Tranexamic Acid Use in Prehospital Uncontrolled Hemorrhage.
ABSTRACT: The use of tranexamic acid (TXA) in the treatment of trauma patients was relatively unexplored until the landmark Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage-2 (CRASH-2) trial in 2010 demonstrated a reduction in mortality with the use of TXA. Although this trial was a randomized, double-blinded, placebo-controlled study incorporating >20,000 patients, numerous limitations and weaknesses have been described. As a result, additional studies have followed, delineating the potential risks and benefits of TXA administration. A systematic review of the literature to date reveals a mortality benefit of early (ideally <1 hour and no later than 3 hours after injury) TXA administration in the treatment of severely injured trauma patients (systolic blood pressure <90 mm Hg, heart rate >110). Combined with abundant literature showing a reduction in bleeding in elective surgery, the most significant benefit may be administration of TXA before the patient goes into shock. Those trials that failed to show a mortality benefit of TXA in the treatment of hemorrhagic shock acknowledged that most patients received blood products before TXA administration, thus confounding the results. Although the use of prehospital TXA in the severely injured trauma patient will become more clear with the trauma studies currently underway, the current literature supports the use of prehospital TXA in this high-risk population. We recommend considering a 1 g TXA bolus en route to definitive care in high-risk patients and withholding subsequent doses until hyperfibrinolysis is confirmed by thromboelastography.
Project description:Abstract Hemorrhage and coagulopathy remain major drivers of early preventable mortality in military and civilian trauma. The development of trauma-induced coagulopathy and hyperfibrinolysis is associated with poor outcomes. Interest in the use of tranexamic acid (TXA) in hemorrhaging patients as an antifibrinolytic agent has grown recently. Additionally, several reports describe immunomodulatory effects of TXA that may confer benefit independent of its antifibrinolytic actions. A large trial demonstrated a mortality benefit for early TXA administration in patients at risk for hemorrhage; however, questions remain about the applicability in developed trauma systems and the mechanism by which TXA reduces mortality. We describe here the rationale, design, and challenges of the Study of Tranexamic Acid during Air Medical Prehospital transport (STAAMP) trial. The primary objective is to determine the effect of prehospital TXA infusion during air medical transport on 30-day mortality in patients at risk of traumatic hemorrhage. This study is a multicenter, placebo-controlled, double-blind, randomized clinical trial. The trial will enroll trauma patients with hypotension and tachycardia from 4 level I trauma center air medical transport programs. It includes a 2-phase intervention, with a prehospital and in-hospital phase to investigate multiple dosing regimens. The trial will also explore the effects of TXA on the coagulation and inflammatory response following injury. The trial will be conducted under exception for informed consent for emergency research and thus required an investigational new drug approval from the U.S. Food and Drug Administration as well as a community consultation process. It was designed to address several existing knowledge gaps and research priorities regarding TXA use in trauma.
Project description:Many trauma systems are examining whether to implement prehospital tranexamic acid (TXA) protocols since hemorrhage remains the leading cause of potentially preventable early trauma mortality, and early in-hospital administration of TXA within 3?hours of injury is associated with reduced mortality. But robust evidence regarding the efficacy of prehospital administration of the antifibrinolytic drug TXA on trauma outcomes is lacking. This review examines the current evidence available regarding prehospital TXA efficacy in both military and civilian trauma, and updates available evidence regarding in-hospital TXA efficacy in trauma.
Project description:Hyperfibrinolysis (HF) is a major contributor to coagulopathy and mortality in trauma patients. This study investigated (i) the rate of HF during the pre-hospital management of patients with multiple injuries and (ii) the effects of pre-hospital tranexamic acid (TxA) administration on the coagulation system.From 27 trauma patients with pre-hospital an estimated injury severity score (ISS) ?16 points blood was obtained at the scene and on admission to the emergency department (ED). All patients received 1 g of TxA after the first blood sample was taken. Rotational thrombelastometry (ROTEM) was performed for both blood samples, and the results were compared. HF was defined as a maximum lysis (ML) >15 % in EXTEM.The median (min-max) ISS was 17 points (4-50 points). Four patients (15 %) had HF diagnosed via ROTEM at the scene, and 2 patients (7.5 %) had HF diagnosed via ROTEM on admission to the ED. The median ML before TxA administration was 11 % (3-99 %) vs. 10 % after TxA administration (4-18 %; p?>?0.05). TxA was administered 37 min (10-85 min) before ED arrival. The ROTEM results before and after TxA administration did not significantly differ. No adverse drug reactions were observed after TxA administration.HF can be present in severely injured patients during pre-hospital care. Antifibrinolytic therapy administered at the scene is a significant time saver. Even in milder trauma fibrinogen can be decreased to critically low levels. Early administration of TxA cannot reverse or entirely stop this decrease.The pre-hospital use of TxA should be considered for severely injured patients to prevent the worsening of trauma-induced coagulopathy and unnecessarily high fibrinogen consumption.ClinicalTrials.gov ID NCT01938768 (Registered 5 September 2013).
Project description:Trauma and hemorrhagic shock can lead to acute traumatic coagulopathy (ATC) that is not fully reversed by prehospital resuscitation as simulated with a limited volume of fresh whole blood (FWB) in a rat model. Tranexamic Acid (TXA) is used as an anti-fibrinolytic agent to reduce surgical bleeding if administered prior to or during surgery, and to improve survival in trauma if given early after trauma. It is not clear from the existing clinical literature whether TXA has the same mechanism of action in both settings. This study sought to explore the molecular mechanisms of TXA activity in trauma and determine whether administration of TXA as a supplement to FWB resuscitation could attenuate the established ATC in a rat model simulating prehospital resuscitation of polytrauma and hemorrhagic shock. In a parallel in-vitro study, the effects on clotting assays of adding plasmin at varying doses along with either simultaneous addition of TXA or pre-incubation with TXA were measured, and the results suggested that maximum anti-fibrinolytic effect of TXA on plasmin-induced fibrinolysis required pre-incubation of TXA and plasmin prior to clot initiation. In the rat model, ATC was induced by polytrauma followed by 40% hemorrhage. One hour after trauma, the rats were resuscitated with FWB collected from donor rats. Vehicle or TXA (10mg/kg) was given as bolus either before trauma (TXA-BT), or 45min after trauma prior to resuscitation (TXA-AT). The TXA-BT group was included to contrast the coagulation effects of TXA when used as it is in elective surgery vs. what is actually feasible in real trauma patients (TXA-AT group). A single dose of TXA prior to trauma significantly delayed the onset of ATC from 30min to 120min after trauma as measured by a rise in prothrombin time (PT). The plasma d-dimer as well as plasminogen/fibrinogen ratio in traumatized liver of TXA-BT were significantly lower as compared to vehicle and TXA-AT. Wet/dry weight ratio and leukocytes infiltration of lungs were significantly decreased only if TXA was administrated later, prior to resuscitation (TXA-AT). In conclusion: Limited prehospital trauma resuscitation that includes FWB and TXA may not correct established systemic ATC, but rather may improve overall outcomes of resuscitation by attenuation of acute lung injury. By contrast, TXA given prior to trauma reduced levels of fibrinolysis at the site of tissue injury and circulatory d-dimer, and delayed development of coagulopathy independent of reduction of fibrinogen levels following trauma. These findings highlight the importance of early administration of TXA in trauma, and suggest that further optimization of dosing protocols in trauma to exploit TXA's various sites and modes of action may further improve patient outcomes.
Project description:BACKGROUND:Patients with major trauma might benefit from treatment in a trauma centre, but early identification of major trauma (Injury Severity Score (ISS) over 15) remains difficult. The aim of this study was to undertake an external validation of existing prognostic models for injured patients to assess their ability to predict mortality and major trauma in the prehospital setting. METHODS:Prognostic models were identified through a systematic literature search up to October 2017. Injured patients transported by Emergency Medical Services to an English hospital from the Trauma Audit and Research Network between 2013 and 2016 were included. Outcome measures were major trauma (ISS over 15) and in-hospital mortality. The performance of the models was assessed in terms of discrimination (concordance index, C-statistic) and net benefit to assess the clinical usefulness. RESULTS:A total of 154?476 patients were included to validate six previously proposed prediction models. Discriminative ability ranged from a C-statistic value of 0·602 (95 per cent c.i. 0·596 to 0·608) for the Mechanism, Glasgow Coma Scale, Age and Arterial Pressure model to 0·793 (0·789 to 0·797) for the modified Rapid Emergency Medicine Score (mREMS) in predicting in-hospital mortality (11?882 patients). Major trauma was identified in 52?818 patients, with discrimination from a C-statistic value of 0·589 (0·586 to 0·592) for mREMS to 0·735 (0·733 to 0·737) for the Kampala Trauma Score in predicting major trauma. None of the prediction models met acceptable undertriage and overtriage rates. CONCLUSION:Currently available prehospital trauma models perform reasonably in predicting in-hospital mortality, but are inadequate in identifying patients with major trauma. Future research should focus on which patients would benefit from treatment in a major trauma centre.
Project description:The CRASH-2 trial showed that early administration of tranexamic acid (TXA) safely reduces mortality in bleeding in trauma patients. Based on data from the CRASH-2 trial, global mortality data and a systematic literature review, we estimated the number of premature deaths that might be averted every year worldwide through the use of TXA.We used CRASH-2 trial data to examine the effect of TXA on death due to bleeding by geographical region. We used WHO mortality data (2008) and data from a systematic review of the literature to estimate the annual number of in-hospital trauma deaths due to bleeding. We then used the relative risk estimates from the CRASH-2 trial to estimate the number of premature deaths that could be averted if all hospitalised bleeding trauma patients received TXA within one hour of injury, and within three hours of injury. Sensitivity analyses were used to explore the effect of uncertainty in the parameter estimates and the assumptions made in the model.There is no evidence that the effect of TXA on death due to bleeding varies by geographical region (heterogeneity p = 0.70). Based on WHO data and our systematic literature review, we estimate that each year worldwide there are approximately 400,000 in-hospital trauma deaths due to bleeding. If patients received TXA within one hour of injury then approximately 128,000 (uncertainty range [UR] ? 72,000 to 172,000) deaths might be averted. If patients received TXA within three hours of injury then approximately 112,000 (UR ? 68,000 to 148,000) deaths might be averted. Country specific estimates show that the largest numbers of deaths averted would be in India and China.The use of TXA in the treatment of traumatic bleeding has the potential to prevent many premature deaths every year. A large proportion of the potential health gains are in low and middle income countries.
Project description:The prevalence of tranexamic acid (TXA) use for trauma and other conditions in children is unknown.The objective of this study was to describe the use of TXA in United States (US) children's hospitals for children in general, and specifically for trauma.We conducted a secondary analysis of a large, administrative database of 36 US children's hospitals. We included children <18 years of age who received TXA (based on pharmacy charge codes) between 2009 and 2013. Patients were grouped into the following diagnostic categories: trauma, congenital heart surgery, scoliosis surgery, craniosynostosis/craniofacial surgery, and other, based on the International Classification of Diseases, Ninth Revision principal procedure and diagnostic codes. TXA administration and dosage, in-hospital clinical variables, and diagnostic and procedure codes were documented.A total of 35,478 pediatric encounters with a TXA charge were included in the study cohort. The proportions of children who received TXA were similar across the years 2009 to 2013. Only 110 encounters (0.31%) were for traumatic conditions. Congenital heart surgery accounted for more than one-half of the encounters (22,863; 64%). Overall, the median estimated weight-based dose of TXA was 22.4 mg/kg (interquartile range, 7.3-84.9 mg/kg).We identified a wide frequency of use and range of doses of TXA for several diagnostic conditions in children. The use of TXA among injured children, however, appears to be rare despite its common use and efficacy among injured adults. Additional work is needed to identify appropriate indications for TXA and provide dosage guidelines among children with a variety of conditions, including trauma.
Project description:Introduction:The CRASH-2 trial demonstrated that tranexamic acid (TXA) reduced mortality with no increase in adverse events in severely injured adults. TXA has since been widely used in injured adults worldwide. Our objective was to estimate mortality and adverse events in adults with trauma receiving TXA in studies published after the CRASH-2 trial. Methods:We systematically searched PubMed, Embase, MicroMedex, and ClinicalTrials.gov for studies that included injured adults who received TXA and reported mortality and/or adverse events. Two reviewers independently assessed study eligibility, abstracted data, and assessed the risk of bias. We conducted meta-analyses using random effects models to estimate the incidence of mortality at 28 or 30 days and in-hospital thrombotic events. Results:We included 19 studies and 13 studies in the systematic review and meta-analyses, respectively. The pooled incidence of mortality at 28 or 30 days (five studies, 1538 patients) was 10.1% (95% confidence interval [CI], 7.8-12.4%) (vs 14.5% [95% CI, 13.9-15.2%] in the CRASH-2 trial), and the pooled incidence of in-hospital thrombotic events (nine studies, 1656 patients) was 5.9% (95% CI, 3.3-8.5%) (vs 2.0% [95% CI, 1.8-2.3%] in the CRASH-2 trial). Conclusion:Compared to the CRASH-2 trial, adult trauma patients receiving TXA identified in our systematic review had a lower incidence of mortality at 28 or 30 days, but a higher incidence of in-hospital thrombotic events. Our findings neither support nor refute the findings of the CRASH-2 trial but suggest that incidence rates in adults with trauma in settings outside of the CRASH-2 trial may be different than those observed in the CRASH-2 trial.
Project description:BACKGROUND:Whether rapid transportation can benefit patients with trauma remains controversial. We determined the association between prehospital time and outcome to explore the concept of the "golden hour" for injured patients. METHODS AND FINDINGS:We conducted a retrospective cohort study of trauma patients transported from the scene to hospitals by emergency medical service (EMS) from January 1, 2016, to November 30, 2018, using data from the Pan-Asia Trauma Outcomes Study (PATOS) database. Prehospital time intervals were categorized into response time (RT), scene to hospital time (SH), and total prehospital time (TPT). The outcomes were 30-day mortality and functional status at hospital discharge. Multivariable logistic regression was used to investigate the association of prehospital time and outcomes to adjust for factors including age, sex, mechanism and type of injury, Injury Severity Score (ISS), Revised Trauma Score (RTS), and prehospital interventions. Overall, 24,365 patients from 4 countries (645 patients from Japan, 16,476 patients from Korea, 5,358 patients from Malaysia, and 1,886 patients from Taiwan) were included in the analysis. Among included patients, the median age was 45 years (lower quartile [Q1]-upper quartile [Q3]: 25-62), and 15,498 (63.6%) patients were male. Median (Q1-Q3) RT, SH, and TPT were 20 (Q1-Q3: 12-39), 21 (Q1-Q3: 16-29), and 47 (Q1-Q3: 32-60) minutes, respectively. In all, 280 patients (1.1%) died within 30 days after injury. Prehospital time intervals were not associated with 30-day mortality. The adjusted odds ratios (aORs) per 10 minutes of RT, SH, and TPT were 0.99 (95% CI 0.92-1.06, p = 0.740), 1.08 (95% CI 1.00-1.17, p = 0.065), and 1.03 (95% CI 0.98-1.09, p = 0.236), respectively. However, long prehospital time was detrimental to functional survival. The aORs of RT, SH, and TPT per 10-minute delay were 1.06 (95% CI 1.04-1.08, p < 0.001), 1.05 (95% CI 1.01-1.08, p = 0.007), and 1.06 (95% CI 1.04-1.08, p < 0.001), respectively. The key limitation of our study is the missing data inherent to the retrospective design. Another major limitation is the aggregate nature of the data from different countries and unaccounted confounders such as in-hospital management. CONCLUSIONS:Longer prehospital time was not associated with an increased risk of 30-day mortality, but it may be associated with increased risk of poor functional outcomes in injured patients. This finding supports the concept of the "golden hour" for trauma patients during prehospital care in the countries studied.
Project description: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.