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

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.

• Authors: Kevin D Broad, Igor Fierens, Bobbi Fleiss, Eridan Rocha-Ferreira, Mojgan Ezzati, Jane Hassell, Daniel Alonso-Alconada, Alan Bainbridge, Go Kawano, Daqing Ma, Ilias Tachtsidis, Pierre Gressens, Xavier Golay, Robert D Sanders, Nicola J Robertson
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 87 Pg. 29-38 (Mar 2016) ISSN: 1095-953X [Electronic] United States
• PMID: 26687546 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015. Published by Elsevier Inc.

Chemical References

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

Topics

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