Hypoxemic Ischemic Encephalopathy

1. Introduction and Definitions

Perinatal Asphyxia:

There is no single global definition. It is context-specific:

• WHO: "Failure to initiate and sustain breathing at birth."
• NNPD (India):
  • Moderate: Slow/gasping breathing or Apgar 4–6 at 1 min.
  • Severe: No breathing or Apgar 0–3 at 1 min.
• AAP & ACOG (Strict criteria for labeling asphyxia): Requires ALL four:
  1. Profound metabolic/mixed acidemia (pH < 7.0) in umbilical cord blood.
  2. Apgar score 0–3 for >5 minutes.
  3. Neonatal neurologic dysfunction (seizures, encephalopathy, tone issues).
  4. Systemic multi-organ dysfunction.

Hypoxic-Ischemic Encephalopathy (HIE):

A clinical syndrome of disturbed neurologic function in the earliest days of life in a term/near-term infant, manifested by difficulty initiating/maintaining respiration, depression of tone/reflexes, subnormal level of consciousness, and often seizures.

Incidence:

1.5 per 1,000 live births in developed countries; 10–15 times higher in low-to-middle-income countries (LMIC).

2. Etiology and Risk Factors

• Sentinel Events (Acute): Uterine rupture, placental abruption, cord prolapse, amniotic fluid embolism.
• Maternal Factors: Preeclampsia, diabetes, hypotension, severe anemia.
• Placental/Fetal Factors: Chorioamnionitis, IUGR, fetal anemia (feto-maternal hemorrhage).
• Postnatal: Failed resuscitation, severe respiratory failure, shock, congenital heart disease.

3. Pathophysiology

The injury occurs in a biphasic manner (the "Two-Hit" Hypothesis):

A. Primary Energy Failure (Acute Phase)

• Hypoxia/Ischemia $\to$ Anaerobic metabolism $\to$ Depletion of ATP.
• Failure of $N{a}^{+}/K^{+}$ pump $\to$ Influx of $N{a}^{+},C{a}^{2+},H_{2}O$.
• Result: Cytotoxic edema and acute necrosis.
• Release of excitatory neurotransmitters (Glutamate) $\to$ NMDA receptor overactivation $\to$ Excitotoxicity.

B. Latent Phase (1–6 Hours)

• Transient recovery of cerebral oxidative metabolism.
• Therapeutic Window: This is the critical period for initiating Therapeutic Hypothermia to prevent secondary injury.

C. Secondary Energy Failure (6–72 Hours)

• Mitochondrial failure, accumulation of free radicals (ROS), Nitric Oxide (NO) toxicity, and inflammation (cytokines).
• Result: Apoptosis (delayed neuronal death).
• Seizures often intensify during this phase.

D. Tertiary Phase (Months to Years)

• Persistent inflammation, impaired neurogenesis, and altered synaptogenesis.

4. Neuropathology Patterns

• Term Infants:
  • Acute Profound Asphyxia: Damages high-metabolic areas $\to$ Basal Ganglia, Thalamus, Brainstem (Deep Gray Matter injury). Associated with dyskinetic CP.
  • Partial Prolonged Asphyxia: Damages "Watershed" zones (parasagittal cortex). Associated with spastic quadriparesis and cognitive deficits.
• Preterm Infants: Periventricular Leukomalacia (PVL) affecting white matter.

5. Clinical Features and Staging

Diagnosis of HIE requires evidence of acute perinatal event, acidosis, and encephalopathy.

Clinical Staging (Sarnat & Sarnat / Modified Sarnat) #score

Levene Staging

Other Staging

• Thompson Staging

Systemic Effects (Multi-organ Dysfunction)

HIE is a systemic disease ("Asphyxia rarely spares the kidneys").

• Renal: Acute Tubular Necrosis (ATN), oliguria, hematuria.
• Cardiac: Myocardial dysfunction, hypotension, elevated Troponin, persistent pulmonary hypertension (PPHN).
• Hepatic: Elevated transaminases (AST/ALT), coagulopathy.
• Gastrointestinal: Necrotizing enterocolitis (NEC), feeding intolerance.
• Hematologic: DIC, thrombocytopenia.

6. Diagnosis and Investigations

A. Inclusion Criteria for HIE (AAP/ACOG) - All 4 should be met

1. Metabolic Acidosis: Cord or early (within 1 hr) arterial pH $<7.0$ or Base Deficit $\ge 12-16$ mmol/L.
2. Low APGAR: Score $\le 5$ at 10 minutes.
3. Resuscitation: Need for PPV/intubation at birth continued at 10 mins.
4. Encephalopathy: Presence of moderate/severe encephalopathy (Stage 2/3).

B. Neuroimaging

• Cranial Ultrasound:
  • Initial: To rule out hemorrhage (IVH, Subdural).
  • Doppler: Low Resistive Index (RI < 0.55) indicates luxury perfusion/vasoparalysis (poor prognosis).
• MRI Brain (Gold Standard):
  • Timing: Best performed between Day 5 and 10 of life.
  • DWI (Diffusion Weighted Imaging): Detects injury early (Day 1–4) as restricted diffusion (bright signal).
  • Patterns:
    • Basal Ganglia/Thalamus (BGT): Predicts motor outcome/CP.
    • Watershed (Cortical): Predicts cognitive outcome.
    • PLIC Sign: Loss of signal in Posterior Limb of Internal Capsule suggests poor prognosis.

C. Neurophysiology

• aEEG (Amplitude-integrated EEG):
  • Bedside tool for severity assessment and seizure monitoring.
  • Trace: Continuous (Normal), Discontinuous, Burst-Suppression, or Flat/Isoelectric.
  • Prognosis: Rapid recovery of background voltage (<24 hrs) is a good prognostic sign.
• Video EEG: Gold standard for seizure confirmation.

7. Management

Management focuses on Supportive Neurocritical Care and Neuroprotection.

A. Neurocritical Care (The "ABC" of HIE)

• Respiratory:
  • Maintain normal oxygenation ($Sp{O}_2$ 90–95%, $Pa{O}_2$ 50–80 mmHg). Avoid Hyperoxia.
  • Maintain Normocapnia ($PaC{O}_2$ 40–50 mmHg). Avoid Hypocarbia (causes cerebral vasoconstriction).
• Cardiovascular:
  • Maintain mean arterial pressure (MAP) in normal range.
  • Treat hypotension/shock judiciously (Volume $\to$ Dobutamine/Dopamine/Epinephrine). Functional Echo is useful.
• Metabolic:
  • Glucose: Maintain euglycemia (70–125 mg/dL). Treat hypoglycemia aggressively; avoid severe hyperglycemia.
  • Calcium/Electrolytes: Maintain normal $C{a}^{2+}$ and $M{g}^{2+}$.
• Fluids: Restrict fluid initially ($40-60$ mL/kg/day) due to risk of SIADH and ATN, monitor urine output.

B. Management of Seizures

• Treat clinical seizures or electrographic seizures detected on aEEG.
• First Line: Phenobarbitone (Loading: 20 mg/kg IV).
• Second Line: Levetiracetam (20–40 mg/kg), Fosphenytoin, or Midazolam.
• Goal: Cessation of clinical and electrographic seizures.

C. Therapeutic Hypothermia (Standard of Care)

The only proven therapy to reduce mortality and major neurodisability in moderate-severe HIE (NNT ~ 6-8).

• Eligibility Criteria (CoolCap/TOBY criteria adapted):
  1. Gestational Age: $\ge 36$ weeks (and birth weight $\ge 1800$g).
  2. Biochemical: pH $\le 7.0$ or Base Deficit $\ge 16$ (within 60 mins).
  3. Clinical: Moderate to Severe Encephalopathy (or seizures).
  4. Timing: Initiate within 6 hours of birth.
• Protocol:
  • Target Temperature: ${33.5}^{\circ }C$ (Rectal/Esophageal).
  • Duration: 72 hours.
  • Method: Servo-controlled whole-body cooling or head cooling. (Low-tech PCM mattresses like MiraCradle used in resource-limited settings).
• Rewarming: Slow rewarming at ${0.5}^{\circ }C$ per hour over 6–12 hours.
• Contraindications: Severe uncontrolled bleeding, major intracranial hemorrhage, moribund state.

8. Prognosis and Follow-up

• Mortality: 15–20% in moderate-severe cases.
• Morbidity: Cerebral Palsy (CP), intellectual disability, epilepsy, cortical visual impairment.
• Poor Prognostic Indicators:
  • Stage 3 (Severe) Sarnat encephalopathy.
  • Abnormal aEEG (Burst suppression/Flat) persisting > 48 hours.
  • MRI: Injury to Basal Ganglia/Thalamus or PLIC.
  • Refractory seizures.
• Follow-up:
  • Multidisciplinary (Neurology, PT/OT, Ophthalmology).
  • Developmental assessment (HINE, Bayley scales) at 18–24 months.

9. Recent Advances / Experimental Therapies

• Erythropoietin: Neurotrophic and anti-apoptotic.
• Xenon / Argon: NMDA antagonism.
• Stem Cells: Umbilical cord blood stem cells (autologous).
• Allopurinol: Xanthine oxidase inhibitor (free radical scavenger).
• Melatonin: Antioxidant.