title: Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia.
abstract: BACKGROUND
  Up to 65% of untreated infants suffering from moderate to severe hypoxic-ischemic encephalopathy (HIE) are at risk of death or major disability. Therapeutic hypothermia (HT) reduces this risk to approximately 50% (number needed to treat: 7-9). Erythropoietin (Epo) is a neuroprotective treatment that is promising as an adjunctive therapy to decrease HIE-induced injury because Epo decreases apoptosis, inflammation, and oxidative injury and promotes glial cell survival and angiogenesis. We hypothesized that HT and concurrent Epo will be safe and effective, improve survival, and reduce moderate-severe cerebral palsy (CP) in a term nonhuman primate model of perinatal asphyxia.
  
  
  METHODS
  Thirty-five Macaca nemestrina were delivered after 15-18 min of umbilical cord occlusion (UCO) and randomized to saline (n = 14), HT only (n = 9), or HT+Epo (n = 12). There were 12 unasphyxiated controls. Epo (3,500 U/kg × 1 dose followed by 3 doses of 2,500 U/kg, or Epo 1,000 U/kg/day × 4 doses) was given on days 1, 2, 3, and 7. Timed blood samples were collected to measure plasma Epo concentrations. Animals underwent MRI/MRS and diffusion tensor imaging (DTI) at <72 h of age and again at 9 months. A battery of weekly developmental assessments was performed.
  
  
  RESULTS
  UCO resulted in death or moderate-severe CP in 43% of saline-, 44% of HT-, and 0% of HT+Epo-treated animals. Compared to non-UCO control animals, UCO animals exhibit poor weight gain, behavioral impairment, poor cerebellar growth, and abnormal brain DTI. Compared to UCO saline, UCO HT+Epo improved motor and cognitive responses, cerebellar growth, and DTI measures and produced a death/disability relative risk reduction of 0.911 (95% CI -0.429 to 0.994), an absolute risk reduction of 0.395 (95% CI 0.072-0.635), and a number needed to treat of 2 (95% CI 2-14). The effects of HT+Epo on DTI included an improved mode of anisotropy, fractional anisotropy, relative anisotropy, and volume ratio as compared to UCO saline-treated infants. No adverse drug reactions were noted in animals receiving Epo, and there were no hematology, liver, or kidney laboratory effects.
  
  
  CONCLUSIONS
  HT+Epo treatment improved outcomes in nonhuman primates exposed to UCO. Adjunctive use of Epo combined with HT may improve the outcomes of term human infants with HIE, and clinical trials are warranted.
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Wash., USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Traudt
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: McPherson
authors.forename: Larry A
authors.initials: LA
authors.lastname: Bauer
authors.forename: Todd L
authors.initials: TL
authors.lastname: Richards
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Burbacher
authors.forename: Ryan M
authors.initials: RM
authors.lastname: McAdams
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Juul
mesh_terms: D000818:Animals; D001237:Asphyxia / Q000188:drug therapy* / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000627:therapeutic use*; D006801:Humans; D007035:Hypothermia / Q000378:metabolism*; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism; D007223:Infant; D008254:Macaca nemestrina; D011994:Recombinant Proteins / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa