Association of Early Dexmedetomidine Utilization With Clinical and Functional Outcomes Following Moderate-Severe Traumatic Brain Injury: A Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study.

OBJECTIVE: To examine early sedation patterns, as well as the association of dexmedetomidine exposure, with clinical and functional outcomes among mechanically ventilated patients with moderate-severe traumatic brain injury (msTBI). DESIGN: Retrospective cohort study with prospectively collected data. SETTING: Eighteen Level-1 Trauma Centers, United States. PATIENTS: Adult (age > 17) patients with msTBI (as defined by Glasgow Coma Scale < 13) who required mechanical ventilation from the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Using propensity-weighted models, we examined the association of early dexmedetomidine exposure (within the first 5 d of ICU admission) with the primary outcome of 6-month Glasgow Outcomes Scale Extended (GOS-E) and the following secondary outcomes: length of hospital stay, hospital mortality, 6-month Disability Rating Scale (DRS), and 6-month mortality. The study population included 352 subjects who required mechanical ventilation within 24 hours of admission. The initial sedative medication was propofol for 240 patients (68%), midazolam for 59 patients (17%), ketamine for 6 patients (2%), dexmedetomidine for 3 patients (1%), and 43 patients (12%) never received continuous sedation. Early dexmedetomidine was administered in 77 of the patients (22%), usually as a second-line agent. Compared with unexposed patients, early dexmedetomidine exposure was not associated with better 6-month GOS-E (weighted odds ratio [OR] = 1.48; 95% CI, 0.98-2.25). Early dexmedetomidine exposure was associated with lower DRS (weighted OR = -3.04; 95% CI, -5.88 to -0.21). In patients requiring ICP monitoring within the first 24 hours of admission, early dexmedetomidine exposure was associated with higher 6-month GOS-E score (OR 2.17; 95% CI, 1.24-3.80), lower DRS score (adjusted mean difference, -5.81; 95% CI, -9.38 to 2.25), and reduced length of hospital stay (hazard ratio = 1.50; 95% CI, 1.02-2.20). CONCLUSION: Variation exists in early sedation choice among mechanically ventilated patients with msTBI. Early dexmedetomidine exposure was not associated with improved 6-month functional outcomes in the entire population, although may have clinical benefit in patients with indications for ICP monitoring.

Predicting Functional Dependency in Patients with Disorders of Consciousness: A TBI-Model Systems and TRACK-TBI Study.

OBJECTIVE: It is not currently possible to predict long-term functional dependency in patients with disorders of consciousness (DoC) after traumatic brain injury (TBI). Our objective was to fit and externally validate a prediction model for 1-year dependency in patients with DoC ≥ 2 weeks after TBI. METHODS: We included adults with TBI enrolled in TBI Model Systems (TBI-MS) or Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) studies who were not following commands at rehabilitation admission or 2 weeks post-injury, respectively. We fit a logistic regression model in TBI-MS and validated it in TRACK-TBI. The primary outcome was death or dependency at 1 year post-injury, defined using the Disability Rating Scale. RESULTS: In the TBI-MS Discovery Sample, 1,960 participants (mean age 40 [18] years, 76% male, 68% white) met inclusion criteria, and 406 (27%) were dependent 1 year post-injury. In a TBI-MS held out cohort, the dependency prediction model's area under the receiver operating characteristic curve was 0.79 (95% CI 0.74-0.85), positive predictive value was 53% and negative predictive value was 86%. In the TRACK-TBI external validation (n = 124, age 40 [16] years, 77% male, 81% white), the area under the receiver operating characteristic curve was 0.66 (0.53, 0.79), equivalent to the standard IMPACTcore + CT score (p = 0.8). INTERPRETATION: We developed a 1-year dependency prediction model using the largest existing cohort of patients with DoC after TBI. The sensitivity and negative predictive values were greater than specificity and positive predictive values. Accuracy was diminished in an external sample, but equivalent to the IMPACT model. Further research is needed to improve dependency prediction in patients with DoC after TBI. ANN NEUROL 2023;94:1008-1023.

The Temporal Relationship Between Moderate to Vigorous Physical Activity and Secondary Conditions During the First Year After Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: To determine the cross-sectional and temporal relationships between minutes per week of moderate to vigorous physical activity (MVPA) as measured by a wrist-worn accelerometer and secondary conditions in the first year after moderate to severe traumatic brain injury (TBI). DESIGN: Prospective longitudinal cohort study. SETTING: Four inpatient rehabilitation centers. PARTICIPANTS: Individuals (N = 180) with moderate-severe TBI enrolled in the TBI Model Systems Study. INTERVENTIONS: Participants wore a wrist accelerometer for 7 days immediately post discharge, and for 7 consecutive days at 6- and 12-months post injury. MAIN OUTCOME MEASURES: Minutes per week of MVPA from daily averages based on wrist worn accelerometer. Secondary conditions included depression (Patient Health Questionnaire-9), fatigue (PROMIS Fatigue), Pain (Numeric Rating Scale), Sleep (Pittsburgh Sleep Quality Index), and cognition (Brief Test of Adult Cognition by Telephone). RESULTS: At baseline, 6 and 12 months, 61%, 70% and 79% of the sample achieved at least 150 minutes per week of MVPA. The correlations between minutes of MVPA between baseline, 6 and 12 months were significant (r = 0.53-0.73), as were secondary conditions over these time points. However, no significant correlations were observed between minutes of MVPA and any secondary outcomes cross-sectionally or longitudinally at any time point. CONCLUSIONS: Given the robust relationships physical activity has with outcomes in the general population, further research is needed to understand the effect of physical activity in individuals with moderate-severe TBI.

Predictors of Physical Activity One Year After Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: To identify predictors of moderate to vigorous physical activity (MVPA) at 12-months post-moderate-severe traumatic brain injury (TBI). Setting: Four inpatient rehabilitation centers. PARTICIPANTS: Individuals enrolled in the TBI Model Systems with moderate to severe TBI, admitted to inpatient rehabilitation, and able to ambulate without physical assistance from another person. DESIGN: Prospective longitudinal cohort study. MVPA was measured by having participants wear an ActiGraph GT3X on their wrist for 7 consecutive days. MAIN ANALYSES: We used multivariate regression to predict minutes per week of MVPA at 12 months after TBI. Three classes of predictors were entered hierarchically-demographic and clinical variables (age, sex, body mass index, education, TBI severity, neighborhood walkability score, and self-reported preinjury physical activity [PA] level), baseline TBI-related comorbid conditions (eg, measures of sleep, pain, mood, fatigue, and cognition), and intention to exercise and exercise self-efficacy assessed approximately 1 week after discharge from inpatient rehabilitation. RESULTS: 180 participants (ages 17.7-90.3 years) were enrolled, and 102 provided at least 5 days of valid accelerometer data at 12 months. At 12 months, participants recorded an average of 703 (587) minutes per week of MVPA. In univariate and multivariate analyses, age was the only significant predictor of 12-month MVPA (r = -0.52). A sharp decline in MVPA was observed in the tertile of participants who were over the age of 61. CONCLUSIONS: Older adults with TBI are at elevated risk of being physically inactive. Assuming PA may enhance health after TBI, older adults are a logical target for prevention or early intervention studies. Studies with longer outcomes are needed to understand the trajectory of PA levels after TBI.

Associations of Preexisting Vascular Risk Factors With Outcomes After Traumatic Brain Injury: A TRACK-TBI Study.

OBJECTIVE: To evaluate associations of preinjury vascular risk factors with traumatic brain injury (TBI) outcomes. SETTING: The level 1 trauma center-based T ransforming R esearch a nd C linical K nowledge in TBI (TRACK-TBI) Study. PARTICIPANTS: A total of 2361 acute TBI patients 18 years or older who presented to the emergency department within 24 hours of head trauma warranting clinical evaluation with a noncontrast head CT between February 26, 2014, and August 8, 2018. DESIGN: A multicenter prospective cohort study. MAIN MEASURES: Vascular risk factors (hypertension, diabetes, hyperlipidemia, and smoking) were assessed at baseline by self- or proxy-report and chart review. The primary outcome was the 6-month Glasgow Outcome Scale-Extended TBI version (GOSE-TBI). Secondary 6-month outcomes included the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), the Satisfaction with Life Scale (SWLS), and the 18-item Brief Symptom Inventory Global Severity Index (BSI-18-GSI). RESULTS: Mean age of participants was 42 years, 31% were women, and 16% were Black. Current smoking was the most common vascular risk factor (29%), followed by hypertension (17%), diabetes (8%), and hyperlipidemia (6%). Smoking was the only risk factor associated with worse scores on all 4 outcome indices. Hypertension and diabetes were associated with worse RPQ scores, and hypertension was associated with worse BSI-18-GSI scores (all P < .05). Compared with individuals with no vascular risk factors, individuals with 1 but not 2 or more vascular risk factors had significantly worse GOSE-TBI and SWLS scores, while a higher burden of vascular risk factors was significantly associated with worse RPQ and BSI-18-GSI scores. CONCLUSION: Our study found that preinjury vascular risk factors, especially smoking, are associated with worse outcomes after TBI. Aggressive postinjury treatment of vascular risk factors may be a promising strategy to improve TBI outcomes.

Chronic frontal neurobehavioural symptoms in combat-deployed military personnel with and without a history of blast-related mild traumatic brain injury.

OBJECTIVE: This study evaluated frontal behavioural symptoms, via the FrSBe self-report, in military personnel with and without a history of blast-related mild traumatic brain injury (mild TBI). METHODS: Prospective observational cohort study of combat-deployed service members leveraging 1-year and 5-year demographic and follow up clinical outcome data. RESULTS: The blast mild TBI group (n = 164) showed greater frontal behavioural symptoms, including clinically elevated apathy, disinhibition, and executive dysfunction, during a 5-year follow-up, compared to a group of combat-deployed controls (n = 107) without mild TBI history or history of blast exposure. We also explored changes inbehaviourall symptoms over a 4-year span, which showed clinically significant increases in disinhibition in the blast mild TBI group, whereas the control group did not show significant increases in symptoms over time. CONCLUSION: Our findings add to the growing evidence that a proportion of individuals who sustain mild TBI experience persistent behavioural symptoms. We also offer a demonstration of a novel use of the FrSBe as a tool for longitudinal symptom monitoring in a military mild TBI population.

Impact of Therapeutic Interventions on Cerebral Autoregulatory Function Following Severe Traumatic Brain Injury: A Secondary Analysis of the BOOST-II Study.

BACKGROUND: The Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II randomized controlled trial used a tier-based management protocol based on brain tissue oxygen (PbtO2) and intracranial pressure (ICP) monitoring to reduce brain tissue hypoxia after severe traumatic brain injury. We performed a secondary analysis to explore the relationship between brain tissue hypoxia, blood pressure (BP), and interventions to improve cerebral perfusion pressure (CPP). We hypothesized that BP management below the lower limit of autoregulation would lead to cerebral hypoperfusion and brain tissue hypoxia that could be improved with hemodynamic augmentation. METHODS: Of the 119 patients enrolled in the Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II trial, 55 patients had simultaneous recordings of arterial BP, ICP, and PbtO2. Autoregulatory function was measured by interrogating changes in ICP and PbtO2 in response to fluctuations in CPP using time-correlation analysis. The resulting autoregulatory indices (pressure reactivity index and oxygen reactivity index) were used to identify the "optimal" CPP and limits of autoregulation for each patient. Autoregulatory function and percent time with CPP outside personalized limits of autoregulation were calculated before, during, and after all interventions directed to optimize CPP. RESULTS: Individualized limits of autoregulation were computed in 55 patients (mean age 38 years, mean monitoring time 92 h). We identified 35 episodes of brain tissue hypoxia (PbtO2 < 20 mm Hg) treated with CPP augmentation. Following each intervention, mean CPP increased from 73 ± 14 mm Hg to 79 ± 17 mm Hg (p = 0.15), and mean PbtO2 improved from 18.4 ± 5.6 mm Hg to 21.9 ± 5.6 mm Hg (p = 0.01), whereas autoregulatory function trended toward improvement (oxygen reactivity index 0.42 vs. 0.37, p = 0.14; pressure reactivity index 0.25 vs. 0.21, p = 0.2). Although optimal CPP and limits remained relatively unchanged, there was a significant decrease in the percent time with CPP below the lower limit of autoregulation in the 60 min after compared with before an intervention (11% vs. 23%, p = 0.05). CONCLUSIONS: Our analysis suggests that brain tissue hypoxia is associated with cerebral hypoperfusion characterized by increased time with CPP below the lower limit of autoregulation. Interventions to increase CPP appear to improve autoregulation. Further studies are needed to validate the importance of autoregulation as a modifiable variable with the potential to improve outcomes.

Outcome Prediction in Patients with Severe Traumatic Brain Injury Using Deep Learning from Head CT Scans.

Background After severe traumatic brain injury (sTBI), physicians use long-term prognostication to guide acute clinical care yet struggle to predict outcomes in comatose patients. Purpose To develop and evaluate a prognostic model combining deep learning of head CT scans and clinical information to predict long-term outcomes after sTBI. Materials and Methods This was a retrospective analysis of two prospectively collected databases. The model-building set included 537 patients (mean age, 40 years ± 17 [SD]; 422 men) from one institution from November 2002 to December 2018. Transfer learning and curriculum learning were applied to a convolutional neural network using admission head CT to predict mortality and unfavorable outcomes (Glasgow Outcomes Scale scores 1-3) at 6 months. This was combined with clinical input for a holistic fusion model. The models were evaluated using an independent internal test set and an external cohort of 220 patients with sTBI (mean age, 39 years ± 17; 166 men) from 18 institutions in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study from February 2014 to April 2018. The models were compared with the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) model and the predictions of three neurosurgeons. Area under the receiver operating characteristic curve (AUC) was used as the main model performance metric. Results The fusion model had higher AUCs than did the IMPACT model in the prediction of mortality (AUC, 0.92 [95% CI: 0.86, 0.97] vs 0.80 [95% CI: 0.71, 0.88]; P < .001) and unfavorable outcomes (AUC, 0.88 [95% CI: 0.82, 0.94] vs 0.82 [95% CI: 0.75, 0.90]; P = .04) on the internal data set. For external TRACK-TBI testing, there was no evidence of a significant difference in the performance of any models compared with the IMPACT model (AUC, 0.83; 95% CI: 0.77, 0.90) in the prediction of mortality. The Imaging model (AUC, 0.73; 95% CI: 0.66-0.81; P = .02) and the fusion model (AUC, 0.68; 95% CI: 0.60, 0.76; P = .02) underperformed as compared with the IMPACT model (AUC, 0.83; 95% CI: 0.77, 0.89) in the prediction of unfavorable outcomes. The fusion model outperformed the predictions of the neurosurgeons. Conclusion A deep learning model of head CT and clinical information can be used to predict 6-month outcomes after severe traumatic brain injury. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Haller in this issue.

Depression in Older Adults 12 Months After Traumatic Brain Injury: A TRACK-TBI Study.

OBJECTIVE: To investigate depression at 12 months after traumatic brain injury (TBI) in older adults compared with younger adults. DESIGN: Prospective longitudinal cohort study of persons with medically documented mild, moderate, and severe TBI at 12 months postinjury. SETTING: Eighteen participating Level 1 trauma centers in the United States. PARTICIPANTS: Participants with TBI (N=1505) and primary outcome data at 12-month follow-up. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patient Health Questionnaire-9 (PHQ-9). RESULTS: PHQ-9 total scores were significantly lower for older adults (age≥65y; M=3.2) compared with younger adults (age<65y; M=5.0; B=-1.63, P<.001), indicating fewer depressive symptoms in older adults. Age did not interact with education, sex, race/ethnicity, psychiatric history, substance use, or Glasgow Coma Scale severity to affect PHQ-9 scores. Of the 29% of older adults who endorsed symptoms consistent with depression, 14% were classified as minor depression and 15% as major depression. The odds of older adults falling in the major depression vs no depression group were significantly lower (decreased by 56%) compared with younger adults (odds ratio=0.44, P=.001). CONCLUSIONS: At 12 months post-TBI, older adults endorse lower depressive symptoms than their younger counterparts and are less likely to experience major depression; however, over one-fourth of older adults endorsed symptoms consistent with depression, warranting evaluation and treatment.

Global Disability Trajectories Over the First Decade Following Combat Concussion.

OBJECTIVE: To examine global disability trajectories in US military with and without traumatic brain injury (TBI) over the first decade following deployment to identify risk profiles for better intervention stratification, hopefully reducing long-term cost. SETTING: Patients and participants were enrolled in combat or directly following medical evacuation at the time of injury and followed up every 6 months for 10 years. PARTICIPANTS: There are 4 main groups (n = 475), 2 primary and 2 exploratory: (1) combat-deployed controls without a history of blast exposure "non-blast- control" (n = 143), (2) concussive blast TBI "'blast-TBI" (n = 236) (primary), (3) combat-deployed controls with a history of blast exposure "blast-control" (n = 54), and (4) patients sustaining a combat concussion not from blast "non-blast-TBI" (n = 42) (exploratory). DESIGN: Prospective, observational, longitudinal study. MAIN MEASURES: Combat concussion, blast exposure, and subsequent head injury exposure over the first decade post-deployment. Global disability measured by the Glasgow Outcome Scale Extended (GOSE). RESULTS: Latent class growth analysis identified 4 main trajectories of global outcome, with service members sustaining combat concussion 37 to 49 times more likely to be in the worse disability trajectories than non-blast-controls (blast-TBI: odds ratio [OR] = 49.33; CI, 19.77-123.11; P < .001; non-blast-TBI: OR = 37.50; CI, 10.01-140.50; P < .001). Even blast-exposed-controls were 5 times more likely to be in these worse disability categories compared with non-blast-controls (OR = 5.00; CI, 1.59-15.99; P = .007). Adjustment for demographic factors and subsequent head injury exposure did not substantially alter these odds ratios. CONCLUSIONS: Very high odds of poor long-term outcome trajectory were identified for those who sustained a concussion in combat, were younger at the time of injury, had lower education, and enlisted in the Army above the risk of deployment alone. These findings help identify a risk profile that could be used to target early intervention and screen for poor long-term outcome to aid in reducing the high public health cost and enhance the long-term quality of life for these service members following deployment.

Association Between TBI-Related Hearing Impairment and Cognition: A TRACK-TBI Study.

OBJECTIVE: To examine the association between hearing impairment and cognitive function after traumatic brain injury (TBI). SETTING: A total of 18 level I trauma centers throughout the United States in the T ransforming R esearch a nd C linical K nowledge in TBI (TRACK-TBI) study. PARTICIPANTS: From February 2014 to June 2018, a total of 2697 participants with TBI were enrolled in TRACK-TBI. Key eligibility criteria included external force trauma to the head, presentation to a participating level I trauma center, and receipt of a clinically indicated head computed tomographic (CT) scan within 24 hours of injury. A total of 1267 participants were evaluated in the study, with 216 participants with hearing impairment and 1051 participants without hearing impairment. Those with missing or unknown hearing status or cognitive assessment were excluded from analysis. DESIGN: Prospective, observational cohort study. MAIN MEASURES: Hearing impairment at 2 weeks post-TBI was based on self-report. Participants who indicated worse hearing in one or both ears were defined as having hearing impairment, whereas those who denied worse hearing in either ear were defined as not having hearing impairment and served as the reference group. Cognitive outcomes at 6 months post-TBI included executive functioning and processing speed, as measured by the Trail Making Test (TMT) B/A and the Wechsler Adult Intelligence Scale, Fourth Edition, Processing Speed Index subscale (WAIS-IV PSI), respectively. RESULTS: TBI-related hearing impairment had a small but significantly greater TMT B/A ratio than without TBI-related hearing impairment: mean difference ( B ) = 0.25; 95% CI, 0.07 to 0.43; P = .005. No significant mean differences on WAIS-IV PSI scores were found between participants with and without TBI-related hearing impairment: B = 0.36; 95% CI, -2.07 to 2.60; P = .825. CONCLUSION: We conclude that TBI-related hearing impairment at 6 months postinjury was significantly associated with worse executive functioning but not cognitive processing speed.

Association of Vasopressor Choice with Clinical and Functional Outcomes Following Moderate to Severe Traumatic Brain Injury: A TRACK-TBI Study.

BACKGROUND: Early hypotension following moderate to severe traumatic brain injury (TBI) is associated with increased mortality and poor long-term outcomes. Current guidelines suggest the use of intravenous vasopressors to support blood pressure following TBI; however, guidelines do not specify vasopressor type, resulting in variation in clinical practice. Minimal data are available to guide clinicians on optimal early vasopressor choice to support blood pressure following TBI. Therefore, we conducted a multicenter study to examine initial vasopressor choice for the support of blood pressure following TBI and its association with clinical and functional outcomes after injury. METHODS: We conducted a retrospective cohort study of patients enrolled in the transforming research and clinical knowledge in traumatic brain injury (TRACK-TBI) study, an 18-center prospective cohort study of patients with TBI evaluated in participating level I trauma centers. We examined adults with moderate to severe TBI (defined as Glasgow Coma Scale score < 13) who were admitted to the intensive care unit and received an intravenous vasopressor within 48 h of admission. The primary exposure was initial vasopressor choice (phenylephrine versus norepinephrine), and the primary outcome was 6-month Glasgow Outcomes Scale Extended (GOSE), with the following secondary outcomes: length of hospital stay, length of intensive care unit stay, in-hospital mortality, new requirement for dialysis, and 6-month Disability Rating Scale. Regression analysis was used to assess differences in outcomes between patients exposed to norepinephrine versus phenylephrine, with propensity weighting to address selection bias due to the nonrandom allocation of the treatment groups and patient dropout. RESULTS: The final study sample included 156 patients, of whom 79 (51%) received norepinephrine, 69 (44%) received phenylephrine, and 8 (5%) received an alternate drug as their initial vasopressor. 121 (77%) of patients were men, with a mean age of 43.1 years. Of patients receiving norepinephrine as their initial vasopressor, 32% had a favorable outcome (GOSE 5-8), whereas 40% of patients receiving phenylephrine as their initial vasopressor had a favorable outcome. Compared with phenylephrine, exposure to norepinephrine was not significantly associated with improved 6-month GOSE (weighted odds ratio 1.40, 95% confidence interval 0.66-2.96, p = 0.37) or any secondary outcome. CONCLUSIONS: The majority of patients with moderate to severe TBI received either phenylephrine or norepinephrine as first-line agents for blood pressure support following brain injury. Initial choice of norepinephrine, compared with phenylephrine, was not associated with improved clinical or functional outcomes.

Hypothermia for Patients Requiring Evacuation of Subdural Hematoma: A Multicenter Randomized Clinical Trial.

BACKGROUND: Hypothermia is neuroprotective in some ischemia-reperfusion injuries. Ischemia-reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia-reperfusion injury and improve global neurologic outcome. METHODS: This international, multicenter randomized controlled trial enrolled adult patients with SDH requiring evacuation of hematoma within 6 h of injury. The intervention was controlled temperature management of hypothermia to 35 °C prior to dura opening followed by 33 °C for 48 h compared with normothermia (37 °C). Investigators randomly assigned patients at a 1:1 ratio between hypothermia and normothermia. Blinded evaluators assessed outcome using a 6-month Glasgow Outcome Scale Extended score. Investigators measured circulating glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 levels. RESULTS: Independent statisticians performed an interim analysis of 31 patients to assess the predictive probability of success and the Data and Safety Monitoring Board recommended the early termination of the study because of futility. Thirty-two patients, 16 per arm, were analyzed. Favorable 6-month Glasgow Outcome Scale Extended outcomes were not statistically significantly different between hypothermia vs. normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p = .35). Plasma levels of glial fibrillary acidic protein (p = .036), but not ubiquitin C-terminal hydrolase L1 (p = .26), were lower in the patients with favorable outcome compared with those with unfavorable outcome, but differences were not identified by temperature group. Adverse events were similar between groups. CONCLUSIONS: This trial of hypothermia after acute SDH evacuation was terminated because of a low predictive probability of meeting the study objectives. There was no statistically significant difference in functional outcome identified between temperature groups.

Association of Early Multiple Organ Dysfunction With Clinical and Functional Outcomes Over the Year Following Traumatic Brain Injury: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study.

OBJECTIVES: Traumatic brain injury is a leading cause of death and disability in the United States. While the impact of early multiple organ dysfunction syndrome has been studied in many critical care paradigms, the clinical impact of early multiple organ dysfunction syndrome in traumatic brain injury is poorly understood. We examined the incidence and impact of early multiple organ dysfunction syndrome on clinical, functional, and disability outcomes over the year following traumatic brain injury. DESIGN: Retrospective cohort study. SETTING: Patients enrolled in the Transforming Clinical Research and Knowledge in Traumatic Brain Injury study, an 18-center prospective cohort study of traumatic brain injury patients evaluated in participating level 1 trauma centers. SUBJECTS: Adult (age > 17 yr) patients with moderate-severe traumatic brain injury (Glasgow Coma Scale < 13). We excluded patients with major extracranial injury (Abbreviated Injury Scale score ≥ 3). INTERVENTIONS: Development of early multiple organ dysfunction syndrome, defined as a maximum modified Sequential Organ Failure Assessment score greater than 7 during the initial 72 hours following admission. MEASUREMENTS AND MAIN RESULTS: The main outcomes were: hospital mortality, length of stay, 6-month functional and disability domains (Glasgow Outcome Scale-Extended and Disability Rating Scale), and 1-year mortality. Secondary outcomes included: ICU length of stay, 3-month Glasgow Outcome Scale-Extended, 3-month Disability Rating Scale, 1-year Glasgow Outcome Scale-Extended, and 1-year Disability Rating Scale. We examined 373 subjects with moderate-severe traumatic brain injury. The mean (sd) Glasgow Coma Scale in the emergency department was 5.8 (3.2), with 280 subjects (75%) classified as severe traumatic brain injury (Glasgow Coma Scale 3-8). Among subjects with moderate-severe traumatic brain injury, 252 (68%) developed early multiple organ dysfunction syndrome. Subjects that developed early multiple organ dysfunction syndrome had a 75% decreased odds of a favorable outcome (Glasgow Outcome Scale-Extended 5-8) at 6 months (adjusted odds ratio, 0.25; 95% CI, 0.12-0.51) and increased disability (higher Disability Rating Scale score) at 6 months (adjusted mean difference, 2.04; 95% CI, 0.92-3.17). Subjects that developed early multiple organ dysfunction syndrome experienced an increased hospital length of stay (adjusted mean difference, 11.4 d; 95% CI, 7.1-15.8), with a nonsignificantly decreased survival to hospital discharge (odds ratio, 0.47; 95% CI, 0.18-1.2). CONCLUSIONS: Early multiple organ dysfunction following moderate-severe traumatic brain injury is common and independently impacts multiple domains (mortality, function, and disability) over the year following injury. Further research is necessary to understand underlying mechanisms, improve early recognition, and optimize management strategies.

Risk Factors for Suicidal Ideation Following Mild Traumatic Brain Injury: A TRACK-TBI Study.

OBJECTIVE: To identify risk factors for suicidal ideation (SI) following mild traumatic brain injury (mTBI). SETTING: Eleven US level 1 trauma centers. PARTICIPANTS: A total of 1158 emergency department patients with mTBI (Glasgow Coma Scale score = 13-15) enrolled in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study. DESIGN: Prospective observational study; weights-adjusted multivariable logistic regression models (n's = 727-883) estimated associations of baseline factors and post-TBI symptoms with SI at 2 weeks and 3, 6, and 12 months postinjury. MAIN MEASURES: Patient Health Questionnaire, Rivermead Post-Concussion Symptoms Questionnaire. RESULTS: Preinjury psychiatric history predicted SI at all follow-ups (adjusted odds ratios [AORs] = 2.26-6.33, P values <.05) and history of prior TBI predicted SI at 2 weeks (AOR = 2.36, 95% confidence interval [CI] = 1.16-4.81, P = .018), 3 months (AOR = 2.62, 95% CI = 1.33-5.16, P = .005), and 6 months postinjury (AOR = 2.54, 95% CI = 1.19-5.42, P = .016). Adjusting for these baseline factors, post-TBI symptoms were strongly associated with SI at concurrent (AORs = 1.91-2.88 per standard deviation unit increase in Rivermead Post-Concussion Symptoms Questionnaire score; P values <.0005) and subsequent follow-up visits (AORs = 1.68-2.53; P values <.005). Most of the associations between post-TBI symptoms and SI were statistically explained by co-occurring depression. CONCLUSION: Screening for psychiatric and prior TBI history may help identify patients at risk for SI following mTBI. Awareness of the strong associations of post-TBI symptoms with SI may facilitate interventions to prevent suicide-related outcomes in patients with mTBI.

Effect of parental education and household poverty on recovery after traumatic brain injury in school-aged children.

OBJECTIVE: While prior studies have found parental socioeconomic status (SES) affects the outcomes of pediatric traumatic brain injury (TBI), the longitudinal trajectory of this effect is not well understood. METHODS: This prospective cohort study included children 8-18 years of age admitted to six sites with a complicated mild (n = 123) or moderate-severe TBI (n = 47). We used caregiver education and household poverty level as predictors, and multiple quality of life and health behavior domains as outcomes. Differences at 6, 12, and 24 months from baseline ratings of pre-injury functioning were compared by SES. We examined the association between measures of SES and domains of functioning over the 24 months post-injury in children with a complicated mild or moderate- severe TBI, and determined how this association varied over time. RESULTS: Parental education was associated with recovery among children with complicated mild TBI; outcomes at 6, 12, and 24 months were substantially poorer than at baseline for children with the least educated parents. After moderate-severe TBI, children in households with lower incomes had poorer outcomes compared to baseline across time. IMPLICATIONS: Parental education and household income were associated with recovery trajectories for children with TBI of varying severity.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Use of Amitriptyline in the Treatment of Headache After Traumatic Brain Injury: Lessons Learned From a Clinical Trial.

OBJECTIVES: The primary outcome of this study was to assess the efficacy and safety of preventive treatment with amitriptyline on headache frequency and severity after mild traumatic brain injury (mTBI). BACKGROUND: Despite the fact that headache is the most common and persistent physical symptom after TBI, there has been little research on the longitudinal course or pharmacologic treatment of this disorder. Of those who have headache after injury, about 60% continue to complain of headache at 3 months post injury, with higher levels of disability than those without headache. There have been no prospective, randomized, controlled trials of a pharmacologic agent for headache after TBI. Additionally, a brain-injured population may be more susceptible to side effects of medication. DESIGN: This is a single-center phase II trial of amitriptyline to prevent persistent headache after an mTBI. Medication dose was gradually increased from 10 to 50 mg daily. RESULTS: Fifty participants were enrolled and 33 who completed the 90-day assessment were included in the final analysis. In order to detect a possible cognitive impact of the study drug, 24 participants were randomly assigned to start amitriptyline immediately after study enrollment and 26 were assigned to start 30 days after enrollment. Forty-nine percent (18/37) of those assigned to take medication took none throughout the study period, with less compliance in younger participants with mean ages of 32.7 in those who did not take any medication, 33.4 who were less than 80% compliant, and 42.3 who were compliant (P = .013). Compliance in keeping a daily headache diary was low, with 29/50 participants (58%) meeting daily entry completion, and only 10 participants maintaining 100% diary completion. No differences were found between those who started medication immediately vs at day 30 in headache frequency or severity. CONCLUSIONS: While headache is the most common symptom following mTBI, current evidence does not support a specific treatment. No differences were noted in headache frequency compared to our prior study. However, the current sample had significantly lower headache severity (15% vs 36% with pain rating of 6 or above, P = .015) compared to our prior study. Our current study was not able to determine whether there is any benefit for the use of amitriptyline as a headache preventive because of difficulty with study recruitment and compliance. The challenges with recruitment and retention in the mTBI population were instructive, and future research in this area will need to identify strategies to improve recruitment, diary compliance, and medication adherence in this population.

IMPACT and CRASH prognostic models for traumatic brain injury: external validation in a South-American cohort.

OBJECTIVE: To develop a robust prognostic model, the more diverse the settings in which the system is tested and found to be accurate, the more likely it will be generalisable to untested settings. This study aimed to externally validate the International Mission for Prognosis and Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticosteroid Randomization after Significant Head Injury (CRASH) models for low-income and middle-income countries using a dataset of patients with severe traumatic brain injury (TBI) from the Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure study and a simultaneously conducted observational study. METHOD: A total of 550 patients with severe TBI were enrolled in the study, and 466 of those were included in the analysis. Patient admission characteristics were extracted to predict unfavourable outcome (Glasgow Outcome Scale: GOS<3) and mortality (GOS 1) at 14 days or 6 months. RESULTS: There were 48% of the participants who had unfavourable outcome at 6 months and these included 38% who had died. The area under the receiver operating characteristic curve (AUC) values were 0.683-0.775 and 0.640-0.731 for the IMPACT and CRASH models respectively. The IMPACT CT model had the highest AUC for predicting unfavourable outcomes, and the IMPACT Lab model had the best discrimination for predicting 6-month mortality. The discrimination for both the IMPACT and CRASH models improved with increasing complexity of the models. Calibration revealed that there were disagreement between observed and predicted outcomes in the IMPACT and CRASH models. CONCLUSION: The overall performance of all IMPACT and CRASH models was adequate when used to predict outcomes in the dataset. However, some disagreement in calibration suggests the necessity for updating prognostic models to maintain currency and generalisability.

Impact of aging on the immune response to traumatic brain injury (AIm:TBI) study protocol.

BACKGROUND: Traumatic brain injury (TBI) in older adults leads to considerable morbidity and mortality. Outcomes among older adults with TBI are disparately worse than in younger adults. Differences in immunological response to injury may account for at least some of this disparity. Understanding how ageing differentially affects the immune response to TBI and how older age and these immunological changes affect the natural history of recovery following TBI are the goals of this study. DESIGN/METHODS: A prospective multiple cohort design is being used to assess the effects of ageing and TBI on immune makers and to test predictors of impairment and disability in older adults following mild TBI. Older adults (>55 years) with mild TBI are enrolled with three comparison groups: younger adults (21-54 years) with mild TBI, non-injured older adults (>55 years) and non-injured young adults (21-54 years). For the primary analysis, we will assess the association between immune markers and Glasgow Outcome Scale-Extended at 6 months, using logistic regression. Predictors of interest will be inflammatory biomarkers. Multivariate linear regression will be used to evaluate associations between biomarkers and other outcomes (symptoms, function and quality of life) at 3 and 6 months. Exploratory analyses will investigate the utility of biomarkers to predict outcome using receiver-operating characteristic curves. DISCUSSION: A better understanding of the recovery trajectory and biological rationale for disparate outcomes following TBI in older adults could allow for development of specific interventions aimed at reducing or eliminating symptoms. Such interventions could reduce impairment and healthcare costs.