title: 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.affiliation: Institute for Women's Health, University College London, United Kingdom.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Broad
authors.affiliation: Institute for Women's Health, University College London, United Kingdom.
authors.forename: Igor
authors.initials: I
authors.lastname: Fierens
authors.affiliation: Centre for the Developing Brain, Kings College, St Thomas's Campus, London, United Kingdom; Inserm, Paris, France; University Paris Diderot, Sorbonne Paris Cite, UMRS, 1141 Paris, France.
authors.forename: Bobbi
authors.initials: B
authors.lastname: Fleiss
authors.affiliation: Institute for Women's Health, University College London, United Kingdom.
authors.forename: Eridan
authors.initials: E
authors.lastname: Rocha-Ferreira
authors.affiliation: Institute for Women's Health, University College London, United Kingdom.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Ezzati
authors.affiliation: Institute for Women's Health, University College London, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Hassell
authors.affiliation: Institute for Women's Health, University College London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Alonso-Alconada
authors.affiliation: Physics and Bioengineering, University College London NHS Trust, London, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Bainbridge
authors.affiliation: Institute for Women's Health, University College London, United Kingdom.
authors.forename: Go
authors.initials: G
authors.lastname: Kawano
authors.affiliation: Department of Anaesthetics, Intensive Care and Pain Medicine, Department of Surgery & Cancer, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom.
authors.forename: Daqing
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Medical Physics and Biomedical Engineering, University College London, United Kingdom.
authors.forename: Ilias
authors.initials: I
authors.lastname: Tachtsidis
authors.affiliation: Centre for the Developing Brain, Kings College, St Thomas's Campus, London, United Kingdom; Inserm, Paris, France; University Paris Diderot, Sorbonne Paris Cite, UMRS, 1141 Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.affiliation: Institute of Neurology, University College London, United Kingdom.
authors.forename: Xavier
authors.initials: X
authors.lastname: Golay
authors.affiliation: Department of Anesthesiology, University of Wisconsin, Madison, United States.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Sanders
authors.affiliation: Institute for Women's Health, University College London, United Kingdom. Electronic address: n.robertson@ucl.ac.uk.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Robertson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001128:Argon / Q000008:administration & dosage*; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001238:Asphyxia Neonatorum / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D001774:Blood Chemical Analysis; D001794:Blood Pressure; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000502:physiology; D004195:Disease Models, Animal; D006339:Heart Rate; D007036:Hypothermia, Induced / Q000379:methods*; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D001239:Inhalation; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D000066829:Neuroprotection; D011897:Random Allocation; D012121:Respiration, Artificial / Q000379:methods*; D034421:Sus scrofa
chemical_list: D001224:Aspartic Acid; D019344:Lactic Acid; D001128:Argon; C000179:N-acetylaspartate
keywords: Argon; Hypoxia–ischemia; Neonatal encephalopathy; Noble gas; Therapeutic hypothermia