Erythropoietin in Infants With Hypoxic Ischemic Encephalopathy (HIE)

• Neurodevelopmental outcomes [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
• EEG changes [ Time Frame: 2-3 weeks ] [ Designated as safety issue: Yes ]
• MRI of the brain [ Time Frame: 3 weeks ] [ Designated as safety issue: Yes ]

During HIE free radicals are generated within mitochondria and also as byproducts in the synthesis of prostaglandins.These free radicals ignite a secondary phase of subsequent damage to the brain by attacking membranal fatty acids. Nitric oxide (NO) is involved in the cascade of metabolic events that contributes to HIE. It mediates, in part, the cytotoxic activity of macrophages, induces relaxation of blood vessels, and also acts as a neurotransmitter in the central and peripheral nervous system. Therefore, the therapeutic value of NO synthase inhibitors, among many other agents used to ameliorate the course of HIE, is currently under investigation in experimental animals.

Erythropoietin (EPO) is a cytokine originally identified for its role in erythropoiesis and more recently shown to be produced in the central nervous system.Relative insufficiency of endogenous EPO during periods of ischemic stress may trigger neuronal apoptosis, whereas the provision of exogenous EPO has been shown to inhibit this process. The potential immediate protective effects of EPO include decreased NO production, activation of antioxidant enzymes, reduction of glutamate toxicity, inhibition of lipid peroxidation, and reduction of inflammation. Long-term protective effects of EPO include the generation of neuronal anti-apoptotic mechanisms, stimulation of angiogenesis, and modulation of neurogenesis.

Preliminary data supports a protective role of exogenous EPO to neuronal cells. The presence of EPO rescues in vitro cultured neurons from NO-induced death. It specifically protects cultured neurons from N-methyl-D-aspartate (NMDA) receptor-mediated glutamate toxicity. Intercerebroventricular injection of EPO offered significant protection of neuronal tissue in animals with focal cerebral ischemia. EPO is able to cross the blood brain barrier, and its concentration in the cerebrospinal fluid in normal rats significantly increases within 30 minutes following intravenous administration. EPO also offered neuronal protection when it was administered systemically to animals suffering from global and focal cerebral ischemia. In adult patients with stroke, the administration of EPO ameliorates the course of the disease. Therefore, EPO has recently received much attention and is speculated to have a role in the protection of HIE infants. However, despite the biological plausibility and the encouraging preliminary data from animals and adult humans, surprisingly EPO has never been tried in newborns with HIE even though it has already been used in neonates for other indications and is known to be safe.

• Drug: Human recombinant erythropoietin
  Epo dse is 2500 IU/kg subcutaneous daily for 5 days.
• Procedure: EEG and Brain MRI
  EEG to be done twice in hte first 48 hours and at 2-3 weeks. MRI to be done at 3 weeks of age.
• Biological: Nitric oxide measurement in the blood
  Concentration of nitric oxide is measured in the blood at enrollment. For the 2 groups with asphyxia, measurement to be repeated in 2 weeks.

• Experimental: EPO HIE Group
  Infants with hypoxic ischemic encephalopathy receive human recombinant erythropoietin
  Interventions:

  • Drug: Human recombinant erythropoietin
  • Procedure: EEG and Brain MRI
  • Biological: Nitric oxide measurement in the blood
• No Intervention: Control HIE
  Infants with hypoxic ischemic encephalopathy who do not receive treatment drug (EPO)
  Interventions:

  • Procedure: EEG and Brain MRI
  • Biological: Nitric oxide measurement in the blood
• Healthy Controls
  Healthy newborn without hypoxic ischemic encephalopathy
  Intervention: Biological: Nitric oxide measurement in the blood

Inclusion Criteria:

• Inborn infants at term gestation (38-42 weeks)
• Apgar score ≤ 3 at 5 minutes and/or delayed first breath beyond five minutes after birth
• Profound metabolic or mixed acidosis with serum bicarbonate <12 mMol/L in initial arterial blood gas
• Evidence of encephalopathy such as stupor, coma, seizures, or hypotonia in the immediate neonatal period

Exclusion Criteria:

• Twin gestation
• Maternal diabetes
• Congenital malformations of the central nervous system
• Chromosomal abnormalities
• Chorioamnionitis and congenital infections
• Intrauterine growth restriction