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Xenon Improves Neurologic Outcome and Reduces Secondary Injury Following Trauma in an In Vivo Model of Traumatic Brain Injury*

Campos-Pires, Rita MD1; Armstrong, Scott P. PhD1; Sebastiani, Anne MD2; Luh, Clara PhD2; Gruss, Marco MD3; Radyushkin, Konstantin MD4; Hirnet, Tobias2; Werner, Christian MD, PhD2; Engelhard, Kristin MD, PhD2; Franks, Nicholas P. PhD5; Thal, Serge C. MD2; Dickinson, Robert PhD1

doi: 10.1097/CCM.0000000000000624
Neurologic Critical Care

Objectives: To determine the neuroprotective efficacy of the inert gas xenon following traumatic brain injury and to determine whether application of xenon has a clinically relevant therapeutic time window.

Design: Controlled animal study.

Setting: University research laboratory.

Subjects: Male C57BL/6N mice (n = 196).

Interventions: Seventy-five percent xenon, 50% xenon, or 30% xenon, with 25% oxygen (balance nitrogen) treatment following mechanical brain lesion by controlled cortical impact.

Measurements and Main Results: Outcome following trauma was measured using 1) functional neurologic outcome score, 2) histological measurement of contusion volume, and 3) analysis of locomotor function and gait. Our study shows that xenon treatment improves outcome following traumatic brain injury. Neurologic outcome scores were significantly (p < 0.05) better in xenon-treated groups in the early phase (24 hr) and up to 4 days after injury. Contusion volume was significantly (p < 0.05) reduced in the xenon-treated groups. Xenon treatment significantly (p < 0.05) reduced contusion volume when xenon was given 15 minutes after injury or when treatment was delayed 1 or 3 hours after injury. Neurologic outcome was significantly (p < 0.05) improved when xenon treatment was given 15 minutes or 1 hour after injury. Improvements in locomotor function (p < 0.05) were observed in the xenon-treated group, 1 month after trauma.

Conclusions: These results show for the first time that xenon improves neurologic outcome and reduces contusion volume following traumatic brain injury in mice. In this model, xenon application has a therapeutic time window of up to at least 3 hours. These findings support the idea that xenon may be of benefit as a neuroprotective treatment in patients with brain trauma.

1Anaesthetics, Pain Medicine and Intensive Care Section, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.

2Department of Anaesthesiology, Medical Center of Johannes Gutenberg University, Mainz, Germany.

3Department of Anaesthesiology, Klinikum Hanau, Hanau, Germany.

4Mouse Behavioral Outcome Unit, Focus Program Translational Neurosciences, Johannes Gutenberg University, Mainz, Germany.

5Department of Life Sciences, Imperial College London, London, United Kingdom.

* See also p. 250.

Drs. Campos-Pires, Armstrong, and Sebastiani contributed equally.

Supported by European Society for Anaesthesiology, Brussels, Belgium, the Association of Anaesthetists of Great Britain & Ireland, London, United Kingdom, The Royal College of Anaesthetists, London, United Kingdom, the Royal Centre for Defence Medicine, Birmingham, United Kingdom, the Medical Research Council, London and Deutscher Akademischer Austauschdienst, German Academic Exchange Service, Bonn, Germany.

Dr. Campos-Pires is the recipient of a doctoral training award from the Fundação para a Ciência e a Tecnologia, Lisbon, Portugal. Dr. Armstrong was the recipient of a studentship from the Medical Research Council, London, United Kingdom. Mr. Hirnet is funded by the German Federal Ministry of Education and Research, Berlin, Germany (grant BMBF 01EO1003). Dr. Gruss received grant support from the University Giessen, Germany (support in 2005 used for some preliminary experiments). Dr. Radyushkin has disclosed that the mouse behavior experiments were conducted on the basis of scientific service within a collaboration between Drs. Dickinson and Radyushkin. Dr. Dickinson covered all costs regarding mouse behavior experiments. Dr. Engelhard served as board member for Fresenius Kabi and lectured for Abbvie. Dr. Franks has disclosed being a named inventor on a number of patents relating to the use of xenon as a neuroprotectant. (There are no current plans to commercialize these patents, although there may be in the future. If there are, then he may have a financial interest in their exploitation.) The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: r.dickinson@imperial.ac.uk

© 2015 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins