6-month Glasgow Outcome Scale Extended Research Articles

Early GFAP and UCH-L1 point-of-care biomarker measurements for the prediction of traumatic brain injury and progression in patients with polytrauma and hemorrhagic shock

OBJECTIVE Traumatic brain injury (TBI) and hemorrhage are responsible for the largest proportion of all trauma-related deaths. In polytrauma patients at risk of hemorrhage and TBI, the diagnosis, prognosis, and management of TBI remain poorly characterized. The authors sought to characterize the predictive capabilities of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) measurements in patients with hemorrhagic shock with and without concomitant TBI. METHODS The authors performed a secondary analysis on serial blood samples derived from a prospective observational cohort study that focused on comparing early whole-blood and component resuscitation. A convenience sample of patients was used in which samples were collected at three time points and the presence of TBI or no TBI via CT imaging was documented. GFAP and UCH-L1 measurements were performed on plasma samples using the i-STAT Alinity point-of-care platform. Using classification tree recursive partitioning, the authors determined the measurement cut points for each biomarker to maximize the abilities for predicting the diagnosis of TBI, Rotterdam CT imaging scores, and 6-month Glasgow Outcome Scale–Extended (GOSE) scores. RESULTS Biomarker comparisons demonstrated that GFAP and UCH-L1 measurements were associated with the presence of TBI at all time points. Classification tree analyses demonstrated that a GFAP level > 286 pg/ml for the sample taken upon the patient’s arrival had an area under the receiver operating characteristic curve of 0.77 for predicting the presence of TBI. The classification tree results demonstrated that a cut point of 3094 pg/ml for the arrival GFAP measurement was the most predictive for an elevated Rotterdam score on the initial and second CT scans and for TBI progression between scans. No significant associations between any of the most predictive cut points for UCH-L1 and Rotterdam CT scores or TBI progression were found. The predictive capabilities of UCH-L1 were limited by the range allowed by the point-of-care platform. Arrival GFAP cut points remained strong independent predictors after controlling for all potential polytrauma confounders, including injury characteristics, shock severity, and resuscitation. CONCLUSIONS Early measurements of GFAP and UCH-L1 on a point-of-care device are significantly associated with CT-diagnosed TBI in patients with polytrauma and shock. Early elevated GFAP measurements are associated with worse head CT scan Rotterdam scores, TBI progression, and worse GOSE scores, and these associations are independent of other injury attributes, shock severity, and early resuscitation characteristics.

445 Performance of the IMPACT and CRASH Prognostic Models for Traumatic Brain Injury in a Contemporary Multicenter Cohort: A TRACK-TBI Study

INTRODUCTION: The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticosteroid Randomisation After Significant Head Injury (CRASH) prognostic models for mortality and functional outcome in traumatic brain injury (TBI) were developed using historical data from 1984-2004. METHODS: The prospective, 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury study enrolled participants aged = 17-years who presented to Level 1 trauma center and received head computed tomography (CT) scan <24-hours of TBI. Data was extracted from participants meeting IMPACT (Glasgow Coma Scale (GCS) 3-12; completed 6-month Glasgow Outcome Scale-Extended (GOSE); N = 441) and CRASH criteria (GCS 3-14; completed 2-week and 6-month GOSE; N = 831). Original model coefficients were applied, and performances were assessed using discrimination (area under the receiver-operating characteristic curve (AUC)) and calibration (intercept; slope; [95% confidence interval]). RESULTS: IMPACT and CRASH models discriminated mortality (AUC = 0.77-0.81, 0.90-0.91, respectively) and unfavorable outcome (0.77-0.81; 0.83, respectively). The IMPACT Lab model overestimated mortality (intercept = -0.79 [-1.05, -0.53]; slope = 1.37 [1.05-1.69]) and acceptably estimated unfavorable outcome (intercept = 0.07 [-0.14, 0.29]; slope = 1.19 [0.96-1.42]). The CRASH CT model overestimated mortality (intercept = -1.06 [-1.36, -0.75]; slope = 0.96 [0.79-1.14]) and unfavorable outcome (intercept = -0.60 [-0.78, -0.41]; slope = 1.20 [1.03-1.37]). Calibration performance differences were observed across the 5 leading enrollment centers (IMPACT Lab model: intercept -1.66 to -0.35, slope 1.07-1.86; CRASH CT model: intercept -1.81 to -0.67, slope 0.67-1.56) and unfavorable outcome (IMPACT Lab model: intercept -0.57 to 0.34, slope 1.28-2.89; CRASH CT model: intercept -1.15 to -0.10, slope 1.02-1.44). CONCLUSIONS: IMPACT and CRASH models discriminated mortality and unfavorable outcome. Observed overestimations of mortality and unfavorable outcome underscore the need to develop prognostic models that incorporate contemporary changes in TBI casemix. Investigations to elucidate the relationships between increased survival, functional outcome, treatment intensity, and center-specific practices will be highly relevant.

Isotonic balanced fluid versus 0.9% saline in patients with moderate to severe traumatic brain injury: A double-blinded randomised controlled trial

Background and importanceTraumatic brain injury (TBI) is a global health concern with significant economic impact. Optimal fluid therapy aims to restore intravascular volume, maintain cerebral perfusion pressure and blood flow, thus preventing secondary brain injury. While 0.9% saline (NS) is commonly used, concerns about acid-base and electrolyte imbalance and development of acute kidney injury (AKI) lead to consideration of balanced fluids as an alternative. ObjectivesThis study aimed to compare the outcomes of patients with moderate to severe TBI treated with Sterofundin (SF) versus NS. Design, settings and participantsA double-blinded randomised controlled trial of patients aged 18 to 65 years with TBI was conducted at the University Malaya Medical Centre from February 2017 to November 2019. Intervention or exposurePatients were randomly assigned to receive either NS or SF. The study fluids were administered for 72 h as continuous infusions or boluses. Participants, investigators, and staff were blinded to the fluid type. Outcomes measure and analysisThe primary outcome was in-hospital mortality. Relative risk (RR) with 95% confidence interval (CI) was calculated. Main resultsA total of 70 patients were included in the analysis, with 38 in the NS group and 32 in the SF group. The in-hospital mortality rate were 3 (7.9%) in the NS group vs. 4 (12.5%) in the SF group, RR = 1.29 (95% CI, 0.64 to 2.59; p = 0.695). No patients developed AKI and required renal replacement therapy. ICP on day 3 was significantly higher in the SF group (18.60 ± 9.26) compared to 12.77 ± 3.63 in the NS group, (95% CI, −11.46 to 0.20; p = 0.037). There were no significant differences in 3-day biochemical parameters and cerebral perfusion pressure, ventilator-free days, length of ICU stay, or Glasgow Outcome Scale-Extended (GOS-E) score at 6 months. ConclusionsIn patients with moderate to severe TBI, the use of SF was not associated with reduced in-hospital mortality, development of AKI, or improved 6-month GOS-E when compared to NS.

Predicting traumatic brain injury outcomes using a posterior dominant rhythm.

Predicting severe traumatic brain injury (sTBI) outcomes is challenging, and existing models have limited applicability to individual patients. This study aimed to identify metrics that could predict recovery following sTBI. The researchers strived to demonstrate that a posterior dominant rhythm on electroencephalography is strongly associated with positive outcomes and to develop a novel machine learning-based model that accurately forecasts the return of consciousness. In this retrospective study, the authors assessed all intubated adults admitted with sTBI (Glasgow Coma Scale [GCS] score ≤ 8) from 2010 to 2021, who underwent EEG recording < 30 days from sTBI (n = 195). Seventy-three clinical, radiographic, and EEG variables were collected. Based on the presence of a PDR within 30 days of injury, two cohorts were created-those with a PDR (PDR[+] cohort, n = 51) and those without (PDR[-] cohort, n = 144)-to assess differences in presentation and four outcomes: in-hospital survival, recovery of command following, Glasgow Outcome Scale-Extended (GOS-E) score at discharge, and GOS-E score at 6 months post discharge. AutoScore, a machine learning-based clinical score generator that selects and assigns weights to important predictive variables, was used to create a prognostic model that predicts in-hospital survival and recovery of command following. Lastly, the MRC-CRASH and IMPACT traumatic brain injury predictive models were used to compare expected patient outcomes with true outcomes. At presentation, the PDR(-) cohort had a lower mean GCS motor subscore (1.97 vs 2.45, p = 0.048). Despite no difference in predicted outcomes (via MRC-CRASH and IMPACT), the PDR(+) cohort had superior rates of in-hospital survival (84.3% vs 63.9%, p = 0.007), recovery of command following (76.5% vs 53.5%, p = 0.004), and mean discharge GOS-E score (3.00 vs 2.39, p = 0.006). There was no difference in the 6-month GOS-E score. AutoScore was then used to identify the 7 following variables that were highly predictive of in-hospital survival and recovery of command: age, body mass index, systolic blood pressure, pupil reactivity, blood glucose, and hemoglobin (all at presentation), and a PDR on EEG. This model had excellent discrimination for predicting in-hospital survival (area under the curve [AUC] 0.815) and recovery of command following (AUC 0.700). A PDR on EEG in sTBI patients predicts favorable outcomes. The authors' prognostic model has strong accuracy in predicting these outcomes, and performed better than previously reported models. The authors' model can be valuable in clinical decision-making as well as counseling families following these types of injuries.

Effect of Dexmedotomdine hydrochloride (Percedex®) on functional outcome of patients with moderate and severe traumatic brain injury

Traumatic brain injury (TBI) is considered among the leading causes of morbidity and mortality worldwide being associated with significant social and economic burden. The best sedative regimen in TBI patients is yet to be identified. This study was designed to determine the effects of dexmedotomdine hydrochloride (Percedex®, DEX) on functional outcome of patients with moderate and severe traumatic brain injury (TBI). This was a retrospective cohort study including patients with severe (3–8) and moderate (9–13) TBI referring to a level I trauma center. We studied two groups of patients, those receiving DEX or routine sedation regimen in neurointensive care unit (NICU). The main outcome measures were the Glasgow outcome scale extended (GOSE) at 3 and 6-month. We have also recorded ICU and hospital length of stay (LOS) and the tracheostomy rate. We included 138 patients in two study groups (each including 69). The baseline characteristics were comparable between groups. DEX was associated with lower LOS in hospital (p = 0.002) and NICU (p = 0.003). The GOSE was comparable between two study groups at 3 (p = 0.245) and 6-month (p = 0.497). Multivariate regression analysis revealed that after LOS of NICU and hospital stay adjustment, DEX group experienced significantly improved 6-month GOSE with the average improvement in score of 0.92 compared to the control group (p = 0.041). DEX administration in patients with moderate and severe TBI was associated with decreased NICU and hospital LOS and improved functional outcome at 6-month.

Prognostic Models for Global Functional Outcome and Post-Concussion Symptoms Following Mild Traumatic Brain Injury: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study.

After mild traumatic brain injury (mTBI), a substantial proportion of individuals do not fully recover on the Glasgow Outcome Scale Extended (GOSE) or experience persistent post-concussion symptoms (PPCS). We aimed to develop prognostic models for the GOSE and PPCS at 6 months after mTBI and to assess the prognostic value of different categories of predictors (clinical variables; questionnaires; computed tomography [CT]; blood biomarkers). From the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, we included participants aged 16 or older with Glasgow Coma Score (GCS) 13-15. We used ordinal logistic regression to model the relationship between predictors and the GOSE, and linear regression to model the relationship between predictors and the Rivermead Post-concussion Symptoms Questionnaire (RPQ) total score. First, we studied a pre-specified Core model. Next, we extended the Core model with other clinical and sociodemographic variables available at presentation (Clinical model). The Clinical model was then extended with variables assessed before discharge from hospital: early post-concussion symptoms, CT variables, biomarkers, or all three categories (extended models). In a subset of patients mostly discharged home from the emergency department, the Clinical model was extended with 2-3-week post-concussion and mental health symptoms. Predictors were selected based on Akaike's Information Criterion. Performance of ordinal models was expressed as a concordance index (C) and performance of linear models as proportion of variance explained (R2). Bootstrap validation was used to correct for optimism. We included 2376 mTBI patients with 6-month GOSE and 1605 patients with 6-month RPQ. The Core and Clinical models for GOSE showed moderate discrimination (C = 0.68 95% confidence interval 0.68 to 0.70 and C = 0.70[0.69 to 0.71], respectively) and injury severity was the strongest predictor. The extended models had better discriminative ability (C = 0.71[0.69 to 0.72] with early symptoms; 0.71[0.70 to 0.72] with CT variables or with blood biomarkers; 0.72[0.71 to 0.73] with all three categories). The performance of models for RPQ was modest (R2 = 4% Core; R2 = 9% Clinical), and extensions with early symptoms increased the R2 to 12%. The 2-3-week models had better performance for both outcomes in the subset of participants with these symptoms measured (C = 0.74 [0.71 to 0.78] vs. C = 0.63[0.61 to 0.67] for GOSE; R2 = 37% vs. 6% for RPQ). In conclusion, the models based on variables available before discharge have moderate performance for the prediction of GOSE and poor performance for the prediction of PPCS. Symptoms assessed at 2-3 weeks are required for better predictive ability of both outcomes. The performance of the proposed models should be examined in independent cohorts.

Spindle wave in intracranial pressure signal analysis for patients with traumatic brain injury: A single-center prospective observational cohort study.

Objective: Intracranial pressure (ICP) monitoring is an integral part of the multimodality monitoring system in the neural intensive care unit. The present study aimed to describe the morphology of the spindle wave (a shuttle shape with wide middle and narrow ends) during ICP signal monitoring in TBI patients and to investigate its clinical significance. Methods: Sixty patients who received ICP sensor placement and admitted to the neurosurgical intensive care unit between January 2021 and September 2021 were prospectively enrolled. The patient's Glasgow Coma Scale (GCS) score on admission and at discharge and length of stay in hospital were recorded. ICP monitoring data were monitored continuously. The primary endpoint was 6-month Glasgow Outcome Scale-Extended (GOSE) score. Patients with ICP spindle waves were assigned to the spindle wave group and those without were assigned to the control group. The correlation between the spindle wave and 6-month GOSE was analyzed. Meanwhile, the mean ICP and two ICP waveform-derived indices, ICP pulse amplitude (AMP) and correlation coefficient between AMP and ICP (RAP) were comparatively analyzed. Results: There were no statistically significant differences between groups in terms of age (p = 0.89), gender composition (p = 0.62), and GCS score on admission (p = 0.73). Patients with spindle waves tended to have a higher GCS score at discharge (12.75 vs. 10.90, p = 0.01), a higher increment in GCS score during hospitalization (ΔGCS, the difference between discharge GCS score and admission GCS score) (4.95 vs. 2.80, p = 0.01), and a better 6-month GOSE score (4.90 vs. 3.68, p = 0.04) compared with the control group. And the total duration of the spindle wave was positively correlated with 6-month GOSE (r = 0.62, p = 0.004). Furthermore, the parameters evaluated during spindle waves, including mean ICP, AMP, and RAP, demonstrated significant decreases compared with the parameters before the occurrence of the spindle wave (all p < 0.025). Conclusion: The ICP spindle wave was associated with a better prognosis in TBI patients. Physiological parameters such as ICP, AMP, and RAP were significantly improved when spindle waves occurred, which may explain the enhancement of clinical outcomes. Further studies are needed to investigate the pathophysiological mechanisms behind this wave.

Incremental prognostic value of acute serum biomarkers for functional outcome after traumatic brain injury (CENTER-TBI): an observational cohort study

Several studies have reported an association between serum biomarker values and functional outcome following traumatic brain injury. We aimed to examine the incremental (added) prognostic value of serum biomarkers over demographic, clinical, and radiological characteristics and over established prognostic models, such as IMPACT and CRASH, for prediction of functional outcome. We used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core study. We included patients aged 14 years or older who had blood sampling within 24 h of injury, results from a CT scan, and outcome assessment according to the Glasgow Outcome Scale-Extended (GOSE) at 6 months. Amounts in serum of six biomarkers (S100 calcium-binding protein B, neuron-specific enolase, glial fibrillary acidic protein, ubiquitin C-terminal hydrolase L1 [UCH-L1], neurofilament protein-light, and total tau) were measured. The incremental prognostic value of these biomarkers was determined separately and in combination. The primary outcome was the GOSE 6 months after injury. Incremental prognostic value, using proportional odds and a dichotomised analysis, was assessed by delta C-statistic and delta R2 between models with and without serum biomarkers, corrected for optimism with a bootstrapping procedure. Serum biomarker values and 6-month GOSE were available for 2283 of 4509 patients. Higher biomarker levels were associated with worse outcome. Adding biomarkers improved the C-statistic by 0·014 (95% CI 0·009-0·020) and R2 by 4·9% (3·6-6·5) for predicting GOSE compared with demographic, clinical, and radiological characteristics. UCH-L1 had the greatest incremental prognostic value. Adding biomarkers to established prognostic models resulted in a relative increase in R2 of 48-65% for IMPACT and 30-34% for CRASH prognostic models. Serum biomarkers have incremental prognostic value for functional outcome after traumatic brain injury. Our findings support integration of biomarkers-particularly UCH-L1-in established prognostic models. European Union's Seventh Framework Programme, Hannelore Kohl Stiftung, OneMind, Integra LifeSciences, and NeuroTrauma Sciences.

The leap to ordinal: Detailed functional prognosis after traumatic brain injury with a flexible modelling approach.

When a patient is admitted to the intensive care unit (ICU) after a traumatic brain injury (TBI), an early prognosis is essential for baseline risk adjustment and shared decision making. TBI outcomes are commonly categorised by the Glasgow Outcome Scale-Extended (GOSE) into eight, ordered levels of functional recovery at 6 months after injury. Existing ICU prognostic models predict binary outcomes at a certain threshold of GOSE (e.g., prediction of survival [GOSE > 1]). We aimed to develop ordinal prediction models that concurrently predict probabilities of each GOSE score. From a prospective cohort (n = 1,550, 65 centres) in the ICU stratum of the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) patient dataset, we extracted all clinical information within 24 hours of ICU admission (1,151 predictors) and 6-month GOSE scores. We analysed the effect of two design elements on ordinal model performance: (1) the baseline predictor set, ranging from a concise set of ten validated predictors to a token-embedded representation of all possible predictors, and (2) the modelling strategy, from ordinal logistic regression to multinomial deep learning. With repeated k-fold cross-validation, we found that expanding the baseline predictor set significantly improved ordinal prediction performance while increasing analytical complexity did not. Half of these gains could be achieved with the addition of eight high-impact predictors to the concise set. At best, ordinal models achieved 0.76 (95% CI: 0.74-0.77) ordinal discrimination ability (ordinal c-index) and 57% (95% CI: 54%- 60%) explanation of ordinal variation in 6-month GOSE (Somers' Dxy). Model performance and the effect of expanding the predictor set decreased at higher GOSE thresholds, indicating the difficulty of predicting better functional outcomes shortly after ICU admission. Our results motivate the search for informative predictors that improve confidence in prognosis of higher GOSE and the development of ordinal dynamic prediction models.

322 Neuroinflammatory Biomarkers for Traumatic Brain Injury Diagnosis and Prognosis: Results From the TRACK-TBI Pilot Study

INTRODUCTION: The relationship between systemic inflammation and traumatic brain injury (TBI) is complex. Primary injury triggers release of pro- and anti-inflammatory cytokines, chemokines, and alarmins/alarmin response proteins. METHODS: The prospective, multicenter TRACK-TBI Pilot study was used. Subjects received head CT and blood draw within 24h of TBI. Biomarkers were extracted from plasma and included: cytokines (IL-6, IL-10, IL-15, IL-16), chemokines (monocyte chemoattractant protein 4 (MCP-4), thymus activation-regulated chemokine (TARC)), alarmin/alarmin response proteins (high mobility group box 1 (HMGB-1), serum amyloid A (SAA), c-reactive protein (CRP)), and others. Area Under the Curve (AUC) was used to evaluate marker discriminability for clinical diagnosis (TBI vs. orthopedic control (OC)/healthy control (HC)), TBI severity (GCS 3-12 vs. 13-15), radiographic injury on CT, and unfavorable vs. favorable 3- and 6-month outcome (Glasgow Outcome Scale Extended (GOSE) 1-4 vs. 5-8). Statistical significance was assessed at p&lt;0.05. RESULTS: One-hundred sixty-eight TBI subjects, 28 OC, and 18 HCs were included. Markers associated with TBI clinical diagnosis were: IL-6, IL-10, IL-16, MCP-4, TARC, HMGB-1, SAA, CRP. Markers for TBI severity: IL-6, IL-10, IL-15, IL-16, TARC, HMGB-1, SAA, CRP. Markers for radiographic TBI: IL-6, IL-10, IL-15, IL-16, HMGB-1, SAA, CRP. Predictors (AUC &gt; 0.70) for TBI vs. OC: HMGB-1 (AUC = 0.84), IL-16 (AUC = 0.78), TARC (AUC = 0.73). Predictors for TBI vs. HC: IL-6 (AUC = 0.92), IL-10 (AUC = 0.87), HMGB-1 (AUC = 0.87), IL-16 (AUC = 0.72). Predictors for radiographic TBI: SAA (AUC = 0.77), IL-6 (AUC = 0.76), CRP (AUC = 0.73). IL-15 predicted 3- and 6-month GOSE (AUC = 0.74/0.70, respectively). SAA predicted 6-month GOSE (AUC = 0.70). CONCLUSION: We identified a distinct profile of cytokines, chemokines and alarmin/alarmin response proteins detectable systemically within 24h of TBI. These markers may have unique importance in TBI detection, severity differentiation, and prognosis. Future research on neuroinflammatory pathways will elucidate the evolution of injury and yield potential targets for therapeutic intervention.

Prognostic Value of Hemorrhagic Brainstem Injury on Early Computed Tomography: A TRACK-TBI Study.

Traumatic brainstem injury has yet to be incorporated into widely used imaging classification systems for traumatic brain injury (TBI), and questions remain regarding prognostic implications for this TBI subgroup. To address this, retrospective data on patients from the multicenter prospective Transforming Research and Clinical Knowledge in TBI study were studied. Patients with brainstem and cerebrum injury (BSI+) were matched by age, sex, and admission Glasgow Coma Scale (GCS) score to patients with cerebrum injuries only. All patients had an interpretable head computed tomography (CT) scan from the first 48 hours after injury and a 6-month Glasgow Outcome Scale Extended (GOSE) score. CT scans were reviewed for brainstem lesions and, when present, characterized by location, size, and type (traumatic axonal injury, contusion, or Duret hemorrhage). Clinical, demographic, and outcome data were then compared between the two groups. Mann-Whitney U-tests showed no significant difference in 6-month GOSE scores in patients with BSI+ (mean 2.7) compared with patients with similar but only cerebrum injuries (mean 3.9), although there is a trend (p=0.10). However, subclassification by brainstem lesion type, traumatic axonal injury (mean 4.0) versus Duret hemorrhage or contusion (mean 1.4), did identify a proportion of BSI+ with significantly less favorable outcome (p=0.002). The incorporation of brainstem lesion type (traumatic axonal injury vs. contusion/Duret), along with GCS into a multivariate logistic regression model of favorable outcome (GOSE score 4-8) did show a significant contribution to the prognostication of this brainstem injury subgroup (odds ratio 0.08, 95% confidence interval 0.00-0.67, p=0.01). These findings suggest two groups of patients with brainstem injuries may exist with divergent recovery potential after TBI. These data support the notion that newer CT imaging classification systems may augment traditional clinical measures, such as GCS in identifying those patients with TBI and brainstem injuries that stand a higher chance of favorable outcome.

Outcome Prediction after Moderate and Severe Traumatic Brain Injury: External Validation of Two Established Prognostic Models in 1742 European Patients.

The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticoid Randomisation After Significant Head injury (CRASH) prognostic models predict functional outcome after moderate and severe traumatic brain injury (TBI). We aimed to assess their performance in a contemporary cohort of patients across Europe. The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core study is a prospective, observational cohort study in patients presenting with TBI and an indication for brain computed tomography. The CENTER-TBI core cohort consists of 4509 TBI patients available for analyses from 59 centers in 18 countries across Europe and Israel. The IMPACT validation cohort included 1173 patients with GCS ≤12, age ≥14, and 6-month Glasgow Outcome Scale-Extended (GOSE) available. The CRASH validation cohort contained 1742 patients with GCS ≤14, age ≥16, and 14-day mortality or 6-month GOSE available. Performance of the three IMPACT and two CRASH model variants was assessed with discrimination (area under the receiver operating characteristic curve; AUC) and calibration (comparison of observed vs. predicted outcome rates). For IMPACT, model discrimination was good, with AUCs ranging between 0.77 and 0.85 in 1173 patients and between 0.80 and 0.88 in the broader CRASH selection (n = 1742). For CRASH, AUCs ranged between 0.82 and 0.88 in 1742 patients and between 0.66 and 0.80 in the stricter IMPACT selection (n = 1173). Calibration of the IMPACT and CRASH models was generally moderate, with calibration-in-the-large and calibration slopes ranging between -2.02 and 0.61 and between 0.48 and 1.39, respectively. The IMPACT and CRASH models adequately identify patients at high risk for mortality or unfavorable outcome, which supports their use in research settings and for benchmarking in the context of quality-of-care assessment.

Prediction of Global Functional Outcome and Post-Concussive Symptoms after Mild Traumatic Brain Injury: External Validation of Prognostic Models in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study.

The majority of traumatic brain injuries (TBIs) are categorized as mild, according to a baseline Glasgow Coma Scale (GCS) score of 13-15. Prognostic models that were developed to predict functional outcome and persistent post-concussive symptoms (PPCS) after mild TBI have rarely been externally validated. We aimed to externally validate models predicting 3-12-month Glasgow Outcome Scale Extended (GOSE) or PPCS in adults with mild TBI. We analyzed data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) project, which included 2862 adults with mild TBI, with 6-month GOSE available for 2374 and Rivermead Post-Concussion Symptoms Questionnaire (RPQ) results available for 1605 participants. Model performance was evaluated based on calibration (graphically and characterized by slope and intercept) and discrimination (C-index). We validated five published models for 6-month GOSE and three for 6-month PPCS scores. The models used different cutoffs for outcome and some included symptoms measured 2 weeks post-injury. Discriminative ability varied substantially (C-index between 0.58 and 0.79). The models developed in the Corticosteroid Randomisation After Significant Head Injury (CRASH) trial for prediction of GOSE <5 discriminated best (C-index 0.78 and 0.79), but were poorly calibrated. The best performing models for PPCS included 2-week symptoms (C-index 0.75 and 0.76). In conclusion, none of the prognostic models for early prediction of GOSE and PPCS has both good calibration and discrimination in persons with mild TBI. In future studies, prognostic models should be tailored to the population with mild TBI, predicting relevant end-points based on readily available predictors.

Brain Tissue Oxygen and Cerebrovascular Reactivity in Traumatic Brain Injury: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Exploratory Analysis of Insult Burden.

Pressure reactivity index (PRx) and brain tissue oxygen (PbtO2) are associated with outcome in traumatic brain injury (TBI). This study explores the relationship between PRx and PbtO2 in adult moderate/severe TBI. Using the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) high resolution intensive care unit (ICU) sub-study cohort, we evaluated those patients with archived high-frequency digital intraparenchymal intracranial pressure (ICP) and PbtO2 monitoring data of, a minimum of 6 h in duration, and the presence of a 6 month Glasgow Outcome Scale -Extended (GOSE) score. Digital physiological signals were processed for ICP, PbtO2, and PRx, with the % time above/below defined thresholds determined. The duration of ICP, PbtO2, and PRx derangements was characterized. Associations with dichotomized 6-month GOSE (alive/dead, and favorable/unfavorable outcome; ≤ 4 = unfavorable), were assessed. A total of 43 patients were included. Severely impaired cerebrovascular reactivity was seen during elevated ICP and low PbtO2 episodes. However, most of the acute ICU physiological derangements were impaired cerebrovascular reactivity, not ICP elevations or low PbtO2 episodes. Low PbtO2 without PRx impairment was rarely seen. % time spent above PRx threshold was associated with mortality at 6 months for thresholds of 0 (area under the curve [AUC] 0.734, p = 0.003), > +0.25 (AUC 0.747, p = 0.002) and > +0.35 (AUC 0.745, p = 0.002). Similar relationships were not seen for % time with ICP >20 mm Hg, and PbtO2 < 20 mm Hg in this cohort. Extreme impairment in cerebrovascular reactivity is seen during concurrent episodes of elevated ICP and low PbtO2. However, the majority of the deranged cerebral physiology seen during the acute ICU phase is impairment in cerebrovascular reactivity, with most impairment occurring in the presence of normal PbtO2 levels. Measures of cerebrovascular reactivity appear to display the most consistent associations with global outcome in TBI, compared with ICP and PbtO2.

Polytrauma Is Associated with Increased Three- and Six-Month Disability after Traumatic Brain Injury: A TRACK-TBI Pilot Study.

Polytrauma and traumatic brain injury (TBI) frequently co-occur and outcomes are routinely measured by the Glasgow Outcome Scale-Extended (GOSE). Polytrauma may confound GOSE measurement of TBI-specific outcomes. Adult patients with TBI from the prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study had presented to a Level 1 trauma center after injury, received head computed tomography (CT) within 24 h, and completed the GOSE at 3 months and 6 months post-injury. Polytrauma was defined as an Abbreviated Injury Score (AIS) ≥3 in any extracranial region.Univariate regressions were performed using known GOSE clinical cutoffs. Multi-variable regressions were performed for the 3- and 6-month GOSE, controlling for known demographic and injury predictors. Of 361 subjects (age 44.9 ± 18.9 years, 69.8% male), 69 (19.1%) suffered polytrauma. By Glasgow Coma Scale (GCS) assessment, 80.1% had mild, 5.8% moderate, and 14.1% severe TBI. On univariate logistic regression, polytrauma was associated with increased odds of moderate disability or worse (GOSE ≤6; 3 month odds ratio [OR] = 2.57 [95% confidence interval (CI): 1.50-4.41; 6 month OR = 1.70 [95% CI: 1.01-2.88]) and death/severe disability (GOSE ≤4; 3 month OR = 3.80 [95% CI: 2.03-7.11]; 6 month OR = 3.33 [95% CI: 1.71-6.46]). Compared with patients with isolated TBI, more polytrauma patients experienced a decline in GOSE from 3 to 6 months (37.7 vs. 24.7%), and fewer improved (11.6 vs. 22.6%). Polytrauma was associated with greater univariate ordinal odds for poorer GOSE (3 month OR = 2.79 [95% CI: 1.73-4.49]; 6 month OR = 1.73 [95% CI: 1.07-2.79]), which was conserved on multi-variable ordinal regression (3 month OR = 3.05 [95% CI: 1.76-5.26]; 6 month OR = 2.04 [95% CI: 1.18-3.42]). Patients with TBI with polytrauma are at greater risk for 3- and 6-month disability compared with those with isolated TBI. Methodological improvements in assessing TBI-specific disability, versus disability attributable to all systemic injuries, will generate better TBI outcomes assessment tools.

Predictors of Change in Functional Outcome at six months and twelve months after Severe Injury: A Retrospective Cohort Study

BackgroundThere is increasing focus on long-term survival, function and quality-of-life for trauma patients. There are few studies tracking longitudinal changes in functional outcome over time. The goal of our study was to compare the Glasgow Outcome Scale-Extended (GOSE) at 6 months and 12 months in blunt trauma survivors with an Injury Severity Score (ISS) of more than 15.MethodsUsing the Singapore National Trauma Registry 2011–2013, patients with 6-month GOSE and 12-month GOSE scores were analysed. Patients were grouped into three categories—those with the same score at 6 months and 12 months, an improvement in score, and a worse score at 12 months. Ordinal regression was used to identify risk factors for improved score. Patients with missing scores at either 6 months or 12 months were excluded.ResultsWe identified 478 patients: 174 had an improvement in score, 233 stayed the same, and 71 had worse scores at 12 months compared to 6 months. On univariate ordinal regression, the following variables were associated with same or better function at 12-months compared to 6-months: male gender, being employed pre-injury, thoracic Abbreviated Injury Scale (AIS) of 3 or more, anatomical polytrauma (AIS of 3 or more in 2 or more body regions), and road traffic injury mechanism. Older age, low fall, increasing Charlson comorbidity scores, new injury severity score, and head and neck AIS of 3 or more were associated with worse function at 12 months compared to 6 months. ISS and revised trauma score were not significant predictors on univariate or multivariable analysis.On multivariable ordinal regression, motor vehicle mechanism (OR 2.78, 1.51–5.12, p = 0.001) was associated with improved function, while male gender (OR 1.36, 95% CI 1.02–1.82, p = 0.039) predicted improved function at 12 months.ConclusionsFemales experience worse functional outcomes at 12 months, potentially due to majority of female injuries being low falls in the elderly. In contrast, motor vehicle injury patients had better functional outcomes at 12 months. Additional interventional strategies for high-risk groups should be explored.

Causes and Consequences of Treatment Variation in Moderate and Severe Traumatic Brain Injury: A Multicenter Study

Although guidelines have been developed to standardize care in traumatic brain injury, between-center variation in treatment approach has been frequently reported. We examined variation in treatment for traumatic brain injury by assessing factors influencing treatment and the association between treatment and patient outcome. Secondary analysis of prospectively collected data. Five level I trauma centers in the Netherlands (2008-2009). Five hundred three patients with moderate or severe traumatic brain injury (Glasgow Coma Scale, 3-13). We examined variation in seven treatment parameters: direct transfer, involvement of mobile medical team, mechanical ventilation, intracranial pressure monitoring, vasopressors, acute neurosurgical intervention, and extracranial operation. Data were collected on patient characteristics, treatment, and 6-month Glasgow Outcome Scale-Extended. Multivariable logistic regression models were used to assess the extent to which treatment was determined by patient characteristics. To examine whether there were between-center differences in treatment, we used unadjusted and adjusted random effect models with the seven treatment parameters as dependent variables. The influence of treatment approach in a center (defined as aggressive and nonaggressive based on the frequency intracranial pressure monitoring) on outcome was assessed using multivariable random effect proportional odds regression models in those patients with an indication for intracranial pressure monitoring. Sensitivity analyses were performed to test alternative definitions of aggressiveness. Treatment was modestly related to patient characteristics (Nagelkerke R range, 0.12-0.52) and varied widely among centers, even after case-mix correction. Outcome was more favorable in patients treated in aggressive centers than those treated in nonaggressive centers (OR, 1.73; 95% CI, 1.05-3.15). Sensitivity analyses, however, illustrated that the aggressiveness-outcome association was dependent on the definition used. The considerable between-center variation in treatment for patients with brain injury can only partly be explained by differences in patient characteristics. An aggressive treatment approach may imply better outcome although further confirmation is required.

Effects of cerebrolysin on functional recovery in patients with severe disability after traumatic brain injury: A historical cohort study

ObjectiveTo determine the effects of cerebrolysin on functional recovery in patients with severe disability after traumatic brain injury (TBI). MethodsThis was a retrospective cohort study being performed during a 2-year period in a level I trauma center in Southern Iran including all the adult patients (>16years) with severe disability (GOS of 2 and 3) 1-month after trauma. We excluded those with posttraumatic seizures and those with meningitis or current infections. Some patients received cerebrolysin (n=65) and some did not (n=64). Cerebrolysin was administered intravenously in 10mL dosage daily for 30days. Patients in two study groups were matched regarding the baseline characteristics including age, gender, GCS on admission, pupil reactivity and Rotterdam score. The administered cerebrolysin dosage was 10mL intravenously daily for 30days. The 3- and 6-month Glasgow Outcome Scale Extended (GOSE) was recorded. The outcome scales were compared between two study groups. ResultsOverall we included 129 patients with severe disability 1-month after TBI. The baseline characteristics were comparable between groups. We found that GOSE at 3-month (p=0.017) and 6-month (p=0.009) was significantly higher in those receiving cerebrolysin. Cerebrolysin administration was associated with lower mortality rate, and higher good recovery after 6 month of therapy (p=0.024). Cerebrolysin administration was also associated with higher favorable and lower unfavorable outcome (p=0.043). Cerebrolysin was associated with higher seizure rate (p=0.042). ConclusionCerebrolysin administration in patients with severe disability after TBI is associated with improved functional recovery, decreased mortality rate and increased favorable outcome. Seizure is important side effect of cerebrolysin administration in TBI patients.

Diffusion tensor imaging for outcome prediction in mild traumatic brain injury: a TRACK-TBI study.

We evaluated 3T diffusion tensor imaging (DTI) for white matter injury in 76 adult mild traumatic brain injury (mTBI) patients at the semiacute stage (11.2±3.3 days), employing both whole-brain voxel-wise and region-of-interest (ROI) approaches. The subgroup of 32 patients with any traumatic intracranial lesion on either day-of-injury computed tomography (CT) or semiacute magnetic resonance imaging (MRI) demonstrated reduced fractional anisotropy (FA) in numerous white matter tracts, compared to 50 control subjects. In contrast, 44 CT/MRI-negative mTBI patients demonstrated no significant difference in any DTI parameter, compared to controls. To determine the clinical relevance of DTI, we evaluated correlations between 3- and 6-month outcome and imaging, demographic/socioeconomic, and clinical predictors. Statistically significant univariable predictors of 3-month Glasgow Outcome Scale-Extended (GOS-E) included MRI evidence for contusion (odds ratio [OR] 4.9 per unit decrease in GOS-E; p=0.01), ≥1 ROI with severely reduced FA (OR, 3.9; p=0.005), neuropsychiatric history (OR, 3.3; p=0.02), age (OR, 1.07/year; p=0.002), and years of education (OR, 0.79/year; p=0.01). Significant predictors of 6-month GOS-E included ≥1 ROI with severely reduced FA (OR, 2.7; p=0.048), neuropsychiatric history (OR, 3.7; p=0.01), and years of education (OR, 0.82/year; p=0.03). For the subset of 37 patients lacking neuropsychiatric and substance abuse history, MRI surpassed all other predictors for both 3- and 6-month outcome prediction. This is the first study to compare DTI in individual mTBI patients to conventional imaging, clinical, and demographic/socioeconomic characteristics for outcome prediction. DTI demonstrated utility in an inclusive group of patients with heterogeneous backgrounds, as well as in a subset of patients without neuropsychiatric or substance abuse history.