Brain Extracellular Fluid Nitrite/Nitrate Levels after Traumatic Brain Injury are Related to Survival

The role of neuroinflammation is increasingly being recognised in a diverse range of cerebral pathologies, including traumatic brain injury (TBI). We used cerebral microdialysis and paired arterial and jugular bulb plasma sampling to characterise the production of 42 cytokines after severe TBI in 12 patients over 5 days. We compared two microdialysis perfusates in six patients: central nervous system perfusion fluid and 3.5% human albumin solution (HAS); 3.5% HAS has a superior fluid recovery (95.8 versus 83.3%), a superior relative recovery in 18 of 42 cytokines (versus 8 of 42), and a qualitatively superior recovery profile. All 42 cytokines were recovered from the human brain. Sixteen cytokines showed a stereotyped temporal peak, at least twice the median value for that cytokine over the monitoring period; day 1: tumour necrosis factor, interleukin (IL)7, IL8, macrophage inflammatory protein (MIP)1α, soluble CD40 ligand, GRO, IL1β, platelet derived growth factor (PDGF)-AA, MIP1β, RANTES; day 2: IL1 receptor antagonist (ra). IL6, granulocyte-colony stimulating factor (G-CSF), chemokine CXC motif ligand 10 (IP10); days 4 to 5: IL12p70, IL10. Brain extracellular fluid concentrations were significantly higher than plasma concentrations for 19 cytokines: basic fibroblast growth factor (FGF2), G-CSF, IL1α, IL1 β, IL1ra, IL3, IL6, IL8, IL10, IL12p40, IL12p70, IP10, monocyte chemotactic protein (MCP)1, MCP3, MIP1α, MIP1β, PDGF-AA, transforming growth factor (TGF)α and vascular endothelial growth factor. No clear arterio-jugular venous gradients were apparent. These data provide evidence for the cerebral production of these cytokines and show a stereotyped temporal pattern after TBI.

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

Journal of Neuroinflammation ◽

10.1186/s12974-021-02264-2 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Philipp Lassarén ◽

Caroline Lindblad ◽

Arvid Frostell ◽

Keri L. H. Carpenter ◽

Mathew R. Guilfoyle ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Information Content ◽

Systemic Inflammation ◽

Injury Severity ◽

Extracellular Fluid ◽

Clinical Infection ◽

Mixed Effect ◽

Markers Of Inflammation ◽

Arterial Blood

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

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Relation between extracellular Chemistry and Patient Outcome for Severe Traumatic Brain Injury within the First 24 hours: A Microdialysis Study

Indian Journal of Neurotrauma ◽

10.1055/s-0038-1649283 ◽

2017 ◽

Vol 14 (02/03) ◽

pp. 122-128

Author(s):

Yutaka Igarashi ◽

Shoji Yokobori ◽

Hidetaka Onda ◽

Tomohiko Masuno ◽

Hiroyuki Yokota

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Injuries ◽

Extracellular Fluid ◽

Intracerebral Microdialysis ◽

Focal Brain Injury ◽

Severe Tbi ◽

Microdialysis Study ◽

The Relationship ◽

Diffuse Brain

Abstract Object Many studies have reported that extracellular chemistry is related to the outcome of patients with traumatic brain injury (TBI). No study has reported that extracellular chemistry predicts outcome in less than 3 days. Moreover, in other studies, both focal brain and diffuse brain injuries have been often discussed. The authors focused on the relationship between extracellular chemistry in a shorter period and the outcome of patients with focal brain injury. Methods By using intracerebral microdialysis monitoring, extracellular fluid concentrations of glucose, lactate, glycerol, glutamate, lactate/pyruvate (L/P), and lactate/glucose (L/G) were determined in 30 patients with severe TBI for initial 24 hours. The results were analyzed between favorable and unfavorable, and between survival and mortality. Results The medians of glycerol and L/P in the favorable group were significantly lower than those in the unfavorable group (124 µmol/L vs. 808 µmol/L, p = 0.002; 31 vs. 48, p = 0.021, respectively). All parameters apart from glutamate differed significantly between the survival and mortality groups (glucose, 25 mmol/L vs. 77 mmol/L, p = 0.035; lactate, 38 mmol/L vs. 73 mmol/L, p = 0.018; glycerol, 168 µmol/L vs. 1462 µmol/L, p = 0.002; glutamate, 14 µmol/L vs. 95 µmol/L, p = 0.019; L/P, 32 vs. 124, p < 0.001; L/G, 1.46 vs. 4.52, p = 0.004). Conclusion Cerebral extracellular glycerol and L/P was the most reliable predictor of outcomes in patients with focal brain injury and can discriminate between favorable and unfavorable outcomes for the first 24 hours, using the threshold of 200 and 40, respectively.

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Systemic Inflammation Alters The Neuroinflammatory Response: A Prospective Clinical Trial In Traumatic Brain Injury

10.21203/rs.3.rs-345717/v2 ◽

2021 ◽

Author(s):

Philipp Lassarén ◽

Caroline Lindblad ◽

Arvid Frostell ◽

Keri LH Carpenter ◽

Mathew R Guilfoyle ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Information Content ◽

Systemic Inflammation ◽

Injury Severity ◽

Extracellular Fluid ◽

Clinical Infection ◽

Mixed Effect ◽

Markers Of Inflammation ◽

Arterial Blood

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 randomized 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 hours. 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, and stresses the need of adequate monitoring of inflammatory markers.

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Recombinant Human Interleukin-1 Receptor Antagonist in Severe Traumatic Brain Injury: A Phase II Randomized Control Trial

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.23 ◽

2014 ◽

Vol 34 (5) ◽

pp. 845-851 ◽

Cited By ~ 96

Author(s):

Adel Helmy ◽

Mathew R Guilfoyle ◽

Keri LH Carpenter ◽

John D Pickard ◽

David K Menon ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Receptor Antagonist ◽

Phase Ii ◽

Interleukin 1 ◽

Safety Data ◽

Extracellular Fluid ◽

Cerebral Microdialysis ◽

Interleukin 1 Receptor Antagonist ◽

Randomized Control

Traumatic brain injury (TBI) is the commonest cause of death and disability in those aged under 40 years. Interleukin-1 receptor antagonist (IL1ra) is an endogenous competitive antagonist at the interleukin-1 type-1 receptor (IL-1R). Antagonism at the IL-1R confers neuroprotection in several rodent models of neuronal injury (i.e., trauma, stroke and excitotoxicity). We describe a single center, phase II, open label, randomized-control study of recombinant human IL1ra (rhIL1ra, anakinra) in severe TBI, at a dose of 100 mg subcutaneously once a day for 5 days in 20 patients randomized 1:1. We provide safety data (primary outcome) in this pathology, utilize cerebral microdialysis to directly determine brain extracellular concentrations of IL1ra and 41 cytokines and chemokines, and use principal component analysis (PCA) to explore the resultant cerebral cytokine profile. Interleukin-1 receptor antagonist was safe, penetrated into plasma and the brain extracellular fluid. The PCA showed a separation in cytokine profiles after IL1ra administration. A candidate cytokine from this analysis, macrophage-derived chemoattractant, was significantly lower in the rh I Lira-treated group. Our results provide promising data for rhIL1ra as a therapeutic candidate by showing safety, brain penetration and a modification of the neuroinflammatory response to TBI by a putative neuroprotective agent in humans for the first time.

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Cognitive control constrains memory attributions

Behavioral and Brain Sciences ◽

10.1017/s0140525x19001869 ◽

2019 ◽

Vol 42 ◽

Author(s):

Colleen M. Kelley ◽

Larry L. Jacoby

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Cognitive Control

Abstract Cognitive control constrains retrieval processing and so restricts what comes to mind as input to the attribution system. We review evidence that older adults, patients with Alzheimer's disease, and people with traumatic brain injury exert less cognitive control during retrieval, and so are susceptible to memory misattributions in the form of dramatic levels of false remembering.

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