Xenon augmented hypothermia reduces early lactate/N-acetylaspartate and cell death in perinatal asphyxia

Stuart Faulkner, Alan Bainbridge, Takenori Kato, Manigandan Chandrasekaran, Andrew B Kapetanakis, Mariya Hristova, Mengyan Liu, Samantha Evans, Enrico De Vita, Dorottya Kelen, Robert D Sanders, A David Edwards, Mervyn Maze, Ernest B Cady, Gennadij Raivich, Nicola J Robertson

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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).

INTERPRETATION: 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.

Original languageEnglish
Pages (from-to)133-50
Number of pages18
JournalAnnals of Neurology
Volume70
Issue number1
DOIs
Publication statusPublished - Jul 2011

Keywords / Materials (for Non-textual outputs)

  • Administration, Inhalation
  • Animals
  • Animals, Newborn
  • Aspartic Acid/analogs & derivatives
  • Asphyxia/metabolism
  • Cell Death/drug effects
  • Hypothermia, Induced/methods
  • Lactic Acid/antagonists & inhibitors
  • Male
  • Random Allocation
  • Swine
  • Time Factors
  • Xenon/administration & dosage

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