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    Effects of antifibrinolytics on systemic and cerebral inflammation after traumatic brain injury. The journal of trauma and acute care surgery BACKGROUND:Administration of antifibrinolytic medications, including tranexamic acid (TXA), may reduce head injury-related mortality. The effect of these medications on post-traumatic brain injury (TBI) inflammatory response is unknown. The goal of this study was to investigate the role of available antifibrinolytic medications on both systemic and cerebral inflammation after TBI. METHODS:An established murine weight drop model was used to induce a moderate TBI. Mice were administered 1, 10, or 100 mg/kg of TXA, 400 mg/kg of aminocaproic acid (Amicar, Hospira, Lake Forest, IL), 100 kIU/kg of aprotonin, or equivalent volume of normal saline (NS) 10 minutes after recovery. Mice were euthanized at 1, 6, or 24 hours. Serum and cerebral tissue were analyzed for neuron-specific enolase and inflammatory cytokines. Hippocampal histology was evaluated at 30 days for phosphorylated tau accumulation. RESULTS:One hour after TBI, mice given TXA displayed decreased cerebral cytokine concentrations of tumor necrosis factor α (TNF-α) and, by 24 hours, displayed decreased concentrations of cerebral TNF-α, interleukin (IL)-6, and monocyte chemoattractant protein 1 compared with TBI-NS. However, serum concentrations of TNF-α and macrophage inflammatory protein 1α (MIP-1α) were significantly elevated from 1 to 24 hours in TBI-TXA groups compared with TBI-NS. The concentration of phosphorylated tau was significantly decreased in a dose-dependent manner in TBI-TXA groups compared with TBI-NS. By contrast, Amicar administration increased cerebral cytokine levels of IL-6 1 hour after TBI, with serum elevations noted in TNF-α, MIP-1α, and monocyte chemoattractant protein 1 at 24 hours compared with TBI-NS. Aprotonin administration increased serum TNF-α, IL-6, and MIP-1α from 1 to 24 hours without differences in cerebral cytokines compared with TBI-NS. CONCLUSION:Tranexamic acid administration may provide acute neuroinflammatory protection in a dose-dependent manner. Amicar administration may be detrimental after TBI with increased cerebral and systemic inflammatory effects. Aprotonin administration may increase systemic inflammation without significant contributions to neuroinflammation. While no antifibrinolytic medication improved systemic inflammation, these data suggest that TXA may provide the most beneficial inflammatory modulation after TBI. 10.1097/TA.0000000000003607
    Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury: A Double-blind, Placebo-Controlled, Randomized Clinical Trial. JAMA surgery IMPORTANCE:In-hospital administration of tranexamic acid after injury improves outcomes in patients at risk for hemorrhage. Data demonstrating the benefit and safety of the pragmatic use of tranexamic acid in the prehospital phase of care are lacking for these patients. OBJECTIVE:To assess the effectiveness and safety of tranexamic acid administered before hospitalization compared with placebo in injured patients at risk for hemorrhage. DESIGN, SETTING, AND PARTICIPANTS:This pragmatic, phase 3, multicenter, double-blind, placebo-controlled, superiority randomized clinical trial included injured patients with prehospital hypotension (systolic blood pressure ≤90 mm Hg) or tachycardia (heart rate ≥110/min) before arrival at 1 of 4 US level 1 trauma centers, within an estimated 2 hours of injury, from May 1, 2015, through October 31, 2019. INTERVENTIONS:Patients received 1 g of tranexamic acid before hospitalization (447 patients) or placebo (456 patients) infused for 10 minutes in 100 mL of saline. The randomization scheme used prehospital and in-hospital phase assignments, and patients administered tranexamic acid were allocated to abbreviated, standard, and repeat bolus dosing regimens on trauma center arrival. MAIN OUTCOMES AND MEASURES:The primary outcome was 30-day all-cause mortality. RESULTS:In all, 927 patients (mean [SD] age, 42 [18] years; 686 [74.0%] male) were eligible for prehospital enrollment (460 randomized to tranexamic acid intervention; 467 to placebo intervention). After exclusions, the intention-to-treat study cohort comprised 903 patients: 447 in the tranexamic acid arm and 456 in the placebo arm. Mortality at 30 days was 8.1% in patients receiving tranexamic acid compared with 9.9% in patients receiving placebo (difference, -1.8%; 95% CI, -5.6% to 1.9%; P = .17). Results of Cox proportional hazards regression analysis, accounting for site, verified that randomization to tranexamic acid was not associated with a significant reduction in 30-day mortality (hazard ratio, 0.81; 95% CI, 0.59-1.11, P = .18). Prespecified dosing regimens and post-hoc subgroup analyses found that prehospital tranexamic acid were associated with significantly lower 30-day mortality. When comparing tranexamic acid effect stratified by time to treatment and qualifying shock severity in a post hoc comparison, 30-day mortality was lower when tranexamic acid was administered within 1 hour of injury (4.6% vs 7.6%; difference, -3.0%; 95% CI, -5.7% to -0.3%; P < .002). Patients with severe shock (systolic blood pressure ≤70 mm Hg) who received tranexamic acid demonstrated lower 30-day mortality compared with placebo (18.5% vs 35.5%; difference, -17%; 95% CI, -25.8% to -8.1%; P < .003). CONCLUSIONS AND RELEVANCE:In injured patients at risk for hemorrhage, tranexamic acid administered before hospitalization did not result in significantly lower 30-day mortality. The prehospital administration of tranexamic acid after injury did not result in a higher incidence of thrombotic complications or adverse events. Tranexamic acid given to injured patients at risk for hemorrhage in the prehospital setting is safe and associated with survival benefit in specific subgroups of patients. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02086500. 10.1001/jamasurg.2020.4350
    Case Series on 2g Tranexamic Acid Flush From the 75th Ranger Regiment Casualty Database. Journal of special operations medicine : a peer reviewed journal for SOF medical professionals Early tranexamic acid (TXA) administration for resuscitation of critically injured warfighters provides a mortality benefit. The 2019 Tactical Combat Casualty Care (TCCC) recommendations of a 1g drip over 10 minutes, followed by 1g drip over 8 hours, is intended to limit potential TXA side effects, including hypotension, seizures, and anaphylaxis. However, this slow and cumbersome TXA infusion protocol is difficult to execute in the tactical care environment. Additionally, the side effect cautions derive from studies of elderly or cardiothoracic surgery patients, not young healthy warfighters. Therefore, the 75th Ranger Regiment developed and implemented a 2g intravenous or intraosseous (IV/IO) TXA flush protocol. We report on the first six cases of this protocol in the history of the Regiment. After-action reports (AARs) revealed no incidences of post-TXA hypotension, seizures, or anaphylaxis. Combined, the results of this case series are encouraging and provide a foundation for larger studies to fully determine the safety of the novel 2g IV/IO TXA flush protocol toward preserving the lives of traumatically injured warfighters. 10.55460/CG6S-N11M
    The Use of Tranexamic Acid in Tactical Combat Casualty Care: TCCC Proposed Change 20-02. Journal of special operations medicine : a peer reviewed journal for SOF medical professionals The literature continues to provide strong support for the early use of tranexamic acid (TXA) in severely injured trauma patients. Questions persist, however, regarding the optimal medical and tactical/logistical use, timing, and dose of this medication, both from the published TXA literature and from the TCCC user community. The use of TXA has been explored outside of trauma, new dosing strategies have been pursued, and expansion of retrospective use data has grown as well. These questions emphasize the need for a reexamination of TXA by the CoTCCC. The most significant updates to the TCCC Guidelines are (i) including significant traumatic brain injury (TBI) as an indication for TXA, (ii) changing the dosing protocol to a single 2g IV/IO administration, and (iii) recommending TXA administration via slow IV/IO push. 10.55460/ZWV3-5CBW
    Efficacy and safety of tranexamic acid for aneurysmal subarachnoid hemorrhage. The American journal of emergency medicine 10.1016/j.ajem.2021.12.045
    Tranexamic Acid and Its Potential Anti-Inflammatory Effect: A Systematic Review. Seminars in thrombosis and hemostasis Tranexamic acid (TXA) is an antifibrinolytic drug primarily used for reducing blood loss in patients with major bleedings. Animal and cell studies have shown that TXA might modulate the inflammatory response by either enhancing or inhibiting cytokine levels. Furthermore, recent human studies have found altered inflammatory biomarkers in patients receiving TXA when compared with patients who did not receive TXA. In this systematic review we investigated the effect of TXA on inflammatory biomarkers in different patient groups. A systematic literature search was conducted on the databases PubMed and Embase to identify all original articles that investigated inflammatory biomarkers in patients receiving TXA and compared them to a relevant control group. The review was performed according to the PRISMA guidelines, and the literature search was performed on November 29, 2021. Thirty-three studies were included, among which 14 studies compared patients receiving TXA with patients getting no medication, another 14 studies investigated different dosing regimens of TXA, and finally five studies examined the administration form of TXA. The present review suggests that TXA has an anti-inflammatory effect in patients undergoing orthopaedic surgery illustrated by decreased levels of C-reactive protein and interleukin-6 in patients receiving TXA compared with patients receiving no or lower doses of TXA. However, the anti-inflammatory effect was not found in patients undergoing cardiac surgery, pediatric craniosynostosis patients, or in rheumatoid arthritis patients. The inflammatory response was not affected by administration form of TXA (oral, intravenous, or topical). In conclusion, an anti-inflammatory effect of TXA was consistently found among orthopaedic patients only. 10.1055/s-0042-1742741
    The effect of early tranexamic acid on bleeding, blood product consumption, mortality and length of hospital stay in trauma cases with hemorrhagic shock: a randomized clinical trial. Journal of preventive medicine and hygiene Introduction:Because no medication has been approved for coagulation support in trauma, the current study was aimed to evaluate the effectiveness of intravenous injection of Tranexamic acid (TXA) in patients with acute traumatic bleeding. Methods:In the current randomized controlled clinical trial, 68 patients with acute bleeding and hemorrhagic shock presentation due to blunt trauma of the abdomen, pelvis, and thorax, randomly assigned into two groups of TXA and placebo. Results:There was no statistically significant difference between the two groups in terms of Systolic blood pressure, pulse rate, Base excess, serum hemoglobin changes, bleeding volume, the incidence of thrombotic events, and the number of deaths (p > 0.05). But Systolic blood pressure, pulse rate, base excess, and serum hemoglobin, changed significantly within each group over time(p < 0.05). The median time for the length of hospital stay among the TXA group was lower than the Placebo group (6 days vs 10 days, p = 0.004). Also, there was a significant difference between the two groups about the median of pack cell, Platelet consumption, and bleeding Volume (p < 0.05). Conclusion:The use of TXA is associated with lower use of blood production and reduced length of hospital stay, however, thrombotic events incidence and mortality rates between the TXA and placebo groups were not different. 10.15167/2421-4248/jpmh2021.62.4.2186
    Use of tranexamic acid in major trauma: a sex-disaggragated analysis of the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2 and CRASH-3) trials and UK trauma registry (Trauma and Audit Research Network) data. British journal of anaesthesia BACKGROUND:Women are less likely than men to receive some emergency treatments. This study examines whether the effect of tranexamic acid (TXA) on mortality in trauma patients varies by sex and whether the receipt of TXA by trauma patients varies by sex. METHODS:First, we conducted a sex-disaggregated analysis of data from the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH)-2 and CRASH-3 trials. We used interaction tests to determine whether the treatment effect varied by sex. Second, we examined data from the Trauma and Audit Research Network (TARN) to explore sex differences in the receipt of TXA. We used logistic regression models to estimate the odds ratio for receipt of TXA in females compared with males. Results are reported as n (%), risk ratios (RR), and odds ratios (OR) with 95% confidence intervals. RESULTS:Overall, 20 211 polytrauma patients (CRASH-2) and 12 737 patients with traumatic brain injuries (CRASH-3) were included in our analysis. TXA reduced the risk of death in females (RR=0.69 [0.52-0.91]) and in males (RR=0.80 [0.71-0.90]) with no significant heterogeneity by sex (P=0.34). We examined TARN data for 216 364 patients aged ≥16 yr with an Injury Severity Score ≥9 with 98 879 (46%) females and 117 485 (54%) males. TXA was received by 7198 (7.3% [7.1-7.4%]) of the females and 19 697 (16.8% [16.6-17.0%]) of the males (OR=0.39 [0.38-0.40]). The sex difference in the receipt of TXA increased with increasing age. CONCLUSIONS:Administration of TXA to patients with bleeding trauma reduces mortality to a similar extent in women and men, but women are substantially less likely to be treated with TXA. 10.1016/j.bja.2022.03.032
    Trauma-induced coagulopathy. Nature reviews. Disease primers Uncontrolled haemorrhage is a major preventable cause of death in patients with traumatic injury. Trauma-induced coagulopathy (TIC) describes abnormal coagulation processes that are attributable to trauma. In the early hours of TIC development, hypocoagulability is typically present, resulting in bleeding, whereas later TIC is characterized by a hypercoagulable state associated with venous thromboembolism and multiple organ failure. Several pathophysiological mechanisms underlie TIC; tissue injury and shock synergistically provoke endothelial, immune system, platelet and clotting activation, which are accentuated by the 'lethal triad' (coagulopathy, hypothermia and acidosis). Traumatic brain injury also has a distinct role in TIC. Haemostatic abnormalities include fibrinogen depletion, inadequate thrombin generation, impaired platelet function and dysregulated fibrinolysis. Laboratory diagnosis is based on coagulation abnormalities detected by conventional or viscoelastic haemostatic assays; however, it does not always match the clinical condition. Management priorities are stopping blood loss and reversing shock by restoring circulating blood volume, to prevent or reduce the risk of worsening TIC. Various blood products can be used in resuscitation; however, there is no international agreement on the optimal composition of transfusion components. Tranexamic acid is used in pre-hospital settings selectively in the USA and more widely in Europe and other locations. Survivors of TIC experience high rates of morbidity, which affects short-term and long-term quality of life and functional outcome. 10.1038/s41572-021-00264-3
    Tranexamic acid in intracerebral hemorrhage: a meta-analysis. The International journal of neuroscience OBJECTIVE:Evidence-based medicine was used to evaluate the efficacy and safety of tranexamic acid in patients with intracerebral hemorrhage. METHODS:Pubmed (MEDLINE), Embase, and Cochrane Library were searched from January 2001 to October 2020 for randomized controlled trials (RCTs), cohort studies, and retrospective case series .The Jadad scale and RevMan software version 5.3 were used for literature quality assessment and meta-analysis. RESULTS:In total, 4 randomized controlled trials and 1 retrospective case series with 2808 participants were included in the meta-analysis. Compared with control intervention in intracerebral hemorrhage, tranexamic acid could significantly reduce growth of hemorrhagic mass (odds ratio (OR) =0.81; 95% confidence interval(CI)=0.68 to 0.99;  = 0.04) and Modified Rankin Scale score (MRS) at 90 days at 0-3 (OR = 1.20; 95% CI = 1.00 to 1.43;  = 0.05), mortality by day 90 (OR= 1.03; 95% CI= 0.85-1.25;  = 0.77) and major thromboembolic events (OR= 1.14; 95% CI= 0.73-1.77;  = 0.58). CONCLUSIONS:Treatment with tranexamic acid could reduce hematoma expansion in intracerebral hemorrhage, and the treatment was safe with no increase in thromboembolic complications. But showed no notable impact on good functional outcomes and mortality. 10.1080/00207454.2021.1953020
    The effect of tranexamic acid dosing regimen on trauma/hemorrhagic shock-related glycocalyx degradation and endothelial barrier permeability: An in vitro model. The journal of trauma and acute care surgery BACKGROUND:Improved outcomes with early tranexamic acid (TXA) following trauma hemorrhagic shock (T/HS) may be related to its antifibrinolytic, as well as anti-inflammatory properties. Previous in vitro studies have shown that early TXA administration protects against T/HS endothelial barrier dysfunction and associated glycocalyx degradation. An intact endothelial glycocalyx may protect against subsequent neutrophil mediated tissue injury. We postulated that early TXA administration would mitigate against glycocalyx damage and resultant neutrophil adherence and transmigration through the endothelial barrier. This was studied in vitro using a microfluidic flow platform. METHODS:Human umbilical vein endothelial cell monolayers were subjected to control or shock conditions (hypoxia + epinephrine) followed by administration of TXA 90 minutes or 180 minutes later. RESULTS:"Early" TXA administration protected against glycocalyx degradation, biomarkers of increased permeability and the development of a fibrinolytic phenotype. This was associated with decreased neutrophil endothelial adherence and transmigration. There were no differences in low versus high TXA concentrations. The protective effects were only significant with "early" TXA administration. CONCLUSION:There was a concentration and temporal effect of TXA administration on endothelial glycocalyx degradation. This was associated with "vascular leakiness" as indexed by the relative ratio of Ang-2/1 and polymorphonuclear neutrophil transmigration. Tranexamic acid if administered in patients with T/HS should be administered "early"; this includes in the prehospital setting. 10.1097/TA.0000000000003548
    Tranexamic Acid in Civilian Trauma Care in the California Prehospital Antifibrinolytic Therapy Study. Neeki Michael M,Dong Fanglong,Toy Jake,Vaezazizi Reza,Powell Joe,Wong David,Mousselli Michael,Rabiei Massoud,Jabourian Alex,Niknafs Nichole,Burgett-Moreno Michelle,Vara Richard,Kissel Shanna,Luo-Owen Xian,O'Bosky Karen R,Ludi Daniel,Sporer Karl,Pennington Troy,Lee Tommy,Borger Rodney,Kwong Eugene The western journal of emergency medicine INTRODUCTION:Hemorrhage is one of the leading causes of death in trauma victims. Historically, paramedics have not had access to medications that specifically target the reversal of trauma-induced coagulopathies. The California Prehospital Antifibrinolytic Therapy (Cal-PAT) study seeks to evaluate the safety and efficacy of tranexamic acid (TXA) use in the civilian prehospital setting in cases of traumatic hemorrhagic shock. METHODS:The Cal-PAT study is a multi-centered, prospective, observational cohort study with a retrospective comparison. From March 2015 to July 2017, patients ≥ 18 years-old who sustained blunt or penetrating trauma with signs of hemorrhagic shock identified by first responders in the prehospital setting were considered for TXA treatment. A control group was formed of patients seen in the five years prior to data collection cessation (June 2012 to July 2017) at each receiving center who were not administered TXA. Control group patients were selected through propensity score matching based on gender, age, Injury Severity Scores, and mechanism of injury. The primary outcome assessed was mortality recorded at 24 hours, 48 hours, and 28 days. Additional variables assessed included total blood products transfused, the hospital and intensive care unit length of stay, systolic blood pressure taken prior to TXA administration, Glasgow Coma Score observed prior to TXA administration, and the incidence of known adverse events associated with TXA administration. RESULTS:We included 724 patients in the final analysis, with 362 patients in the TXA group and 362 in the control group. Reduced mortality was noted at 28 days in the TXA group in comparison to the control group (3.6% vs. 8.3% for TXA and control, respectively, odds ratio [OR]=0.41 with 95% confidence interval [CI] [0.21 to 0.8]). This mortality difference was greatest in severely injured patients with ISS >15 (6% vs 14.5% for TXA and control, respectively, OR=0.37 with 95% CI [0.17 to 0.8]). Furthermore, a significant reduction in total blood product transfused was observed after TXA administration in the total cohort as well as in severely injured patients. No significant increase in known adverse events following TXA administration were observed. CONCLUSION:Findings from the Cal-PAT study suggest that TXA use in the civilian prehospital setting may safely improve survival outcomes in patients who have sustained traumatic injury with signs of hemorrhagic shock. 10.5811/westjem.2018.8.39336
    Efficacy and safety of tranexamic acid administration in traumatic brain injury patients: a systematic review and meta-analysis. Journal of intensive care BACKGROUND:The exacerbation of intracranial bleeding is critical in traumatic brain injury (TBI) patients. Tranexamic acid (TXA) has been used to improve outcomes in TBI patient. However, the effectiveness of TXA treatment remains unclear. This study aimed to assess the effect of administration of TXA on clinical outcomes in patients with TBI by systematically reviewing the literature and synthesizing evidence of randomized controlled trials (RCTs). METHODS:MEDLINE, the Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi (ICHUSHI) Web were searched. Selection criteria included randomized controlled trials with clinical outcomes of adult TBI patients administered TXA or placebo within 24 h after admission. Two investigators independently screened citations and conducted data extraction. The primary "critical" outcome was all-cause mortality. The secondary "important" outcomes were good neurological outcome rates, enlargement of bleeding, incidence of ischemia, and hemorrhagic intracranial complications. Random effect estimators with weights calculated by the inverse variance method were used to report risk ratios (RRs). RESULTS:A total of 640 records were screened. Seven studies were included for quantitative analysis. Of 10,044 patients from seven of the included studies, 5076 were randomly assigned to the TXA treatment group, and 4968 were assigned to placebo. In the TXA treatment group, 914 patients (18.0%) died, while 961 patients (19.3%) died in the placebo group. There was no significant difference between groups (RR, 0.93; 95% confidence interval, 0.86-1.01). No significant differences between the groups in other important outcomes were also observed. CONCLUSIONS:TXA treatment demonstrated a tendency to reduce head trauma-related deaths in the TBI population, with no significant incidence of thromboembolic events. TXA treatment may therefore be suggested in the initial TBI care. 10.1186/s40560-020-00460-5
    Tranexamic acid reduces perioperative bleeding. Nature reviews. Cardiology 10.1038/s41569-022-00710-z
    To Tranexamic Acid or Not to Tranexamic Acid? Accuracy of Antifibrinolytic Administration at Altitude. Air medical journal OBJECTIVE:Tranexamic acid (TXA) has demonstrated a reduction in all-cause mortality in trauma patients with hemorrhage. Administering TXA in the prehospital setting presents unique challenges because the identification of bleeding is based on clinical suspicion without advanced imaging or diagnostic tools. The objective of this study was to examine whether prehospital suspicion of bleeding is validated by in-hospital computed tomographic imaging and examination and to determine if patients received TXA in the absence of hemorrhage. The study was conducted at a level 1 trauma center supported by air medical transport services. METHODS:This is a retrospective cohort study examining 88 trauma patients receiving prehospital TXA to treat suspected hemorrhage. Adult trauma patients who received TXA during the study period and were transported to our level 1 trauma center were included. A panel of trauma surgeons reviewed CT imaging and examination findings to retrospectively identify significant hemorrhage. RESULTS:Forty-three percent of patients who received TXA during air medical transport did not have confirmed hemorrhage upon arrival. CONCLUSION:TXA was given to a significant number of patients who did not have confirmed hemorrhage upon arrival. We recommend that institutions using TXA perform this internal validation to ensure they are accurately identifying hemorrhage in the prehospital setting. 10.1016/j.amj.2021.11.009
    Variations and obstacles in the use of coagulation factor concentrates for major trauma bleeding across Europe: outcomes from a European expert meeting. European journal of trauma and emergency surgery : official publication of the European Trauma Society PURPOSE:Trauma is a leading cause of mortality, with major bleeding and trauma-induced coagulopathy (TIC) contributing to negative patient outcomes. Treatments for TIC include tranexamic acid (TXA), fresh frozen plasma (FFP), and coagulation factor concentrates (CFCs, e.g. prothrombin complex concentrates [PCCs] and fibrinogen concentrate [FCH]). Guidelines for TIC management vary across Europe and a clear definition of TIC is still lacking. METHODS:An advisory board involving European trauma experts was held on 02 February 2019, to discuss clinical experience in the management of trauma-related bleeding and recommendations from European guidelines, focusing on CFC use (mainly FCH). This review summarises the discussions, including TIC definitions, gaps in the guidelines that affect their implementation, and barriers to use of CFCs, with suggested solutions. RESULTS:A definition of TIC, which incorporates clinical (e.g. severe bleeding) and laboratory parameters (e.g. low fibrinogen) is suggested. TIC should be treated immediately with TXA and FCH/red blood cells; subsequently, if fibrinogen ≤ 1.5 g/L (or equivalent by viscoelastic testing), treatment with FCH, then PCC (if bleeding continues) is suggested. Fibrinogen concentrate, and not FFP, should be administered as first-line therapy for TIC. Several initiatives may improve TIC management, with improved medical education of major importance; generation of new and stronger data, simplified clinical practice guidance, and improved access to viscoelastic testing are also critical factors. CONCLUSIONS:Management of TIC is challenging. A standard definition of TIC, together with initiatives to facilitate effective CFC administration, may contribute to improved patient care and outcomes. 10.1007/s00068-020-01563-2
    Prehospital synergy: Tranexamic acid and blood transfusion in patients at risk for hemorrhage. The journal of trauma and acute care surgery BACKGROUND:Growing evidence supports improved survival with prehospital blood products. Recent trials show a benefit of prehospital tranexamic acid (TXA) administration in select subgroups. Our objective was to determine if receiving prehospital packed red blood cells (pRBC) in addition to TXA improved survival in injured patients at risk of hemorrhage. METHODS:We performed a secondary analysis of all scene patients from the Study of Tranexamic Acid during Air and ground Medical Prehospital transport trial. Patients were randomized to prehospital TXA or placebo. Some participating EMS services utilized pRBC. Four resuscitation groups resulted: TXA, pRBC, pRBC+TXA, and neither. Our primary outcome was 30-day mortality and secondary outcome was 24-hour mortality. Cox regression tested the association between resuscitation group and mortality while adjusting for confounders. RESULTS:A total of 763 patients were included. Patients receiving prehospital blood had higher Injury Severity Scores in the pRBC (22 [10, 34]) and pRBC+TXA (22 [17, 36]) groups than the TXA (12 [5, 21]) and neither (10 [4, 20]) groups (p < 0.01). Mortality at 30 days was greatest in the pRBC+TXA and pRBC groups at 18.2% and 28.6% compared with the TXA only and neither groups at 6.6% and 7.4%, respectively. Resuscitation with pRBC+TXA was associated with a 35% reduction in relative hazards of 30-day mortality compared with neither (hazard ratio, 0.65; 95% confidence interval, 0.45-0.94; p = 0.02). No survival benefit was observed in 24-hour mortality for pRBC+TXA, but pRBC alone was associated with a 61% reduction in relative hazards of 24-hour mortality compared with neither (hazard ratio, 0.39; 95% confidence interval, 0.17-0.88; p = 0.02). CONCLUSION:For injured patients at risk of hemorrhage, prehospital pRBC+TXA is associated with reduced 30-day mortality. Use of pRBC transfusion alone was associated with a reduction in early mortality. Potential synergy appeared only in longer-term mortality and further work to investigate mechanisms of this therapeutic benefit is needed to optimize the prehospital resuscitation of trauma patients. LEVEL OF EVIDENCE:Therapeutic/Care Management; Level III. 10.1097/TA.0000000000003620
    The role of tranexamic acid in traumatic brain injury. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Evidence from recent trials evaluating efficacy of antifibrinolytic agents in the context of traumatic brain injury may lead to changes in the management of patients with traumatic brain injury. Tranexamic acid (TXA) reduces the proteolytic action of plasmin on fibrin clots, resulting in an inhibition of fibrinolysis and stabilisation of established blood clots. There has been significant interest in use of the drug as a therapeutic agent in the context of severe haemorrhage; however, considerable controversies regarding its efficacy remain. A number of trials have demonstrated a small but significant decrease in mortality following its administration, but the results have been somewhat inconsistent and may not be generalisable. The results of the CRASH-3 trial were that there was no statistical difference in the number of traumatic brain injury related deaths (18.5% with TXA and 19.8% with placebo; relative risk [RR] 0·94; 95% confidence interval [CI] 0·86-1·02). Nonetheless, there was a subgroup of patients for whom TXA appeared to provide benefit, and this was in patients with mild and moderate injury (with a Glasgow Coma Score > 8). This is potentially a very important finding that may have huge potential implications; however, we believe it does not currently provide indisputable evidence to support the administration of TXA to all patients with TBI. Further work is required to better define the subset of patients who may benefit as well as to evaluate the long-term functional benefit in order to determine which types of severe traumatic brain injury patients would derive more benefits than harms from TXA. 10.1016/j.jocn.2022.02.029
    Tranexamic acid - A narrative review for the emergency medicine clinician. The American journal of emergency medicine INTRODUCTION:Over the last decade, tranexamic acid (TXA) has been incorporated into treatment algorithms for a multitude of emergent conditions and the evidence surrounding its role in emergency medicine continues to evolve. OBJECTIVE:The objective of this literature review is to provide an evidence-based approach to the utilization of TXA in the emergency department. DISCUSSION:The most robust trials suggest TXA may offer a modest improvement in mortality in patients at risk of significant bleeding from trauma, but is not beneficial in spontaneous intracranial hemorrhage or gastrointestinal bleeding. The role of TXA in other clinical scenarios is less clear and requires clinical judgment. CONCLUSION:Tranexamic acid appears to be a reasonable adjunct for the emergency medicine clinician to consider in the management of many hemorrhagic conditions and angiotensin converting enzyme inhibitor-induced angioedema. Additional high-quality research in these areas is needed to further identity patients who may benefit most from TXA. 10.1016/j.ajem.2022.03.027
    Tranexamic acid is not inferior to placebo with respect to adverse events in suspected traumatic brain injury patients not in shock with a normal head computed tomography scan: A retrospective study of a randomized trial. The journal of trauma and acute care surgery BACKGROUND:A 2-g bolus of tranexamic acid (TXA) has been shown to reduce 28-day mortality in a randomized controlled trial. This study investigates whether out-of-hospital TXA use is associated with adverse events or unfavorable outcomes in suspected traumatic brain injury (TBI) when intracranial hemorrhage (ICH) is absent on initial computed tomography. METHODS:This study used data from a 2015 to 2017, multicenter, randomized trial studying the effect of the following TXA doses on moderate to severe TBI: 2-g bolus, 1-g bolus plus 1-g infusion over 8 hours, and a placebo bolus with placebo infusion. Of the 966 participants enrolled, 395 with an initial computed tomography negative for ICH were included in this analysis. Fifteen adverse events (28-day incidence) were studied: myocardial infarction, deep vein thrombosis, seizure, pulmonary embolism, acute respiratory distress syndrome, cardiac failure, liver failure, renal failure, cerebrovascular accident, cardiac arrest, cerebral vasospasm, "any thromboembolism," hypernatremia, acute kidney injury, and infection. Other unfavorable outcomes analyzed include mortality at 28 days and 6 months, Glasgow Outcome Scale-Extended score of ≤4 at discharge and 6 months, intensive care unit-free days, ventilator-free days, hospital-free days, and combined unfavorable outcomes. In both study drug groups, the incidence of dichotomous outcomes and quantity of ordinal outcomes were compared with placebo. RESULTS:No statistically significant increase in adverse events or unfavorable outcomes was found between either TXA dosing regimen and placebo. Demographics and injury scores were not statistically different other than two methods of injury, which were overrepresented in the 1-g TXA bolus plus 1-g TXA infusion. CONCLUSION:Administration of either a 2-g TXA bolus or a 1-g TXA bolus plus 1-g TXA 8-hour infusion in suspected TBIs without ICH is not associated with increased adverse events or unfavorable outcomes. Because the out-of-hospital 2-g bolus is associated with a mortality benefit, it should be administered in suspected TBI. LEVEL OF EVIDENCE:Therapeutic/Care Management; Level II. 10.1097/TA.0000000000003635
    Resuscitation with blood products in patients with trauma-related haemorrhagic shock receiving prehospital care (RePHILL): a multicentre, open-label, randomised, controlled, phase 3 trial. The Lancet. Haematology BACKGROUND:Time to treatment matters in traumatic haemorrhage but the optimal prehospital use of blood in major trauma remains uncertain. We investigated whether use of packed red blood cells (PRBC) and lyophilised plasma (LyoPlas) was superior to use of 0·9% sodium chloride for improving tissue perfusion and reducing mortality in trauma-related haemorrhagic shock. METHODS:Resuscitation with pre-hospital blood products (RePHILL) is a multicentre, allocation concealed, open-label, parallel group, randomised, controlled, phase 3 trial done in four civilian prehospital critical care services in the UK. Adults (age ≥16 years) with trauma-related haemorrhagic shock and hypotension (defined as systolic blood pressure <90 mm Hg or absence of palpable radial pulse) were assessed for eligibility by prehospital critial care teams. Eligible participants were randomly assigned to receive either up to two units each of PRBC and LyoPlas or up to 1 L of 0·9% sodium chloride administered through the intravenous or intraosseous route. Sealed treatment packs which were identical in external appearance, containing PRBC-LyoPlas or 0·9% sodium chloride were prepared by blood banks and issued to participating sites according to a randomisation schedule prepared by the co-ordinating centre (1:1 ratio, stratified by site). The primary outcome was a composite of episode mortality or impaired lactate clearance, or both, measured in the intention-to-treat population. This study is completed and registered with ISRCTN.com, ISRCTN62326938. FINDINGS:From Nov 29, 2016 to Jan 2, 2021, prehospital critical care teams randomly assigned 432 participants to PRBC-LyoPlas (n=209) or to 0·9% sodium chloride (n=223). Trial recruitment was stopped before it achieved the intended sample size of 490 participants due to disruption caused by the COVID-19 pandemic. The median follow-up was 9 days (IQR 1 to 34) for participants in the PRBC-LyoPlas group and 7 days (0 to 31) for people in the 0·9% sodium chloride group. Participants were mostly white (62%) and male (82%), had a median age of 38 years (IQR 26 to 58), and were mostly involved in a road traffic collision (62%) with severe injuries (median injury severity score 36, IQR 25 to 50). Before randomisation, participants had received on average 430 mL crystalloid fluids and tranexamic acid (90%). The composite primary outcome occurred in 128 (64%) of 199 participants randomly assigned to PRBC-LyoPlas and 136 (65%) of 210 randomly assigned to 0·9% sodium chloride (adjusted risk difference -0·025% [95% CI -9·0 to 9·0], p=0·996). The rates of transfusion-related complications in the first 24 h after ED arrival were similar across treatment groups (PRBC-LyoPlas 11 [7%] of 148 compared with 0·9% sodium chloride nine [7%] of 137, adjusted relative risk 1·05 [95% CI 0·46-2·42]). Serious adverse events included acute respiratory distress syndrome in nine (6%) of 142 patients in the PRBC-LyoPlas group and three (2%) of 130 in 0·9% sodium chloride group, and two other unexpected serious adverse events, one in the PRBC-LyoPlas (cerebral infarct) and one in the 0·9% sodium chloride group (abnormal liver function test). There were no treatment-related deaths. INTERPRETATION:The trial did not show that prehospital PRBC-LyoPlas resuscitation was superior to 0·9% sodium chloride for adult patients with trauma related haemorrhagic shock. Further research is required to identify the characteristics of patients who might benefit from prehospital transfusion and to identify the optimal outcomes for transfusion trials in major trauma. The decision to commit to routine prehospital transfusion will require careful consideration by all stakeholders. FUNDING:National Institute for Health Research Efficacy and Mechanism Evaluation. 10.1016/S2352-3026(22)00040-0
    Effect of age on the efficacy of tranexamic acid: An analysis of heterogeneity of treatment effect within the CRASH-2 dataset. The American journal of emergency medicine BACKGROUND:Trauma is a major cause of morbidity and mortality in older adults and will become more common as the population ages. Tranexamic acid (TXA) is a lysine analogue frequently used in the setting of significant trauma with hemorrhage. The aim of this study is to investigate the heterogeneity of treatment effect of TXA as it relates to patient age during trauma care. METHODS:We included patients from the CRASH-2 trial who were randomized within 3 h of injury. Patients were stratified into age groups <26 years, 26 to 35 years, 36 to 45 years, 46 to 55 years, and >55 years. Multiple logistic regression models were utilized to evaluate adjusted odds ratios (OR) with 95% confidence intervals (CI) for mortality. Heterogeneity of treatment effect was evaluated using Akaike and Bayesian information criteria to determine the optimum logistic regression model after which a Wald Chi-square test was utilized to evaluate statistical significance. RESULTS:On univariate analysis, TXA administration decreased mortality within the <26 years cohort (decrease of 2.1%, 95% CI 0.2 to 4.0), 46 to 55 years cohort (decrease 6.7%, 95% CI 2.7 to 10.7), and >55 years cohort (decrease of 5.3%, 95% CI 0.4 to 10.3). On adjusted analysis, when compared to the 36 to 45 years cohort, the <26 year cohort experienced a decreased mortality (OR 0.72, 95% CI 0.62 to 0.85) whereas the >55 year cohort experienced increased mortality (OR 1.8, 95% CI 1.5 to 2.2). Assessment for heterogeneity of treatment effect of TXA administration between groups approached but did not reach statistical significance (p = 0.11). CONCLUSIONS:Mortality related to trauma increases with age, however, there does not appear to be heterogeneity of treatment effect for TXA administration among different age groups. 10.1016/j.ajem.2021.12.033
    Prehospital Tranexamic Acid Administration in Injured Patients. JAMA surgery 10.1001/jamasurg.2021.0251
    Tranexamic acid for major trauma patients in Ireland. Walsh Kieran,O'Keeffe Francis,Brent Louise,Mitra Biswadev World journal of emergency medicine BACKGROUND:The Clinical Randomisation of an Anti-fibrinolytic in Significant Hemorrhage-2 (CRASH-2) is the largest randomized control trial (RCT) examining circulatory resuscitation for trauma patients to date and concluded a statistically significant reduction in all-cause mortality in patients administered tranexamic acid (TXA) within 3 hours of injury. Since the publication of CRASH-2, significant geographical variance in the use of TXA for trauma patients exists. This study aims to assess TXA use for major trauma patients with hemorrhagic shock in Ireland after the publication of CRASH-2. METHODS:A retrospective cohort study was conducted using data derived from the Trauma Audit and Research Network (TARN). All injured patients in Ireland between January 2013 and December 2018 who had evidence of hemorrhagic shock on presentation (as defined by systolic blood pressure [SBP] <100 mmHg [1 mmHg=0.133 kPa] and administration of blood products) were eligible for inclusion. Death at hospital discharge was the primary outcome. RESULTS:During the study period, a total of 234 patients met the inclusion criteria. Among injured patients presenting with hemorrhagic shock, 133 (56.8%; 95% confidence interval [] 50.2%-63.3%) received TXA. Of patients that received TXA, a higher proportion of patients presented with shock index >1 (70.68% vs.57.43%) and higher Injury Severity Score (ISS >25; 49.62% vs. 23.76%). Administration of TXA was not associated with mortality at hospital discharge (odds ratio [] 0.86, 95% 0.31-2.38). CONCLUSIONS:Among injured Irish patients presenting with hemorrhagic shock, TXA was administered to 56.8% of patients. Patients administered with TXA were on average more severely injured. However, a mortality benefit could not be demonstrated. 10.5847/wjem.j.1920-8642.2022.003
    Association Between Prehospital Tranexamic Acid Administration and Outcomes of Severe Traumatic Brain Injury. Bossers Sebastiaan M,Loer Stephan A,Bloemers Frank W,Den Hartog Dennis,Van Lieshout Esther M M,Hoogerwerf Nico,van der Naalt Joukje,Absalom Anthony R,Peerdeman Saskia M,Schwarte Lothar A,Boer Christa,Schober Patrick, JAMA neurology Importance:The development and expansion of intracranial hematoma are associated with adverse outcomes. Use of tranexamic acid might limit intracranial hematoma formation, but its association with outcomes of severe traumatic brain injury (TBI) is unclear. Objective:To assess whether prehospital administration of tranexamic acid is associated with mortality and functional outcomes in a group of patients with severe TBI. Design, Setting, and Participants:This multicenter cohort study is an analysis of prospectively collected observational data from the Brain Injury: Prehospital Registry of Outcome, Treatments and Epidemiology of Cerebral Trauma (BRAIN-PROTECT) study in the Netherlands. Patients treated for suspected severe TBI by the Dutch Helicopter Emergency Medical Services between February 2012 and December 2017 were included. Patients were followed up for 1 year after inclusion. Data were analyzed from January 10, 2020, to September 10, 2020. Exposures:Administration of tranexamic acid during prehospital treatment. Main Outcomes and Measures:The primary outcome was 30-day mortality. Secondary outcomes included mortality at 1 year, functional neurological recovery at discharge (measured by Glasgow Outcome Scale), and length of hospital stay. Data were also collected on demographic factors, preinjury medical condition, injury characteristics, operational characteristics, and prehospital vital parameters. Results:A total of 1827 patients were analyzed, of whom 1283 (70%) were male individuals and the median (interquartile range) age was 45 (23-65) years. In the unadjusted analysis, higher 30-day mortality was observed in patients who received prehospital tranexamic acid (odds ratio [OR], 1.34; 95% CI, 1.16-1.55; P < .001), compared with patients who did not receive prehospital tranexamic acid. After adjustment for confounders, no association between prehospital administration of tranexamic acid and mortality was found across the entire cohort of patients. However, a substantial increase in the odds of 30-day mortality persisted in patients with severe isolated TBI who received prehospital tranexamic acid (OR, 4.49; 95% CI, 1.57-12.87; P = .005) and after multiple imputations (OR, 2.05; 95% CI, 1.22-3.45; P = .007). Conclusions and Relevance:This study found that prehospital tranexamic acid administration was associated with increased mortality in patients with isolated severe TBI, suggesting the judicious use of the drug when no evidence for extracranial hemorrhage is present. 10.1001/jamaneurol.2020.4596
    Tranexamic acid in acute traumatic brain injury. Baron Tanya,Novak Alex BMJ evidence-based medicine 10.1136/bmjebm-2019-111319
    Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet (London, England) BACKGROUND:Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. METHODS:We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. FINDINGS:Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82-1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). INTERPRETATION:We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial. FUNDING:UK National Institute for Health Research Health Technology Assessment Programme. 10.1016/S0140-6736(20)30848-5
    Is Tranexamic Acid Associated With Mortality or Multiple Organ Failure Following Severe Injury? Richards Justin E,Fedeles Benjamin T,Chow Jonathan H,Morrison Jonathan J,Renner Corinne,Trinh Anthony T,Schlee Caroline S,Koerner Ken,Grissom Thomas E,Betzold Richard D,Scalea Thomas M,Kozar Rosemary A Shock (Augusta, Ga.) BACKGROUND:Tranexamic acid (TXA) administration is recommended in severely injured trauma patients. We examined TXA administration, admission fibrinolysis phenotypes, and clinical outcomes following traumatic injury and hypothesized that TXA was associated with increased multiple organ failure (MOF). METHODS:Two-year, single-center, retrospective investigation. Inclusion criteria were age ≥ 18 years, Injury Severity Score (ISS) >16, admitted from scene of injury, thromboelastography within 30 min of arrival. Fibrinolysis was evaluated by lysis at 30 min (LY30) and fibrinolysis phenotypes were defined as: Shutdown: LY30 ≤ 0.8%, Physiologic: LY30 0.81-2.9%, Hyperfibrinolysis: LY30 ≥ 3.0%. Primary outcomes were 28-day mortality and MOF. The association of TXA with mortality and MOF was assessed among the entire study population and in each of the fibrinolysis phenotypes. RESULTS:Four hundred twenty patients: 144/420 Shutdown (34.2%), 96/420 Physiologic (22.9%), and 180/410 Hyperfibrinolysis (42.9%). There was no difference in 28-day mortality by TXA administration among the entire study population (P = 0.52). However, there was a significant increase in MOF in patients who received TXA (11/46, 23.9% vs 16/374, 4.3%; P < 0.001). TXA was associated MOF (OR: 3.2, 95% CI 1.2-8.9), after adjusting for confounding variables. There was no difference in MOF in patients who received TXA in the Physiologic (1/5, 20.0% vs 7/91, 7.7%; P = 0.33) group. There was a significant increase in MOF among patients who received TXA in the Shutdown (3/11, 27.3% vs 5/133, 3.8%; P = 0.001) and Hyperfibrinolysis (7/30, 23.3% vs 5/150, 3.3%; P = 0.001) groups. CONCLUSIONS:Administration of TXA following traumatic injury was associated with MOF in the fibrinolysis shutdown and hyperfibrinolysis phenotypes and warrants continued evaluation. 10.1097/SHK.0000000000001608
    Tranexamic acid-loaded hemostatic nanoclay microsphere frameworks. Denry Isabelle,Nédélec Jean-Marie,Holloway Julie A Journal of biomedical materials research. Part B, Applied biomaterials Fast acting topical hemostatic agents play a key role in hemorrhage control. Retarding fibrinolysis is also critical in improving coagulation, thereby expanding chances of survival. The purpose of the present work was to investigate the physical properties, loading capacity and hemostatic efficacy of newly developed nanoclay microsphere frameworks (NMFs) loaded with tranexamic acid (TA), as antifibrinolytic agent. Nanoclay compositions were prepared with increasing levels of TA. Results showed that TA was successfully incorporated into the nanoclay structure and released when solvated with ethanol. Both doped and undoped NMFs significantly decreased activated partial thromboplastin time and increased clot stiffness, which was attributed to significantly thinner fibrin fibers and a denser clot structure. 10.1002/jbm.b.34918
    Temporal Transitions in Fibrinolysis after Trauma: Adverse Outcome Is Principally Related to Late Hypofibrinolysis. Rossetto Andrea,Vulliamy Paul,Lee Kim May,Brohi Karim,Davenport Ross Anesthesiology BACKGROUND:The relationship between late clinical outcomes after injury and early dynamic changes between fibrinolytic states is not fully understood. The authors hypothesized that temporal transitions in fibrinolysis states using rotational thromboelastometry (ROTEM) would aid stratification of adverse late clinical outcomes and improve understanding of how tranexamic acid modulates the fibrinolytic response and impacts mortality. METHODS:The authors conducted a secondary analysis of previously collected data from trauma patients enrolled into an ongoing prospective cohort study (International Standard Randomised Controlled Trial Number [ISRCTN] 12962642) at a major trauma center in the United Kingdom. ROTEM was performed on admission and at 24 h with patients retrospectively grouped into three fibrinolysis categories: tissue factor-activated ROTEM maximum lysis of less than 5% (low); tissue factor-activated ROTEM maximum lysis of 5 to 15% (normal); or tissue factor-activated ROTEM maximum lysis of more than 15% (high). Primary outcomes were multiorgan dysfunction syndrome and 28-day mortality. RESULTS:Seven-hundred thirty-one patients were included: 299 (41%) were treated with tranexamic acid and 432 (59%) were untreated. Two different cohorts with low-maximum lysis at 24 h were identified: (1) severe brain injury and (2) admission shock and hemorrhage. Multiple organ dysfunction syndrome was greatest in those with low-maximum lysis on admission and at 24 h, and late mortality was four times higher than in patients who remained normal during the first 24 h (7 of 42 [17%] vs. 9 of 223 [4%]; P = 0.029). Patients that transitioned to or remained in low-maximum lysis had increased odds of organ dysfunction (5.43 [95% CI, 1.43 to 20.61] and 4.85 [95% CI, 1.83 to 12.83], respectively). Tranexamic acid abolished ROTEM hyperfibrinolysis (high) on admission, increased the frequency of persistent low-maximum lysis (67 of 195 [34%]) vs. 8 of 79 [10%]; P = 0.002), and was associated with reduced early mortality (28 of 195 [14%] vs. 23 of 79 [29%]; P = 0.015). No increase in late deaths, regardless of fibrinolysis transition patterns, was observed. CONCLUSIONS:Adverse late outcomes are more closely related to 24-h maximum lysis, irrespective of admission levels. Tranexamic acid alters early fibrinolysis transition patterns, but late mortality in patients with low-maximum lysis at 24 h is not increased. EDITOR’S PERSPECTIVE: 10.1097/ALN.0000000000004036
    Efficacy and safety of the second in-hospital dose of tranexamic acid after receiving the prehospital dose: double-blind randomized controlled clinical trial in a level 1 trauma center. El-Menyar Ayman,Ahmed Khalid,Hakim Suhail,Kanbar Ahad,Mathradikkal Saji,Siddiqui Tariq,Jogol Hisham,Younis Basil,Taha Ibrahim,Mahmood Ismail,Ajaj Ahmed,Atique Sajid,Alaieb Abubaker,Bahey Ahmed Abdel-Aziz,Asim Mohammad,Alinier Guillaume,Castle Nicholas R,Mekkodathil Ahammed,Rizoli Sandro,Al-Thani Hassan European journal of trauma and emergency surgery : official publication of the European Trauma Society BACKGROUND:Prehospital administration of tranexamic acid (TXA) to injured patients is increasing worldwide. However, optimal TXA dose and need of a second infusion on hospital arrival remain undetermined. We investigated the efficacy and safety of the second in-hospital dose of TXA in injured patients receiving 1 g of TXA in the prehospital setting. We hypothesized that a second in-hospital dose of TXA improves survival of trauma patients. METHODS:A prospective, double-blind, placebo-controlled randomized, clinical trial included adult trauma patients receiving 1 g of TXA in the prehospital settings. Patients were then blindly randomized to Group I (second 1-g TXA) and Group II (placebo) on hospital arrival. The primary outcome was 24-h (early) and 28-day (late) mortality. Secondary outcomes were thromboembolic events, blood transfusions, hospital length of stay (HLOS) and organs failure (MOF). RESULTS:A total of 220 patients were enrolled, 110 in each group. The TXA and placebo groups had a similar early [OR 1.000 (0.062-16.192); p = 0.47] and late mortality [OR 0.476 (95% CI 0.157-1.442), p = 0.18].The cause of death (n = 15) was traumatic brain injury (TBI) in 12 patients and MOF in 3 patients. The need for blood transfusions in the first 24 h, number of transfused blood units, HLOS, thromboembolic events and multiorgan failure were comparable in the TXA and placebo groups. In seriously injured patients (injury severity score > 24), the MTP activation was higher in the placebo group (31.3% vs 11.10%, p = 0.13), whereas pulmonary embolism (6.9% vs 2.9%, p = 0.44) and late mortality (27.6% vs 14.3%, p = 0.17) were higher in the TXA group but did not reach statistical significance. CONCLUSION:The second TXA dose did not change the mortality rate, need for blood transfusion, thromboembolic complications, organ failure and HLOS compared to a single prehospital dose and thus its routine administration should be revisited in larger and multicenter studies. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03846973. 10.1007/s00068-021-01848-0
    Tranexamic Acid Treatment for Trauma Victims. Roberts Ian,Brenner Amy,Shakur-Still Haleema Seminars in thrombosis and hemostasis Worldwide, traumatic injury is responsible for over 5 million deaths per year, the majority due to exsanguination and head injury. The antifibrinolytic drug tranexamic acid is the only drug proven to reduce deaths after traumatic injury. Several large randomized controlled trials have provided high-quality evidence of its effectiveness and safety in trauma patients. Early tranexamic acid reduces deaths on the day of the injury in polytrauma patients and patients with isolated traumatic brain injury by around 20%. Treatment is time critical; for patients to benefit, tranexamic acid must be given as soon as possible after injury. Intramuscular administration is well tolerated and rapidly absorbed, with the potential to reduce time to treatment. Because the proportional reduction in bleeding death with tranexamic acid does not vary by baseline risk, a wide range of trauma patients stands to benefit. There are far more low-risk trauma patients than high-risk patients, with a substantial proportion of bleeding deaths in the low-risk group. As such, treatment should not be limited to patients with severe traumatic hemorrhage. We must give paramedics and physicians the confidence to treat a far wider range of trauma patients while emphasizing the importance of early treatment. 10.1055/s-0041-1725097
    Tranexamic acid use in severely injured patients, is it always appropriate? Duque P,Gonzalez-Zarco L,Martínez R,Gago S,Varela J A Revista espanola de anestesiologia y reanimacion Recently, it has been suggested that tranexamic acid should be administered only in those patients with hyperfibrinolysis determined using viscoelastic assays, as severely injured patients may present with fibrinolytic shutdown. However the last European guidelines on management of major bleeding and coagulopathy following trauma endorse the use of tranexamic acid to the trauma patient who is bleeding or at risk of significant hemorrhage as soon as possible without waiting for viscoelastic results. We present a severely blunt trauma patient treated with on-scene administration of tranexamic acid that developed immediate pulmonary embolism. 10.1016/j.redare.2020.06.016
    Transfusion strategies in bleeding critically ill adults: a clinical practice guideline from the European Society of Intensive Care Medicine. Intensive care medicine PURPOSE:To develop evidence-based clinical practice recommendations regarding transfusion practices and transfusion in bleeding critically ill adults. METHODS:A taskforce involving 15 international experts and 2 methodologists used the GRADE approach to guideline development. The taskforce addressed three main topics: transfusion support in massively and non-massively bleeding critically ill patients (transfusion ratios, blood products, and point of care testing) and the use of tranexamic acid. The panel developed and answered structured guideline questions using population, intervention, comparison, and outcomes (PICO) format. RESULTS:The taskforce generated 26 clinical practice recommendations (2 strong recommendations, 13 conditional recommendations, 11 no recommendation), and identified 10 PICOs with insufficient evidence to make a recommendation. CONCLUSIONS:This clinical practice guideline provides evidence-based recommendations for the management of massively and non-massively bleeding critically ill adult patients and identifies areas where further research is needed. 10.1007/s00134-021-06531-x
    The effect of prehospital tranexamic acid on outcome in polytrauma patients with associated severe brain injury. European journal of trauma and emergency surgery : official publication of the European Trauma Society INTRODUCTION:Tranexamic acid (TXA) has shown to be beneficial in selected patients with hemorrhagic shock. Recently, TXA has gained interest in isolated traumatic brain injury (TBI) patients with variable results. There are limited data on TXA in polytrauma with associated TBI. This study investigated the role of TXA in severely injured patients with associated severe TBI. METHODS:A 7.5-year prospective cohort study was performed to investigate the relation between prehospital TXA and mortality in consecutive trauma patients with associated severe TBI (Abbreviated Injury Scale (AIS)head ≥ 3) admitted to a Level-1 Trauma Center ICU. Indication for prehospital TXA administration was (suspicion of) hemorrhagic shock, and/or systolic blood pressure (SBP) ≤ 90 mmHg. Demographics, data on physiology, resuscitation, and outcomes were prospectively collected. RESULTS:Two hundred thirty-four patients (67% males) with median age of 49 years and ISS 33 (98% blunt injuries) were included. Thirteen patients (6%) developed thromboembolic complications; mortality rate was 24%. Fifty-one percent of patients received prehospital TXA. TXA patients were younger, had more deranged physiology on arrival, and received more crystalloids and blood products ≤ 24 h. There was, however, no difference in overall outcome between TXA patients and no-TXA patients. CONCLUSIONS:Despite having a more deranged physiology TXA patients had similar outcome compared to no-TXA patients who were much older. Thromboembolic complication rate was low. Prehospital tranexamic acid has no evident effect on outcome in polytrauma patients with associated critical brain injury. 10.1007/s00068-021-01827-5
    Tranexamic acid for head injuries: on the CRASH-3 trial. Emergencias : revista de la Sociedad Espanola de Medicina de Emergencias
    Tranexamic acid for ACE inhibitor induced angioedema - A case report. Wang Kellie,Geiger Haden,McMahon Andre The American journal of emergency medicine Tranexamic acid (TXA) is an antifibrinolytic agent which inhibits conversion of plasminogen to plasmin, a key step in kallikrein activation and bradykinin formation. Tranexamic acid is used in prophylactic management of hereditary angioedema; however, evidence for TXA in angiotensin converting enzyme (ACE) inhibitor-induced angioedema (ACEI-AE) is limited. We describe a patient who presented to the emergency department with ACEI-AE who was successfully treated with TXA. This case suggests that TXA may be a beneficial treatment modality in the management of ACEI-AE and warrants further investigation. 10.1016/j.ajem.2020.10.029
    Tranexamic acid administration in the field does not affect admission thromboelastography after traumatic brain injury. Dixon Alexandra L,McCully Belinda H,Rick Elizabeth A,Dewey Elizabeth,Farrell David H,Morrison Laurie J,McMullan Jason,Robinson Bryce R H,Callum Jeannie,Tibbs Brian,Dries David J,Jui Jonathan,Gandhi Rajesh R,Garrett John S,Weisfeldt Myron L,Wade Charles E,Aufderheide Tom P,Frascone Ralph J,Tallon John M,Kannas Delores,Williams Carolyn,Rowell Susan E,Schreiber Martin A The journal of trauma and acute care surgery BACKGROUND:No Food and Drug Administration-approved medication improves outcomes following traumatic brain injury (TBI). A forthcoming clinical trial that evaluated the effects of two prehospital tranexamic acid (TXA) dosing strategies compared with placebo demonstrated no differences in thromboelastography (TEG) values. We proposed to explore the impact of TXA on markers of coagulation and fibrinolysis in patients with moderate to severe TBI. METHODS:Data were extracted from a placebo-controlled clinical trial in which patients 15 years or older with TBI (Glasgow Coma Scale, 3-12) and systolic blood pressure of ≥90 mm Hg were randomized prehospital to receive placebo bolus/placebo infusion (placebo), 1 g of TXA bolus/1 g of TXA infusion (bolus maintenance), or 2 g of TXA bolus/placebo infusion (bolus only). Thromboelastography was performed, and coagulation measures including prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, D-dimer, plasmin-antiplasmin (PAP), thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were quantified at admission and 6 hours later. RESULTS:Of 966 patients receiving study drug, 700 had laboratory tests drawn at admission and 6 hours later. There were no statistically significant differences in TEG values, including LY30, between groups (p > 0.05). No differences between prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were demonstrated across treatment groups. Concentrations of D-dimer in TXA treatment groups were less than placebo at 6 hours (p < 0.001). Concentrations of PAP in TXA treatment groups were less than placebo on admission (p < 0.001) and 6 hours (p = 0.02). No differences in D-dimer and PAP were observed between bolus maintenance and bolus only. CONCLUSION:While D-dimer and PAP levels reflect a lower degree of fibrinolysis following prehospital administration of TXA when compared with placebo in a large prehospital trial of patients with TBI, TEG obtained on admission and 6 hours later did not demonstrate any differences in fibrinolysis between the two TXA dosing regimens and placebo. LEVEL OF EVIDENCE:Diagnostic test, level III. 10.1097/TA.0000000000002932
    Effect of tranexamic acid on thrombotic events and seizures in bleeding patients: a systematic review and meta-analysis. Murao Shuhei,Nakata Hidekazu,Roberts Ian,Yamakawa Kazuma Critical care (London, England) BACKGROUND:Tranexamic acid (TXA) reduces surgical bleeding and reduces death from bleeding after trauma and childbirth. However, its effects on thrombotic events and seizures are less clear. We conducted a systematic review and meta-analysis to examine the safety of TXA in bleeding patients. METHODS:For this systematic review and meta-analysis, we searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled trials from inception until June 1, 2020. We included randomized trials comparing intravenous tranexamic acid and placebo or no intervention in bleeding patients. The primary outcomes were thrombotic events, venous thromboembolism, acute coronary syndrome, stroke and seizures. A meta-analysis was performed using a random effects model and meta-regression analysis was performed to evaluate how effects vary by dose. We assessed the certainty of evidence using the grading of recommendations, assessment, development and evaluations (GRADE) approach. RESULTS:A total of 234 studies with 102,681 patients were included in the meta-analysis. In bleeding patients, there was no evidence that TXA increased the risk of thrombotic events (RR = 1.00 [95% CI 0.93-1.08]), seizures (1.18 [0.91-1.53]), venous thromboembolism (1.04 [0.92-1.17]), acute coronary syndrome (0.88 [0.78-1.00]) or stroke (1.12 [0.98-1.27]). In a dose-by-dose sensitivity analysis, seizures were increased in patients receiving more than 2 g/day of TXA (3.05 [1.01-9.20]). Meta-regression showed an increased risk of seizures with increased dose of TXA (p = 0.011). CONCLUSION:Tranexamic acid did not appear to increase the risk of thrombotic events in bleeding patients. However, because there may be dose-dependent increase in the risk of seizures, very high doses should be avoided. 10.1186/s13054-021-03799-9
    Tranexamic Acid for Adult Patients with Spontaneous Intracerebral Hemorrhage: A Systematic Review with Meta-analysis. Wang Xing,Ma Lu,Song Jinlei,You Chao CNS drugs BACKGROUND:The effects of tranexamic acid on spontaneous intracerebral hemorrhage in reducing hematoma expansion and mortality as well as its role in thromboembolic complications and in the improvement of functional outcomes remain substantially uncertain. OBJECTIVE:The objective of this systematic review was to evaluate the efficacy and safety of tranexamic acid in patients with spontaneous intracerebral hemorrhage. METHODS:Several databases were searched from inception up to 20 June, 2021. We included randomized controlled trials that compared tranexamic acid with placebo or no treatment for the management of intracerebral hemorrhage. The primary outcomes were hematoma expansion and 90-day mortality. The secondary outcomes were hemorrhagic volume change, thromboembolic complications, and functional outcomes. RESULTS:Overall, six trials with 2800 patients were included in this meta-analysis. Tranexamic acid was associated with a reduced risk of hematoma expansion (relative risk 0.87, 95% confidence interval [CI] 0.77-0.99, p = 0.03, I = 0%, six trials with 2800 participants) and a lessening of hematoma volume change (mean difference - 1.28, 95% CI - 2.44 to - 0.12; p = 0.03; I = 0%, four trials with 2626 participants), without a corresponding higher rate of major thromboembolic complications (relative risk 1.20, 95% CI 0.85-1.69; p = 0.80; I = 0%, five trials with 2759 participants). The present analysis also demonstrated that tranexamic acid had no effect on reducing 90-day mortality (relative risk 1.02, 95% CI 0.88-1.19; p = 0.80; I = 0%, five trials with 2770 participants). CONCLUSIONS:In adults with spontaneous intracerebral hemorrhage, tranexamic acid reduced the risk of intracerebral hemorrhage growth compared with the control. The effects on 90-day mortality remained inconclusive. Further studies should report death within 24 h and death due to bleeding whenever possible. 10.1007/s40263-021-00865-2
    Use of Tranexamic Acid in Traumatic Resuscitation in a Prehospital Setting: A Case Report. Lima Lilyan Paula de Sousa Teixeira,Santos Paulo Regis Souza,Martins Herberth Jessie,Rodrigues Daniel Augusto de Souza,Silva Larissa Michetti,Libardi Mônica Beatriz Ortolan,Azevedo Nathan Almeida Milward Air medical journal This study describes the use of tranexamic acid associated with other measures in the initial approach to contain bleeding in a situation of hemorrhagic shock in a trauma patient. The case describes the care of a young man with multiple thorax punctures by a melee weapon, quickly progressing to a condition of severe shock, in addition to the action of a helicopter emergency medical team supporting the patient's transportation from a low-complexity emergency care unit to a specialized unit. 10.1016/j.amj.2021.05.010
    Safety and efficacy of thromboelastography guidance of antifibrinolytic therapy in trauma patients: An observational cohort analysis. International journal of critical illness and injury science BACKGROUND:Tranexamic acid (TXA) is an antifibrinolytic therapy intended to decrease blood loss and improve hemostasis in traumatic hemorrhage. Viscoelastic assays, such as thromboelastography (TEG), allow for the identification of a patient's specific hemostasis. The purpose of this research study was to explore the safety and efficacy of TEG-guided antifibrinolytic therapy in trauma patients. METHODS:This study was a retrospective review of trauma patients meeting institution-specific inclusion criteria for TXA. Patients were assigned to fibrinolytic groups per TEG LY30 data. Safety outcomes (24-h mortality, overall in-hospital mortality, and thromboembolic events) were compared between patients who did or did not receive TXA and within fibrinolytic groups. Mortality outcomes were adjusted for baseline Injury Severity Score (ISS). Secondary aims included blood product utilization, length of hospital, and intensive care unit stay. RESULTS:Hypofibrinolysis was the most common fibrinolytic phenotype. Adjusting for ISS, there were no significant differences in mortality. A 30.7% thromboembolism incidence was identified in the TXA group compared to 16.6% not receiving TXA ( = 0.26), with 72.7% of these patients experiencing fibrinolytic shutdown. CONCLUSIONS:There were no differences in 24-h mortality, all-cause mortality, or secondary outcomes. The difference in thromboembolic rates between patients receiving TXA and those who did not, while not statistically significant, poses clinical concern. 10.4103/IJCIIS.IJCIIS_79_20
    The impact of prehospital TXA on mortality among bleeding trauma patients: A systematic review and meta-analysis. Almuwallad Ateeq,Cole Elaine,Ross Jennifer,Perkins Zane,Davenport Ross The journal of trauma and acute care surgery BACKGROUND:Tranexamic acid (TXA) is an antifibrinolytic drug associated with improved survival among trauma patients with hemorrhage. Tranexamic acid is considered a primary hemostatic intervention in prehospital for treatment of bleeding alongside blood product transfusion. METHODS:A systematic review and meta-analysis was conducted to investigate the impact of prehospital TXA on mortality among trauma patients with bleeding. A systematic search was conducted using the National Institute for Health and Care Excellence Healthcare Databases Advanced Search library which contain the following of databases: EMBASE, Medline, PubMed, BNI, EMCARE, and HMIC. Other databases searched included SCOPUS and the Cochrane Central Register for Clinical Trials Library. Quality assessment tools were applied among included studies; Cochrane Risk of Bias for randomized control trials and Newcastle-Ottawa Scale for cohort observational studies. RESULTS:A total of 797 publications were identified from the initial database search. After removing duplicates and applying inclusion/exclusion criteria, four studies were included in the review and meta-analysis which identified a significant survival benefit in patients who received prehospital TXA versus no TXA. Three observational cohort and one randomized control trial were included into the review with a total of 2,347 patients (TXA, 1,169 vs. no TXA, 1,178). There was a significant reduction in 24 hours mortality; odds ratio (OR) of 0.60 (95% confidence interval [CI], 0.37-0.99). No statistical significant differences in 28 days to 30 days mortality; OR of 0.69 (95% CI, 0.47-1.02), or venous thromboembolism OR of 1.49 (95% CI, 0.90-2.46) were found. CONCLUSION:This review demonstrates that prehospital TXA is associated with significant reductions in the early (24 hour) mortality of trauma patients with suspected or confirmed hemorrhage but no increase in the incidence of venous thromboembolism. LEVEL OF EVIDENCE:Systematic review and meta-analysis. Level I. 10.1097/TA.0000000000003120
    Tranexamic acid and the risk of delirium after isolated "on-pump" coronary artery bypass grafting: A propensity score modeled analysis in 3392 patients. Hulde Nikolai,Zittermann Armin,Gummert Jan F,von Dossow Vera,Koster Andreas Journal of clinical anesthesia 10.1016/j.jclinane.2021.110426
    Thromboelastometry assessment of the effects of fibrinogen, activated prothrombin complex concentrate, and tranexamic acid on clot formation and fibrinolysis in a model of trauma-induced coagulopathy. Budnik Ivan,Shenkman Boris,Morozova Olga,Einav Yulia European journal of trauma and emergency surgery : official publication of the European Trauma Society PURPOSE:Coagulation abnormalities are common following major trauma. The aim of this study was to assess the improvement of trauma-induced coagulopathy (TIC) in an in vitro model. METHODS:TIC was created on blood taken from healthy individuals by inducing hemodilution, acidosis, hypothermia and fibrinolysis. Next, blood samples were subjected to rotational thromboelastometry to assess the effect of hemostasis modulators on blood coagulation and fibrinolysis. RESULTS:Introducing to blood fibrinogen at 0.75 mg/mL, prothrombin complex concentrate at 0.66 IU/mL or tranexamic acid at 95 µg/mL increased clot strength. Higher effect was observed by combination of fibrinogen with tranexamic acid and prothrombin complex with tranexamic acid, whereas the maximal effect was achieved using all agents together. Fibrinolysis was inhibited by tranexamic acid and stronger by triple combination of the agents. Selective treating the TIC blood with fibrinogen, prothrombin complex or tranexamic acid at two time lower concentrations did not affect clot strength. Combining fibrinogen with prothrombin complex or with tranexamic acid stimulated clot strength but at lower extent compared to higher concentrations. Lysis onset time was prolonged by tranexamic acid. Maximal effect on both clot formation and fibrinolysis was achieved using all three agents together. CONCLUSIONS:Blood clotting stimulation and fibrinolysis inhibition in the TIC model was enough combining subthreshold concentrations of fibrinogen, prothrombin complex and tranexamic acid. Further experiments are warranted in both in vitro and in vivo conditions with minimally effective concentrations of both pro-coagulant and anti-fibrinolytic drugs assuming that this combinatorial approach may not only improve coagulopathy but also minimize the risk of thrombotic complications. 10.1007/s00068-019-01283-2
    Importance of the Assessment Time Window for Intravenous Tranexamic Acid and Thromboembolic Events. Sentilhes Loïc,Mattuizzi Aurélien,Deneux-Tharaux Catherine JAMA surgery 10.1001/jamasurg.2021.4138
    Effect of tranexamic acid on intracranial haemorrhage and infarction in patients with traumatic brain injury: a pre-planned substudy in a sample of CRASH-3 trial patients. Mahmood Abda,Needham Kelly,Shakur-Still Haleema,Harris Tim,Jamaluddin Sabariah Faizah,Davies David,Belli Antonio,Mohamed Fatahul Laham,Leech Caroline,Lotfi Hamzah Mohd,Moss Phil,Lecky Fiona,Hopkins Philip,Wong Darin,Boyle Adrian,Wilson Mark,Darwent Melanie,Roberts Ian Emergency medicine journal : EMJ BACKGROUND:Early tranexamic acid (TXA) treatment reduces head injury deaths after traumatic brain injury (TBI). We used brain scans that were acquired as part of the routine clinical practice during the CRASH-3 trial (before unblinding) to examine the mechanism of action of TXA in TBI. Specifically, we explored the potential effects of TXA on intracranial haemorrhage and infarction. METHODS:This is a prospective substudy nested within the CRASH-3 trial, a randomised placebo-controlled trial of TXA (loading dose 1 g over 10 min, then 1 g infusion over 8 hours) in patients with isolated head injury. CRASH-3 trial patients were recruited between July 2012 and January 2019. Participants in the current substudy were a subset of trial patients enrolled at 10 hospitals in the UK and 4 in Malaysia, who had at least one CT head scan performed as part of the routine clinical practice within 28 days of randomisation. The primary outcome was the volume of intraparenchymal haemorrhage (ie, contusion) measured on a CT scan done after randomisation. Secondary outcomes were progressive intracranial haemorrhage (post-randomisation CT shows >25% of volume seen on pre-randomisation CT), new intracranial haemorrhage (any haemorrhage seen on post-randomisation CT but not on pre-randomisation CT), cerebral infarction (any infarction seen on any type of brain scan done post-randomisation, excluding infarction seen pre-randomisation) and intracranial haemorrhage volume (intraparenchymal + intraventricular + subdural + epidural) in those who underwent neurosurgical haemorrhage evacuation. We planned to conduct sensitivity analyses excluding patients who were severely injured at baseline. Dichotomous outcomes were analysed using relative risks (RR) or hazard ratios (HR), and continuous outcomes using a linear mixed model. RESULTS:1767 patients were included in this substudy. One-third of the patients had a baseline GCS (Glasgow Coma Score) of 3 (n=579) and 24% had unilateral or bilateral unreactive pupils. 46% of patients were scanned pre-randomisation and post-randomisation (n=812/1767), 19% were scanned only pre-randomisation (n=341/1767) and 35% were scanned only post-randomisation (n=614/1767). In all patients, there was no evidence that TXA prevents intraparenchymal haemorrhage expansion (estimate=1.09, 95% CI 0.81 to 1.45) or intracranial haemorrhage expansion in patients who underwent neurosurgical haemorrhage evacuation (n=363) (estimate=0.79, 95% CI 0.57 to 1.11). In patients scanned pre-randomisation and post-randomisation (n=812), there was no evidence that TXA reduces progressive haemorrhage (adjusted RR=0.91, 95% CI 0.74 to 1.13) and new haemorrhage (adjusted RR=0.85, 95% CI 0.72 to 1.01). When patients with unreactive pupils at baseline were excluded, there was evidence that TXA prevents new haemorrhage (adjusted RR=0.80, 95% CI 0.66 to 0.98). In patients scanned post-randomisation (n=1431), there was no evidence of an increase in infarction with TXA (adjusted HR=1.28, 95% CI 0.93 to 1.76). A larger proportion of patients without (vs with) a post-randomisation scan died from head injury (38% vs 19%: RR=1.97, 95% CI 1.66 to 2.34, p<0.0001). CONCLUSION:TXA may prevent new haemorrhage in patients with reactive pupils at baseline. This is consistent with the results of the CRASH-3 trial which found that TXA reduced head injury death in patients with at least one reactive pupil at baseline. However, the large number of patients without post-randomisation scans and the possibility that the availability of scan data depends on whether a patient received TXA, challenges the validity of inferences made using routinely collected scan data. This study highlights the limitations of using routinely collected scan data to examine the effects of TBI treatments. TRIAL REGISTRATION NUMBER:ISRCTN15088122. 10.1136/emermed-2020-210424
    Emerging approaches to pre-hospital hemorrhage control: a narrative review. Jamal Leila,Saini Aman,Quencer Keith,Altun Izzet,Albadawi Hassan,Khurana Aditya,Naidu Sailendra,Patel Indravadan,Alzubaidi Sadeer,Oklu Rahmi Annals of translational medicine In the United States, trauma claims the lives of over 150,000 civilians each year. In military settings, trauma and exsanguination result in 50% of combat related deaths. The majority of these deaths result from uncontrolled non-compressible hemorrhage. Non-compressible hemorrhage often results from deep vascular injuries within the torso, however can also occur secondary to penetrating injuries that involve the extremities. Given the high mortality rates for non-compressible hemorrhage, rapid and effective management of patients suffering from hemorrhage is essential to good patient outcomes. Consequently, there has been increasing interest in solutions for point-of-injury hemorrhage control in trauma and military medicine. Undoubtedly there is a great need for prehospital hemostatic interventions that can be deployed by trained and untrained personnel. Since 2001, various hemostatic agents have been developed, each with its advantages based upon the type and severity of injury, wound size, wound location, accessibility to injury site, and the coagulation status of the patient. These agents are often used in the military setting as a temporizing measure prior to definitive therapy and include techniques such as resuscitative endovascular balloon occlusion of the aorta (REBOA) and bioengineered agents including ResQFoam, RevMedx's XSTAT, Tranexamic acid (TXA), and QuikClot Combat Gauze (QCG). Here, we review the indications, composition, technique, efficacy, and outcomes of these hemostatic agents. 10.21037/atm-20-5452
    Tranexamic acid for subarachnoid haemorrhage - Authors' reply. Post René,Germans Menno R,Vandertop W Peter,Verbaan Dagmar Lancet (London, England) 10.1016/S0140-6736(21)00574-2
    Prehospital tranexamic acid: READY for primetime? Nemeth Joe,Ackery Alun,de Champlain François CJEM 10.1007/s43678-021-00093-z
    The efficacy of tranexamic acid for brain injury. Kawada Tomoyuki The American journal of emergency medicine 10.1016/j.ajem.2020.07.048
    Tranexamic acid to reduce operative blood loss in brain tumor surgery: A meta-analysis. Surgical neurology international BACKGROUND:Major blood loss during neurosurgery may result in a variety of complications, such as potentially fatal hemodynamic instability. Brain tumor and skull base surgery is among the high bleeding risk procedures. Tranexamic acid (TXA) has been found to reduce bleeding events in various fields of medicine. METHODS:We searched for all randomized controlled trials published in English or Bahasa which compared the use of TXA with placebo in brain tumor surgery. The studies should include adult patients with intracranial tumor who received TXA before skin incision. The primary and secondary outcomes are intraoperative blood loss and the need of transfusion. RESULTS:This meta-analysis included a total of 200 patients from three studies. TXA resulted in less blood loss with pooled mean difference of -292.80 (95% CI, -431.63, -153.96, <0.05). The need of transfusion was not significant between TXA and control group (pooled mean difference -85.36, 95% CI, -213.23 - (42.51), P=0.19). CONCLUSION:TXA reduced the volume of blood loss but did not reduce the need of blood transfusion. 10.25259/SNI_19_2021
    Tranexamic acid for subarachnoid haemorrhage. Jimenez Adrian E,Khalafallah Adham M,Mukherjee Debraj Lancet (London, England) 10.1016/S0140-6736(21)00573-0
    Tranexamic acid in non-traumatic intracranial bleeding: a systematic review and meta-analysis. Bouillon-Minois Jean-Baptiste,Croizier Carolyne,Baker Julien S,Pereira Bruno,Moustafa Farès,Outrey Justin,Schmidt Jeannot,Peschanski Nicolas,Dutheil Frédéric Scientific reports Non-traumatic intracranial bleeding (NTIB), comprising subarachnoid hemorrhage (SAH) and intra-cranial bleeding (ICH) is a significant public health concern. Tranexamic acid (TXA) is a promising treatment with benefits yet to be fully demonstrated. We conducted a systematic review and meta-analysis on the impact of TXA on mortality in NTIB. We searched the PubMed, Cochrane Library, Google Scholar and ScienceDirect databases for studies reporting mortality data following the use of TXA in NTIB for comparisons with a control group. We computed random-effect meta-analysis on estimates of risk and sensitivity analyses. We computed meta-regression to examine the putative effects of the severity of NTIB, sociodemographic data (age, sex), and publication date. Among potentially 10,008 articles, we included 15 studies representing a total of 4883 patients: 2455 receiving TXA and 2428 controls; 1110 died (23%) during the follow-up. The meta-analysis demonstrated a potential of 22% decrease in mortality for patients treated by TXA (RR = 0.78, 95%CI 0.58-0.98, p = 0.002). Meta-regression did not demonstrate any influence of the severity of NTIB, age, sex, length of treatment or date of publication. Sensitivity analyses confirmed benefits of TXA on mortality. TXA appears to be a therapeutic option to reduce non-traumatic intracranial bleeding mortality, particularly in patients with SAH. 10.1038/s41598-021-94727-y
    The impact of prehospital tranexamic acid on mortality and transfusion requirements: match-pair analysis from the nationwide German TraumaRegister DGU®. Imach Sebastian,Wafaisade Arasch,Lefering Rolf,Böhmer Andreas,Schieren Mark,Suárez Victor,Fröhlich Matthias, Critical care (London, England) BACKGROUND:Outcome data about the use of tranexamic acid (TXA) in civilian patients in mature trauma systems are scarce. The aim of this study was to determine how severely injured patients are affected by the widespread prehospital use of TXA in Germany. METHODS:The international TraumaRegister DGU® was retrospectively analyzed for severely injured patients with risk of bleeding (2015 until 2019) treated with at least one dose of TXA in the prehospital phase (TXA group). These were matched with patients who had not received prehospital TXA (control group), applying propensity score-based matching. Adult patients (≥ 16) admitted to a trauma center in Germany with an Injury Severity Score (ISS) ≥ 9 points were included. RESULTS:The matching yielded two comparable cohorts (n = 2275 in each group), and the mean ISS was 32.4 ± 14.7 in TXA group vs. 32.0 ± 14.5 in control group (p = 0.378). Around a third in both groups received one dose of TXA after hospital admission. TXA patients were significantly more transfused (p = 0.022), but needed significantly less packed red blood cells (p ≤ 0.001) and fresh frozen plasma (p = 0.023), when transfused. Massive transfusion rate was significantly lower in the TXA group (5.5% versus 7.2%, p = 0.015). Mortality was similar except for early mortality after 6 h (p = 0.004) and 12 h (p = 0.045). Among non-survivors hemorrhage as leading cause of death was less in the TXA group (3.0% vs. 4.3%, p = 0.021). Thromboembolic events were not significantly different between both groups (TXA 6.1%, control 4.9%, p = 0.080). CONCLUSION:This is the largest civilian study in which the effect of prehospital TXA use in a mature trauma system has been examined. TXA use in severely injured patients was associated with a significantly lower risk of massive transfusion and lower mortality in the early in-hospital treatment period. Due to repetitive administration, a dose-dependent effect of TXA must be discussed. 10.1186/s13054-021-03701-7
    Early Prehospital Tranexamic Acid Following Injury Is Associated With a 30-day Survival Benefit: A Secondary Analysis of a Randomized Clinical Trial. Li Shimena R,Guyette Francis,Brown Joshua,Zenati Mazen,Reitz Katherine M,Eastridge Brian,Nirula Raminder,Vercruysse Gary A,O'Keeffe Terence,Joseph Bellal,Neal Matthew D,Zuckerbraun Brian S,Sperry Jason L Annals of surgery OBJECTIVE:We sought to characterize the timing of administration of prehospital tranexamic acid (TXA) and associated outcome benefits. BACKGROUND:TXA has been shown to be safe in the prehospital setting post-injury. METHODS:We performed a secondary analysis of a recent prehospital randomized TXA clinical trial in injured patients. Those who received prehospital TXA within 1 hour (EARLY) from time of injury were compared to those who received prehospital TXA beyond 1 hour (DELAYED). We included patients with a shock index of >0.9. Primary outcome was 30-day mortality. Kaplan-Meier and Cox Hazard regression were utilized to characterize mortality relationships. RESULTS:EARLY and DELAYED patients had similar demographics, injury characteristics, and shock severity but DELAYED patients had greater prehospital resuscitation requirements and longer prehospital times. Stratified Kaplan-Meier analysis demonstrated significant separation for EARLY patients (N = 238, log-rank chi-square test, 4.99; P = 0.03) with no separation for DELAYED patients (N = 238, log-rank chi-square test, 0.04; P = 0.83). Stratified Cox Hazard regression verified, after controlling for confounders, that EARLY TXA was associated with a 65% lower independent hazard for 30-day mortality [hazard ratio (HR) 0.35, 95% confidence interval (CI) 0.19-0.65, P = 0.001] with no independent survival benefit found in DELAYED patients (HR 1.00, 95% CI 0.63-1.60, P = 0.999). EARLY TXA patients had lower incidence of multiple organ failure and 6-hour and 24-hour transfusion requirements compared to placebo. CONCLUSIONS:Administration of prehospital TXA within 1 hour from injury in patients at risk of hemorrhage is associated with 30-day survival benefit, lower incidence of multiple organ failure, and lower transfusion requirements. 10.1097/SLA.0000000000005002
    Does Liberal Prehospital and In-Hospital Tranexamic Acid Influence Outcome in Severely Injured Patients? A Prospective Cohort Study. van Wessem Karlijn J P,Leenen Luke P H World journal of surgery BACKGROUND:Early hemorrhage control is important in trauma-related death prevention. Tranexamic acid (TXA) has shown to be beneficial in patients in hemorrhagic shock, although widespread adoption might result in incorrect TXA administration leading to increased morbidity and mortality. METHODS:A 7-year prospective cohort study with consecutive trauma patients admitted to a Level-1 Trauma Center ICU was performed to investigate administration of both pre- and in-hospital TXA and its relation to morbidity and mortality. Indication for prehospital and in-hospital TXA administration was (suspicion of) hemorrhagic shock, and/or systolic blood pressure (SBP) ≤ 90 mmHg. Demographics, data on physiology, resuscitation and outcomes were prospectively collected. RESULTS:Four hundred and twenty-two patients (71% males, median ISS 29, 95% blunt injuries) were included. Even though TXA patients were more severely injured with more deranged physiology, no differences in outcome were noted. Overall, thrombo-embolic complication rate was 8%. In half the patients, hemorrhagic shock was the indication for prehospital TXA, whereas 79% of in-hospital TXA was given based on suspicion of hemorrhagic shock. Thirteen percent of patients with SBP ≤ 90 mmHg in ED received no TXA at all. Based on SBP alone, 22% of prehospital TXA and 25% of in-hospital TXA were justified. CONCLUSIONS:Despite being more severely injured, TXA patients had similar outcome compared to patients without TXA. Thrombo-embolic complication rate was low despite liberal use of both prehospital and in-hospital TXA. Caution should be exercised in selecting patients for TXA, although this might be challenging based on SBP alone in patients who do not yet show signs of deranged physiology on arrival in ED. 10.1007/s00268-021-06143-y