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Causes of neonatal mortality Congenital 7% Other 7% Sepsis/pneumon ia 26% Asphyxia 23% Tetanus 7% Diarrhea 3% Preterm 27% Lawn JE, et al. Intl J Epidemiol (2006) Processes involved in HI Brain Injury 1o energy failure ↑ Excitatory amino acids Loss of ionic balance ↑ Intracellular Ca++ ↑ Lipases, proteases ↑ Free radicals 2o energy failure Activated microglia Apoptosis ↓ Growth factors ↓ Protein synthesis Oxidative injury ↑ Excitatory amino acids NICHD Trial: Primary Outcome Percent Death or Disability 100 90 80 70 60 50 40 30 20 10 0 RR: O.72 95% CI 0.54-0.95 P value= 0.01 Disability defined as: 62% Bayley MDI <70 GMFCS ≥ level 2 Hearing impairment Seizure disorder Blindness 44% Hypothermia n = 102 Control Group n = 106 Shankaran S, et al. NEJM (2005) Shankaran S et al., N Engl J Med (2005) Erythropoietin (Epo) Generally used for erythropoiesis, may also provide neuroprotection Mechanisms include: decreased apoptosis enhanced neurogenesis decreased inflammation decreased susceptibility to glutamate toxicity Preterm infants treated with Epo for anemia have demonstrated improved neurodevelopmental outcomes Neubauer AP, et al. Ann Neurol 2010 Term infants treated with Epo have decreased seizures, improved EEG, and better neurologic outcome Zhu C, et al. Pediatrics 2009, Elmahdy H, et al. Pediatrics 2010 Erythropoietin improves neurologic outcome in newborns with HIE: Primary outcomes Epo (N=73) Control (n=80) RR (95% CI) P value 24.6 4.1 21.4 43.8 5.0 40.8 0.62 (0.41-0.94) 0.89 (0.37-2.13) 0.59 (0.38-0.93) .017 .999 .013 Primary outcome Death Disability Conclusion: Low dose Epo given for 2 weeks reduced the risk of disability for infants with moderate HIE without apparent side effects. Zhu C et al. Pediatrics (2009) Zhu C, et al. Pediatrics (2009) Erythropoietin Improves neurologic outcome in HIE : Secondary outcomes Epo (n=73) Control (n=80) RR (95% CI) P value Death or disability Moderate HIE Severe HIE Male Female 6.4 57.7 29.8 6.3 32.2 76.2 45.5 40.0 0.26 (0.48-2.47) 0.70 (0.43-1.15) 0.71 (0.47-1.08) 0.18 (0.03-1.22) .001 .227 .118 .029 MDI <70 Moderate HIE Severe HIE 10.0 4.3 21.7 22.4 15.8 42.1 0.56 (0.30-1.08) 0.38 (0.11-1.34) 0.62 (0.29-1.30) .048 .106 .193 Cerebral palsy Moderate HIE Severe HIE 6.8 2.1 17.4 18.4 14.0 31.6 0.51 (0.23-1.11) 0.23 (0.04-1.47) 0.67 (0.30-1.52) .051 .039 .468 Zhu C et al. Pediatrics (2009) Zhu C, et al. Pediatrics (2009) NEATO: A Phase II trial Objective: To determine if Epo administered for 7 days improves neuroradiographic and short term outcomes for moderate to severe HIE Intervention: Epo 1000 units/kg IV or placebo at 1, 2, 3, 5 and 7 days of age Outcome measures: MRI brain injury score and neurodevelopmental outcome at 12-14 months using Warner Initial Developmental Evaluations (WIDEA) and Alberta Infant Motor Scale (AIMS) Brain MRI Injury Score Outcome Epo (n=23) Placebo (n=25) P value Age at MRI (days) 5.6 4.9 0.28 Global brain injury score None Mild Moderate Severe 0.01 35% 61% 0% 4% 12% 44% 24% 20% Presence of brain injury by region Subcortical Cortical White matter Brainstem Cerebellar 2 or more regions 30% 17% 52% 4% 0% 30% 68% 36% 60% 16% 20% 56% 0.02 0.26 0.80 0.35 0.05 0.14 Wu Y, et al. WSPR 2016 Neurodevelopmental Outcomes Outcome Epo (n=21) Placebo (n=21) P value WIDEA at 6 months Total score 75.3 68.8 0.04 WIDEA at 12 months Total score 122 110 0.15 Alberta Infant Motor Score (AMIS) 53.3 42.8 0.03 Moderate to severe NDI 8% 19% 0.42 Wu Y, et al. WSPR 2016 NEATO Phase II trial: Results Neonatal deaths did not differ between Epo and placebo groups (8% versus 19%, p=0.42) Brain MRI at mean 5 days showed a lower global brain injury score in Epo treated (2 versus 11, p=0.01) Moderate/severe brain injury, subcortical and cerebellar injury were less frequent. At 1 year, infant motor scores were higher among Epo treated based on WIDEA (p=0.05) and AIMS (p=0.03). NEATO Phase II Trial: Conclusions High doses of Epo, in conjunction with hypothermia, resulted in less MRI brain injury and in improved short-term motor outcomes following moderate to severe hypoxic ischemic encephalopathy A phase III trial has been designed and a grant application has been submitted to NINDS.