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Updates on Neonatal Neonatal Asphyxia Asphyxia Keeping a “COOL” Head Lina Chalak, MD Assistant Professor Division of Neonatology, Pediatrics University of Arkansas Medical Center
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OutlineOutline
Importance of Pathogenesis/ DefinitionsImportance of Pathogenesis/ Definitions
Early Identification of High risk NBNEarly Identification of High risk NBN
New Treatment strategies: Cooling.New Treatment strategies: Cooling.
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PathogenesisPathogenesis
Impaired cerebral blood flow is Impaired cerebral blood flow is the principal mechanism leading the principal mechanism leading to perinatal brain injury to perinatal brain injury
It occurs as a consequence of It occurs as a consequence of interruption of placental blood interruption of placental blood flow and gas exchangeflow and gas exchange
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Neuropathology- Importance of Cerebral Blood FlowNeuropathology- Importance of Cerebral Blood Flow
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DefinitionsDefinitions
HypoxiaHypoxia - - refers to an abnormal reduction in refers to an abnormal reduction in oxygen delivery to the tissueoxygen delivery to the tissue
IschemiaIschemia - - refers to a reduction in blood flow to refers to a reduction in blood flow to the tissuethe tissue
AsphyxiaAsphyxia - - refers to progressive hypoxia, refers to progressive hypoxia, hypercarbia and acidosis. hypercarbia and acidosis.
Severe Fetal AcidemiaSevere Fetal Acidemia: : Cord arterial pH Cord arterial pH << 7.00 7.00
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Hypoxic-Ischemic EncephalopathyHypoxic-Ischemic Encephalopathy
A sentinel perinatal event at Delivery A sentinel perinatal event at Delivery
+ Apgar Score < 3 at 5 min + Apgar Score < 3 at 5 min
+ Cord pH < 7.00+ Cord pH < 7.00
+ Encephalopathy by exam (stage 2-3) + Encephalopathy by exam (stage 2-3)
+ Evidence of Non CNS dysfunction+ Evidence of Non CNS dysfunction
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FactFact
Although interference in placental Although interference in placental blood flow and consequently gas blood flow and consequently gas exchange is fairly common, residual exchange is fairly common, residual neurologic sequelae are infrequent neurologic sequelae are infrequent and are more likely to occur when and are more likely to occur when the asphyxial event is severe.the asphyxial event is severe.
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Why?Why?
The fetus immediately adapts The fetus immediately adapts to an asphyxial event to to an asphyxial event to preserve cerebral blood flow preserve cerebral blood flow
and oxygen deliveryand oxygen delivery
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CARDIOVASCULAR RESPONSES TO ASPHYXIACARDIOVASCULAR RESPONSES TO ASPHYXIA
ASPHYXIA (ASPHYXIA (PaOPaO22, , PaCOPaCO22,, pH)pH)
Redistribution of Cardiac OutputRedistribution of Cardiac Output
Cerebral, Coronary, AdrenalCerebral, Coronary, Adrenal Renal, IntestinalRenal, Intestinal
Blood FlowBlood Flow Blood Flow Blood Flow
Ongoing AsphyxiaOngoing Asphyxia
Cardiac OutputCardiac Output
Cerebral Blood FlowCerebral Blood Flow
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Early Identification of High Risk Infants Early Identification of High Risk Infants Requires a Combination of FactorsRequires a Combination of Factors
1) Evidence of an Acute Perinatal Insult Indicated by a combination of markers* 1) Sentinel event 2) Delivery room resuscitation 3) 5 Minute Apgar score 5 4) Cord arterial pH 7.00 +2) Postnatal evidence of encephalopathy 1) Clinical 2) EEG
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Clinical: Assessment of Encephalopathy
Sarnat Arch of Neurol. 33;696,1976
Neurologic EvaluationLevel of ConsciousnessNeuromuscular controlReflexesAutonomic functionEvidence of Seizures
Staging of Encephalopathy Stage 1 - Mild Stage 2 - Moderate Stage3 - Severe
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DeathDeathDisabilityDisability
MildMild 0 0 0 0
Moderate 6%Moderate 6% 30% 30%
SevereSevere 60% 60% 100% 100%
Long term outcome of term infants with HIELong term outcome of term infants with HIE
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FactFact
The ability to identify EARLY on, infants at The ability to identify EARLY on, infants at highest risk for HIE is critical :highest risk for HIE is critical :
The therapeutic window for intervention The therapeutic window for intervention strategies to be effective in preventing the strategies to be effective in preventing the processes of ongoing injury in the newborn processes of ongoing injury in the newborn brain is short (< 6 hours)brain is short (< 6 hours)
Novel therapeutic strategies to prevent Novel therapeutic strategies to prevent ongoing injury have the potential for ongoing injury have the potential for significant side effectssignificant side effects
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a-EEG: Assessment of Cerebral Functiona-EEG: Assessment of Cerebral Function
A Cerebral Function Monitor via a single A Cerebral Function Monitor via a single channel EEG (a-EEG), records activity from channel EEG (a-EEG), records activity from biparietal electrodes. The signal is smoothed biparietal electrodes. The signal is smoothed and the amplitude integrated. and the amplitude integrated.
Naqeeb, et al. Pediatrics 1999:103:1263
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Representative aEEG tracings
NormalLow line tracing above 5 cuttoffHigh line above 10 cuttoff
Moderately SuppressedLow line below 5 cutoffHigh line above 10 cutoff
Severely SuppressedLow line below 5 cutoffHigh line above 10 cutoff
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• 50 infants with an acute perinatal insult• Clinical examination/Sarnat stage 2 or 3 • a-EEG assessment/ Mod or severe• Outcome: Persistent encephalopathy > 5 days Occurred in 14/50 infants
Abnormalities in both the Clinical and a-Abnormalities in both the Clinical and a-EEG evaluation enhances the early EEG evaluation enhances the early detection of infants who progress to detection of infants who progress to
irreversible brain injuryirreversible brain injury..
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Management Beyond the Management Beyond the Delivery RoomDelivery Room
General MeasuresGeneral Measures
Neuroprotective StrategiesNeuroprotective Strategies
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HYPOXIA-ISCHEMIA
ANAEROBIC GLYCOGLYSIS
ADENOSINE
ATP
GLUTAMATE
HYPOXANTHINE
Ca++
LIPASES
NITRIC OXIDESYNTHASEinhibitors
XANTHINE ARACHIDONICACID
FREE RADICALS
EICOSANOIDS
MAGNESIUM SULFATEDEXTROMETHORPHAN
KETAMINE
SUPEROXIDE DISMUTASELAZEROIDS
ALLOPURINOL NOSINHIBITORS
POTENTIAL STRATEGIES FOR PREVENTING REPERFUSION INJURY
XANTHINE OXIDASE INHIBITORS
MILD HYPOTHERMIA
NMDA RECEPTOR BLOCKER
NMDA RECEPTOR
FREE RADICAL SCAVENGERS
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• Recent evidence indicates that mechanisms mediating neuronal death following ischemia are temperture dependent.
• Mild to modest decreases in brain temperature may greatly influence the resistance of the Brain to brief periods of ischemia.
A COOL HEAD !!!!A COOL HEAD !!!!
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Reduces cerebral metabolismPreserves ATP levelsDecreases energy utilization Suppresses Excitotoxic AA accumulationReduces NO synthase activity Suppresses free radical activity Inhibits apoptosis Prolongs therapeutic window?
Potential Mechanisms of Action of Potential Mechanisms of Action of HypothermiaHypothermia
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Hypertension Cardiac arrhythmia Persistent acidosis Increased oxygen consumption Increased blood viscosity Reduction in platelet count Pulmonary hemorrhage SepsisNecrotizing enterocolitis
Potential Adverse Effects of Potential Adverse Effects of Hypothermia in NeonatesHypothermia in Neonates
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COOLING METHODSCOOLING METHODS
COOLING BLANKET COOLING CAP
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Available therapies in 2005Available therapies in 2005 Brain cooling vs. Total body cooling Brain cooling vs. Total body cooling
- Must be initiated within 6 hrs after birth- Must be initiated within 6 hrs after birth
- Duration of cooling is 72 hours - Duration of cooling is 72 hours
- Extent of cooling is 33 degrees celcius. - Extent of cooling is 33 degrees celcius.
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Lancet. 2005;365:663-70.Lancet. 2005;365:663-70.
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Selective Head CoolingSelective Head Cooling
July 1999-2002, 25 centers UK/USJuly 1999-2002, 25 centers UK/US 234 term infants with 234 term infants with
encephalopathy and abnormal Aeegencephalopathy and abnormal Aeeg Randomized by 6 hours after birthRandomized by 6 hours after birth Control vs. cooling cap for 72 hoursControl vs. cooling cap for 72 hours Goal rectal temperature 34-35 cGoal rectal temperature 34-35 c Primary outcome death or severe Primary outcome death or severe
disability by 18 monthsdisability by 18 months
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N Engl J Med 2005;353:1574-84N Engl J Med 2005;353:1574-84
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Whole Body Cooling TrialWhole Body Cooling Trial 208 infants > 36 weeks gestation with HIE 208 infants > 36 weeks gestation with HIE
(Moderate to severe encephalopathy)(Moderate to severe encephalopathy) Enrolled within 6 hours after birth in a Enrolled within 6 hours after birth in a
randomized controlled trialrandomized controlled trial Control vs. whole body cooling with goal Control vs. whole body cooling with goal
esophageal temperature of 33.5 c for 72 esophageal temperature of 33.5 c for 72 hourshours
Follow up 18-22 monthsFollow up 18-22 months Main outcome death or moderate or severe Main outcome death or moderate or severe
disabilitydisability (BAYLEY, HEARING, BLINDNESS) (BAYLEY, HEARING, BLINDNESS)
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Primary Outcomes in 2 TrialsPrimary Outcomes in 2 Trials
Control Cool OR pControl Cool OR p
Cool capCool cap 66% 55% 0.61 0.166% 55% 0.61 0.1
Whole bodyWhole body62% 44% 0.72 0.0162% 44% 0.72 0.01
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Control Cool P Control Cool P
Cool capCool cap 66% 55% 0.166% 55% 0.1
-Mod-Mod EEG 66% 48% 0.02 EEG 66% 48% 0.02
-Severe EEG 68% 79% 0.51-Severe EEG 68% 79% 0.51
Whole bodyWhole body 62% 44% 0.0162% 44% 0.01
-Sarnat-Sarnat 2 48% 32% 0.09 2 48% 32% 0.09
-Sarnat 3-Sarnat 3 85% 72% 0.2485% 72% 0.24
Secondary Outcomes for 2 TrialsSecondary Outcomes for 2 Trials
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Keeping a cool head ….Keeping a cool head ….
Thank you