1. Hypoxic Ischemic Encephalopathy
Martine Chagnon
Linda Morneault

2. Perinatal Asphyxia
Condition of impaired blood gas exchange that can lead to hypoxemia and hypercapnia with metabolic acidosis
The mature fetus redistributes the blood flow to the heart, brain, and adrenals to ensure adequate oxygen and substrate delivery to these vital organs

3. HIE Incidence: 15-20% of affected infants dies in the postnatal period
Affects 1-6/1000 live births developed countries
Higher in countries with limited resources
15-20% of affected infants dies in the postnatal period
25% sustain childhood disabilities
Abnormal findings on the neurologic exam in first few days after birth is the single most useful predictor in childhood that a brain insult has occurred in the perinatal period

4. Hypothermia Criteria
Gestational age ≥ 36 weeks and birth weight ≥ 1800 g
AND
Evidence of ≥ 1 sign of fetal distress
history of acute perinatal event (e.g. abruptio placenta, cord prolapse, severe fetal heart rate abnormality, variable or late decelerations)
cord pH ≤ 7.0 or BE ≥ -16 mEq/L
Evidence of ≥ 1 sign of neonatal distress
Apgar ≤ 5 at 10 minutes
postnatal blood gas at < 1h of life: pH ≤ 7.0 or BE ≥ -16 mEq/L
need for ventilation at birth and continued for at least 10 min
All consecutive term newborns with HIE admitted to the NICU and meeting the criteria for induced hypothermia were enrolled prospectively in this study.

5. History
Event: placental abruption, uterine rupture, amniotic fluid embolism, tight nuchal cord, cord prolapsed/avulsion, maternal hemorrhage, trauma, cardio respiratory arrest, severe and sustained bradycardia, prolonged labor,
Apgar score are an indication of how the resuscitation is going but not a tool for decision making
Hence the blood gas at birth or at one hour of life.
Most infants do not have an obvious cause

6. Management Delivery room – follow NRP guidelines – normal temperature
Post natal avoid hyperthermia
Maintain good oxygenation/ventilation
Promptly treat hypotension
Fluid restriction
Maintain normal glucose
Avoid hypocalcaemia
Treat seizures
Monitor electrolytes, glucose, magnesium
Assess for adequate respiratory function – frequent apnea episodes – may continue to require assisted ventilation; changes in can affect CBF elevated increases and hypocarbia decreases (also associated with hearing loss)
Hypotension may be related to myocardial dysfunction, endothelial cell damage, rarely volume loss; treatment is directed towards the cause; hypertension often associated with seizures
Fluid overload must be avoided – could be secondary to renal (acute tubular necrosis) or SIADH; managed with fluid restriction – sodium chloride small dose can be started by dol #2.
Hypoglycemia in association with HIE is detremental – if pH < 7.0 with glucose < 2.6 = infants have greater risk of developing moderate to severe encephalopathy
Hyperglycemia is known to accentuate brain damage in adults and older infants – in premature infants it can be neuroprotective
Seizure should be treated promptly

7. Pathophysiology
Primary energy failure is characterized by reductions in cerebral blood flow and oxygen/substrates
Anaerobic metabolism - acidosis is prominent
Associated with acute cellular derangement – loss of membrane integrity
Calcium enters the cell – neuronal nitric oxide – oxygen free radicals – resulting in apoptosis (cell death)
Once energy supply is gone
Well studied and associated with two phases of pathologic events that culminate in brain injury
Metabolic acidosis secondary to energy failure – resulting in anarobic metabolism
Cellular derangement leads to calcium entering the cell and osmotic deregulation
Calcium triggers a number of destructive pathways by activating lipase and neuronal nitric oxyde synthase, leading to the release of oxygen free radical nitric oxide which disrupts mitochondiral respiration resulting apoptosis or programmed cell death as long as energy supplies persist but once exhausted it results in cellular necrosis

8. Pathophysiology
Secondary energy failure differs from primary in that declines in energy are not accompanied by brain acidosis.
The presence and severity depends on the extent of the primary
Not as well understood
inflammatory response
apoptosis
Reduction in growth factors and protein synthesis
Secondary phase is basically a continuation of the excitotoxic-oxidation cascade, apoptosis, inflammation and altered growth factor levels and protein synthesis

9. Pathophysiology
Latent phase: interval between primary and secondary energy failure corresponds to a therapeutic window
Duration of the window was noted to be about 6 hours (in animal studies)
Initiation of therapies during this phase in perinatal animals has been successful in reducing brain damage

10. Essential criteria Metabolic acidosis Early onset of encephalopathy
pH < 7.00 (metabolic acidosis)
BE of > -16 mEq/L
Early onset of encephalopathy
Multisystem organ dysfunction
Exclusion of other causes such as trauma, coagulation disorder, metabolic disorder, genetic
Suggested as prerequisites for a diagnosis of HIE resulting in moderate or severe encephalopathy in term newborns include:

11. Therapeutic Hypothermia
Blanketrol II and III hyper-hypothermia system
B II – two mattress at all times (adult on pole + baby)
B III - one mattress disposable or re-usable
Cool for 72 hours
Temperature at 33.5 celcius
Re-warming is done over 6 hours with gradual 0.5 degree increment every hour
Infant and blanket temperature are recorded every hour

12. Mechanism of Action of Hypothermia
Reduces extent of brain injury
Reduces cerebral metabolism
Decreases energy utilization
Inhibits platelet activating factor, inflammatory cascade
Suppresses free radical activity
Attenuates secondary energy failure
Inhibits apoptosis (cell death)

14. Therapeutic hypothermia
Complications
Cardiac arrhythmias (bradycardia)
Skin breakdown
Thrombocytopenia
Subcutaneous fat necrosis
Difficult for IV access peripherally
Uncomfortable for the infant

15. Safety of hypothermia No increase in incidence or severity of:
persistent pulmonary hypertension
Need for nitric oxide or ECMO
No increase in metabolic disturbances
No increase in cardiac arrhythmias
Demonstrated in all the studies between the infants receiving treatment and those in the control groups

16. Neuro Assessment Sarnat stage I Level of consciousness: Hyperalert
Activity - normal or decreased
Muscle tone – normal or slightly increased
Posture – mild distal flexion
Primitive reflex
Suck – weak
Moro – strong, low threshold
Autonomic function
Pupils – mydriasis
Heart rate – tachycardia
respirations
Neuromuscular:

17. Neuro Assessment Sarnat stage II Level of consciousness – lethargic
Activity – decreased
Muscle tone – mild hypotonia
Posture – strong distal flexion
Primitive reflexes
Suck – weak or absent
Moro – weak incomplete, high threshold
Autonomic function
Pupils – miosis
Heart rate – bradycardia
Respirations
Seizures – common focal or multifocal

18. Neuro assessment Sarnat stage III Level of consciousness – stupor/coma
Activity – absent
Muscle tone – flaccid
Posture – intermittent decerebration (extension)
Primitive reflexes
Suck – absent
Moro – absent
Autonomic function
Pupils – variable, unequal, fixed, dilated
Heart rate – variable
Respirations = apneic (if ventilated always score 3)
Neuromuscular control

19. Investigations
Head ultrasound – IVH and necrosis of basal ganglia and thalamus – limited in first week of life (sensitive to white matter injury); can tell us about cerebral perfusion
CT scan – best when done 5 to 7 days of life, early (cerebral edema) r/o intracranial hemorrhage, assessment of diffused cortical neuronal injury

20. Investigations Magnetic resonance injury (MRI)
Technique of choice for evaluation hypoxic- ischemic cerebral injury – provides information about basal ganglia and thalamus
Done between day 3-4 of life and after day 10 of life
Can be done while on cooling, not during re- warming
Sites of neuronal injury:
Cerebral cortex
Deep nuclear structures – thalamus, basal ganglia
Brain stem – cranial nerve nuclei, pons, neuronal injury found in the neurons of the oculomotor and trochlear nuclei; in the pons 5th and 7th cranial nerve; in medulla ninth and tenth nerve
Cerebellum
Spinal cord anterior horn cells.

21. Investigations EEG – provide information on the severity
Depressed
Burst suppression
Electrographic seizures
Epileptiform
AABR/ABR – screening for hearing 8th cranial nerve
SER – evaluation of cortical function
EEG – records the changes in electrical potential from neurons and axions under the surface electrodes
Why do we do EEG – Brain most complex structure
Protecting the brain is central objective
Essence of cerebral activity is to produce electrical impulses
Monitoring electrical impulses is monitoring brain activity
Burst suppression is recognized by periodic pattern of low voltage and short pattern of high amplitude.

22. Cerebral function monitoring
Amplitude-integrated electroencephalography
Uses EEG signals from 4 electrodes placed on the infants head and one ground electrode placed on the infant’s torso.
The signal is filtered, rectified, compressed and displayed using an internal algorithm focusing on changes in peak to peak EEG amplitude.
Resultant aEEG trace reveals where the infant’s brain is spending the majority of its time in terms of microvoltage and creates repeatable and recognizable patterns.
Patterns are assessed and categorized based on upper and lower margin microvoltage and presence or absence of sleep wake cycle.

23. Normal Tracing lower margin > 5 μV upper margin > 10 μV
widening and narrowing of the trace within the above margins = Sleep Wake Cycling (SWC), variation from approximately μV

24. Moderately Abnormal Function
lower margin < 5 μV
upper margin > 10 μV
no Sleep Wake Cycling (SWC)
Discontinuous normal voltage

25. Severely Abnormal Function
lower margin < 5 μV
upper margin < 10 μV
no Sleep Wake Cycling (SWC)
Burst suppression pattern, indicative of the brain going through bursts of brain activity followed by periods of suppression
Looks like a fine tooth comb

26. Seizures
Categorized by a sudden rise in the lower margin sometimes accompanied by a rise in the upper margin.
Often appears as a rhythmic discharge on the raw EEG