B3: Hyperoxia after traumatic brain injury and hemorrhagic shock with pre-existing atherosclerosis

PI: C. Hartmann, P. Radermacher

Hemorrhagic shock (HS) and/or traumatic brain injury (TBI) determine post-traumatic outcome. Rapid “repayment of the O2 debt” and prevention of brain tissue hypoxia are cornerstones of the management of HS and TBI. Restoring tissue perfusion represents an ischemia/reperfusion (I/R) injury due to formation of reactive oxygen (ROS) and nitrogen (RNS) species, ultimately leading to multi-organ failure (MOF). Hyperoxia (i.e. ventilation with 100% O2) can counteract tissue hypoxia, but may cause damage due to excess ROS release, in particular in distributive shock with impaired cellular O2 extraction. However, hyperoxia may be beneficial in shock with reduced O2 transport capacity, e.g. HS. Coronary artery disease (CAD) may increase mortality after HS and TBI, but in the first funding period, we showed that hyperoxia attenuated acute kidney injury (AKI) and improved survival after HS in swine with CAD. Hyperoxia is particularly controversial in patients with TBI due to ROS-induced cerebral vasoconstriction. Moreover, catecholamine infusion- or I/R-injury-induced ROS release can impair mitochondrial respiration, a crucial factor for MOF, but we showed that hyperoxia attenuated ROS and RNS formation and improved mitochondrial respiration. Using a newly established, long-term model of acute subdural hematoma (ASDH)-induced TBI with/without HS in swine with/without CAD, the project therefore investigates the role of hyperoxia and pre-existing CAD for neurological function and brain injury after TBI with HS. ASDH-induced TBI is studied, because it is a well-reproducible model of large animal TBI and particularly important in vascular co-morbid TBI patients. Readouts comprise neurological function, multi- model brain monitoring, markers of brain damage and ROS/RNS release, mitochondrial respiration and post mortem brain region-specific analyses of cell death, diffuse axonal damage and neuro-inflammation. In vivodata are complemented by quantification of glucose utilization, oxidative phosphorylation and ROS production in immune cells to characterize adaptive metabolic switching to trauma-induced activation.

Projektleiter

Dr. med. Clair Hartmann
Universitätsklinikum Ulm
Klinik für Anästhesiologie
Albert-Einstein-Allee 23
89081 Ulm
Tel.: +49 731 500 60232
E-mail: clair.hartmann(at)uni-ulm.de

Prof. Dr. med. Dr. h.c. Peter Radermacher
Universitätsklinikum Ulm
Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung (APV)  
Helmholtzstr. 8/1
89081 Ulm
Tel.: +49 731 500 60214
Fax: +49 731 500 60162
peter.radermacher(at)uni-ulm.de