bubble_chart Overview

Neonatal hypoxic-ischemic encephalopathy (HIE) is a brain lesion in perinatal newborns caused by hypoxia, primarily resulting from intrauterine distress or neonatal asphyxia and hypoxia, with a few cases occurring due to brain damage from other causes. It mostly occurs in full-term infants with asphyxia but can also occur in premature infants.

bubble_chart Pathogenesis

The pathogenesis of the disease is not yet fully understood and requires further research.

1. Decreased cerebral blood flow regulation: In normal newborns, cerebral blood vessels regulate blood flow into brain tissue through dilation and contraction. When blood flow decreases, the blood vessels dilate, and when blood flow increases, they constrict, maintaining relatively stable blood 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 impaired. When blood pressure drops and blood flow decreases, the blood vessels fail to dilate promptly, leading to hypoperfusion. 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 human organs, 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, damaging them. When capillary wall cells are damaged, permeability increases, leading to 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 result in softening, necrosis, hemorrhage, and cavity formation.
3. Brain regions vulnerable to hypoxia-ischemia: (1) The maturity of brain regions varies with gestational age in fetuses and newborns, leading to different susceptibilities 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 preterm infants, the vulnerable area is the germinal matrix beneath the ventricular membrane, as this region is most metabolically active around 28±a cycle of day and night in the fetus. Additionally, the 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 stirred pulse end-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 marginal zones of stirred pulse, with their limited blood supply and low blood pressure, are prone to hypoxia-ischemia. In full-term infants, the parietotemporal region, where the anterior, middle, and posterior stirred pulse end-zones intersect, is most susceptible to lesions. In preterm infants, the periventricular white matter, also part of the stirred pulse end-zone, is prone to tissue softening.

bubble_chart Pathological Changes

After hypoxia-ischemia, the brain initially develops edema, softening, hemorrhage, and necrosis, followed by the formation of cavities. Hemorrhage may occur in the ventricles, subarachnoid space, or subdural space. 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. If small cystic cavities form, it is termed **multicystic encephalomalacia (spelencephaly)**; if large cavities form, it is called **porencephaly**.
2. **Intracranial Hemorrhage** In premature infants, bleeding often occurs in the subependymal region and ventricles, while 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 affect the brainstem nuclei or white matter. The brainstem can also undergo secondary atrophy due to cortical damage.

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

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, and reflexes may persist, even leading to convulsions. Based on the severity, it can be divided into grade III:

1. Grade I: Manifested 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.
2. Grade II: The infant exhibits 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 usually resolve within about a week. Survivors may have sequelae.
3. Severe cases: The infant is unconscious, with 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 have 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: Improved diagnostic accuracy.
   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 effects, and allows for multiple follow-up examinations, offering many advantages. It clearly shows cerebral edema, parenchymal lesions, and ventricular enlargement.
   2. Cranial Computed Tomography (CT) Scan: Multi-level horizontal cross-sectional imaging of the head is performed. It provides clearer visualization of small subdural hemorrhages and subarachnoid hemorrhages compared to B-ultrasound. Therefore, complementary use of CT and B-ultrasound can further enhance diagnostic accuracy.
2. Electroencephalogram (EEG) and Brain Electrical Activity Mapping (BEAM) Examination: The EEG may show abnormal spike waves, and the BEAM may reveal decreased power or misalignment.
3. Cerebrospinal Fluid (CSF) Examination: To minimize disturbance to the infant, 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 pale yellow 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: Select 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 disturbances: 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 doses 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 encephalopathy post-asphyxia, some practitioners trial naloxone (5–10 μg/kg/h IV infusion) up to a total dose of 0.1 mg/kg/d to counteract encephalopathy.
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 those with grade I have a good prognosis, severe cases may result in early neonatal death or irreversible brain damage, including intellectual disability, cerebral palsy, epilepsy, and ataxia.