bubble_chart Overview

HIE is a brain lesion in perinatal newborns caused by hypoxia, primarily due to intrauterine distress or neonatal asphyxia, and a few cases may result from other causes of brain damage. It mostly occurs in full-term infants with asphyxia but can also happen in premature infants.

bubble_chart Pathogenesis

Not yet fully understood, requiring further research.

1. Decreased cerebral blood flow regulation function  In normal newborns, cerebral blood vessels regulate the blood flow entering brain tissue through dilation and contraction. When blood flow decreases, the blood vessels dilate, and when blood flow increases, they constrict, maintaining a relatively stable flow into the brain tissue. During hypoxia-ischemia, blood pressure fluctuates significantly, and blood flow changes frequently, but the regulatory function of cerebral blood vessels is already diminished. When blood pressure drops and blood flow decreases, the blood vessels fail to dilate promptly, leading to hypoperfusion in the brain. Conversely, when blood pressure rises and blood flow increases, the blood vessels fail to constrict in time, resulting in hyperperfusion. During this transition, cerebral edema and intracranial hemorrhage are most likely to occur. Moreover, hypoperfusion itself can also lead to hypoxic-ischemic encephalopathy.

2. Abnormal brain tissue metabolism  Among all organs and tissues in the human body, the brain requires the highest amounts of oxygen and glucose for metabolism. During hypoxia-ischemia, insufficient energy supply has the greatest impact on brain tissue metabolism, manifesting as: ① Oxygen free radicals (O₂^-) cause peroxidation of cell membranes, leading to damage. When capillary wall cells are damaged, permeability increases, causing cerebral edema. ② Calcium ion channels on cell membranes open, allowing extracellular Ca⁺⁺

to flow into cells, disrupting cell survival. ③ Increased enkephalins in brain tissue directly suppress respiration, exacerbating hypoxia. ④ Metabolic and respiratory acidosis occur during hypoxia-ischemia. These metabolic abnormalities in brain tissue lead to softening, necrosis, hemorrhage, and cavity formation.

3. Vulnerable areas of the brain to hypoxia-ischemia  ① The maturity of brain regions varies with gestational age in fetuses and newborns, leading to differing susceptibility to hypoxia-ischemia. Areas rich in cells, blood vessels, and with high metabolic rates require more oxygen and are most sensitive to hypoxia-ischemia. In premature infants, the vulnerable area is the germinal matrix beneath the ventricular membrane, as this region is most metabolically active at around 28±a cycle of day and night in fetal development. Additionally, capillaries in this area lack connective tissue support, making them prone to hemorrhage. By 32–34 weeks of gestation, the active cells in the germinal matrix gradually migrate to the cerebral cortex, leaving the germinal layer replaced by white matter. However, due to its location in the watershed zone, blood supply remains insufficient, making it still susceptible to hypoxia-ischemia. In full-term infants, the cerebral cortex becomes the vulnerable area due to the migration of active cells. ② The watershed zones, characterized by low blood supply and low blood pressure, are prone to hypoxia-ischemia. In full-term infants, the parietal-temporal region, where the anterior, middle, and posterior cerebral artery watersheds converge, is most susceptible to lesions. In premature infants, the periventricular white matter, also a watershed zone, is prone to tissue softening.

bubble_chart Pathological Changes

After hypoxia-ischemia, the brain initially presents with edema, softening, hemorrhage, and necrosis, followed by the formation of cavities. Hemorrhage may occur in the ventricles, subarachnoid membrane, or subdural membrane. In prolonged cases, the brain may atrophy.

1. Cerebral lesions: In full-term infants, lesions are mostly in the cerebral cortex, with hemorrhage and necrosis in addition to edema. The formation of small cystic cavities is termed multicystic encephalomalacia (spelencephaly), while larger cavities are referred to as porencephaly.

2. Intracranial hemorrhage: In premature infants, hemorrhage often occurs in the subependymal membrane and intraventricular regions, whereas in full-term infants, it is more common in the cerebral parenchyma (IPH). Other types, such as subdural hemorrhage (SDH) and subarachnoid hemorrhage (SAH), can occur in both full-term and premature infants.

3. Brainstem lesions: Lesions may involve the brainstem nuclei or white matter. The brainstem can also exhibit secondary atrophy due to cortical lesions.

Hypoxic-ischemic encephalopathy is often caused by asphyxia in full-term infants. The more severe and prolonged the asphyxia, the more severe the encephalopathy and the higher the incidence of sequelae. This condition can also occur in premature infants, manifesting as periventricular leukomalacia (PVL).

bubble_chart Clinical Manifestations

There may be a history suggestive of intrauterine distress before birth. During childbirth, the fetal heart rate may increase or decrease, or the second stage of labor may be prolonged, with meconium-stained amniotic fluid. There may be a history of asphyxia at birth, and after resuscitation, changes in consciousness, muscle tone, respiratory rhythm, reflexes, and even convulsions may persist. The condition can be classified into grade III:

Grade I manifests as hyperexcitability, irritability, possible limb tremors, normal or increased muscle tone, slightly active Moro reflex and sucking reflex, generally no convulsions, regular breathing, and no changes in pupils. Symptoms improve within one day, with a good prognosis.

Grade II presents with drowsiness, sluggish responses, decreased muscle tone, weakened Moro reflex and sucking reflex, frequent convulsions, possibly irregular breathing, and possibly constricted pupils. Symptoms become pronounced within three days and typically resolve within about a week. Survivors may have sequelae.

Severe cases involve unconsciousness, flaccid muscle tone, absent Moro reflex and sucking reflex, recurrent convulsions, irregular breathing, asymmetrical pupils, and absent light reflex. The mortality rate is high, with most deaths occurring within one episode. Survivors may experience symptoms lasting several weeks, with sequelae.

Common sequelae include cerebral palsy, hydrocephalus, intellectual disability, epilepsy, etc. For example, periventricular leukomalacia may result in motor impairments.

bubble_chart Diagnosis

1. Imaging Diagnosis has improved the accuracy of diagnosis.

(1) Cranial B-mode ultrasound (B-ultrasound) examination: Using the infant's anterior fontanelle as the window, coronal and sagittal sector ultrasound scans are performed. It can be performed bedside, has no radiation exposure, and allows for multiple follow-up examinations, offering many advantages. It clearly shows brain edema, parenchymal lesions, and ventricular enlargement.

(2) Cranial computed tomography (CT) examination: Multi-level horizontal cross-sectional imaging of the head is performed. CT provides clearer visualization of small subdural hemorrhages and subarachnoid hemorrhages compared to B-ultrasound, making CT and B-ultrasound complementary in improving diagnostic accuracy.

2. Electroencephalogram (EEG) and Brain Electrical Activity Mapping (BEAM) Examination EEG may show abnormal spike waves, while BEAM can detect decreased power or misalignment.

3. Cerebrospinal Fluid (CSF) Examination To minimize disturbance to the child, CSF examination should be avoided unless necessary to rule out purulent meningitis. It is noteworthy that normal neonatal CSF may contain very few red blood cells or appear slightly yellowish due to jaundice, which does not indicate intracranial hemorrhage.

bubble_chart Treatment Measures

Prevention is better than cure. Once fetal distress is detected, immediately provide oxygen to the mother and prepare for neonatal resuscitation and oxygen supply. After birth, place the infant in a supine position with the head slightly elevated and minimize disturbances.

1. Oxygen therapy: Choose appropriate oxygen delivery methods based on the condition, maintaining PaO₂ above 6.6–9.31 kPa (50–70 mmHg) and PaCO₂ below 5.32 kPa (40 mmHg). However, avoid excessively low PaCO₂ to prevent reduced cerebral blood flow.

2. Maintain normal blood pressure and avoid significant fluctuations to ensure stable cerebral blood perfusion. For hypotension, use dopamine (3–μg/kg/min continuous IV infusion) and dobutamine (3–10 μg/kg/min continuous IV infusion), while monitoring blood pressure.

3. Correct metabolic disorders: Mild acidosis and respiratory acidosis can be corrected by improving ventilation. Sodium bicarbonate is only used for moderate to severe (grade III) metabolic acidosis, with the dose kept moderate to maintain blood pH at 7.3–7.4. For hypoglycemia, administer 10% glucose intravenously, starting with an initial dose of 2 ml/kg, followed by 5 ml/kg/h, to maintain blood glucose at 2.80–5.04 mmol/L (50–90 mg/dl). Due to increased encephalins after asphyxia, some clinicians trial naloxone (5–10 μg/kg/h IV infusion, up to a total of 0.1 mg/kg/d) to counteract encephalins.

4. Control seizures: Use phenobarbital with a loading dose of 15–20 mg/kg IV, followed by a maintenance dose of 3–5 mg/kg/d after 12 hours.

5. Manage cerebral edema: Restrict fluid intake to 60–80 ml/kg/d. Mannitol can be used as a dehydrating agent (0.5–0.75 g/kg every 4–6 hours), but avoid excessive use. While dehydrating agents can reduce cerebral edema, they do not mitigate brain injury.

Hypoxic-ischemic intracranial hemorrhage

Hypoxic-ischemic intracranial hemorrhage is more common in premature infants, with incidence increasing with lower gestational age. The most frequent site of hemorrhage is the subependymal region of the caudate nucleus, which often ruptures into the adjacent lateral ventricle, resulting in subependymal-intraventricular hemorrhage (SEH-IVH).

bubble_chart Prognosis

Especially in severe asphyxia, 60-80% develop HIE. While grade I cases have a good prognosis, severe cases may result in early neonatal death or irreversible brain damage, including intellectual disability, cerebral palsy, epilepsy, and ataxia.