Can educational videos reduce opioid consumption in trauma inpatients? A cluster-randomized pilot study.

BACKGROUND: Opioids are often used to treat pain after traumatic injury, but patient education on safe use of opioids is not standard. To address this gap, we created a video-based opioid education program for patients. We hypothesized that video viewing would lead to a decrease in overall opioid use and morphine equivalent doses (MEDs) on their penultimate hospital day. Our secondary aim was to study barriers to video implementation. METHODS: We performed a prospective pragmatic cluster-randomized pilot study of video education for trauma floor patients. One of two equivalent trauma floors was selected as the intervention group; patients were equally likely to be admitted to either floor. Nursing staff were to show videos to English-speaking or Spanish-literate patients within 1 day of floor arrival, excluding patients with Glasgow Coma Scale score less than 15. Opioid use and MEDs taken on the day before discharge were compared. Intention to treat (ITT) (intervention vs. control) and per-protocol groups (video viewers vs. nonviewers) were compared (α = 0.05). Protocol compliance was also assessed. RESULTS: In intention to treat analysis, there was no difference in percent of patients using opioids or MEDs on the day before discharge. In per-protocol analysis, there was no different in percent of patients using opioids on the day before discharge. However, video viewers still on opioids took significantly fewer MEDs than patients who did not see the video (26 vs. 38, p < 0.05). Protocol compliance was poor; only 46% of the intervention group saw the videos. CONCLUSION: Video-based education did not reduce inpatient opioid consumption, although there may be benefits in specific subgroups. Implementation was hindered by staffing and workflow limitations, and staff bias may have limited the effect of randomization. We must continue to establish effective methods to educate patients about safe pain management and translate these into standard practices. LEVEL OF EVIDENCE: Therapeutic, Level IV.

Is more better? Do statewide increases in trauma centers reduce injury-related mortality?

OBJECTIVES: Trauma centers are inconsistently distributed throughout the United States. It is unclear if new trauma centers improve care and decrease mortality. We tested the hypothesis that increases in trauma centers are associated with decreases in injury-related mortality (IRM) at the state level. METHODS: We used data from the American Trauma Society to geolocate every state-designated or American College of Surgeons-verified trauma center in all 50 states and the District of Columbia from 2014 to 2018. These data were merged with publicly available IRM data from the Centers for Disease Control and Prevention. We used geographic information systems methods to map and study the relationships between trauma center locations and state-level IRM over time. Regression analysis, accounting for state-level fixed effects, was used to calculate the effect of total statewide number of trauma center on IRM and year-to-year changes in statewide trauma center with the IRM (shown as deaths per additional trauma center per 100,000 population, p value). RESULTS: Nationwide between 2014 and 2018, the number of trauma center increased from 2,039 to 2,153. Injury-related mortality also increased over time. There was notable interstate variation, from 1 to 284 trauma centers. Four patterns in statewide trauma center changes emerged: static (12), increased (29), decreased (5), or variable (4). Of states with trauma center increases, 26 (90%) had increased IRM between 2014 and 2017, while the remaining 3 saw a decline. Regression analysis demonstrated that having more trauma centers in a state was associated with a significantly higher IRM rate (0.38, p = 0.03); adding new trauma centers was not associated with changes in IRM (0.02, p = 0.8). CONCLUSION: Having more trauma centers and increasing the number of trauma center within a state are not associated with decreases in state-level IRM. In this case, more is not better. However, more work is needed to identify the optimal number and location of trauma centers to improve IRM. LEVEL OF EVIDENCE: Epidemiologic, level III; Care management, level III.

Dimethyl fumarate attenuates reactive microglia and long-term memory deficits following systemic immune challenge.

BACKGROUND: Systemic inflammation is associated with increased cognitive decline and risk for Alzheimer's disease. Microglia (MG) activated during systemic inflammation can cause exaggerated neuroinflammatory responses and trigger progressive neurodegeneration. Dimethyl fumarate (DMF) is a FDA-approved therapy for multiple sclerosis. The immunomodulatory and anti-oxidant properties of DMF prompted us to investigate whether DMF has translational potential for the treatment of cognitive impairment associated with systemic inflammation. METHODS: Primary murine MG cultures were stimulated with lipopolysaccharide (LPS) in the absence or presence of DMF. MG cultured from nuclear factor (erythroid-derived 2)-like 2-deficient (Nrf2 -/- ) mice were used to examine mechanisms of DMF actions. Conditioned media generated from LPS-primed MG were used to treat hippocampal neuron cultures. Adult C57BL/6 and Nrf2 -/- mice were subjected to peripheral LPS challenge. Acute neuroinflammation, long-term memory function, and reactive astrogliosis were examined to assess therapeutic effects of DMF. RESULTS: DMF suppressed inflammatory activation of MG induced by LPS. DMF suppressed NF-κB activity through Nrf2-depedent and Nrf2-independent mechanisms in MG. DMF treatment reduced MG-mediated toxicity towards neurons. DMF suppressed brain-derived inflammatory cytokines in mice following peripheral LPS challenge. The suppressive effect of DMF on neuroinflammation was blunted in Nrf2 -/- mice. Importantly, DMF treatment alleviated long-term memory deficits and sustained reactive astrogliosis induced by peripheral LPS challenge. DMF might mitigate neurotoxic astrocytes associated with neuroinflammation. CONCLUSIONS: DMF treatment might protect neurons against toxic microenvironments produced by reactive MG and astrocytes associated with systemic inflammation.

A Combination of Three Repurposed Drugs Administered at Reperfusion as a Promising Therapy for Postischemic Brain Injury.

Cerebral ischemia leads to multifaceted injury to the brain. A polytherapeutic drug that can be administered immediately after reperfusion may increase protection to the brain by simultaneously targeting multiple deleterious cascades. This study evaluated efficacy of the combination of three clinically approved drugs: lamotrigine, minocycline, and lovastatin, using two mouse models: global and focal cerebral ischemia induced by transient occlusion of the common carotid arteries or the middle cerebral artery, respectively. In vitro, the combination drug, but not single drug, protected neurons against oxygen-glucose deprivation (OGD)-induced cell death. The combination drug simultaneously targeted cell apoptosis and DNA damage induced by ischemia. Besides acting on neurons, the combination drug suppressed inflammatory processes in microglia and brain endothelial cells induced by ischemia. In a transient global ischemia model, the combination drug, but not single drug, suppressed microglial activation and inflammatory cytokine production, and reduced neuronal damage. In a transient focal ischemia model, the combination drug, but not single drug, attenuated brain infarction, suppressed infiltration of peripheral neutrophils, and reduced neurological deficits following ischemic stroke. In summary, the combination drug confers a broad-spectrum protection against ischemia/reperfusion (I/R) injury and could be a promising approach for early neuroprotection after out-of-hospital cardiac arrest or ischemic stroke.

3H-1,2-Dithiole-3-thione as a novel therapeutic agent for the treatment of ischemic stroke through Nrf2 defense pathway.

Cerebral ischemic stroke accounts for more than 80% of all stroke cases. During cerebral ischemia, reactive oxygen species produced in brain tissue induce oxidative stress and inflammatory responses. D3T, the simplest compound of the cyclic, sulfur-containing dithiolethiones, is found in cruciferous vegetables and has been reported to induce antioxidant genes and glutathione biosynthesis through activation of Nrf2. In addition to antioxidant activity, D3T was also reported to possess anti-inflammatory effects. In this study, we evaluated the therapeutic potential of D3T for the treatment of ischemic stroke and investigated the mechanisms underlying the protective effects of D3T in ischemic stroke. Mice subjected to transient middle cerebral artery occlusion/reperfusion (tMCAO/R) were administered with vehicle or D3T to evaluate the effect of D3T in cerebral brain injury. We observed D3T reduced infarct size, decreased brain edema, lessened blood-brain barrier disruption, and ameliorated neurological deficits. Further investigation revealed D3T suppressed microglia (MG) activation and inhibited peripheral inflammatory immune cell infiltration of CNS in the ischemic brain. The protective effect of D3T in ischemic stroke is mediated through Nrf2 induction as D3T-attenuated brain injury was abolished in Nrf2 deficient mice subjected to tMCAO/R. In addition, in vitro results indicate the induction of Nrf2 by D3T is required for its suppressive effect on MG activation and cytokine production. In summary, we demonstrate for the first time that D3T confers protection against ischemic stroke, which is mediated through suppression of MG activation and inhibition of CNS peripheral cell infiltration, and that the protective effect of D3T in ischemic stroke is dependent on the activation of Nrf2.