out. It is worth noting that normal neonatal cerebrospinal fluid may have a very small amount of red blood cells entering the cerebrospinal fluid, or the cerebrospinal fluid may be pale yellow due to jaundice. Does not indicate cranial bleeding.

Diagnosis of ischemic hypoxic encephalopathy

Clinical diagnosis basis: The clinical diagnosis basis of neonatal hypoxic-ischemic encephalopathy mainly depends on the obstetric history and neonatal neurological symptoms, as follows:

1. Have a clear history of abnormal obstetrics that can lead to intrauterine ischemia and hypoxia, such as umbilical cord around the neck, around the body, placenta previa or placental abruption, the mother has severe pregnancy-induced hypertension, and prolonged labor.

2. Severe intrauterine distress, such as significantly reduced fetal movement, slowed fetal heart rate <120 beats / min, meconium-contaminated amniotic fluid was ° turbid.

3. Severe asphyxia at birth, Apgar score 1 minute <3, 5 minutes <5; or pale asphyxia, spontaneous breathing after rescue for 10 minutes; or positive oxygen pressure with tracheal intubation, artificial ventilation for more than 2 minutes.

4. Shortly after birth (within 12 hours), the following abnormal neurological symptoms appear: disturbance of consciousness, such as excessive excitement (irritability, limb tremor, increased spontaneous movements, long eye opening time, gaze, etc.), lethargy (three times playing with the soles of the feet) Crying), dullness (flicking the soles of the feet 5 times), or even coma; changes in limb muscle tension, such as increased tension, weakening, or even softness; abnormal primary reflexes, such as hug reflexes that are too active, weakened or disappeared, sucking reflexes weakened or disappear.

5. In severe cases, there may be convulsions or frequent seizures, and cardia tension increases due to cerebral edema.

6. In severe cases, symptoms of brain stem damage may occur, showing symptoms of central respiratory failure such as respiratory rhythm irregularity, slowed breathing, and apnea. Pupils shrink or expand, respond to light slowly or even disappear, and some children have nystagmus.

Treatment of ischemic hypoxic encephalopathy

There is no complete and unified treatment plan for HIE so far. After years of clinical practice, the treatment of HIE in China has indeed improved, and the prognosis of HIE has also improved to a certain extent. The treatment of HIE should be started as soon as possible. For some severely asphyxiated children, if there is excitement or drowsiness after resuscitation, the limb muscle tension and original reflex should be carefully checked for changes. If it is in line with the clinical diagnosis of HIE , You should start treatment immediately. Although hypoxic-ischemic brain injury occurs in the utero, it can continue to develop or even worsen after birth. Early treatment can prevent the neuron's hypoxic injury from continuing to increase and prevent reperfusion injury from further worsening the condition. The most fundamental measure in the treatment is to maintain the stability of the internal environment of the body, maintain the normal operation of the functions of various organs, and ensure that the damaged nerve cell metabolism is gradually restored. On this basis, various symptomatic treatments, treatments for reperfusion injury, and brain cell metabolism activators can fully play their role. The specific treatment is as follows.

Supportive therapy

Maintain blood gas and pH in the normal range: those with bruising and dyspnea who breathe oxygen, metabolic acidosis with sodium bicarbonate, and reported increases in blood flow up to about 20%. Maintain heart rate, blood pressure, blood sugar, etc. in the normal range.

2. Symptomatic treatment

Symptomatic treatment can prevent the pathophysiological changes that have been formed from further damaging damaged nerve cells, shorten the course of the neonatal period, and reduce the occurrence of sequelae. Treatment of convulsions, brain edema and brainstem symptoms should be active and timely, and once they occur, strive to control or eliminate them in the shortest time.

(1) Increased intracranial pressure HIE The increase in intracranial pressure can occur as early as 4 hours after birth, and is usually the most obvious on the second day. The amount of liquid should be properly restricted within 3 days after birth. Because of asphyxia, children have increased secretion of antidiuretic hormone and impaired renal function. Urine volume is usually low. The first day after birth has increased intracranial pressure. You can use furosemide, dexamethasone, intravenous injection, repeated application after 4 to 6 hours, and use of hormones 2 to 3 times will not inhibit the body's immune function. effect. The cranial pressure is still high after the second day. Mannitol can be injected intravenously, 2 to 3 times in a row, with an interval of 4 to 6 hours. Strive to reduce the cranial pressure significantly within 48 to 72 hours after birth, rarely after 72 hours. If the intracranial pressure increases slowly and does not decrease, CT or B-ultrasound should be performed to check whether there is a large area of hypoxic-ischemic damage to the brain parenchyma. The use of hypertonic drugs in the neonatal period should be cautious, and the dosage should be small each time to avoid excessive dehydration of the brain tissue and induce intracranial hemorrhage.

(2) Control of convulsions In children with HIE, convulsions often occur within 12 hours after birth. After excluding hypoglycemia and hypocalcemia, phenobarbital is preferred to control convulsions. This drug can reduce brain metabolic rate and make convulsions caused by HIE more likely. As appropriate. You can also add short-acting sedatives such as chloral hydrate anal injection; or intravenous injection of diazepam until clinical symptoms have improved significantly.

(3) Elimination of brainstem symptoms In children with severe HIE, coma is often caused, and brainstem symptoms do not recover, which prolongs the course of the disease, is prone to sequelae and is even life-threatening. In recent years, the levels of -endorphin in children with HIE have been significantly increased. -endorphin is an endogenous opioid, and damage to the central nervous system caused by any cause will lead to increased release, and can cause secondary damage to the central nervous system, causing psychiatric disorders and autonomic nervous disorders. And even long-term coma and death. Naloxone is a specific antagonist of opioid receptors, which can effectively block the disturbance of consciousness, respiratory depression and cardiovascular sympathetic function caused by endogenous opioids. Improved central respiratory failure, increased cardiac output, improved blood circulation throughout the body, and increased blood oxygen supply to the brain. Domestic scholars report that naloxone can significantly improve the cure rate and reduce the mortality rate in children with severe HIE, such as central respiratory failure, convulsions, and gastrointestinal disorders. This is of great significance for clinical rescue of children with severe HIE.

The indications for using naloxone are: children with severe HIE in deep coma. accompanied by obvious central respiratory failure such as respiratory rhythm irregularities, slowed breathing or apnea. There are symptoms of circulatory dysfunction such as low heart sound, slow heart rate, pale face, cold extremities, prolonged refilling time of skin capillaries, and so on. Frequent seizures. Have abdominal distension, vomiting, vomiting blood and other symptoms of gastrointestinal disorders. Among them, and are indispensable conditions, and can meet one of them.

3. Drug treatments such as brain cell metabolism activators

Such drugs include cerebrolysin, citicoline, and fructose 1,6-diphosphate, all of which were trial-produced in the 1970s and 1980s and used in clinical neurology. Its common feature is to promote the metabolic function of nerve cells through different pathways, prevent or reduce the damage caused by various pathological stimuli to nerve cells, and thus restore neural function. Glucocorticoids, as anti-inflammatory, anti-shock, and rescue medications for critically ill patients, have been in clinical use for many years, and their brain-protective effects have been controversial. Gangliosides are a class of sialic acid-containing glycosphingolipids, which are widely present in the cell membranes of various vertebrate tissues and are most abundant in nerve cells. Gangliosides can promote neural cell differentiation, neurite growth and synapse formation, and participate in the regulation of neural plasticity and functional recovery after brain injury. Therefore, gangliosides are considered to have neurotrophic and neuroprotective effects on the central and peripheral nervous system. Edaravone eliminates or reduces the generation of oxygen radicals, especially the superhydroxide ions, and reduces the lipid peroxidation reaction that lags behind the generation of oxygen radicals. Both of them work together to reduce the damage to nerve cells and thus the brain. Edema.

4. Hyperbaric oxygen therapy

Former Soviet scholars in the 1950s have reported satisfactory results with hyperbaric oxygen (HBO) in the treatment of neonatal asphyxia. Recently, a transparent oxygen chamber for infants has been developed in China, and the clinical application of neonatal hyperbaric oxygen therapy has been gradually developed, mainly for the treatment of HIE. According to domestic reports, the efficacy of hyperbaric oxygen in the treatment of HIE in the neonatal period is satisfactory, but the long-term follow-up results are lacking, and further studies on its long-term efficacy and possible side effects are needed in the future.

Mechanism of hyperbaric oxygen:

(1) Increase blood oxygen partial pressure, improve tissue oxygen supply, inhale pure oxygen at 2 atmospheres, the partial pressure of alveolar oxygen and the amount of physically dissolved oxygen in the blood, increase by more than 10 times compared with inhaled air at normal pressure, and significantly improve each Oxygen supply of organ tissues, thereby exerting a therapeutic effect on systemic and local hypoxic diseases.

(2) Improve brain cell metabolism and promote brain damage repair.

(3) The vasoconstriction and blood flow of the brain tissue in the normal part are reduced, which is conducive to the prevention and treatment of cerebral edema.

(4) Under 2 atmospheres of hyperbaric oxygen, the deformability of red blood cells can be increased, the ability of red blood cells to pass through capillaries is enhanced, and tissue oxygenation is enhanced.

Prognosis of ischemic hypoxic encephalopathy

Neonatal HIE can not only cause perinatal neonatal death, but also be one of the main causes of disability in children after neonatal period. Therefore, how to correctly determine the prognosis of children with HIE in the neonatal period is a concern of the majority of medical workers and their families. In recent years, domestic reports have reported that after treatment, the incidence of HIE sequelae is between 25% and 35%. If treatment continues to improve, the incidence of sequelae can still be reduced.