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

TRAJECTORY CLUSTERING USING LATENT CLASS MODELS FOR UNSUPERVISED TBI BIOMARKER TEMPORAL PHENOTYPE DISCOVER

Background: TBI biomarkers display population-level time-varying kinetics [1] which may be a rich source of pathobiological information [2]. At an individual level, deviations from stereotypical trajectories may represent different pathological processes or secondary insults. A method for discovering such phenotypes may be useful in in- dividualising treatments in real-time. Methods: Serial blood (12hourly) and CSF (6hourly) samples were obtained from seventeen adult patients with severe TBI (Stockholm ethics committee approval #2009/1112-31). S100B and neuron-specific enolase (NSE) concentrations were measured along with blood:CSF albumin quotient Qa as a measure of blood-brain-barrier (BBB) integrity. S100B and NSE concentrations were log-transformed: Equivalent to the assumption of baseline exponential decay. We used trajectory modeling combining a quadratic mixed effects model with latent group analysis to search for characteristic trajectories in the measured parameter. Results: For serum S100B, we discovered two phenotypes with fast and slow kinetics. The fast group corresponded with patients with more severe extracranial injury. For serum NSE, again two phenotypes were discovered; a time-decaying group and another with a peak around day 4. CSF analysis yielded two latent groups for both S100B and NSE: a time-decaying group and another displaying prolonged elevation over several days. Qa data clustered into three groups: two with fast, slow decay and another with prolonged elevation. The group with prolonged BBB permeability had corresponding poorer outcomes. Conclusions: Small numbers prevent statistical comparison, but trajectory modeling identified a number of phenotypes with plausible pathobiological significance. In particular the technique revealed a group of patients with secondary serum NSE release and another with sustained BBB permeability. Such groups seem to relate to injury profile and outcome suggesting biological relevance. To our knowledge this is the first use of an unsupervised clustering technique in kinetic phenotype discovery. References: [1] Ercole A, Thelin EP, Holst A, Bellander BM, Nelson DW. Kinetic modelling of serum S100b after traumatic brain injury. BMC Neurol. 2016;16:93. [2] Thelin EP, Zeiler FA, Ercole A, Mondello S, Büki A, Bellander BM, Helmy A, Menon DK, Nelson DW. Serial Sampling of Serum Protein Biomarkers for Monitoring Human Traumatic Brain Injury Dynamics: A Systematic Review. Front Neurol. 2017;8:300

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

Evaluation of novel computerized tomography scoring systems in human traumatic brain injury : An observational, multicenter study

Background Traumatic brain injury (TBI) is a major contributor to morbidity and mortality. Computerized tomography (CT) scanning of the brain is essential for diagnostic screening of intracranial injuries in need of neurosurgical intervention, but may also provide information concerning patient prognosis and enable baseline risk stratification in clinical trials. Novel CT scoring systems have been developed to improve current prognostic models, including the Stockholm and Helsinki CT scores, but so far have not been extensively validated. The primary aim of this study was to evaluate the Stockholm and Helsinki CT scores for predicting functional outcome, in comparison with the Rotterdam CT score and Marshall CT classification. The secondary aims were to assess which individual components of the CT scores best predict outcome and what additional prognostic value the CT scoring systems contribute to a clinical prognostic model. Methods and findings TBI patients requiring neuro-intensive care and not included in the initial creation of the Stockholm and Helsinki CT scoring systems were retrospectively included from prospectively collected data at the Karolinska University Hospital (n = 720 from 1 January 2005 to 31 December 2014) and Helsinki University Hospital (n = 395 from 1 January 2013 to 31 December 2014), totaling 1,115 patients. The Marshall CT classification and the Rotterdam, Stockholm, and Helsinki CT scores were assessed using the admission CT scans. Known outcome predictors at admission were acquired (age, pupil responsiveness, admission Glasgow Coma Scale, glucose level, and hemoglobin level) and used in univariate, and multivariable, regression models to predict long-term functional outcome (dichotomizations of the Glasgow Outcome Scale [GOS]). In total, 478 patients (43%) had an unfavorable outcome (GOS 1-3). In the combined cohort, overall prognostic performance was more accurate for the Stockholm CT score (Nagelkerke's pseudo-R-2 range 0.24-0.28) and the Helsinki CT score (0.18-0.22) than for the Rotterdam CT score (0.13-0.15) and Marshall CT classification (0.03-0.05). Moreover, the Stockholm and Helsinki CT scores added the most independent prognostic value in the presence of other known clinical outcome predictors in TBI (6% and 4%, respectively). The aggregate traumatic subarachnoid hemorrhage (tSAH) component of the Stockholm CT score was the strongest predictor of unfavorable outcome. The main limitations were the retrospective nature of the study, missing patient information, and the varying follow-up time between the centers. Conclusions The Stockholm and Helsinki CT scores provide more information on the damage sustained, and give a more accurate outcome prediction, than earlier classification systems. The strong independent predictive value of tSAH may reflect an underrated component of TBI pathophysiology. A change to these newer CT scoring systems may be warranted.Peer reviewe

Serial S100B Sampling Detects Intracranial Lesion Development in Patients on Extracorporeal Membrane Oxygenation

Introduction: Intracranial lesion development is a recognized complication in adults treated with extracorporeal membrane oxygenation (ECMO) and is associated with increased mortality. As neurological assessment during ECMO treatment remains challenging, protein biomarkers of cerebral injury could provide an opportunity to detect intracranial lesion development at an early stage. The aim of this study was to determine if serially sampled S100B could be used to detect intracranial lesion development during ECMO treatment.Methods: We conducted an observational cohort study of all patients treated with ECMO at ECMO Center Karolinska (Karolinska University Hospital, Stockholm, Sweden) between January and August 2018, excluding patients who did not undergo a computerized tomography scan (CT) during treatment. S100B was prospectively collected at hospital admission and then once daily. The primary end-point was any type of CT verified intracranial lesion. Receiver operating characteristics (ROC) curves and Cox proportional hazards models were employed.Results: Twenty-nine patients were included, of which 15 (52%) developed an intracranial lesion and exhibited higher levels of S100B overall. S100B had a robust association with intracranial lesion development, especially during the first 200 hours following admission. The best area-under-curve (AUC) to predict intracranial lesion development was 40 and 140 hours following ECMO initiation, were a S100B level of 0.69μg/L had an AUC of 0.81 (0.628-0.997). S100B levels were markedly increased following the development of intracranial hemorrhage.Conclusions: Serial serum S100B samples in ECMO patients were both significantly elevated and had an increasing trajectory in patients developing intracranial lesions. Larger prospective trials are warranted to validate these findings and to ascertain their clinical utility

Correction to: Predictors of intracranial hemorrhage in adult patients on extracorporeal membrane oxygenation: an observational cohort study

In the original publication of this article [1], the first author’s name should be changed from Alexander Fletcher Sandersjöö to Alexander Fletcher-Sandersjöö. The family name of the author is Fletcher-Sandersjöö

Influence of Blood-Brain Barrier Integrity on Brain Protein Biomarker Clearance in Severe Traumatic Brain Injury: A Longitudinal Prospective Study.

Brain protein biomarker clearance to blood in traumatic brain injury (TBI) is not fully understood. The aim of this study was to analyze the effect that a disrupted blood-brain barrier (BBB) had on biomarker clearance. Seventeen severe TBI patients admitted to Karolinska University Hospital were prospectively included. Cerebrospinal fluid (CSF) and blood concentrations of S100 calcium binding protein B (S100B) and neuron-specific enolase (NSE) were analyzed every 6-12 h for ∼1 week. Blood and CSF albumin were analyzed every 12-24 h, and BBB integrity was assessed using the CSF:blood albumin quotient (QA). We found that time-dependent changes in the CSF and blood levels of the two biomarkers were similar, but that the correlation between the biomarkers and QA was lower for NSE (ρ = 0.444) than for S100B (ρ = 0.668). Because data were longitudinal, we also conducted cross correlation analyses, which indicated a directional flow and lag-time of biomarkers from CSF to blood. For S100B, this lag-time could be ascribed to BBB integrity, whereas for NSE it could not. Upon inferential modelling, using generalized least square estimation (S100B) or linear mixed models (NSE), QA (p = 0.045), time from trauma (p < 0.001), time from trauma2 (p = 0.023), and CSF biomarker levels (p = 0.008) were independent predictors of S100B in blood. In contrast, for NSE, only time from trauma was significant (p < 0.001). These findings are novel and important, but must be carefully interpreted because of different characteristics between the two proteins. Nonetheless, we present the first data that indicate that S100B and NSE are cleared differently from the central nervous system, and that both the disrupted BBB and additional alternative pathways, such as the recently described glymphatic system, may play a role. This is of importance both for clinicians aiming to utilize these biomarkers and for the pathophysiological understanding of brain protein clearance, but warrants further examination

Predictors of intracranial hemorrhage in adult patients on extracorporeal membrane oxygenation: an observational cohort study.

BACKGROUND: Intracranial hemorrhage (ICH) is a recognized complication of adults treated with extracorporeal membrane oxygenation (ECMO) and is associated with increased morbidity and mortality. However, the predictors of ICH in this patient category are poorly understood. The purpose of this study was to identify predictors of ICH in ECMO-treated adult patients. METHODS: We conducted a retrospective review of adult patients (≥18 years) treated with ECMO at the Karolinska University Hospital (Stockholm, Sweden) between September 2005 and June 2016, excluding patients with ICH upon admission or those who were treated with ECMO for less than 12 h. In a comparative analysis, the primary end-points were the difference in baseline characteristics and predictors of hemorrhage occurrence (ICH vs. non-ICH cohorts). The secondary end-point was difference in mortality between groups. Paired testing and uni- and multivariate regression models were applied. RESULTS: Two hundred and fifty-three patients were included, of which 54 (21%) experienced an ICH during ECMO treatment. The mortality for patients with ICH was 81% at 1 month and 85% at 6 months, respectively, compared to 28 and 33% in patients who did not develop ICH. When comparing ICH vs. non-ICH cohorts, pre-admission antithrombotic therapy (p = 0.018), high pre-cannulation Sepsis-related Organ Failure Assessment (SOFA) coagulation score (p = 0.015), low platelet count (p < 0.001), and spontaneous extracranial hemorrhage (p = 0.045) were predictors of ICH. In a multivariate regression model predicting ICH, pre-admission antithrombotic therapy and low platelet count demonstrated independent risk association. When comparing the temporal trajectories for coagulation variables in the days leading up to the detection of an ICH, plasma antithrombin significantly increased per patient over time (p = 0.014). No other temporal trajectories were found. CONCLUSIONS: ICH in adult ECMO patients is associated with a high mortality rate and independently associated with pre-admission antithrombotic therapy and low platelet count, thus highlighting important areas of potential treatment strategies to prevent ICH development

Correction to: Predictors of intracranial hemorrhage in adult patients on extracorporeal membrane oxygenation: an observational cohort study.

[This corrects the article DOI: 10.1186/s40560-017-0223-2.]

Secondary insults following traumatic brain injury enhance complement activation in the human brain and release of the tissue damage marker S100B

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.OBJECT: Complement activation has been suggested to play a role in the development of secondary injuries following traumatic brain injury (TBI). The present study was initiated in order to analyze complement activation in relation to the primary brain injury and to secondary insults, frequently occurring following TBI. METHODS: Twenty patients suffering from severe TBI (Glasgow coma score ≤ 8) were included in the study. The "membrane attack complex," C5b9, which is the cytolytic end product of the complement system was analyzed in cerebrospinal fluid (CSF). The degree of brain tissue damage was assessed using the release of S100B and neuron-specific enolase (NSE) to the CSF and blood. The blood-brain barrier was assessed using the CSF/serum quotient of albumin (Q (A)). RESULTS: Following impact, initial peaks (0-48 h) of C5b9, S100B, and NSE with a concomitant loss of integrity of the blood-brain barrier were observed. Secondary insults at the intensive care unit were monitored. Severe secondary insults were paralleled by a more pronounced complement activation (C5b9 in CSF) as well as increased levels of S100B (measured in CSF), but not with NSE. CONCLUSION: This human study indicates that complement activation in the brain is triggered not only by the impact of trauma per se but also by the amount of secondary insults that frequently occur at the scene of accident as well as during treatment in the neurointensive care unit. Complement activation and in particular the end product C5b9 may in turn contribute to additional secondary brain injuries by its membrane destructive properties