Hypoxic ischemic encephalopathy (HIE)

HYPOXIC-ISCHEMIC ENCEPHALOPATHY

DR. ELFADIL EISA IDRIS SULIMAN

Introduction

Hypoxic-Ischemic Encephalopathy (HIE) refers to brain injury caused by inadequate oxygen (hypoxia) and/or blood flow (ischemia) to the brain, usually occurring around the time of birth (perinatal asphyxia).

It is a major cause of neonatal morbidity, mortality, and long-term neurological disability such as cerebral palsy.

• Incidence: Estimated at 1 - 8/1000 live birth in developed world and as 26/1000 in developing world.
• Mortality/Morbidity: Depending on the severity, about 20 - 30% of infants with HIE die in the neonatal period and 33 - 50% of survivors are left with permanent neurodevelopmental abnormalities eg. CP, cognitive impairment, decrease IQ and learning disability.

Etiology

HIE is usually caused by perinatal events (antenatal, natal or postnatal periods → perinatal asphyxia) that lead to neonatal asphyxia.

The average normal umbilical cord arteria blood gases:

• PH: 7.15 - 7.35
• PO₂: 16 mmHg
• PCO₂: 25 mmHg
• BE: -3
• Note: If PH < 7, BE > -16 → this indicates high risk of fetal compromise.

Maternal Causes of Fetal Hypoxia

1. Inadequate oxygenation of maternal blood: Anesthesia, Cyanotic heart disease, Respiratory disease.
2. Low maternal blood pressure: Acute blood loss, Spinal anesthesia, Compression of vena cava by the gravid uterus.
3. Prolonged uterine contraction: Use of excessive oxytocin.
4. Premature separation of the placenta.
5. Umbilical cord compression: (by knotting of the cord, prolapse or compression by the presenting part of the fetus).
6. Pain killer? (histotoxic anoxia?).
7. Placental insufficiency: from maternal infection, DM, ….etc.

Fetal Causes

• Anemia, hemolytic disease of the newborn (ABO or Rh incompatibility), fetofetal or fetomaternal transfusion.

Postnatal Causes

1. Cyanotic CHD: Severe pulmonary disease.
2. Severe anemia: severe hemorrhage, hemolytic disease.
3. Neonatal shock: severe sepsis, massive blood loss, Intracranial or adrenal hemorrhage.
4. Failure to breathe after birth: due to in utero CNS injury or drug induced suppression.

Pathophysiology

• Energy Failure: Hypoxia and /or reduced cerebral blood flow (ischemia) will lead to energy failure, so the brain depends heavily on anaerobic metabolism for ATP production.
• Cytotoxic Edema: After minutes to two hours ATP will drop leading to failure of ion pumps (Na⁺/K⁺-ATPase) which leads to sodium and water enter cells causing cytotoxic edema and mitochondrial damage → cell death.
• Affected Areas: mainly Basal ganglia z, thalamus z, hippocampus, brainstem, and cortical regions.

Clinical Features

HIE usually presents within the first 6 hours of life. Symptoms develop over days, making it important to perform several neurological examination.

History and Initial Signs

• Evidence of perinatal asphyxia: Low Apgar score (<5 at 5 minutes).
• Need for resuscitation.
• Meconium-stained liquor: (confirmed by testing umblical cord blood).
• Abnormal fetal heart tracing.
• Initial Signs: Pallor, cyanosis, apnea, a slow heart rate and unresponsiveness to stimulation (ie. very low apgar score). and initial signs of potential HIE

Progression of Symptoms

• Altered consciousness: (irritable → lethargic → comatose).
• Abnormal tone: (hypotonia or hypertonia; may change from hypotonic to hypertonic state or appear normal).
• Reflexes/Feeding: Poor feeding, weak cry, seizures (often within 24 hours), abnormal respiration and reflexes.
• Cerebral Edema: May develop during the next 24 hours and result in profound brain stem depression and severe seizure may occur.

Sarnat and Sarnat Staging

Severity depends on the severity of the insult (Mild/Stage 1, Moderate/Stage 2, or Severe/Stage 3).

Table 120.7: Hypoxic-Ischemic Encephalopathy in Term Infants

SIGNS	STAGE 1	STAGE 2	STAGE 3
Level of consciousness	Hyperalert	Lethargic	Stuporous, coma
Muscle tone	Normal	Hypotonic	Flaccid
Posture	Normal	Flexion	Decerebrate
Tendon reflexes/clonus	Hyperactive	Hyperactive	Absent
Myoclonus	Present	Present	Absent
Moro reflex	Strong	Weak	Absent
Pupils	Mydriasis	Miosis	Unequal, poor light reflex
Seizures	None	Common	Decerebration
EEG findings	Normal	Low voltage changing to seizure	Burst suppression to isoelectric
Duration	<24 hr if progresses	24 hr to 14 days	Days to weeks
Outcome	Good	Variable	Death, severe deficits

Adapted from Sarnat HB, Sarnat MS: Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study, Arch Neurol 33:696-705, 1976. Copyright 1976, American Medical Association.

Associated Systemic Organ Dysfunction

Seizures in asphyxiated newborns most often results of HIE but may also be caused by hemorrhage, ischemic stroke, hypoglycemia,

In addition to CNS dysfunction, ‘systemic organs dysfunction’ is noted in up to 80% of affected neonates eg:

• Cardiovascular: Myocardial dysfunction and cardiogenic shock.
• Respiratory: PPH, RDS.
• Gastrointestinal: Gastrointestinal perforation.
• Renal/Hepatic: Acute kidney and liver injury.

Diagnosis

Diagnosis is based on a combination of factors including history of perinatal asphyxia and neurologic symptoms within 24 hours.

Diagnostic Criteria

The diagnosis is based on a combination of factors including : History of perinatal asphyxia + neurologic symptoms within 24 hours

1. Apgar Score: Persistent low Apgar score of 0 - 3 for longer than 5 minutes.
2. Acidemia: Profound metabolic (↑lactate) and respiratory (or mixed) acidemia (PH < 7 or base deficit ≥ 12) in an umbilical artery blood sample.
3. Metabolic Imbalance: hypoglycemia, hypocalcemia.
4. Neonatal Neurological Sequelae: seizure, coma, hypotonia.
5. Multi-organ involvement: lungs, heart, kidneys, liver and GIT.

Investigations and Neuroimaging

• Cranial Ultrasound: Early screening.
• MRI (best): Detects early pattern and extent of brain injury, and has a high sensitivity and specificity.
• CT: Identify focal hemorrhage and basal ganglia damage.
• EEG/aEEG: is the most useful for seizure detection and prognosis.

Management

Management begins with the identification of perinatal patients at high risk for asphyxia, and optimal resuscitation in the delivery room.

General Supportive Measures (ABC)

• Airway/Breathing: Maintain airway, breathing, and circulation(ABC); ensure adequate tissue oxygenation.
• Metabolic Stability: Avoidance of hypoglycemia, hypocalcemia, and acidosis. Correct electrolyte imbalance.
• Environment: Optimal environmental temperature.
• Nutrition: Careful attention to nutrition.
• Other: Careful fluid management, Treatment of infection, and Correction of coagulation disturbances.

Seizure Management

Seizures in asphyxiated newborns most often results of HIE but may also be caused by hemorrhage, ischemic stroke, hypoglycemia, hypocalcemia, CNS infection and cerebral dysgenesis or genetic disorders.

• First-line: Phenobarbital.
• Second-line: Add phenytoin (or benzodiazepine) if needed.

Complication Management

• Fluid Restriction: (to prevent SIADH).
• Multi-organ support: Treat multi-organ dysfunction.

Therapeutic Hypothermia

Standard evidence‑based treatment to reduce neurological injury in moderate to severe HIE

• Indicated in moderate to severe HIE within 6 hours of birth
• Cooling to 33.5 °C for 72 hours
• Shown to reduce mortality and neurodisability

Therapeutic hypothermia

•  Is the only proven treatment for hypoxic‑ischemic encephalopathy.

•  Selective head or whole‑body cooling (to a core rectal or esophageal temperature of 33.5 °C within the first 6 hours after birth and maintained for 72 hours) will reduce mortality and major neurodevelopmental impairment at 18 months of age.

•  The therapeutic effect of hypothermia results from decreased secondary neuronal injury, achieved by:

  • Reducing rates of apoptosis (i.e., cell death produced by HIE).
  • Reducing production of neurotoxic mediators (e.g., extracellular glutamate, free radicals, nitric oxide, and lactate).
  • There is also benefit in seizure reduction.

Side Effects of Therapeutic Hypothermia:

• Bradycardia (HR of 80 - 100 b/m).
• Hypotension.
• Thrombocytopenia.
• Persistent pulmonary hypertension.
• Prolonged bleeding time.
• Subcutaneous fat necrosis.

Prognosis and Long-term Complications

Prognosis depends on the severity of HIE.

• Severe HIE: The mortality is about 25 - 50%. 100% of surviving infants develop minor to serious neurological complications.

• Moderate HIE: 40 - 70% will have mild to serious neurological complications.

• Mild HIE: Usually the infants tend to be free from serious CNS complications.

• Summary: Therapeutic hypothermia reduces adverse outcome in infant with HIE.

:Long-term Complications of HIE:

• Cerebral palsy
• Epilepsy
• Cognitive impairment
• Visual/hearing deficits
• Learning disabilities

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GOOD LUCK