Erythropoietin in Infants With Hypoxic Ischemic Encephalopathy (HIE)

Study Overview
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Brief Summary
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In this prospective trial the investigators plan to study the efficacy of erythropoietin as a therapeutic agent in neonates who suffer from brain injury following perinatal asphyxia.

Detailed Description
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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.

Official Title
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Human Recombinant Erythropoietin (HrEPO) in Asphyxia Neonatorum: A Pilot Trial

Conditions
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Hypoxic Ischemic Encephalopathy

Intervention / Treatment
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* Drug: Human recombinant erythropoietin
* Procedure: EEG and Brain MRI
* Biological: Nitric oxide measurement in the blood


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 24 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EPO HIE Group<br>Infants with hypoxic ischemic encephalopathy receive human recombinant erythropoietin | Drug: Human recombinant erythropoietin<br>* Epo dse is 2500 IU/kg subcutaneous daily for 5 days.<br>Procedure: EEG and Brain MRI<br>* EEG to be done twice in hte first 48 hours and at 2-3 weeks. MRI to be done at 3 weeks of age.<br>Biological: Nitric oxide measurement in the blood<br>* Concentration of nitric oxide is measured in the blood at enrollment. For the 2 groups with asphyxia, measurement to be repeated in 2 weeks.<br>|
| No Intervention: Control HIE<br>Infants with hypoxic ischemic encephalopathy who do not receive treatment drug (EPO) | Procedure: EEG and Brain MRI<br>* EEG to be done twice in hte first 48 hours and at 2-3 weeks. MRI to be done at 3 weeks of age.<br>Biological: Nitric oxide measurement in the blood<br>* Concentration of nitric oxide is measured in the blood at enrollment. For the 2 groups with asphyxia, measurement to be repeated in 2 weeks.<br>|
| Other: Healthy Controls<br>Healthy newborn without hypoxic ischemic encephalopathy | Biological: Nitric oxide measurement in the blood<br>* Concentration of nitric oxide is measured in the blood at enrollment. For the 2 groups with asphyxia, measurement to be repeated in 2 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurodevelopmental outcomes |  | 6 months | 
| EEG changes |  | 2-3 weeks | 
| MRI of the brain |  | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nitric oxide concentrations in the plasma |  | 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asphyxia neonatorum, Infants, EEG, Brain MRI, Nitric oxide