Hypoxic-Ischemic Encephalopathy (HIE) Dezhi Mu MD/PhD Department of Pediatrics/Children’s Medical Center West China Second University Hospital, Sichuan University

Contents 1. Etiology 2. Pathophysiology 3. Clinical manifestations 4. Laboratory tests 5. Treatment

Definition HIE Incidence: 3~9 per 1000 live births Hypoxia: PaO2↓ + Ischemia: Blood flow↓

Etiology HIE 1. Maternal Causes 2. Placental / Unbilical Causes 3. Neonatal Causes

Etiology Maternal Causes 1. Reduced maternal oxygen delivery Anemia Cardiovascular disease Hypotension/hypertension 2. Reduced uterine blood flow Abnormal uterine contractions

Etiology Placental Causes 1. Early placental separation 2. Placental dysfunction Prematurity、Postmaturity Placentitis Placental edema Placenta Umbilical vein Umbilical arteries

Etiology Umbilical Causes Reduced umbilical blood flow Excessive length of umbilical cord Short of umbilical cord Knots of umbilical cord Placenta Umbilical vein umbilical cord Umbilical arteries

Etiology Neonatal Causes 1. Preterm、Low birth weight、SGA、LGA 2. Diseases Asphxia、Septicemia Pulmonary disease Congenital cardiovascular disease

Pathophysiology Hypoxemia Brain hypoxia and ischemia Reperfusion injury Depleting ATP: energy failure Secondary energy failure Primary cell death (necrotic) Secondary cell death (apoptotic) 6 h 6~24h HIE

Depending on HIE severity Clinical Manifestations Mild Depending on HIE severity Moderate Severe

Clinical Manifestations (CNS) Mild Moderate Severe Consciousness Hyperalert Lethargic Stupor Primary Reflexes Normal or No No Pupils Mydriasis Miosis Variable Muscle tone hypotonia Flaccid Seizures Common Yes EEG low-voltage Isopotential Time < 3 d < 14d weeks

Clinical Manifestations (CNS)

Accessory tests- laboratory test No specific test to confirm the diagnosis. Tests are performed to assess the injury and to monitor functional status of the organs.

Accessory tests Electroencephalogram (EEG) 1. Assess the severity of the injury 2. Evaluate for subclinical seizures 3. A suppressed or seizure activity of EEG A poor prognosis

Accessory tests Cranial Computed tomograph scan 1、Cerebral edema 2、Hemorrhage Potentially harmful radiation

Accessory tests CT: Cerebral edema Normal Cerebral edema

Accessory tests CT Normal Hemorrhage

Accessory tests Brain MRI 1、Accurately demonstrate the injury pattern as area of hyperintensity 2、Diagnosis and follow-up of infants with moderate-to-severe HIE

Accessory tests MRI: Cerebral edema Normal Cerebral edema

Accessory tests Hypoperfusion injury；signal intensity Normal

Treatments Supportive treatment Specific treatment: N/A Recovery treatment

Treatments Management aims at: 1. Early identification 2. To maintain adequate perfusion 3. To stop the processes of ongoing injury

Treatments Therapeutic Window 1. Clinic: No direct evidence 2. Studies: Animal models 3. When: 6h

Treatments Supportive treatments 1. Adequate ventilation 2. Adequate perfusion 3. Adequate Glucose

Treatments Adequate ventilation 80mmHg<PaO2<100mmHg 20mmHg<PaCO2<40mmHg pH: 7.35~7.45

Treatments Supportive care 1. Adequate ventilation 2. Adequate perfusion 3. Adequate Glucose

Treatments Adequate perfusion Peripheral perfusion Blood pressure: 70/50 mmHg Echocardiography (ECHO) Fluids: 60~80 mL/kg .d Dopamine: 2.5～5μg/kg. min

Treatments Supportive care 1. Adequate ventilation 2. Adequate perfusion 3. Adequate glucose

Treatments Aim: Avoidance of hypoglycemia/hyperglycemia Maintain the glucose: 40~90mg/dl Maintain the normal electrolytes

Treatments Symptomatic treatment 1. Treatment of seizures 2. Treatment of intracranial pressure

Treatments Neonatal seizures 1. HIE is the most common cause of seizures 2. About 30% of HIE at the first 24 hours 3. Increase the risk of additional injury

Treatments Treatment of seizures Drug: Phenobarbitone (first line treatment) 20 mg/kg, intravenously repeated once as needed daily dosing 5 mg/kg/day (target level 40–60 g/mL)

Treatments Symptomatic treatment 1. Treatment of seizures 2. Treatment of intracranial pressure

Treatments Treatment of intracranial pressure Fluids: 60~80 mL/kg .d Furosemide ？ Mannitol ？

Treatments Current potential treatment Hypothermia

Treatments Hypothermia is used for the following: ≥ 35 weeks gestational age ≥ 1800g moderate to severe encephalopathy intrapartum hypoxia indicated as following: (1) Apgar score ≤ 5 at 10 minutes (2) blood gas with pH ≤ 7.00

Treatments Optimal timing of initiation Within 6 hours, the earlier the better Temperature 3~4℃ below baseline temperature, 33.0~34.0℃ Optimal duration 72h, the greater severity, the longer Methods Selective head / Whole body cooling

Prognosis Death: 15~20% in neonatal period Neurodevelopmental abnormalities: 25~30% survivors Mild: recover completely Moderate: about 20% neurological complications Severe: most die or severe brain injury

Case discussion Male infant, 30 minutes. Complaint: Poor response after resuscitation for 30 minutes, convulsed once. History: Born by emergency CS for suspected fetal distress. Apgar score: 0, 0, 2 at 1, 5, 10minutes. Meconium-staining of amniotic fluid. 4 pregnancies, 2 term infants, 0 premature, 1 abortion, and 2 living children

To be continued No breath and heart beat at birth, intubated in the delivery room. Hypotonia and pale skin were noted. Face-masked pressure respiration, chest compression and epinephrine were used. 10 minutes after resuscitation, his eyes starred for about 1 minute.

To be continued PE: Poor response, cyanotic lips. Normal anterior fontanelle tension. Muscular tension was low. Primary reflections could not be elicited.

To be continued Investigation: Chest X-ray: neonate pneumonia. Blood gas analysis: pH 6.948，SaO2 82%， HCO3- 11mmol/L. Liver and kidney function, blood electrolytes, Blood-Rt, CRP: normality partial pressure of carbon dioxide, partial pressure of oxygen, Arterial Oxygen Saturation, bicarbonate radical, base excess

Case discussion continued Question: 1. What is the diagnosis? 2. What is the investigation? 3. What is the treatment?

Case discussion continued Diagnosis: 1. Hypoxic ischemic encephalopathy (severe) 2. Neonatal asphyxia (severe)

Case discussion continued Investigation: 1. Brain CT and MRI: decreased density of intracranial cerebral white matter; the left frontal top soft tissue swelling. 2. EEG: abnormal, a spike or wide sharp wave repeatedly issuing.

Case discussion continued Treatment: 1. supportive treatment. 2. hypothermia 3. rehabilitation

Thank you! mudz@scu.edu.cn 028-85501313(O)