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

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Lassarén, Philipp 
Lindblad, Caroline 
Frostell, Arvid 
Carpenter, Keri L. H. 
Guilfoyle, Mathew R. 


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:


Funder: Swedish Brain Foundation

Funder: Karolinska Institutet; doi:

Funder: Region Stockholm

Funder: National Institute for Health Research Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme)

Funder: National Institute for Health Research (NIHR)

Funder: NIHR Cambridge Biomedical Research Centre

Funder: Royal College of Surgeons of England; doi:

Funder: Royal College of Surgeons of England Pump Priming Grant

Funder: Swedish Society for Medical Research

Funder: StratNeuro

Funder: Stockholms Läns Landsting; doi:

Funder: Karolinska Institute


Research, Traumatic brain injury, Inflammation, Cytokines, IL1-ra, Human, Neuroinflammation, Infection

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Journal of Neuroinflammation

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BioMed Central
NIHR Global Health Research Group on Neurotrauma a European Union Seventh Framework Program grant (Collaborative European NeuroTrauma Effectiveness Research in TBI [CENTER-TBI]) (602150)
MRC/Royal of Surgeons of England Clinical Research Training Fellowship (G0802251)
MRC Grant (MR/R005036/1)