Systemic inflammation alters the neuroinflammatory response: a prospective clinical trial in traumatic brain injury

Abstract

Background Neuroinflammation following traumatic brain injury (TBI) has been shown to be associated with secondary injury development; however, how systemic inflammatory mediators affect this is not fully understood. The aim of this study was to see how systemic inflammation affects markers of neuroinflammation, if this inflammatory response had a temporal correlation between compartments and how different compartments differ in cytokine composition. Methods TBI patients recruited to a previous randomised controlled trial studying the effects of the drug anakinra (Kineret®), a human recombinant interleukin-1 receptor antagonist (rhIL1ra), were used (n = 10 treatment arm, n = 10 control arm). Cytokine concentrations were measured in arterial and jugular venous samples twice a day, as well as in microdialysis-extracted brain extracellular fluid (ECF) following pooling every 6 h. C-reactive protein level (CRP), white blood cell count (WBC), temperature and confirmed systemic clinical infection were used as systemic markers of inflammation. Principal component analyses, linear mixed-effect models, cross-correlations and multiple factor analyses were used. Results Jugular and arterial blood held similar cytokine information content, but brain-ECF was markedly different. No clear arterial to jugular gradient could be seen. No substantial delayed temporal associations between blood and brain compartments were detected. The development of a systemic clinical infection resulted in a significant decrease of IL1-ra, G-CSF, PDGF-ABBB, MIP-1b and RANTES (p < 0.05, respectively) in brain-ECF, even if adjusting for injury severity and demographic factors, while an increase in several cytokines could be seen in arterial blood. Conclusions Systemic inflammation, and infection in particular, alters cytokine levels with different patterns seen in brain and in blood. Cerebral inflammatory monitoring provides independent information from arterial and jugular samples, which both demonstrate similar information content. These findings could present potential new treatment options in severe TBI patients, but novel prospective trials are warranted to confirm these associations. Graphical abstract

Inflammatory Biomarkers of Traumatic Brain Injury

“…It is estimated that in the United States there are 3.17 million people suffering with long term disability resulting from TBI, representing an annual economic impact in excess of Pharmaceuticals 2022, 15, 660 2 of 18 $56 billion [6]. TBI presents as a biphasic pathology in which the effects of the initial traumatic insult results in persistent inflammation and the chronic activation of the innate immune system [7][8][9][10]. Primary injury involves the release of damage associated molecular patterns (DAMPS) from injured tissue resulting in the activation of the innate immune response and formation of the inflammasome [11][12][13][14].…”

Negligible In Vitro Recovery of Macromolecules from Microdialysis Using 100 kDa Probes and Dextran in Perfusion Fluid

“…These small molecules offer a snapshot of energy metabolism but fail to discriminate underlying mechanisms such as inflammation. Larger proinflammatory molecules, such as cytokines and chemokines, have been targeted as possible pathogenic mediators [ 7 , 9 , 14 ]. To monitor these molecules, catheters with larger pore sizes are necessary [ 7 , 14 ], while measurement of small molecules must not be affected.…”

Monitoring Neurochemistry in Traumatic Brain Injury Patients Using Microdialysis Integrated with Biosensors: A Review

“…Delayed secondary injury evolves hours or days after the initial primary mechanical trauma due to neuronal and glial dysfunction, neuroinflammation, cerebral oedema, and metabolic changes. Consequently, this leads to various physiologic alterations including hypoperfusion, blood–brain barrier (BBB) disruption, oxidative injury, and mitochondrial dysfunction [ 11 , 12 , 13 , 14 , 15 , 16 ]. This complexity of secondary brain injury poses diagnostic and therapeutic challenges; therefore, additional invasive monitoring interventions are required during neurocritical care of severe TBI patients.…”