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

Domain	Stage I – Mild	Stage II – Moderate	Stage III – Severe
Spontaneous activity	Normal or increased	Decreased	Absent
Level of consciousness (Alertness)	Hyperalert, irritable	Lethargic, obtunded	Stupor / coma
Primitive reflexes
– Suck	Strong	Weak	Absent
– Moro	Exaggerated	Incomplete	Absent
Posture	Normal	Distal flexion	Decerebrate / flaccid
Autonomic nervous system
– Pupils	Mydriasis	Miosis	Unequal / fixed / dilated
– Heart rate	Tachycardia	Bradycardia	Variable
– Respiration	Normal	Periodic breathing	Apnea
Muscle tone	Normal or ↑	Hypotonia	Flaccid
Seizures	Absent	Common	Rare / late
EEG	Normal	Low voltage, periodic	Burst suppression / isoelectric
Duration	< 24 h	2–14 days	Hours–weeks
Prognosis	Excellent	Variable	Poor

6 Important Domains of SARNAT staging - Mnemonic

S - Spontaneous Activity A - Alertness (Consciousness) R - Reflexes (Moro ,Suck) N - Normal/Abnormal Posture A - Autonomous Nervous System T - Tone

Seizure and EEG are supportive Finding

Levene Staging

Feature	Mild (Grade I)	Moderate (Grade II)	Severe (Grade III)
Feeding	Poor suck	Unable to suck (requires tube feeding)	Unable to suck
Alertness/ Consciousness	Irritable / Hyper-alert	Lethargic	Comatose
Convulsions (Seizures)	No	Yes	Prolonged or intractable
Tone	Mild hypotonia (floppy)	Marked hypotonia	Severe hypotonia / Flaccid
Respiration	Normal	Spontaneous respiration present	Failure to maintain spontaneous respiration (requires ventilation)

Mnemonic

F — Feeding (Sucking ability) A — Alertness (Level of Consciousness) C — Convulsions (Seizures) T — Tone (Muscle tone) S — Spontaneous Respiration (Breathing effort)

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

If all 4 criteria are not met it is called Perinatal Depression

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.

HELIX trail

Recent HELIX trial suggests caution/potential lack of benefit in LMIC settings where “passive cooling” or lack of tertiary support may exist, or where insult is primarily antenatal.

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.