Hypoxic-ischaemic encephalopathy (HIE) is a serious neurological condition that is caused by inadequate cerebral oxygen supply (asphyxiation). It is commonly associated with perinatal asphyxia, but can also be caused by severe systemic hypoxia and cardiac arrest (in adults).
HIE is a major cause of morbidity in preterm infants and is the most common cause of neonatal seizures.
The term birth asphyxia or perinatal asphyxia is considered when infants with clinical features of HIE have:
- Evidence of severe hypoxia antenatally or during delivery
- Resuscitation was needed at birth
- Features of encephalopathy
- Evidence of hypoxic damage to organs, and
- No other prenatal or postnatal cause can be identified.
Types of asphyxial insults
| Type | Description | Causes |
|---|---|---|
| Acute total asphyxia | Sudden, complete interruption of placental blood flow, with no time for fetal compensation. This leads to severe hypoxic injury. | Placental abruption, uterine rupture, cord prolapse |
| Subacute (prolonged) asphyxia | Gradual reduction in oxygen delivery over time, with some degree of fetal compensation initially. This leads to moderate to severe hypoxic injury. | Prolonged labour, uteroplacental insufficiency |
| Chronic asphyxia | Long-standing reduced oxygen delivery during pregnancy. The fetus adjusts over time, leading to growth restriction and redistribution of blood flow (”brain-sparing”). This leads to increased perinatal morbidity and long-term effects. | Placental insufficiency, maternal hypertension, IUGR |
| Acute on chronic asphyxia | Chronic hypoxia with a superimposed acute event. The fetus is already compromised and has poor tolerance to the acute insult, leading to severe hypoxic injury. | Placental insufficiency and cord accident |
Clinical manifestation of HIE
| Category | Signs and symptoms |
|---|---|
| Cross-cutting symptoms | Poor feeding, irritability, crying, and lethargy |
| Mild encephalopathy | Increased muscle tone, brisk deep tendon reflexes |
| Moderate encephalopathy | Hypotonia, diminished deep tendon reflexes, diminished neonatal reflexes, seizures |
| Severe encephalopathy | Coma, hypotonia, diminished deep tendon reflexes, diminished neonatal reflexes, apnoea |
Complications of hypoxic insult immediately before or during birth
| Category | Complications |
|---|---|
| Central Nervous System (CNS) | Hypoxic-ischemic encephalopathy, seizures, hypotonia, hypertonia, altered level of consciousness, cerebral oedema, intraventricular hemorrhage, periventricular leukomalacia (especially in pre-term infants), cerebral palsy, intellectual disability, microcephaly |
| Cardiovascular | Persistent pulmonary hypertension of the newborn, myocardial dysfunction (ischemic cardiomyopathy), hypotension due to myocardial dysfunction, arrhythmia, heart failure |
| Respiratory system | Respiratory distress syndrome, meconium aspiration syndrome, pulmonary hemorrhage, persistent pulmonary hypertension |
| Renal system | Renal failure, acute kidney injury (pre-renal or intrinsic), oliguria or anuria |
| Metabolic | Metabolic acidosis, hyperkalemia, hypocalcemia, hypoglycaemia, |
| Gastrointestinal | Necrotizing enterocolitis, feeding intolerance, hepatic dysfunction (shock-liver) |
| Hematologic | Disseminated intravascular coagulation, thrombocytopaenia, polycythemia |
| Long-term | Cerebral palsy, epilepsy, cognitive deficits, blindness, and hearing impairment |
Scoring systems
| Scoring system | Description |
|---|---|
| Sarnat & Sarnat staging | An initial classification system, used to grade the severity of HIE into mild (grade I), moderate (grade II), and severe (grade III), based on clinical findings |
| Thompson score | A daily scoring system (0-22) is used to assess severity and monitor progression over time, particularly in low-resource settings. |
- Hypoxic events that may lead to neonatal encephalopathy
- Failure of gas exchange across the placenta
- Excessive or prolonged uterine contractions
- Placental abruption
- Uterine rupture
- Interruption of the umbilical blood flow
- Cord compression (including shoulder dystocia)
- Cord prolapse
- Inadequate maternal placental perfusion
- Maternal hypotension
- Hypertension and pre-eclampsia/eclampsia
- Fetal factors
- Intrauterine growth restriction
- Anaemia
- Infection
- Failure of cardiorespiratory adaptation at birth (failure to breathe)
- Failure of gas exchange across the placenta
- Pathophysiology of HIE
- Neonates lack extensive autoregulatory mechanisms of cerebral blood flow regulation (cerebral autoregulation). Cerebral autoregulation is present in adults, and this maintains cerebral blood flow (CBF) at a range of 60 – 100 mmHg.
- Hypoxia, hypotension, and metabolic disturbances affect brain oxygenation and require compensation of the cerebral vasculature to regulate perfusion
- Initially, during asphyxia, hypoxia, and hypercarbia lead to an increase in cerebral blood flow (CBF). This is accompanied by redistribution of blood flow to essential organs, including the heart, brain, and adrenal glands. Blood pressure also increases due to increased release of epinephrine, which further enhances this compensatory response.
- A sufficient disturbance overwhelms the ability to autoregulate in neonates, leading to ischemic injury. Brain perfusion begins to depend on systemic blood pressure, and as systemic blood pressure falls, the brain suffers further ischemic injury
- Primary energy failure (occurs in minutes): decreased oxygen and glucose disrupts oxidative phosphorylation in mitochondria. ATP production declines, leading to failure of ion pumps (Na+/K+ ATPase). Intracellular Na+ and Ca2+ accumulate, causing cytotoxic edema
- Excitotoxicity: excess glutamate release overactivates NMDA and AMPA receptors, causing increased Ca2+ influx that triggers an intracellular enzyme cascade (phospholipases, proteases, and endonucleases), which damages cellular structures
- Oxidative stress (perfusion-reperfusion injury): Delayed injury can occur. Reperfusion after ischemia generates reactive oxygen species and nitrogen species. Immature antioxidant defenses in neonates make them vulnerable to free radical damage.
- Inflammation and apoptosis: apoptotic pathways are activated by the release of TNF-a and IL-1β by microglia and astrocytes, and after mitochondrial damage (release of cytochrome c) and
- Secondary energy failure (occurs in hours to days): persistent mitochondrial dysfunction and ongoing excitotoxicity lead to further neuronal death. Blood-brain barrier dysfunction exacerbates edema and inflammation
- Tertiary phase (occurs weeks to months later): Chronic remodelling occurs in this stage. Ongoing gliosis, impaired neurogenesis, and white matter injury contribute to long-term neurological deficits.
- The subependymal germinal matrix is most susceptible to hypoxic injury. This region contains precursors to glial cells and is packed full of mitochondria (very oxygen dependent).
- Patient history
- Investigations
- Urea, electrolytes, and creatinine
- Blood glucose
- Liver function tests
- Cardiac enzymes
- Blood gas analysis for metabolic acidosis, hypercarbia, or hypoxaemia
- Coagulation studies
- Cranial ultrasound: This is the first-line imaging modality in neonates. It is used to detect intracranial hemorrhage and structural abnormalities.
- Diffusion weighted imaging (DWI): DWI MRI is the gold standard for diagnosing HIE. It is performed within 2 – 5 days post-injury to assess the extent of brain injury.
- Echocardiography
- MRI spectroscopy: this can be done earlier
- Treatment
- Treatment of hypotension by fluid resuscitation and vasopressors. Stabilise blood pressure and keep MAP >40 mmHg to prevent hypoperfusion
- Correction of hypoglycaemia and electrolyte imbalances, especially hypocalcemia
- Respiratory support
- Fluid restriction because of transient renal impairment (there may be acute kidney injury)
- EEG to monitor for asymptomatic seizures and appropriate treatment of seizures with anticonvulsants
- amplitude-integrated EEG (aEEG) for continuous bedside monitoring in the neonatal unit
- Therapeutic cooling: avoid hyperthermia (> 37.5 C) by cooling to a temperature of 33 °C to 34 °C for 72 hours using a cooling blanket to prevent secondary neuronal death from secondary energy failure
- Indicated for moderate to severe neonatal encephalopathy
- Therapeutic hypothermia should be started within 6 hours (before secondary energy failure) if all of the 5 are present
- Management of any concurrent complications
- Umbilical artery catheter placement (confirm placement with X-ray) for frequent blood gas analysis, blood tests, and continuous BP monitoring
- Routine lab investigations
- Indications for therapeutic hypothermia
- Prognosis
- Complete recovery can be expected if HIE is mild
- Neonates with moderate HIE who have recovered fully (clinically) and are feeding normally by 2 weeks have a good long-term prognosis
- Severe HIE has a mortality of 30 – 40%, and without therapeutic cooling, 80% have neurodevelopmental disabilities