150 research outputs found

    On biomarkers in traumatic brain injury

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    Traumatic brain injury (TBI) is a common cause of death and disability. Unfortunately, TBI patients will be affected by secondary insults, such as hypoxia and increased intracranial pressure, which may lead to secondary brain injuries. Because of this, these patients are treated in specialized neuro-intensive care units (NICU) where the brain is monitored in order to prevent secondary lesion development. Cerebral monitoring is limited by its locality and more generalized markers to monitor the injured brain are warranted. Biomarkers have been introduced in the field of TBI, where they may be evaluated to examine potential pathophysiological processes. S100B, a primarily astrocytic protein, is the most studied serum biomarker in TBI, but other candidates exist. The aims of this thesis were to validate biomarkers toward long-term functional outcome, to evaluate the effect of biomarkers and a new global method of microdialysis in multimodal monitoring of NICU patients and in a translational methodology assess how biomarkers may facilitate in the damage analysis in a hypoxic-TBI animal model. In Paper I, a retrospective study including 265 NICU TBI patients, where S100B samples were acquired at admission and every 12 hours the first 48 hours after injury, we detected a significant, and independent, correlation between S100B levels and long-term functional outcome. The predictive capabilities increased sharply after 12 hours and remained high up to 36 hours after injury. S100B levels were only significantly correlated to pathology detected on computerized tomography (CT) and not to extracranial trauma. In Paper II, a retrospective study including 250 NICU TBI patients, we analyzed S100B samples acquired later than 48 hours after injury. We noted that secondary increases of S100B even as low as 0.05μg/L is sensitive and specific enough to detect radiological verified cerebral deteriorations, undetected by conventional monitoring. In Paper III, a prospective study including 14 NICU TBI patients, we monitored patients using microdialysis (MD) in flowing cerebrospinal fluid (CSF) for a more “global” overview of cerebral metabolism. We validated the method using conventional CSF samples, and found that the MD-CSF method yielded adequate results. Also, albeit a small sample size, we noted that lactate and pyruvate levels were significantly elevated in patients with an unfavorable outcome. In Paper IV, a retrospective study including 182 NICU TBI patients, we analyzed serum and CSF levels of Neurofilament light, a protein of axonal origin thus different from S100B. We showed that NFL levels significantly correlated independently to outcome, even in the presence of S100B. However, we could not correlate NFL levels to injuries visible on CT and magnetic resonance imaging (MRI). In Paper V, a preclinical study including 73 Sprague-Dawley rats, we analyzed how hypoxia exacerbates TBI. We detected increased neuronal death using immunohistochemistry and increased lesion size on MRI in the hypoxic animals compared to normoxic animals. A trend was found towards higher S100B levels in serum after 24 hours in the hypoxic group. Vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (HIF1α) expressions were significantly increased in the normoxic group. In summary, the biomarker S100B provides important information towards long-term outcome, even more so than other known predictors of long-term outcome. Outcome prediction models including both S100B and NFL presents the highest explanatory variance, presumably by monitoring different pathophysiological processes. S100B is a valuable asset in the multimodal monitoring in order to detect secondary cerebral injuries and together with the MD-CSF technique; it could improve conventional NICU care with a more global approach. Hypoxic insults following TBI aggravate injury development and this pathophysiological process could presumably be monitored using S100B as an indicator of injury severity

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

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    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

    Current state of high-fidelity multimodal monitoring in traumatic brain injury

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    Introduction Multimodality monitoring of patients with severe traumatic brain injury (TBI) is primarily performed in neurocritical care units to prevent secondary harmful brain insults and facilitate patient recovery. Several metrics are commonly monitored using both invasive and non-invasive techniques. The latest Brain Trauma Foundation guidelines from 2016 provide recommendations and thresholds for some of these. Still, high-level evidence for several metrics and thresholds is lacking. Methods Regarding invasive brain monitoring, intracranial pressure (ICP) forms the cornerstone, and pressures above 22 mmHg should be avoided. From ICP, cerebral perfusion pressure (CPP) (mean arterial pressure (MAP)-ICP) and pressure reactivity index (PRx) (a correlation between slow waves MAP and ICP as a surrogate for cerebrovascular reactivity) may be derived. In terms of regional monitoring, partial brain tissue oxygen pressure (PbtO(2)) is commonly used, and phase 3 studies are currently ongoing to determine its added effect to outcome together with ICP monitoring. Cerebral microdialysis (CMD) is another regional invasive modality to measure substances in the brain extracellular fluid. International consortiums have suggested thresholds and management strategies, in spite of lacking high-level evidence. Although invasive monitoring is generally safe, iatrogenic hemorrhages are reported in about 10% of cases, but these probably do not significantly affect long-term outcome. Non-invasive monitoring is relatively recent in the field of TBI care, and research is usually from single-center retrospective experiences. Near-infrared spectrometry (NIRS) measuring regional tissue saturation has been shown to be associated with outcome. Transcranial doppler (TCD) has several tentative utilities in TBI like measuring ICP and detecting vasospasm. Furthermore, serial sampling of biomarkers of brain injury in the blood can be used to detect secondary brain injury development. Conclusions In multimodal monitoring, the most important aspect is data interpretation, which requires knowledge of each metric's strengths and limitations. Combinations of several modalities might make it possible to discern specific pathologic states suitable for treatment. However, the cost-benefit should be considered as the incremental benefit of adding several metrics has a low level of evidence, thus warranting additional research.Peer reviewe

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

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    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

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

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    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

    Cellular infiltration in traumatic brain injury

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    Abstract: Traumatic brain injury leads to cellular damage which in turn results in the rapid release of damage-associated molecular patterns (DAMPs) that prompt resident cells to release cytokines and chemokines. These in turn rapidly recruit neutrophils, which assist in limiting the spread of injury and removing cellular debris. Microglia continuously survey the CNS (central nervous system) compartment and identify structural abnormalities in neurons contributing to the response. After some days, when neutrophil numbers start to decline, activated microglia and astrocytes assemble at the injury site—segregating injured tissue from healthy tissue and facilitating restorative processes. Monocytes infiltrate the injury site to produce chemokines that recruit astrocytes which successively extend their processes towards monocytes during the recovery phase. In this fashion, monocytes infiltration serves to help repair the injured brain. Neurons and astrocytes also moderate brain inflammation via downregulation of cytotoxic inflammation. Depending on the severity of the brain injury, T and B cells can also be recruited to the brain pathology sites at later time points

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

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    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
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