Circulation - Tranexamic Acid (TXA)

#### TRANEXAMIC ACID (TXA)

J Surg Res. 2019 Jan;233:132-138

# Prehospital Tranexamic Acid Administration During Aeromedical Transport After Injury.

Boudreau R, Deshpande K, Day G, Hinckley W, Harger N, Pritts T, Makley A, Goodman M

BACKGROUND: Tranexamic acid (TXA) has been shown to reduce mortality in the treatment of traumatic hemorrhage. This effect seems most profound when given early after injury. We hypothesized that extending a protocol for TXA administration into the prehospital aeromedical setting would improve outcomes while maintaining a similar safety profile to TXA dosed in the emergency department (ED).

MATERIALS AND METHODS: We identified all trauma patients who received TXA during prehospital aeromedical transport or in the ED at our urban level I trauma center over an 18-mo period. These patients had been selected prospectively for TXA administration using a protocol that selected adult trauma patients with high-risk mechanism and concern for severe hemorrhage to receive TXA. Patient demographics, vital signs, lab values including thromboelastography, blood administration, mortality, and complications were reviewed retrospectively and analyzed.

RESULTS: One hundred sixteen patients were identified (62 prehospital versus 54 ED). Prehospital TXA patients were more likely to have sustained blunt injury (76% prehospital versus 46% ED, P = 0.002). There were no differences between groups in injury severity score or initial vital signs. There were no differences in complication rates or mortality. Patients receiving TXA had higher rates of venous thromboembolic events (8.1% in prehospital and 18.5% in ED) than the overall trauma population (2.1%, P < 0.001).

CONCLUSIONS: Prehospital administration of TXA during aeromedical transport did not improve survival compared with ED administration. Treatment with TXA was associated with increased risk of venous thromboembolic events. Prehospital TXA protocols should be refined to identify patients with severe hemorrhagic shock or traumatic brain injury.

World Neurosurg. 2019 Feb 2 Epub ahead of print

# Improving Survival with Tranexamic Acid in Cerebral Contusions or Traumatic Subarachnoid Hemorrhage: Univariate and Multivariate Analysis of Independent Factors Associated with Lower Mortality.

Chan D, Tsang A, Li L, Cheng K, Tsang F, Taw B, Pu J, Ho W, Lui W, Leung G

BACKGROUND: Fall with head injury is a pervasive challenge, especially in the aging population. Contributing factors for mortality include the development of cerebral contusions and delayed traumatic intracerebral hematoma. Currently, there is no established specific treatment for these conditions.

OBJECT: This study aimed to investigate the impact of independent factors on the mortality rate of traumatic brain injury with contusions or traumatic subarachnoid hemorrhage.

METHODS: Data were collected from consecutive patients admitted for cerebral contusions or traumatic subarachnoid hemorrhage at an academic trauma center from 2010 to 2016. The primary outcome was the 30-day mortality rate. Independent factors for analysis included patient factors and treatment modalities. Univariate and multivariate analyses were conducted to identify independent factors related to mortality. Secondary outcomes included thromboembolic complication rates associated with the use of tranexamic acid.

RESULTS: In total, 651 consecutive patients were identified. For the patient factors, low Glasgow Coma Scale on admission, history of renal impairment, and use of warfarin were identified as independent factors associated with higher mortality from univariate and multivariate analyses. For the treatment modalities, univariate analysis identified tranexamic acid as an independent factor associated with lower mortality (P = 0.021). Thromboembolic events were comparable in patients with or without tranexamic acid.

CONCLUSION: Tranexamic acid was identified by univariate analysis as an independent factor associated with lower mortality in cerebral contusions or traumatic subarachnoid hemorrhage. Further prospective studies are needed to validate this finding.

Emerg Med J. 2019 Feb;36(2):78-81

# Implementation of tranexamic acid for bleeding trauma patients: a longitudinal and cross-sectional study.

Coats T, Fragoso-Iñiguez M, Roberts I

OBJECTIVE: To describe the use of tranexamic acid (TXA) in trauma care in England and Wales since the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (CRASH-2) trial results were published in 2010.

METHODS: A national longitudinal and cross-sectional study using data collected through the Trauma Audit and Research Network (TARN), the clinical audit of major trauma care for England and Wales. All patients in the TARN database injured in England and Wales were included apart from those with an isolated traumatic brain injury, with a primary outcome of the proportion of patients given TXA and the secondary outcome of time to treatment.

RESULTS: Among 228 250 patients, the proportion of trauma patients treated with TXA increased from near zero in 2010 to 10% (4593) in 2016. In 2016, most patients (82%) who received TXA did so within 3 hours of injury, however, only 30% of patients received TXA within an hour of injury. Most (80%) of the patients who had an early blood transfusion were given TXA. Patients treated with TXA by an ambulance paramedic received treatment at a median of 49 min (IQR 33-72) compared with 111 min (IQR 77-162) for patients treated in hospital.

CONCLUSIONS: There is a low proportion of patients treated with TXA across the range of injury severity and the range of physiological indicators of severity of bleeding. Most patients receive treatment within the existing target of 3 hours from injury, however there remains the potential to further improve major trauma outcomes by the earlier treatment of a wider patient group.

Anaesth Crit Care Pain Med. 2019 Feb 23 Epub ahead of print

# Effects of modification of trauma bleeding management: A before and after study.

Guth C, Vassal O, Friggeri A, Wey P, Inaba K, Decullier E, Ageron F, David J

OBJECTIVE: We hypothesised that the association of tranexamic acid (TXA) administration and thromboelastometry-guided haemostatic therapy (TGHT) with implementation of Damage Control Resuscitation (DCR) reduced blood products (BP) use and massive transfusion (MT).

METHODS: Retrospective comparison of 2 cohorts of trauma patients admitted in a university hospital, before (Period 1) and after implementation of DCR, TXA (first 3-hours) and TGHT (Period 2). Patients were included if they received at least 1 BP (RBC, FFP or platelet) or coagulation factor concentrates (fibrinogen or prothrombin complex) during the first 24-hours following the admission.

RESULTS: 380 patients were included. Patients in Period 2 (n = 182) received less frequently a MT (8% vs. 33%, P < 0.01), significantly less BP (RBC: 2 units [1-5] vs. 6 [3-11]; FFP: 0 units [0-2] vs. 4 [2-8]) but more fibrinogen concentrates (3.0 g [1.5-4.5] vs. 0.0 g [0.0-3.0], P < 0.01). Multivariate logistic regression analysis identified Period 1 as being associated with an increased risk of receiving MT (OR: 26.1, 95% CI: 9.7-70.2) and decreased survival at 28 days (OR: 2.0, 95% CI: 1.0-3.9). After propensity matching, the same results were observed but there was no difference for survival and a significant decrease for the cost of BP (2370 ± 2126 vs. 3284 ± 3812 €, P: 0.036).

CONCLUSION: Following the implementation of a bundle of care including DCR, TGHT and administration of TXA, we observed a decrease to the use of blood products, need for MT and an improvement of survival.

J Arthroplasty. 2018 Oct 25;Epub ahead of print

# Topical Tranexamic Acid in Revision Total Knee Arthroplasty Reduces Transfusion Rates and May Be Associated With Earlier Recovery.

Huerfano E, Huerfano M, Shanaghan K, Gonzalez Della Valle A

BACKGROUND: The use of tranexamic acid (TXA) has been proved to be effective in reducing blood loss and transfusion requirements after primary total knee arthroplasty (TKA). However, the evidence for its use in revision surgery is scant. We assessed the safety and efficacy of topical TXA in revision TKA.

METHODS: We retrospectively compared 76 revision TKA patients who received topical TXA (3 g before tourniquet deflation) "study group" with a historic control group of 205 revision TKA patients in which TXA was not used. Each group was further stratified into subgroups according to the type of revision. All patients were followed for a minimum of 6 weeks. Blood loss, transfusion requirements, changes in hemoglobin-hematocrit levels, Knee Society Score, and complications were recorded.

RESULTS: The mean estimated blood loss, hemoglobin drop, and transfusion rate were significantly lower in the study group than in the control group (P = .008, P < .001, P < .001, respectively). Hidden blood loss was similar between the 2 groups (P = .12). Six weeks postoperatively, the improvement in the knee-specific Knee Society Score was significantly higher in the study group than in the control group (P < .001). No significant differences were found in thromboembolic complications between the 2 groups (P = .92). In the subgroup analysis, when both components (femur and tibia) were revised, the relative risk of transfusion was significantly lower with the use of TXA (relative risk 0.227, confidence interval 0.0593-0.860, P = .004).

CONCLUSION: Topical TXA in revision TKA is safe and effective in reducing blood loss and transfusions. This effect is enhanced when both components are revised. Additionally, the use of TXA may improve early outcomes.

Cochrane Database Syst Rev. 2018 Dec 31;12:CD004328. doi: 10.1002/14651858.CD004328.pub3.

# Tranexamic acid for patients with nasal haemorrhage (epistaxis).

Joseph J, Martinez-Devesa P, Bellorini J, Burton M

BACKGROUND: Epistaxis (nosebleed) most commonly affects children and the elderly. The majority of episodes are managed at home with simple measures. In more severe cases medical intervention is required to either cauterise the bleeding vessel, or to pack the nose with various materials. Tranexamic acid is used in a number of clinical settings to stop bleeding by preventing clot breakdown (fibrinolysis). It may have a role in the management of epistaxis as an adjunct to standard treatments, reducing the need for further intervention.

OBJECTIVES: To determine the effects of tranexamic acid (oral, intravenous or topical) compared with placebo, no additional intervention or any other haemostatic agent in the management of patients with epistaxis.

SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register (via CRS Web); Central Register of Controlled Trials (CENTRAL) (via CRS Web); PubMed; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 29 October 2018.

SELECTION CRITERIA: Randomised controlled trials (RCTs) of tranexamic acid (in addition to usual care) compared with usual care plus placebo, usual care alone or usual care plus any other haemostatic agent, to control epistaxis in adults or children.

DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. The primary outcomes were control of epistaxis: re-bleeding (as measured by the proportion of patients re-bleeding within a period of up to 10 days) and significant adverse effects (seizures, thromboembolic events). Secondary outcomes were control of epistaxis as measured by the time to stop initial bleeding (the proportion of patients whose bleeding is controlled within a period of up to 30 minutes); severity of re-bleeding (as measured by (a) the proportion of patients requiring any further intervention and (b) the proportion of patients requiring blood transfusion); length of hospital stay and other adverse effects. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics.

MAIN RESULTS: We included six RCTs (692 participants). The overall risk of bias in the studies was low. Two studies assessed oral administration of tranexamic acid, given regularly over several days, and compared it to placebo. In the other four studies, a single application of topical tranexamic acid was compared with placebo (one study) and a combination of epinephrine and lidocaine or phenylephrine (three studies). All participants were adults. Tranexamic acid versus placeboFor our primary outcome, control of epistaxis: re-bleeding (proportion re-bleeding within 10 days), we were able to pool data from three studies. The pooled result demonstrated a benefit of tranexamic acid compared to placebo, the risk of re-bleeding reducing from 67% to 47% (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.56 to 0.90; three studies; 225 participants; moderate-quality evidence).When we compared the effects of oral and topical tranexamic acid separately the risk of re-bleeding with oral tranexamic acid reduced from 69% to 49%, RR 0.73 (95% CI 0.55 to 0.96; two studies, 157 participants; moderate-quality evidence) and with topical tranexamic acid it reduced from 66% to 43%, RR 0.66 (95% CI 0.41 to 1.05; single study, 68 participants). We rated the quality of evidence provided by the single study as low, therefore it is uncertain whether topical tranexamic acid is effective in stopping bleeding in the 10-day period after a single application. No study specifically sought to identify and report our primary outcome: significant adverse effects (i.e. seizures, thromboembolic events).The secondary outcome time to stop initial bleeding (proportion with bleeding controlled within 30 minutes) was measured in one study using topical tranexamic acid and there was no evidence of a difference at 30 minutes (RR 0.79, 95% CI 0.56 to 1.11; 68 participants; low-quality evidence).No studies reported the proportion of patients requiring any further intervention (e.g. repacking, surgery, embolisation).One study of oral tranexamic acid reported the proportion of patients requiring blood transfusion and found no difference between groups: 5/45 (11%) versus 6/44 (14%) (RR 0.81, 95% CI 0.27 to 2.48; 89 participants; low-quality evidence).Two studies reported hospital length of stay. One study reported a significantly shorter stay in the oral tranexamic acid group (mean difference (MD) -1.60 days, 95% CI -2.49 to -0.71; 68 participants). The other study found no evidence of a difference between the groups. Tranexamic acid versus other haemostatic agents. When we pooled the data from three studies the proportion of patients whose bleeding stopped within 10 minutes was significantly higher in the topical tranexamic acid group compared to the group receiving another haemostatic agent (70% versus 30%: RR 2.35, 95% CI 1.90 to 2.92; 460 participants) (moderate-quality evidence). Adverse effects across all studies Five studies recorded 'adverse effects' in a generalway. None found any difference between the groups in the occurrence of minor adverse effects (e.g. mild nausea and diarrhoea, 'bad taste' of gel). In one study a patient developed a superficial thrombophlebitis of both legs following discharge, however it is not reported in which group this occurred. No "other serious adverse effect" was reported in any study.

AUTHORS' CONCLUSIONS: We found moderate-quality evidence that there is probably a reduction in the risk of re-bleeding with the use of either oral or topical tranexamic acid in addition to usual care in adult patients with epistaxis, compared to placebo with usual care. However, the quality of evidence relating solely to topical tranexamic acid was low (one study only), so we are uncertain whether or not topical tranexamic acid is effective in stopping bleeding in the 10-day period after a single application. We found moderate-quality evidence that topical tranexamic acid is probably better than other topical agents in stopping bleeding in the first 10 minutes. There have been only three RCTs on this subject since 1995. Since then there have been significant changes in nasal cauterization and packing techniques (for example, techniques including nasal endoscopy and more invasive approaches such as endoscopic sphenopalatine artery ligation). New trials would inform us about the effectiveness of tranexamic acid in light of these developments.

BMC Obes. 2018 Dec 3;5:36. doi: 10.1186/s40608-018-0213-5. eCollection 2018.

# Tranexamic acid therapy for postoperative bleeding after bariatric surgery.

Klaassen R, Selles C, van den Berg J, Poelman M, van der Harst E

Background: Tranexamic acid reduces blood loss associated with various surgical procedures. Postoperative bleeding caused by dissection or bleeding of the enteric staple lines is a well-known complication following bariatric surgery. Reoperation in order to restore hemostasis is frequently necessary (up to 2.5% in literature). The effect of conservative therapy using tranexamic acid for postoperative hemorrhage after bariatric surgery is still very much a novel technique. The aim is to present our results (reoperation rate and thrombo-embolic complication rate) of tranexamic acid therapy for postoperative bleeding after bariatric surgery in comparison to those in existing literature.

Methods: We retrospectively reviewed 1388 patients who underwent bariatric surgery (laparoscopic gastric bypass or laparoscopic gastric sleeve). Use of tranexamic acid, reoperation rate, transfusion rate and rate of thrombo-embolic complications were reviewed.

Results: Forty-five of 1388 (3.2%) total patients experienced significant hemorrhage after bariatric surgery. Tranexamic acid was administered in 44 of these patients. A failure of the treatment with tranexamic acid was observed in four patients. The incidence of reoperation was 0.4% for the entire population. No thrombo-embolic complications were registered for patients receiving tranexamic acid.

Conclusion: These findings suggest that the administration of tranexamic acid appears to be safe in reducing the reoperation rate for bleeding after bariatric

J Craniofac Surg. 2019 Jan;30(1):120-126

# Tranexamic Acid Decreases Blood Transfusion Burden in Open Craniosynostosis Surgery Without Operative Compromise.

Lu V, Goyal A, Daniels D

In the surgical management of craniosynostosis, there is a high red blood cell (RBC) transfusion burden due to the small blood volume of the patients combined with significant blood loss that can occur with open surgery (OS). Tranexamic acid (TXA) is an antifibrinolytic which has been shown to decrease such a burden in particular surgeries. The aim of this study was to compare the operative outcomes of craniosynostosis OS which did and did not utilize TXA. Searches of 7 electronic databases from inception to February 2018 were conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. There were 206 articles screened against selection criteria for inclusion. Relevant data were extracted and analyzed using meta-analysis of proportions. A total of 9 comparative studies were included for meta-analysis. Compared with the control cohort, craniosynostosis OS utilizing TXA demonstrated significantly lower intraoperative RBC transfusion volumes (mean difference, -8.25 mL/kg; P < 0.001), blood loss (mean difference, -10.96 mL/kg; P < 0.001) and postoperative RBC transfusion incidence (odds ratio, OR, 0.12; P = 0.005). Fresh frozen plasma and crystalloid transfusion, operation time, length of stay, and complications were not significantly different with TXA use. Based on the comparative evidence currently available, TXA significantly decreased RBC transfusion burden during craniosynostosis OS without operative compromise. There is significant heterogeneity in reported TXA regimes in the literature. Future studies that are larger, randomized, and account for these factors will further enhance the authors' understanding.

J Trauma Acute Care Surg. 2019 Jan;86(1):20-27. doi: 10.1097/TA.0000000000002061.

# Tranexamic acid administration is associated with an increased risk of posttraumatic venous thromboembolism.

Myers S, Kutcher M, Rosengart M, Sperry J, Peitzman A, Brown J, Neal M

BACKGROUND: Tranexamic acid (TXA) is used as a hemostatic adjunct for hemorrhage control in the injured patient and reduces early preventable death. However, the risk of venous thromboembolism (VTE) has been incompletely explored. Previous studies investigating the effect of TXA on VTE vary in their findings. We performed a propensity matched analysis to investigate the association between TXA and VTE following trauma, hypothesizing that TXA is an independent risk factor for VTE.

METHODS: This retrospective study queried trauma patients presenting to a single Level I trauma center from 2012 to 2016. Our primary outcome was composite pulmonary embolism or deep vein thrombosis. Mortality, transfusion, intensive care unit and hospital lengths of stay were secondary outcomes. Propensity matched mixed effects multivariate logistic regression was used to determine adjusted odds ratio (aOR) and 95% confidence intervals (95% CI) of TXA on outcomes of interest, adjusting for prespecified confounders. Competing risks regression assessed subdistribution hazard ratio of VTE after accounting for mortality.

RESULTS: Of 21,931 patients, 189 pairs were well matched across propensity score variables (standardized differences <0.2). Median Injury Severity Score was 19 (interquartile range, 12-27) and 14 (interquartile range, 8-22) in TXA and non-TXA groups, respectively (p = 0.19). Tranexamic acid was associated with more than threefold increase in the odds of VTE (aOR, 3.3; 95% CI, 1.3-9.1; p = 0.02). Tranexamic acid was not significantly associated with survival (aOR, 0.86; 95% CI, 0.23-3.25; p = 0.83). Risk of VTE remained elevated in the TXA cohort despite accounting for mortality (subdistribution hazard ratio, 2.42; 95% CI, 1.11-5.29; p = 0.03).

CONCLUSION: Tranexamic acid may be an independent risk factor for VTE. Future investigation is needed to identify which patients benefit most from TXA, especially given the risks of this intervention to allow a more individualized treatment approach that maximizes benefits and mitigates potential harms.

LEVEL OF EVIDENCE: Therapeutic, level III.

West J Emerg Med. 2018 Nov;19(6):977-986.

# Tranexamic Acid in Civilian Trauma Care in the California Prehospital Antifibrinolytic Therapy Study.

Neeki M, Dong F, Toy J, Vaezazizi R, Powell J, Wong D, Mousselli M, Rabiei M, Jabourian A, Niknafs N, Burgett-Moreno M, Vara R, Kissel S, Luo-Owen X, O'Bosky K, Ludi D, Sporer K, Pennington T, Lee T, Borger R, Kwong E

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.

J Anaesthesiol Clin Pharmacol. 2018 Oct-Dec;34(4):529-534.

# Single intravenous bolus versus perioperative continuous infusion of tranexamic acid to reduce blood loss in abdominal oncosurgical procedures: A prospective randomized double-blind clinical study.

Prasad R, Patki A, Padhy S, Ramchandran G

Background and Aims: Intraoperative use of a single bolus dose of tranexamic acid may not be sufficient to prevent bleeding in the early postoperative period. The present study was carried out to compare the effect of two dose regimens of tranexamic acid in reducing perioperative blood loss and the amount of allogenic blood transfusion in abdominal tumor surgery.

Material and Methods: In this prospective, controlled, and double-blind investigation, 60 patients electively posted for abdominal oncosurgical procedures were randomly assigned to receive a single bolus dose of tranexamic acid (10 mg/kg) (Group A), a bolus dose of tranexamic acid (10 mg/kg) followed by infusion (1 mg/kg/h) till 4 h postoperatively (Group B), and a bolus followed by infusion of normal saline (group C). Total intraoperative blood loss, amount of allogenic blood transfusion, postoperative drain collections, and hemoglobin and hematocrit levels were recorded at different time intervals. Data obtained after comparing three groups were analyzed by analysis of variance test for variables following normal distribution, Kruskal-Wallis test for nonparametric data, and post-hoc Tukey-Kramer test for intergroup analysis. A probability value of less than 5% was considered significant.

Results: There was no significant difference in intraoperative blood loss in all the three groups. Both the tranexamic acid groups showed reduction in postoperative blood collection in drain at 6 h and 24 h in comparison to the control group (P < 0.001). There was also a significant difference in the amount of blood in postoperative drain at 24 h within the tranexamic acid groups, where lesser collection was seen in the infusion group (P = 0.007). Hemoglobin and hematocrit levels measured at different postoperative time intervals showed a significant reduction from the baseline in the control group compared to the tranexamic acid groups together.

Conclusion: Tranexamic acid causes more effective reduction in post-operative blood loss when used as a bolus followed by an infusion continued in the postoperative period in comparison to its use as a single intravenous bolus in abdominal tumor surgery.

World Neurosurg. 2019 Mar;123:128-135

# Effect of Tranexamic Acid in Patients with Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Weng S, Wang W, Wei Q, Lan H, Su J, Xu Y

OBJECTIVE: Tranexamic acid (TXA) reduces hemorrhage volume and consequently the need for operative intervention. However, its effectiveness and safety in patients with traumatic brain injury (TBI) is unclear. We conducted this systematic review and meta-analysis to evaluate the safety and efficacy of TXA in patients with TBI.

METHODS: In July 2018, a systematic search for studies including patients with TBI treated with TXA was conducted using PubMed, Embase, and the Cochrane Library databases. Only related randomized controlled trials were included. Main outcomes included hematoma expansion, surgery rate, death rate, neurologic outcome, and any thrombosis events.

RESULTS: Of the identified 426 studies, 5 randomized controlled trials involving 917 patients met our inclusion criteria. For hematoma expansion, pooled results showed that TXA significantly decreased hemorrhage growth rate and total hemorrhage growth in patients with TBI. Regarding clinical outcomes, pooled results of surgery, mortality, and neurologic outcome showed no significant difference between the groups, and rate of thrombosis events was similar. Following sensitivity analysis, one study was excluded due to low quality. Then, results of TXA effect on mortality and neurologic outcomes became significant. We confirm that the earlier the TXA treatment is performed, the smaller the size of hematoma will be.

CONCLUSIONS: TXA demonstrates significant effect in reducing the risk of hematoma expansion by lowering the mortality rate and improving favorable neurologic outcomes in patients with TBI while not affecting thrombosis event rates. In addition, early TXA treatment is more effective in decreasing hematomas.

Medicine (Baltimore). 2018 Dec;97(50):e13643

# The efficacy and safety of tranexamic acid in reducing perioperative blood loss in patients with multilevel thoracic spinal stenosis: A retrospective observational study.

Xue P, Yang J, Xu X, Liu T, Huang Y, Qiao F, Huang X

STUDY DESIGN: A retrospective study.

OBJECTIVE: To investigate the effectiveness and safety of intravenous tranexamic acid for reducing perioperative blood loss in patients with multilevel thoracic spinal stenosis (TSS).

METHODS: This is a retrospective observational study of 42 patients with multilevel TSS admitted from December 2016 to October 2017 to the spine department of Honghui Hospital who underwent posterolateral bone graft fusion with posterior laminectomy and decompression fixation. The patients were divided into 2 groups. All the surgeries were completed by the same surgeon. Group A received an intravenous infusion of 15 mg/kg 15 min prior to surgery. Continuous infuse on of tranexamic acid (TXA) at a dose of 1 mg/kg/h was provided throughout the operation until the skin was closed. Group B received no TXA as a blank control group. Group A comprised 10 males and 10 females with an average age of 53.41 ± 7.93 years; group B comprised 11 males and 11 females with an average age of 55.10 ± 8.43 years. The need for blood transfusion, volume of blood transfusion, blood coagulation function, extubation time, postoperative hospital stay and incidence of postoperative deep venous thrombosis (DVT) were recorded during and after the operation for the 2 groups.

RESULTS: There was no significant difference between the 2 groups in general characteristics, such as age, sex and body mass index (BMI) (P > .05). There was no significant difference between the 2 groups in the levels are instrumented and the laminectomy levels in each group. The average postoperative blood loss, need for blood transfusion, time to postoperative extubation and length of postoperative hospital stay in group A were lower than those in group B, and there was a significant difference between the 2 groups (P < .05). The preoperative and postoperative coagulation, and postoperative DVT did not occur 48 h after operation.

CONCLUSION: In the treatment of multilevel thoracic spinal canal stenosis using trabeculectomy with posterior laminectomy and posterolateral bone graft fusion, TXA can reduce the amount of blood transfused and the need for blood transfusion and can shorten the extubation time and the length of postoperative hospital stay without increasing the incidence of postoperative coagulation dysfunction or postoperative DVT.

J Clin Neurosci. 2019 Mar;61:114-119

# Topical tranexamic acid in spinal surgery: A systematic review and meta-analysis.

Yerneni K, Burke J, Tuchman A, Li X, Metz L, Lehman R, Lenke L, Tan L

Tranexamic acid (TXA) is a commonly used antifibrinolytic agent for perioperative blood conservation in several surgical specialties. Although historically administered intravenously, such systemic administration may be accompanied by severe side effects. Thus, the topical usage of TXA has been established in several fields but remains poorly evaluated in spine surgery. In this study, the authors aimed to review the medical literature on topical TXA usage in spine surgery to evaluate its safety and efficacy. We reviewed manuscripts and clinical trials exploring topical TXA usage in spine surgery published by April 1st, 2018. Postoperative blood loss volumes and hospitalization lengths of stay were evaluated with separate meta-analyses. We identified five articles and one unpublished clinical trial that were placebo-controlled and comprised 218 patients receiving topical TXA in spine surgery. Patients receiving topical TXA demonstrated significantly lower postoperative blood loss as compared to the placebo group (Standardized Mean Difference [SMD] 2.21, 95% CI 0.79-3.62, p < 0.001) and had a lower hospitalization duration (MD 0.99, 95% CI 0.49-1.49, p < 0.001). Overall, topical TXA favorably reduced postoperative blood loss and hospitalization duration in patients undergoing spinal surgery. However, further randomized controlled trials will be needed to definitively establish the optimal therapeutic doses needed for hemorrhage management, and the pharmacodynamics of tTXA in spinal surgery.

Spine (Phila Pa 1976). 2018 Dec 11;Epub ahead of print

# Intravenous and Oral Tranexamic Acid are Equivalent at Reducing Blood Loss in Thoracolumbar Spinal Fusion: A Prospective Randomized Trial.

Yu C, Kadri O, Kadado A, Buraimoh M, Pawloski J, Bartol S, Graziano G

STUDY DESIGN: A prospective randomized trial of patients enrolled at a university affiliated tertiary medical center between February and December 2017.

OBJECTIVE: To compare perioperative blood loss in patients undergoing elective posterior thoracolumbar fusion who were treated with IV versus PO TXA.

SUMMARY OF BACKGROUND DATA: The use of antifibrinolytic agents such as tranexamic acid (TXA) to decrease operative blood loss and allogenic blood transfusions is well documented in the literature. While evidence supports the use of intravenous (IV) and topical formulations of TXA in spine surgery, the use of oral (PO) TXA has not been studied.

METHODS: 83 patients undergoing thoracolumbar fusion were randomized to receive 1.95 g of PO TXA 2 hours preoperatively or 2 g IV TXA (1 g before incision and 1 g before wound closure) intraoperatively. The sample was further stratified into 3 categories based on number of levels fused (1-2 level fusions, 3-5, and >5). The primary outcome was the reduction of hemoglobin. Secondary outcomes included calculated blood loss, drain output, postoperative transfusion, complications, and length of hospital stay. Equivalence analysis was performed with a two one-sided test (TOST). A P-value of <0.05 suggested equivalence between treatments.

RESULTS: 43 patients received IV TXA and 40 patients received PO TXA. Patient demographic factors were similar between groups except for BMI. The mean reduction of hemoglobin was similar between IV and PO groups (3.36 g/dL vs. 3.43 g/dL, respectively; P = 0.01, equivalence). Similarly, the calculated blood loss was equivalent (1235 mL vs. 1312 mL, respectively; P = 0.02, equivalence). Eight patients (19%) in IV TXA group received a transfusion compared to five patients in PO TXA group (13%) (P = 0.44). One patient (2% and 3% in IV and PO, respectively) in each group experienced a DVT/PE (P = 0.96).

CONCLUSION: Patients treated with IV and PO TXA experienced the same perioperative blood loss after spinal fusions. Given its lower cost, PO TXA represents an excellent alternative to IV TXA in patients undergoing elective posterior thoracolumbar fusion and may improve healthcare cost-efficiency in the studied population.

LEVEL OF EVIDENCE: 1

Br J Anaesth. 2019 Jun;122(6):760-766

# Reduced perioperative blood loss in children undergoing craniosynostosis surgery using prolonged tranexamic acid infusion: a randomised trial.

Fenger-Eriksen C, D'Amore Lindholm A, Nørholt S, von Oettingen G, Tarpgaard M, Krogh L, Juul N, Hvas A, Rasmussen M

BACKGROUND: Tranexamic acid (TXA) reduces intraoperative blood loss and transfusion during paediatric craniosynostosis surgery. Additional reduction of postoperative blood loss may further reduce exposure to allogeneic blood products. We studied the effect of combined intra- and postoperative TXA treatment on postoperative blood loss in children.

METHODS: Thirty children admitted for craniosynostosis surgery were randomised to combined intra- and postoperative TXA treatment or placebo. The primary endpoint was postoperative blood loss. Secondary endpoints included total blood loss, transfusion requirements, and clot stability evaluated by tissue plasminogen activator-stimulated clot lysis assay.

RESULTS: TXA reduced postoperative blood loss by 18 ml kg-1 (95% confidence interval 8.9) and total blood loss from a mean of 52 ml kg-1 (standard deviation [SD]; 20) ml kg-1 to 28 (14) ml kg-1 (P<0.001). Intraoperative red blood cell (RBC) and fresh frozen plasma (FFP) transfusions were reduced in the treatment group from RBC 14.0 (5.2) ml kg-1 to 8.2 (5.1) ml kg-1 (P=0.01) and from FFP 13.0 (6.3) ml kg-1 to 7.8 (5.9) ml kg-1 (P=0.03). Postoperative RBC transfusion median was 5 (inter-quartile range [IQR] 0-6) ml kg-1 in the placebo group and 0 (0-5.7) ml kg-1 in the TXA group. Resistance to lysis was higher in the treatment group (P<0.001).

CONCLUSIONS: Combined intra- and postoperative tranexamic acid treatment reduced postoperative and overall blood loss and transfusion requirements. Improved clot stability represents a possible mechanism for blood loss reduction.

Curr Opin Anaesthesiol. 2019 Jun;32(3):343-352

Tranexamic acid and perioperative bleeding in children: what do we still need to know?

Goobie S, Faraoni D

PURPOSE OF REVIEW: Perioperative bleeding and blood product transfusion are associated with significant morbidity and mortality. Prevention and optimal management of bleeding decreases risk and lowers costs. Tranexamic acid (TXA) is an antifibrinolytic agent that reduces bleeding and transfusion in a broad number of adult and pediatric surgeries, as well as in trauma and obstetrics. This review highlights the current pediatric indications and contraindications of TXA. The efficacy and safety profile, given current and evolving research, will be covered.

RECENT FINDINGS: Based on the published evidence, prophylactic or therapeutic TXA administration is a well-tolerated and effective strategy to reduce bleeding, decrease allogeneic blood product transfusion, and improve pediatric patients' outcomes. TXA is now recommended in recent guidelines as an important part of pediatric blood management protocols.

SUMMARY: Based on TXA pharmacokinetics, the authors recommend a dosing regimen of between 10 to 30 mg/kg loading dose followed by 5 to 10 mg/kg/h maintenance infusion rate for pediatric trauma and surgery. Maximal efficacy and minimal side-effects with this dosage regime will have to be determined in larger prospective trials including high-risk groups. Furthermore, future research should focus on determining the ideal TXA plasma therapeutic concentration for maximum efficacy and minimal side-effects.

Medicine (Baltimore). 2019 Mar;98(11):e14564

# Tranexamic acid can reduce blood loss in patients undergoing intertrochanteric fracture surgery: A meta-analysis.

Jiang W, Shang L.

BACKGROUND: This meta-analysis aimed to assess whether administration tranexamic acid (TXA) could reduce blood loss and transfusion requirements in patients undergoing intertrochanteric fracture surgery.

METHODS: We performed an electronic search of PubMed (1950-October 2018), EMBASE (1974-October 2018), the Cochrane Library (October 2018 Issue 3), the Google database (1950-October 2018), and the Chinese Wanfang database (1950-October 2018). Studies were included in accordance with Population, Intervention, Comparison, Outcomes, and Setting (PICOS) including criteria. Intertrochanteric fracture patients prepared for surgery were selected. Administration with TXA and the placebo or no interventions were considered as an intervention and comparators, respectively. Measures related to total blood loss, blood loss in drainage, hemoglobin on postoperative day were analyzed. A fixed/random-effects model was used according to the heterogeneity assessed by the I statistic. Data analysis was performed using Stata 12.0 software.

RESULTS: A total of five RCTs with 584 patients (TXA group = 289, control group = 298) were included in the meta-analysis. Based on the results, administration of TXA was associated with a reduction in total blood loss, blood loss in drainage, need for transfusion, length of hospital stay, and occurrence of hematoma (P < .05). Administration of TXA increased the hemoglobin level at 3 days after surgery (P < .05). There were no significant differences between the two groups in terms of the occurrence of deep venous thrombosis, pulmonary embolism, or infection (P > .05).

CONCLUSION: Administration of TXA is associated with reduced total blood loss, postoperative hemoglobin decline, and transfusion requirements in patients with intertrochanteric fractures. Additional high-quality RCTs should be conducted in the future.

J Clin Orthop Trauma. 2019 Mar-Apr;10(2):286-289

# Effects of tranexamic acid on reducing blood loss in pelvic trauma: A randomised double-blind placebo controlled study.

Monsef Kasmaei V, Javadi A, Naseri Alavi S

Background: Management of pelvic trauma is complicated with patients' instability and remains high in skeletal injuries. The patients usually are young and in middle age and the management of bleeding is more important. The aim of this study is to assess the effects of Tranexamic Acid in Reducing Blood Loss in pelvic trauma: A Randomised Double-Blind Placebo Controlled Study.

Method and materials: In this randomized clinical trial study 106 patients with Pelvic Trauma (PT) were randomly divided into two groups. The case group received 1 g Intravenous TXA for loading dose and 3 dose per 8 h for the maintenance and control group received only serum 0.9% N.S (Normal Saline) or placebo. The Hemoglobin (Hb), Hematocrit (HCT), Pulse Rate (PR) and Blood Pressure (BP) was checked at admission, 24 h, 48 h and 72 h after admission.

Results: From 106 patients 61(%57.54) male and 45 (%42.46) female patients enrolled to the study. The mean age was 48.14 ± 13.54 and the range was 18-60 years old. There was no difference between two groups based on Blood Pressure at admission, 24 h, 48 h and 72 h after admission. There was a significant difference between two groups in 24 h, 48 h and 72 h after admission based on Hb and HCT amount.

Conclusion: based on our findings it appears that TXA can reduce bleeding amount in the first, second and third 24 h after surgery based on Hb and HCT without any effect on systolic and diastolic BP and PR. In other hand no side effect reported by any patients.

Indian J Orthop. 2019 Mar-Apr;53(2):263-269

# Efficacy and Safety of Tranexamic Acid for Controlling Bleeding During Surgical Treatment of Intertrochanteric Fragility Fracture with Proximal Femoral Nail Anti-rotation: A Randomized Controlled Trial.

Luo X, He S, Lin Z, Li Z, Huang C, Li Q

Background: Intertrochanteric fragility fracture (IFF) treated with proximal femoral nail anti-rotation (PFNA) is associated with significant hidden blood loss and high blood transfusion rate. The purpose of the present study was to evaluate the efficacy and safety of tranexamic acid (TXA) in reducing blood loss in these patients.

Materials and Methods: Consecutive eligible patients were recruited and randomly assigned to a TXA group or a control group. The TXA group received 15 mg/kg body weight of TXA intravenously 15 min before incision and the same dose 3 h later. The control group received 100 mL of saline intravenously 15 min before incision. The efficacy outcomes included the total perioperative blood loss, postoperative transfusion rate, postoperative hemoglobin level, and length of the hospital stay. The safety outcomes were the incidence of thrombotic events and the mortality rate within 6 weeks after surgery.

Results: We had 44 patients in the TXA group and 46 patients in the control group for the final analysis. The TXA group had significantly lower total perioperative blood loss than the control group (384.5 ± 366.3 mL vs. 566.2 ± 361.5 mL; P < 0.020). Postoperative transfusion rate was 15.9% in the TXA group versus 36.9% in the control group (P = 0.024). Each group had one patient with postoperative deep venous thrombosis. In the control group, three patients had cerebral infarction, and one patient died within 6 weeks after the operation.

Conclusion: Intravenous TXA is effective in reducing total perioperative blood loss and transfusion rate in IFF treated with PFNA. No increased risk of thrombotic events was observed with the use of TXA; however, this study was underpowered for detecting this outcome. Further research is necessary before TXA can be recommended for high-risk patients.

Chest. 2019 Apr;155(4):876. doi: 10.1016/j.chest.2018.12.027.

# Tranexamic Acid Inhalations in Nonmassive Hemoptysis: A Word of Caution.

Messika J, Prat D, Sztrymf B

NO ABSTRACT AVAILABLE

J Trauma Acute Care Surg. 2019 Mar 22;Epub ahead of print]

# Tranexamic Acid (TXA) Administration Following Head Trauma in a Combat Setting: Does TXA Result in Improved Neurologic Outcomes?

Morte D, Lammers D, Bingham J, Kuckelman J, Eckert M, Martin M

BACKGROUND: Tranexamic acid (TXA) has been shown to decrease mortality and blood product requirements in severely injured patients. TXA has also been hypothesized to prevent secondary brain injury in patients with TBI. While prior studies have demonstrated improved neurologic outcomes associated with TXA administration in severely injured pediatric patients, no such studies have been performed in adults.

METHODS: A retrospective review of all adult trauma admissions to North Atlantic Treaty Organization hospitals in Iraq and Afghanistan between 2008-2015. Univariate and multivariate analysis was used to identify factors associated with TXA administration. Patients without a documented head abbreviated injury scale (AIS) were excluded. Patients were propensity matched based on demographics, mechanism of injury, injury scores (AIS/ISS), presenting Glasgow Coma Score (GCS), initial vitals/labs, and initial transfusion requirement. Primary outcomes were in-hospital mortality and neurologic outcomes measured by discharge GCS scores. Secondary outcomes were respiratory failure and rates of thromboembolic events.

RESULTS: 4476 injured patients 18 years or older were evaluated. 265 (5.9%) of these patients required a massive transfusion in the first 24 hours and 174 (3.9%) received TXA. TXA patients had significantly higher ISS, more penetrating injuries, lower presenting GCS, higher incidence of severe head injury (AIS>3), and higher transfusion requirements. 92 patients were included in the propensity matched cohort. Of these, patients who received TXA had significantly lower mortality rate (0% vs 10.1%, p=0.02) and improvement of GCS to 14-15 irrespective of admission GCS compared to patients who did not receive TXA (100% vs 87%, p=0.01). There were no significant differences in number of thromboembolic events recorded between the two groups.

CONCLUSIONS: TXA administration in adult combat trauma patients was independently associated with decreased mortality and improved neurologic outcomes, with no increase in thromboembolic events. Further study of the possible mechanisms and effect of TXA on brain injury and neurologic outcomes is warranted.

LEVEL OF EVIDENCE: Level IV; Therapeutic.

Anaesthesia. 2019 Jul;74(7):831-833

# Spinal tranexamic acid - a new killer in town.

Palanisamy A, Kinsella S

NO ABSTRACT AVAILABLE

Anaesthesia. 2019 Jul;74(7):904-914

# Catastrophic drug errors involving tranexamic acid administered during spinal anaesthesia.

Patel S, Robertson B, McConachie I

We have reviewed accidental spinal administration of tranexamic acid. We performed a MEDLINE search of cases of administration of tranexamic acid during epidural or spinal anaesthesia between 1960 and 2018. No reports of epidural administration were identified. We identified 21 cases of spinal tranexamic acid administration. Life-threatening neurological and/or cardiac complications, requiring resuscitation and/or intensive care, occurred in 20 patients; 10 patients died. We used a Human Factors Analysis Classification System model to analyse any contributing factors, and the reports were also assessed using four published recommendations for the reduction in neuraxial drug error. In 20 cases, ampoule error was the cause; in the last case a spinal catheter was mistaken for an intravenous catheter. All were classified as skill-based errors. Several human factors related to organisational policy; dispensing and storage of drugs and preparation for spinal anaesthesia tasks were present. All errors could have been prevented by implementing the four published recommendations.

J Orthop Trauma. 2019 Mar 29; Epub ahead of print

# Tranexamic Acid Use in Open Reduction and Internal Fixation of Fractures of the Pelvis, Acetabulum, and Proximal Femur: A Randomized Controlled Trial.

Spitler C, Kiner D, Row E, Gardner W, Swafford R, Hankins M, Nowotarski P

OBJECTIVES: Assess the safety and efficacy of tranexamic acid(TXA) use in fractures of the pelvic ring, acetabulum, and proximal femur

DESIGN: Prospective, randomized controlled trial

SETTING: Single Level 1 trauma center

PATIENTS: Fourty-seven patients were randomized to the study group and 46 patients comprised the control group INTERVENTION:: The study group received 15mg/kg IV TXA prior to incision and a second identical dose 3 hours after the initial dose.

MAIN OUTCOME MEASUREMENTS: transfusion rates, total blood loss (via hemoglobin dilutional method, rates of venous thromboembolic events)

RESULTS: Total blood loss was significantly higher in the control group (TXA=952mL, No TXA=1325mL, p=0.028). The total transfusion rates between the TXA and control groups were not significantly different (TXA 1.51, No TXA= 1.17, P=0.41). There were no significant differences between the TXA and control groups in inpatient VTE events (p=0.57) CONCLUSION:: The use of TXA in high-energy fractures of the pelvis, acetabulum and femur significantly decreased calculated total blood loss but did not decrease overall transfusion rates. TXA did not increase the rate of VTE. Further study is warranted prior to making broad recommendations for use of TXA in these fractures.

Medicine (Baltimore). 2018 Dec;97(50):e13643

# The efficacy and safety of tranexamic acid in reducing perioperative blood loss in patients with multilevel thoracic spinal stenosis: A retrospective observational study.

Xue P, Yang J, Xu X, Liu T, Huang Y, Qiao F, Huang X

STUDY DESIGN: A retrospective study.

OBJECTIVE: To investigate the effectiveness and safety of intravenous tranexamic acid for reducing perioperative blood loss in patients with multilevel thoracic spinal stenosis (TSS).

METHODS: This is a retrospective observational study of 42 patients with multilevel TSS admitted from December 2016 to October 2017 to the spine department of Honghui Hospital who underwent posterolateral bone graft fusion with posterior laminectomy and decompression fixation. The patients were divided into 2 groups. All the surgeries were completed by the same surgeon. Group A received an intravenous infusion of 15 mg/kg 15 min prior to surgery. Continuous infuse on of tranexamic acid (TXA) at a dose of 1 mg/kg/h was provided throughout the operation until the skin was closed. Group B received no TXA as a blank control group. Group A comprised 10 males and 10 females with an average age of 53.41 ± 7.93 years; group B comprised 11 males and 11 females with an average age of 55.10 ± 8.43 years. The need for blood transfusion, volume of blood transfusion, blood coagulation function, extubation time, postoperative hospital stay and incidence of postoperative deep venous thrombosis (DVT) were recorded during and after the operation for the 2 groups.

RESULTS: There was no significant difference between the 2 groups in general characteristics, such as age, sex and body mass index (BMI) (P > .05). There was no significant difference between the 2 groups in the levels are instrumented and the laminectomy levels in each group. The average postoperative blood loss, need for blood transfusion, time to postoperative extubation and length of postoperative hospital stay in group A were lower than those in group B, and there was a significant difference between the 2 groups (P < .05). The preoperative and postoperative coagulation, and postoperative DVT did not occur 48 h after operation.

CONCLUSION: In the treatment of multilevel thoracic spinal canal stenosis using trabeculectomy with posterior laminectomy and posterolateral bone graft fusion, TXA can reduce the amount of blood transfused and the need for blood transfusion and can shorten the extubation time and the length of postoperative hospital stay without increasing the incidence of postoperative coagulation dysfunction or postoperative DVT.

Emerg Med J. 2019 Jul;36(7):395-400

# Prehospital tranexamic acid shortens the interval to administration by half in Major Trauma Networks: a service evaluation.

Marsden M, Rossetto A, Duffield C, Woolley T, Buxton W, Steynberg S, Bagga R, Tai N

INTRODUCTION: Tranexamic acid (TXA) reduces bleeding and mortality. Recent trials have demonstrated improved survival with shorter intervals to TXA administration. The aims of this service evaluation were to assess the interval from injury to TXA administration and describe the characteristics of patients who received TXA pre-hospital and in-hospital.

METHODS: We reviewed Trauma and Audit Research Network records and local trauma registries to identify patients of any age that received TXA at all London Major Trauma Centres and Queen's Medical Centre, Nottingham, during 2017. We used the 2016 NICE Guidelines (NG39) which state that TXA should be given within 3 hours of injury.

RESULTS: We identified 1018 patients who received TXA, of whom 661 (65%) had sufficient data to assess the time from injury to TXA administration. The median interval was 74 min (IQR: 47-116). 92% of patients received TXA within 3 hours from injury, and 59% within 1 hour. Half of the patients (54%) received prehospital TXA. The median time to TXA administration when given prehospital was 51 min (IQR: 39-72), and 112 min (IQR: 84-160) if given in-hospital (p<0.001). In-hospital TXA patients had less haemodynamic derangement and lower base deficit on admission compared with patients given prehospital TXA.

CONCLUSION: Prehospital administration of TXA is associated with a shorter interval from injury to drug delivery. Identifying a proportion of patients at risk of haemorrhage remains a challenge. However, further reinforcement is needed to empower pre-hospital clinicians to administer TXA to trauma patients without overt signs of shock.

Shock. 2019 Jun 4;Epub ahead of print

# The Use of Tranexamic acid (TXA) for The Management of Haemorrhage In Trauma Patients In The Prehospital Environment: Literature Review and Descriptive Analysis of Principal Themes.

Stansfield R, Morris D, Jesulola E

Tranexamic acid (TXA) is an anti-fibrinolytic agent used to prevent traumatic exsanguination. It was first introduced to clinical practice for the management of patients with bleeding disorders, especially adapted to reduce bleeding in haemophiliacs undergoing oral surgical interventions. TXA exerts its action on the coagulation process by competitively inhibiting plasminogen activation, thereby reducing conversion of plasminogen into plasmin. This ultimately prevents fibrinolysis and reduces haemorrhage. Thus, TXA may be well suited for the management of traumatic haemorrhage in the pre-hospital setting.Despite multiplicity of studies on the use of TXA in clinical practice, there is no consensus regarding the use of TXA for the management of haemorrhage in trauma patients in the prehospital environment. Thus, a review on this topic was warranted. An extensive literature search yielded 14 full journal articles which met the inclusion criteria. These articles were thoroughly analysed and the and following themes were identified: "Dose of TXA administration", "Route of TXA administration", "Optimal window of TXA administration", "Safety of TXA use", "Clinical Effectiveness of TXA application" and the "Feasibility of TXA use in the prehospital setting".Overall, to achieve the best possible outcomes, literature supports the use of a loading dose of 1 gram of TXA, followed by 1 gram infusion over 8 hours, given by intravenous administration within a 3 hour window period of traumatic injury. TXA is very effective and safe to use in the pre-hospital setting, and its use is clinically and economically feasible.

Acad Emerg Med. 2019 Oct;26(10):1181-1182

# Tranexamic Acid for Upper Gastrointestinal Bleeding.

Beyda R, Johari D

NO ABSTRACT AVAILABLE

J Trauma Nurs. 2019 May/Jun;26(3):128-133

# A Retrospective Study of Transfusion Requirements in Trauma Patients receiving Tranexamic Acid.

Cornelius B, Moody K, Hopper K, Kilgore P, Cvek U, Trutschl M, Cornelius A

The Military Application of Tranexamic Acid in Trauma Emergency Resuscitation Study (MATTERs) and Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage-2 (CRASH-2) studies demonstrate that tranexamic acid (TXA) reduces mortality in patients with traumatic hemorrhage. However, their results, conducted in foreign countries and U.S. military soldiers, provoke concerns over generalizability to civilian trauma patients in the United States. We report the evaluation of patient outcomes and transfusion requirements following treatment with TXA by a civilian air medical program. We conducted a retrospective chart review of trauma patients transported by air service to a Level 1 trauma center. For the purposes of intervention evaluation, patients meeting this criterion for the 2 years (2012-2014) prior to therapy implementation were compared with patients treated during the 2-year study period (2014-2016). Goals were to evaluate morbidity, mortality, transfusion requirements, and length of stay.

During the review, 52 control (non-TXA) and 43 study (TXA) patients were identified as meeting inclusion criteria. Patients in the control group were found to be less acute, which correlated with shorter hospitals stays. There was reduced mortality for patients receiving TXA in spite of their increased acuity and decreased likelihood of survival. Trauma patients from this cohort study receiving TXA demonstrate decreased mortality in spite of increased acuity. This increased acuity is associated with increased transfusion requirements. Future research should evaluate patient selection with concern for fibrinolysis and provider bias. Randomized controlled trial is needed to evaluate the role of TXA administration in the United States.

Lancet. 2019 Nov 9;394(10210):1713-1723

# Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial.

CRASH-3 trial collaborators.

BACKGROUND: Tranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI.

METHODS: This randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277).

RESULTS: Between July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among patients treated within 3 h of injury, the risk of head injury-related death was 18·5% in the tranexamic acid group versus 19·8% in the placebo group (855 vs 892 events; risk ratio [RR] 0·94 [95% CI 0·86-1·02]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80-1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64-0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91-1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74-1·28). The risk of seizures was also similar between groups (1·09 [95% CI 0·90-1·33]).

INTERPRETATION: Our results show that tranexamic acid is safe in patients with TBI and that treatment within 3 h of injury reduces head injury-related death. Patients should be treated as soon as possible after injury.

FUNDING: National Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme).

Am J Surg. 2019 Dec;218(6):1110-1113

# Does tranexamic acid really work in an urban US level I trauma center? A single level 1 trauma center's experience.

Dixon A, Emigh B, Spitz K, Teixeira P, Coopwood B, Trust M, Daley M, Ali S, Brown C, Aydelotte J

BACKGROUND: The use of Tranexamic Acid (TXA) in trauma patients remains controversial. The CRASH II trial, while randomized and prospective, did not include patients suffering from major bleeding. We wanted to examine our population of patients who underwent a massive transfusion protocol (MTP) (greater than 10 Units of packed red blood cells in the first 24 h of admission) to see if those who were undergoing massive transfusion and received TXA had any benefit in mortality. Our hypothesis was that massively transfused patients who received TXA and those that did not had no difference in mortality.

METHODS: We performed a single institution retrospective review of our Trauma Registry for all patients who received a massive transfusion between 2010 and 2017. Patients were separated into two cohorts, those who received TXA within the first 24 h of admission and those who did not. The primary outcome of the study was mortality. Secondary outcomes included total blood products transfused, Deep Venous Thrombosis (DVT), Pulmonary Embolus (PE), Myocardial Infarction (MI), and cardiac arrest.

RESULTS: 283 patients received MTP between 2010 and 2017. 179 (63%) did not receive TXA and 104 (37%) were treated with TXA. The groups were then propensity matched and yielded 62 patients in each group (124 total) (ISS 36 ± 12 no TXA vs. 37 ± 13 TXA; p = 0.59). There was no significant difference observed in mortality (50% no TXA vs. 39% TXA; p = 0.21), total PRBC's transfused (20 ± 11 no TXA vs. 23 ± 18 TXA; p = 0.45), DVT (8% no TXA vs. 6% TXA; p = 0.99), PE (2% no TXA vs. 3% TXA; p = 0.99), MI (3% no TXA vs. 0% TXA; p = 0.50), or cardiac arrest (26% no TXA vs. 18% TXA; p = 0.28).

CONCLUSION: There does not appear to be any benefit to TXA administration in Trauma Patients in our institution. This is a single-center retrospective review. More data from other similar centers in the region or the United States is warranted.

J Emerg Med. 2019 Nov;57(5):646-652

# An Analysis of Adherence to Tactical Combat Casualty Care Guidelines for the Administration of Tranexamic Acid.

Fisher A, Carius B, April M, Naylor J, Maddry J, Schauer S

BACKGROUND: Hemorrhage is the leading cause of potentially survivable deaths in combat. Previous research demonstrated that tranexamic acid (TXA) administration decreased mortality among casualties. For casualties expected to receive a transfusion, the Committee on Tactical Combat Casualty Care (TCCC) recommends TXA. Despite this, the use and adherence of TXA in the military prehospital combat setting, in accordance with TCCC guidelines, is low.

OBJECTIVES: We sought to analyze TXA administration and use among combat casualties reasonably expected to require blood transfusion, casualties with tourniquet placement, amputations, and gunshot wounds.

METHODS: Based on TCCC guidelines, we measured proportions of patients receiving prehospital TXA: casualties undergoing tourniquet placement, casualties sustaining amputation proximal to the phalanges, patients sustaining gunshot wounds, and patients receiving ≥10 units of blood products within 24 h of injury. Univariable and multivariable analyses were also completed.

RESULTS: Within our dataset, 255 subjects received TXA. Four thousand seventy-one subjects had a tourniquet placed, of whom 135 (3.3%) received prehospital TXA; 1899 subjects had an amputation proximal to the digit with 106 (5.6%) receiving prehospital TXA; and 6660 subjects had a gunshot wound with 88 (1.3%) receiving prehospital TXA. Of 4246 subjects who received ≥10 units of blood products within the first 24 h, 177 (4.2%) received prehospital TXA.

CONCLUSIONS: We identified low TXA administration despite TCCC recommendations. Future studies should seek to both identify reasons for limited TXA administration and methods to increase future utilization.

BMC Emerg Med. 2019 Oct 18;19(1):56

# Introduction of a standardised protocol, including systematic use of tranexamic acid, for management of severe adult trauma patients in a low-resource setting: the MSF experience from Port-au-Prince, Haiti.

Jachetti A, Massénat R, Edema N, Woolley S, Benedetti G, Van Den Bergh R, Trelles M

BACKGROUND: Bleeding is an important cause of death in trauma victims. In 2010, the CRASH-2 study, a multicentre randomized control trial on the effect of tranexamic acid (TXA) administration to trauma patients with suspected significant bleeding, reported a decreased mortality in randomized patients compared to placebo. Currently, no evidence on the use of TXA in humanitarian, low-resource settings is available. We aimed to measure the hospital outcomes of adult patients with severe traumatic bleeding in the Médecins Sans Frontières Tabarre Trauma Centre in Port-au-Prince, Haiti, before and after the implementation of a Massive Haemorrhage protocol including systematic early administration of TXA.

METHODS: Patients admitted over comparable periods of four months (December2015- March2016 and December2016 - March2017) before and after the implementation of the Massive Haemorrhage protocol were investigated. Included patients had blunt or penetrating trauma, a South Africa Triage Score ≥ 7, were aged 18-65 years and were admitted within 3 h from the traumatic event. Measured outcomes were hospital mortality and early mortality rates, in-hospital time to discharge and time to discharge from intensive care unit.

RESULTS: One-hundred and sixteen patients met inclusion criteria. Patients treated after the introduction of the Massive Haemorrhage protocol had about 70% less chance of death during hospitalization compared to the group "before" (adjusted odds ratio 0.3, 95%confidence interval 0.1-0.8). They also had a significantly shorter hospital length of stay (p = 0.02).

CONCLUSIONS: Implementing a Massive Haemorrhage protocol including early administration of TXA was associated with the reduced mortality and hospital stay of severe adult blunt and penetrating trauma patients in a context with poor resources and limited availability of blood products.

Anesth Analg. 2019 Dec;129(6):1574-1584

# Tranexamic Acid for Acute Hemorrhage: A Narrative Review of Landmark Studies and a Critical Reappraisal of Its Use Over the Last Decade.

Lier H, Maegele M, Shander A

The publication of the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage-2 (CRASH-2) study and its intense dissemination prompted a renaissance for the use of the antifibrinolytic agent tranexamic acid (TXA) in acute trauma hemorrhage. Subsequent studies led to its widespread use as a therapeutic as well as prophylactic agent across different clinical scenarios involving bleeding, such as trauma, postpartum, and orthopedic surgery. However, results from the existing studies are confounded by methodological and statistical ambiguities and are open to varied interpretations. Substantial knowledge gaps remain on dosing, pharmacokinetics, mechanism of action, and clinical applications for TXA. The risk for potential thromboembolic complications with the use of TXA must be balanced against its clinical benefits. The present article aims to provide a critical reappraisal of TXA use over the last decade and a "thought exercise" in the potential downsides of TXA. A more selective and individualized use of TXA, guided by extended and functional coagulation assays, is advocated in the context of the evolving concept of precision medicine.

Adv Anesth. 2019 Dec;37:87-110

# Tranexamic Acid in the Perioperative Period: Yes, No, Maybe?

Richards J, Samet R, Koerner A, Grissom T

NO ABSTRACT AVAILABLE

Shock. 2019 Aug 5;Epub ahead of print

# Pharmacokinetics of Tranexamic Acid Given as an Intramuscular Injection Compared to Intravenous Infusion in a Swine Model of Ongoing Hemorrhage.

Spruce M, Beyer C, Caples C, DeSoucy E, Kashtan H, Hoareau G, Grayson J, Johnson M

INTRODUCTION: Tranexamic acid (TXA) improves survival in traumatic hemorrhage, but difficulty obtaining intravenous (IV) access may limit its use in austere environments, given its incompatibility with blood products. The bioavailability of intramuscular (IM) TXA in a shock state is unknown. We hypothesized that IM and IV administration have similar pharmacokinetics and ability to reverse in vitro hyperfibrinolysis in a swine controlled-hemorrhage model.

METHODS: Twelve Yorkshire cross swine were anesthetized, instrumented, and subjected to a 35% controlled hemorrhage, followed by resuscitation. During hemorrhage, they were randomized to receive a 1 g IV TXA infusion over 10 minutes, 1 g IM TXA in two 5 mL injections, or 10 mL normal saline IM injection as a placebo group to assess model adequacy. Serum TXA concentrations were determined using liquid chromatography-mass spectrometry, and plasma samples supplemented with tissue plasminogen activator (tPA) were analyzed by rotational thromboelastometry (ROTEM).

RESULTS: All animals achieved class III shock. There was no difference in the concentration-time areas under the curve (AUC) between TXA given by either route. The absolute bioavailability of IM TXA was 97%. IV TXA resulted in a higher peak serum concentration during the infusion, with no subsequent differences. Both IV and IM TXA administration caused complete reversal of in vitro tPA-induced hyperfibrinolysis.

CONCLUSION: The pharmacokinetics of IM TXA were similar to IV TXA during hemorrhagic shock in our swine model. IV administration resulted in a higher serum concentration only during the infusion, but all levels were able to successfully correct in vitro hyperfibrinolysis. There was no difference in total body exposure to equal doses of TXA between the two routes of administration. IM TXA may prove beneficial in scenarios where difficulty establishing dedicated IV access could otherwise limit or delay its use.

J Cardiothorac Vasc Anesth. 2019 Jul 4. pii: S1053-0770(19)30596-8

# Current Evidence and Future Directions of Tranexamic Acid Use, Efficacy, and Dosing for Major Surgical Procedures.

Taam J, Yang Q, Pang K, Karanicolas P, Choi S, Wasowicz M, Jerath A

Tranexamic acid reduces blood loss and transfusion requirements with nosignificant thrombotic adverse effects. Postoperative seizures have been seen in cardiac surgical patients in association with patient (advanced age, underlying neurologic disease, chronic kidney disease); surgical (open cardiac procedures, long bypass times); and drug (high tranexamic acid dose) risk factors. Tranexamic acid dosing regimens should be decreased in patients with chronic kidney dysfunction secondary to reduced clearance and drug accumulation. Optimal dosing for cardiac surgical patients has been recommended. Additional research is required to determine dosing regimens in major noncardiac surgery and plasma concentration levels associated with inducing seizures.

Medicina (Kaunas). 2019 Sep 2;55

# Geographical Variance in the Use of Tranexamic Acid for Major Trauma Patients.

Walsh K, O'Keeffe F, Mitra B

Background and Objectives: The CRASH-2 trial is the largest randomised control trial examining tranexamic acid (TXA) for injured patients. Since its publication, debate has arisen around whether results could be applied to mature trauma systems in developed nations, with global opinion divided. The aim of this study was to determine if, among trauma patients in or at significant risk of major haemorrhages, there is an association of geographic region with the proportion of patients that received tranexamic acid.

Materials and Methods: We conducted a systematic review of the literature. Potentially eligible papers were first screened via title and abstract screening. A full copy of the remaining papers was then obtained and screened for final inclusion. The Newcastle-Ottawa Scale for non-randomised control trials was used for quality assessment of the final studies included. A meta-analysis was conducted using a random-effects model, reporting variation in use sub-grouped by geographical location.

Results: There were 727 papers identified through database searching and 23 manuscripts met the criteria for final inclusion in this review. There was a statistically significant variation in the use of TXA for included patients. Europe and Oceania had higher usage rates of TXA compared to other continents. Use of TXA in Asia and Africa was significantly less than other continents and varied use was observed in North America. Conclusions: A large geographical variance in the use of TXA for trauma patients in or at significant risk of major haemorrhage currently exists. The populations in Asia and Africa, where the results of CRASH-2 could be most readily generalised to, reported low rates of use. The reason why remains unclear and further research is required to standardise the use of TXA for trauma resuscitation.