Early VTE prophylaxis in severe traumatic brain injury: A propensity score weighted EAST multicenter study.

BACKGROUND: Patients with traumatic brain injury (TBI) are at high risk of venous thromboembolism events (VTE). We hypothesized that early chemical VTE prophylaxis initiation (≤24 hours of a stable head CT) in severe TBI would reduce VTE without increasing risk of intracranial hemorrhage expansion (ICHE). METHODS: A retrospective review of adult patients 18 years or older with isolated severe TBI (Abbreviated Injury Scale score, ≥ 3) who were admitted to 24 Level I and Level II trauma centers from January 1, 2014 to December 31 2020 was conducted. Patients were divided into those who did not receive any VTE prophylaxis (NO VTEP), who received VTE prophylaxis ≤24 hours after stable head CT (VTEP ≤24) and who received VTE prophylaxis >24 hours after stable head CT (VTEP>24). Primary outcomes were VTE and ICHE. Covariate balancing propensity score weighting was utilized to balance demographic and clinical characteristics across three groups. Weighted univariate logistic regression models were estimated for VTE and ICHE with patient group as predictor of interest. RESULTS: Of 3,936 patients, 1,784 met inclusion criteria. Incidences of VTE was significantly higher in the VTEP>24 group, with higher incidences of DVT in the group. Higher incidences of ICHE were observed in the VTEP≤24 and VTEP>24 groups. After propensity score weighting, there was a higher risk of VTE in patients in VTEP >24 compared with those in VTEP≤24 (odds ratio, 1.51; 95% confidence interval, 0.69-3.30; p = 0.307), however was not significant. Although, the No VTEP group had decreased odds of having ICHE compared with VTEP≤24 (odds ratio, 0.75; 95% confidence interval, 0.55-1.02, p = 0.070), the result was not statistically significant. CONCLUSION: In this large multi-center analysis, there were no significant differences in VTE based on timing of initiation of VTE prophylaxis. Patients who never received VTE prophylaxis had decreased odds of ICHE. Further evaluation of VTE prophylaxis in larger randomized studies will be necessary for definitive conclusions. LEVEL OF EVIDENCE: Therapeutic Care Management; Level III.

Combining the Antipsychotic Drug Haloperidol and Environmental Enrichment after Traumatic Brain Injury Is a Double-Edged Sword.

Environmental enrichment (EE) confers significant benefits after experimental traumatic brain injury (TBI). In contrast, the antipsychotic drug (APD) haloperidol (HAL) exerts deleterious effects on neurobehavioral and cognitive recovery. Neurorehabilitation and management of agitation, however, are integral components of the treatment strategy for patients with TBI. Hence, the goal of this study was to determine how the two therapeutic approaches interact and influence motor and cognitive recovery. Anesthetized adult male rats received a controlled cortical impact (2.8 mm tissue deformation at 4 m/sec) or sham injury and then were provided HAL (0.5 mg/kg; intraperitoneally [IP]) or vehicle (VEH; 1 mL/kg; IP) commencing 24 h after surgery and once daily for 19 days while housed in EE or standard (STD) conditions. Beam balance/walk and Morris water maze performance were assessed on post-injury days 1-5 and 14-19, respectively, followed immediately by quantification of cortical lesion volumes. The data revealed both expected and unexpected findings. It was not surprising that the TBI groups receiving EE performed significantly better than those in STD housing and that the TBI + STD + HAL group performed worse than the TBI + STD + VEH group (p < 0.05). What was surprising was that the therapeutic effects of EE were greatly reduced by concomitant administration of HAL. No differences in cortical lesion volumes were observed among the groups (p > 0.05). The potential clinical implications of these findings suggest that administering HAL to patients undergoing neurorehabilitation may be a double-edged sword because agitation must be controlled before rehabilitation can be safely initiated and executed, but its use may compromise therapeutic efficacy.

Abbreviated environmental enrichment confers neurobehavioral, cognitive, and histological benefits in brain-injured female rats.

Environmental enrichment (EE) promotes behavioral recovery after experimental traumatic brain injury (TBI). However, the chronic rehabilitation provided in the laboratory is not analogous to the clinic where physiotherapy is typically limited. Moreover, females make up approximately 40% of the clinical TBI population, yet they are seldom studied in brain trauma. Hence, the goal of this study was to test the hypothesis that abbreviated EE would confer neurobehavioral, cognitive, and histological benefits in brain injured female rats. Anesthetized rats received a cortical impact of moderate-to-severe injury (2.8mm tissue deformation at 4m/s) or sham surgery and then were randomly assigned to groups receiving standard (STD) housing or 4h, 6h, or 24h of EE daily. Motor function (beam-balance/walk and rotarod) was assessed on post-operative days 1-5 and every other day from 1 to 19, respectively. Spatial learning/memory (Morris water maze) was evaluated on days 14-19, and cortical lesion volume was quantified on day 21. No statistical differences were appreciated among the sham controls in any assessment and thus the data were pooled. All EE conditions improved motor function and memory retention, but only 6h and 24h enhanced spatial learning relative to STD (p<0.05). Moreover, EE, regardless of duration reduced cortical lesion volume (p<0.05). These data confirm that abbreviated EE confers robust neurobehavioral, cognitive, and histological benefits in TBI female rats, which supports the hypothesis and strengthens the utility of EE as a pre-clinical model of neurorehabilitation.

A combined therapeutic regimen of buspirone and environmental enrichment is more efficacious than either alone in enhancing spatial learning in brain-injured pediatric rats.

Buspirone, a 5-HT1A receptor agonist, and environmental enrichment (EE) enhance cognition and reduce histopathology after traumatic brain injury (TBI) in adult rats, but have not been fully evaluated after pediatric TBI, which is the leading cause of death in children. Hence, the aims of this study were to assess the efficacy of buspirone alone (Experiment 1) and in combination with EE (Experiment 2) in TBI postnatal day-17 male rats. The hypothesis was that both therapies would confer cognitive and histological benefits when provided singly, but their combination would be more efficacious. Anesthetized rats received a cortical impact or sham injury and then were randomly assigned to receive intraperitoneal injections of buspirone (0.08 mg/kg, 0.1 mg/kg, and 0.3 mg/kg) or saline vehicle (1.0 mL/kg) 24 h after surgery and once daily for 16 days (Experiment 1). Spatial learning and memory were assessed using the Morris water maze (MWM) on post-operative days 11-16, and cortical lesion volume was quantified on day 17. Sham controls for each condition were significantly better than all TBI groups. In the TBI groups, buspirone (0.1 mg/kg) enhanced MWM performance versus vehicle and buspirone (0.08 mg/kg and 0.3 mg/kg) (p<0.05) and reduced lesion volume relative to vehicle (p=0.038). In Experiment 2, buspirone (0.1 mg/kg) or vehicle was combined with EE after TBI, and the data were compared to the standard (STD)-housed groups from Experiment 1. EE lead to a significant enhancement of spatial learning and a reduction in lesion size versus STD. Moreover, the combined treatment group (buspirone+EE) performed markedly better than the buspirone+STD and vehicle+EE groups, which suggests an additive effect and supports the hypothesis. The data replicate previous studies assessing these therapies in adult rats. These novel findings may have important rehabilitation-relevant implications for clinical pediatric TBI.

Donepezil is ineffective in promoting motor and cognitive benefits after controlled cortical impact injury in male rats.

The acetylcholinesterase (AChE) inhibitor donepezil is used as a therapy for Alzheimer's disease and has been recommended as a treatment for enhancing attention and memory after traumatic brain injury (TBI). Although select clinical case studies support the use of donepezil for enhancing cognition, there is a paucity of experimental TBI studies assessing the potential efficacy of this pharmacotherapy. Hence, the aim of this pre-clinical study was to evaluate several doses of donepezil to determine its effect on functional outcome after TBI. Ninety anesthetized adult male rats received a controlled cortical impact (CCI; 2.8 mm cortical depth at 4 m/sec) or sham injury, and then were randomly assigned to six TBI and six sham groups (donepezil 0.25, 0.5, 1.0, 2.0, or 3.0 mg/kg, and saline vehicle 1.0 mL/kg). Treatments began 24 h after surgery and were administered i.p. once daily for 19 days. Function was assessed by motor (beam balance/walk) and cognitive (Morris water maze) tests on days 1-5 and 14-19, respectively. No significant differences were observed among the sham control groups in any evaluation, regardless of dose, and therefore the data were pooled. Furthermore, no significant differences were revealed among the TBI groups in acute neurological assessments (e.g., righting reflex), suggesting that all groups received the same level of injury severity. None of the five doses of donepezil improved motor or cognitive function relative to vehicle-treated controls. Moreover, the two highest doses significantly impaired beam-balance (3.0 mg/kg), beam-walk (2.0 mg/kg and 3.0 mg/kg), and cognitive performance (3.0 mg/kg) versus vehicle. These data indicate that chronic administration of donepezil is not only ineffective in promoting functional improvement after moderate CCI injury, but depending on the dose is actually detrimental to the recovery process. Further work is necessary to determine if other AChE inhibitors exert similar effects after TBI.