Hypoxic ischemic encephalopathy (HIE) is a brain injury caused by impaired oxygen delivery to the brain before, during or after birth. It affects 2-3% of live births globally and can result in death or disabilities like cerebral palsy. The primary injury is due to energy failure in neurons from lack of oxygen and glucose, leading to cell death. Secondary energy failure occurs later from oxidative stress and inflammation, worsening the injury. Clinical presentation ranges from mild abnormalities to severe complications involving multiple organ systems. Management involves supportive care, seizure control, ventilation and therapeutic hypothermia in severe cases to prevent further brain injury. Outcomes depend on severity of the initial insult and subsequent care.

1. HYPOXIC ISCHAEMIC
ENCEPHALOPATHY

2. DEFINITION
• It is an abnormal neurobehavioural state in which the predominant pathogenic mechanism is
impaired cerebral blood flow and oxygen delivery to the brain
• It is a brain injury that prevents adequate blood flow to the brain occurring as a result of prenatal,
intrapartum or postnatal period
• It affects 2.3-2.6 of live births in lower to middle income countries
• The mortality rate has been reported to be as high as 50-75% due to multiple organ failure or
termination of care
• Some infants with severe neurologic disabilities die in their infancy from aspiration pneumonia or
systemic infections
• By the age of 2 years up to 60% of infants with HIE will die or have severe mental retardation,
eoilepsy or cerebral palsy

3. PATHOPHYSIOLOGY
• PRIMARY ENERGY FAILURE: reduction of cerebral blood flow>>>>decrease in oygen and
glucose>>>decreased ATP which leads to failure of mechanisms maintaining cell integrity eg.
Na+/K+ pump
• This leads to mass depolarization of neurons>>>>release of glutamate >>>>> increased
intracellular calcium and sodium which leads to cerebral edema, ischaemia, microvascular
damage>>>>necrosis. The extent of primary failure determines the secondary
• SECONDARY ENERGY FAILURE: occurs 6 to 48 hours after initial injury. Exact mechanisms are
unclear but are related to oxidative stress, excitotoxicity and inflammation

4. As fetal respiration is controlled by placental, fetal hypoxia implies some degree of placental
ischaemia
The systemic response to hypoxia, hypercarbia and mixed acidosis is maintenance of cerebral blood
flow at the expense of other organs
If an episode of hypoxia is sufficiently prolonged and severe other organs will be affected. With
further decreased cardiac output, hypotension occurs and perfusion of the brain, kidney, lung and
gut is compromised

5. AETIOLOGY/RISK FACTORS
ANTEPARTUM INTRAPARTUM POSTPARTUM
Abnormal umbilical flow eg.
Pre/eclampsia; cord prolapse/knot
CPD Abnormal transition
Uterine rupture Shoulder dystocia narcotics
Placenta previa/abruptio Breech presentation Neonatal hypotension
Maternal hypotension

6. CLINICAL CRITERIA
ACOG demand the following criteria are all met
• Evidence of metabolic acidosis with a pH <7 or mixed academia in umbilical artery if obtained
• Persistent APGAR score of 0-3 for longer than 5 min
• Neonatal neurologic sequelae (eg. Seizures, coma, hypotonia)
• Multiple organ involvement

7. PRESENTATION
• Staging system proposed by Sarnat and Sarnat’s 1976
MILD:
Slightly increased tone, deep tendon reflexes may be brisk. Transient behavioural abnormalities such as
poor feeding, irritability, excessive crying or sleepiness. By 3-4 days CNS findings may be normal
An initial period of well-being or mild HIE may be followed by sudden deterioration suggesting ongoing
brain cell dysfunction, injury and death. Seizure intensity may increase
MODERATE
Lethargic, significant hypotonia and diminished deep tendon reflexes
Sluggish or absent suck, Moro and grasp
Occasional apnea. Seizures may occur within the first 24 hours
Full recovery within 1-2 weeks is possible with better long term outcome

8. • Severe:
• Stupor or coma
• Irregular breathing of a Cheyne-Stokes pattern, often requiring ventilator support
• Generalized hypotonia and depressed deep tendon reflexes
• Neonatal reflexes absent –eg. Moro, suck and grasp
• Disturbances of ocular motion eg. Deviation of eyes, nystagmus and loss or doll’s eye movemets
(ie, conjugate) may be revealed by cranial nerve exam
• Pupilas may be dilated, fixed or poorly reactive to light
• Seizures occur early and are often initially resistant to medications
• Seizures are generalized and frequency may increase progressively
• Irregularities in heart rate and BP are common in the period of reperfusion injury (ie. Secondary
energy insult)
Those who survive – alertness improves by day 4-5. hypotonia and feeding difficulties may persist

9. Summary

10. Multi System Disorder
• HEART: Hypoxic damage, decreased function
• LUNGS: severe pulmonary hypertension requiring assisted ventilation
• LIVER: deranged LFT
• RENAL: AKI, oliguria
• GI: poor peristalsis, delayed gastric emptying, increased risk of NEC

11. Thompson score
• Neonatal scoring system developed for assessing severity of perinatal asphyxia. Found to have
high sensitivity and specificity for HIE outcomes
• 0-10 Mild HIE
• 11-14 Moderate HIE
• >_ 15 Severe HIE

12. INVESTIGATIONS
No specific test can confirm the diagnosis. It is bassed on history and clinical assessment and
neurological exams
• Serum electrolytes: In severe HIE cases, daily assessment of serum electrolytes are of value until the
infant's status improved
*low serum sodium, potassium, and chloride
*reduced urine flow and excessive weight gain may indicate acute tubular damage or inappropriate
antidiuretic hormone (IADH), particularly during the initial 2-3 days of life.
Similar changes may be seen during recovery, with increased urine flow, might indicate ongoing
tubular damage and excessive sodium loss relative to water loss.
• Renal function studies: Serum creatinine, creatinine clearance, and BUN
• Cardiac and liver enzymes values are of value to assess the degree of hypoxic-ischemic injury to these
other organs.
• These studies also provide some insight into injuries to other organs, such as the bowel.

13. Imaging
• Routine imaging studies may or may not consistently reveal abnormal findings. Therefore, a
normal cranial imaging study does not rule out HIE.
• Cranial ultrasound: Although ultrasound is portable and convenient, the findings in many HIE may
be imprecise.
• A CT scan of the head can be especially useful to confirm cerebral edema. It may shows zones of
infarction or hemorrhage .
• • MRI is valuable in moderately severe and severe HIE. However, the interpretation of MRI in
infants requires considerable expertise.

14.  Echocardiography: In infants requiring inotropic support, echocardiography (ECHO)
helps to define myocardial contractility and the existence of structural heart defects
 EEG: with its different types:
*Amplitude-integrated electroencephalography (aEEG)
*Standard EEG
*Traditional, multichannel EEG
 Retinal and ophthalmic examination: This examination may be valuable,
particularly as part of an evaluation for developmental abnormalities of the brain.
 Special sensory evaluation: Screening for hearing is now mandatory due to
increased incidence of deafness among infants with HIE that require assisted ventilation.

15. Management
Supportive management mostly
1. Sezures –
• Anticipate, monitor for and treat seizures
• Phenobarbitone 20mg/kg p.o loading dose, rpt loading dose if pt fits again (doses 30min apart)
then maintain on Phenobarbitone 5mg/kg nocte
• Phenytoin 20mg/kg iv diluted in normal saline. Maintain on 3-5mg/kg iv in 2-4 divided doses
2. Ventilation – O2 PNP/BCPAP to maintain ventilation and prevent hypoxia, hypercapnia
3. Fluid and glucose homeostasis should be achieved. Avoid hypoglycemia or hyperglycemia, as both
are known to cause brain injury – maintain on adequate feeds/iv fluids
4. Monitor BPs – avoiding hypo and hypertension
5. Support and counsel parents

16. New treatment modalities – Brain cooling
to about 3-4°C below the baseline temperature (i.e., to 33-34°C) may be neuroprotective.
The optimal level of hypothermia for maximal neuroprotection is not known. Extreme
hypothermia may cause significant systemic side effects.
• The possible explanations of the mechanism of neuroprotection of the hypothermia are:
(1) reduced metabolic rate and energy depletion
(2) decreased excitatory transmitter release
(3) reduced alterations in ion flux
(4) reduced apoptosis due to HIE
(5) reduced vascular permeability, edema, and disruptions of blood-brain barrier
functions.

17. • Up to 48-72 hours of cooling may be needed to prevent secondary neuronal loss.
The greater the severity of the initial injury, the longer the duration of hypothermia
needed .
• Cooling must begin early, within 1 hour of injury, if possible; however, a favorable
outcome may be possible if the cooling begins up to 6 hours after injury.
• Two methods have been used in clinical trials for brain cooling. In selective head
cooling, a cap (Cool-Cap) .The other method is to provide whole body hypothermia.
The infant is placed over a commercially available cooling blanket.

18. But we must take in consideration the side effects of the hypothermia
which include:
*coagulation defects
*leukocyte malfunctions
*pulmonary hypertension
*worsening of metabolic acidosis
*abnormalities of cardiac rhythm, especially during rewarming

19. References
• 1. Coovadia’s Paediatrics and Child Health
• 2. Hypoxic Ischemic Encephalopathy: Pathophysiology and Experimental Treatments, NCBI article
• 3. EDLIZ 2020
• Hypoxic Ischaemic Encephalopathy lecture notes – Dr Alex Stevenson