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

Outline Importance of Pathogenesis/ Definitions Early Identification of High risk NBN New Treatment strategies: Cooling.

Pathogenesis Impaired cerebral blood flow is the principal mechanism leading to perinatal brain injury It occurs as a consequence of interruption of placental blood flow and gas exchange

Neuropathology- Importance of Cerebral Blood Flow

Definitions Hypoxia - refers to an abnormal reduction in oxygen delivery to the tissue Ischemia - refers to a reduction in blood flow to the tissue Asphyxia - refers to progressive hypoxia, hypercarbia and acidosis. Severe Fetal Acidemia: Cord arterial pH < 7.00

Hypoxic-Ischemic Encephalopathy A sentinel perinatal event at Delivery + Apgar Score < 3 at 5 min + Cord pH < 7.00 + Encephalopathy by exam (stage 2-3) + Evidence of Non CNS dysfunction

Fact Although interference in placental blood flow and consequently gas exchange is fairly common, residual neurologic sequelae are infrequent and are more likely to occur when the asphyxial event is severe.

Why? The fetus immediately adapts to an asphyxial event to preserve cerebral blood flow and oxygen delivery

CARDIOVASCULAR RESPONSES TO ASPHYXIA ASPHYXIA (PaO2, PaCO2, pH) Redistribution of Cardiac Output Cerebral, Coronary, Adrenal Renal, Intestinal Blood Flow Blood Flow Ongoing Asphyxia Cardiac Output Cerebral Blood Flow

Early Identification of High Risk Infants Requires 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 Neurologic Evaluation Level of Consciousness Neuromuscular control Reflexes Autonomic function Evidence of Seizures Staging of Encephalopathy Stage 1 - Mild Stage 2 - Moderate Stage3 - Severe Sarnat Arch of Neurol. 33;696,1976

Long term outcome of term infants with HIE Death Disability Mild 0 0 Moderate 6% 30% Severe 60% 100%

Fact The ability to identify EARLY on, infants at highest risk for HIE is critical : The therapeutic window for intervention strategies to be effective in preventing the processes of ongoing injury in the newborn brain is short (< 6 hours) Novel therapeutic strategies to prevent ongoing injury have the potential for significant side effects

a-EEG: Assessment of Cerebral Function A Cerebral Function Monitor via a single channel EEG (a-EEG), records activity from biparietal electrodes. The signal is smoothed and the amplitude integrated. Naqeeb, et al. Pediatrics 1999:103:1263

Representative aEEG tracings Normal Low line tracing above 5 cuttoff High line above 10 cuttoff Moderately Suppressed Low line below 5 cutoff High line above 10 cutoff Severely Suppressed Low line below 5 cutoff High 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-EEG evaluation enhances the early detection of infants who progress to irreversible brain injury.

Management Beyond the Delivery Room General Measures Neuroprotective Strategies

inhibitors POTENTIAL STRATEGIES FOR PREVENTING REPERFUSION INJURY HYPOXIA-ISCHEMIA ANAEROBIC GLYCOGLYSIS MILD HYPOTHERMIA ATP ADENOSINE GLUTAMATE NMDA RECEPTOR BLOCKER MAGNESIUM SULFATE DEXTROMETHORPHAN KETAMINE NMDA RECEPTOR HYPOXANTHINE Ca++ XANTHINE OXIDASE INHIBITORS NOS INHIBITORS ALLOPURINOL LIPASES XANTHINE ARACHIDONIC ACID NITRIC OXIDE SYNTHASE inhibitors FREE RADICAL SCAVENGERS SUPEROXIDE DISMUTASE LAZEROIDS FREE RADICALS EICOSANOIDS

mediating neuronal death following ischemia are temperture dependent. A COOL HEAD !!!! 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.

Potential Mechanisms of Action of Hypothermia Reduces cerebral metabolism Preserves ATP levels Decreases energy utilization Suppresses Excitotoxic AA accumulation Reduces NO synthase activity Suppresses free radical activity Inhibits apoptosis Prolongs therapeutic window?

Potential Adverse Effects of Hypothermia in Neonates Hypertension Cardiac arrhythmia Persistent acidosis Increased oxygen consumption Increased blood viscosity Reduction in platelet count Pulmonary hemorrhage Sepsis Necrotizing enterocolitis

COOLING METHODS COOLING CAP COOLING BLANKET

Available therapies in 2005 Brain cooling vs. Total body cooling - Must be initiated within 6 hrs after birth - Duration of cooling is 72 hours - Extent of cooling is 33 degrees celcius.

Lancet. 2005;365:663-70.

Selective Head Cooling July 1999-2002, 25 centers UK/US 234 term infants with encephalopathy and abnormal Aeeg Randomized by 6 hours after birth Control vs. cooling cap for 72 hours Goal rectal temperature 34-35 c Primary outcome death or severe disability by 18 months

N Engl J Med 2005;353:1574-84

Whole Body Cooling Trial 208 infants > 36 weeks gestation with HIE (Moderate to severe encephalopathy) Enrolled within 6 hours after birth in a randomized controlled trial Control vs. whole body cooling with goal esophageal temperature of 33.5 c for 72 hours Follow up 18-22 months Main outcome death or moderate or severe disability (BAYLEY, HEARING, BLINDNESS)

Primary Outcomes in 2 Trials Control Cool OR p Cool cap 66% 55% 0.61 0.1 Whole body62% 44% 0.72 0.01

Secondary Outcomes for 2 Trials Control Cool P Cool cap 66% 55% 0.1 -Mod EEG 66% 48% 0.02 -Severe EEG 68% 79% 0.51 Whole body 62% 44% 0.01 -Sarnat 2 48% 32% 0.09 -Sarnat 3 85% 72% 0.24

Keeping a cool head …. Thank you