bubble_chart Overview

Neonatal hypoxic-ischemic encephalopathy (HIE) refers to a disease characterized by central nervous system abnormalities caused by hypoxic-ischemic damage to the neonatal brain due to perinatal asphyxia.

bubble_chart Etiology

disease cause

Perinatal asphyxia mainly occurs before or during delivery, with a few cases occurring postpartum. Severe maternal conditions such as cardiopulmonary diseases, pregnancy-induced hypertension syndrome, severe anemia, massive hemorrhage, and shock, as well as abnormalities in the placenta or umbilical cord like placenta previa, placental abruption, cord around the neck, prolonged labor, precipitous labor, and abnormal fetal positions leading to difficult delivery can all result in reduced blood oxygen levels in the fetus and newborn. Additionally, conditions that cause ischemic-hypoxic damage to the central nervous system include recurrent apnea, hyaline membrane disease, meconium aspiration, grade III heart failure, and peripheral circulatory failure.

pathogenesis and pathology

During hypoxia, blood flow is redistributed throughout the body, increasing to the heart, brain, and adrenal glands while decreasing to the lungs, kidneys, and gastrointestinal tract. If hypoxia persists, oxidative metabolism in brain neurons is impaired, the sodium pump in brain capillary endothelial cells malfunctions, vascular permeability increases, and intravascular fluid can shift to the extravascular space. Due to impaired vascular autoregulation, systemic blood pressure drops, leading to insufficient cerebral blood flow and exacerbating brain hypoxia. Swelling and degeneration of vascular endothelial cells narrow or even occlude the lumen, causing cerebral ischemia. Neuronal hypoxia increases glycolysis, depleting energy and leading to metabolic dysfunction, degeneration, and necrosis of brain cells. The loss of vascular support around necrotic brain tissue causes vascular dilation and post-necrotic hemorrhage. Cerebral edema, fluid shifts from intravascular to extravascular spaces, and intracranial hemorrhage elevate intracranial pressure.

The primary impact of neonatal asphyxia on the body occurs not during the ischemic phase but after ischemia-reperfusion. Brain cell injury occurs during the hypoperfusion and reperfusion phases of hypoxia-ischemia, making reperfusion injury a critical factor in the pathogenesis of hypoxic-ischemic damage.
Role of oxygen free radicals: During hypoxia, the massive production of oxygen free radicals can lead to cell membrane lysis, disruption of the blood-brain barrier, and cerebral edema formation, exacerbating brain damage.
Calcium imbalance: Due to calcium pump failure, the ion gradient across cell membranes rises, causing excessive calcium influx and opening of calcium channels. This results in secondary membrane injury and energy depletion, further damaging brain cell structure.
The pathological changes in hypoxic-ischemic encephalopathy primarily include cerebral edema, brain tissue necrosis, and intracranial hemorrhage. In severely asphyxiated full-term infants, brain lesions mainly involve cortical necrosis, particularly in the sulci. In severe cases, cortical atrophy, glial cell proliferation, and demyelination occur, potentially progressing to injury in the basal ganglia and brainstem nuclei. Common hemorrhage sites include the brain parenchyma and subarachnoid space. Advanced stages often lead to scarred gyri and marbled striatal changes in the basal ganglia. Premature infants are prone to subependymal and intraventricular hemorrhage, as well as periventricular leukomalacia. Advanced stages may result in cavitation and hydrocephalus.

bubble_chart Clinical Manifestations

After asphyxia, if abnormal neurological symptoms such as impaired consciousness, changes in muscle tone, and abnormal Moro and sucking reflexes occur, a clinical diagnosis can be made. Based on the condition, it is classified into mild, moderate, and severe grade III.

1. Grade I is characterized by no obvious impairment of consciousness, only manifesting as excessive excitability such as irritability, hyperresponsiveness to stimuli, tremors in limbs and jaw, and an active Moro reflex, with ankle clonus elicitable. Symptoms are most pronounced within 24 hours and gradually diminish thereafter. Muscle tone is normal, there are no convulsions, the anterior fontanel is not tense, and there are no severe neurological sequelae.
2. Grade II involves impaired consciousness, often starting as drowsiness and progressing to lethargy, with reduced spontaneous activity, weakened muscle tone and strength, diminished or absent Moro and sucking reflexes. Half of the cases experience convulsions, and sustained ankle clonus can be elicited. Most cases show improvement in consciousness within 48–72 hours, with gradual recovery of muscle tone and reflexes. If consciousness worsens, convulsions become frequent, or no improvement is seen within a week, the prognosis is poor.
3. Grade III presents with unconsciousness from birth, frequent convulsions beginning mostly within 12 hours, and loss of spontaneous movement. When brainstem dysfunction occurs, the pupillary light reflex disappears. The fontanel bulges, and the condition often deteriorates within 72 hours, with death occurring within a week. Survivors may remain in a shallow unconscious state for weeks, and most will have severe neurological sequelae.

﹝Auxiliary Examinations﹞

1. In EEG, most grade III infants show widespread abnormalities, with waveforms improving as symptoms alleviate.
2. Cranial ultrasound revealing narrowed or vanished ventricles and shallow sulci suggests cerebral edema; periventricular hyperechoic areas indicate periventricular leukomalacia; focal or widespread cerebral ischemia or edema may present as localized or scattered hyperechoic areas.
3. CT findings of post-asphyxial brain injury can be divided into four grades: (1) normal density in all brain regions; (2) localized low density in 1–2 regions; (3) localized low density in more than 2 regions; (4) generalized low density throughout the brain, loss of gray-white matter differentiation, and narrowed lateral ventricles.
4. Serum enzyme tests show elevated activity of brain-type creatine phosphokinase isoenzyme.

bubble_chart Diagnosis

A full-term infant with a history of perinatal asphyxia who develops impaired consciousness, altered muscle tone, and abnormal primitive reflexes within 2 days after birth should be considered for this condition. Enzyme activity assays, cranial ultrasound, and CT scans aid in diagnosis and differential diagnosis, and are also valuable for prognosis estimation.

bubble_chart Treatment Measures

﹝Treatment﹞

1. Ensure oxygen supply and blood perfusion to the brain, enhance monitoring, correct hypoxia and hypercapnia, and provide artificial ventilation if necessary; for metabolic acidosis, correct with sodium bicarbonate; maintain heart rate above 100 beats per minute, systolic blood pressure at 6.67 kPa (50 mmHg), and blood pH above 7.20.
2. Control fluid intake to 60–80 ml/kg·d within 3 days, strictly regulate infusion speed, and maintain blood glucose at 2.78–5.58 mmol/L (50–100 mg/dL).
3. For convulsions, phenobarbital is the first choice, with a loading dose of 20 mg/kg and a maintenance dose of 3–5 mg/kg·d, administered intravenously or intramuscularly. If phenobarbital fails to control convulsions, diazepam or chloral hydrate may be added.
4. For brain edema treatment, administer dexamethasone, furosemide, and mannitol intravenously every 4–6 hours.
5. For brain cell metabolism activators, administer cytochrome C, adenosine triphosphate, and coenzyme A intravenously once daily; citicoline 100–125 mg/d may also be given intravenously concurrently.
6. Antioxidants such as vitamin C and E may be used.
7. Hyperbaric oxygen therapy, if conditions permit, once daily for one week as a treatment course.

bubble_chart Prognosis

The disease may leave permanent neurological sequelae. The following conditions may lead to sequelae: (1) Grade III encephalopathy. (2) Grade III asphyxia with resuscitation lasting over 20 minutes. (3) Recurrent apnea within 1 week. (4) Persistent neurological symptoms after 1 week, including inability to suckle. (5) Abnormal EEG findings after 2 weeks. (6) Significantly elevated serum enzyme activity. (7) Grade III–IV intraventricular hemorrhage. (8) Large areas of hypoxic-ischemic changes in the brain parenchyma, with brain atrophy appearing after 1 week.

bubble_chart Prevention

Preventing asphyxia is the fundamental measure to avoid the occurrence of this disease. Proper management of difficult delivery is essential; fetal distress should be promptly addressed by administering oxygen to the mother and intravenous glucose infusion, and pregnancy should be terminated at the appropriate time. Newborns with asphyxia should be resuscitated as quickly as possible and closely monitored to prevent prolonged hypoxia from causing injury to brain tissue, while also maintaining cardiac and renal function.