To investigate the effects of recombinant human erythropoietin on brain oxygenation in a model of diffuse traumatic brain injury.
Adult male Wistar rats.
Neurosciences and physiology laboratories.
Thirty minutes after diffuse traumatic brain injury (impact-acceleration model), rats were intravenously administered with either a saline solution or a recombinant human erythropoietin (5000 IU/kg). A third group received no traumatic brain injury insult (sham-operated).
Three series of experiments were conducted 2 hours after traumatic brain injury to investigate: 1) the effect of recombinant human erythropoietin on brain edema using diffusion-weighted magnetic resonance imaging and measurements of apparent diffusion coefficient (n = 11 rats per group); local brain oxygen saturation, mean transit time, and blood volume fraction were subsequently measured using a multiparametric magnetic resonance–based approach to estimate brain oxygenation and brain perfusion in the neocortex and caudoputamen; 2) the effect of recombinant human erythropoietin on brain tissue PO2 in similar experiments (n = 5 rats per group); and 3) the cortical ultrastructural changes after treatment (n = 1 rat per group). Compared with the sham-operated group, traumatic brain injury saline rats showed a significant decrease in local brain oxygen saturation and in brain tissue PO2 alongside brain edema formation and microvascular lumen collapse at H2. Treatment with recombinant human erythropoietin reversed all of these traumatic brain injury–induced changes. Brain perfusion (mean transit time and blood volume fraction) was comparable between the three groups of animals.
Our findings indicate that brain hypoxia can be related to microcirculatory derangements and cell edema without evidence of brain ischemia. These changes were reversed with post-traumatic administration of recombinant human erythropoietin, thus offering new perspectives in the use of this drug in brain injury.
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1INSERM, U836, Grenoble, France.
2Université Joseph Fourier, Grenoble Institut des Neurosciences, Grenoble, France.
3Pôle d’Anesthésie-Réanimation, Hôpital Michallon, Grenoble, France.
4Département de Réanimation Pédiatrique, Hôpital Couple-Enfant, Grenoble, France.
*See also p. 1380.
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Drs. Bouzat, Barbier, and Payen designed the investigation. Drs. Bouzat, Millet, Boue, Pernet-Gallay, Trouve-Buisson, Gaide-Chevronnay, and Barbier performed the investigation. Drs. Bouzat, Millet, Boue, Pernet-Gallay, and Payen analyzed data. Drs. Bouzat, Barbier, and Payen wrote the paper.
Supported, in part, by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Fondation des Gueules-Cassées, Association pour la Recherche en Néonatologie, and Ministère de l’Education, de la Recherche et de la Technologie, France.
Dr. Payen consulted for Biocodex, S.A., Baxter; has received grant support from Hutchinson Tech., Novonordisk; and received payment for lectures from Abbott, LFB, GE Healthcare, and Integra Lifescience. The remaining authors have not disclosed any potential conflicts of interest.
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