title: Excitotoxicity and Metabolic Crisis Are Associated with Spreading Depolarizations in Severe Traumatic Brain Injury Patients.
abstract: Cerebral microdialysis has enabled the clinical characterization of excitotoxicity (glutamate >10 μM) and non-ischemic metabolic crisis (lactate/pyruvate ratio [LPR] >40) as important components of secondary damage in severe traumatic brain injury (TBI). Spreading depolarizations (SD) are pathological waves that occur in many patients in the days following TBI and, in animal models, cause elevations in extracellular glutamate, increased anaerobic metabolism, and energy substrate depletion. Here, we examined the association of SD with changes in cerebral neurochemistry by placing a microdialysis probe alongside a subdural electrode strip in peri-lesional cortex of 16 TBI patients requiring neurosurgery. In 107 h (median; range: 76-117 h) of monitoring, 135 SDs were recorded in six patients. Glutamate (50 μmol/L) and lactate (3.7 mmol/L) were significantly elevated on day 0 in patients with SD compared with subsequent days and with patients without SD, whereas pyruvate was decreased in the latter group on days 0 and 1 (two-way analysis of variance [ANOVA], p values <0.05). In patients with SD, both glutamate and LPR increased in a dose-dependent manner with the number of SDs in the microdialysis sampling period (0, 1, ≥2 SD) [glutamate: 2.1→7.0→52.3 μmol/L; LPR: 27.8→29.9→45.0, p values <0.05]. In these patients, there was a 10% probability of SD occurring when glutamate and LPR were in normal ranges, but a 60% probability when both variables were abnormal (>10 μmol/L and >40 μmol/L, respectively). Taken together with previous studies, these preliminary clinical results suggest SDs are a key pathophysiological process of secondary brain injury associated with non-ischemic glutamate excitotoxicity and severe metabolic crisis in severe TBI patients.
authors.affiliation: 1 Department of Neurosurgery, University of Cincinnati (UC) College of Medicine , Cincinnati, Ohio.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Hinzman
authors.affiliation: 1 Department of Neurosurgery, University of Cincinnati (UC) College of Medicine , Cincinnati, Ohio.
authors.forename: J Adam
authors.initials: JA
authors.lastname: Wilson
authors.affiliation: 2 Division of Neurosurgery, Virginia Commonwealth University , Richmond, Virginia.|3 Department Anesthesia and Intensive Care, University of Torino , Torino, Italy .
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Mazzeo
authors.affiliation: 2 Division of Neurosurgery, Virginia Commonwealth University , Richmond, Virginia.|4 Department of Neurosurgery, University of Miami , Miami, Florida.
authors.forename: M Ross
authors.initials: MR
authors.lastname: Bullock
authors.affiliation: 1 Department of Neurosurgery, University of Cincinnati (UC) College of Medicine , Cincinnati, Ohio.|5 Neurotrauma Center, UC Neuroscience Institute , Cincinnati, Ohio.|6 Mayfield Clinic , Cincinnati, Ohio.
authors.forename: Jed A
authors.initials: JA
authors.lastname: Hartings
keywords: electrocorticography; multi-modal monitoring; spreading depression