Updates on Neonatal Neonatal Asphyxia Asphyxia Keeping a “COOL” Head Lina Chalak, MD Assistant Professor Division of Neonatology, Pediatrics University of Arkansas Medical Center

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.

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

Neuropathology- Importance of Cerebral Blood FlowNeuropathology- Importance of Cerebral Blood Flow

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

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

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.

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

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

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

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

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

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

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

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

• 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..

Management Beyond the Management Beyond the Delivery RoomDelivery Room

General MeasuresGeneral Measures

Neuroprotective StrategiesNeuroprotective Strategies

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

• 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 !!!!

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

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

COOLING METHODSCOOLING METHODS

COOLING BLANKET COOLING CAP

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.

Lancet. 2005;365:663-70.Lancet. 2005;365:663-70.

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

N Engl J Med 2005;353:1574-84N Engl J Med 2005;353:1574-84

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)

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

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

Keeping a cool head ….Keeping a cool head ….

Thank you