Search

Background Whilst there has been progress in supportive treatment for traumatic brain injury (TBI), specific neuroprotective interventions are lacking. Models of ischaemic heart and brain injury show the therapeutic potential of argon gas, but it is still not known whether inhaled argon (iAr) is protective in TBI. We tested the effects of acute administration of iAr on brain oedema, tissue micro-environmental changes, neurological functions, and structural outcome in a mouse model of TBI. Methods Anaesthetised adult C57BL/6J mice were subjected to severe TBI by controlled cortical impact. Ten minutes after TBI, the mice were randomised to 24 h treatments with iAr 70%/O2 30% or air (iCtr). Sensorimotor deficits were evaluated up to 6 weeks post-TBI by three independent tests. Cognitive function was evaluated by Barnes maze test at 4 weeks. MRI was done to examine brain oedema at 3 days and white matter damage at 5 weeks. Microglia/macrophages activation and functional commitment were evaluated at 1 week after TBI by immunohistochemistry. Results iAr significantly accelerated sensorimotor recovery and improved cognitive deficits 1 month after TBI, with less white matter damage in the ipsilateral fimbria and body of the corpus callosum. Early changes underpinning protection included a reduction of pericontusional vasogenic oedema and of the inflammatory response. iAr significantly reduced microglial activation with increases in ramified cells and the M2-like marker YM1. Conclusions iAr accelerates recovery of sensorimotor function and improves cognitive and structural outcome 1 month after severe TBI in adult mice. Early effects include a reduction of brain oedema and neuroinflammation in the contused tissue.

Mesenchymal stromal cells (MSCs) are widely used in preclinical models of traumatic brain injury (TBI). Results are promising in terms of neurological improvement but are hampered by wide variability in treatment responses. We made a systematic review and meta-analysis: (1) to assess the quality of evidence for MSC treatment in TBI rodent models; (2) to determine the effect size of MSCs on sensorimotor function, cognitive function, and anatomical damage; (3) to identify MSC-related and protocol-related variables associated with greater efficacy; (4) to understand whether MSC manipulations boost therapeutic efficacy. The meta-analysis included 80 studies. After TBI, MSCs improved sensorimotor and cognitive deficits and reduced anatomical damage. Stratified meta-analysis on sensorimotor outcome showed similar efficacy for different MSC sources and for syngeneic or xenogenic transplants. Efficacy was greater when MSCs were delivered in the first-week post-injury, and when implanted directly into the lesion cavity. The greatest effect size was for cells embedded in matrices or for MSC-derivatives. MSC therapy is effective in preclinical TBI models, improving sensorimotor, cognitive, and anatomical outcomes, with large effect sizes. These findings support clinical studies in TBI.

Prognostic models for traumatic brain injury (TBI) are important tools both in clinical practice and research if properly validated, preferably by external validation. Prognostic models also offer the possibility of monitoring performance by comparing predicted outcomes with observed outcomes. In this study, we applied the prognostic models developed by the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) in an Italian multi-center database (Neurolink) with two aims: to compare observed with predicted outcomes and to check for a possible improvement of clinical outcome over the 11 years of patient inclusion in Neurolink. We applied the IMPACT models to patients included in Neurolink between 1997 and 2007. Performance of the models was assessed by determining calibration (with calibration plots) and discrimination (by the area under the receiver operating characteristic curve [AUC]). Logistic regression analysis was used to analyze a possible trend in outcomes over time, adjusted for predicted outcomes. A total of 1401 patients were studied. Patients had a median age of 40 years and 51% had a Glasgow Coma Scale motor score of 5 or 6. The models showed good discrimination, with AUCs of 0.86 (according to the Core Model) and 0.88 (Extended Model), and adequate calibration, with the overall observed risk of unfavorable outcome and mortality being less than predicted. Outcomes significantly improved over time. This study shows that the IMPACT models performed reasonably well in the Neurolink data and can be used for monitoring performance. After adjustment for predicted outcomes with the prognostic models, we observed a substantial improvement of patient outcomes over time in the three Neurolink centers.

Mannose-binding lectin is present in the contusion area of traumatic brain-injured patients and in that of traumatic brain-injured mice, where mannose-binding lectin-C exceeds mannose-binding lectin-A. The reduced susceptibility to traumatic brain injury of mannose-binding lectin double knock-out mice (mannose-binding lectin−/−) when compared to wild type mice suggests that mannose-binding lectin may be a therapeutic target following traumatic brain injury. Here, we evaluated the effects of a multivalent glycomimetic mannose-binding lectin ligand, Polyman9, following traumatic brain injury in mice. In vitro surface plasmon resonance assay indicated that Polyman9 dose-dependently inhibits the binding to immobilized mannose residues of plasma mannose-binding lectin-C selectively over that of mannose-binding lectin-A. Male C57Bl/6 mice underwent sham/controlled cortical impact traumatic brain injury and intravenous treatment with Polyman9/saline. Ex-vivo surface plasmon resonance studies confirmed that Polyman9 effectively reduces the binding of plasma mannose-binding lectin-C to immobilized mannose residues. In vivo studies up to four weeks post injury, showed that Polyman9 induces significant improvement in sensorimotor deficits (by neuroscore and beam walk), promotes neurogenesis (73% increase in doublecortin immunoreactivity), and astrogliosis (28% increase in glial fibrillary acid protein). Polyman9 administration in brain-injured mannose-binding lectin−/− mice had no effect on post-traumatic brain-injured functional deficits, suggestive of the specificity of its neuroprotective effects. The neurobehavioral efficacy of Polyman9 implicates mannose-binding lectin-C as a novel therapeutic target for traumatic brain injury.

Objective: To quantify the occurrence of high intracranial pressure (HICP) refractory to conventional medical therapy after traumatic brain injury (TBI) and to describe the use of more aggressive therapies (profound hyperventilation, barbiturates, decompressive craniectomy). Design: Prospective study of 407 consecutive TBI patients Setting: Three neurosurgical intensive care units (ICU). Measurements and results: Intracranial pressure (ICP) was studied during the first week after TBI; 153 patients had at least 1 day of ICP > 20 mmHg. Early surgery was necessary for 221 cases, and standard medical therapy [sedation, mannitol, cerebrospinal fluid (CSF) withdrawal, PaCO2 30-35 mmHg] was used in 135 patients. Reinforced treatment (PaCO2 25-29 mmHg, induced arterial hypertension, muscle relaxants) was used in 179 cases (44%), and second-tier therapies in 80 (20%). Surgical decompression and/or barbiturates were used in 28 of 407 cases (7%). Six-month outcome was recorded in 367 cases using the Glasgow outcome scale (GOS). The outcome was favorable (good recovery or moderate disability) in 195 cases (53%) and unfavorable (all the other categories) in 172 (47%). HICP was associated with worse outcome. Outcome for cases who had received second-tier therapies was significantly worse (43% favorable at 6 months, p = 0.03). Conclusions: HICP is frequent and is associated with worse outcome. ICP was controlled by early surgery and first-tier therapies in the majority of cases. Profound hyperventilation, surgical decompression and barbiturates were used in various combinations in a minority of cases. The indications for surgical decompression and/or barbiturates seem restricted to less than 10% of severe TBI. © 2007 Springer-Verlag.

Neuroprotective strategies that limit secondary tissue loss and/or improve functional outcomes have been identified in multiple animal models of ischemic, hemorrhagic, traumatic and nontraumatic cerebral lesions. However, use of these potential interventions in human randomized controlled studies has generally given disappointing results. In this paper, we summarize the current status in terms of neuroprotective strategies, both in the immediate and later stages of acute brain injury in adults. We also review potential new strategies and highlight areas for future research., SCOPUS: re.j, info:eu-repo/semantics/published

Objectives: (a) To quanti- fy the occurrence of pyrexia during the first week after head injury; (b) to elucidate the relationships be- tween pyrexia and neurological se- verity, length of stay in the ICU, in- tracranial hypertension, and cerebral perfusion pressure (CPP); and (c) to describe the effects of antipyretic therapy on temperature, intracranial pressure (ICP) and CPP. Design and setting: Multicenter retrospective ob- servational study in three ICUs in the Milan area. Patients: 110 pa- tients with traumatic brain injury. Measurements and results: Eighty patients suffered pyrexia, defined as an external temperature higher than 38°C or internal temperature higher than 38.4°C. Occurrence and dura- tion of pyrexia were associated with the degree of neurological impair- ment and with prolonged ICU stay. In patients with normal perimesence- phalic cisterns the episodes of in- creased ICP were more frequent in febrile cases. Various antipyretic therapies were used in 66 patients. Pharmacological treatment was slightly effective (mean temperature reduction 0.58±0.7°C) but caused a significant drop in CPP (6.5±12.5 mmHg). Conclusions: Py- rexia is extremely frequent in the acute phase after head injury. Its in- cidence is higher in more severe cases and is correlated with a longer ICU stay. It may affect ICP, but its contribution is difficult to assess when other major causes of in- creased intracranial volume are present. Antipyretic therapy is poor- ly effective for controlling body tem- perature and may be deleterious for CPP.

The need for immunosuppression after allo/xenogenic mesenchymal stromal cell (MSC) transplantation is debated. This study compared the long-term effects of human (h) bone marrow MSC transplant in immunocompetent or immunosuppressed traumatic brain injured (TBI) mice. C57Bl/6 male mice were subjected to TBI or sham surgery followed 24 h later by an intracerebroventricular infusion of phosphate buffer saline (PBS, control) or hMSC (150,000/5 μl). Immunocompetent and cyclosporin A immunosuppressed (CsA) mice were analyzed for gene expression at 72 h, functional deficits and histological analysis at five weeks. Gene expression analysis showed the effectiveness of immunosuppression (INFγ reduction in CsA treated groups), with no evidence of early rejection (no changes of MHCII and CD86 in all TBI groups) and selective induction of T-reg (increase of Foxp3) only in the TBI hMSC group. Five weeks after TBI, hMSC had comparable efficacy, with functional recovery (on both sensorimotor and cognitive deficits) and structural protection (contusion volume, vessel rescue effect, gliotic scar reduction, induction of neurogenesis) in immunosuppressed and immunocompetent mice. Therefore, long-term hMSC efficacy in TBI is not dependent on immunosuppressive treatment. These findings could have important clinical implication since immunosuppression in acute TBI patients may increase their risk of infection and not be tolerated. © 2013 Elsevier Ltd. All rights reserved.