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

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

3. 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

4. Neuropathology- Importance of Cerebral Blood Flow

5. 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

6. 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

7. 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.

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

9. 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

10. 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

11. 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

12. Long term outcome of term infants with HIE
Death Disability
Mild
Moderate % %
Severe 60% %

13. 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

14. 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

15. 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

16. 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.

17. Management Beyond the Delivery Room
General Measures
Neuroprotective Strategies

18. 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

19. 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.

20. 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?

21. 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

22. COOLING METHODS
COOLING CAP
COOLING BLANKET

23. 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.

24. Lancet. 2005;365:

25. Selective Head Cooling
July , 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 c
Primary outcome death or severe disability by 18 months

26. N Engl J Med 2005;353:

27. 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 months
Main outcome death or moderate or severe disability (BAYLEY, HEARING, BLINDNESS)

28. Primary Outcomes in 2 Trials
Control Cool OR p
Cool cap 66% %
Whole body62% %

29. Secondary Outcomes for 2 Trials
Control Cool P
Cool cap % %
-Mod EEG % %
-Severe EEG % %
Whole body % %
-Sarnat % %
-Sarnat % %

30. Keeping a cool head ….
Thank you