The effects of prehospital TXA on mortality and neurologic outcomes in patients with traumatic intracranial hemorrhage: a subgroup analysis from the prehospital TXA for TBI trial.

BACKGROUND: In the Prehospital Tranexamic Acid (TXA) for TBI Trial, TXA administered within two hours of injury in the out-of-hospital setting did not reduce mortality in all patients with moderate/severe traumatic brain injury (TBI). We examined the association between TXA dosing arms, neurologic outcome, and mortality in patients with intracranial hemorrhage (ICH) on computed tomography (CT). METHODS: This was a secondary analysis of the Prehospital Tranexamic Acid for TBI Trial (ClinicalTrials.gov [NCT01990768]) that randomized adults with moderate/severe TBI (Glasgow Coma Scale<13) and systolic blood pressure > =90 mmHg within two hours of injury to a 2-gram out-of-hospital TXA bolus followed by an in-hospital saline infusion, a 1-gram out-of-hospital TXA bolus/1-gram in-hospital TXA infusion, or an out-of-hospital saline bolus/in-hospital saline infusion (placebo). This analysis included the subgroup with ICH on initial CT. Primary outcomes included 28-day mortality, 6-month Glasgow Outcome Scale-Extended (GOSE) < = 4, and 6-month Disability Rating Scale (DRS). Outcomes were modeled using linear regression with robust standard errors. RESULTS: The primary trial included 966 patients. Among 541 participants with ICH, 28-day mortality was lower in the 2-gram TXA bolus group (17%) compared to the other two groups (1-gram bolus/1-gram infusion 26%, placebo 27%). The estimated adjusted difference between the 2-gram bolus and placebo groups was -8·5 percentage points (95% CI, -15.9 to -1.0) and between the 2-gram bolus and 1-gram bolus/1-gram infusion groups was -10.2 percentage points (95% CI, -17.6 to -2.9). DRS at 6 months was lower in the 2-gram TXA bolus group than the 1-gram bolus/1-gram infusion (estimated difference -2.1 [95% CI, -4.2 to -0.02]) and placebo groups (-2.2 [95% CI, -4.3, -0.2]). Six-month GOSE did not differ among groups. CONCLUSIONS: A 2-gram out-of-hospital TXA bolus in patients with moderate/severe TBI and ICH resulted in lower 28-day mortality and lower 6-month DRS than placebo and standard TXA dosing. LEVEL OF EVIDENCE: Therapeutic/Care Management, Level II.

Predicting Progression of Intracranial Hemorrhage in the Prehospital TXA for TBI Trial.

Progression of intracranial hemorrhage is a common, potentially devastating complication after moderate/severe traumatic brain injury (TBI). Clinicians have few tools to predict which patients with traumatic intracranial hemorrhage on their initial head computed tomography (hCT) scan will progress. The objective of this investigation was to identify clinical, imaging, and/or protein biomarkers associated with progression of intracranial hemorrhage (PICH) after moderate/severe TBI and to create an accurate predictive model of PICH based on clinical features available at presentation. We analyzed a subset of subjects from the phase II double-blind, multi-center, randomized "Prehospital Tranexamic Acid Use for TBI" trial. This subset was limited to the placebo arm of the parent trial with evidence of hemorrhage on the initial hCT and a follow-up hCT 6 h after. PICH was defined as an increase in hemorrhage size by 30% or more, or the development of new hemorrhage in the intra- and extra-axial intracranial vault between the initial and the follow-up hCT. Two independent radiologists evaluated each hCT, and conflicts were adjudicated by a third. Clinical and radiographic characteristics were collected, along with plasma protein biomarkers at admission. Principal component analysis (PCA) was performed, and each principal component (PC) was interrogated for its association with PICH. Finally, expert opinion and recursive feature extraction (RFE) were used to select input features for the construction of several supervised classification models. Their ability to predict PICH was quantified and compared. In this subset of subjects (n = 104), 46% (n = 48) demonstrated PICH. Univariate analyses showed no association between PICH and age, sex, admission Glasgow Coma Scale (GCS), GCS motor subscore, presence of midline shift, admission platelet count or admission INR. Radiographic severity scores (Marshall score [p = 0.007], Rotterdam score [p = 0.004]), and initial hematoma volume [p = 0.005] were associated with PICH. Higher levels of admission glial fibrillary acidic protein (p < 0.001) and MAP (p = 0.011) were also associated with PICH. Of the PCs, PC1 was significantly associated with PICH (p = 0.0125). Using multimodal data input, machine learning classifiers successfully discriminated patients with or without PICH. Models composed of machine-selected features performed better than models composed of expert-selected variables (reaching an average of 77% accuracy, AUC = 0.78 versus AUC = 0.68 for the expert-selected variables). Predictive models utilizing variables measured at admission can accurately predict PICH, confirmed by the 6-hour follow-up hCT. Our best-performing models must now be externally validated in a separate cohort of TBI patients with low GCS and initial hCT positive for hemorrhage.

Prehospital tranexamic acid is associated with a survival benefit without an increase in complications: results of two harmonized randomized clinical trials.

INTRODUCTION: Recent randomized clinical trials have demonstrated that prehospital tranexamic acid (TXA) administration following injury is safe and improves survival. However, the effect of prehospital TXA on adverse events, transfusion requirements and any dose response relationships require further elucidation. METHODS: A secondary analysis was performed using harmonized data from two large, double-blinded, randomized prehospital TXA trials. Outcomes, including 28-day mortality, pertinent adverse events and 24-hour red cell transfusion requirements were compared between TXA and placebo groups. Regression analyses were utilized to determine the independent associations of TXA after adjusting for study enrollment, injury characteristics and shock severity across a broad spectrum of injured patients. Dose response relationships were similarly characterized based upon grams of prehospital TXA administered. RESULTS: A total of 1744 patients had data available for secondary analysis and were included in the current harmonized secondary analysis. The study cohort had an overall mortality of 11.2% and a median injury severity score of 16 (IQR: 5-26). TXA was independently associated with a lower risk of 28-day mortality (HR: 0.72, 95% CI 0.54, 0.96, p = 0.03). Prehospital TXA also demonstrated an independent 22% lower risk of mortality for every gram of prehospital TXA administered (HR: 0.78, 95% CI 0.63, 0.96, p = 0.02). Multivariable linear regression verified that patients who received TXA were independently associated with lower 24-hour red cell transfusion requirements (ß: -0.31, 95% CI -0.61, -0.01, p = 0.04) with a dose-response relationship (ß: -0.24, 95% CI -0.45, -0.02, p = 0.03). There was no independent association of prehospital TXA administration on VTE, seizure, or stroke. CONCLUSIONS: In this secondary analysis of harmonized data from two large randomized interventional trials, prehospital TXA administration across a broad spectrum of injured patients is safe. Prehospital TXA is associated with a significant 28-day survival benefit, lower red cell transfusion requirements at 24 hours and demonstrates a dose-response relationship. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

State-Level Analysis of Intimate Partner Violence, Abortion Access, and Peripartum Homicide: Call for Screening and Violence Interventions for Pregnant Patients.

BACKGROUND: Despite representing 4% of the global population, the US has the fifth highest number of intentional homicides in the world. Peripartum people represent a unique and vulnerable subset of homicide victims. This study aimed to understand the risk factors for peripartum homicide. STUDY DESIGN: We used data from the 2018 to 2020 National Violent Death Reporting System to compare homicide rates of peripartum and nonperipartum people capable of becoming pregnant (12 to 50 years of age). Peripartum was defined as currently pregnant or within 1-year postpartum. We additionally compared state-level peripartum homicide rates between states categorized as restrictive, neutral, or protective of abortion. Pearson's chi-square and Wilcoxon rank-sum tests were used. RESULTS: There were 496 peripartum compared with 8,644 nonperipartum homicide victims. The peripartum group was younger (27.4 ± 71 vs 33.0 ± 9.6, p < 0.001). Intimate partner violence causing the homicide was more common in the peripartum group (39.9% vs 26.4%, p < 0.001). Firearms were used in 63.4% of homicides among the peripartum group compared with 49.5% in the comparison (p < 0.001). A significant difference was observed in peripartum homicide between states based on policies regarding abortion access (protective 0.37, neutral 0.45, restrictive 0.64; p < 0.01); the same trend was not seen with male homicides. CONCLUSIONS: Compared with nonperipartum peers, peripartum people are at increased risk for homicide due to intimate partner violence, specifically due to firearm violence. Increasing rates of peripartum homicide occur in states with policies that are restrictive to abortion access. There is a dire need for universal screening and interventions for peripartum patients. Research and policies to reduce violence against pregnant people must also consider the important role that abortion access plays in protecting safety.

Association of fibrinolysis phenotype with patient outcomes following traumatic brain injury.

BACKGROUND: Impaired coagulation is associated with elevated risk of mortality in trauma patients. Prior studies have demonstrated increased mortality in patients with hyperfibrinolysis (HF) and fibrinolysis shutdown (SD). In addition, prior studies have demonstrated no effect of tranexamic acid (TXA) on fibrinolysis phenotypes. We examined the association of admission fibrinolysis phenotype with traumatic brain injury (TBI) patient outcomes. METHODS: Data were extracted from a placebo-controlled multicenter clinical trial. Patients ≥15 years with TBI (Glasgow Coma Scale score, 3-12) and systolic blood pressure ≥90 mm Hg were randomized in the out-of-hospital setting to receive placebo bolus/placebo infusion (Placebo), 1 gram (g) TXA bolus/1 g TXA infusion (bolus maintenance [BM]); or 2 g TXA bolus/placebo infusion (bolus only [BO]). Fibrinolysis phenotypes on admission were determined by clot lysis at 30 minutes (LY30): SD, ≤0.8%; physiologic, 0.9% to 2.9%; HF, ≥3%. Logistic regression was used to control for age, sex, penetrating injury, Injury Severity Score, maximum head AIS, and TXA treatment group. RESULTS: Seven hundred forty-seven patients met inclusion criteria. Fibrinolysis shutdown was the most common phenotype in all treatment groups and was associated with increased age, Injury Severity Score, and presence of intracranial hemorrhage (ICH). Inpatient mortality was 15.2% for SD and HF, and 10.6% for physiologic ( p = 0.49). No differences in mortality, disability rating scale at 6 months, acute kidney injury, acute respiratory distress syndrome, or multi-organ failure were noted between fibrinolysis phenotypes. CONCLUSION: SD is the most common phenotype expressed in moderate to severe TBI. In TBI, there is no association between fibrinolysis phenotype and mortality or other major complications. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

TXA does not affect levels of TBI-related biomarkers in blunt TBI with ICH: A secondary analysis of the prehospital TXA for TBI trial.

BACKGROUND: Brain specific biomarkers such as glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), and microtubule-associated protein-2 (MAP-2) have been identified as tools for diagnosis in traumatic brain injury (TBI). Tranexamic acid (TXA) has been shown to decrease mortality in patients with intracranial hemorrhage (ICH). The effect of TXA on these biomarkers is unknown. We investigated whether TXA affects levels of GFAP, UCH-L1, and MAP-2, and whether biomarker levels are associated with mortality in patients receiving TXA. METHODS: Patients enrolled in the prehospital TXA for TBI trial had GFAP, UCHL-1 and MAP-2 levels drawn at 0 hour and 24 hours postinjury (n = 422). Patients with ICH from blunt trauma with a GCS <13 and SBP >90 were randomized to placebo, 2 g TXA bolus, or 1 g bolus +1 g/8 hours TXA infusion. Associations of TXA and 24-hour biomarker change were assessed with multivariate linear regression. Association of biomarkers with 28-day mortality was assessed with multivariate logistic regression. All models were controlled for age, GCS, ISS, and AIS head. RESULTS: Administration of TXA was not associated with a change in biomarkers over 24 hours postinjury. Changes in biomarker levels were associated with AIS head and age. On admission, higher GFAP (odds ratio [OR], 1.75; confidence interval [CI], 1.31-2.38; p < 0.001) was associated with increased 28-day mortality. At 24 hours postinjury, higher levels of GFAP (OR, 2.09; CI, 1.37-3.30; p < 0.001 and UCHL-1 (OR, 2.98; CI, 1.77-5.25; p < 0.001) were associated with mortality. A change in UCH levels from 0 hour to 24 hours postinjury was also associated with increased mortality (OR, 1.68; CI, 1.15-2.49; p < 0.01). CONCLUSION: Administration of TXA does not impact change in GFAP, UCHL-1, or MAP-2 during the first 24 hours after blunt TBI with ICH. Higher levels of GFAP and UCH early after injury may help identify patients at high risk for 28-day mortality. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Tranexamic Acid, Mortality, and Intracranial Hemorrhage Type in Moderate or Severe Traumatic Brain Injury.

This cohort study examines the association of tranexamic acid administration with intracranial hemorrhage type, neurologic outcomes, and mortality in patients with traumatic brain injury.

Comparative Effectiveness of Intracranial Pressure Monitoring vs No Monitoring in Severe Penetrating Brain Injury Management.

Importance: Civilian penetrating brain injury (PBI) is associated with high mortality. However, scant literature is available to guide neurocritical care monitoring and management of PBI. Objective: To examine the association of intracranial pressure (ICP) monitoring with mortality, intensive care unit (ICU) length of stay (LOS), and dispositional outcomes in patients with severe PBI. Design, Setting, and Participants: This comparative effectiveness research study analyzed data from the Trauma Quality Improvement Program of the National Trauma Data Bank in the US from January 1, 2017, to December 31, 2019. Patients with PBI were identified, and those aged 16 and 60 years who met these inclusion criteria were included: ICU LOS of more than 2 days, Glasgow Coma Scale (GCS) score lower than 9 on arrival and at 24 hours, and Abbreviated Injury Scale score of 3 to 5 for the head region and lower than 3 for other body regions. Patients with bilaterally fixed pupils or incomplete data were excluded. A 1:1 propensity score (PS) matching was used to create a subgroup of patients. Patients were divided into 2 groups: with vs without ICP monitoring. Data analysis was conducted between September and December 2022. Exposures: Intracranial pressure monitoring vs no monitoring. Main Outcomes and Measures: Outcomes were mortality, rate of withdrawal, ICU LOS, and dispositional outcome. Measures were age, initial systolic blood pressure, initial oxygen saturation level on a pulse oximeter, first-recorded GCS score, GCS score at 24 hours, Abbreviated Injury Scale score, midline shift, and pupillary reactivity. Results: A total of 596 patients (505 males [84.7%]; mean [SD] age, 32.2 [12.3] years) were included, among whom 220 (36.9%) died and 288 (48.3%) had ICP monitoring. The PS matching yielded 466 patients (233 in each group with vs without ICP monitoring). Overall mortality was 35.8%; 72 patients with ICP monitoring (30.9%) died compared with 95 patients (40.8%) without ICP monitoring . Patients with ICP monitoring were more likely to survive (odds ratio [OR], 1.54; 95% CI, 1.05-2.25; P = .03; number needed to treat, 10). No difference in favorable discharge disposition was observed. The PS-weighted analysis included all 596 patients and found that patients with ICP monitoring were more likely to survive than those without (OR, 1.40; 95% CI, 1.10-1.78; P = .005). The E-value for the OR calculated from the PS-matched data set was 1.79. In addition, ICP monitoring vs no monitoring was associated with an increase in median (IQR) ICU LOS (15.0 [8.0-21.0] days vs 7.0 [4.0-12.0] days; P < .001). Conclusions and Relevance: In this comparative effectiveness research study, PBI management guided by ICP monitoring was associated with decreased mortality and increased ICU LOS, challenging the notion of universally poor outcomes after civilian PBI. Randomized clinical trials that evaluate the efficacy of ICP monitoring in PBI are warranted.

The effects of timing of prehospital tranexamic acid on outcomes after traumatic brain injury: Subanalysis of a randomized controlled trial.

BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic that has shown some promise in improving outcomes in traumatic brain injury (TBI), but only when given early after injury. We examined the association between timing of prehospital TXA administration and outcomes in patients with moderate to severe TBI. METHODS: Patients enrolled in the multi-institutional, double-blind randomized prehospital TXA for TBI trial with blunt or penetrating injury and suspected TBI (Glasgow Coma Scale score ≤ 12, SBP ≥90) who received either a 2-g TXA bolus or a 1-g bolus plus 1 g 8 hour infusion within 2 hours of injury were analyzed. Outcomes were compared between early administration (<45 minutes from injury) and late administration ≥45 minutes from injury) using a χ 2 , Fischer's exact test, t test, or Mann-Whitney U test as indicated. Logistic regression examined time to drug as an independent variable. A p value less than 0.05 was considered significant. RESULTS: Six hundred forty-nine patients met inclusion criteria (354 early and 259 late). Twenty-eight-day and 6-month mortalities, 6-month Glasgow Outcome Scale-Extended, and disability rating scale scores were not different between early and late administration. Late administration was associated with higher rates of deep venous thrombosis (0.8 vs. 3.4%, p = 0.02), cerebral vasospasm (0% vs. 2%, p = 0.01), as well as prolonged EMS transport and need for a prehospital airway ( p < 0.01). CONCLUSION: In patients with moderate or severe TBI who received TXA within 2 hours of injury, no mortality benefit was observed in those who received treatment within 45 minutes of injury, although lower rates of select complications were seen. These results support protocols that recommend TXA administration within 45 minutes of injury for patients with suspected TBI. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level II.

Tranexamic acid is not inferior to placebo with respect to adverse events in suspected traumatic brain injury patients not in shock with a normal head computed tomography scan: A retrospective study of a randomized trial.

BACKGROUND: A 2-g bolus of tranexamic acid (TXA) has been shown to reduce 28-day mortality in a randomized controlled trial. This study investigates whether out-of-hospital TXA use is associated with adverse events or unfavorable outcomes in suspected traumatic brain injury (TBI) when intracranial hemorrhage (ICH) is absent on initial computed tomography. METHODS: This study used data from a 2015 to 2017, multicenter, randomized trial studying the effect of the following TXA doses on moderate to severe TBI: 2-g bolus, 1-g bolus plus 1-g infusion over 8 hours, and a placebo bolus with placebo infusion. Of the 966 participants enrolled, 395 with an initial computed tomography negative for ICH were included in this analysis. Fifteen adverse events (28-day incidence) were studied: myocardial infarction, deep vein thrombosis, seizure, pulmonary embolism, acute respiratory distress syndrome, cardiac failure, liver failure, renal failure, cerebrovascular accident, cardiac arrest, cerebral vasospasm, "any thromboembolism," hypernatremia, acute kidney injury, and infection. Other unfavorable outcomes analyzed include mortality at 28 days and 6 months, Glasgow Outcome Scale-Extended score of ≤4 at discharge and 6 months, intensive care unit-free days, ventilator-free days, hospital-free days, and combined unfavorable outcomes. In both study drug groups, the incidence of dichotomous outcomes and quantity of ordinal outcomes were compared with placebo. RESULTS: No statistically significant increase in adverse events or unfavorable outcomes was found between either TXA dosing regimen and placebo. Demographics and injury scores were not statistically different other than two methods of injury, which were overrepresented in the 1-g TXA bolus plus 1-g TXA infusion. CONCLUSION: Administration of either a 2-g TXA bolus or a 1-g TXA bolus plus 1-g TXA 8-hour infusion in suspected TBIs without ICH is not associated with increased adverse events or unfavorable outcomes. Because the out-of-hospital 2-g bolus is associated with a mortality benefit, it should be administered in suspected TBI. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level II.

Developing a National Trauma Research Action Plan: Results from the prehospital and mass casualty research Delphi survey.

BACKGROUND: The National Academies of Sciences, Engineering, and Medicine 2016 trauma system report recommended a National Trauma Research Action Plan to strengthen and guide future trauma research. To address this recommendation, 11 expert panels completed a Delphi survey process to create a comprehensive research agenda, spanning the continuum of trauma care. We describe the gap analysis and high-priority research questions generated from the National Trauma Research Action Plan panel on prehospital and mass casualty trauma care. METHODS: We recruited interdisciplinary national experts to identify gaps in the prehospital and mass casualty trauma evidence base and generate prioritized research questions using a consensus-driven Delphi survey approach. We included military and civilian representatives. Panelists were encouraged to use the Patient/Population, Intervention, Compare/Control, and Outcome format to generate research questions. We conducted four Delphi rounds in which participants generated key research questions and then prioritized the questions on a 9-point Likert scale to low-, medium-, and high-priority items. We defined consensus as ≥60% agreement on the priority category and coded research questions using a taxonomy of 118 research concepts in 9 categories. RESULTS: Thirty-one interdisciplinary subject matter experts generated 490 research questions, of which 433 (88%) reached consensus on priority. The rankings of the 433 questions were as follows: 81 (19%) high priority, 339 (78%) medium priority, and 13 (3%) low priority. Among the 81 high-priority questions, there were 46 taxonomy concepts, including health systems of care (36 questions), interventional clinical trials and comparative effectiveness (32 questions), mortality as an outcome (30 questions), prehospital time/transport mode/level of responder (24 questions), system benchmarks (17 questions), and fluid/blood product resuscitation (17 questions). CONCLUSION: This Delphi gap analysis of prehospital and mass casualty care identified 81 high-priority research questions to guide investigators and funding agencies for future trauma research.

Viscoelastic Testing in Traumatic Brain Injury: Key Research Insights.

The role of viscoelastic testing in the evaluation and management of traumatic brain injury (TBI) remains a subject of ongoing exploration. This review highlights four key publications that provide significant insights into this subject. Holcomb et al. provided early evidence of the relationship between thromboelastography (TEG) and conventional coagulation tests (CCTs). Later, Samuels et al. used TEG to identify a unique coagulopathy phenotype in TBI characterized by a notable absence of fibrinolytic abnormalities. Dixon et al. built upon these findings by exploring the application of TEG in the context of antifibrinolytic administration, noting a similar lack of effect on LY30. Finally, Guillotte et al. demonstrated the utility of TEG-PM in assessing platelet dysfunction in TBI. While these studies provide key early support for the utility of viscoelastic testing in the TBI, further exploration is needed to define evidence-based guidelines for clinical application.

Fibrinolysis in Traumatic Brain Injury: Diagnosis, Management, and Clinical Considerations.

Posttraumatic coagulopathy involves disruption of both the coagulation and fibrinolytic pathways secondary to tissue damage, hypotension, and inflammatory upregulation. This phenomenon contributes to delayed complications after traumatic brain injury (TBI), including intracranial hemorrhage progression and systemic disseminated intravascular coagulopathy. Development of an early hyperfibrinolytic state may result in uncontrolled bleeding and is associated with increased mortality in patients with TBI. Although fibrinolytic assays are not routinely performed in the assessment of posttraumatic coagulopathy, circulating biomarkers such as D-dimer and fibrin degradation products have demonstrated potential utility in outcome prediction. Unfortunately, the relatively delayed nature of these tests limits their clinical utility. In contrast, viscoelastic tests are able to provide a rapid global assessment of coagulopathy, although their ability to reliably identify disruptions in the fibrinolytic cascade remains unclear. Limited evidence supports the use of hypertonic saline, cryoprecipitate, and plasma to correct fibrinolytic disruption; however, some studies suggest more harm than benefit. Recently, early use of tranexamic acid in patients with TBI and confirmed hyperfibrinolysis has been proposed as a strategy to further improve clinical outcomes. Moving forward, further delineation of TBI phenotypes and the clinical implications of fibrinolysis based on phenotypic variation is needed. In this review, we summarize the clinical aspects of fibrinolysis in TBI, including diagnosis, treatment, and clinical correlates, with identification of targeted areas for future research efforts.

Fibrinolytic Activation in Patients with Progressive Intracranial Hemorrhage after Traumatic Brain Injury.

Progression of intracranial hemorrhage (PICH) is a significant cause of secondary brain injury in patients with traumatic brain injury (TBI). Previous studies have implicated a variety of mediators that contribute to PICH. We hypothesized that patients with PICH would display either a hypocoagulable state, hyperfibrinolysis, or both. We conducted a prospective study of adult trauma patients with isolated TBI. Blood was obtained for routine coagulation assays, platelet count, fibrinogen, thrombelastography, markers of thrombin generation, and markers of fibrinolysis at admission and 6, 12, 24, and 48 h. Univariate analyses were performed to compare baseline characteristics between groups. Linear regression models were created, adjusting for baseline differences, to determine the relationship between individual assays and PICH. One hundred forty-one patients met entry criteria, of whom 71 had hemorrhage progression. Patients with PICH had a higher Injury Severity Score and Abbreviated Injury Scale score (head), a lower Glasgow Coma Scale score, and lower plasma sodium on admission. Patients with PICH had higher D-dimers on admission. After adjusting for baseline differences, elevated D-dimers remained significantly associated with PICH compared to patients without PICH at admission. Hypocoagulation was not significantly associated with PICH in these patients. The association between PICH and elevated D-dimers early after injury suggests that fibrinolytic activation may contribute to PICH in patients with TBI.

Blood Biomarkers for Detection of Brain Injury in COVID-19 Patients.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus attacks multiple organs of coronavirus disease 2019 (COVID-19) patients, including the brain. There are worldwide descriptions of neurological deficits in COVID-19 patients. Central nervous system (CNS) symptoms can be present early in the course of the disease. As many as 55% of hospitalized COVID-19 patients have been reported to have neurological disturbances three months after infection by SARS-CoV-2. The mutability of the SARS-COV-2 virus and its potential to directly affect the CNS highlight the urgency of developing technology to diagnose, manage, and treat brain injury in COVID-19 patients. The pathobiology of CNS infection by SARS-CoV-2 and the associated neurological sequelae of this infection remain poorly understood. In this review, we outline the rationale for the use of blood biomarkers (BBs) for diagnosis of brain injury in COVID-19 patients, the research needed to incorporate their use into clinical practice, and the improvements in patient management and outcomes that can result. BBs of brain injury could potentially provide tools for detection of brain injury in COVID-19 patients. Elevations of BBs have been reported in cerebrospinal fluid (CSF) and blood of COVID-19 patients. BB proteins have been analyzed in CSF to detect CNS involvement in patients with infectious diseases, including human immunodeficiency virus and tuberculous meningitis. BBs are approved by the U.S. Food and Drug Administration for diagnosis of mild versus moderate traumatic brain injury and have identified brain injury after stroke, cardiac arrest, hypoxia, and epilepsy. BBs, integrated with other diagnostic tools, could enhance understanding of viral mechanisms of brain injury, predict severity of neurological deficits, guide triage of patients and assignment to appropriate medical pathways, and assess efficacy of therapeutic interventions in COVID-19 patients.

Can QuickBrain MRI replace CT as first-line imaging for select pediatric head trauma?

OBJECTIVE: The current standard of care for initial neuroimaging in injured pediatric patients suspected of having traumatic brain injury is computed tomography (CT) that carries risks associated with radiation exposure. The primary objective of this trial was to evaluate the ability of a QuickBrain MRI (qbMRI) protocol to detect clinically important traumatic brain injuries in the emergency department (ED). The secondary objective of this trial was to compare qbMRI to CT in identifying radiographic traumatic brain injury. METHODS: This was a prospective study of trauma patients less than 15 years of age with suspected traumatic brain injury at a level 1 pediatric trauma center in Portland, Oregon between August 2017 and March 2019. All patients in whom a head CT was deemed clinically necessary were approached for enrollment to also obtain a qbMRI in the acute setting. Clinically important traumatic brain injury was defined as the need for neurological surgery procedure, intubation, pediatric intensive care unit stay greater than 24 hours, a total hospital length of stay greater than 48 hours, or death. RESULTS: A total of 73 patients underwent both CT and qbMRI. The median age was 4 years (interquartile range [IQR] = 1-10 years). Twenty-two patients (30%) of patients had a clinically important traumatic brain injury, and of those, there were 2 deaths (9.1%). QbMRI acquisition time had a median of 4 minutes and 52 seconds (IQR = 3 minutes 49 seconds-5 minutes 47 seconds). QbMRI had sensitivity for detecting clinically important traumatic brain injury of 95% (95% confidence interval [CI] = 77%-99%). For any radiographic injury, qbMRI had a sensitivity of 89% (95% CI = 78%-94%). CONCLUSION: Our results suggest that qbMRI has good sensitivity to detect clinically important traumatic brain injuries. Further multi-institutional, prospective trials are warranted to either support or refute these findings.

Tranexamic acid administration in the field does not affect admission thromboelastography after traumatic brain injury.

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.

Early Tranexamic Acid Administration After Traumatic Brain Injury Is Associated With Reduced Syndecan-1 and Angiopoietin-2 in Patients With Traumatic Intracranial Hemorrhage.

OBJECTIVE: To evaluate the effect of early tranexamic acid (TXA) administration on circulating markers of endotheliopathy. SETTING: Twenty trauma centers in the United States and Canada. PARTICIPANTS: Patients with moderate-to-severe traumatic brain injury (TBI) (MS-TBI) and intracranial hemorrhage who were not in shock (systolic blood pressure ≥90 mm Hg). DESIGN: TXA (2 g) or placebo administered prior to hospital arrival, less than 2 hours postinjury. Blood samples and head computed tomographic scan collected upon arrival. Plasma markers measured using Luminex analyte platform. Differences in median marker levels evaluated using t tests performed on log-transformed variables. Comparison groups were TXA versus placebo and less than 45 minutes versus 45 minutes or more from time of injury to treatment administration. MAIN MEASURES: Plasma levels of angiopoietin-1, angiopoietin-2, syndecan-1, thrombomodulin, thrombospondin-2, intercellular adhesion molecule 1, vascular adhesion molecule 1. RESULTS: Demographics and Injury Severity Score were similar between the placebo (n = 129) and TXA (n = 158) groups. Levels of syndecan-1 were lower in the TXA group (median [interquartile range or IQR] = 254.6 pg/mL [200.7-322.0] vs 272.4 pg/mL [219.7-373.1], P = .05. Patients who received TXA less than 45 minutes postinjury had significantly lower levels of angiopoietin-2 (median [IQR] = 144.3 pg/mL [94.0-174.3] vs 154.6 pg/mL [110.4-209.8], P = .05). No differences were observed in remaining markers. CONCLUSIONS: TXA may inhibit early upregulation of syndecan-1 and angiopoietin-2 in patients with MS-TBI, suggesting attenuation of protease-mediated vascular glycocalyx breakdown. The findings of this exploratory analysis should be considered preliminary and require confirmation in future studies.

Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury.

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.