Assessment of Platelet Function in Traumatic Brain Injury-A Retrospective Observational Study in the Neuro-Critical Care Setting.

BACKGROUND: Despite seemingly functional coagulation, hemorrhagic lesion progression is a common and devastating condition following traumatic brain injury (TBI), stressing the need for new diagnostic techniques. Multiple electrode aggregometry (MEA) measures platelet function and could aid in coagulopathy assessment following TBI. The aims of this study were to evaluate MEA temporal dynamics, influence of concomitant therapy, and its capabilities to predict lesion progression and clinical outcome in a TBI cohort. MATERIAL AND METHODS: Adult TBI patients in a neurointensive care unit that underwent MEA sampling were retrospectively included. MEA was sampled if the patient was treated with antiplatelet therapy, bled heavily during surgery, or had abnormal baseline coagulation values. We assessed platelet activation pathways involving the arachidonic acid receptor (ASPI), P2Y12 receptor, and thrombin receptor (TRAP). ASPI was the primary focus of analysis. If several samples were obtained, they were included. Retrospective data were extracted from hospital charts. Outcome variables were radiologic hemorrhagic progression and Glasgow Outcome Scale assessed prospectively at 12 months posttrauma. MEA levels were compared between patients on antiplatelet therapy. Linear mixed effect models and uni-/multivariable regression models were used to study longitudinal dynamics, hemorrhagic progression and outcome, respectively. RESULTS: In total, 178 patients were included (48% unfavorable outcome). ASPI levels increased from initially low values in a time-dependent fashion (p < 0.001). Patients on cyclooxygenase inhibitors demonstrated low ASPI levels (p < 0.001), while platelet transfusion increased them (p < 0.001). The first ASPI (p = 0.039) and TRAP (p = 0.009) were significant predictors of outcome, but not lesion progression, in univariate analyses. In multivariable analysis, MEA values were not independently correlated with outcome. CONCLUSION: A general longitudinal trend of MEA is identified in this TBI cohort, even in patients without known antiplatelet therapies. Values appear also affected by platelet inhibitory treatment and by platelet transfusions. While significant in univariate models to predict outcome, MEA values did not independently correlate to outcome or lesion progression in multivariable analyses. Further prospective studies to monitor coagulation in TBI patients are warranted, in particular the interpretation of pathological MEA values in patients without antiplatelet therapies

A systematic review of cerebral microdialysis and outcomes in TBI: relationships to patient functional outcome, neurophysiologic measures, and tissue outcome.

OBJECTIVE: To perform a systematic review on commonly measured cerebral microdialysis (CMD) analytes and their association to: (A) patient functional outcome, (B) neurophysiologic measures, and (C) tissue outcome; after moderate/severe TBI. The aim was to provide a foundation for next-generation CMD studies and build on existing pragmatic expert guidelines for CMD. METHODS: We searched MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to October 2016). Strength of evidence was adjudicated using GRADE. RESULTS: (A) Functional Outcome: 55 articles were included, assessing outcome as mortality or Glasgow Outcome Scale (GOS) at 3-6 months post-injury. Overall, there is GRADE C evidence to support an association between CMD glucose, glutamate, glycerol, lactate, and LPR to patient outcome at 3-6 months. (B) Neurophysiologic Measures: 59 articles were included. Overall, there currently exists GRADE C level of evidence supporting an association between elevated CMD measured mean LPR, glutamate and glycerol with elevated ICP and/or decreased CPP. In addition, there currently exists GRADE C evidence to support an association between elevated mean lactate:pyruvate ratio (LPR) and low PbtO2. Remaining CMD measures and physiologic outcomes displayed GRADE D or no evidence to support a relationship. (C) Tissue Outcome: four studies were included. Given the conflicting literature, the only conclusion that can be drawn is acute/subacute phase elevation of CMD measured LPR is associated with frontal lobe atrophy at 6 months. CONCLUSIONS: This systematic review replicates previously documented relationships between CMD and various outcome, which have driven clinical application of the technique. Evidence assessments do not address the application of CMD for exploring pathophysiology or titrating therapy in individual patients, and do not account for the modulatory effect of therapy on outcome, triggered at different CMD thresholds in individual centers. Our findings support clinical application of CMD and refinement of existing guidelines

A review of the clinical utility of serum S100B protein levels in the assessment of traumatic brain injury.

BACKGROUND: In order to improve injury assessment of brain injuries, protein markers of pathophysiological processes and tissue fate have been introduced in the clinic. The most studied protein "biomarker" of cerebral damage in traumatic brain injury (TBI) is the protein S100B. The aim of this narrative review is to thoroughly analyze the properties and capabilities of this biomarker with focus on clinical utility in the assessment of patients suffering from TBI. RESULTS: S100B has successfully been implemented in the clinic regionally (1) to screen mild TBI patients evaluating the need to perform a head computerized tomography, (2) to predict outcome in moderate-to-severe TBI patients, (3) to detect secondary injury development in brain-injured patients and (4) to evaluate treatment efficacy. The potential opportunities and pitfalls of S100B in the different areas usually refer to its specificity and sensitivity to detect and assess intracranial injury. CONCLUSION: Given some shortcomings that should be realized, S100B can be used as a versatile screening, monitoring and prediction tool in the management of TBI patients

Dextran 500 Improves Recovery of Inflammatory Markers: An In Vitro Microdialysis Study.

Cerebral microdialysis (CMD) is used in severe traumatic brain injury (TBI) in order to recover metabolites in brain extracellular fluid (ECF). To recover larger proteins and avoid fluid loss, albumin supplemented perfusion fluid (PF) has been utilized, but because of regulatory changes in the European Union, this is no longer practicable. The aim with this study was to see whether fluid, absolute (AR), and relative (RR) recovery for the novel carrier, Dextran 500, was better than conventional PF for a range of cytokines and chemokines. An in vitro setup mimicking conditions observed in the neurocritical care of TBI patients was used, utilizing 100-kDa molecular-weight cut-off CMD catheters inserted through a triple-lumen bolt cranial access device into an external solution with diluted cytokine standards in known concentrations for 48 h (divided into 6-h epochs). Samples were run on a 39-plex Luminex (Luminex Corporation, Austin, TX) assay to assess cytokine concentrations. We found that fluid recovery was inadequate in 50% of epochs with conventional PF, whereas Dextran PF overcame this limitation. The AR was higher in the Dextran PF samples for a majority of cytokines, and RR was significantly increased for macrophage colony-stimulating factor and transforming growth factor-alpha. In summary, Dextran PF improved fluid and cytokine recovery as compared to conventional PF and is a suitable alternative to albumin supplemented PF for protein microdialysis.The work was supported by funding for SGC and KLHC from the National Institute for Health Research Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). PJH is funded by a National Institute for Health Research (NIHR) Professorship, Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship and the National Institute for Health Research Biomedical Research Centre, Cambridge. EPT has received salary support from Swedish Society for Medical Research. AH is supported by the Royal College of Surgeons of England and the National Institute for Health Research Biomedical Research Centre, Cambridge. The study consumables were purchased through the NIHR Research Professorship (Peter Hutchinson) and the Luminex 200 analyser was purchased with Medical Research Council (MRC) funding (G0600986 ID79068)

Case Report: Extreme Levels of Serum S-100B in a Patient with Chronic Subdural Hematoma.

The protein S-100B is a biomarker increasingly used within neurosurgery and neurointensive care. As a relatively sensitive, yet unspecific, indicator of CNS pathology, potential sources of error must be clearly understood when interpreting serum S-100B levels. This case report studied the course of a 46-year-old gentleman with a chronic subdural hemorrhage, serum S-100B levels of 22 μg/l, and a history of malignant melanoma. Both intra- and extra-cranial sources of S-100B are evaluated and imply an unclear contribution of several sources to the total serum concentration. Potential sources of error when interpreting serum concentrations of S-100B are discussed

Prehospital Intubation and Outcome in Traumatic Brain Injury-Assessing Intervention Efficacy in a Modern Trauma Cohort.

BACKGROUND: Prehospital intubation in traumatic brain injury (TBI) focuses on limiting the effects of secondary insults such as hypoxia, but no indisputable evidence has been presented that it is beneficial for outcome. The aim of this study was to explore the characteristics of patients who undergo prehospital intubation and, in turn, if these parameters affect outcome. MATERIAL AND METHODS: Patients ≥15 years admitted to the Department of Neurosurgery, Stockholm, Sweden with TBI from 2008 through 2014 were included. Data were extracted from prehospital and hospital charts, including prospectively collected Glasgow Outcome Score (GOS) after 12 months. Univariate and multivariable logistic regression models were employed to examine parameters independently correlated to prehospital intubation and outcome. RESULTS: A total of 458 patients were included (n = 178 unconscious, among them, n = 61 intubated). Multivariable analyses indicated that high energy trauma, prehospital hypotension, pupil unresponsiveness, mode of transportation, and distance to the hospital were independently correlated with intubation, and among them, only pupil responsiveness was independently associated with outcome. Prehospital intubation did not add independent information in a step-up model versus GOS (p = 0.154). Prehospital reports revealed that hypoxia was not the primary cause of prehospital intubation, and that the procedure did not improve oxygen saturation during transport, while an increasing distance from the hospital increased the intubation frequency. CONCLUSION: In this modern trauma cohort, prehospital intubation was not independently associated with outcome; however, hypoxia was not a common reason for prehospital intubation. Prospective trials to assess efficacy of prehospital airway intubation will be difficult due to logistical and ethical considerations

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

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

The cerebrospinal fluid proteome of preterm infants predicts neurodevelopmental outcome

BackgroundSurvival rate increases for preterm infants, but long-term neurodevelopmental outcome predictors are lacking. Our primary aim was to determine whether a specific proteomic profile in cerebrospinal fluid (CSF) of preterm infants differs from that of term infants and to identify novel biomarkers of neurodevelopmental outcome in preterm infants.MethodsTwenty-seven preterm infants with median gestational age 27 w + 4 d and ten full-term infants were enrolled prospectively. Protein profiling of CSF were performed utilizing an antibody suspension bead array. The relative levels of 178 unique brain derived proteins and inflammatory mediators, selected from the Human Protein Atlas, were measured.ResultsThe CSF protein profile of preterm infants differed from that of term infants. Increased levels of brain specific proteins that are associated with neurodevelopment and neuroinflammatory pathways made up a distinct protein profile in the preterm infants. The most significant differences were seen in proteins involved in neurodevelopmental regulation and synaptic plasticity, as well as components of the innate immune system. Several proteins correlated with favorable outcome in preterm infants at 18–24 months corrected age. Among the proteins that provided strong predictors of outcome were vascular endothelial growth factor C, Neurocan core protein and seizure protein 6, all highly important in normal brain development.ConclusionOur data suggest a vulnerability of the preterm brain to postnatal events and that alterations in protein levels may contribute to unfavorable neurodevelopmental outcome