Translational approaches to coagulopathy after trauma: Towards targeted treatment.

Mitchell J. Cohen discusses why trauma care must go beyond restoring perfusion to target disorders of inflammation and coagulation in severely injured patients.

Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial.

IMPORTANCE: Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. OBJECTIVE: To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. DESIGN, SETTING, AND PARTICIPANTS: Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. INTERVENTIONS: Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). MAIN OUTCOMES AND MEASURES: Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. RESULTS: No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, -4.2% [95% CI, -9.6% to 1.1%]; P = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, -3.7% [95% CI, -10.2% to 2.7%]; P = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, -5.4% [95% CI, -10.4% to -0.5%]; P = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P < .001) and platelets (12 U vs 6 U, P < .001) and similar amounts of red blood cells (9 U) over the first 24 hours, no differences between the 2 groups were found for the 23 prespecified complications, including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications. CONCLUSIONS AND RELEVANCE: Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01545232.

The natural history and effect of resuscitation ratio on coagulation after trauma: a prospective cohort study.

OBJECTIVE: To investigate the natural history of coagulation factor perturbation after injury and identify longitudinal differences in clotting factor repletion by red blood cell:fresh frozen plasma (RBC:FFP) transfusion ratio. BACKGROUND: Hemostatic transfusion ratios of RBC to FFP approaching 1:1 are associated with a survival advantage in traumatic hemorrhage, even in patients with normal coagulation studies. METHODS: Plasma was prospectively collected from 336 trauma patients during their intensive care unit stay for up to 72 hours from February, 2005, to October, 2011. Standard coagulation studies as well as pro- and anticoagulant clotting factors were measured. RBC:FFP transfusion ratios were calculated at 6 hours after arrival and dichotomized into "low ratio" (RBC:FFP ≤ 1.5:1) and "high ratio" (RBC:FFP > 1.5:1) groups. RESULTS: Factor-level measurements from 193 nontransfused patients provide an early natural history of clotting factor-level changes after injury. In comparison, 143 transfused patients had more severe injury, prolonged prothrombin time and partial thromboplastin time (PTT), and lower levels of both pro- and anticoagulants up to 24 hours. PTT was prolonged up to 12 hours and only returned to admission baseline at 48 hours in "high ratio" patients versus correction by 6 hours in "low ratio" patients. Better repletion of factors V, VIII, and IX was seen longitudinally, and both unadjusted and injury-adjusted survival was significantly improved in "low ratio" versus "high ratio" groups. CONCLUSIONS: Resuscitation with a "low ratio" of RBC:FFP leads to earlier correction of coagulopathy, and earlier and prolonged repletion of some but not all procoagulant factors. This prospective evidence suggests hemostatic resuscitation as an interim standard of care for transfusion in critically injured patients pending the results of ongoing randomized study.

Silencing Glypican-1 enhances the antitumor effects of Pictilisib via downregulating PI3K/Akt/ERK signaling in chemo-resistant esophageal adenocarcinoma.

Poorly differentiated esophageal adenocarcinoma (PDEAC) has a dismal prognosis. Glypican-1(GPC-1) is known to be upregulated in several cancer types in contrast to healthy tissues, rendering it as a biomarker. Nevertheless, the potential therapeutic targeting of GPC-1 has not been explored in PDEAC. There is accumulating evidence that GPC-1, via upregulation of PI3K/Akt/ERK signaling, plays a crucial role in the progression and chemoresistance in cancer. Pictilisib, a class I pan PI3K inhibitor, has shown promising antitumor results in clinical trials, however, has not gained widespread success due to acquired drug resistance. This study investigated the role of GPC-1 in chemo-resistant PDEAC and appraises the impact of targeted silencing of GPC-1 on the antitumor effects of Pictilisib in PDEAC cell lines. Immunohistochemistry assays in PDEAC tissue specimens demonstrated a pronounced intensity of staining with GPC-1. Upregulation of GPC-1 was found to be correlated with advanced stage and poor prognosis. In-vitro studies examined the influence of GPC-1 knockdown and Pictilisib, both as individual agents and in combination, on cytotoxicity, cell cycle distribution, apoptosis, and gene expression profiles. Silencing GPC-1 alone showed significantly reduced cell viability, migration, colony formation, epithelial-mesenchymal transition, and stemness in PDEAC cells. Significantly, knockdown of GPC-1 combined with low-dose Pictilisib led to enhancement of cytotoxicity, cell cycle arrest, and apoptosis in ESO-26 and OE-33 cells. In the xenograft mouse model, the combination of Pictilisib and GPC-1 knockdown exhibited synergy. These findings suggest that GPC-1 represents a promising target to augment chemosensitivity in esophageal adenocarcinoma.

Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients.

BACKGROUND: Recent studies have identified an acute traumatic coagulopathy that is present on admission to the hospital and is independent of iatrogenic causes. We have previously reported that this coagulopathy is due to the association of severe injury and shock and is characterized by a decrease in plasma protein C (PC) levels. Whether this early coagulopathy and later propensity to infection, multiple organ failure and mortality are associated with the activation of PC pathway has not been demonstrated and constitutes the aim of this study. METHODS AND FINDINGS: This was a prospective cohort study of 203 major trauma patients. Serial blood samples were drawn on arrival in the emergency department, and at 6, 12, and 24 hours after admission to the hospital. PT, PTT, Va, VIIIa, PC aPC t-PA, and D-dimer levels were assayed. Comprehensive injury, resuscitation, and outcome data were prospectively collected. A total of 203 patients were enrolled. Patients with tissue hypoperfusion and severe traumatic injury showed a strong activation of the PC which was associated with a coagulopathy characterized by inactivation of the coagulation factors V and VIII and a derepression of the fibrinolysis with high plasma levels of plasminogen activator and high D-dimers. Elevated plasma levels of activated PC were significantly associated with increased mortality, organ injury, increased blood transfusion requirements, and reduced ICU ventilator-free days. Finally early depletion of PC after trauma is associated with a propensity to posttraumatic ventilator-associated pneumonia. CONCLUSIONS: Acute traumatic coagulopathy occurs in the presence of tissue hypoperfusion and severe traumatic injury and is mediated by activation of the PC pathway. Higher plasma levels of aPC upon admission are predictive of poor clinical outcomes after major trauma. After activation, patients who fail to recover physiologic plasma values of PC have an increased propensity to later nosocomial lung infection.

Prohemostatic interventions in trauma: resuscitation-associated coagulopathy, acute traumatic coagulopathy, hemostatic resuscitation, and other hemostatic interventions.

Trauma is the most common cause of death in the young and hemorrhage is the most important cause of death in patients with trauma. Recently redefined pathways of inflammation and coagulation, together with hypothermia and acidosis contribute to trauma-associated coagulopathy and aggravation of bleeding. Pharmacological prohemostatic agents may be useful to (partly) correct the coagulopathy in trauma patients and may serve as useful adjunctive treatment options in patients with severe blood loss after trauma. Recombinant factor VIIa, fibrinogen and prothrombin complex concentrates, and antifibrinolytic agents have been evaluated in clinical trials. These interventions show promising effects but their efficacy in reducing clinically important outcome parameters need to be confirmed in clinical studies.

Finding the sweet spot: identification of optimal glucose levels in critically injured patients.

BACKGROUND: Conflicting data exist regarding optimal glycemic control in critically ill trauma patients. We therefore compared glucose parameters and outcomes among three different glycemic control regimens in a single trauma intensive care unit (ICU), hypothesizing that a moderate regimen would yield optimal avoidance of hyper- and hypoglycemia with equivalent outcomes when compared with a more aggressive approach. METHODS: We retrospectively reviewed 1,422 trauma patients with at least 3-day ICU stay and five glucose measurements from May 2001 to January 2010, spanning three nonoverlapping, sequential glucose control protocols: "relaxed," "aggressive," and "moderate." For each, we extracted mean blood glucose, hypoglycemic and hyperglycemic event frequency, and glucose variability and investigated their association with outcomes. RESULTS: Mortality was associated with elevated mean glucose (135.6 mg/dL vs. 126.2 mg/dL), more frequent hypoglycemic (2.67 ± 7 vs. 1.28 ± 5) and hyperglycemic (30.6 ± 28 vs. 16.0 ± 22 per 100 patient-ICU days) events, and higher glucose variability (37.1 ± 20 vs. 29.4 ± 20; all p < 0.001). Regression identified hyperglycemic episodes (p < 0.05) as an independent predictor of mortality. The "moderate" regimen had rare hyperglycemia, low glucose variability, and intermediate mean blood glucose range and frequency of hypoglycemia. Multiorgan failure and mortality did not differ between groups. CONCLUSIONS: Hyperglycemic events (glucose >180 mg/dL) most strongly predicted mortality. Of glucose control protocols analyzed, the "moderate" protocol had fewest hyperglycemic events. As outcomes were otherwise equivalent between "moderate" and "aggressive" protocols, we conclude that hyperglycemia can be safely avoided using a moderate glycemic control protocol without inducing hypoglycemia.

Characterization of organ dysfunction and mortality in pediatric patients with trauma with acute traumatic coagulopathy.

BACKGROUND: Traumatic injuries are a leading cause of mortality and morbidity in pediatric patients and abnormalities in hemostasis play an important role in these poor outcomes. One such abnormality, acute traumatic coagulopathy (ATC), is a near immediate endogenous response to injury and has recently been described in the pediatric population. This study aims to evaluate the epidemiology of pediatric ATC, specifically its association with organ dysfunction. METHODS: All patients with trauma presenting to the University of California, Benioff Children's Hospital Oakland between 2006 and 2015 with coagulation testing drawn at presentation were included. Patients were excluded if they (1) were >18 years of age, (2) were admitted with a non-mechanical mechanism of injury, (3) were on anticoagulation medications, or (4) had coagulation testing >4 hours after injury. ATC was defined as an international normalized ratio (INR) ≥1.3. The primary outcome was new or progressive multiple organ dysfunction syndrome (MODS) and secondary outcomes included in-hospital mortality and other morbidities. RESULTS: Of the 7382 patients that presented in the 10-year study period, 545 patients met criteria for analysis and 88 patients (16%) presented with ATC. Patients with ATC were more likely to develop MODS than those without ATC (68.4% vs 7.7%, p<0.001) and had higher in-hospital mortality (26.1% vs 0.4%, p<0.001) than those without ATC. Along with arterial hypotension and an Injury Severity Score ≥30, ATC was independent predictor of MODS and in-hospital mortality. An isolated elevated INR was associated with MODS and in-hospital mortality while an isolated elevated partial thromboplastin time was not. CONCLUSIONS: Pediatric ATC was associated with organ dysfunction, mortality, and other morbidities. ATC along with arterial hypotension and high injury severity were independent predictors of organ dysfunction and mortality. Pediatric ATC may be biologically distinct from adult ATC and further studies are needed. LEVEL OF EVIDENCE: IV, epidemiologic.

Group A emergency-release plasma in trauma patients requiring massive transfusion.

BACKGROUND: Both groups A and AB plasma have been approved for emergency-release transfusion in acutely bleeding trauma patients before blood grouping being performed. The safety profile associated with this practice has not been well characterized, particularly in patients requiring massive transfusion. METHODS: This secondary analysis of the Pragmatic, Randomized, Optimal Platelet and Plasma Ratios trial examined whether exposure to group A emergency-release plasma (ERP) was noninferior to group AB ERP. We also examined patients whose blood groups were compatible with group A ERP versus patients whose blood groups were incompatible with group A ERP. Outcomes included 30-day mortality and complication rates including systemic inflammatory response syndrome, infection, renal injury, pulmonary dysfunction, and thromboembolism. RESULTS: Of the 680 patients predicted to receive a massive transfusion, 584 (85.9%) received at least 1 U of ERP. Of the 584 patients analyzed, 462 (79.1%) received group AB and 122 (20.9%) received group A ERP. Using a hazard ratio (HR) of 1.35 as the noninferiority margin, transfusion with group A versus group AB ERP was not associated with increased thromboembolic rates (HR, 0.52; 95% confidence interval [CI], 0.31-0.90). Mortality (HR, 1.15; 95% CI, 0.91-1.45) and nonfatal complication rates (HR, 1.24; 95% CI, 0.87-1.77) were inconclusive. In the subgroup analysis, transfusion with incompatible ERP (group B or AB patients receiving group A ERP) was not associated with increased nonfatal complications (HR, 1.02; 95% CI, 0.80-1.30). There were no reported hemolytic transfusion reactions. CONCLUSION: The use of ERP is common in patients requiring massive transfusion and facilitates the rapid balanced resuscitation of patients who have sustained blood loss. Group A ERP is an acceptable option for patients requiring massive transfusion, especially if group AB ERP is not readily available. LEVEL OF EVIDENCE: Therapeutic/Care Management, level IV; Prognostic, level III.

Not all in your head (and neck): Stroke after blunt cerebrovascular injury is associated with systemic hypercoagulability.

BACKGROUND: Stroke secondary to blunt cerebrovascular injury (BCVI) most often occurs before initiation of antithrombotic therapy. Earlier treatment, especially in multiply injured patients with relative contraindications to antithrombotic agents, could be facilitated with improved risk stratification; furthermore, the relationship between BCVI-attributed stroke and hypercoagulability remains unknown. We hypothesized that patients who suffer BCVI-related stroke are hypercoagulable compared with those with BCVI who do not stroke. METHODS: Rapid thromboelastography (TEG) was evaluated for patients with BCVI-attributed stroke at an urban Level I trauma center from 2011 to 2018. Contemporary controls who had BCVI but did not stroke were selected for comparison using propensity-score matching with 20% caliper that accounted for age, sex, injury severity, and BCVI location and grade. RESULTS: During the study period, 15,347 patients were admitted following blunt trauma. Blunt cerebrovascular injury was identified in 435 (3%) patients, of whom 28 experienced associated stroke and had a TEG within 24 hours of arrival. Forty-nine patients who had BCVI but did not suffer stroke served as matched controls. Stroke patients formed clots faster as evident in their larger angle (77.5 degrees vs. 74.6 degrees, p = 0.03) and had greater clot strength as indicated by their higher maximum amplitude (MA) (66.9 mm vs. 61.9 mm, p < 0.01). Activated clotting time was shorter among stroke patients but not significantly (113 seconds vs. 121 seconds, p > 0.05). Increased angle and elevated MA were significant predictors of stroke with odds ratios of 2.97 for angle greater than 77.3 degrees and 4.30 for MA greater than 63.0 mm. CONCLUSION: Patients who suffer BCVI-related stroke are hypercoagulable compared with those with BCVI who remain asymptomatic. Increased angle or MA should be considered when assessing the risk of thrombosis and determining the optimal time to initiate antithrombotic therapy in patients with BCVI. LEVEL OF EVIDENCE: Prognostic, Level III.

Discrepancies between conventional and viscoelastic assays in identifying trauma-induced coagulopathy.

BACKGROUND: Trauma-induced coagulopathy can present as abnormalities in a conventional or viscoelastic coagulation assay or both. We hypothesized that patients with discordant coagulopathies reflect different clinical phenotypes. METHODS: Blood samples were collected prospectively from critically injured patients upon arrival at two urban Level I trauma centers. International normalized ratio (INR), partial thromboplastin time (PTT), thromboelastography (TEG), and coagulation factors were assayed. RESULTS: 278 patients (median ISS 17, mortality 26%) were coagulopathic: 20% with isolated abnormal INR and/or PTT (CONVENTIONAL), 49% with isolated abnormal TEG (VISCOELASTIC), and 31% with abnormal INR/PTT and TEG (BOTH). Compared with VISCOELASTIC, CONVENTIONAL and BOTH had higher ISS, lower GCS, larger base deficit, and decreased factor activities (all p < 0.017). They received more blood products and had more ICU/ventilation days (all p < 0.017). Mortality was higher in CONVENTIONAL (40%) and BOTH (49%) than VISCOELASTIC (6%, p < 0.017). CONCLUSIONS: Although TEG-guided resuscitation improves survival after injury, INR and PTT identify coagulopathic patients with highest mortality regardless of TEG and likely represent distinct mechanisms independent of biochemical clot strength.

Predictors of postinjury acute respiratory distress syndrome: Lung injury persists in the era of hemostatic resuscitation.

BACKGROUND: Acute respiratory distress syndrome (ARDS) following trauma is historically associated with crystalloid and blood product exposure. Advances in resuscitation have occurred over the last decade, but their impact on ARDS is unknown. We sought to investigate predictors of postinjury ARDS in the era of hemostatic resuscitation. METHODS: Data were prospectively collected from arrival to 28 days for 914 highest-level trauma activations who required intubation and survived more than 6 hours from 2005 to 2016 at a Level I trauma center. Patients with ratio of partial pressure of oxygen to fraction of inspired oxygen of 300 mmHg or less during the first 8 days were identified. Two blinded expert clinicians adjudicated all chest radiographs for bilateral infiltrates in the first 8 days. Those with left-sided heart failure detected were excluded. Multivariate logistic regression was used to define predictors of ARDS. RESULTS: Of the 914 intubated patients, 63% had a ratio of partial pressure of oxygen to fraction of inspired oxygen of 300 or less, and 22% developed ARDS; among the ARDS cases, 57% were diagnosed early (in the first 24 hours), and 43% later. Patients with ARDS diagnosed later were more severely injured (ISS 32 vs. 20, p = 0.001), with higher rates of blunt injury (84% vs. 72%, p = 0.008), chest injury (58% vs. 36%, p < 0.001), and traumatic brain injury (72% vs. 48%, p < 0.001) compared with the no ARDS group. In multivariate analysis, head/chest Abbreviated Injury Score scores, crystalloid from 0 to 6 hours, and platelet transfusion from 0 to 6 hours and 7 to 24 hours were independent predictors of ARDS developing after 24 hours. CONCLUSIONS: Blood and plasma transfusion were not independently associated with ARDS. However, platelet transfusion was a significant independent risk factor. The role of platelets warrants further investigation but may be mechanistically explained by lung injury models of pulmonary platelet sequestration with peripheral thrombocytopenia. LEVEL OF EVIDENCE: Prognostic study, level IV.

The why and how our trauma patients die: A prospective Multicenter Western Trauma Association study.

BACKGROUND: Historically, hemorrhage has been attributed as the leading cause (40%) of early death. However, a rigorous, real-time classification of the cause of death (COD) has not been performed. This study sought to prospectively adjudicate and classify COD to determine the epidemiology of trauma mortality. METHODS: Eighteen trauma centers prospectively enrolled all adult trauma patients at the time of death during December 2015 to August 2017. Immediately following death, attending providers adjudicated the primary and contributing secondary COD using standardized definitions. Data were confirmed by autopsies, if performed. RESULTS: One thousand five hundred thirty-six patients were enrolled with a median age of 55 years (interquartile range, 32-75 years), 74.5% were male. Penetrating mechanism (n = 412) patients were younger (32 vs. 64, p < 0.0001) and more likely to be male (86.7% vs. 69.9%, p < 0.0001). Falls were the most common mechanism of injury (26.6%), with gunshot wounds second (24.3%). The most common overall primary COD was traumatic brain injury (TBI) (45%), followed by exsanguination (23%). Traumatic brain injury was nonsurvivable in 82.2% of cases. Blunt patients were more likely to have TBI (47.8% vs. 37.4%, p < 0.0001) and penetrating patients exsanguination (51.7% vs. 12.5%, p < 0.0001) as the primary COD. Exsanguination was the predominant prehospital (44.7%) and early COD (39.1%) with TBI as the most common later. Penetrating mechanism patients died earlier with 80.1% on day 0 (vs. 38.5%, p < 0.0001). Most deaths were deemed disease-related (69.3%), rather than by limitation of further aggressive care (30.7%). Hemorrhage was a contributing cause to 38.8% of deaths that occurred due to withdrawal of care. CONCLUSION: Exsanguination remains the predominant early primary COD with TBI accounting for most deaths at later time points. Timing and primary COD vary significantly by mechanism. Contemporaneous adjudication of COD is essential to elucidate the true understanding of patient outcome, center performance, and future research. LEVEL OF EVIDENCE: Epidemiologic, level II.

Trauma training in simulation: translating skills from SIM time to real time.

BACKGROUND: : Training surgical residents to manage critically injured patients in a timely fashion presents a significant challenge. Simulation may have a role in this educational process, but only if it can be demonstrated that skills learned in a simulated environment translate into enhanced performance in real-life trauma situations. METHODS: : A five-part, scenario-based trauma curriculum was developed specifically for this study. Midlevel surgical residents were randomized to receiving this curriculum in didactic lecture (LEC) fashion or with the use of a human performance simulator (HPS). A written learning objectives test was administered at the completion of the training. The first four major trauma resuscitations performed by each participating resident were captured on videotape in the emergency department and graded by two experienced judges blinded to the method of training. The assessment tool used by the judges included an evaluation of both initial trauma evaluation or treatment skills (part I) and crisis management skills (part II) as well as an overall score (poor/fail, adequate, or excellent). RESULTS: : The two groups of residents received almost identical scores on the posttraining written test. Average SIM and LEC scores for part I were also similar between the two groups. However, SIM-trained residents received higher overall scores and higher scores for part II crisis management skills compared with the LEC group, which was most evident in the scores received for the teamwork category (p = 0.04). CONCLUSIONS: : A trauma curriculum incorporating simulation shows promise in developing crisis management skills that are essential for evaluation of critically injured patients.

Trauma Early Mortality Prediction Tool (TEMPT) for assessing 28-day mortality.

BACKGROUND: Prior mortality prediction models have incorporated severity of anatomic injury quantified by Abbreviated Injury Severity Score (AIS). Using a prospective cohort, a new score independent of AIS was developed using clinical and laboratory markers present on emergency department presentation to predict 28-day mortality. METHODS: All patients (n=1427) enrolled in an ongoing prospective cohort study were included. Demographic, laboratory, and clinical data were recorded on admission. True random number generator technique divided the cohort into derivation (n=707) and validation groups (n=720). Using Youden indices, threshold values were selected for each potential predictor in the derivation cohort. Logistic regression was used to identify independent predictors. Significant variables were equally weighted to create a new mortality prediction score, the Trauma Early Mortality Prediction Tool (TEMPT) score. Area under the curve (AUC) was tested in the validation group. Pairwise comparison of Trauma Injury Severity Score (TRISS), Revised Trauma Score, Glasgow Coma Scale, and Injury Severity Score were tested against the TEMPT score. RESULTS: There was no difference between baseline characteristics between derivation and validation groups. In multiple logistic regression, a model with presence of traumatic brain injury, increased age, elevated systolic blood pressure, decreased base excess, prolonged partial thromboplastin time, increased international normalized ratio (INR), and decreased temperature accurately predicted mortality at 28 days (AUC 0.93, 95% CI 0.90 to 0.96, P<0.001). In the validation cohort, this score, termed TEMPT, predicted 28-day mortality with an AUC 0.94 (95% CI 0.92 to 0.97). The TEMPT score preformed similarly to the revised TRISS score for severely injured patients and was highly predictive in those having mild to moderate injury. DISCUSSION: TEMPT is a simple AIS-independent mortality prediction tool applicable very early following injury. TEMPT provides an AIS-independent score that could be used for early identification of those at risk of doing poorly following even minor injury. LEVEL OF EVIDENCE: Level II.

Dynamic coagulability after injury: Is delaying venous thromboembolism chemoprophylaxis worth the wait?

BACKGROUND: Severely injured patients often progress from early hypocoagulable to normal and eventually hypercoagulable states, developing increased risk for venous thromboembolism (VTE). Prophylactic anticoagulation can decrease this risk, but its initiation is frequently delayed for extended periods due to concerns for bleeding. To facilitate timely introduction of VTE chemoprophylaxis, we characterized the transition from hypo- to hypercoagulability and hypothesized that trauma-induced coagulopathy resolves within 24 hours after injury. METHODS: Serial blood samples were collected prospectively from critically injured patients for 120 hours after arrival at an urban Level I trauma center. Extrinsic thromboelastometry maximum clot firmness was used to classify patients as hypocoagulable (HYPO, <49 mm), normocoagulable (NORM, 49-71 mm), or hypercoagulable (HYPER, >71 mm) at each time point. Changes in coagulability over hospital course, VTE occurrence, and timing of prophylaxis initiation were analyzed. RESULTS: 898 patients (median Injury Severity Score, 13; mortality, 12%; VTE, 8%) were enrolled. Upon arrival, 3% were HYPO (90% NORM, 7% HYPER), which increased to 9% at 6 hours before down-trending. Ninety-seven percent were NORM by 24 hours, and 53% were HYPER at 120 hours. Median maximum clot firmness began in the NORM range, up-trended gradually, and entered the HYPER range at 120 hours. Patients with traumatic brain injury (TBI) followed a similar course and were not more HYPO at any time point than those without TBI. Failure to initiate prophylaxis by 72 hours was predicted by TBI and associated with VTE development (27% vs 16%, p < 0.05). CONCLUSIONS: Regardless of injury pattern, trauma-induced coagulopathy largely resolves within 24 hours, after which hypercoagulability becomes increasingly more prevalent. Deferring initiation of chemoprophylaxis, which is often biased toward patients with intracranial injuries, is associated with VTE development. LEVEL OF EVIDENCE: Prognostic study, level III; Therapeutic, level IV.

Exposing the bidirectional effects of alcohol on coagulation in trauma: Impaired clot formation and decreased fibrinolysis in rotational thromboelastometry.

BACKGROUND: Alcohol has been associated with altered viscoelastic testing in trauma, indicative of impaired coagulation. Such alterations, however, show no correlation to coagulopathy-related outcomes. Other data suggest that alcohol may inhibit fibrinolysis. We sought to clarify these mechanisms after traumatic injury using thromboelastometry (ROTEM), hypothesizing that alcohol-related clot formation impairment may be counter-balanced by inhibited fibrinolysis. METHODS: Laboratory, demographic, clinical, and outcome data were prospectively collected from 406 critically injured trauma patients at a Level I trauma center. ROTEM and standard coagulation measures were conducted in parallel. Univariate comparisons were performed by alcohol level (EtOH), with subsequent regression analysis. RESULTS: Among 274 (58%) patients with detectable EtOH, median EtOH was 229 mg/dL. These patients were primarily bluntly injured and had lower GCS (p < 0.05) than EtOH-negative patients, but had similar admission pH and injury severity (p = NS). EtOH-positive patients had prolonged ROTEM clotting time and rate of clot formation time (CFT/α); they also had decreased fibrinolysis (max lysis %; all p < 0.05). In linear regression, for every 100 mg/dL increase in EtOH, clotting time increased by 13 seconds and fibrinolysis decreased by 1.5% (both p < 0.05). However, EtOH was not an independent predictor of transfusion requirements or mortality. In high-EtOH patients with coagulopathic ROTEM tracings, transfusion rates were significantly lower than expected, relative to EtOH-negative patients with similar ROTEM findings. CONCLUSION: As assayed by ROTEM, alcohol appears to have a bidirectional effect on coagulation in trauma, both impairing initial clot formation and inhibiting fibrinolysis. This balancing of mechanisms may explain lack of correlation between altered ROTEM and coagulopathy-related outcomes. Viscoelastic testing should be used with caution in intoxicated trauma patients. LEVEL OF EVIDENCE: Epidemiological study, level III.

Machine learning without borders? An adaptable tool to optimize mortality prediction in diverse clinical settings.

BACKGROUND: Mortality prediction aids clinical decision making and is necessary for quality improvement initiatives. Validated metrics rely on prespecified variables and often require advanced diagnostics, which are unfeasible in resource-constrained contexts. We hypothesize that machine learning will generate superior mortality prediction in both high-income and low- and middle-income country cohorts. METHODS: SuperLearner, an ensemble machine-learning algorithm, was applied to data from three prospective trauma cohorts: a highest-activation cohort in the United States, a high-volume center cohort in South Africa (SA), and a multicenter registry in Cameroon. Cross-validation was used to assess model discrimination of discharge mortality by site using receiver operating characteristic curves. SuperLearner discrimination was compared with standard scoring methods. Clinical variables driving SuperLearner prediction at each site were evaluated. RESULTS: Data from 28,212 injured patients were used to generate prediction. Discharge mortality was 17%, 1.3%, and 1.7% among US, SA, and Cameroonian cohorts. SuperLearner delivered superior prediction of discharge mortality in the United States (area under the curve [AUC], 94-97%) and vastly superior prediction in Cameroon (AUC, 90-94%) compared with conventional scoring algorithms. It provided similar prediction to standard scores in the SA cohort (AUC, 90-95%). Context-specific variables (partial thromboplastin time in the United States and hospital distance in Cameroon) were prime drivers of predicted mortality in their respective cohorts, whereas severe brain injury predicted mortality across sites. CONCLUSIONS: Machine learning provides excellent discrimination of injury mortality in diverse settings. Unlike traditional scores, data-adaptive methods are well suited to optimizing precise site-specific prediction regardless of diagnostic capabilities or data set inclusion allowing for individualized decision making and expanded access to quality improvement programming. LEVEL OF EVIDENCE: Prognostic and therapeutic, level II and III.