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Purpose With the publication of a large randomized-controlled trial (RCT) suggesting that tranexamic acid (TXA) may improve head-injury-related deaths, we aimed to determine the safety and efficacy of TXA in acute traumatic brain injury (TBI). Methods In this systematic review and meta-analysis, we searched MEDLINE, PubMed, EMBASE, CINHAL, ACPJC, Google Scholar, and unpublished sources from inception until June 24, 2020 for randomized-controlled trials comparing TXA and placebo in adults and adolescents (≥ 15 years of age) with acute TBI. We screened studies and extracted summary estimates independently and in duplicate. We assessed the quality of evidence using the grading of recommendations assessment, development, and evaluation approach. This study is registered with PROSPERO (CRD42020164232). Results Nine RCTs enrolled 14,747 patients. Compared to placebo, TXA had no effect on mortality (RR 0.95; 95% CI 0.88–1.02; RD 1.0% reduction; 95% CI 2.5% reduction to 0.4% increase, moderate certainty) or disability assessed by the Disability Rating Scale (MD, − 0.18 points; 95% CI − 0.43 to 0.08; moderate certainty). TXA may reduce hematoma expansion on subsequent imaging (RR 0.77; 95% CI 0.58–1.03, RD 3.6%, 95% CI 6.6% reduction to 0.5% increase, low certainty). Risks of adverse events (all moderate, low, or very low certainty) were similar between placebo and TXA. Conclusions In patients with acute TBI, TXA probably has no effect on mortality or disability. TXA may decrease hematoma expansion on subsequent imaging; however, this outcome is likely of less importance to patients. The use of TXA probably does not increase the risk of adverse events.

Traumatic brain injury (TBI) is a complex condition where heterogeneity impedes the advancement of care. Understanding the diverse presentations of TBI is crucial for personalized medicine. Our study aimed to identify clinically relevant patient endotypes in TBI using latent class analysis based on comorbidity data. We used the Medical Information Mart for Intensive Care III database, which includes 2,629 adult TBI patients. We identified five stable endotypes characterized by specific comorbidity profiles: Heart Failure and Arrhythmia, Healthy, Renal Failure with Hypertension, Alcohol Abuse, and Hypertension. Each endotype had distinct clinical characteristics and outcomes: The Heart Failure and Arrhythmia endotype had lower survival rates than the Renal Failure with Hypertension despite featuring fewer comorbidities overall. Patients in the Hypertension endotype had higher rates of neurosurgical intervention but shorter stays in contrast to the Alcohol Abuse endotype which had lower rates of neurosurgical intervention but significantly longer hospital stays. Both endotypes had high overall survival rates comparable to the Healthy endotype. Logistic regression models showed that endotypes improved the predictability of survival compared to individual comorbidities alone. This study validates clinical endotypes as an approach to addressing heterogeneity in TBI and demonstrates the potential of this methodology in other complex conditions.

Intracranial hemorrhage (ICH) after head injury is a concern among older adult patients on anticoagulation. We evaluated the risk of ICH after an emergency department visit for head injury among patients 65 years and older taking warfarin or a direct oral anticoagulant (DOAC) compared with patients not taking anticoagulants. We also evaluated risk of 30-day mortality and neurosurgical intervention among patients with ICH. In this retrospective cohort study, we used population-based data of patients 65 years and older seen in an Ontario emergency department with a head injury. We matched patients on the propensity score to create 3 pairwise-matched cohorts based on anticoagulation status (warfarin v. DOAC, warfarin v. no anticoagulant, DOAC v. no anticoagulant). For each cohort, we calculated the relative risk of ICH at the index emergency department visit and 30-day mortality. We also calculated the hazard of neurosurgical intervention among patients with ICH. We identified 77 834 patients with head injury, including 64 917 (83.4%) who were not on anticoagulation, 9214 (11.8%) who were on DOACs and 3703 (4.8%) who were on warfarin. Of these, 5.9% of patients had ICH at the index emergency department visit. Patients on warfarin had an increased risk of ICH compared with matched patients on DOACs (relative risk [RR] 1.43, 95% confidence interval [CI] 1.20–1.69) and patients not on anticoagulation (RR 1.36, 95% CI 1.15–1.61). We did not observe a difference in ICH between patients on DOACs compared with matched patients not on anticoagulation. In patients with ICH, 30-day mortality did not differ by anticoagulation status or type. Patients on warfarin had an increased hazard of neurosurgery compared with patients not on anticoagulation. Patients on warfarin seen in the emergency department with a head injury had higher relative risks of ICH than matched patients on a DOAC and patients not on anticoagulation, respectively. The risk of ICH for patients on a DOAC was not significantly different compared with no anticoagulation. Further research should confirm that older adults using warfarin are the only group at higher risk of ICH after head injury.

•Dabigatran-associated intracranial hemorrhage (ICH) has proven difficult to manage.•Idarucizumab was FDA approved as the first reversal agent of dabigatran in 2015.•It is unclear if idarucizumab can be used effectively in ICH due to paucity of study.•Systematic review of the current literature indicates it is feasible. Idarucizumab is the first Food and Drugs Administration (FDA) approved reversal agent for anticoagulant dabigatran, a direct thrombin inhibitor. Emerging evidence suggests idarucizumab can improve clinical outcome following dabigatran-associated hemorrhage, however, its specific use in intracranial hemorrhage has been poorly described. The aim of this study was to systematically review the available literature of idarucizumab in the setting of dabigatran-associated ICH to evaluate its efficacy in the stabilizing/resolving of the primary hemorrhage. A systematic search of 7 electronic databases from their earliest records to August 2018 was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. There were 864 articles identified for screening against selection criteria. The search identified 9 articles to be included in our analysis, describing hemorrhage outcomes in 23 dabigatran-associated cases of ICH managed by idarucizumab. Mean overall age was 76.2 years, with 43% females, and bleeding was subdural, subarachnoid and intracerebral in 43%, 13% and 43% cases respectively. Surgical intervention was pursued in 48% of cases. During the course of the hospitalization, the hemorrhages stabilized/resolved in 87% of patients, and worsened in 13%. In-hospital complications occurred in 4% of cases, and mortality occurred in 4% of cases as well. The available literature suggests that idarucizumab can be applied in the setting of ICH, for its therapeutic effect in patients presenting with dabigatran-associated ICH appears acceptable with no compromise to clinical safety. However, currently there is a paucity of data about various aspects that are involved in other aspects of ICH treatment, including recovery, that limits the significance of the current literature. As more evidence is published relating specifically to long-term ICH outcomes that have been treated by idarucizumab, we will be better placed to establish the optimal role of idarucizumab in the setting of dabigatran-associated ICH.

Ground-level falls are common among older adults and are the most frequent cause of traumatic intracranial bleeding. The aim of this study was to derive a clinical decision rule that safely excludes clinically important intracranial bleeding in older adults who present to the emergency department after a fall, without the need for a computed tomography (CT) scan of the head. This prospective cohort study in 11 emergency departments in Canada and the United States enrolled patients aged 65 years or older who presented after falling from standing on level ground, off a chair or toilet seat, or out of bed. We collected data on 17 potential predictor variables. The primary outcome was the diagnosis of clinically important intracranial bleeding within 42 days of the index emergency department visit. An independent adjudication committee, blinded to baseline data, determined the primary outcome. We derived a clinical decision rule using logistic regression. The cohort included 4308 participants, with a median age of 83 years; 2770 (64%) were female, 1119 (26%) took anticoagulant medication and 1567 (36%) took antiplatelet medication. Of the participants, 139 (3.2%) received a diagnosis of clinically important intracranial bleeding. We developed a decision rule indicating that no head CT is required if there is no history of head injury on falling; no amnesia of the fall; no new abnormality on neurologic examination; and the Clinical Frailty Scale score is less than 5. Rule sensitivity was 98.6% (95% confidence interval [CI] 94.9%–99.6%), specificity was 20.3% (95% CI 19.1%–21.5%) and negative predictive value was 99.8% (95% CI 99.2%–99.9%). We derived a Falls Decision Rule, which requires external validation, followed by clinical impact assessment. Trial registration: ClinicalTrials. gov, no. NCT03745755.

Guidelines recommend the treatment of emergent large vessel ischemic stroke (ELVIS) patients presenting beyond 6 hours of last known well time with endovascular thrombectomy (EVT) based on perfusion computed tomography (CT) neuroimaging. We compared the outcomes (long-term good clinical outcomes, symptomatic intracranial hemorrhage (sICH), and mortality) of ELVIS patients according to the type of CT neuroimaging they underwent. We searched the following databases: Medline, Embase, CENTRAL, and Scopus from January 1, 2015, to June 14, 2023. We included studies of late-presenting ELVIS patients undergoing EVT that had with data for non-perfusion and perfusion CT neuroimaging. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data were pooled using a random effects model. We found 7 observational cohorts. Non-perfusion versus perfusion CT was not statistically significantly different for both long-term clinical (n = 3,224; RR: 0.96; 95% CI 0.86 to 1.06; I2 = 18%) and sICH (n = 3,724; RR: 1.08 95% CI 0.60 to 1.94; I2 = 76%). Perfusion CT had less mortality (n = 3874; RR: 1.22; 95% CI 1.07 to 1.40; I2 = 0%). The certainty of these findings is very low because of limitations in the risk of bias, indirectness, and imprecision domains of the Grading of Recommendations, Assessment, Development and Evaluations. The use of either non-perfusion or perfusion CT neuroimaging may have little to no effect on long-term clinical outcomes and sICH for late-presenting EVT patients. Perfusion CT neuroimaging may be associated with a reduced the risk of mortality. Evidence uncertainty warrants randomized trial data.

Guidelines recommend the use of perfusion computed tomography (CT) to identify emergent large vessel ischemic stroke (ELVIS) patients who are likely to benefit from endovascular thrombectomy (EVT) if they present within 6-24 hour (late window) of stroke onset. We aim to determine if the interrater and intrarater reliability among physicians when recommending EVT is significantly different when perfusion CT or non-perfusion CT is reviewed. A total of 30 non-consecutive patients will be selected from our institutional database comprising 3144 cranial CT scans performed for acute stroke symptoms January 2018 to August 2022. The clinical and radiologic data of the 30 patients will be presented in random order to a group of 29 physicians in two separate sessions at least three weeks apart. In each session, the physicians will evaluate each patient once with automated perfusion images and once without. We will use non-overlapping 95% confidence intervals and difference in agreement classification as criteria to suggest a difference between the Gwet AC1 statistics (κG). The results obtained from this study, combined with the clinical outcomes data of patients categorized through the two imaging techniques and a cost-effectiveness analysis, will offer a comprehensive evaluation of the clinical utility of perfusion CT neuroimaging. Should there be no significant disparity in the reliability of decisions made by clinicians using the two neuroimaging protocols, it may be necessary to revise existing recommendations regarding neuroimaging in the later time window to align with these findings.

Background Elevated intracranial pressure due to cerebral edema is associated with very poor survival in patients with acute liver failure (ALF). Placing an intracranial pressure monitor (ICPm) aids in management of intracranial hypertension, but is associated with potentially fatal hemorrhagic complications related to the severe coagulopathy associated with ALF. Methods An institutional Acute Liver Failure Clinical Protocol (ALF-CP) was created to correct ALF coagulopathy prior to placing parenchymal ICP monitoring bolts. We aimed to investigate the frequency, severity, and clinical significance of hemorrhagic complications associated with ICPm bolt placement in the setting of an ALF-CP. All assessed patients were managed with the ALF-CP and had rigorous radiologic follow-up allowing assessment of the occurrence and chronology of hemorrhagic complications. We also aimed to compare our outcomes to other studies that were identified through a comprehensive review of the literature. Results Fourteen ALF patients were included in our analysis. There was no symptomatic hemorrhage after ICP monitor placement though four patients were found to have minor intraparenchymal asymptomatic hemorrhages after liver transplant when the ICP monitor had been removed, making the rate of radiographically identified clinically asymptomatic hemorrhage 28.6%. These results compare favorably to those found in a comprehensive review of the literature which revealed rates as high as 17.5% for symptomatic hemorrhages and 30.4% for asymptomatic hemorrhage. Conclusion This study suggests that an intraparenchymal ICPm can be placed safely in tertiary referral centers which utilize a protocol such as the ALF-CP that aggressively corrects coagulopathy. The ALF-CP led to advantageous outcomes for ICPm placement with a 0% rate of symptomatic and low rate of asymptomatic hemorrhagic complications, which compares well to results reported in other series. A strict ICPm placement protocol in this setting facilitates management of ALF patients with cerebral edema during the wait time to transplantation or spontaneous recovery.

BackgroundTraumatic brain injury (TBI) is a major cause of death and disability worldwide. Beta blockers have shown promise in improving mortality and functional outcomes after TBI. The aim of this article is to synthesize the available clinical data on the use of beta blockers in acute TBI.MethodsA systematic search was conducted through MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for studies including one or more outcomes of interest associated with use of beta blockers in TBI. Independent reviewers evaluated the quality of the studies and extracted data on all patients receiving beta blockers during their hospital stay compared with placebo or non-intervention. Pooled estimates, CIs, and risk ratios (RRs) or ORs were calculated for all outcomes.Results13 244 patients from 17 studies were eligible for analysis. Pooled analysis demonstrated a significant mortality benefit of overall use of beta blocker (RR 0.8, 95% CI 0.68 to 0.94, I2=75%). Subgroup analysis of patients with no preinjury use of beta blocker compared with patients on preinjury beta blockers showed no mortality difference (RR 0.99, 95% CI 0.7 to 1.39, I2=84%). There was no difference in rate of good functional outcome at hospital discharge (OR 0.94, 95% CI 0.56 to 1.58, I2=65%); however, there was a functional benefit at longer-term follow-up (OR 1.75, 95% CI 1.09 to 2.8, I2=0%). Cardiopulmonary and infectious complications were more likely in patients who received beta blockers (RR 1.94, 95% CI 1.69 to 2.24, I2=0%; RR 2.36, 95% CI 1.42 to 3.91, I2=88%). Overall quality of the evidence was very low.ConclusionsUse of beta blockers is associated with decreased mortality at acute care discharge as well as improved functional outcome at long-term follow-up. Lack of high-quality evidence limits definitive recommendations for use of beta blockers in TBI; therefore, high-quality randomized trials are needed to further elucidate the utility of beta blockers in TBI.PROSPERO registration numberCRD42021279700.

IntroductionVenous thromboembolism (VTE) is a common complication of traumatic brain injury (TBI) and is associated with increased morbidity and mortality. Low molecular weight heparin (LMWH) is recommended for prophylaxis against VTE after trauma but may increase the risk of progression of intracranial bleeding. Limited evidence exists to guide clinicians regarding the optimal timing of VTE prophylaxis in patients with acute TBI. This randomised controlled trial (RCT) will directly compare the safety and effectiveness of early versus delayed initiation of LMWH in patients with moderate to severe TBI.Methods and analysisThe study design is a Bayesian adaptive RCT comparing early (within three calendar days of injury) versus delayed (after study Day 7) VTE prophylaxis with the LMWH, dalteparin. All patients receive sequential compression devices until study Day 8. The co-primary effectiveness outcome is the development of clinically important VTE at study Day 8. The co-primary safety outcome is the development of clinically important intracranial bleeding at study Day 8. Secondary outcomes are mortality and functional outcomes (Glasgow Outcome Scale Extended and EQ-5D) measured at study Days 30 and 180; clinically diagnosed VTE to Day 30 and progression of intracranial bleeding to Day 8.Ethics and disseminationThis study has been approved through Clinical Trials Ontario’s streamlined ethics review process (board of record, Sunnybrook Health Sciences Centre) and all participating centres. It is conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines and Health Canada regulatory requirements. We anticipate that the trial will achieve wide dissemination through publication in a peer-reviewed medical journal and presentation at international conferences targeting the fields of critical care, trauma and neurosurgery. The results of this trial will help guide clinicians aiming to balance the risks and benefits of early anticoagulant prophylaxis after TBI and will inform guideline development.Trial registration numberNCT03559114.