Inhaled 45-50% argon augments hypothermic brain protection in a piglet model of perinatal asphyxia

Neurobiol Dis. 2016 Mar:87:29-38. doi: 10.1016/j.nbd.2015.12.001. Epub 2015 Dec 10.

Abstract

Cooling to 33.5°C in babies with neonatal encephalopathy significantly reduces death and disability, however additional therapies are needed to maximize brain protection. Following hypoxia-ischemia we assessed whether inhaled 45-50% Argon from 2-26h augmented hypothermia neuroprotection in a neonatal piglet model, using MRS and aEEG, which predict outcome in babies with neonatal encephalopathy, and immunohistochemistry. Following cerebral hypoxia-ischemia, 20 Newborn male Large White piglets<40h were randomized to: (i) Cooling (33°C) from 2-26h (n=10); or (ii) Cooling and inhaled 45-50% Argon (Cooling+Argon) from 2-26h (n=8). Whole-brain phosphorus-31 and regional proton MRS were acquired at baseline, 24 and 48h after hypoxia-ischemia. EEG was monitored. At 48h after hypoxia-ischemia, cell death (TUNEL) was evaluated over 7 brain regions. There were no differences in body weight, duration of hypoxia-ischemia or insult severity; throughout the study there were no differences in heart rate, arterial blood pressure, blood biochemistry and inotrope support. Two piglets in the Cooling+Argon group were excluded. Comparing Cooling+Argon with Cooling there was preservation of whole-brain MRS ATP and PCr/Pi at 48h after hypoxia-ischemia (p<0.001 for both) and lower (1)H MRS lactate/N acetyl aspartate in white (p=0.03 and 0.04) but not gray matter at 24 and 48h. EEG background recovery was faster (p<0.01) with Cooling+Argon. An overall difference between average cell-death of Cooling versus Cooling+Argon was observed (p<0.01); estimated cells per mm(2) were 23.9 points lower (95% C.I. 7.3-40.5) for the Cooling+Argon versus Cooling. Inhaled 45-50% Argon from 2-26h augmented hypothermic protection at 48h after hypoxia-ischemia shown by improved brain energy metabolism on MRS, faster EEG recovery and reduced cell death on TUNEL. Argon may provide a cheap and practical therapy to augment cooling for neonatal encephalopathy.

Keywords: Argon; Hypoxia–ischemia; Neonatal encephalopathy; Noble gas; Therapeutic hypothermia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Argon / administration & dosage*
  • Aspartic Acid / analogs & derivatives
  • Aspartic Acid / metabolism
  • Asphyxia Neonatorum / pathology
  • Asphyxia Neonatorum / physiopathology
  • Asphyxia Neonatorum / therapy*
  • Blood Chemical Analysis
  • Blood Pressure
  • Brain / pathology
  • Brain / physiopathology
  • Cell Death / physiology
  • Disease Models, Animal
  • Heart Rate
  • Hypothermia, Induced / methods*
  • Hypoxia-Ischemia, Brain / pathology
  • Hypoxia-Ischemia, Brain / physiopathology
  • Hypoxia-Ischemia, Brain / therapy*
  • Inhalation
  • Lactic Acid / metabolism
  • Male
  • Neuroprotection
  • Random Allocation
  • Respiration, Artificial / methods*
  • Sus scrofa

Substances

  • Aspartic Acid
  • Lactic Acid
  • Argon
  • N-acetylaspartate