Hypoxic Ischemic Encephalopathy Martine Chagnon Linda Morneault

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

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

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.

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

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 CO@ 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

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

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

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

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:

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

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)

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

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

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:

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

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

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

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.

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.

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.

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 10-40 μV

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

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

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