Acute Severe Traumatic Brain Injury Research Articles

Sevoflurane in the Acute Phase of Severe Traumatic Brain Injury

The aim of the study was to evaluate the usefulness and safety of sevoflurane in patients in the acute phase of severe traumatic brain injury (TBI).Materials and methods. A prospective, randomized, pilot clinical trial was conducted at the Sklifosovsky Research Institute for Emergency Medicine (Moscow) in adults with acute severe TBI, aged 18 years and older, undergoing intensive intracranial pressure (ICP)-guided therapy. To achieve the desired sedative effect, the inhaled anesthetic sevoflurane was administered in the main group, and standard doses of intravenous propofol were administered in the control group. ICP and cerebral oxygen extraction fraction (OEF) were monitored in all patients. Hemodynamic and respiratory support parameters, transcranial Doppler ultrasound scan, brain bioelectrical activity, brain CT scan, laboratory parameters, markers of inflammation, patients' need for sedation and mechanical ventilation, and length of ICU stay were also evaluated.Results. The use of inhalation sedation contributed to the reduction of ICP on day 2 (9.5 mmHg in the sevoflurane group and 17.3 mmHg in the propofol group, P=0.003) and day 3 (10 mmHg and 14.2 mmHg, respectively, P=0.005). BIS monitoring showed no significant difference in depth of sedation between groups on day 2 (60 vs. 48.5, P=0.070) and day 3 (61 vs. 46, P=0.095). Inhalation sedation reduced cerebral OEF on the injury side compared to propofol on day 2 (23.3 vs. 30.2%, P=0.006) and day 3 (22.7 vs. 31.2%, P<0.001). After 24 hours of sedation therapy, there was a significant difference in P/F (PaO₂/FiO₂) ratios between the groups. On days 1, 3, and 7, the sevoflurane group had P/F ratios of 340, 324, and 323 mmHg, while the propofol group had significantly lower ratios of 271, 278, and 275 mmHg (P<0.001). Pneumonia was documented in 9 cases in the sevoflurane group vs. 18 cases in the propofol group (P=0.028), and a similar trend was observed in the total number of infectious complications: 13 vs. 21 cases, respectively (P=0.046).Conclusion. Sevoflurane in the acute phase of severe TBI was not only safe, but also improved several vital functions, including ICP, blood pressure, P/F ratio, and also slowed brain metabolism via reduced oxygen consumption without affecting the depth of sedation according to BIS monitoring data. All of the above suggests that inhalation sedation may improve the prognosis for patient recovery. However, multicenter randomized clinical trials are needed to identify and verify all positive and negative effects of inhalation sedation in this patient population.

Standardized reporting for Head CT Scans in patients suspected of traumatic brain injury (TBI): An international expert endeavor.

Traumatic brain injury (TBI) is a major source of health loss and disability worldwide. Accurate and timely diagnosis of TBI is critical for appropriate treatment and management of the condition. Neuroimaging plays a crucial role in the diagnosis and characterization of TBI. Computed tomography (CT) is the first-line diagnostic imaging modality typically utilized in patients with suspected acute mild, moderate and severe TBI. Radiology reports play a crucial role in the diagnostic process, providing critical information about the location and extent of brain injury, as well as factors that could prevent secondary injury. However, the complexity and variability of radiology reports can make it challenging for healthcare providers to extract the necessary information for diagnosis and treatment planning. In this article, we report the efforts of an international group of TBI imaging experts to develop a clinical radiology report template for CT scans obtained in patients suspected of TBI and consisting of fourteen different subdivisions (CT technique, mechanism of injury or clinical history, presence of scalp injuries, fractures, potential vascular injuries, potential injuries involving the extra-axial spaces, brain parenchymal injuries, potential injuries involving the cerebrospinal fluid spaces and the ventricular system, mass effect, secondary injuries, prior or coexisting pathology).

Assessment of Sleep Stages in Unconscious Patients with Acute Severe Traumatic Brain Injury

Abstract Background The existence of a sleep cycle in deeply unconscious patients with severe traumatic brain injury (TBI) remains unknown. Evaluating the sleep patterns of these patients may provide insights into their consciousness and help predict functional recovery. Aims and Objectives This prospective observational study aimed to assess the usefulness of monitoring the sleep cycle in the prognostication of unconscious TBI patients. Materials and Methods A purposive sampling technique was employed to include 39 patients with severe TBI (Glasgow Coma Scale [GCS] ≤ 8). The average GCS score at admission was (5.76 ± 1.65). Sleep was monitored using an actigraphy smartwatch for 4 consecutive days, (3.15 ± 2.49) days postbrain injury. Sleep cycle monitoring tool and unconscious patient outcome monitoring tool were employed. An outcome assessment was done based on the GCS score. Results Severe TBI patients exhibit intact sleep cycle (i.e., deep sleep, light sleep, and rapid eye movement sleep) despite being deeply unconscious, even in the acute stage. Total sleep duration was found to be significantly higher at a mean of 19.97 hours as compared to the mean of 8 hours as per the smartwatch reference value for normal individuals. Patients with improved sleep cycles had a higher likelihood of GCS improvement (p < 0.05). Conclusion This study is the first of its kind to demonstrate that the sleep cycle is a reliable prognostic factor for the recovery of consciousness in the acute phase of severe TBI among unconscious patients, with improvement in the sleep cycle mirroring neurological improvement.

Development and validation of a nomogram for predicting mortality in patients with acute severe traumatic brain injury: A retrospective analysis.

Recent evidence links the prognosis of traumatic brain injury (TBI) to various factors, including baseline clinical characteristics, TBI specifics, and neuroimaging outcomes. This study focuses on identifying risk factors for short-term survival in severe traumatic brain injury (sTBI) cases and developing a prognostic model. Analyzing 430 acute sTBI patients from January 2018 to December 2023 at the 904th Hospital's Neurosurgery Department, this retrospective case-control study separated patients into survival outcomes: 288 deceased and 142 survivors. It evaluated baseline, clinical, hematological, and radiological data to identify risk and protective factors through univariate and Lasso regression. A multivariate model was then formulated to pinpoint independent prognostic factors, assessing their relationships via Spearman's correlation. The model's accuracy was gauged using the Receiver Operating Characteristic (ROC) curve, with additional statistical analyses for quantitative factors and model effectiveness. Internal validation employed ROC, calibration curves, Decision Curve Analysis (DCA), and Clinical Impact Curves (CIC) to assess model discrimination, utility, and accuracy. The International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) and Corticosteroid Randomization After Significant Head injury (CRASH) models were also compared through multivariate regression. Factors like unilateral and bilateral pupillary non-reactivity at admission, the derived neutrophil to lymphocyte ratio (dNLR), platelet to lymphocyte ratio (PLR), D-dimer to fibrinogen ratio (DFR), infratentorial hematoma, and Helsinki CT score were identified as independent risk factors (OR > 1), whereas serum albumin emerged as a protective factor (OR < 1). The model showed superior predictive performance with an AUC of 0.955 and surpassed both IMPACT and CRASH models in predictive accuracy. Internal validation confirmed the model's high discriminative capability, clinical relevance, and effectiveness. Short-term survival in sTBI is significantly influenced by factors such as pupillary response, dNLR, PLR, DFR, serum albumin levels, infratentorial hematoma occurrence, and Helsinki CT scores at admission. The developed nomogram accurately predicts sTBI outcomes, offering significant clinical utility.

Levetiracetam or Phenytoin as Prophylaxis for Status Epilepticus: Secondary Analysis of the "Approaches and Decisions in Acute Pediatric Traumatic Brain Injury Trial" (ADAPT) Dataset, 2014-2017.

To compare levetiracetam and phenytoin as prophylaxis for the short-term development of status epilepticus (SE) during care of pediatric patients with acute severe traumatic brain injury (TBI). Nonprespecified secondary analysis using propensity score matching. We used the Approaches and Decisions in Acute Pediatric TBI Trial (ADAPT NCT04077411) dataset (2014-2017). Patients less than 18 years old with Glasgow Coma Scale Score less than or equal to 8 who received levetiracetam or phenytoin as a prophylactic anticonvulsant therapy. None. Of the 516 total patients who qualified for the case-control study, 372 (72.1%) patients received levetiracetam, and 144 (27.9%) received phenytoin. After propensity score matching, the pair-matched analysis with 133 in each group failed to identify an association between levetiracetam versus phenytoin use and occurrent of SE (3.8% vs. 0.8%, p = 0.22), or mortality (i.e., in-hospital, 30-d and 60-d). However, on closer inspection of the statistical testing, we cannot exclude the possibility that selecting levetiracetam rather than phenytoin for prophylaxis was associated with the following: up to a mean difference of 7.3% greater prevalence of SE; up to a mean difference of 13.9%, 12.1%, and 13.9% greater mortality during the hospital stay, and 30-, and 60-days after hospital arrival, respectively. Last, analysis of 6 months Glasgow Outcome Scale Extended score in those without premorbid comorbidities, there was an association between favorable outcomes and use of phenytoin rather than levetiracetam prophylaxis. In ADAPT, the decision to use prophylactic levetiracetam versus phenytoin failed to show an association with occurrence of subsequent SE, or mortality. However, we are unable to exclude the possibility that selecting levetiracetam rather than phenytoin for prophylaxis was associated with greater prevalence of SE and mortality. We are unable to make any recommendation about one prophylactic anticonvulsant medication over the other, but recommend that further larger, contemporary studies in severe pediatric TBI are carried out.

Transcranial Doppler Ultrasound Role for Patients with Traumatic Brain Injury

Neurologists, neurosurgeons, and neurointensivists, including military, have a large armamentarium of diagnostic and monitoring devices available to detect primary and secondary brain injury and guide therapy in patients with acute traumatic brain injury (TBI) to avoid cerebral ischemia due to the posttraumatic vasospasm (PTV) and intracranial hypertension (ICH). This review summarizes the advantages and the specific roles of transcranial Doppler (TCD) ultrasonography for patients with acute and longterm effects of TBI. In critical care setting numerous publications showed that TCD is predictive of angiographic PTV and onset of ICH. The post TBI status of cerebrovascular reactivity and cerebral hemodynamics also has important implications with regard to the treatment of long-term effects of mild TBI (mTBI). Today it is abundant evidence that TCD is an important tool for monitoring the natural course of acute moderate and severe TBI, for evaluating the effect of medical treatment or intervention, for forecasting, and for identifying high-risk patients for onset of cerebral ischemia after TBI. TCD makes good clinical and economic sense as it is a reliable, quantitative, non-invasive and non-expensive “biomarker” to the acute clinical manifestations of TBI. TCD clinical utilization holds promise for better detection, characterization, and monitoring of objective cerebral hemodynamics changes in symptomatic patients with TBI not readily apparent by standard CT or conventional MRI techniques. TCD utilization will improve the sensitivity of neuroimaging to subtle brain perturbations and combining these objective measures with careful clinical characterization of patients may facilitate better understanding of the neural bases and treatment of the signs and symptoms of TBI. This review summarizes the advantages and the specific roles of TCD ultrasonography for patients with acute and long-term effects of TBI.

DIAGNOSTICS OF MICROCIRCULATION DISTURBANCES IN CRITICAL CONDITIONS IN PATIENTS WITH ACUTE CEREMONIAL CIRCULATION DISORDER AND SEVERE CRANIO-BRAIN INJURY

A new emergency method is proposed for determining the degree of microcirculation disorders in critical conditions in patients with acute cerebrovascular accident and severe traumatic brain injury, based on the capillary-venous difference in blood hemoglobin. The technical method is simple and convenient for any clinical laboratory and allows you to control the dynamics of the effectiveness of ongoing intensive care.

Automated detection of axonal damage along white matter tracts in acute severe traumatic brain injury

New techniques for individualized assessment of white matter integrity are needed to detect traumatic axonal injury (TAI) and predict outcomes in critically ill patients with acute severe traumatic brain injury (TBI). Diffusion MRI tractography has the potential to quantify white matter microstructure in vivo and has been used to characterize tract-specific changes following TBI. However, tractography is not routinely used in the clinical setting to assess the extent of TAI, in part because focal lesions reduce the robustness of automated methods. Here, we propose a pipeline that combines automated tractography reconstructions of 40 white matter tracts with multivariate analysis of along-tract diffusion metrics to assess the presence of TAI in individual patients with acute severe TBI. We used the Mahalanobis distance to identify abnormal white matter tracts in each of 18 patients with acute severe TBI as compared to 33 healthy subjects. In all patients for which a FreeSurfer anatomical segmentation could be obtained (17 of 18 patients), including 13 with focal lesions, the automated pipeline successfully reconstructed a mean of 37.5 ± 2.1 white matter tracts without the need for manual intervention. A mean of 2.5 ± 2.1 tracts resulted in partial or failed reconstructions and needed to be reinitialized upon visual inspection. The pipeline detected at least one abnormal tract in all patients (mean: 9.1 ± 7.9) and accurately discriminated between patients and controls (AUC: 0.91). The number and neuroanatomic location of abnormal tracts varied across patients and levels of consciousness. The premotor, temporal, and parietal sections of the corpus callosum were the most commonly damaged tracts (in 10, 9, and 8 patients, respectively), consistent with prior histopathological studies of TAI. TAI measures were not associated with concurrent behavioral measures of consciousness. In summary, we provide proof-of-principle evidence that an automated tractography pipeline has translational potential to detect and quantify TAI in individual patients with acute severe TBI.

Correcting cardiorespiratory noise in resting-state functional MRI data acquired in critically ill patients.

Resting-state functional MRI is being used to develop diagnostic, prognostic and therapeutic biomarkers for critically ill patients with severe brain injuries. In studies of healthy volunteers and non-critically ill patients, prospective cardiorespiratory data are routinely collected to remove non-neuronal fluctuations in the resting-state functional MRI signal during analysis. However, the feasibility and utility of collecting cardiorespiratory data in critically ill patients on a clinical MRI scanner are unknown. We concurrently acquired resting-state functional MRI (repetition time = 1250 ms) and cardiac and respiratory data in 23 critically ill patients with acute severe traumatic brain injury and in 12 healthy control subjects. We compared the functional connectivity results from two approaches that are commonly used to correct cardiorespiratory noise: (i) denoising with cardiorespiratory data (i.e. image-based method for retrospective correction of physiological motion effects in functional MRI) and (ii) standard bandpass filtering. Resting-state functional MRI data in 7 patients could not be analysed due to imaging artefacts. In 6 of the remaining 16 patients (37.5%), cardiorespiratory data were either incomplete or corrupted. In patients (n = 10) and control subjects (n = 10), the functional connectivity results corrected with the image-based method for retrospective correction of physiological motion effects in functional MRI did not significantly differ from those corrected with bandpass filtering of 0.008-0.125 Hz. Collectively, these findings suggest that, in critically ill patients with severe traumatic brain injury, there is limited feasibility and utility to denoising the resting-state functional MRI signal with prospectively acquired cardiorespiratory data.

Aberrant brain functional hubs convergence in the acute severe traumatic brain injury patients with rapidly recovering.

We aimed to identify the aberrant functional hubs in patients with acute severe traumatic brain injury (sTBI) and investigate whether they could help inform prognosis. Twenty-eight sTBI patients and health controls underwent imaging scanning. The graph-theoretical measure of degree centrality (DC) was applied to identify the abnormal brain functional hubs and conjoined with regions of interest-based analysis to investigate their interaction and impact on whole-brain. We further split sTBI patients into two subgroups according to their recovery to explore whether the fractional amplitude of low-frequency fluctuation (fALFF) roles in functional connectivity (FC) differential areas to help inform the patients' long-term prognosis. We identified the part of prefrontal cortex (PFC), precentral and postcentral gyrus (Pre-/Post-CG), cingulate gyrus (CgG), posterior medial cortex (PMC), and brainstem that could be core hubs whose DC was significantly increased in patients with acute sTBI. The interaction strength of the paired hubs could be enhanced (CG-PFC, CgG-PFC, CG-brainstem, CgG-brainstem, PMC-brainstem, and PFC-brainstem) and weakened (CG-CgG, CG-PMC, CgG-PMC, and PMC-PFC), compared with healthy controls. We also found abnormal FC in 5 hubs to whole-brain. The spontaneous brain activities in the FC differential regions [e.g., the fALFF and mean fALFF value] were valid to predict outcome at 6-month in patients with sTBI. We demonstrated a compensatory mechanism that part of brain regions will converge into abnormal functional hubs in patients with acute sTBI, which provides a potential approach to objectively predicting patients' long-term outcome.

The effect of Riluzole on neurological outcomes, blood-brain barrier, brain water and neuroinflammation in traumatic brain injury

BackgroundRiluzole (RLZ) is a potent anticonvulsant drug that reveals neuroprotective effects on neurological disease by inhibiting the release of glutamate and increasing its uptake. This study aims to investigate the potential neuroprotective effects of Riluzole in a rat model with acute severe traumatic brain injury (TBI). Materials and MethodsIn this study, seven groups of male Wistar rats were investigated including Sham, Intact, TBI, Saline (TBI + intraperitoneal (i.p) injection of normal saline), TBI + i.p injection of Riluzole in 2,4 and 8 mg/kg doses (RLZ 2, RLZ 4 and RLZ 8 groups), induction of severe diffuse TBI performed by weight dropping Marmarou model, and evaluation of short-term neurological deficits by using veterinary coma scale (VCS), beam-balance and beam-walk tasks. Histopathological changes in neural tissue were evaluated by using hematoxylin and eosin staining and light microscopy. Evaluation of blood-brain barrier (BBB) permeability was performed by using the Evans Blue method 6 h after traumatization. Brain water content assessment was performed by using the wet-dry method and the level of IL-1β and IL-10 was determined by using an enzyme-linked immunosorbent assay (ELISA). ResultsTreatment with Riluzole improves neurological function, VCS score, and vestibulomotor function, reduces pathological changes of neural tissue, brain edema, and level of IL-1β, and increases IL-10 concentration in CSF compared to the saline group (p < 0.0001). Treatment with 4 and 8 mg/kg of Riluzole reveals a significant therapeutic effect on consequences of TBI. This effect was enhanced by an increase in the dose of Riluzole from 4 to 8 mg/kg, but no significant changes were seen after administration of 2 mg/kg of Riluzole. ConclusionRiluzole can reduce the first and second phase of TBI damage by lowering inflammation, brain edema, histopathological destruction, BBB permeability, level of IL- 1β, and increasing IL-10 in CSF; it is highly suggested to use Riluzole in further studies and human trials, and also to consider it as a therapeutic compound in the treatment of traumatic brain injury.

Incidence and Associated Factors of Anemia in Patients with Acute Moderate and Severe Traumatic Brain Injury

BackgroundAnemia might contribute to the development of secondary injury in patients with acute traumatic brain injury (TBI). Potential determinants of anemia are still poorly acknowledged, and reported incidence of declined hemoglobin concentration varies widely between different studies. The aim of this study was to investigate the incidence of severe anemia among patients with moderate to severe TBI and to evaluate patient- and trauma-related factors that might be associated with the development of anemia.MethodsThis retrospective cohort study involved all adult patients admitted to Tampere University Hospital’s emergency department for moderate to severe TBI (August 2010 to July 2012). Detailed information on patient demographics and trauma characteristics were obtained, including data on posttraumatic care, data on neurosurgical procedures, and all measured in-hospital hemoglobin values. Severe anemia was defined as a hemoglobin level less than 100 g/L. Both univariate and multivariable analyses were performed, and hemoglobin trajectories were created.ResultsThe study included 145 patients with moderate to severe TBI (male 83.4%, mean age 55.0 years). Severe anemia, with a hemoglobin level less than 100 g/L, was detected in 66 patients (45.5%) and developed during the first 48 h after the trauma. In the univariate analysis, anemia was more common among women (odds ratio [OR] 2.84; 95% confidence interval [CI] 1.13–7.15), patients with antithrombotic medication prior to trauma (OR 3.33; 95% CI 1.34–8.27), patients with cardiovascular comorbidities (OR 3.12; 95% CI 1.56–6.25), patients with diabetes (OR 4.56; 95% CI 1.69–12.32), patients with extracranial injuries (OR 3.14; 95% CI 1.69–12.32), and patients with midline shift on primary head computed tomography (OR 2.03; 95% CI 1.03–4.01). In the multivariable analysis, midline shift and extracranial traumas were associated with the development of severe anemia (OR 2.26 [95% CI 1.05–4.48] and OR 4.71 [95% CI 1.74–12.73], respectively).ConclusionsSevere anemia is common after acute moderate to severe TBI, developing during the first 48 h after the trauma. Possible anemia-associated factors include extracranial traumas and midline shift on initial head computed tomography.

Electrophysiological correlates of thalamocortical function in acute severe traumatic brain injury

Tools assaying the neural networks that modulate consciousness may facilitate tracking of recovery after acute severe brain injury. The ABCD framework classifies resting-state EEG into categories reflecting levels of thalamocortical network function that correlate with outcome in post-cardiac arrest coma. In this longitudinal cohort study, we applied the ABCD framework to 20 patients with acute severe traumatic brain injury requiring intensive care (12 of whom were also studied at ≥6-months post-injury) and 16 healthy controls. We tested four hypotheses: 1) EEG ABCD classifications are spatially heterogeneous and temporally variable; 2) ABCD classifications improve longitudinally, commensurate with the degree of behavioral recovery; 3) ABCD classifications correlate with behavioral level of consciousness; and 4) the Coma Recovery Scale-Revised arousal facilitation protocol yields improved ABCD classifications. Channel-level EEG power spectra were classified based on spectral peaks within pre-defined frequency bands: ‘A’ = no peaks above delta (<4 Hz) range (complete thalamocortical disruption); ‘B’ = theta (4–8 Hz) peak (severe thalamocortical disruption); ‘C’ = theta and beta (13–24 Hz) peaks (moderate thalamocortical disruption); or ‘D’ = alpha (8–13 Hz) and beta peaks (normal thalamocortical function). Acutely, 95% of patients demonstrated ‘D’ signals in at least one channel but exhibited within-session temporal variability and spatial heterogeneity in the proportion of different channel-level ABCD classifications. By contrast, healthy participants and patients at follow-up consistently demonstrated signals corresponding to intact thalamocortical network function. Patients demonstrated longitudinal improvement in ABCD classifications (p < .05) and ABCD classification distinguished patients with and without command-following in the subacute-to-chronic phase of recovery (p < .01). In patients studied acutely, ABCD classifications improved after the Coma Recovery Scale-Revised arousal facilitation protocol (p < .05) but did not correspond with behavioral level of consciousness. These findings support the use of the ABCD framework to characterize channel-level EEG dynamics and track fluctuations in functional thalamocortical network integrity in spatial detail.

The human anti-ganglioside GM1 autoantibody response following traumatic and surgical central nervous system insults

Predictors of the central nervous system (CNS) directed autoantibody response after acute CNS injury are poorly understood. We analyzed titers of IgG and IgM autoantibodies to ganglioside GM1 in serial serum specimens collected from human patients following acute spinal cord injury (SCI), traumatic brain injury (TBI) and brain tumor resection. We also assessed putative predictors of the autoantibody titers. We enrolled 19 patients with acute SCI, 14 patients with acute severe TBI, and 19 patients undergoing brain tumor resection. We also enrolled 25 control subjects. Some SCI, TBI and tumor patients exhibited elevated IgG titers as compared with control values; some SCI and TBI patients exhibited an acute peak in IgG titers, most commonly 14 days after insult. Some clinical and radiographic measures of injury severity correlated with IgG titer elevation in SCI and TBI patients but not tumor patients. Our study demonstrates that diverse CNS insults are followed by increased IgG autoimmune antibody titers to the CNS antigen ganglioside GM1, however the response inherent to each insult type is unique. IgG autoimmune antibody titers to GM1 merit further study as a biomarker of traumatic injury severity that can be measured in delayed fashion after CNS insult. These human data help to inform which patients with CNS insults are at risk for CNS-directed autoimmunity as well as the time course of the response.

Prolonged Automated Robotic TCD Monitoring in Acute Severe TBI: Study Design and Rationale.

Transcranial Doppler ultrasonography (TCD) is a portable, bedside, noninvasive diagnostic tool used for the real-time assessment of cerebral hemodynamics. Despite the evident utility of TCD and the ability of this technique to function as a stethoscope to the brain, its use has been limited to specialized centers because of the dearth of technical and clinical expertise required to acquire and interpret the cerebrovascular parameters. Additionally, the conventional pragmatic episodic TCD monitoring protocols lack dynamic real-time feedback to guide time-critical clinical interventions. Fortunately, with the recent advent of automated robotic TCD technology in conjunction with the automated software for TCD data processing, we now have the technology to automatically acquire TCD data and obtain clinically relevant informationin real-time. By obviating the need for highly trained clinical personnel, this technology shows great promise toward a future of widespread noninvasive monitoring to guide clinical care in patients with acute brain injury. Here, we describe a proposal for a prospective observational multicenter clinical trial to evaluate the safety and feasibility of prolonged automated robotic TCD monitoring in patients with severe acute traumatic brain injury (TBI). We will enroll patients with severe non-penetratingTBI with concomitant invasive multimodal monitoring including, intracranial pressure, brain tissue oxygenation, and brain temperature monitoring as part of standard of care in centers with varying degrees of TCD availability and experience. Additionally, we propose to evaluate the correlation of pertinent TCD-based cerebral autoregulation indicessuch as the critical closing pressure, and the pressure reactivity index withthe brain tissue oxygenationvaluesobtained invasively. The overarching goal of this study is to establish safety and feasibility of prolonged automated TCD monitoring for patients with TBI in the intensive care unit and identify clinically meaningful and pragmatic noninvasive targets for future interventions.

Intradermal injection of icariin-HP-β-cyclodextrin improved traumatic brain injury via the trigeminal epineurium-brain dura pathway

The lower bioavailability after oral administration limited icariin applications in central nervous system. Icariin/HP-β-cyclodextrin (HP-β-CD) inclusion complex was prepared for acute severe opening traumatic brain injury (TBI) via facial intradermal (i.d.) in the mystacial pad. After fluid percussion-induced TBI, icariin/HP-β-CD at 0.4 mg/kg i.d. preserved more neurons and oligodendrocytes than intranasal injection (i.n.) or intravenous injection via tail vein (i.v.) and decreased microglia and astrocyte activation. Icariin/HP-β-CD i.d. reduced apoptosis in cortical penumbra while i.n. and i.v. showed weak or no effects. Icariin/HP-β-CD i.d. reduced Evans blue leakage and altered CD34, ZO-1, Claudin-5, and beta-catenin expression after TBI. Moreover, icariin/HP-β-CD promoted human umbilical vein endothelial cells proliferation. Thus, Icariin/HP-β-CD i.d. improved TBI, including blood–brain barrier opening. Fluorescein 5-isothiocyanate (FITC) and 3,3'-Dioctadecyloxacarbocyanine perchlorate (DiOC18(3)) mimic HP-β-CD and icariin respectively. FITC and DiOC18(3) were similarly delivered to trigeminal epineurium, perineurium and perivascular spaces or tissues, caudal dura mater, and scattered in trigeminal fasciculus, indicating that icariin/HP-β-CD was delivered to the brain via trigeminal nerve-dura mater-brain pathways. In sum, intradermal injection in mystacial pad might deliver icariin/HP-β-CD to the brain and icariin/HP-β-CD improved acute severe opening TBI.

Placebo-controlled trial of oral amantadine and zolpidem efficacy on the outcome of patients with acute severe traumatic brain injury and diffuse axonal injury.

Background:A constituent of diffuse axonal injury (DAI) is supposed to be present in about 1/3 of all severe traumatic brain injury (TBI) as specified by pathologic documents. Diffuse axonal injury is categorized by extensive injury to axons in the brain. A rise in the incidences of TBI, and the limited study to verified effect of drugs like amantadine and zolpidem in improving the consciousness levels of patients with acute traumatic brain injury with axonal injury enthused us to initiate this study in the acute TBI patients.Methods:In our randomized, controlled trial involving patients with acute severe TBI, we studied 66 patients in 3 groups. Group 1 (n=22) received oral amantadine, Group 2 (n=22) received oral zolpidem, whereas group 3 (n=22) received placebo, the first 8 days after injury respectively. The primary outcome measures included GCS (Glashow coma scale) through the initial admission, a complete medical history was recorded, and each patient had a meticulous physical and neurological investigation.Results:We found that the administration of amantadine in an acute phase after injury improved the rate of patients GCS and GOS (Glasgow Outcome Scale) compared with zolpidem and placebo groups, but without any significant statistical difference.Conclusion:Our results has emphasized that because amantadine has intense biochemical effects on several ways, it appears to be beneficial in acute period after DAI-associated TBI.

Reemergence of the language network during recovery from severe traumatic brain injury: A pilot functional MRI study

ABSTRACT Primary Objective We hypothesized that, in patients with acute severe traumatic brain injury (TBI) who recover basic language function, speech-evoked blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) responses within the canonical language network increase over the first 6 months post-injury. Research Design We conducted a prospective, longitudinal fMRI pilot study of adults with acute severe TBI admitted to the intensive care unit. We also enrolled age- and sex-matched healthy subjects. Methods and Procedures We evaluated BOLD signal in bilateral superior temporal gyrus (STG) and inferior frontal gyrus (IFG) regions of interest acutely and approximately 6 months post-injury. Given evidence that regions outside the canonical language network contribute to language processing, we also performed exploratory whole-brain analyses. Main Outcomes and Results Of the 16 patients enrolled, eight returned for follow-up fMRI, all of whom recovered basic language function. We observed speech-evoked longitudinal BOLD increases in the left STG, but not in the right STG, right IFG, or left IFG. Whole-brain analysis revealed increases in the right supramarginal and middle temporal gyri but no differences between patients and healthy subjects (n = 16). Conclusion This pilot study suggests that, in patients with severe TBI who recover language function, speech-evoked responses in bihemispheric language-processing cortex reemerge by 6 months post-injury.

Morphine attenuates neuroinflammation and blood-brain barrier disruption following traumatic brain injury through the opioidergic system

Endogenous opiates are suggested to have a role in the pathophysiology of traumatic brain injury (TBI). Furthermore, administration of opioidergic agents in TBI injured animals have been shown to affect the brain injury and provide neuroprotection post-TBI. This study aims to investigate the potential neuroprotective effects of morphine through inhibition of neuroinflammatory pathways in acute severe TBI. Male Wistar rats were divided into seven groups (24 rats per group): Sham, Vehicle (TBI + intraperitoneal (i.p) injection of normal saline), TBI + i.p injection of morphine in 1, 5 and 10 mg/kg doses (MOR 1, MOR 5 and MOR 10 groups), TBI + morphine (5 mg/kg i.p) + Naloxone (NAL + MOR), and TBI + morphine (5 mg/kg i.p) + Naltrindole (NALT + MOR). A severe diffuse TBI model (weight dropping Marmarou model) was used to induce TBI in rats. The veterinary coma scale (VCS), beam-walk, and beam-balance tasks were used to assess short-term neurological deficits. Histolopathological changes of brain tissue was evaluated using light microscopy and hematoxilin and eosin staining. Blood-Brain barrier (BBB) disruption was evaluated by the Evans Blue method 6 h post-injury. Brain water content and cerebrospinal fluid (CSF) content of IL-1β and IL-10 were assessed by the wet-dry method and enzyme-linked immunosorbent assay (ELISA), respectively. Morphine (1 and 5 mg/kg doses) attenuated BBB leakage, improved VCS score, pathological changes of brain tissue, and vestibulomotor function compared to the vehicle group (p < 0.0001). Only 5 mg/kg morphine attenuated brain edema (p < 0.0001). Furthermore, 1 and 5 mg/kg morphine significantly changed CSF concentration of IL-1β and IL-10 compared to the vehicle group (p < 0.0001). Inhibition of opioid receptors by naloxone and naltrindole abolished morphine neuroprotective effects (p < 0.0001 vs. MOR 5 group). This study suggests that morphine administration inhibits TBI-mediated neuroinflammation via opioid receptors and improves neurobehavioral function following TBI, which provides a potential therapeutic opportunity in the treatment of traumatic brain injury.

Location of Subcortical Microbleeds and Recovery of Consciousness After Severe Traumatic Brain Injury.

In patients with severe traumatic brain injury (TBI), coma is associated with impaired subcortical arousal mechanisms. However, it is unknown which nuclei involved in arousal (arousal nuclei) are implicated in coma pathogenesis and are compatible with coma recovery. We mapped an atlas of arousal nuclei in the brainstem, thalamus, hypothalamus, and basal forebrain onto 3 tesla susceptibility-weighted images (SWI) in 12 patients with acute severe TBI who presented in coma and recovered consciousness within 6 months. We assessed the spatial distribution and volume of SWI microbleeds and evaluated the association of microbleed volume with the duration of unresponsiveness and functional recovery at 6 months. There was no single arousal nucleus affected by microbleeds in all patients. Rather, multiple combinations of microbleeds in brainstem, thalamic, and hypothalamic arousal nuclei were associated with coma and were compatible with recovery of consciousness. Microbleeds were frequently detected in the midbrain (100%), thalamus (83%), and pons (75%). Within the brainstem, the microbleed incidence was largest within the mesopontine tegmentum (e.g., pedunculotegmental nucleus, mesencephalic reticular formation) and ventral midbrain (e.g., substantia nigra, ventral tegmental area). Brainstem arousal nuclei were partially affected by microbleeds, with microbleed volume not exceeding 35% of brainstem nucleus volume on average. Compared to microbleed volume within nonarousal brainstem regions, the microbleed volume within arousal brainstem nuclei accounted for a larger proportion of variance in the duration of unresponsiveness and 6-month Glasgow Outcome Scale-Extended scores. These results suggest resilience of arousal mechanisms in the human brain after severe TBI.