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Abstract: When pregnant patients are involved in traumatic incidents, the trauma clinician encounters two patients-both the mother and the unborn child. Advanced trauma life support dictates that the first priority is the life of the mother; however, there are rare situations where to provide the greatest chance of survival for both the mother and baby, an emergency cesarean section (perimortem cesarean delivery [PMCD]) must be performed. The decision to perform this procedure must occur quickly, and the reality is that a board-certified obstetrician is rarely present, particularly in rural areas. In this review, we provide a rationale for why trauma clinicians should be conversant with PMCDs, present the specific time limitations for performing a PMCD, and discuss the technique to perform a successful PMCD that makes it distinctly different from an elective cesarean delivery. Finally, we will discuss some things that a trauma program can do proactively in an obstetrical resource-poor area of the country to prepare for the rare instances where these procedures are necessary., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Postpartum hemorrhage is the leading cause of preventable maternal illness and death globally and carries a disproportionately high burden of mortality in low- to middle-income countries. Tranexamic acid, an antifibrinolytic drug, has been widely adopted to control bleeding in trauma and other surgical conditions. Within the last decade, the World Health Organization updated their guidelines for the treatment of postpartum hemorrhage to include the use of tranexamic acid in all cases of postpartum hemorrhage. However, despite these guidelines and the proven utility of tranexamic acid to treat postpartum hemorrhage, widespread adoption of tranexamic acid into global standards of care across professional organizations has not been achieved. It is important for healthcare providers to understand the etiologies of postpartum hemorrhage, the mechanism of action and adverse effect profile of tranexamic acid, and the available literature regarding the use of tranexamic acid to prevent and treat postpartum hemorrhage to provide the best care for the pregnant patient., Competing Interests: The author reports no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Introduction: Tranexamic acid (TXA) is a potent antifibrinolytic drug that inhibits the activation of plasmin by plasminogen. While not a new medication, TXA has quickly gained traction across a variety of surgical subspecialties to prevent and treat bleeding. Knowledge on the use of this drug is essential for the modern surgeon to continue to provide excellent care to their patients., Methods: A comprehensive review of the PubMed database was conducted of articles published within the last 10 y (2014-2024) relating to TXA and its use in various surgical subspecialties. Seminal studies regarding the use of TXA older than 10 y were included from the author's archives., Results: Indications for TXA are not limited to trauma alone, and TXA is utilized across a variety of surgical subspecialties from neurosurgery to hepatic surgery to control hemorrhage. Overall, TXA is well tolerated with common dose-dependent adverse effects, including headache, nasal symptoms, dizziness, nausea, diarrhea, and fatigue. More severe adverse events are rare and easily mitigated by not exceeding a dose of 50 mg/kg., Conclusions: The administration of TXA as an adjunct to treat trauma saves lives. The ability of TXA to induce seizures is dose dependent with identifiable risk factors, making this serious adverse effect predictable. As for the potential for TXA to cause thrombotic events, uncertainty remains. If this association is proven to be real, the risk will likely be small, since the use of TXA is still advantageous in most situations because of its efficacy for a more common concern, bleeding., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Since the beginning of time, man has been intrigued with the question of when a person is considered dead. Traditionally, death has been considered the cessation of all cardiorespiratory function. At the end of the last century a new definition was introduced into the lexicon surrounding death in addition to cessation of cardiac and respiratory function: Brain Death/Death by Neurologic Criteria (BD/DNC). There are medical, legal, ethical, and even theological controversies that surround this diagnosis. In addition, there is no small amount of confusion among medical practitioners regarding the diagnosis of BD/DNC. For families enduring the devastating development of BD/DNC in their loved one, it is the duty of the principal caregiver to provide a transparent presentation of the clinical situation and clear definitive explanation of what constitutes BD/DNC. In this report, we present a historical outline of the development of BD/DNC as a clinical entity, specifically how one goes about making a determination of BD/DNC, what steps are taken once a diagnosis of BD/DNC is made, a brief discussion of some of the ethical/moral issues surrounding this diagnosis, and finally the caregiver approach to the family of a patient who had been declared with BD/DNC. It is our humble hope that with a greater understanding of the myriad of complicated issues surrounding the diagnosis of BD/DNC that the bedside caregiver can provide needed closure for both the patient and the family enduring this critical time in their life., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Shock is a life-threatening circulatory failure that results in inadequate tissue perfusion and oxygenation. Vasopressors and inotropes are vasoactive medications that are vital in increasing systemic vascular resistance and cardiac contractility, respectively, in patients presenting with shock. To be well versed in using these agents is an important skill to have in the critical care setting where patients can frequently exhibit symptoms of shock. In this review, we will discuss the pathophysiological mechanisms of shock and evaluate the current evidence behind the management of shock with an emphasis on vasopressors and inotropes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: There are 3 pillars upon which the foundation of a teaching program in health care is founded: research, education, and clinical care. However, in a busy academic trauma practice, the unfortunate reality is that research is often a low priority in the frenzy of mandates for clinical productivity., Objective: The purpose of this report is to advise hospitals on how to create a modest trauma research program that supports research interests without significantly impacting the overall clinical productivity of the department., Methods: Relevant literature related to the development of an academic trauma research department was reviewed. Relevant articles were then compared to this manuscript to assess the novelty of the topic., Results: There are 4 essential components of a trauma research program: (1) a zealot, (2) institutional commitment and support, (3) a statistician, and (4) registry data access., Conclusion: The creation of a trauma research program may seem like a herculean effort, but this work is necessary for institutions hoping to achieve status as a Level I/II trauma center. Following the steps outlined in this report, trauma providers can create a robust research program at their institution without sacrificing clinical productivity., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Society of Trauma Nurses.)

Injury is both a national and international epidemic that affects people of all age, race, religion, and socioeconomic class. Injury was the fourth leading cause of death in the United States (U.S.) in 2021 and results in an incalculable emotional and financial burden on our society. Despite this, when prevention fails, trauma centers allow communities to prepare to care for the traumatically injured patient. Using lessons learned from the military, trauma care has grown more sophisticated in the last 50 years. In 1966, the first civilian trauma center was established, bringing management of injury into the new age. Now, the American College of Surgeons recognizes 4 levels of trauma centers (I-IV), with select states recognizing Level V trauma centers. The introduction of trauma centers in the U.S. has been proven to reduce morbidity and mortality for the injured patient. However, despite the proven benefits of trauma centers, the U.S. lacks a single, unified, trauma system and instead operates within a "system of systems" creating vast disparities in the level of care that can be received, especially in rural and economically disadvantaged areas. In this review we present the history of trauma system development in the U.S, define the different levels of trauma centers, present evidence that trauma systems and trauma centers improve outcomes, outline the current state of trauma system development in the U.S, and briefly mention some of the current challenges and opportunities in trauma system development in the U.S. today., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Level of Evidence: Therapeutic/Care Management: Level V., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The benefits of organized trauma systems have been well-documented during 50 years of trauma system development in the United States. Unfortunately, despite this evidence, trauma system development has occurred only sporadically in the 50 states., Methods: The relevant literature related to trauma system design and development was reviewed based on relevance to the study. Information from these sources was summarized into a SWOT (strengths, weaknesses, opportunities, and threats) analysis., Results: Strengths discovered were leadership brought forth by the American College of Surgeons Committee on Trauma and meaningful change generated from The National Academy of Sciences, Engineering, and Medicine report addressing the fractionation of the nation's trauma systems, whereas weaknesses included patient outcome disparities due to the lack of a national governing authority, undertriage, underresourced rural trauma, and underfunded trauma research. Opportunities included the creation of level IV trauma centers; telemedicine; the development of rural trauma management courses; air medical transport to bring high-intensity care to the patient, particularly in rural areas; trauma research; and trauma prevention through outreach and educational programs. The following threats were determined: mass casualty incidents, motor vehicle collisions because of the high rate of motor vehicle collision deaths in the United States relative to other developed countries, and underfunded trauma systems., Conclusion: Much work remains to be done in the development of an American trauma system. Recommendations include implementation of trauma care governance at the federal level; national oversight and support of emergency medical services systems, particularly in rural areas with strict reporting processes for emergency medical services programs; national organization of our mass casualty response; increased federal and state funding allocated to trauma centers; a consistent model for trauma system development; and trauma research., (Copyright © 2023 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)

Surgical science has driven innovation and inquiry across adult and pediatric disciplines that provide critical care regardless of location. Surgically originated but broadly applicable knowledge has been globally shared within the pages Critical Care Medicine over the last 50 years., Competing Interests: Dr. Coopersmith reports funding form the National Institute of Health (NIH) under grants GM072808, GM104323, and AA027396. Drs. Napolitano and Efron have previously served as Council members of the Society of Critical Care Medicine. Drs. Coopersmith, Efron, and Kaplan all serve on the editorial board of Critical Care Medicine. Dr. Cannon received funding from UptoDate; he disclosed that he is a consultant for CSL Behring. Drs. Kozar’s and Coopersmith’s institutions received funding from the NIH. Dr. Kozar’s institution received funding form the Department of Defense (DoD). Dr. Sugrue received funding from Novus Scientific and Smith and Nephew. Dr. Tiserhman’s institution received funding from the DoD (W81XWH-07-1-068 and W81XWH-18-1-0601); he disclosed that he is co-author of a patent for “Emergency Preservation and Resuscitation Method”; he disclosed the off-label product use of cardiopulmonary bypass equipment and saline. Dr. Coopersmith received support for article research from the NIH. Dr. Kaplan received funding from Society of Critical Care Medicine. Dr. Tisherman is a co-author of a patent for “Emergency Preservation and Resuscitation Method.” The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: Head-elevated body positioning, a default clinical practice, predictably increases end-expiratory transpulmonary pressure and aerated lung volume. In acute respiratory distress syndrome (ARDS), however, the net effect of such vertical inclination on tidal mechanics depends upon whether lung recruitment or overdistension predominates. We hypothesized that in moderate to severe ARDS, bed inclination toward vertical unloads the chest wall but adversely affects overall respiratory system compliance (C rs )., Design: Prospective physiologic study., Setting: Two medical ICUs in the United States., Patients: Seventeen patients with ARDS, predominantly moderate to severe., Intervention: Patients were ventilated passively by volume control. We measured airway pressures at baseline (noninclined) and following bed inclination toward vertical by an additional 15°. At baseline and following inclination, we manually loaded the chest wall to determine if C rs increased or paradoxically declined, suggestive of end-tidal overdistension., Measurements and Main Results: Inclination resulted in a higher plateau pressure (supineΔ: 2.8 ± 3.3 cm H 2 O [ p = 0.01]; proneΔ: 3.3 ± 2.5 cm H 2 O [ p = 0.004]), higher driving pressure (supineΔ: 2.9 ± 3.3 cm H 2 O [ p = 0.01]; proneΔ: 3.3 ± 2.8 cm H 2 O [ p = 0.007]), and lower C rs (supine Δ: 3.4 ± 3.7 mL/cm H 2 O [ p = 0.01]; proneΔ: 3.1 ± 3.2 mL/cm H 2 O [ p = 0.02]). Following inclination, manual loading of the chest wall restored C rs and driving pressure to baseline (preinclination) values., Conclusions: In advanced ARDS, bed inclination toward vertical adversely affects C rs and therefore affects the numerical values for plateau and driving tidal pressures commonly targeted in lung protective strategies. These changes are fully reversed with manual loading of the chest wall, suggestive of end-tidal overdistension in the upright position. Body inclination should be considered a modifiable determinant of transpulmonary pressure and lung protection, directionally similar to tidal volume and positive end-expiratory pressure., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Background: Chest wall loading has been shown to paradoxically improve respiratory system compliance (C RS ) in patients with moderate to severe acute respiratory distress syndrome (ARDS). The most likely, albeit unconfirmed, mechanism is relief of end-tidal overdistension in 'baby lungs' of low-capacity. The purpose of this study was to define how small changes of tidal volume (V T ) and positive end-expiratory pressure (PEEP) affect C RS (and its associated airway pressures) in patients with ARDS who demonstrate a paradoxical response to chest wall loading. We hypothesized that small reductions of V T or PEEP would alleviate overdistension and favorably affect C RS and conversely, that small increases of V T or PEEP would worsen C RS ., Methods: Prospective, multi-center physiologic study of seventeen patients with moderate to severe ARDS who demonstrated paradoxical responses to chest wall loading. All patients received mechanical ventilation in volume control mode and were passively ventilated. Airway pressures were measured before and after decreasing/increasing V T by 1 ml/kg predicted body weight and decreasing/increasing PEEP by 2.5 cmH 2 O., Results: Decreasing either V T or PEEP improved C RS in all patients. Driving pressure (DP) decreased by a mean of 4.9 cmH 2 O (supine) and by 4.3 cmH 2 O (prone) after decreasing V T , and by a mean of 2.9 cmH 2 O (supine) and 2.2 cmH 2 O (prone) after decreasing PEEP. C RS increased by a mean of 3.1 ml/cmH 2 O (supine) and by 2.5 ml/cmH 2 O (prone) after decreasing V T. C RS increased by a mean of 5.2 ml/cmH 2 O (supine) and 3.6 ml/cmH 2 O (prone) after decreasing PEEP (P < 0.01 for all). Small increments of either V T or PEEP worsened C RS in the majority of patients., Conclusion: Patients with a paradoxical response to chest wall loading demonstrate uniform improvement in both DP and C RS following a reduction in either V T or PEEP, findings in keeping with prior evidence suggesting its presence is a sign of end-tidal overdistension. The presence of 'paradox' should prompt re-evaluation of modifiable determinants of end-tidal overdistension, including V T , PEEP, and body position., (© 2022. The Author(s).)

Lung injury from smoke inhalation manifests as airway and parenchymal damage, at times leading to the acute respiratory distress syndrome. From the beginning of this millennium, the approach to mechanical ventilation in the patient with ARDS was based on reduction of tidal volume to 6 milliliters/kilogram of ideal body weight, maintaining a ceiling of plateau pressure, and titration of driving pressure (plateau pressure minus PEEP). Beyond these broad constraints, there is little specification for the mechanics of ventilator settings, consideration of the metabolic impact of the disease process on the patient, or interaction of patient disease and ventilator settings. Various studies suggest that inhomogeneity of lung injury, which increases the risk of regional lung trauma from mechanical ventilation, may be found in the patient with smoke inhalation. We now appreciate that energy transfer principles may affect optimal ventilator management and come into play in damaged heterogenous lungs. Mechanical ventilation in the patient with inhalation injury should consider various factors. Self-injurious respiratory demand by the patient can be reduced using analgesia and sedation. Dynamic factors beginning with rate management can reduce the incidence of potentially damaging ventilation. Moreover, preclinical study is underway to examine the flow of gas based on the ventilator mode selected, which may also be a factor triggering regional lung injury., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rationale: Monitoring tidal cycle mechanics is key to lung protection. For this purpose, compliance and driving pressure of the respiratory system are often measured clinically using the plateau pressure, obtained after imposing an extended end-inspiratory pause, which allows for relaxation of the respiratory system and redistribution of inflation volume (method A). Alternative methods for estimating compliance and driving pressure utilize the measured pressure at the earliest instance of zero flow (method B), the inspiratory slope of the pressure-time tracing during inflation with constant flow (method C), and the expiratory time constant (method D)., Methods: Ten passive mechanically ventilated subjects, at a large tertiary referral center, underwent measurements of compliance and driving pressure using the four different methods. The inspiratory tidal volume, inspiratory to expiratory ratio, and positive end expiratory pressures were then adjusted from baseline and the measurements re-obtained., Results: Method A yielded consistently higher compliance and lower driving pressure calculations compared to methods B and C. Methods B and C most closely approximated one another. Method D did not yield a consistent reliable pattern., Conclusion: Static measurements of compliance and driving pressure using the plateau pressure may underestimate the maximum pressure experienced by the most vulnerable lung units during dynamic inflation. Utilizing the pressure at zero flow as a static measurement, or the inspiratory slope as a dynamic measurement, may calculate a truer estimate of the maximum alveolar pressure that generates stress upon compromised lung units., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tawfik, Syed, Elmufdi, Evans, Dries and Marini.)

Background: Ventilator-induced lung injury (VILI) requires repetitive transfer of energy from the ventilator to the compromised lung. To understand this phenomenon, 2 sets of equations have been developed to partition total inflation energy into harmless and hazardous components using an arbitrary level of alveolar pressure as a threshold beyond which further energy increments may become damaging. One set of equations uses premeasured resistance and compliance as inputs to predict the energy that would be delivered by typical ventilator settings, whereas the other equation set uses observed output values for end-inspiratory peak and plateau pressure of an already completed inflation., Methods: Our aim for this study was to compare the relative accuracy of these equation sets against the performance of a physical one-compartment model of the respiratory system, programmed with information readily available at the bedside and ventilated using both constant and decelerating flow profiles. Accordingly, equations of each set were compared against the corresponding energy areas measured by digital planimetry of pressure-volume curves for 76 ventilator and patient parameter combinations and over 500 power calculations., Results: With few exceptions, all equations strongly correlated with their corresponding measurements by planimetry., Conclusions: This validation of threshold-partitioned energy equations suggests their potential utility for implementing practical strategies for VILI avoidance., Competing Interests: The authors have disclosed a relationship with Medtronic., (Copyright © 2022 by Daedalus Enterprises.)

Competing Interests: The author reports no conflicts of interest.

Background: High rates of inflation energy delivery coupled with transpulmonary tidal pressures of sufficient magnitude may augment the risk of damage to vulnerable, stress-focused units within a mechanically heterogeneous lung. Apart from flow amplitude, the clinician-selected flow waveform, a relatively neglected dimension of inflation power, may distribute inflation energy of each inflation cycle non-uniformly among alveoli with different mechanical properties over the domains of time and space. In this initial step in modeling intracycle power distribution, our primary objective was to develop a mathematical model of global intracycle inflation power that uses clinician-measurable inputs to allow comparisons of instantaneous ICP profiles among the flow modes commonly encountered in clinical practice: constant, linearly decelerating, exponentially decelerating (pressure control), and spontaneous (sinusoidal)., Methods: We first tested the predictions of our mathematical model of passive inflation with the actual physical performance of a mechanical ventilator-lung system that simulated ventilation to three types of patients: normal, severe ARDS, and severe airflow obstruction. After verification, model predictions were then generated for 5000 'virtual ARDS patients'. Holding constant the tidal volume and inflation time between modes, the validated model then varied the flow profile and quantitated the resulting intensity and timing of potentially damaging 'elastic' energy and intracycle power (pressure-flow product) developed in response to random combinations of machine settings and severity levels for ARDS., Results: Our modeling indicates that while the varied flow patterns ultimately deliver similar total amounts of alveolar energy during each breath, they differ profoundly regarding the potentially damaging pattern with which that energy distributes over time during inflation. Pressure control imposed relatively high maximal intracycle power., Conclusions: Flow amplitude and waveform may be relatively neglected and modifiable determinants of VILI risk when ventilating ARDS., (© 2021. The Author(s).)

Background: Although specific interventions previously demonstrated benefit in patients with ARDS, use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown., Research Question: What is the impact of treatment variability on mortality in patients with moderate to severe ARDS in the United States?, Study Design and Methods: We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and Pao 2 to Fio 2 ratio of ≤ 150 with positive end-expiratory pressure of ≥ 5 cm H 2 O, who were admitted to 29 US centers between October 1, 2016, and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality also were assessed., Results: A total of 2,466 patients were enrolled. Median baseline Pao 2 to Fio 2 ratio was 105 (interquartile range, 78.0-129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (LPV; tidal volume, ≤ 6.5 mL/kg predicted body weight; plateau pressure, or when unavailable, peak inspiratory pressure, ≤ 30 mm H 2 O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), methods used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7%-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early LPV was correlated with SMR., Interpretation: Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes., Trial Registry: ClinicalTrials.gov; No.: NCT03021824; URL: www.clinicaltrials.gov., (Copyright © 2021. Published by Elsevier Inc.)

Competing Interests: The authors have disclosed no conflicts of interest.

Background: No Food and Drug Administration-approved medication improves outcomes following traumatic brain injury (TBI). A forthcoming clinical trial that evaluated the effects of two prehospital tranexamic acid (TXA) dosing strategies compared with placebo demonstrated no differences in thromboelastography (TEG) values. We proposed to explore the impact of TXA on markers of coagulation and fibrinolysis in patients with moderate to severe TBI., Methods: Data were extracted from a placebo-controlled clinical trial in which patients 15 years or older with TBI (Glasgow Coma Scale, 3-12) and systolic blood pressure of ≥90 mm Hg were randomized prehospital to receive placebo bolus/placebo infusion (placebo), 1 g of TXA bolus/1 g of TXA infusion (bolus maintenance), or 2 g of TXA bolus/placebo infusion (bolus only). Thromboelastography was performed, and coagulation measures including prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, D-dimer, plasmin-antiplasmin (PAP), thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were quantified at admission and 6 hours later., Results: Of 966 patients receiving study drug, 700 had laboratory tests drawn at admission and 6 hours later. There were no statistically significant differences in TEG values, including LY30, between groups (p > 0.05). No differences between prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were demonstrated across treatment groups. Concentrations of D-dimer in TXA treatment groups were less than placebo at 6 hours (p < 0.001). Concentrations of PAP in TXA treatment groups were less than placebo on admission (p < 0.001) and 6 hours (p = 0.02). No differences in D-dimer and PAP were observed between bolus maintenance and bolus only., Conclusion: While D-dimer and PAP levels reflect a lower degree of fibrinolysis following prehospital administration of TXA when compared with placebo in a large prehospital trial of patients with TBI, TEG obtained on admission and 6 hours later did not demonstrate any differences in fibrinolysis between the two TXA dosing regimens and placebo., Level of Evidence: Diagnostic test, level III.

Importance: Traumatic brain injury (TBI) is the leading cause of death and disability due to trauma. Early administration of tranexamic acid may benefit patients with TBI., Objective: To determine whether tranexamic acid treatment initiated in the out-of-hospital setting within 2 hours of injury improves neurologic outcome in patients with moderate or severe TBI., Design, Setting, and Participants: Multicenter, double-blinded, randomized clinical trial at 20 trauma centers and 39 emergency medical services agencies in the US and Canada from May 2015 to November 2017. Eligible participants (N = 1280) included out-of-hospital patients with TBI aged 15 years or older with Glasgow Coma Scale score of 12 or less and systolic blood pressure of 90 mm Hg or higher., Interventions: Three interventions were evaluated, with treatment initiated within 2 hours of TBI: out-of-hospital tranexamic acid (1 g) bolus and in-hospital tranexamic acid (1 g) 8-hour infusion (bolus maintenance group; n = 312), out-of-hospital tranexamic acid (2 g) bolus and in-hospital placebo 8-hour infusion (bolus only group; n = 345), and out-of-hospital placebo bolus and in-hospital placebo 8-hour infusion (placebo group; n = 309)., Main Outcomes and Measures: The primary outcome was favorable neurologic function at 6 months (Glasgow Outcome Scale-Extended score >4 [moderate disability or good recovery]) in the combined tranexamic acid group vs the placebo group. Asymmetric significance thresholds were set at 0.1 for benefit and 0.025 for harm. There were 18 secondary end points, of which 5 are reported in this article: 28-day mortality, 6-month Disability Rating Scale score (range, 0 [no disability] to 30 [death]), progression of intracranial hemorrhage, incidence of seizures, and incidence of thromboembolic events., Results: Among 1063 participants, a study drug was not administered to 96 randomized participants and 1 participant was excluded, resulting in 966 participants in the analysis population (mean age, 42 years; 255 [74%] male participants; mean Glasgow Coma Scale score, 8). Of these participants, 819 (84.8%) were available for primary outcome analysis at 6-month follow-up. The primary outcome occurred in 65% of patients in the tranexamic acid groups vs 62% in the placebo group (difference, 3.5%; [90% 1-sided confidence limit for benefit, -0.9%]; P = .16; [97.5% 1-sided confidence limit for harm, 10.2%]; P = .84). There was no statistically significant difference in 28-day mortality between the tranexamic acid groups vs the placebo group (14% vs 17%; difference, -2.9% [95% CI, -7.9% to 2.1%]; P = .26), 6-month Disability Rating Scale score (6.8 vs 7.6; difference, -0.9 [95% CI, -2.5 to 0.7]; P = .29), or progression of intracranial hemorrhage (16% vs 20%; difference, -5.4% [95% CI, -12.8% to 2.1%]; P = .16)., Conclusions and Relevance: Among patients with moderate to severe TBI, out-of-hospital tranexamic acid administration within 2 hours of injury compared with placebo did not significantly improve 6-month neurologic outcome as measured by the Glasgow Outcome Scale-Extended., Trial Registration: ClinicalTrials.gov Identifier: NCT01990768.