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Yohaimi E. Cosme-Ayala, MDHypoxic-IschemicEncephalopathy
1) Know the etiology of hypoxic-ischemic encephalopathy(HIE)2) Know the criteria used to diagnose HIE3) Review the clinical severity grading of HIE4) Be able to describe the pathophysiology ofposthypoxic brain injury5) Become familiar with the assessment tools available toevaluate infants with HIE6) Know how hypothermia is used for neuroprotectionand the criteria for using itLearning Objectives
Definitions• Hypoxia or Anoxia: A partial (hypoxia) orcomplete (anoxia) lack of oxygen in the brain orblood• Asphyxia: The state in which placental orpulmonary gas exchange is compromised orceases altogether• Ischemia: The reduction or cessation of bloodflowto an organ which compromises both oxygen andsubstrate delivery to the tissue• Hypoxic-Ischemic Encephalopathy: Abnormalneurologic behavior in the neonatal period arisingas a result of a hypoxic-ischemic event.
Etiology of HIE• Maternal: Cardiac arrest Asphyxiation Severe anaphylaxis Status epilepticus Hypovolemic shock• Uteroplacental: Placental abruption Cord prolapse Uterine rupture Hyperstimulation withoxytocic agents• Fetal: Fetomaternal hemorrhage Twin to twin transfusion Severe isoimmune hemolyticdisease Cardiac arrhythmia
Incidence of HIE Occurs in 1-6 per 1000 live term births in developedcountries 25% die or have multiple disabilities 4% have mild to moderate forms of cerebral palsy 10% have developmental delay (this is similar to thecontrol population!)
Pathophysiology• The immature brain is in some ways more resistant tohypoxic-ischemic events compared to older children &adults– This may be due to:• Lower cerebral metabolic rate• Immaturity in the development of the balance ofneurotransmitters• Plasticity of the immature CNS
Pathophysiology• Gestational age plays an important role inthe susceptibility of CNS structures < 20 weeks: Insult leads to neuronal heterotopia orpolymicrogyria 26-36 weeks: Insult affects white matter, leading toperiventricular leukomalacia Term: Insult affects primarily gray matter
Pathophysiology• Other factors that influence the distributionof CNS injury: Cellular susceptibility (neuron most susceptible) Vascular territories (watershed areas) Regional susceptibility (areas of higher metabolicrates, ie. Thalamus) Degree of asphyxia
PathophysiologyAcute HIE leads to primary and secondary events: Primary neuronal damage: cytotoxic changes due tofailure of microcirculation inhibition of energy-producing molecular processes ATPase membranepump failure cytotoxic edema and free radicalformation compromised cellular integrity Secondary neuronal damage: May extend up to 72hours or more after the acute insult and results in aninflammatory response and cell necrosis or apoptosis(fueled by reperfusion)
Diagnosis• There is no clear diagnostic test for HIE• Abnormal findings on the neurologic examin the first few days after birth is the singlemost useful predictor that brain insult hasoccurred in the perinatal period• Essential Criteria for Diagnosis of HIE:– Metabolic acidosis (cord pH <7 or base deficitof >12)– Early onset of encephalopathy– Multisystem organ dysfunction
Clinical Staging of HIE(Sarnat and Sarnat, 1976)HIE can be divided into Mild, Moderate, and Severe
Systemic Complications ofHIE• Acute renal failure in up to 20% ofasphyxiated term infants• Myocardial dysfunction and hypotension in28-50% of term infants• Elevated LFTs in 80-85% of term infants• Coagulation impairment is relativelycommon in severely asphyxiated infants• Supportive care required!!
Assessment Tools in HIE• Amplitude-integrated EEG (aEEG)– When performed early, it may reflectdysfunction rather than permanent injury– Most useful in infants who have moderate tosevere encephalopathy• Marginally abnormal or normal aEEG is veryreassuring of good outcome• Severely abnormal aEEG in infants with moderateHIE raises the probability of death or severedisability from 25% to 75%
Assessment Tools in HIE• Evoked Potentials– Brainstem auditory evoked potentials, visual evokedpotentials and somatosensory evoked potentials canbe used in full-term infants with HIE– More sensitive and specific than aEEG alone– However, not as available as aEEG and there is alack of experience among pediatric neurologists• Therefore aEEG is preferred because of easyaccess, application, and interpretation
Assessment Tools in HIE• Neuroimaging Cranial ultrasound: Not the best in assessingabnormalities in term infants. Echogenicity developsgradually over days CT: Less sensitive than MRI for detecting changes inthe central gray nuclei MRI: Most appropriate technique and is able to showdifferent patterns of injury. Presence of signalabnormality in the internal capsule later in the firstweek has a very high predictive value forneurodevelopmental outcome
Management -Hypothermia• Has become standard of care• Whole-body and head-cooling– Unclear if one regimen is superior to the other - currentlyeither one is utilized, based on availability• Aim to get core (rectal) temperatureto 33-35º C for 72 hours– based on Cool Cap and NICHD NeonatalResearch Network trials
Mechanism of Action• Reduces cerebral metabolism, prevents edema• Decreases energy utilization• Reduces/suppresses cytotoxic amino acid accumulationand nitric oxide• Inhibits platelet-activating factor, inflammatory cascade• Suppresses free radical activity• Attenuates secondary neuronal damage• Inhibits cell death• Reduces extent of brain damage– DEATH OR SEVERE DISABILITY AT 18 MONTHSOF AGE SIGNIFICANTLY REDUCED!!
Criteria for Hypothermia• Hypothermia is not effective for every baby– Currently only used in infants > 35 weeks• Time interval between birth and initiation oftreatment important– Treatment must be started within 6 hours of birth to beeffective
PharmacologicManagement• Allopurinol– Some trials have shown a decrease in mortality and abeneficial effect on free radical formation, cerebralblood flow and electrical brain activity– Meta-analysis concluded that more trials need to bedone using allopurinol as an adjunct to hypothermia tomake a conclusion on its effectiveness in treating HIE
PharmacologicManagement• Opioids– A few studies have demonstrated that morphine andfentanyl may have a neuroprotective effect after HIEwith less severe signs of brain damage on MRI at 7days of life and better neurologic outcomes at 13months of age– However, long term effects of these medications arenot known and more prospective randomized trialsare warranted.
References• Allan WC. The clinical spectrum and prediction of outcome inhypoxic-ischemic encephalopathy. Neoreviews 2002; 3; e108-e115• Delivoria-Papadopoulos M, et al. Biochemical basis ofhypoxic-ischemic encephalopathy. Neoreviews 2010; 11; e184-e193• Fanaroff and Martin’s Neonatal-Perinatal Medicine: Diseasesof the Fetus and Infant, 9th edition. 2011, p 952-976• Marro, PJ, et al. Pharmacology review: Neuroprotectivetreatments for hypoxic-ischemic injury. Neoreviews 2010; 11;e311-e315• Shankaran S. Neonatal encephalopathy: Treatment withhypothermia. Neoreviews 2010; 11; e85-e92