Post-Traumatic Hypoxia Is Associated with Prolonged Cerebral Cytokine Production, Higher Serum Biomarker Levels, and Poor Outcome in Patients with Severe Traumatic Brain Injury

Abstract

Secondary hypoxia is a known contributor to adverse outcomes in patients with traumatic brain injury (TBI). Based on the evidence that hypoxia and TBI in isolation induce neuroinflammation, we investigated whether TBI combined with hypoxia enhances cerebral cytokine production. We also explored whether increased concentrations of injury biomarkers discriminate between hypoxic (Hx) and normoxic (Nx) patients, correlate to worse outcome, and depend on blood-brain barrier (BBB) dysfunction. Forty-two TBI patients with Glasgow Coma Scale ≤8 were recruited. Cerebrospinal fluid (CSF) and serum were collected over 6 days. Patients were divided into Hx (n=22) and Nx (n=20) groups. Eight cytokines were measured in the CSF; albumin, S100, myelin basic protein (MBP) and neuronal specific enolase (NSE) were quantified in serum. CSF/serum albumin quotient was calculated for BBB function. Glasgow Outcome Scale Extended (GOSE) was assessed at 6 months post-TBI. Production of granulocye macrophage-colony stimulating factor (GM-CSF) was higher, and profiles of GM-CSF, interferon (IFN)-γ and, to a lesser extent, tumor necrosis factor (TNF), were prolonged in the CSF of Hx but not Nx patients at 4-5 days post-TBI. Interleukin (IL)-2, IL-4, IL-6, and IL-10 increased similarly in both Hx and Nx groups. S100, MBP, and NSE were significantly higher in Hx patients with unfavorable outcome. Among these three biomarkers, S100 showed the strongest correlations to GOSE after TBI-Hx. Elevated CSF/serum albumin quotients lasted for 5 days post-TBI and displayed similar profiles in Hx and Nx patients. We demonstrate for the first time that post-TBI hypoxia is associated with prolonged neuroinflammation, amplified extravasation of biomarkers, and poor outcome. S100 and MBP could be implemented to track the occurrence of post-TBI hypoxia, and prompt adequate treatment.

Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

“…24,25 Post-traumatic hypoxia in patients with closed head trauma increases GM-CSF in the cerebrospinal fluid. 26 Whole body radiation that included brain induced increased synthesis of G-CSF that, although it contributes to BM recovery, 27 contributed to systemic immunosuppression (see section "Elevated G(M)-CSF is immunosuppressive in GB").…”

Low-Level Light in Combination with Metabolic Modulators for Effective Therapy of Injured Brain

“…Adequate function of mitochondria is pivotal for the survival and activity of all brain cells, and even brief periods of oxygen or glucose deprivation could shut down brain functions within seconds, damaging neurons within minutes. 4 Abundant data from retrospective studies and prospective clinical trials have shown brain hypoxia to be an early predictor of adverse outcomes after TBI, [5][6][7] because efficient ATP production by the mitochondrial respiratory chain relies on continuous oxygen supply.…”

Hypocalcaemia and Its Role in Traumatic Brain Injury

“…In TBI the expression of S100 is upregulated and therefore could be responsible for hypocalcaemia by elevated calcium binding [19,27].…”