Nonpenetrating Traumatic Brain Injury Research Articles

Calcium and Non-Penetrating Traumatic Brain Injury: A Proposal for the Implementation of an Early Therapeutic Treatment for Initial Head Insults.

Finding an effective treatment for traumatic brain injury is challenging for multiple reasons. There are innumerable different causes and resulting levels of damage for both penetrating and non-penetrating traumatic brain injury each of which shows diverse pathophysiological progressions. More concerning is that disease progression can take decades before neurological symptoms become obvious. Currently, the primary treatment for non-penetrating mild traumatic brain injury, also called concussion, is bed rest despite the fact the majority of emergency room visits for traumatic brain injury are due to this mild form. Furthermore, one-third of mild traumatic brain injury cases progress to long-term serious symptoms. This argues for the earliest therapeutic intervention for all mild traumatic brain injury cases which is the focus of this review. Calcium levels are greatly increased in damaged brain regions as a result of the initial impact due to tissue damage as well as disrupted ion channels. The dysregulated calcium level feedback is a diversity of ways to further augment calcium neurotoxicity. This suggests that targeting calcium levels and function would be a strong therapeutic approach. An effective calcium-based traumatic brain injury therapy could best be developed through therapeutic programs organized in professional team sports where mild traumatic brain injury events are common, large numbers of subjects are involved and professional personnel are available to oversee treatment and documentation. This review concludes with a proposal with that focus.

Comparative Analysis of Clinical Severity and Outcomes in Penetrating Versus Blunt Traumatic Brain Injury Propensity Matched Cohorts.

Traumatic brain injury (TBI) is a global health challenge; however, penetrating brain injury (PBI) remains under-represented in evidence-based knowledge and research efforts. This study utilized data from the Trauma Quality Improvement Program (TQIP) of the National Trauma Data Bank (NTDB) to investigate outcomes of PBI as compared with clinical-severity-matched non-penetrating or blunt TBI. A total of 1765 patients with PBI were 1:1 propensity score-matched for clinical severity with blunt TBI patients. The intent of PBI was self-inflicted in 34.1% of the cases, and the mechanism was firearm-inflicted in 89.1%. Mortality was found to be significantly more common in PBI than in the severity- matched TBI cohort (33.9% vs. 14.3 %, p < 0.001) as was unfavorable outcome. Mortality was mediated by withdrawal of life-sustaining therapies (WOLST) 30% of the time, and WOLST occurred earlier (median 3 days vs. 6 days, p < 0.001) in PBI. Increased rate of mortality was observed with a Glasgow Coma Scale (GCS) of <11 in PBI as compared with <7 in blunt TBI. In conclusion, PBI patients exhibited higher mortality rates and unfavorable outcomes; one third of excess mortality was mediated by WOLST. The study also brings into question the applicability of the conventional TBI classification, based on GCS, in PBI. We emphasize the need to address the observed disparities and better understand the distinctive characteristics and mechanisms underlying PBI outcomes to improve patient care and reduce mortality.

Multiorgan Dysfunction Syndrome in Abusive and Accidental Pediatric Traumatic Brain Injury.

Abusive head trauma (AHT) is a mechanism of pediatric traumatic brain injury (TBI) with high morbidity and mortality. Multiorgan dysfunction syndrome (MODS), defined as organ dysfunction in two or more organ systems, is also associated with morbidity and mortality in critically ill children. Our objective was to compare the frequency of MODS and evaluate its association with outcome between AHT and accidental TBI (aTBI). This was a single center, retrospective cohort study including children under 3 years old admitted to the pediatric intensive care unit with nonpenetrating TBI between 2014 and 2021. Presence or absence of MODS on days 1, 3, and 7 using the Pediatric Logistic Organ Dysfunction-2 score and new impairment status (Functional Status Scale score change > 1 compared with preinjury) at hospital discharge (HD), short-term timepoint, and long-term timepointwere abstracted from the electronic health record. Multiple logistic regression was performed to examine the association between MODS and TBI mechanism with new impairment status. Among 576 children, 215 (37%) had AHT and 361 (63%) had aTBI. More children with AHT had MODS on days 1 (34% vs. 23%, p = 0.003), 3 (28% vs. 6%, p < 0.001), and 7 (17% vs. 3%, p < 0.001) compared with those with aTBI. The most common organ failures were cardiovascular ([AHT] 66% vs. [aTBI] 66%, p = 0.997), neurologic (33% vs. 16%, p < 0.001), and respiratory (34% vs. 15%, p < 0.001). MODS was associated with new impairment in multivariable logistic regression at HD (odds ratio 19.1 [95% confidence interval 9.8-38.6, p < 0.001]), short-term discharge (7.4 [3.7-15.2, p < 0.001]), and long-term discharge (4.3 [2.0-9.4, p < 0.001])]. AHT was also associated with new impairment at HD (3.4 [1.6-7.3, p = 0.001]), short-term discharge (2.5 [1.3-4.7, p = 0.005]), and long-term discharge (2.1 [1.1-4.1, p = 0.036]). Abusive head trauma as a mechanism was associated with MODS following TBI. Both AHT mechanism and MODS were associated with new impairment at all time points.

Intracranial pressure monitoring with and without brain tissue oxygen pressure monitoring for severe traumatic brain injury in France (OXY-TC): an open-label, randomised controlled superiority trial

Optimisation of brain oxygenation might improve neurological outcome after traumatic brain injury. The OXY-TC trial explored the superiority of a strategy combining intracranial pressure and brain tissue oxygen pressure (PbtO2) monitoring over a strategy of intracranial pressure monitoring only to reduce the proportion of patients with poor neurological outcome at 6 months. We did an open-label, randomised controlled superiority trial at 25 French tertiary referral centres. Within 16 h of brain injury, patients with severe traumatic brain injury (aged 18-75 years) were randomly assigned via a website to be managed during the first 5 days of admission to the intensive care unit either by intracranial pressure monitoring only or by both intracranial pressure and PbtO2 monitoring. Randomisation was stratified by age and centre. The study was open label due to the visibility of the intervention, but the statisticians and outcome assessors were masked to group allocation. The therapeutic objectives were to maintain intracranial pressure of 20 mm Hg or lower, and to keep PbtO2 (for those in the dual-monitoring group) above 20 mm Hg, at all times. The primary outcome was the proportion of patients with an extended Glasgow Outcome Scale (GOSE) score of 1-4 (death to upper severe disability) at 6 months after injury. The primary analysis was reported in the modified intention-to-treat population, which comprised all randomly assigned patients except those who withdrew consent or had protocol violations. This trial is registered with ClinicalTrials.gov, NCT02754063, and is completed. Between June 15, 2016, and April 17, 2021, 318 patients were randomly assigned to receive either intracranial pressure monitoring only (n=160) or both intracranial pressure and PbtO2 monitoring (n=158). 27 individuals with protocol violations were not included in the modified intention-to-treat analysis. Thus, the primary outcome was analysed for 144 patients in the intracranial pressure only group and 147 patients in the intracranial pressure and PbtO2 group. Compared with intracranial pressure monitoring only, intracranial pressure and PbtO2 monitoring did not reduce the proportion of patients with GOSE score 1-4 (51% [95% CI 43-60] in the intracranial pressure monitoring only group vs 52% [43-60] in the intracranial pressure and PbtO2 monitoring group; odds ratio 1·0 [95% CI 0·6-1·7]; p=0·95). Two (1%) of 144 participants in the intracranial pressure only group and 12 (8%) of 147 participants in the intracranial pressure and PbtO2 group had catheter dysfunction (p=0.011). Six patients (4%) in the intracranial pressure and PbtO2 group had an intracrebral haematoma related to the catheter, compared with none in the intracranial pressure only group (p=0.030). No significant difference in deaths was found between the two groups at 12 months after injury. At 12 months, 33 deaths had occurred in the intracranial pressure group: 25 (76%) were attributable to the brain trauma, six (18%) were end-of-life decisions, and two (6%) due to sepsis. 34 deaths had occured in the intracranial pressure and PbtO2 group at 12 months: 25 (74%) were attributable to the brain trauma, six (18%) were end-of-life decisions, one (3%) due to pulmonary embolism, one (3%) due to haemorrhagic shock, and one (3%) due to cardiac arrest. After severe non-penetrating traumatic brain injury, intracranial pressure and PbtO2 monitoring did not reduce the proportion of patients with poor neurological outcome at 6 months. Technical failures related to intracerebral catheter and intracerebral haematoma were more frequent in the intracranial pressure and PbtO2 group. Further research is needed to assess whether a targeted approach to multimodal brain monitoring could be useful in subgroups of patients with severe traumatic brain injury-eg, those with high intracranial pressure on admission. The French National Program for Clinical Research, La Fondation des Gueules Cassées, and Integra Lifesciences.

Relationship Between Time of Hospital Arrival and Clinical and Fluid Biomarker Outcomes in Traumatic Brain Injury (P14-7.003)

<h3>Objective:</h3> Identify variables related to delayed emergency department (ED) presentation after traumatic brain injury (TBI). <h3>Background:</h3> Delayed presentation to ED after TBI may differ based on demographic and clinical variables and may confound interpretation of clinical assessments and blood biomarker testing. <h3>Design/Methods:</h3> Patients with non-penetrating TBI were enrolled after admission to an urban trauma center. Time between injury and ED arrival was categorized as &lt;1 hour, 1–6 hours, and &gt;6 hours. Blood was drawn on Day 1, Day 3, 2 weeks, and 6 months post-injury and analyzed using Simoa HD-X Neuro4plex assay for NfL, GFAP, and UCH-L1 levels. Demographic variables and clinical outcomes by arrival time category were assessed with Chi-Square or Kruskal-Wallis tests. For fluid blood-biomarkers, log2 levels were compared between arrival time categories using one-way ANOVA. <h3>Results:</h3> 187 individuals with TBI (mean age 47.7 years, 71% male, 50% white, and median Glasgow Coma Score (GCS) of 15) were included in this analysis. 60% arrived in &lt;1 hour, 24% 1–6 hours, and 11% &gt;6 hours (only 3% presented &gt;24 hours after injury). There were significant differences by arrival time categories by injury mechanism, with 84% motor vehicle incidents presenting within an hour (χ²=27.6, <i>p</i>&lt;0.001). Additionally, younger patients (H=13.6, <i>p</i>=0.001), and Black individuals (χ²=17.2, <i>p</i>=0.002), also were most likely to arrive within an hour. There were no differences in arrival time category by sex, head CT findings, or GCS. For blood-biomarkers, there were no differences between arrival time categories for NfL, UCH-L1, and GFAP. <h3>Conclusions:</h3> Mechanism of injury, age, and race are identifiable factors that may influence both arrival time at ED and clinical outcomes and interpretation of biomarker results after TBI. Since our cohort mostly presented within 12 hours, and CT and biomarker results were not influenced, future research should focus on a small cohort of patients with ED presentation beyond 12 hours. <b>Disclosure:</b> Mr. Anandarajah has nothing to disclose. Alexa Walter has nothing to disclose. Dr. Gugger has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Ceribell. The institution of Dr. Gugger has received research support from American Epilepsy Society. Cillian Lynch has nothing to disclose. Dr. Schneider has nothing to disclose. The institution of Dr. Sandsmark has received research support from NINDS. Dr. Diaz-Arrastia has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ischemix, Inc. Dr. Diaz-Arrastia has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pinteon Therapeutics. Dr. Diaz-Arrastia has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BrainBox, LLC. Dr. Diaz-Arrastia has received stock or an ownership interest from BrainBox, LLC. Dr. Diaz-Arrastia has received stock or an ownership interest from NovaSignal . Dr. Diaz-Arrastia has received stock or an ownership interest from Nia Therpeutics. The institution of Dr. Diaz-Arrastia has received research support from National Institutes of Health. The institution of Dr. Diaz-Arrastia has received research support from Department of Defense.

Longitudinal Abnormalities in White Matter Extracellular Free Water Volume Fraction and Neuropsychological Functioning in Patients with Traumatic Brain Injury.

Traumatic brain injury is a global public health problem associated with chronic neurological complications and long-term disability. Biomarkers that map onto the underlying brain pathology driving these complications are urgently needed to identify individuals at risk for poor recovery and to inform design of clinical trials of neuroprotective therapies. Neuroinflammation and neurodegeneration are two endophenotypes potentially associated with increases in brain extracellular water content, but the nature of extracellular free water abnormalities after neurotrauma and its relationship to measures typically thought to reflect traumatic axonal injury are not well characterized. The objective of this study was to describe the relationship between a neuroimaging biomarker of extracellular free water content and the clinical features of a cohort with primarily complicated mild traumatic brain injury. We analyzed a cohort of 59 adult patients requiring hospitalization for non-penetrating traumatic brain injury of all severities as well as 36 healthy controls. Patients underwent brain magnetic resonance imaging (MRI) at 2 weeks (n = 59) and 6 months (n = 29) post-injury, and controls underwent a single MRI. Of the participants with TBI, 50 underwent clinical neuropsychological assessment at 2 weeks and 28 at 6 months. For each subject, we derived a summary score representing deviations in whole brain white matter extracellular free water volume fraction (VF) and free water-corrected fractional anisotropy (fw-FA). The summary specific anomaly score (SAS) for VF was significantly higher in TBI patients at 2 weeks and 6 months post-injury relative to controls. SAS for VF exhibited moderate correlation with neuropsychological functioning, particularly on measures of executive function. These findings indicate abnormalities in whole brain white matter extracellular water fraction in patients with TBI and are an important step toward identifying and validating noninvasive biomarkers that map onto the pathology driving disability after TBI.

Biofidelic dynamic compression of human cortical spheroids reproduces neurotrauma phenotypes.

ABSTRACTFundamental questions about patient heterogeneity and human-specific pathophysiology currently obstruct progress towards a therapy for traumatic brain injury (TBI). Human in vitro models have the potential to address these questions. Three-dimensional spheroidal cell culture protocols for human-origin neural cells have several important advantages over their two-dimensional monolayer counterparts. Three-dimensional spheroidal cultures may mature more quickly, develop more biofidelic electrophysiological activity and/or reproduce some aspects of brain architecture. Here, we present the first human in vitro model of non-penetrating TBI employing three-dimensional spheroidal cultures. We used a custom-built device to traumatize these spheroids in a quantifiable, repeatable and biofidelic manner, and correlated the heterogeneous mechanical strain field with the injury phenotype. Trauma reduced cell viability, mitochondrial membrane potential and spontaneous synchronous electrophysiological activity in the spheroids. Electrophysiological deficits emerged at lower injury severities than changes in cell viability. Also, traumatized spheroids secreted lactate dehydrogenase, a marker of cell damage, and neurofilament light chain, a promising clinical biomarker of neurotrauma. These results demonstrate that three-dimensional human in vitro models can reproduce important phenotypes of neurotrauma in vitro.

Risk factors for post-traumatic epilepsy

PurposeThe aim of the current study was to investigate the risk factors for post-traumatic epilepsy (PTE) in a large cohort of patients after severe non-penetrating civilian traumatic brain injury (TBI). MethodsThis was a longitudinal study. All patients with a severe non-penetrating TBI, who were admitted at the neuro-intensive care unit of Shahid Rajaee Trauma Hospital, affiliated with Shiraz University of Medical Sciences, Shiraz, Iran, from 2015 until 2019, were studied. Severe TBI was defined as a Glasgow Coma Scale-Motor score below six. Post-traumatic epilepsy was defined as any seizures that occurred after being discharged from the hospital. ResultsIn total, 803 patients with severe non-penetrating TBI were studied; 82 patients (10.2%) reported any late post-traumatic seizures (PTSs). A higher Glasgow outcome scale (extended) at discharge was significantly inversely associated with PTE [Odds Ratio (OR)= 0.76, 95% Confidence Interval (CI): 0.65–0.87; p = 0.0001]. Depressed skull fracture (OR= 1.88, 95% CI: 0.92–3.80; p = 0.081), epi‑dural hematoma (OR= 1.67, 95% CI: 0.93–2.97; p = 0.083), and sub-dural hematoma (OR= 1.64, 95% CI: 0.96–2.78; p = 0.068) were associated with PTE as trends. ConclusionOur study adds to the literature on the risk of PTE after severe non-penetrating civilian TBI. Our large sample size and also the application of a logistic regression analysis model may suggest that other variables (e.g., depressed skull fracture and intracranial hematoma) are indeed associated with the Glasgow outcome scale (extended) at discharge and that is why they lost their significance in the model.

Rivastigmine Transdermal Patch Treatment for Moderate to Severe Cognitive Impairment in Veterans with Traumatic Brain Injury (RiVET Study): A Randomized Clinical Trial.

Cognitive impairment is common in veterans with histories of traumatic brain injury (TBI). Cholinergic deficits have been hypothesized as contributors to this impairment. We report the effects of cholinesterase inhibitor rivastigmine transdermal patch treatment in veterans with TBI and post-traumatic memory impairment. Our objective was to evaluate the efficacy and safety of a 9.5 mg/24 h (10 cm2) rivastigmine patch in veterans of military conflicts with persistent moderate to severe memory impairment at least 12 weeks after TBI. This randomized, outpatient, double-blind, placebo-controlled 12-week trial with an exploratory double-blind phase of an additional 14 weeks was conducted at 5 VA Medical Centers, among veterans with closed, non-penetrating TBI who met or exceeded modified American Congress of Rehabilitation Medicine criteria for mild TBI with verbal memory deficits, as assessed by the Hopkins Verbal Learning Test, Revised (HVLT-R). Patients were randomized 1:1 to rivastigmine or matching placebo patches after a 1-week single-blind, placebo run-in phase. At randomization, patients received 4.6 mg/24 h rivastigmine patches or matching placebo increased to a 9.5 mg/24 h patch after 4 weeks. The primary efficacy outcome measure was the proportion of participants who had at least a five-word improvement on the HVLT-R Total Recall Index (Trials 1-3). A total of 3671 participants were pre-screened, of whom 257 (7.0%) were screened; 96 (37%) randomized, and 94 included in study analyses. Responder rates were 40.8% (20 of 49) and 51.1% (23 of 45) in the rivastigmine and placebo groups, respectively (p = 0.41). A mixed-effect model including treatment, time, and treatment-by-time interaction indicated no significant difference in treatment effect over time between the groups (p = 0.24). Overall, there were no significant differences in changes for all secondary outcomes between the rivastigmine and placebo groups. The most commonly observed adverse events were application site reactions. This trial provides the largest sample to date of veterans with TBI and post-traumatic memory deficits enrolled in a pharmacological trial. Trial Registration: clinicaltrials.gov Identifier: NCT01670526.

49193 The Association Between Specialized Pro-resolving Lipid Mediators and Markers of Neuroinflammation and Disease Severity in Acute Traumatic Brain Injury: A Prospective, Observational Cohort Study

ABSTRACT IMPACT: Characterizing specialized pro-resolving lipid mediators (SPMs) of inflammation in a cohort of adult patients with traumatic brain injury (TBI) will potentially identify novel biomarkers of disease and would generate hypotheses regarding the role of SPMs in the pathophysiology and recovery after brain injury OBJECTIVES/GOALS: Primary aim: evaluate the association between plasma and cerebrospinal fluid (CSF) SPM levels with inflammatory markers known to mediate blood brain barrier (BBB) disruption. Secondary aim: evaluate the association between SPM levels and disease severity, 14-day Glasgow Coma Scale score (GCS) and survival. METHODS/STUDY POPULATION: This is a single-center, prospective, observational cohort study (target N=50). Adult participants with moderate-to-severe non-penetrating TBI will have blood and CSF sampled serially for laboratory measures of SPMs (resolvins, protectins, lipoxins, maresins) and inflammatory peptides (TNF-α, IL-1β, IL-6, MMP-9, TIMP-1) by liquid chromatography’‘ mass spectrometry and RT-PCR &amp; ELISA, respectively. Baseline patient characteristics, admission GCS, and 14-day GCS and mortality will be prospectively collected. To evaluate the association between SPMs and other continuous variables, Pearson’s and Spearman’s correlation will be used. Cox regression will be used to evaluate the association between SPM lipidomes and 14-day survival. RESULTS/ANTICIPATED RESULTS: As the primary outcome measure, the association between SPM levels with assayed inflammatory markers will be determined at 24 and 72 hours post-TBI. We hypothesize that SPMs will be negatively correlated with TNF-α, IL-1β, IL-6, MMP-9 and positively correlated with TIMP-1. As secondary outcome measures, the association between SPM levels with disease severity by admission GCS will be determined at 24 hours post-TBI, and the association between SPM levels and GCS and mortality will be determined at 14-days. We hypothesize that SPM levels will be positively associated with admission and 14-day GCS and will be independently associated with 14-day survival. DISCUSSION/SIGNIFICANCE OF FINDINGS: Using the SPM lipidome as a biomarker of disease is a novel tool for future translational research. It will inform a foundational mechanistic framework for TBI pathophysiology and attenuation of neuroinflammation post-TBI, providing rationale for pre-clinical and clinical research focused on novel therapeutics

Sleep and Tau Pathology in Vietnam War Veterans with Preclinical and Prodromal Alzheimer's Disease.

Background:The increasing prevalence of Alzheimer’s disease (AD) and lack of effective medications has led to a need to identify modifiable risk factors as targets for interventions.Objective:In this cross-sectional study, we sought to determine whether worse sleep quality is associated with increased pathological tau, and whether this relationship is affected by amyloid pathology.Methods:66 male participants underwent Florbetapir (AV45) positron emission tomography (PET) and Flortaucipir (FTP) PET and completed the Pittsburgh Sleep Quality Index questionnaire (PSQI) as part of the Department of Defense Alzheimer’s Disease Neuroimaging Initiative, a multicenter study collecting data from Vietnam War veterans, some of whom have a history of post-traumatic stress disorder, or non-penetrating traumatic brain injury. AV45 PET was used to determine the presence of significant amyloid pathology. We used regression models to determine the effects of amyloid pathology and PSQI on tau deposition in brain regions associated with Braak stages.Results:Among the 66 participants, 14 individuals were amyloid positive (21%) and 52 were amyloid negative (79%). In regions associated with Braak stages III-IV, there was a significant interaction of amyloid status on PSQI (β= 0.04, p = 0.003) with higher PSQI correlating with higher FTP SUVr in amyloid-positive individuals only (β= 0.031, p = 0.005).Conclusion:Our study found that an AD profile of tau deposition was associated with an interaction between self-reported sleep quality and amyloid pathology such that worse self-reported sleep was related to higher tau in regions usually associated with AD progression, but only in individuals with high cerebral amyloid deposition.

Relating Self-Reported Balance Problems to Sensory Organization and Dual-Tasking in Chronic Traumatic Brain Injury.

Individuals who have experienced a traumatic brain injury (TBI) often have residual balance problems. It remains unclear whether these balance problems are driven by vestibular dysfunction or gait automaticity deficits, particularly in the chronic stages of TBI recovery, because most studies include only acute/subacute cases. Compare performance on the Sensory Organization Test vestibular score and Dual-Task test in individuals with and without subjective balance problems at least 1 year after a TBI. Investigate the ability of each test to predict perceived balance problems. Prospective cohort study. Rehabilitation department within a single institution. Fifty adults (21-71 years) with a history of mild, moderate, or severe TBI 1 to 5 years following nonpenetrating TBI. N/A. Measures included the Dual-Task test, Sensory Organization Test, Neurobehavioral Symptom Inventory, Dizziness Handicap Inventory, and assessments of four cognitive domains and depression. Participants who endorsed "feeling dizzy" and "loss of balance" on the Neurobehavioral Symptom Inventory were classified as symptomatic (n = 26) and others as asymptomatic (n = 24). T-tests, chi-square, and regression analyses predicting the Dizziness Handicap Inventory total score were performed. Dual-task gait cost was negatively associated with the Dizziness Handicap Inventory (P = .044), controlling for depression and gender, whereas vestibular scores failed to predict balance-related disability. Symptomatic individuals endorsed more balance problems (P < .001) and depression symptoms (P = .007), had poorer dual-task cognitive output (P = .036), and slower dual-task gait velocity (P = .036) than asymptomatic participants. Groups did not differ on Sensory Organization Test scores. The nature of balance problems in chronic TBI may be related to automaticity of gait. These findings suggest that patients in the chronic stages of TBI may benefit from dual-task assessments and interventions. Balance rehabilitation should be tailored to patient needs and assess cognition and affect.

Comparison of Weight-Based Dosing versus Fixed Dosing of 23.4% Hypertonic Saline for Intracranial Pressure Reduction in Patients with Severe Traumatic Brain Injury.

Context:Hypertonic saline (HTS) is a pharmacologic therapy used in patients with severe traumatic brain injuries to decrease intracranial pressure (ICP) associated with cerebral edema.Aims:The purpose of this study was to compare ICP reduction between fixed doses of 23.4% HTS and weight-based doses.Setting and Design:This was a retrospective study that included adult patients at a level 1 trauma center who had nonpenetrating traumatic brain injury, an ICP monitor, and received at least one dose of 23.4% HTS.Subjects and Methods:Doses were classified as either high weight-based (>0.6 ml/kg), low weight-based (<0.6 ml/kg), or standard fixed dose (30 ml). Only doses given within 5 days post-injury were evaluated. Percent reduction in ICP was compared pre- and post-dose between dosing groups, and each dose was evaluated as a separate episode.Statistical Analysis:The primary and secondary endpoints for the study were analyzed using mixed-model, repeated-measures analysis of covariance.Results:A total of 97 doses of HTS were evaluated. The primary endpoint of ICP reduction showed a 42.5% decrease in ICP after the administration of a high weight-based dose, a 36.7% reduction after a low weight-based dose, and a 31.5% reduction after a fixed dose. There was no significant relationship between dose group and percent change in ICP (P = 0.25). A sub-analysis of doses received within 48 h postinjury found a significant relationship between both dose group and percent change in ICP, and initial ICP and percent change in ICP (P = 0.04, and <0.0001 respectively).Conclusions:Our data did not show a significant difference between fixed- and weight-based doses of 23.4% HTS for ICP reduction.

The Incidence and Magnitude of Cerebral Desaturation in Traumatic Brain Injury: An Observational Cohort Study.

Cerebral ischemia in patients with traumatic brain injury (TBI) may propagate secondary neurological injury. Episodes of cerebral ischemia can be revealed through the use of cerebral oximetry monitoring. The objective of this study was to determine the incidence and severity of regional cerebral oxygen (rSO2) desaturation (rSO2<65%) in patients with severe TBI. Secondary outcomes included changes in other monitoring parameters associated with cerebral desaturation. In this single-center prospective observational cohort study, cerebral oximetry data were collected continuously for up to 72 hours in 18 adult patients with a diagnosis of severe nonpenetrating TBI who were being mechanically ventilated and undergoing intracranial pressure (ICP) monitoring an in intensive care unit in Canada. Mean arterial pressure (MAP), ICP, and cerebral perfusion pressure were collected at 5-minute intervals during the study period. Twelve of 18 (67%) patients experienced an episode of cerebral desaturation. The median (interquartile range) nadir rSO2 was 57% (51% to 62%). The duration of desaturation was 265 (57 to 1277) minutes or 8.1% (2.6% to 26.0%) of recording time. In all patients, a linear regression analysis of the area under threshold of 65% for rSO2 was moderately correlated with the area above an ICP threshold of 20 mm Hg (R2=0.52; P<0.01). Similarly, there was a modest correlation between rSO2 and MAP (R2=0.41; P<0.01). These relationships also held true for those patients who experienced cerebral desaturation. Patients having episodes of ICP >20 mm Hg were 6 times more likely to have a cerebral desaturation (relative risk: 6.0; 95% confidence interval: 1.3-34.7). Cerebral desaturations occur frequently in patients with severe TBI, and their duration can be protracted. Episodes of desaturation were moderately correlated with increased ICP and decreased MAP.

Effect of American College of Surgeons Level 1 Trauma Center Designation on Management of Adult Severe TBI Patients

Abstract INTRODUCTION Severe traumatic brain injury (TBI) remains a leading cause of morbidity and mortality. There is a wide variability in treatment paradigm for patients with severe TBI. American College of Surgeons (ACS) level 1 trauma centers have access to 24 h neurosurgical coverage. In this study, we use the National Trauma Database (NTDB) to evaluate if ACS trauma center designation correlates with the management and outcomes of severe TBI in adults. METHODS Adult patients (&lt;65 yr) with a severe isolated nonpenetrating TBI were identified in the NTDB from years 2007 to 2014. ICD-9 procedure codes were used to identify primary treatment approaches: intracranial pressure monitoring and cranial surgery. Multivariate logistic regression was used to determine the impact of ACS designation on procedures and patient outcomes. Patient and injury characteristics were included in the analysis. RESULTS A total of 54 769 TBI patients were identified. Among those, 22 316 (42%) were treated at an ACS level 1 trauma center and 31 835 (58%) were treated elsewhere. Level 1 designated patients had significantly more intracranial pressure (ICP) monitors placed (12.3% vs10.8%; P &lt; .0001) and more cranial surgeries performed (17.7% vs 15.7%; P &lt; .0001). A greater percentage of patients were admitted to the intensive care unit (ICU; 89.9% vs 83.9%; P &lt; .0001) and had a longer hospital stay (16.1 vs 15.2; P &lt; .0001) at ACS level 1 trauma centers. In a regression analysis, patients at level 1 centers were associated with a 14% and 17% increased odds of obtaining a cranial surgery or ICP monitor, respectively. Patients treated at a level 1 center were associated with a 6% decrease in odds of mortality (P = .01). CONCLUSION ACS level 1 designation did correlate with increased rates of neurosurgical intervention and ICU admissions. This translated into patient outcomes as those treated at level 1 facilities were associated with lower rates of mortality.

The EEG Ictal-Interictal Continuum-A Metabolic Roar But a Whimper of a Functional Outcome.

To investigate the correlation between characteristics of lateralized periodic discharges (LPDs) and glucose metabolism measured by (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET). We retrospectively reviewed medical records to identify patients who underwent FDG-PET during electroencephalography (EEG) monitoring with LPDs present during the FDG uptake period. Two blinded board-certified neurophysiologists independently interpreted EEGs. (18)F-fluorodeoxyglucose uptake was measured using standardized uptake value (SUV). Structural images were fused with PET images to aid with localization of SUV. Two PET readers independently measured maximum SUV. Relative SUV values were obtained by normalization of the maximum SUV to the SUV of pons (SUVRpons). Lateralized periodic discharge frequency was analyzed both as a categorical variable and as a continuous measure. Other secondary variables included duration, amplitude, presence of structural lesion, and "plus" EEG features such as rhythmic or fast sharp activity. Nine patients were identified and 7 had a structural etiology for LPDs. Analysis using frequency as a categorical variable and continuous variable showed an association between increased LPD frequency and increased ipsilateral SUVRpons (P = .02). Metabolism associated with LPDs (0.5 Hz as a baseline) increased by a median of 100% at 1 Hz and for frequencies >1 Hz increased by a median of 309%. There were no statistically significant differences in SUVRpons for other factors including duration (P = .10), amplitude (P = .80), structural etiology (P = .55), or "plus" features such as rhythmic or fast sharp activity (P = .84). Metabolic activity increases monotonically with LPD frequency. Lateralized periodic discharge frequency should be a measure of interest when developing neuroprotection strategies in critical neurologic illness. Continuous Electroencephalography After Moderate to Severe Traumatic Brain Injury Lee H, Mizrahi MA, Hartings JA, Sharma S, Pahren L, Ngwenya LB, Moseley BD, Privitera M, Tortella FC, Foreman B. Crit Care Med. 2019;47(4):574-582. After traumatic brain injury, continuous electroencephalography is widely used to detect electrographic seizures. With the development of standardized continuous electroencephalography terminology, we aimed to describe the prevalence and burden of ictal-interictal patterns, including electrographic seizures after moderate to severe traumatic brain injury, and to correlate continuous electroencephalography features with functional outcome. Post hoc analysis of the prospective, randomized controlled phase 2 multicenter INTREPID study ( ClinicalTrials.gov : NCT00805818). Continuous electroencephalography was initiated upon admission to the intensive care unit. The primary outcome was the 3-month Glasgow Outcome Scale-Extended. Consensus electroencephalography reviews were performed by raters certified in standardized continuous electroencephalography terminology blinded to clinical data. Rhythmic, periodic, or ictal patterns were referred to as "ictal-interictal continuum"; severe ictal-interictal continuum was defined as greater than or equal to 1.5 Hz lateralized rhythmic delta activity or generalized periodic discharges and any lateralized periodic discharges or electrographic seizures. Twenty US level I trauma centers. Patients with nonpenetrating traumatic brain injury and postresuscitation Glasgow Coma Scale score of 4 to 12 were included. None. Among 152 patients with continuous electroencephalography (age = 34 ± 14 years; 88% male), 22 (14%) had severe ictal-interictal continuum including electrographic seizures in 4 (2.6%). Severe ictal-interictal continuum burden correlated with initial prognostic scores, including the International Mission for Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (r = 0.51; P = .01) and Injury Severity Score (r = 0.49; P = .01), but not with functional outcome. After controlling clinical covariates, unfavorable outcome was independently associated with absence of posterior dominant rhythm (common odds ratio, 3.38; 95% confidence interval, 1.30-9.09), absence of N2 sleep transients (3.69; 1.69-8.20), predominant delta activity (2.82; 1.32-6.10), and discontinuous background (5.33; 2.28-12.96) within the first 72 hours of monitoring. Severe ictal-interictal continuum patterns, including electrographic seizures, were associated with clinical markers of injury severity but not functional outcome in this prospective cohort of patients with moderate to severe traumatic brain injury. Importantly, continuous electroencephalography background features were independently associated with functional outcome and improved the area under the curve of existing, validated predictive models.

Continuous Electroencephalography After Moderate to Severe Traumatic Brain Injury.

After traumatic brain injury, continuous electroencephalography is widely used to detect electrographic seizures. With the development of standardized continuous electroencephalography terminology, we aimed to describe the prevalence and burden of ictal-interictal patterns, including electrographic seizures after moderate-to-severe traumatic brain injury and to correlate continuous electroencephalography features with functional outcome. Post hoc analysis of the prospective, randomized controlled phase 2 multicenter INTREPID study (ClinicalTrials.gov: NCT00805818). Continuous electroencephalography was initiated upon admission to the ICU. The primary outcome was the 3-month Glasgow Outcome Scale-Extended. Consensus electroencephalography reviews were performed by raters certified in standardized continuous electroencephalography terminology blinded to clinical data. Rhythmic, periodic, or ictal patterns were referred to as "ictal-interictal continuum"; severe ictal-interictal continuum was defined as greater than or equal to 1.5 Hz lateralized rhythmic delta activity or generalized periodic discharges and any lateralized periodic discharges or electrographic seizures. Twenty U.S. level I trauma centers. Patients with nonpenetrating traumatic brain injury and postresuscitation Glasgow Coma Scale score of 4-12 were included. None. Among 152 patients with continuous electroencephalography (age 34 ± 14 yr; 88% male), 22 (14%) had severe ictal-interictal continuum including electrographic seizures in four (2.6%). Severe ictal-interictal continuum burden correlated with initial prognostic scores, including the International Mission for Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (r = 0.51; p = 0.01) and Injury Severity Score (r = 0.49; p = 0.01), but not with functional outcome. After controlling clinical covariates, unfavorable outcome was independently associated with absence of posterior dominant rhythm (common odds ratio, 3.38; 95% CI, 1.30-9.09), absence of N2 sleep transients (3.69; 1.69-8.20), predominant delta activity (2.82; 1.32-6.10), and discontinuous background (5.33; 2.28-12.96) within the first 72 hours of monitoring. Severe ictal-interictal continuum patterns, including electrographic seizures, were associated with clinical markers of injury severity but not functional outcome in this prospective cohort of patients with moderate-to-severe traumatic brain injury. Importantly, continuous electroencephalography background features were independently associated with functional outcome and improved the area under the curve of existing, validated predictive models.

Cerebral metabolism is not affected by moderate hyperventilation in patients with traumatic brain injury

BackgroundHyperventilation-induced hypocapnia (HV) reduces elevated intracranial pressure (ICP), a dangerous and potentially fatal complication of traumatic brain injury (TBI). HV decreases the arteriolar diameter of intracranial vessels, raising the risk of cerebral ischemia. The aim of this study was to characterize the effects of moderate short-term HV in patients with severe TBI by using concomitant monitoring of cerebral metabolism, brain tissue oxygen tension (PbrO2), and cerebral hemodynamics with transcranial color-coded duplex sonography (TCCD).MethodsThis prospective trial was conducted between May 2014 and May 2017 in the surgical intensive care unit (ICU) at the University Hospital of Zurich. Patients with nonpenetrating TBI older than 18 years of age with a Glasgow Coma Scale (GCS) score < 9 at presentation and with ICP monitoring, PbrO2, and/or microdialysis (MD) probes during ICU admission within 36 h after injury were included in our study. Data collection and TCCD measurements were performed at baseline (A), at the beginning of moderate HV (C), after 50 min of moderate HV (D), and after return to baseline (E). Moderate HV was defined as arterial partial pressure of carbon dioxide 4–4.7 kPa. Repeated measures analysis of variance was used to compare variables at the different time points, followed by post hoc analysis with Bonferroni adjustment as appropriate.ResultsEleven patients (64% males, mean age 36 ± 14 years) with an initial median GCS score of 7 (IQR 3–8) were enrolled. During HV, ICP and mean flow velocity (CBFV) in the middle cerebral artery decreased significantly. Glucose, lactate, and pyruvate in the brain extracellular fluid did not change significantly, whereas PbrO2 showed a statistically significant reduction but remained within the normal range.ConclusionModerate short-term hyperventilation has a potent effect on the cerebral blood flow, as shown by TCCD, with a concomitant ICP reduction. Under the specific conditions of this study, this degree of hyperventilation did not induce pathological alterations of brain metabolites and oxygenation.Trial registrationNCT03822026. Registered on 30 January 2019.

Diagnosis, monitoring and prognosis of secondary brain damage in icu patients with traumatic brain injuries

Traumatic brain injury (TBI) is the brain injury that occurs whenever a physical force that impacts the head leads to neuropathology. The types of primary TBI are penentrating TBI or non-penetrating TBI and it can lead to intracerebral contusions, hemorrhages or extra-axial hematomas. Patients with TBI can also have skull fractures or concussions. The injury severity can be classified in many ways but the most established and common used is the Glascow Coma Scale (GCS). However, with the GCS, each of the severity criteria has limitations and might mot be an accurate predictor of TBI severity and outcome when used alone. For this reason it is often used in conjunction with other parameters (Abbreviated Injury Scale - AIS). Secondary Brain Damage is the injury that occurs to the TBI patient not at the time of the accident, but during the following minutes, hours or days. There are many mechanisms that lead to development of cerebral edema, blood-brain barrier disruption, vasospasm, increase in volume of bleeding, contusions and intracranial hypertension. These mechanisms can act either in cellular level or systemic level. The cellular mechanisms that lead to secondary brain damage include necrosis or apoptosis, mitochondrial dysfunction, excitotoxicicty, formation of free radicals, changes in cerebral glucose metabolism and inflammation. The mechanisms at systemic level include hypoxia-cerebral oxygenation, hypo or hypertension, hypo or hyper-capnia, anemia, hyponatremia and hyper or hypoglycemia. The first tool to diagnose severe TBI and secondary brain injury is neurological assessment. Neuroimaging is one of the most important ways for diagnosis. Computed Tomography (CT scan), Magnetic Resonance Imaging (MRI), cerebral angiography, transcranial Doppler, CT perfusion, Xenon CT, MRI diffusion, MRI perfusion, MRI spectrometry and Positron Emission Tomography (PET) are possible ways of imaging that not only help in the diagnosis but give important information that help in choosing the correct management. Moreover, neuromonitoring, helps in the correct management of the patient.

Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study

More than 50 million people worldwide sustain a traumatic brain injury (TBI) annually. Detection of intracranial injuries relies on head CT, which is overused and resource intensive. Blood-based brain biomarkers hold the potential to predict absence of intracranial injury and thus reduce unnecessary head CT scanning. We sought to validate a test combining ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), at predetermined cutoff values, to predict traumatic intracranial injuries on head CT scan acutely after TBI. This prospective, multicentre observational trial included adults (≥18 years) presenting to participating emergency departments with suspected, non-penetrating TBI and a Glasgow Coma Scale score of 9-15. Patients were eligible if they had undergone head CT as part of standard emergency care and blood collection within 12 h of injury. UCH-L1 and GFAP were measured in serum and analysed using prespecified cutoff values of 327 pg/mL and 22 pg/mL, respectively. UCH-L1 and GFAP assay results were combined into a single test result that was compared with head CT results. The primary study outcomes were the sensitivity and the negative predictive value (NPV) of the test result for the detection of traumatic intracranial injury on head CT. Between Dec 6, 2012, and March 20, 2014, 1977 patients were recruited, of whom 1959 had analysable data. 125 (6%) patients had CT-detected intracranial injuries and eight (<1%) had neurosurgically manageable injuries. 1288 (66%) patients had a positive UCH-L1 and GFAP test result and 671 (34%) had a negative test result. For detection of intracranial injury, the test had a sensitivity of 0·976 (95% CI 0·931-0·995) and an NPV of 0·996 (0·987-0·999). In three (<1%) of 1959 patients, the CT scan was positive when the test was negative. These results show the high sensitivity and NPV of the UCH-L1 and GFAP test. This supports its potential clinical role for ruling out the need for a CT scan among patients with TBI presenting at emergency departments in whom a head CT is felt to be clinically indicated. Future studies to determine the value added by this biomarker test to head CT clinical decision rules could be warranted. Banyan Biomarkers and US Army Medical Research and Materiel Command.