Neonatal Neuroprotection

1. Neonatal Neuroprotection Shannon E. G. Hamrick, MD Assistant Professor Divisions of Neonatology and Cardiology Department of Pediatrics Emory University

2. Disclosure • I have no relevant financial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in this CME activity. • I do not intend to discuss an unapproved/investigative use of a commercial product/device in my presentation.

3. Neonatal Neuroprotection: Learning Objectives • Discuss the pathogenesis of neuronal injury in the setting of perinatal hypoxia-ischemia. • Describe why the immature brain is uniquely susceptible to hypoxic-ischemic injury and how this impacts treatment options. • Explain strategies for neuroprotection, and specifically the efficacy of hypothermia.

4. Overview • Mechanisms of neonatal brain injury • Term hypoxia-ischemia • Preterm and other high-risk groups • Treatment Strategies • Clinical Standards • Neuroprotection with Hypothermia

5. Cerebralenergy Membranedepolarization Neurotransmitterrelease Ca++ Free radicals Neuronaldamage Reperfusion Free radicals Celldeath necrosis apoptosis

6. Why is the immature brain particularly susceptible? Intervascular Boundary Zone Basal Ganglia Increased requirement for oxidative metabolism Increased amounts of excitatory amino acid receptors Immature vascular regulation Response to inflammation Selective cell type vulnerabilities Maturational differences in free radical management

7. Superoxide Dismutase Catalase O•2 H2O2 H2O GSH Glutathione peroxidase Fe++ GSSG H2O OH- 1.Immature brain has altered balance of antioxidants 2. The iron rich neonatal brain is vulnerable Fe2+ + H2O2 Fe3+ + HO. + OH-

8. Patterns in Neonatal Hypoxia-Ischemia Term Deep Grey Nuclei Preterm & Cardiac Periventricular White Matter

9. Take-Home Points: pathogenesis • Key to the cascade of injury: • ATP, glutamate, calcium, free radicals • Injury evolves over time • Immature brain has unique susceptibilities • Patterns of brain injury depend on maturational state of the brain • Term = injury to basal ganglia, intervascular boundary zones • Preterm = injury to periventricular white matter • Heart disease = blurs this distinction

10. Overview • Mechanisms of neonatal brain injury • Term hypoxia-ischemia • Preterm and other high-risk groups • Treatment Strategies • Clinical Standards • Experimental Neuroprotection

11. Secure airway; maintain normal ventilation and oxygenation parameters Severe hyperoxygenation (paO2 >200) and hypocarbia (pCo2 <20) associated with worse outcomes in HIE infants Maintain systemic circulation to maintain cerebral perfusion Cerebral edema maximal between 36-96 hours Antiedema agents not helpful Control seizures, use EEG to monitor for subclinical seizures Evaluate and treat electrolyte disturbances- avoid hypoglycemia HYPOTHERMIA Avoid hyperthermia Clinical Standards

12. Hypothermia: potential mechanisms • Decreased metabolism/ATP preservation • Inhibition of glutamate release • Decreased free radical generation • Decreased apoptosis • Decreased inflammatory response • Prolongation of therapeutic window?

13. Hypothermia eligibility criteria • ≥ 36 weeks gestational age • ≤ 6 hours of age • History of perinatal event • Apgar score < 5 at 10 minutes • Cord pH or any postnatal blood gas pH within 1 hour of birth ≤ 7.0. • Base deficit on cord gas or any postnatal blood gas within 1 hour of birth ≥16 mEq/L. • Continued need for ventilation at 10 minutes • Neurological exam consistent with moderate to severe encephalopathy OR presence of seizures before 6 hours of life

14. Hypothermia efficacy studies: eligibility criteria- neuro exam

15. Hypothermia efficacy studies, 2005 • Gunn et al- Lancet • Head cooling, n= 234, used aEEG as additional criteria • Overall no difference in death/severe disability, but subgroup analysis of moderately affected infants showed positive effect: OR 0.42 (95% CI .22-.8, p = 0.009). • NICHD- NEJM • Systemic cooling, n = 239 • 18% decrease in composite outcome with hypothermia (44% vs. 62%, RR .72, 95% CI .54-.95, p = 0.01) • No significant difference in CP in survivors of either group • Eicher et al- Pediatric Neurology • Systemic cooling, n= 65 • Tested ability to initiate tx in referral hospitals • Composite outcome 52% treated, 84% control, p= 0.019.

16. Hypothermia • Summary in 2005: • Short-term benefit (18 month follow-up) in affected neonates using experimental protocols • Safe therapy • Survey Oct. 05: 6.4% respondents offered, mainly academic centers

17. Shah et al, 2007 Arch Pediatric Adol. Med Epub

18. Cochrane Review • October 2007 • 8 RCT, 638 term infants, mod-sev HIE • Composite outcome • RR 0.76, 95% CI 0.65-0.89, NNT 7 • Mortality alone: RR.74 (.58-.94) NNT 11 • Disability alone: RR.68 (.51-.92) NNT 8 • Cooling reduces mortality without increasing disability, benefits outweigh short-term adverse effects, but review comprises data from less than half infants currently randomized . . . So questions remained

19. Systematic Review 2010 Up to 1440 patients Shah, Semin Fetal Neonatal Med., 2010

20. Systematic Review 2010 Shah, Semin Fetal Neonatal Med., 2010

21. Systematic Review 2010 Shah, Semin Fetal Neonatal Med., 2010

22. Hypothermia: Questions Remain Is it effective in the severely affected? How late can you initiate cooling and still see an effect? 6-24 hour hypothermia trial underway What is the optimum degree and duration of cooling? optimizing cooling trial just begun Can we extend this protection down to the preterm population? trial of hypothermia proposed for 33-35 wk GA Should the degree/duration of cooling be based on cause, severity and stage of brain injury?

23. Overview • Mechanisms of neonatal brain injury • Term hypoxia-ischemia • Preterm and other high-risk groups • Treatment Strategies • Clinical Standards • Experimental Neuroprotection • Developmentally appropriate

24. The Ideal Neuroprotectant • Cross the blood brain barrier • Accumulate at desired site of action • Act for appropriate duration of time • No drug interactions • No adverse side effects • Does not prevent normal maturation • Would work post-injury

25. HIE: Treatment Strategies • Maintain energy stores to reduce depletion of ATP • Inhibit glutamate release • Block Calcium entry • Inhibit degradative enzymes • Scavenge free radicals, reduce Fenton chemistry • Block apoptosis • Modulate inflammation

26. Treatment Strategies in Hypoxia Ischemia Cerebral blood flow Hypothermia Energy failure Glutamate release NMDA-2nd messenger modulation FBP Calcium-dependent ‘excitotoxicity’ Necrotic cell death Apoptotic cell death Free radical injury Antioxidants, desferoxamine Delayed cell death Caspase inhibitors Anti-inflammitory agents Inflammation Repair Restoration Stem cells Neurotrophins Plasticity & Recovery

27. Cocktail approach Ferriero, D. M., N Engl J Med 2004

28. Take-Home Points: treatment • Maintain “ABCs” • Avoid hyperoxygenation, hypocarbia, seizures, hypoglycemia, or hyperthermia • Hypothermia now proven therapy for moderate, ?severe HIE • Additional hypothermia trials underway • Late, “optimizing” and ??33-35 weekers • Neuroprotection must not disrupt normal maturational process • Successes are possible