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.

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.

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.

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.

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.

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.

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.

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.

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.

Characterization of distinct coagulopathic phenotypes in injury: Pathway-specific drivers and implications for individualized treatment.

BACKGROUND: International normalized ratio (INR) and partial thromboplastin time (PTT) are used interchangeably to diagnose acute traumatic coagulopathy but reflect disparate activation pathways. In this study, we identified injury/patient characteristics and coagulation factors that drive contact pathway, tissue factor pathway (TF), and common pathway dysfunction by examining injured patients with discordant coagulopathies. We hypothesized that patients with INR/PTT discordance reflect differing phenotypes representing contact versus tissue factor pathway perturbations and that characterization will provide targets to guide individualized resuscitation. METHODS: Plasma samples were prospectively collected from 1,262 critically injured patients at a single Level I trauma center. Standard coagulation measures and an extensive panel of procoagulant and anticoagulant factors were assayed and analyzed with demographic and outcome data. RESULTS: Fourteen percent of patients were coagulopathic on admission. Among these, 48% had abnormal INR and PTT (BOTH), 43% had isolated prolonged PTT (PTT-CONTACT), and 9% had isolated elevated INR (INR-TF). PTT-CONTACT and BOTH had lower Glasgow Coma Scale score than INR-TF (p < 0.001). INR-TF had decreased factor VII activity compared with PTT-CONTACT, whereas PTT-CONTACT had decreased factor VIII activity compared with INR-TF. All coagulopathic patients had factor V deficits, but activity was lowest in BOTH, suggesting an additive downstream effect of disordered activation pathways. Patients with PTT-CONTACT received half as much packed red blood cell and fresh frozen plasma as did the other groups (p < 0.001). Despite resuscitation, mortality was higher for coagulopathic patients; mortality was highest in BOTH and higher in PTT-CONTACT than in INR-TF (71%, 60%, 41%; p = 0.04). CONCLUSIONS: Discordant phenotypes demonstrate differential factor deficiencies consistent with dysfunction of contact versus tissue factor pathways with additive effects from common pathway dysfunction. Recognition and treatment of pathway-specific factor deficiencies driving different coagulopathic phenotypes in injured patients may individualize resuscitation and improve outcomes. LEVEL OF EVIDENCE: Prognostic/epidemiological study, level II.

Characterizing the gut microbiome in trauma: significant changes in microbial diversity occur early after severe injury.

BACKGROUND: Recent studies have demonstrated the vital influence of commensal microbial communities on human health. The central role of the gut in the response to injury is well described; however, no prior studies have used culture-independent profiling techniques to characterize the gut microbiome after severe trauma. We hypothesized that in critically injured patients, the gut microbiome would undergo significant compositional changes in the first 72 hours after injury. METHODS: Trauma stool samples were prospectively collected via digital rectal examination at the time of presentation (0 hour). Patients admitted to the intensive care unit (n=12) had additional stool samples collected at 24 hours and/or 72 hours. Uninjured patients served as controls (n=10). DNA was extracted from stool samples and 16S rRNA-targeted PCR amplification was performed; amplicons were sequenced and binned into operational taxonomic units (OTUs; 97% sequence similarity). Diversity was analyzed using principle coordinates analyses, and negative binomial regression was used to determine significantly enriched OTUs. RESULTS: Critically injured patients had a median Injury Severity Score of 27 and suffered polytrauma. At baseline (0 hour), there were no detectable differences in gut microbial community diversity between injured and uninjured patients. Injured patients developed changes in gut microbiome composition within 72 hours, characterized by significant alterations in phylogenetic composition and taxon relative abundance. Members of the bacterial orders Bacteroidales, Fusobacteriales and Verrucomicrobiales were depleted during 72 hours, whereas Clostridiales and Enterococcus members enriched significantly. DISCUSSION: In this initial study of the gut microbiome after trauma, we demonstrate that significant changes in phylogenetic composition and relative abundance occur in the first 72 hours after injury. This rapid change in intestinal microbiota represents a critical phenomenon that may influence outcomes after severe trauma. A better understanding of the nature of these postinjury changes may lead to the ability to intervene in otherwise pathological clinical trajectories. LEVEL OF EVIDENCE: III. STUDY TYPE: Prognostic/epidemiological.

New understandings of post injury coagulation and resuscitation.

Coagulopathy following injury is common and it predicts poor outcomes and increased mortality. For many decades, coagulopathy in trauma was considered as an iatrogenic phenomenon, and clinical practice focused on a resuscitation strategy using large volume crystalloid and packed red blood cells. The discovery of Acute Traumatic Coagulopathy as a distinct pathophysiologic state coupled with a transition towards balanced product resuscitation has fundamentally changed the paradigm of trauma care and represents one of the most active areas of current research in the field of trauma. In this review, we examine the development and current understanding of the mechanisms, implicated mediators, and physiology of Acute Traumatic Coagulopathy, with an emphasis on the role of the activated Protein C pathway. We will also review the state of resuscitation practice including the evidence for balanced product administration and the previously under-appreciated importance of platelet count and function. Importantly, we highlight ongoing knowledge deficits in traumatic coagulopathy and resuscitation as directions for future investigation in order to facilitate further insight into these rapidly evolving fields.

Recursive partitioning identifies greater than 4 U of packed red blood cells per hour as an improved massive transfusion definition.

BACKGROUND: Massive transfusion (MT) is classically defined as greater than 10 U of packed red blood cells (PRBCs) in 24 hours. This fails to capture the most severely injured patients. Extending the previous work of Savage and Rahbar, a rolling hourly rate-based definition of MT may more accurately define critically injured patients requiring early, aggressive resuscitation. METHODS: The Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) trial collected data from 10 Level 1 trauma centers. Patients were placed into rate-based transfusion groups by maximal number of PRBCs transfused in any hour within the first 6 hours. A nonparametric analysis using classification trees partitioned data according to mortality at 24 hours using a predictor variable of maximum number PRBC units transfused in an hour. Dichotomous variables significant in previous scores and models as predictors of MT were used to identify critically ill patients: a positive finding on Focused Assessment with Sonography in Trauma (FAST) examination, Glasgow Coma Scale (GCS) score less than 8, heart rate greater than 120 beats/min, systolic blood pressure less than 90 mm Hg, penetrating mechanism of injury, international normalized ratio greater than 1.5, hemoglobin less than 11, and base deficit greater than 5. These critical indicators were then compared among the nodes of the classification tree. Patients omitted included those who did not receive PRBCs (n = 24) and those who did not have all eight critical indicators reported (n = 449). RESULTS: In a population of 1,245 patients, the classification tree included 772 patients. Analysis by recursive partitioning showed increased mortality among patients receiving greater than 13 U/h (73.9%, p < 0.01). In those patients receiving less than or equal to 13 U/h, mortality was greater in patients who received more than 4 U/h (16.7% vs. 6.0%, p < 0.01) (Fig. 1). Nodal analysis showed that the median number of critical indicators for each node was 3 (2-4) (≤4 U/h), 4 (3-5) (>4 U/h and ≤13 U/h), and 5 (4-5.5) (>13 U/h). CONCLUSION: A rate-based transfusion definition identifies a difference in mortality in patients who receive greater than 4 U/h of PRBCs. Redefining MT to greater than 4 U/h allows early identification of patients with a significant mortality risk who may be missed by the current definition. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III.

The found down patient: A Western Trauma Association multicenter study.

BACKGROUND: Unconscious patients who present after being "found down" represent a unique triage challenge. These patients are selected for either trauma or medical evaluation based on limited information and have been shown in a single-center study to have significant occult injuries and/or missed medical diagnoses. We sought to further characterize this population in a multicenter study and to identify predictors of mistriage. METHODS: The Western Trauma Association Multicenter Trials Committee conducted a retrospective study of patients categorized as found down by emergency department triage diagnosis at seven major trauma centers. Demographic, clinical, and outcome data were collected. Mistriage was defined as patients being admitted to a non-triage-activated service. Logistic regression was used to assess predictors of specified outcomes. RESULTS: Of 661 patients, 33% were triaged to trauma evaluations, and 67% were triaged to medical evaluations; 56% of all patients had traumatic injuries. Trauma-triaged patients had significantly higher rates of combined injury and a medical diagnosis and underwent more computed tomographic imaging; they had lower rates of intoxication and homelessness. Among the 432 admitted patients, 17% of them were initially mistriaged. Even among properly triaged patients, 23% required cross-consultation from the non-triage-activated service after admission. Age was an independent predictor of mistriage, with a doubling of the rate for groups older than 70 years. Combined medical diagnosis and injury was also predictive of mistriage. Mistriaged patients had a trend toward increased late-identified injuries, but mistriage was not associated with increased length of stay or mortality. CONCLUSION: Patients who are found down experience significant rates of mistriage and triage discordance requiring cross-consultation. Although the majority of found down patients are triaged to nontrauma evaluation, more than half have traumatic injuries. Characteristics associated with increased rates of mistriage, including advanced age, may be used to improve resource use and minimize missed injury in this vulnerable patient population. LEVEL OF EVIDENCE: Epidemiologic study, level III.