Moderate-severe Traumatic Brain Injury Patients Research Articles

Imaging Findings in Acute Traumatic Brain Injury: a National Institute of Neurological Disorders and Stroke Common Data Element-Based Pictorial Review and Analysis of Over 4000 Admission Brain Computed Tomography Scans from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study.

In 2010, the National Institute of Neurological Disorders and Stroke (NINDS) created a set of common data elements (CDEs) to help standardize the assessment and reporting of imaging findings in traumatic brain injury (TBI). However, as opposed to other standardized radiology reporting systems, a visual overview and data to support the proposed standardized lexicon are lacking. We used over 4000 admission computed tomography (CT) scans of patients with TBI from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study to develop an extensive pictorial overview of the NINDS TBI CDEs, with visual examples and background information on individual pathoanatomical lesion types, up to the level of supplemental and emerging information (e.g., location and estimated volumes). We documented the frequency of lesion occurrence, aiming to quantify the relative importance of different CDEs for characterizing TBI, and performed a critical appraisal of our experience with the intent to inform updating of the CDEs. In addition, we investigated the co-occurrence and clustering of lesion types and the distribution of six CT classification systems. The median age of the 4087 patients in our dataset was 50 years (interquartile range, 29-66; range, 0-96), including 238 patients under 18 years old (5.8%). Traumatic subarachnoid hemorrhage (45.3%), skull fractures (37.4%), contusions (31.3%), and acute subdural hematoma (28.9%) were the most frequently occurring CT findings in acute TBI. The ranking of these lesions was the same in patients with mild TBI (baseline Glasgow Coma Scale [GCS] score 13-15) compared with those with moderate-severe TBI (baseline GCS score 3-12), but the frequency of occurrence was up to three times higher in moderate-severe TBI. In most TBI patients with CT abnormalities, there was co-occurrence and clustering of different lesion types, with significant differences between mild and moderate-severe TBI patients. More specifically, lesion patterns were more complex in moderate-severe TBI patients, with more co-existing lesions and more frequent signs of mass effect. These patients also had higher and more heterogeneous CT score distributions, associated with worse predicted outcomes. The critical appraisal of the NINDS CDEs was highly positive, but revealed that full assessment can be time consuming, that some CDEs had very low frequencies, and identified a few redundancies and ambiguity in some definitions. Whilst primarily developed for research, implementation of CDE templates for use in clinical practice is advocated, but this will require development of an abbreviated version. In conclusion, with this study, we provide an educational resource for clinicians and researchers to help assess, characterize, and report the vast and complex spectrum of imaging findings in patients with TBI. Our data provides a comprehensive overview of the contemporary landscape of TBI imaging pathology in Europe, and the findings can serve as empirical evidence for updating the current NINDS radiologic CDEs to version 3.0.

Adaptation and Validation of the Standardized Swallowing Assessment Tool for Patients With Moderate-Severe Traumatic Brain Injury and Cervical Spinal Cord Injury.

Oropharyngeal dysphagia is common in moderate-severe traumatic brain injury (TBI) and cervical spinal cord injury (SCI) patients and can have serious consequences. Delaying feeding in these patients can also be detrimental. Nonetheless, the psychometric properties of screening tools that can promptly identify dysphagia have never been tested in these neurotrauma populations. This study aimed to: (1) adapt, translate, and validate the content of the French-Canadian version of the the Standardized Swallowing Assessment (SSA) tool to meet the needs of moderate-severe TBI and cervical SCI patients, (2) examine its inter-rater reliability and criterion-concurrent validation, and (3) evaluate its clinical utility from the perspectives of critical care nurses. The SSA tool was adapted and translated using an integrated method for the cultural adaptation and translation of tools. Eleven experts participated in the adaptation of the SSA tool, which led to the clarification of one item, as well as a new step and instructions for the screening procedure. Content validation (i.e., item and scale relevance) was evaluated by multidisciplinary team members (n = 17). The mean content validity index (CVI) score was 0.97 for the entire scale, while the mean CVI scores for individual items ranged from 0.82 to 1.0. A total of 60 neurotrauma patients were enrolled for inter-rater reliability and criterion-concurrent validation. Interrater reliability was determined by comparing two scores: one score from nurses responsible for the care of enrolled patients and one score from the research nurse. The weighted kappa coefficients for inter-rater reliability were 0.86 for moderate-severe TBI patients (n = 30) and 0.73 for cervical SCI patients (n = 30). A speech language therapist (SLT) also assessed dysphagia and results were used as the standard clinical reference criterion to determine concurrent validity (sensibility and specificity) of the adapted SSA tool. The sensitivity and specificity were 92% and 50% for moderate-severe TBI, and 77% and 75% for cervical SCI, respectively. The positive predictive value (PPV) and the negative predictive value (NPV) were 65% and 87% in TBI patients, and 75% and 76% in SCI patients. Test accuracy was 71% and 77% for these same groups. The clinical utility of the tool was evaluated according to the following domains: appropriateness, accessibility of the required material, applicability, perceived effectiveness, and acceptability. Acceptability was the only domain with a level of agreement <80% (74%) among trauma critical care nurses (n = 49). Findings support the content validation and inter-rater reliability of the adapted French-Canadian version of the SSA tool in moderate-severe TBI and cervical SCI patients. Sensitivity was acceptable in both groups, but the specificity was lower, especially in moderate-severe TBI patients. Further validation of the adapted French-Canadian version of the SSA tool is needed in neurotrauma patients to confirm these results and to ensure safe dysphagia screening while avoiding oral feeding deferrals.

Serial Measurements of Serum Glial Fibrillary Acidic Protein in Moderate-Severe Traumatic Brain Injury: Potential Utility in Providing Insights into Secondary Insults and Long-Term Outcome.

In patients with traumatic brain injury (TBI), serum biomarkers may have utility in assessing the evolution of secondary brain injury. A panel of nine brain-injury- associated biomarkers was measured in archived serum samples over 10 days post-injury from 100 patients with moderate-severe TBI. Among the biomarkers evaluated, serum glial fibrillary acidic protein (GFAP) had the strongest associations with summary measures of acute pathophysiology, including intracranial pressure (ICP), cerebral perfusion pressure (CPP), and brain tissue pO2 (PbtO2). Group based trajectory (TRAJ) analysis was used to identify three distinct GFAP subgroups. The low TRAJ group (n = 23) had peak levels of 9.4 + 1.2 ng/mL that declined rapidly. The middle TRAJ group (n = 48) had higher peak values (31.5 + 5.0 ng/mL) and a slower decline over time. The high TRAJ group (n = 26) had very high, sustained peak values (59.6 + 12.5 ng/mL) that even rose among some patients over 10 days. Patients in the high TRAJ group had significantly higher mortality rate than patients in low and middle TRAJ groups (26.9% vs. 7.0%, p = 0.028). The frequency of poor neurological outcome (Glasgow Outcome Score Extended [GOS-E] 1-4) was 88.5% in the high TRAJ group, 54.2% in the middle TRAJ group, and 30.4% in the low TRAJ group (p < 0.001). ICP was highest in the high TRAJ group (median 17.6 mm Hg), compared with 14.4 mmHg in the low and 15.9 mm Hg in middle TRAJ groups (p = 0.002). High TRAJ patients spent the longest time with ICP >25 mm Hg, median 23 h, compared with 2 and 6 h in the low and middle TRAJ groups (p = 0.006), and the longest time with ICP >30 mm Hg, median 5 h, compared with 0 and 1 h in the low and middle TRAJ groups, respectively (p = 0.013). High TRAJ group patients more commonly required tier 2 or 3 treatment to control ICP. The high TRAJ group had the longest duration when CPP was <50 mm Hg (p = 0.007), and PbtO2 was <10 mm Hg (p = 0.002). Logistical regression was used to study the relationship between temporal serum GFAP patterns and 6-month GOS-E. Here, the low and middle TRAJ groups were combined to form a low-risk group, and the high TRAJ group was designated the high-risk group. High TRAJ group patients had a greater chance of a poor 6-month GOS-E (p < 0.0001). When adjusting for baseline injury characteristics, GFAP TRAJ group membership remained associated with GOS-E (p = 0.003). When an intensive care unit (ICU) injury burden score, developed to quantify physiological derangements, was added to the model, GFAP TRAJ group membership remained associated with GOS-E (p = 0.014). Mediation analysis suggested that ICU burden scores were in the causal pathway between TRAJ group and 6-month mortality or GOS-E. Our results suggest that GFAP may be useful to monitor serially in moderate-severe TBI patients. Future studies in larger cohorts are needed to confirm these results.

Optic nerve sheath diameter and pulsatility index for the diagnosis and follow-up in pediatric traumatic brain injury: a prospective observational cohort study.

Invasive neuromonitoring could be difficult in children with traumatic brain injury (TBI). This study aimed to determine whether noninvasive intracranial pressure (nICP), calculated via pulsatility index (PI) and optic nerve sheath diameter (ONSD) had correlated with each other and patient outcome. All moderate-severe TBI patients were eligible. Patients with a diagnosis of intoxication that did not affect the mental status or cardiovascular system were enrolled as controls. The PI measurements were routinely performed bilaterally on the middle cerebral artery. A software (QLAB's Q-Apps) was used to calculate PI, which further placed the ICP equation of Bellner et al. Linear probe with a 10MHz frequency transducer to measure ONSD, which further placed the ICP equation of Robba et al. All measurements were performed by a point-of-care ultrasound certified pediatric intensivist under the supervision of a neurocritical care specialist, before and 30min after a hypertonic saline (HTS) infusion for every 6h when the patient's mean arterial pressure, heart rate, body temperature, hemoglobin, and blood CO2 levels were within normal ranges. The secondary outcome was the effect of hypertonic saline (HTS) on nICP. Delta-sodium values of each HTS infusion were calculated as a difference between pre- and post-measurements. Twenty-five TBI patients (200 measurements) and 19 controls (57 measurements) were included. Median nICP-PI and nICP-ONSD on admission were significantly higher in the TBI group (11.03 (9.98-12.63), p = 0.004, and 13.14 (12.27-14.64), p < 0.001, respectively). Median nICP-ONSD of severe TBI patients were higher than moderate TBI patients (13.58 (13.14-15.71) and 12.30 (9.83-13.14), respectively, p = 0.013). The median nICP-PI was the same across the type of injury (falls and motor vehicle accidents), while the median nICP-ONSD of the motor vehicle accident group was higher than falls. The first nICP-PI and nICP-ONSD measurements in PICU and admission pGCS were negatively correlated (r = - 0.562, p = 0.003 and r = - 0.582, p = 0.002, respectively). The mean nICP-ONSD during the study period and admission pGCS and GOS-E peds score significantly correlated. However, the Bland-Altman plots showed significant bias between the two methods of ICP except after 5th dose of HTS. All nICP values significantly decreased in time, and it was most obvious after the 5th dose of HTS. No significant correlations were found between delta sodium levels and nICP. Noninvasive estimation of ICP is helpful for the management of pediatric severe TBI patients. nICP driven by ONSD is more consistent with clinical findings of increased ICP but not useful as a follow-up tool in acute management because of slow circulation of CSF around the optic sheath. The correlation between admission GCS scores and GOS-E peds score favors ONSD as a good candidate for determining disease severity and predicting long-term outcomes.

Associations between intracranial pressure thresholds and multimodal monitoring in acute traumatic neural injury: a scoping review

Current moderate/severe traumatic brain injury (TBI) guidelines suggest the use of an intracranial pressure (ICP) treatment threshold of 20 mmHg or 22 mmHg. Over the past decade, the use of various cerebral physiology monitoring devices has been incorporated into neurocritical care practice and termed "multimodal monitoring." Such modalities include those that monitor systemic hemodynamics, systemic and brain oxygenation, cerebral blood flow (CBF), cerebral autoregulation, electrophysiology, and cerebral metabolism. Given that the relationship between ICP and outcomes is not yet entirely understood, a comprehensive review of the literature on the associations between ICP thresholds and multimodal monitoring is still needed. We conducted a scoping review of the literature for studies that present an objective statistical association between ICP above/below threshold and any multimodal monitoring variable. MEDLINE, BIOSIS, Cochrane library, EMBASE, Global Health, and SCOPUS were searched from inception to July 2022 for relevant articles. Full-length, peer-reviewed, original works with a sample size of ≥50 moderate-severe TBI patients were included in this study. A total of 13 articles were deemed eligible for final inclusion. The included articles were significantly heterogenous in terms of their designs, demographics, and results, making it difficult to draw any definitive conclusions. No literature describing the association between guideline-based ICP thresholds and measures of brain electrophysiology, cerebral metabolism, or direct metrics of CBF was found. There is currently little literature that presents objective statistical associations between ICP thresholds and multimodal monitoring physiology. However, overall, the literature indicates that having ICP above guideline based thresholds is associated with increased blood pressure, increased cardiac decoupling, reduced parenchymal brain oxygen tension, and impaired cerebral autoregulation, with no association with CBF velocity within the therapeutic range of ICP. There was insufficient literature to comment on other multimodal monitoring measures.

The Efficacy of Hyperbaric Oxygen Therapy in Traumatic Brain Injury Patients: Literature Review and Clinical Guidelines

Introduction: The application of hyperbaric oxygen therapy for patients with both acute and chronic traumatic brain injury has been suggested for over five decades. In the past decade, the design and quality of studies were more detailed and thorough leading to an improved unerstanding of the uses of HBOT and the profiles of the patients who can benefit the most. Objectives: Perform a comprehensive literature review of hyperbaric oxygen therapy application for the treatment of patients with both acute, subacute and chronic traumatic brain injury. Methods: Extensive literature search from 1969 to April 2023 was performed on April 1st 2023 within the following databases: Cochrane Library, PubMed, Google Scholar, and Web of Science, including humans clinical data, in articles providing information on the type of treatment and clinical outcomes. Articles were first categorized into acute-subacute traumatic brain inury and chronic traumatic brain injury and further classified into low, medium or high level quality. Results: There was high level evidence including nine randomized controlled trials, one meta-analysis and two prospective study evaluating the clinical effects of hyperbaric oxygen therapy in patients suffering from traumatic brain injuries in the acute and subacute settings. Mortality was significantly reduced in all studies that used it as an endpoint, while favorable functional outcomes in survivors showed mixed results. In chronic severe traumatic brain injury, there is low to moderate evidence including two uncontrolled prospective studies, two cohort studies and eight case reports suggesting improved outcomes. In chronic mild traumatic brain injury, there is high level evidence including seven randomized controlled trials, and six prospective studies suggesting significant improvement in cognitive function, symptoms and quality of life. Conclusions: Hyperbaric oxygen therapy may be recommended in acute moderate-severe traumatic brain injury patients (Type 2a recommendation, level A evidence). However, further studies are needed to both evaluate outcomes and to determine the optimal treatment protocols for the different types of injuries (Type 1 recommendation, level A evidence). Hyperbaric oxygen threrapy should be recommended in chronic traumatic brain injury for a selected group of patients suffering from prolonged post-concussion syndrome who have clear evidence of metabolic dysfunctional brain regions as determined by neuroimaging (Type 2a recommendation, level B-R evidence). Patients should be properly evaluated by standardized cognitive tests and functional brain imaging (Type 1 recommendation, level B-R evidence).

Olfactory Dysfunction Following Moderate to Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Reports of smell loss following traumatic brain injury (TBI) are a well-documented but understudied phenomenon. Given the broad consequences of olfactory loss, we characterized psychophysical olfactory dysfunction in individuals with moderate to severe TBI using systematic review and meta-analytic methods. Following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) protocol, five databases (PubMed, EMBASE, Cochrane Library, Web of Science, Scopus) were reviewed for studies investigating olfactory dysfunction in persons with moderate to severe TBI. Of the 5,223 studies reviewed, 19 met our inclusion criteria for the systematic review and 11 met inclusion criteria for meta-analysis. We calculated effect sizes (Hedges' g) to characterize the degree of olfactory dysfunction between patients with moderate to severe TBI and controls. A total of 951 moderate-severe TBI patients from 19 studies were included in the systematic review, which largely demonstrated poorer olfactory psychophysical performances in this patient population. Meta-analysis demonstrated a large effect size for olfactory dysfunction in moderate-severe TBI relative to healthy controls (g=-2.43, 95%CI: -3.16 < δ<-1.69). The magnitude of the effect was moderated by age and patient sex, with larger effect sizes associated with older age (following exclusion of a pediatric population) and larger compositions of women in the patient group. Moderate to severe TBI is associated with prominent olfactory dysfunction. Significant research gaps remain regarding the mechanism, recovery and natural history of olfactory dysfunction following moderate to severe TBI, which has significant clinical implications for the identification and treatment for those with post-traumatic olfactory dysfunction.

Decreased homotopic functional connectivity in traumatic brain injury.

Homotopic functional connectivity (HoFC), the synchrony in activity patterns between homologous brain regions, is a fundamental characteristic of resting-state functional connectivity (RsFC). We examined the difference in HoFC, computed as the correlation between atlas-based regions and their counterpart on the opposite hemisphere, in 16 moderate-severe traumatic brain injury patients (msTBI) and 36 healthy controls. Regions of decreased HoFC in msTBI patients were further used as seeds for examining differences between groups in correlations with other brain regions. Finally, we computed logistic regression models of regional HoFC and fractional anisotropy (FA) of the corpus callosum (CC). TBI patients exhibited decreased HoFC in the middle and posterior cingulate cortex, thalamus, superior temporal pole, and cerebellum III. Furthermore, decreased RsFC was found between left cerebellum III and right parahippocampal cortex and vermis, between superior temporal pole and left caudate and medial left and right frontal orbital gyri. Thalamic HoFC and FA of the CC discriminate patients as msTBI with a high accuracy of 96%. TBI is associated with regionally decreased HoFC. Moreover, a multimodality model of interhemispheric connectivity allowed for a high degree of accuracy in disease discrimination and enabled a deeper understanding of TBI effects on brain interhemispheric reorganization post-TBI.

Methodology and feasibility of neurofeedback to improve visual attention to letters in mild Alzheimer's disease

Background: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality globally. Currently, the association between hyperoxia and outcomes in patients with TBI remains debatable. We assessed the effect of hyperoxia on the neurological outcomes and survival of critically ill patients with moderate-severe TBI. Methods: This was a retrospective cohort study of all adults with moderatesevere TBI admitted to the ICU between 1st January 2016 and 31st December 2019 who required invasive mechanical ventilation. We noted ABGs performed with the first 3 hours of intubation, then 6-12 hours and 24-48 hours. The patients were divided into two categories: normoxia (PaO2 60-99 mmHg) and hyeroxia (PaO2 >100 mmHg). Multivariable logistic regression was performed to assess predictors of hospital mortality and good neurologic outcome (Glasgow outcome score [GOS] ≥ 4). In a second analysis the patients were divided into survivors and non-survivors. Results: The study included 308 patients: 23.4% (n=72) in normoxia group and 76.6% (n=236) in hyeroxia group. Hyperoxia was not associated with increased hospital (43% vs. 18%, p=0.20) mortality. Further, the hospital discharge GCS (10 ± 5 vs. 11 ± 4, p=0.10) and GOS (3 ± 1 vs. 3 ± 1, p=0.35) were similar. In multivariable logistic regression analysis, hyperoxia was not associated with increased mortality (adjusted odds ratio [aOR] 0.99, 95% CI 0.99-1.00, p=0.11). PaO2 within different ranges was also not associated with mortality: 100-200 mmHg: aOR 0.60, 95% CI 0.29-1.52; 201-300 mmHg: aOR 0.66, 95% CI 0.29-1.52; 301-400 mmHg: aOR 0.80, 95% CI 0.31-2.09; and >400 mmHg: aOR 0.39, 95% CI 0.14-1.08; reference: PaO2 60-99 mmHg. The Kaplan-Meier survival curve for normoxia verses hyperoxia showed no significant difference for all-cause mortality. In the survivors verse nonsurvivors analysis, the PaO2 were (median, IQT) 199 mmHg (111-329) and 165 mmHg (84-252), respectively. Conclusion: Hyperoxia (PaO2 >100 mmHg) was not associated with increased mortality or poor neurological outcomes (determined by GOS) in moderatesevere TBI patients.

Paroxysmal Sympathetic Hyperactivity in Moderate-to-Severe Traumatic Brain Injury and the Role of Beta-Blockers: A Scoping Review.

Introduction Most cases of paroxysmal sympathetic hyperactivity (PSH) result from traumatic brain injury (TBI). Little is known about its pathophysiology and treatment, and several neuroprotective drugs are used including beta-blockers. The aim of our study is to collate existing evidence of the role of beta-blockers in the treatment of PSH. Methods We searched MEDLINE, ResearchGate, and Google Scholar, for keywords related to PSH and the role of beta-blockers in moderate-to-severe TBI on September 23, 2020. Two authors blindly screened the articles found with Rayyan. Both resolved their conflicts by mutual consent. If no solution was found, a third author was consulted. Simple descriptive data analysis was performed and the results were presented both in a narrative and tabular form. Results Of the 19 items found, 10 met the criteria for inclusion. 50% were systematic reviews without meta-analysis, 40% were observational studies, and 10% were experimental studies. Propranolol was the main beta-blocker found in 80% of the studies and was the only molecule used in the treatment of paroxysmal sympathetic hyperactivity in 40% of the included studies. Only two studies evaluated and showed a significant association between beta-blockers and mortality rate (5.1% vs. 10.8%; P=0.03), (3% vs. 15%; P=0.002), respectively. Conclusion Propranolol is the beta-blocker that has been shown to be effective in reducing the length of stay and mortality rate in moderate-severe traumatic brain injury patients with PSH. However, further studies are needed to precisely define the terms and conditions of its use.

Incidence and Clinical Impact of Myocardial Injury Following Traumatic Brain Injury: A Pilot TRACK-TBI Study.

Traumatic brain injury (TBI) is a major global health problem. Little research has addressed extracranial organ dysfunction following TBI, particularly myocardial injury. Using a sensitive marker of myocardial injury-high sensitivity troponin (hsTn)-we examined the incidence of early myocardial injury following TBI and explored its association with neurological outcomes following moderate-severe TBI. We conducted a pilot cohort study of 133 adult (age above 17 y) subjects enrolled in the TRACK-TBI 18-center prospective cohort study. Descriptive statistics were used to examine the incidence of myocardial injury (defined as hsTn >99th percentile for a standardized reference population) across TBI severities, and to explore the association of myocardial injury with a 6-month extended Glasgow Outcome Score among patients with moderate-severe TBI. The mean (SD) age of the participants was 44 (17) years, and 87 (65%) were male. Twenty-six patients (20%) developed myocardial injury following TBI; myocardial injury was present in 15% of mild TBI patients and 29% of moderate-severe TBI patients (P=0.13). Median (interquartile range) hsTn values were 3.8 ng/L (2.1, 9.0), 5.8 ng/L (4.5, 34.6), and 10.2 ng/L (3.0, 34.0) in mild, moderate, and severe TBI participants, respectively (P=0.04). Overall, 11% of participants with moderate-severe TBI and myocardial injury experienced a good outcome (6-mo extended Glasgow Outcome Score≥5) at 6 months, compared with 65% in the group that did not experience myocardial injury (P=0.01). Myocardial injury is common following TBI, with a likely dose-response relationship with TBI severity. Early myocardial injury was associated with poor 6-month clinical outcomes following moderate-severe TBI.

The Effect of Hyperoxia in Traumatic Brain Injury Patients in the Intensive Care Unit of a Tertiary Care Center

Background: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality globally. Currently, the association between hyperoxia and outcomes in patients with TBI remains debatable. We assessed the effect of hyperoxia on the neurological outcomes and survival of critically ill patients with moderate-severe TBI. Methods: This was a retrospective cohort study of all adults with moderatesevere TBI admitted to the ICU between 1st January 2016 and 31st December 2019 who required invasive mechanical ventilation. We noted ABGs performed with the first 3 hours of intubation, then 6-12 hours and 24-48 hours. The patients were divided into two categories: normoxia (PaO2 60-99 mmHg) and hyeroxia (PaO2 >100 mmHg). Multivariable logistic regression was performed to assess predictors of hospital mortality and good neurologic outcome (Glasgow outcome score [GOS] ≥ 4). In a second analysis the patients were divided into survivors and non-survivors. Results: The study included 308 patients: 23.4% (n=72) in normoxia group and 76.6% (n=236) in hyeroxia group. Hyperoxia was not associated with increased hospital (43% vs. 18%, p=0.20) mortality. Further, the hospital discharge GCS (10 ± 5 vs. 11 ± 4, p=0.10) and GOS (3 ± 1 vs. 3 ± 1, p=0.35) were similar. In multivariable logistic regression analysis, hyperoxia was not associated with increased mortality (adjusted odds ratio [aOR] 0.99, 95% CI 0.99-1.00, p=0.11). PaO2 within different ranges was also not associated with mortality: 100-200 mmHg: aOR 0.60, 95% CI 0.29-1.52; 201-300 mmHg: aOR 0.66, 95% CI 0.29-1.52; 301-400 mmHg: aOR 0.80, 95% CI 0.31-2.09; and >400 mmHg: aOR 0.39, 95% CI 0.14-1.08; reference: PaO2 60-99 mmHg. The Kaplan-Meier survival curve for normoxia verses hyperoxia showed no significant difference for all-cause mortality. In the survivors verse nonsurvivors analysis, the PaO2 were (median, IQT) 199 mmHg (111-329) and 165 mmHg (84-252), respectively. Conclusion: Hyperoxia (PaO2 >100 mmHg) was not associated with increased mortality or poor neurological outcomes (determined by GOS) in moderatesevere TBI patients.

Multiplex Networks to Characterize Seizure Development in Traumatic Brain Injury Patients.

Traumatic brain injury (TBI) may cause secondary debilitating problems, such as post-traumatic epilepsy (PTE), which occurs with unprovoked recurrent seizures, months or even years after TBI. Currently, the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) has been enrolling moderate-severe TBI patients with the goal to identify biomarkers of epileptogenesis that may help to prevent seizure occurrence and better understand the mechanism underlying PTE. In this work, we used a novel complex network approach based on segmenting T1-weighted Magnetic Resonance Imaging (MRI) scans in patches of the same dimension (network nodes) and measured pairwise patch similarities using Pearson's correlation (network connections). This network model allowed us to obtain a series of single and multiplex network metrics to comprehensively analyze the different interactions between brain components and capture structural MRI alterations related to seizure development. We used these complex network features to train a Random Forest (RF) classifier and predict, with an accuracy of 70 and a 95% confidence interval of [67, 73%], which subjects from EpiBioS4Rx have had at least one seizure after a TBI. This complex network approach also allowed the identification of the most informative scales and brain areas for the discrimination between the two clinical groups: seizure-free and seizure-affected subjects, demonstrating to be a promising pilot study which, in the future, may serve to identify and validate biomarkers of PTE.

Distinct patterns of structural damage underlie working memory and reasoning deficits after traumatic brain injury.

It is well established that chronic cognitive problems after traumatic brain injury relate to diffuse axonal injury and the consequent widespread disruption of brain connectivity. However, the pattern of diffuse axonal injury varies between patients and they have a correspondingly heterogeneous profile of cognitive deficits. This heterogeneity is poorly understood, presenting a non-trivial challenge for prognostication and treatment. Prominent amongst cognitive problems are deficits in working memory and reasoning. Previous functional MRI in controls has associated these aspects of cognition with distinct, but partially overlapping, networks of brain regions. Based on this, a logical prediction is that differences in the integrity of the white matter tracts that connect these networks should predict variability in the type and severity of cognitive deficits after traumatic brain injury. We use diffusion-weighted imaging, cognitive testing and network analyses to test this prediction. We define functionally distinct subnetworks of the structural connectome by intersecting previously published functional MRI maps of the brain regions that are activated during our working memory and reasoning tasks, with a library of the white matter tracts that connect them. We examine how graph theoretic measures within these subnetworks relate to the performance of the same tasks in a cohort of 92 moderate-severe traumatic brain injury patients. Finally, we use machine learning to determine whether cognitive performance in patients can be predicted using graph theoretic measures from each subnetwork. Principal component analysis of behavioural scores confirm that reasoning and working memory form distinct components of cognitive ability, both of which are vulnerable to traumatic brain injury. Critically, impairments in these abilities after traumatic brain injury correlate in a dissociable manner with the information-processing architecture of the subnetworks that they are associated with. This dissociation is confirmed when examining degree centrality measures of the subnetworks using a canonical correlation analysis. Notably, the dissociation is prevalent across a number of node-centric measures and is asymmetrical: disruption to the working memory subnetwork relates to both working memory and reasoning performance whereas disruption to the reasoning subnetwork relates to reasoning performance selectively. Machine learning analysis further supports this finding by demonstrating that network measures predict cognitive performance in patients in the same asymmetrical manner. These results accord with hierarchical models of working memory, where reasoning is dependent on the ability to first hold task-relevant information in working memory. We propose that this finer grained information may be useful for future applications that attempt to predict long-term outcomes or develop tailored therapies.

Hyperchloremia, not Concomitant Hypernatremia, Independently Predicts Early Mortality in Critically Ill Moderate-Severe Traumatic Brain Injury Patients.

Hypernatremia has been associated with mortality in neurocritically ill patients, with and without traumatic brain injury (TBI). These studies, however, lack concomitant adjustment for hyperchloremia as a physiologically co-occurring finding despite the associations with hyperchloremia and worse outcomes after trauma, sepsis, and intracerebral hemorrhage. The objective of our study was to examine the association of concomitant hypernatremia and hyperchloremia with in-hospital mortality in moderate-severe TBI (msTBI) patients. We retrospectively analyzed prospectively collected data from the OPTIMISM-study and included all msTBI patients consecutively enrolled between 11/2009 and 1/2017. Time-weighted average (TWA) sodium and chloride values were calculated for all patients to examine the unadjusted mortality rates associated with the burden of hypernatremia and hyperchloremia over the entire duration of the intensive care unit stay. Multivariable logistic regression modeling predicting in-hospital mortality adjusted for validated confounders of msTBI mortality was applied to evaluate the concomitant effects of hypernatremia and hyperchloremia. Internal bootstrap validation was performed. Of the 458 patients included for analysis, 202 (44%) died during the index hospitalization. Fifty-five patients (12%) were excluded due to missing data. Unadjusted mortality rates were nearly linearly increasing for both TWA sodium and TWA chloride, and were highest for patients with a TWA sodium > 160mmol/L (100% mortality) and TWA chloride > 125mmol/L (94% mortality). When evaluated separately in the multivariable analysis, TWA sodium (per 10mmol/L change: adjusted OR 4.0 [95% CI 2.1-7.5]) and TWA chloride (per 10mmol/L change: adjusted OR 3.9 [95% CI 2.2-7.1]) independently predicted in-hospital mortality. When evaluated in combination, TWA chloride remained independently associated with in-hospital mortality (per 10mmol/L change: adjusted OR 2.9 [95% CI 1.1-7.8]), while this association was no longer observed with TWA sodium values (per 10mmol/L change: adjusted OR 1.5 [95% CI 0.51-4.4]). When concomitantly adjusting for the burden of hyperchloremia and hypernatremia, only hyperchloremia was independently associated with in-hospital mortality in our msTBI cohort. Pending validation, our findings may provide the rationale for future studies with targeted interventions to reduce hyperchloremia and improve outcomes in msTBI patients.

Speckle Tracking Analysis of Left Ventricular Systolic Function Following Traumatic Brain Injury: A Pilot Prospective Observational Cohort Study.

Systolic dysfunction and reduction in left ventricular ejection fraction (LVEF) has been documented after traumatic brain injury (TBI). Speckle tracking is an emerging technology for myocardial strain assessment which has been utilized to identify subclinical myocardial dysfunction, and is most commonly reported as global longitudinal strain (GLS). We examined myocardial strain and regional strain patterns following moderate-severe TBI. We conducted a prospective cohort study of moderate-severe TBI patients (Glasgow Coma Scale≤12) and age/sex-matched controls. Transthoracic echocardiography was performed within the first day and 1 week following TBI. Myocardial function was assessed using both GLS and LVEF, and impaired systolic function was defined as GLS >-16% or LVEF ≤50%. Regional strain patterns and individual strain trajectories were examined. Thirty subjects were included, 15 patients with TBI and 15 age/sex-matched controls. Among patients with adequate echocardiographic windows, systolic dysfunction was observed in 2 (17%) patients using LVEF and 5 (38%) patients using GLS within the first day after TBI. Mean GLS was impaired in patients with TBI compared with controls (-16.4±3.8% vs. -20.7±1.8%, P=0.001). Regional myocardial examination revealed impaired strain primarily in the basal and mid-ventricular segments. There was no improvement in GLS from day 1 to day 7 (P=0.81). Myocardial strain abnormalities are common and persist for at least 1 week following moderate-severe TBI. Speckle tracking may be useful for the early diagnosis and monitoring of systolic dysfunction following TBI.

Dopamine D2/D3 receptor abnormalities after traumatic brain injury and their relationship to post-traumatic depression.

ObjectiveTo investigate dopamine D2/D3 receptor availability following traumatic brain injury (TBI) and their relationship to the presence of DSM-IV Major Depressive Disorder (MDD) and patterns of axonal injury.MethodsTwelve moderate-severe TBI patients and 26 controls were imaged using [11C]PHNO positron emission tomography (PET) and structural magnetic resonance imaging (MRI). TBI patients and a second group of 32 controls also underwent diffusion tensor imaging (DTI) and neuropsychological assessment. Patients included six with post-injury MDD (TBI-MDD) and six without (TBI-NON). Non-displaceable binding potential (BPND) [11C]PHNO values were used to index D2/D3 receptor availability, and were calculated using a reference region procedure. Differences in BPND were examined using voxelwise and region-of-interest analyses. White matter microstructure integrity, quantified by fractional anisotropy (FA), was assessed and correlated with BPND.ResultsLower [11C]PHNO BPND was found in the caudate across all TBI patients when compared to controls. Lower [11C]PHNO BPND was observed in the caudate of TBI-MDD patients and increased [11C]PHNO BPND in the Amygdala of TBI-NON patients compared to controls. There were no significant differences in [11C]PHNO BPND between TBI-MDD and TBI-NON patients. Furthermore, DTI provided evidence of axonal injury following TBI. The uncinate fasciculus and cingulum had abnormally low FA, with the uncinate particularly affected in TBI-MDD patients. Caudate [11C]PHNO BPND correlated with FA within the nigro-caudate tract.Conclusions[11C]PHNO BPND is abnormal following TBI, which indicates post-traumatic changes in D2/D3 receptors. Patterns of [11C]PHNO BPND seen in patients with and without MDD suggest that further research would be beneficial to determine whether the use of dopaminergic treatment might be effective in the treatment of post-traumatic depression.

Research Advances in Hypothalamic-pituitary Dysfunction Related to Traumatic Brain Injury

Traumatic brain injury(TBI)is a major cause of hypothalamopituitary dysfunction. TBI-related hypothalamopituitary dysfunction is more common in the acute phase. Disturbance of pituitary/gonadal axis and growth hormone axis,as well as posterior pituitary dysfunction including central diabetes insipidus and syndrome of inappropriate antidiuretic hormone secretion,are the most frequently seen. During the chronic phase of TBI,anterior hypopituitarism is the major concern,which affects the quality of life. Risk factors for hypothalamopituitary dysfunction following TBI include low Glasgow score,high body mass index,hypoxia,older age,longer intensive care unit stay and longer coma status,radiological evidence of acute brain injury,and increased intracranial pressure. Children and adolescents are in a crucial period of growth and development,and therefore TBI-related pituitary dysfunction during this period can substantially affect the cognition and behaviors. There is currently no reliable biochemical marker predicting hypothalamopituitary dysfunctions. Therefore,it is of great importance to evaluate the pituitary function and take appropriate hormone replacement for moderate-severe TBI patients or mild TBI patients with apparent symptoms,especially for patients with water-electrolyte disturbance and adrenal deficiency. Growth hormone and gonadal hormone replacement therapies are crucial for children and adolescents.

Longitudinal Recovery of Executive Control Functions After Moderate-Severe Traumatic Brain Injury: Examining Trajectories of Variability and Ex-Gaussian Parameters

Background. Executive control deficits are deleterious and enduring consequences of moderate-severe traumatic brain injury (TBI) that disrupt everyday functioning. Clinically, such impairments can manifest as behavioural inconsistency, measurable experimentally by the degree of variability across trials of a reaction time (RT) task (also known as intraindividual variability [IIV]). Growing research on cognition after TBI points to cognitive deterioration in the chronic stages postinjury. Objective. To examine the longitudinal recovery of RT characteristics (IIV and more detailed ex-Gaussian components, as well as the number of impulsively quick responses) following moderate-severe TBI. Methods. Seventy moderate-severe TBI patients were assessed at 2, 5, 12, and 24+ months postinjury on a go/no-go RT task. RT indices (ex-Gaussian parameters mu and sigma [mean and variability of the normal distribution component], and tau [extremely slow responses]; mean, intraindividual coefficient of variation [ICV], and intraindividual standard deviation [ISD]) were analyzed with repeated-measures multivariate analysis of variance. Results. ICV, ISD, and ex-Gaussian tau significantly decreased (ie, improved) over time in the first year of injury, but worsened from 1 to 2+ years, as did the frequency of extremely fast responses. These quadratic patterns were accentuated by age and shown primarily in tau (extremely slow) and extremely fast (impulsive) responses. Conclusions. The pattern of early recovery followed by decline in executive control function is consistent with growing evidence that moderate-severe TBI is a progressive and degenerative disorder. Given the responsiveness to treatment of executive control deficits, elucidating the trajectory and underpinnings of inconsistent behavioral responding may reveal novel prognostic and clinical management opportunities.

Executive functioning in relation to coping in mild versus moderate-severe traumatic brain injury.

To examine associations between executive functioning (EF) and coping styles, separately for mild and moderate-severe traumatic brain injury (TBI) in the chronic phase postinjury. Patients with mild (n = 47) and moderate-severe TBI (n = 59) were included, in addition to healthy controls (HCs; n = 51). Assessment consisted of EF tests (Trail Making Test, Zoo Map Test, Controlled Oral Word Association Test) and questionnaires examining EF (Dysexecutive Questionnaire) and coping styles (Utrecht Coping List). Moderate-severe TBI patients showed significant more EF deficits, lower active coping and higher passive coping than mild TBI patients and HCs, whereas mild TBI patients did not differ from HCs. In the moderate-severe TBI group, a higher number of self-reported EF problems was related to lower levels of active coping, r = -.43, p < .01 and higher levels of passive coping, r = .58, p < .001, with proxy-reports relating to lower levels of active coping, r = -.33, p < .05. For mild TBI, a higher amount of self-reported EF problems was related to lower levels of active coping, r = -.38, p < .05 and higher levels of passive coping, r = .55, p < .001, with proxy-reports relating to higher levels of passive coping, r = .39, p < .05. Except for mental flexibility, EF performances were not associated with coping. This study shows strong associations between reported EF problems in daily life and coping styles. For moderate-severe TBI, proxy-reports may reflect EF impairments that complicate active problem-solving. However, reported EF problems by mild and moderate-severe TBI patients are also likely to reflect a psychological distress related to the way patients are inclined to deal with stressing situations that put a demand on their executive abilities. (PsycINFO Database Record