title: Xenon augmented hypothermia reduces early lactate/N-acetylaspartate and cell death in perinatal asphyxia.
abstract: OBJECTIVE
  Additional treatments for therapeutic hypothermia are required to maximize neuroprotection for perinatal asphyxial encephalopathy. We assessed neuroprotective effects of combining inhaled xenon with therapeutic hypothermia after transient cerebral hypoxia-ischemia in a piglet model of perinatal asphyxia using magnetic resonance spectroscopy (MRS) biomarkers supported by immunohistochemistry.
  
  
  METHODS
  Thirty-six newborn piglets were randomized (all groups n = 9), with intervention from 2 to 26 hours, to: (1) normothermia; (2) normothermia + 24 hours 50% inhaled xenon; (3) 24 hours hypothermia (33.5°C); or (4) 24 hours hypothermia (33.5°C) + 24 hours 50% inhaled xenon. Serial MRS was acquired before, during, and up to 48 hours after hypoxia-ischemia.
  
  
  RESULTS
  Mean arterial blood pressure was lower in all treatment groups compared with normothermia (p < 0.01) (although >40mmHg); the combined therapy group required more fluid boluses (p < 0.05) and inotropes (p < 0.001). Compared with no intervention, both hypothermia and xenon-augmented hypothermia reduced the temporal regression slope magnitudes for phosphorus-MRS inorganic phosphate/exchangeable phosphate pool (EPP) and phosphocreatine/EPP (both p < 0.05); for lactate/N-acetylaspartate (NAA), only xenon-augmented hypothermia reduced the slope (p < 0.01). Xenon-augmented hypothermia also reduced transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)(+) nuclei and caspase 3 immunoreactive cells in parasagittal cortex and putamen and increased microglial ramification in midtemporal cortex compared with the no treatment group (p < 0.05). Compared with hypothermia, however, combination treatment did not reach statistical significance for any measure. Lactate/NAA showed a strong positive correlation with TUNEL; nucleotide triphosphate/EPP showed a strong negative correlation with microglial ramification (both p < 0.01).
  
  
  CONCLUSIONS
  Compared with no treatment, xenon-augmented hypothermia reduced cerebral MRS abnormalities and cell death markers in some brain regions. Compared with hypothermia, xenon-augmented hypothermia did not reach statistical significance for any measure. The safety and possible improved efficacy support phase II trials.
authors.affiliation: Institute for Women's Health, University College London, London, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Faulkner
authors.forename: Alan
authors.initials: A
authors.lastname: Bainbridge
authors.forename: Takenori
authors.initials: T
authors.lastname: Kato
authors.forename: Manigandan
authors.initials: M
authors.lastname: Chandrasekaran
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Kapetanakis
authors.forename: Mariya
authors.initials: M
authors.lastname: Hristova
authors.forename: Mengyan
authors.initials: M
authors.lastname: Liu
authors.forename: Samantha
authors.initials: S
authors.lastname: Evans
authors.forename: Enrico
authors.initials: E
authors.lastname: De Vita
authors.forename: Dorottya
authors.initials: D
authors.lastname: Kelen
authors.forename: Robert D
authors.initials: RD
authors.lastname: Sanders
authors.forename: A David
authors.initials: AD
authors.lastname: Edwards
authors.forename: Mervyn
authors.initials: M
authors.lastname: Maze
authors.forename: Ernest B
authors.initials: EB
authors.lastname: Cady
authors.forename: Gennadij
authors.initials: G
authors.lastname: Raivich
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Robertson
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000831:Animals, Newborn; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D001237:Asphyxia / Q000378:metabolism* / Q000628:therapy*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D007036:Hypothermia, Induced / Q000379:methods*; D019344:Lactic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D011897:Random Allocation; D013552:Swine; D013997:Time Factors; D014978:Xenon / Q000008:administration & dosage*
chemical_list: D001224:Aspartic Acid; D019344:Lactic Acid; D014978:Xenon; C000179:N-acetylaspartate